Biochimica et biophysica acta. Molecular cell research最新文献_第6页

Importin α/β1 dependent nuclear import of black sea bass polyomavirus large tumor antigen is mediated by a classical NLS located downstream of the SF3 helicase domain 黑鲈多瘤病毒大肿瘤抗原的输入蛋白α/β1依赖核输入是由位于SF3解旋酶结构域下游的经典NLS介导的。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-10-29 DOI: 10.1016/j.bbamcr.2025.120074

Mikayla Hoad , Silvia Pavan , Sepehr Nematollahzadeh , Ole Tietz , Jospeh Reeman , Jade K. Forwood , Gualtiero Alvisi

Polyomaviruses (PyVs) are small dsDNA viruses replicating in the host cell nucleus, thanks to the viral encoded large tumor antigen (LTA). Aided by recent advances in molecular biology techniques, the list of known PyVs is rapidly growing, revealing unexpected broad sequence, and host heterogenicity. Given their dependence on nuclear localization, LTAs represent an attractive model for studying the nuclear transport process. A comprehensive analysis of the evolution of classical nuclear localization signals (cNLSs) within LTAs encoded by PyVs infecting mammals highlighted strong positional conservation of cNLSs between the LXCXE motif and the origin-binding domain (OBD). Here we extend such analysis to PyVs infecting non-mammalian hosts. We combined biochemical, structural and functional assays to demonstrate that black sea bass (BSB) PyV-LTA is transported into the nucleus by the Importin (IMP)α/β1 heterodimer thanks to the recognition of a bipartite cNLS located downstream of the SF3 helicase domain, rather than between the LXCXE motif and the OBD. Such cNLS binds with high affinity to several IMPα paralogs by simultaneously interacting with the minor and major binding sites. Substitution of NLS key basic residues abrogating binding to IMPα, or co-expression with the well characterized IMPα/β1 inhibitor Bimax2 suppressed nuclear localization. Intriguingly a cNLS could be identified in a similar position in LTAs from other PyVs infecting ray-finned fishes, but not cartilaginous fishes, birds or scorpions, where cNLSs were predicted elsewhere. Our study suggests that LTAs from PyVs infecting different non-mammalian hosts might bear cNLS in distinctive positions, possibly reflecting processes of virus-host adaptation.

多瘤病毒（pyv）是一种在宿主细胞核内复制的小dsDNA病毒，这要归功于病毒编码的大肿瘤抗原（LTA）。在分子生物学技术最新进展的帮助下，已知pyv的列表正在迅速增长，揭示了意想不到的广泛序列和宿主异质性。考虑到它们对核局部化的依赖性，LTAs是研究核输运过程的一个有吸引力的模型。对pyv感染哺乳动物编码的LTAs内经典核定位信号（cNLSs）进化的综合分析表明，cNLSs在LXCXE基序和起源结合域（OBD）之间具有很强的位置保守性。在这里，我们将这种分析扩展到感染非哺乳动物宿主的pyv。我们结合生化、结构和功能分析证明，黑海鲈鱼（BSB） PyV-LTA是通过Importin (IMP)α/β1异源二聚体转运到细胞核中的，这是由于它识别了位于SF3解旋酶结构域下游的二部分cNLS，而不是位于LXCXE基序和OBD之间。这种cNLS通过同时与次要和主要结合位点相互作用，与多个IMPα相似物具有高亲和力。NLS关键碱基取代与IMPα的结合，或与表征良好的IMPα/β1抑制剂Bimax2共表达抑制了核定位。有趣的是，cNLS可以在其他感染鳍状鱼类的pyv的LTAs中识别出类似的位置，但在软骨鱼，鸟类或蝎子中却没有，在其他地方预测了cNLS。我们的研究表明，感染不同非哺乳动物宿主的pyv LTAs可能在不同的位置携带cNLS，可能反映了病毒-宿主适应的过程。

