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

Exploring the intersection of Alzheimer's disease and comorbidities: a review of the interplay between multiple chronic conditions 探索阿尔茨海默病和合并症的交集：多种慢性疾病之间相互作用的回顾。

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: 2026-02-09 DOI: 10.1016/j.bbadis.2026.168190

Sumaiya Khan , Ali Imam , Sunidhi Singh , Anwar Ahmed , Md. Imtaiyaz Hassan , Mohammad Shahid , Fareeda Athar , Asimul Islam

Alzheimer's disease (AD) represents degenerative brain disorder that impairs both cognitive functions and daily living activities gradually. It is frequently linked with other disorders such as psychosis, cardiovascular disorders, diabetes, and depression, all of which may influence the disease's onset, trajectory, and treatment approaches. These comorbidities can affect the onset, progression, and management of AD. This review focuses to explore the interplay of AD and comorbidities, and to examine the interplay between multiple chronic conditions. The review found that AD and comorbidities have a complex and bidirectional relationship. Comorbidities can affect the onset, progression, and management of AD, and AD can also affect the management and outcomes of comorbidities. The review also found that comorbidities may have an impact on caregiver burden, healthcare utilization and mortality. The findings suggest that the management of AD should take into account the presence and management of comorbidities to improve the overall outcomes for patients with AD. The literature also suggests that the management of comorbidities should be integrated in the management of AD patients. Furthermore, the review highlights the critical role of timely detection and treatment of comorbidities in AD patients to delay onset and mitigate disease progression. Additionally, it is crucial to consider the influence of comorbidities when selecting treatment options and the management of side effects and adverse events in AD patients. The literature reviewed in this article suggests that a multidisciplinary approach is needed in managing AD patients with comorbidities, which includes regular screening, early detection, and management of comorbidities in addition to managing AD.

阿尔茨海默病（AD）是一种逐渐损害认知功能和日常生活活动的退行性大脑疾病。它经常与其他疾病，如精神病、心血管疾病、糖尿病和抑郁症有关，所有这些都可能影响疾病的发病、发展轨迹和治疗方法。这些合并症会影响阿尔茨海默病的发病、进展和治疗。这篇综述的重点是探讨阿尔茨海默病和合并症的相互作用，以及多种慢性疾病之间的相互作用。综述发现，AD与合并症具有复杂的双向关系。合并症可以影响阿尔茨海默病的发病、进展和治疗，而阿尔茨海默病也可以影响合并症的治疗和结果。该综述还发现，合并症可能对护理人员负担、医疗保健利用和死亡率有影响。研究结果表明，AD的管理应考虑到合并症的存在和管理，以改善AD患者的总体预后。文献还表明，合并症的管理应纳入AD患者的管理。此外，该综述强调了及时发现和治疗AD患者的合并症对于延迟发病和减缓疾病进展的关键作用。此外，在选择治疗方案和处理AD患者的副作用和不良事件时，考虑合并症的影响是至关重要的。本文综述的文献提示，除了对AD进行管理外，还需要多学科的方法来管理AD患者的合并症，包括定期筛查、早期发现和合并症的管理。

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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 : 2026-04-01 Epub 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

Circ_0075691 regulates lipid metabolism in granulosa cells by interacting with EIF4A3 to promote PTGS2 mRNA stability Circ_0075691通过与EIF4A3相互作用促进PTGS2 mRNA的稳定性，调控颗粒细胞的脂质代谢

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: 2026-01-26 DOI: 10.1016/j.bbadis.2026.168173

Pengyu Huang , Jianshu Cai , Gangxin Chen , Huiling Xu , Suzhu Chen , Haiyan Li , Yun Fu , Beihong Zheng , Zhengmian Zhang

Background

Circular RNAs (circRNAs) are implicated in polycystic ovary syndrome (PCOS), yet their roles in granulosa cell dysfunction remain unclear. This study explores the mechanistic role of circ_0075691 in PCOS-associated metabolic dysregulation.

Methods

The circular structure of circ_0075691 was confirmed through gel electrophoresis and RNase R resistance assays. Its expression levels and subcellular localization were assessed using RT-PCR and fluorescence in situ hybridization (FISH). Subsequent to the overexpression of circ_0075691, the cell function assays were conducted, including CCK-8, colony formation, flow cytometry, and analyses of oxidative stress and lipid metabolism-related indicators. Bioinformatics analyses were employed to predict RNA-binding proteins (RBPs) that potentially interact with circ_0075691, and these interactions were validated using RNA immunoprecipitation (RIP) and RNA pulldown assays.

Results

Circ_0075691 was verified to possess a circular structure and was predominantly localized in the nucleus. Its expression was significantly elevated in both follicular fluid (FF) and granulosa cells from PCOS patients compared to normal controls. In vitro experiments demonstrated that overexpression of circ_0075691 led to reduced cell viability and proliferation, decreased oxygen consumption rate (OCR), and increased apoptosis, oxidative stress, and lipid accumulation. Mechanistically, circ_0075691 was found to interact with and stabilize the EIF4A3 protein, thereby enhancing the stability of PTGS2 mRNA. Silencing PTGS2 mitigated the metabolic and apoptotic abnormalities induced by circ_0075691.