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引用次数: 0

CAT1 modulates hepatic fibrosis via IL-6-mediated inflammatory and fibrogenic pathways in hepatic stellate cells CAT1通过il -6介导的肝星状细胞炎症和纤维化途径调节肝纤维化。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-10-27 DOI: 10.1016/j.bbamcr.2025.120075

Xiaofeng Deng , Zongjuan Li , Zhenyu Xu , Feng Peng

Hepatic fibrosis is characterized by excessive extracellular matrix deposition and chronic inflammation, primarily driven by the activation of hepatic stellate cells (HSCs). The cationic amino acid transporter 1 (CAT1) has been identified as a key regulator of HSCs activation and fibrosis progression, but its interaction with inflammatory pathways remains unclear. This study investigated the role of CAT1 in hepatic fibrosis and its regulatory effect on interleukin-6 (IL-6)-mediated inflammatory and fibrogenic responses. Bioinformatic analysis of published single-cell RNA sequencing data revealed that CAT1 expression was significantly upregulated in activated HSCs and positively correlated with IL-6 levels. Functional assays demonstrated that IL-6 promotes HSCs proliferation, migration, inflammation, and fibrotic marker expression and inhibited apoptosis, while CAT1 knockdown attenuated these effects. IL-6 overexpression reversed the inhibitory effects of CAT1 knockdown on HSCs activation by regulating JAK2/STAT3 signaling pathway, suggesting that IL-6 acts downstream of CAT1 in promoting fibrosis. In vivo, CAT1 knockdown mitigated liver injury, reduced collagen deposition, and suppressed inflammation in both carbon tetrachloride (CCl₄)-induced hepatic fibrosis and non-alcoholic fatty liver disease (NAFLD) models. However, IL-6 overexpression abolished these protective effects, highlighting the CAT1-IL-6 axis as a crucial regulator of liver fibrosis. These findings suggest that targeting CAT1 may provide a novel therapeutic strategy for hepatic fibrosis by modulating IL-6-mediated inflammatory and fibrogenic pathways.

肝纤维化的特征是过度的细胞外基质沉积和慢性炎症，主要由肝星状细胞（hsc）的激活驱动。阳离子氨基酸转运蛋白1 （CAT1）已被确定为造血干细胞活化和纤维化进展的关键调节因子，但其与炎症途径的相互作用尚不清楚。本研究探讨CAT1在肝纤维化中的作用及其对白细胞介素-6 （IL-6）介导的炎症和纤维化反应的调节作用。已发表的单细胞RNA测序数据的生物信息学分析显示，活化的hsc中CAT1表达显著上调，且与IL-6水平呈正相关。功能分析表明，IL-6促进造血干细胞增殖、迁移、炎症和纤维化标志物表达，抑制细胞凋亡，而CAT1的敲除减弱了这些作用。IL-6过表达通过调节JAK2/STAT3信号通路逆转CAT1下调对hsc活化的抑制作用，提示IL-6在CAT1的下游作用促进纤维化。在体内，在四氯化碳（CCl₄）诱导的肝纤维化和非酒精性脂肪性肝病（NAFLD）模型中，CAT1敲低可减轻肝损伤、减少胶原沉积并抑制炎症。然而，IL-6过表达消除了这些保护作用，强调CAT1-IL-6轴是肝纤维化的关键调节因子。这些发现表明，通过调节il -6介导的炎症和纤维化途径，靶向CAT1可能为肝纤维化提供一种新的治疗策略。

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引用次数: 0

Hotspot mutant p53-R273H enhances mitochondrial biogenesis and cell migration in primary colorectal cancer in response to oxaliplatin 热点突变体p53-R273H对奥沙利铂的响应增强了原发性结直肠癌的线粒体生物发生和细胞迁移。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-10-27 DOI: 10.1016/j.bbamcr.2025.120073

Toni Martinez-Bernabe , Pere Miquel Morla-Barcelo , Alessandra Fiore , Massimo Donadelli , Pilar Roca , Jordi Oliver , Jorge Sastre-Serra , Daniel G. Pons

Oxaliplatin is commonly known as a successful chemotherapy for advanced colorectal cancer, improving patient survival and eradicating micro-metastases, but its use in early stages remains controversial. Mitochondria fuel energy-intensive programs such as cell migration, yet how oxaliplatin regulates the mitochondrial network in CRC - and how TP53 context shapes this - remains unclear. We investigated a matched pair of CRC cell lines from the same patient - SW480 (primary) and SW620 (lymph-node metastasis) - both harboring TP53-R273H mutation, to define differential responses in mitochondrial biogenesis, dynamics and respiration and the mechanisms underlying them. The results indicate that primary-derived colorectal cancer cell line increased cell migration, mitochondrial biogenesis, and mitochondrial respiration capacity in response to oxaliplatin through a new and firstly described gain-of-function (GOF) of p53-R273H. Additionally, in the primary-derived CRC line, oxaliplatin elicited fate heterogeneity - coexisting apoptotic and senescent fractions alongside an R273H-driven, bioenergetically primed migratory subpopulation - together with increased mitochondrial biogenesis and respiratory capacity; by contrast, the metastatic-derived line was more sensitive and displayed structural mitochondrial injury with reduced maximal respiration. More broadly, this work underscores the importance of p53 gain-of-function mutations in CRC: the same GOF (TP53-R273H) amplifies cell migration by coupling an enhanced mitochondrial biogenesis/OXPHOS program to motility. Oxaliplatin further accentuates this energetically primed, pre-metastatic state, arguing for mitochondrial-targeted combination strategies in early-stage CRC.

奥沙利铂通常被认为是一种成功的晚期结直肠癌化疗药物，可以提高患者的生存率并根除微转移，但在早期阶段使用奥沙利铂仍存在争议。线粒体为细胞迁移等能量密集型程序提供燃料，但奥沙利铂如何调节结直肠癌中的线粒体网络，以及TP53环境如何影响线粒体网络，目前尚不清楚。我们研究了来自同一患者的一对匹配的CRC细胞系- SW480（原发）和SW620（淋巴结转移）-都携带TP53-R273H突变，以确定线粒体生物发生，动力学和呼吸的差异反应及其潜在机制。结果表明，原发结直肠癌细胞系通过p53-R273H的新功能获得（GOF），增加了奥沙利铂对细胞迁移、线粒体生物发生和线粒体呼吸能力的反应。此外，在原发CRC细胞系中，奥沙利铂引发了命运异质性——与r273h驱动的、生物能量启动的迁移亚群共存的凋亡和衰老部分，以及线粒体生物发生和呼吸能力的增加；相比之下，转移源系更敏感，表现出结构性线粒体损伤，最大呼吸减少。更广泛地说，这项工作强调了p53功能获得突变在结直肠癌中的重要性：相同的GOF （TP53-R273H）通过将增强的线粒体生物发生/OXPHOS程序与运动性耦合来放大细胞迁移。奥沙利铂进一步强化了这种能量启动的前转移状态，主张在早期CRC中采用线粒体靶向联合策略。

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引用次数: 0

Loss of Sugen Kinase 495 in macrophages alleviates chronic colitis by improving mitochondrial stress 巨噬细胞中糖激酶495的缺失通过改善线粒体应激来缓解慢性结肠炎

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-10-25 DOI: 10.1016/j.bbamcr.2025.120072

Jikai He , Yuanmei Lou , Pingan Yao , Shiguang Yang , Jinliang Dong , Qifeng Yu

Inflammatory bowel disease (IBD), highlighted by chronic intestinal inflammation, is an escalating global health concern. The pathogenesis of IBD is not fully understood, with DSS-induced chronic colitis in mice serving as a prevalent model, characterized by an increase in Ly6C^high macrophages—a signature of IBD. Sugen Kinase 495 (Sgk495), also known as serine/threonine kinase 40 (STK40), is known to influence cell differentiation, has an obscure role in mitochondrial in macrophage and its molecular mechanisms. Our research demonstrates that Sgk495 exacerbates chronic colitis in mice by disrupting colon structure and function and enhancing colonic pathology. The absence of Sgk495 in macrophage cells resulted in a reduction in the proportion of Ly6C^high macrophage. Mechanistically, Sgk495 silencing also improved mitochondrial stress by upregulated PINK1, Parkin, TOMM20 and DRP1, while reducing FOXO3a phosphorylation. Knockout of Sgk495 downregulates FOXO3a phosphorylation and improves mitochondrial stress, inhibits Ly6C^high macrophage polarization, and alleviates chronic colonic inflammation. Sgk495 may serve as a new potential therapeutic target for IBD.

炎症性肠病（IBD），以慢性肠道炎症为重点，是一个不断升级的全球健康问题。IBD的发病机制尚不完全清楚，dss诱导的小鼠慢性结肠炎是一种普遍的模型，其特征是ly6 - high巨噬细胞的增加，这是IBD的标志。Sugen Kinase 495 (Sgk495)，也被称为丝氨酸/苏氨酸激酶40 (STK40)，已知影响细胞分化，在巨噬细胞线粒体中的作用及其分子机制尚不清楚。我们的研究表明，Sgk495通过破坏结肠结构和功能以及增强结肠病理来加重小鼠慢性结肠炎。巨噬细胞中Sgk495缺失导致ly6high巨噬细胞比例降低。机制上，Sgk495沉默也通过上调PINK1、Parkin、TOMM20和DRP1来改善线粒体应激，同时降低FOXO3a的磷酸化。敲除Sgk495下调FOXO3a磷酸化，改善线粒体应激，抑制ly6高巨噬细胞极化，减轻慢性结肠炎症。Sgk495可能成为IBD新的潜在治疗靶点。

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引用次数: 0

Cell-penetrant peptides as novel inhibitors of the interaction of coatomer protein COPB2/RACK2 with protein kinase Cε and cargo proteins 细胞渗透肽作为涂层蛋白COPB2/RACK2与蛋白激酶Cε和货物蛋白相互作用的新抑制剂。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-10-18 DOI: 10.1016/j.bbamcr.2025.120071

Abisola A. Olushola-Siedoks , Lewin Small , Kathryn J. Fincham , Dorothy C.C. Wai , Dhruv Monteiro , James R.W. Conway , Antonia Cadell , Benjamin J. Parker , David R. Croucher , Carsten Schmitz-Peiffer , Raymond S. Norton

The lipid-activated novel protein kinase C isoform, PKCε, plays a key role in the progression of Type 2 Diabetes Mellitus (T2DM) and has also been implicated in cancer, cardiac hypertrophy, pain and anxiety. As the spatial regulation of PKCε activity is linked to its interaction with the Receptor for Activated C Kinase 2 (RACK2, also known as COPB2), blockade of this interaction has potential therapeutic benefits for the treatment of several pathologies. Using a proximity-based chemiluminescent assay to monitor the binding of lipid-activated PKCε to RACK2, we discovered inhibitory peptides derived from the PKCε sequence; pentapeptides with a KxKxx motif and a C-terminal carboxylate potently inhibited this interaction, whereas other short sequences containing cationic residues were less effective. An alanine scan of the KIKIC peptide showed that the two Lys residues and C-terminal carboxylate were the most important for inhibitory activity. A previously described PKCε translocation inhibitory peptide from PKCε, εV1-2, exhibited much weaker inhibition of the PKCe-RACK2 interaction, with significant inhibitory activity observed only when it was conjugated to cell-penetrating peptides. KIKIC exhibited moderate cell-penetrating ability, showed no evidence of cytotoxicity, and modified PKCε translocation in response to lipid treatment. Several proteins that were captured in a RACK2 pulldown of a liver lysate in a KIKIC-peptide sensitive manner were identified as part of a PKCε-RACK2 complex isolated from intact cells. These results provide a basis for the rational design of peptides or peptidomimetics that inhibit the PKCε-RACK2 interaction and have potential for the prevention and/or treatment of T2DM.

脂质活化的新型蛋白激酶C异构体PKCε在2型糖尿病（T2DM）的进展中起关键作用，也与癌症、心脏肥厚、疼痛和焦虑有关。由于PKCε活性的空间调控与其与活化C激酶2受体（RACK2，也称为COPB2）的相互作用有关，阻断这种相互作用对治疗多种疾病具有潜在的治疗益处。使用基于接近度的化学发光法来监测脂质活化PKCε与RACK2的结合，我们发现了来自PKCε序列的抑制肽；带有KxKxx基序和c端羧酸的五肽可以有效地抑制这种相互作用，而其他含有阳离子残基的短序列则效果较差。对KIKIC肽的丙氨酸扫描表明，两个赖氨酸残基和c端羧酸是抑制活性最重要的。先前描述的PKCε易位抑制肽，εV1-2，对PKCe-RACK2相互作用的抑制作用要弱得多，只有当它与细胞穿透肽结合时才有显著的抑制活性。KIKIC表现出中等的细胞穿透能力，没有细胞毒性，并在脂质处理下改变pkce ε易位。以kikic肽敏感的方式在肝裂解物的RACK2下拉中捕获的几个蛋白被鉴定为从完整细胞中分离的PKCε-RACK2复合体的一部分。这些结果为合理设计抑制PKCε-RACK2相互作用的肽或肽拟物提供了基础，并具有预防和/或治疗T2DM的潜力。

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引用次数: 0

Tumor suppressor collateral damage screens reveal mRNA homeostasis protein HBS1L as a novel vulnerability in ch9p21 driven FOCAD deleted cancer 肿瘤抑制子附带损伤筛查显示mRNA稳态蛋白HBS1L在ch9p21驱动的FOCAD缺失癌中是一个新的易损性。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-10-14 DOI: 10.1016/j.bbamcr.2025.120070

Hongxiang Zhang, Matthew R. Tonini, Lauren Catherine M. Martires, Helena N. Jenkins, Charlotte B. Pratt, Eden N. Gordon, Shanchuan Zhao, Ashley H. Choi, Samuel R. Meier, Tenzing Khendu, Shangtao Liu, Binzhang Shen, Hannah Stowe, Katerina Pashiardis, Xuewen Pan, Madhavi Bandi, Minjie Zhang, Yi Yu, Chengyin Min, Alan Huang, Teng Teng

Chromosomal deletion of tumor suppressor genes often occurs in an imprecise manner, leading to co-deletion of neighboring genes. This collateral damage can create novel dependencies specific to the co-deleted context. One notable example is the dependency on PRMT5 activity in tumors with MTAP deletion, which co-occurs with CDKN2A/B loss, leading to the development of MTA-cooperative PRMT5 inhibitors. To identify additional collateral damage context/target pairs for chromosome 9p and other common loci of chromosomal deletions, we conducted a combinatorial CRISPR screen knocking out frequently co-deleted genes in combination with a focused target library. We identified the gene encoding the ribosome rescue factor PELO as synthetic lethal with the SKI complex interacting exonuclease FOCAD, which is frequently co-deleted alongside MTAP and CDKN2A/B on chromosome 9p. A genome-wide screen in FOCAD isogenic cells further identified the ribosome rescue GTPase and PELO binding partner HBS1L as the top synthetic lethal target for FOCAD loss. Analysis of publicly available data and genetic manipulation of HBS1L using orthogonal modalities validated this interaction. HBS1L dependency in FOCAD-deleted cells was rescued by FOCAD re-expression, and FOCAD intact cells could be rendered HBS1L-dependent by FOCAD knockout, demonstrating the context specificity of this interaction. Mechanistically, HBS1L loss led to translational arrest and activated the unfolded protein response in FOCAD-deleted cells. In vivo, HBS1L deletion eliminated growth of FOCAD-deleted tumors. Here we propose a model where the FOCAD/SKI complex and HBS1L/PELO work together to resolve aberrant mRNA-induced ribosomal stalling, making the HBS1L/PELO complex an intriguing novel target for treating FOCAD-deleted tumors.

肿瘤抑制基因的染色体缺失通常以不精确的方式发生，导致邻近基因的共缺失。这种附带损害可能会创建特定于共同删除上下文的新依赖。一个值得注意的例子是MTAP缺失的肿瘤中对PRMT5活性的依赖，这与CDKN2A/B缺失共同发生，导致mta协同PRMT5抑制剂的发展。为了确定染色体9p和其他常见染色体缺失位点的附加附带损伤上下文/靶对，我们进行了组合CRISPR筛选，结合重点靶文库敲除频繁共缺失的基因。我们发现编码核糖体拯救因子PELO的基因与SKI复合物相互作用的外切酶FOCAD合成致死，该基因经常与染色体9p上的MTAP和CDKN2A/B共同删除。在FOCAD等基因细胞中进行的全基因组筛选进一步确定了核糖体拯救GTPase和PELO结合伙伴HBS1L是FOCAD缺失的首要合成致死靶点。利用正交模式对公开数据和HBS1L基因操作进行分析，验证了这种相互作用。FOCAD缺失细胞中的HBS1L依赖性通过FOCAD的重新表达得以恢复，而FOCAD完整细胞可以通过敲除FOCAD而使HBS1L依赖，这证明了这种相互作用的上下文特异性。在机制上，HBS1L缺失导致了focad缺失细胞的翻译阻滞并激活了未折叠蛋白反应。在体内，HBS1L的缺失消除了focad缺失肿瘤的生长。在这里，我们提出了一个模型，其中FOCAD/SKI复合物和HBS1L/PELO共同解决异常mrna诱导的核糖体延迟，使HBS1L/PELO复合物成为治疗FOCAD缺失肿瘤的一个有趣的新靶点。

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引用次数: 0

Canagliflozin inhibits p38MAPK signaling to protect tubular epithelial cell against pyroptosis in sepsis-induced acute kidney injury 卡格列净抑制p38MAPK信号保护脓毒症诱导的急性肾损伤小管上皮细胞免于焦亡。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-10-12 DOI: 10.1016/j.bbamcr.2025.120069

Yun-feng Zhu , Jing Wang , Rong-xin Bian , Chun-lin Guo , Li-ge Song , Chun-ying Nie , Gang Liu

This paper aimed to investigate the impacts and mechanisms of canagliflozin (CANA) in sepsis-induced acute kidney injury (SAKI). SAKI models were established using HK2 cells treated with lipopolysaccharide (LPS) and mice received cecum ligation puncture (CLP) surgery. The pathological examination was applied to evaluate mouse kidney damage. Inflammatory cytokines were evaluated using ELISA and RT-qPCR assay. Flow cytometry and TUNEL staining were employed to check cell apoptosis. The expression of apoptosis-, inflammation-, pyroptosis-, and pathway-related proteins were assessed via western blot. In CLP-induced mouse SAKI model, CANA attenuated renal pathological injury, inflammation response, pyroptosis and inhibited the p38MAPK pathway, as evidenced by the decrease of serum Scr and BUN levels, cell apoptosis, IL-1β and IL-18 levels, as well as GSDMD-N, cleaved caspase-1, and p38MAPK expression. In HK2 cells treated with LPS, inflammation response, pyroptosis, and the p38MAPK pathway were inhibited by CANA. Moreover, overexpression of p38MAPK reversed CANAs' effects on apoptosis, inflammation response, and pyroptosis in HK2 cells. In SAKI, CANA inhibited the p38MAPK pathway, thereby reducing cell apoptosis, inflammation response, and pyroptosis, which ultimately alleviating disease progression.

本文旨在探讨卡格列净（canagliflozin， CANA）在脓毒症致急性肾损伤（SAKI）中的作用及其机制。采用脂多糖（LPS）处理HK2细胞和盲肠结扎穿刺（CLP）手术小鼠建立SAKI模型。采用病理检查方法评价小鼠肾损害。采用ELISA和RT-qPCR检测炎症因子。流式细胞术和TUNEL染色检测细胞凋亡情况。western blot检测细胞凋亡蛋白、炎症蛋白、焦亡蛋白和通路相关蛋白的表达。在clp诱导的小鼠SAKI模型中，CANA可减轻肾脏病理损伤、炎症反应、焦亡，抑制p38MAPK通路，表现为降低血清Scr和BUN水平、细胞凋亡、IL-1β和IL-18水平，以及GSDMD-N、cleaved caspase-1和p38MAPK表达。在LPS处理的HK2细胞中，CANA抑制了炎症反应、焦亡和p38MAPK通路。此外，p38MAPK的过表达逆转了CANAs对HK2细胞凋亡、炎症反应和焦亡的影响。在SAKI中，CANA抑制p38MAPK通路，从而减少细胞凋亡、炎症反应和焦亡，最终缓解疾病进展。

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引用次数: 0

Arabidopsis thaliana loss-of-function chloroplast tata mutants display an albino phenotype indicating a chloroplast-only function 拟南芥叶绿体功能缺失突变体显示白化表型，表明仅具有叶绿体功能。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-10-09 DOI: 10.1016/j.bbamcr.2025.120068

Sarah Jessup , Ruchira Sepali Mallawa Arachchi , Chris Carrie

A functional mitochondrial Tat (mtTat) pathway has been confirmed in plants, but the existence or need for a TatA subunit remains unanswered.

Two competing hypotheses have suggested that either plant mitochondria contain an unusual Tat pathway with no TatA contribution, or the chloroplast TatA (cpTatA) is dually targeted to chloroplasts and mitochondria.

Arabidopsis thaliana cptata loss-of-function mutants display an albino phenotype consistent with a dysfunctional chloroplast Tat pathway with no quantitative impact on mitochondrial complex III biogenesis, reiterating a chloroplast-specific role of cpTatA.

While these findings reject the dual-targeting hypothesis, the roles and components of the plant mitochondrial Tat pathway are yet to be fully elucidated.

一种功能性线粒体Tat （mtTat）途径已在植物中得到证实，但TatA亚基的存在或需要仍未得到解答。两种相互竞争的假设表明，要么植物线粒体含有不寻常的Tat途径而没有TatA贡献，要么叶绿体TatA （cpTatA）双重靶向叶绿体和线粒体。拟南芥cptata功能丧失突变体表现出与功能失调的叶绿体Tat途径一致的白化表型，对线粒体复合体III的生物发生没有定量影响，重申了cptata在叶绿体中的特异性作用。虽然这些发现否定了双靶向假说，但植物线粒体Tat通路的作用和组成尚未得到充分阐明。

引用次数: 0

Comprehensive analysis of androgen receptor splice variant target gene expression in prostate cancer 前列腺癌中雄激素受体剪接变异靶基因表达的综合分析。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-09-30 DOI: 10.1016/j.bbamcr.2025.120062

Neele Wüstmann, Julissa Reimann, Julia Vieler, Verena Humberg, Katrin Schlack, Martin Bögemann, Andres Jan Schrader, Christof Bernemann

This study aimed to comprehensively analyze AR-V specific target gene expression using a physiological system that simulates the actual situation of AR-FL and AR-V co-appearance in prostate cancer patients. Clinically described AR splice variants AR-V3, AR-V7 and AR-V9 were transfected along with AR-FL in AR-negative prostate cancer PC-3 cells. RNA sequencing analysis showed only slight differences in differentially expressed genes between AR-FL and AR-V co-expressing cells compared to solely AR-FL expressing cells. Immunofluorescence analysis and luciferase assays revealed hormonal dependency of AR-FL, constitutive activity of AR-V7, and ambivalent activity of AR-V9, while AR-V3 showed no activity. Analysis of a set of published target genes showed steady upregulation of EDN2 and FKBP5. Yet, clinical analysis revealed no significant differences in overall survival data in prostate cancer patients. The study challenges the existence of an AR-V specific transcriptome responsible for treatment resistance and tumor progression and highlights the need for further investigation into the molecular mechanism by which AR-V proteins route resistance to ARTA treatment.

本研究旨在通过模拟前列腺癌患者AR-FL与AR-V共现实际情况的生理系统，全面分析AR-V特异性靶基因表达。临床描述的AR剪接变体AR- v3， AR- v7和AR- v9与AR- fl一起转染AR阴性前列腺癌PC-3细胞。RNA测序分析显示，与单独表达AR-FL的细胞相比，AR-FL和AR-V共表达细胞之间的差异表达基因仅略有差异。免疫荧光分析和荧光素酶测定显示AR-FL的激素依赖性、AR-V7的组成活性和AR-V9的矛盾价活性，而AR-V3没有活性。对一组已发表的靶基因的分析显示，EDN2和FKBP5稳定上调。然而，临床分析显示前列腺癌患者的总体生存数据没有显著差异。该研究挑战了AR-V特异性转录组的存在，该转录组负责治疗耐药性和肿瘤进展，并强调需要进一步研究AR-V蛋白对ARTA治疗产生耐药性的分子机制。

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引用次数: 0

Plasma membrane Bile acid TGR5 receptor specific stimulation induces Ca2+ mobilisation, ATP secretion and P2Y receptors activation in cholangiocytes 质膜胆汁酸TGR5受体特异性刺激诱导胆管细胞Ca2+动员、ATP分泌和P2Y受体激活。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-09-30 DOI: 10.1016/j.bbamcr.2025.120067

Xuanmeng Chen , Amr Al-Shebel , Thibault Pebrier , Thierry Tordjmann , Olivier Dellis

The Bile Acid receptor TGR5 is well known to activate the cAMP pathway leading to CFTR activation and Cl⁻ ions secretion, needed for bile alkalinization and hydration. However, during cystic fibrosis development, only 10 to 15 % of the patients present liver defects due to bile duct disorders, meaning that another process should compensate for the loss of CFTR activity. Interestingly, some bile acids had also been reported to mobilize Ca²⁺ ions in cholangiocytes. Using normal human cholangiocytes and cholangiocarcinoma cell lines, we confirmed by using a specific agonist, that TGR5 stimulation induced a Ca²⁺ release from the endoplasmic reticulum and an influx of extracellular Ca²⁺ ions. Next, this Ca²⁺ mobilisation allows an ATP (and UTP) release, leading to the activation of P2Y receptors, reinforcing this Ca²⁺ mobilisation. This study shows that activation of the BA receptor TGR5 has the capacity to induce the two main intracellular pathways, cAMP and IP₃-Ca²⁺ in cholangiocytes. From our data, we speculate that the pathway we described will allow activation of the Ca²⁺-activated Cl⁻ channels TMEM16A, to compensate in part or in totality the loss of CFTR in CF patients.

众所周知，胆汁酸受体TGR5可激活cAMP通路，导致CFTR激活和胆汁碱化和水化所需的Cl-离子分泌。然而，在囊性纤维化的发展过程中，只有10%至15% %的患者由于胆管疾病而出现肝脏缺陷，这意味着另一个过程应该补偿CFTR活性的丧失。有趣的是，一些胆汁酸也被报道在胆管细胞中调动Ca2+离子。使用正常的人类胆管细胞和胆管癌细胞系，我们通过使用一种特定的激动剂证实，TGR5刺激诱导Ca2+从内质网释放和细胞外Ca2+离子的流入。接下来，这种Ca2+动员允许ATP（和UTP）释放，导致P2Y受体的激活，加强这种Ca2+动员。本研究表明，BA受体TGR5的激活具有诱导胆管细胞内cAMP和IP3-Ca2+两种主要细胞内通路的能力。根据我们的数据，我们推测我们描述的途径将允许激活Ca2+激活的Cl-通道TMEM16A，以部分或全部补偿CF患者CFTR的损失。

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