Conclusion

This study revealed that circ_0075691 played a crucial role in PCOS-related granulosa cell functions and lipid metabolism. The circ_0075691/EIF4A3/PTGS2 axis provided new insights into the molecular mechanism of PCOS and potential therapeutic targets.

环状rna （circRNAs）与多囊卵巢综合征（PCOS）有关，但其在颗粒细胞功能障碍中的作用尚不清楚。本研究探讨了circ_0075691在pcos相关代谢失调中的机制作用。方法通过凝胶电泳和RNase R耐药试验证实circ_0075691为圆形结构。采用RT-PCR和荧光原位杂交（FISH）技术检测其表达水平和亚细胞定位。过表达circ_0075691后，进行细胞功能检测，包括CCK-8、集落形成、流式细胞术、氧化应激和脂质代谢相关指标分析。利用生物信息学分析预测RNA结合蛋白（rbp）可能与circ_0075691相互作用，并利用RNA免疫沉淀（RIP）和RNA拉下试验验证这些相互作用。结果证实scirc_0075691具有圆形结构，主要定位于细胞核。与正常对照相比，PCOS患者的卵泡液（FF）和颗粒细胞中其表达均显著升高。体外实验表明，circ_0075691过表达导致细胞活力和增殖降低，氧消耗率（OCR）降低，细胞凋亡、氧化应激和脂质积累增加。机制上，circ_0075691与EIF4A3蛋白相互作用并稳定EIF4A3蛋白，从而增强PTGS2 mRNA的稳定性。沉默PTGS2可减轻circ_0075691诱导的代谢和凋亡异常。结论circ_0075691在pcos相关颗粒细胞功能和脂质代谢中发挥重要作用。circ_0075691/EIF4A3/PTGS2轴为PCOS的分子机制和潜在的治疗靶点提供了新的见解。

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引用次数: 0

NADPH oxidase 5 promotes adhesion and infiltration of immune cells in the brain. Implications in ischemic stroke NADPH氧化酶5促进大脑中免疫细胞的粘附和浸润。缺血性卒中的意义。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-04-01 Epub Date: 2026-02-09 DOI: 10.1016/j.bbadis.2026.168188

Javier Marqués , Leyre Basurco , Elena Ainzúa , Victor Marqués , Maite Solas , Enrique Santamaría , Joaquín Fernández-Irigoyen , Davide Maselli , María Martínez-Azcona , Carmen Roncal , Maria S. Aymerich , Aleksandar Ivetic , Josune Orbe , Guillermo Zalba

Blood-brain barrier (BBB) disruption and immune cell infiltration increase the pathological outcomes present in aging, neurodegenerative diseases, and stroke. NADPH oxidase 5 (NOX5) is a ROS-producing enzyme that promotes BBB-permeability in vivo by altering the endothelial junctions (EJs). The aim of this project was to elucidate the mechanisms by which NOX5 dysregulates EJs in endothelial cells and whether it increases immune infiltrates in a systemic inflammatory condition, using a murine model of ischemic stroke. A brain microvascular endothelial cell line (hCMEC/D3) and HUVECs infected with a NOX5 overexpressing adenovirus were used to study the effects of this protein on EJs, endothelial phenotype, and immune cell adhesion and infiltration in vitro. An endothelial NOX5 knock-in mouse was used to study EJs expression in the brain. Finally, in an experimental model of ischemic stroke induced by FeCl₃ we analyzed the potential effects of NOX5 on the infiltration of immune cells to the brain. NOX5 overexpression dysregulated EJs and increased permeability in hCMEC/D3 cells. In HUVECs, overexpression of NOX5 promoted the remodeling of the cytoskeleton and increased inflammatory cell adhesion and infiltration. Under inflammatory conditions, such as those present in ischemic stroke, mice expressing endothelial NOX5 exhibited an increase in the infiltration of immune cells in the brain across the vasculature of the non-infarcted (contralateral) hemisphere and increased inflammatory markers in the infarcted (ipsilateral) hemisphere. NOX5 promotes the dysregulation of EJs and cytoskeletal changes in endothelial cells, which leads to an increased immune cell infiltration in the brain at proinflammatory situations.

血脑屏障（BBB）破坏和免疫细胞浸润增加了衰老、神经退行性疾病和中风的病理结果。NADPH氧化酶5 （NOX5）是一种ros生成酶，通过改变内皮连接（EJs）促进血脑屏障的通透性。本项目的目的是通过小鼠缺血性中风模型阐明NOX5在内皮细胞中失调EJs的机制，以及它是否会增加全身炎症条件下的免疫浸润。利用过表达NOX5腺病毒感染脑微血管内皮细胞系（hCMEC/D3）和HUVECs，研究了该蛋白对EJs、内皮表型和免疫细胞粘附和浸润的影响。用内皮细胞NOX5敲入小鼠研究EJs在脑中的表达。最后，在FeCl3诱导的缺血性脑卒中实验模型中，我们分析了NOX5对免疫细胞向大脑浸润的潜在影响。在hCMEC/D3细胞中，NOX5过表达失调EJs和通透性增加。在HUVECs中，NOX5的过表达促进了细胞骨架的重塑，增加了炎症细胞的粘附和浸润。在炎症条件下，例如在缺血性中风中，表达内皮细胞NOX5的小鼠表现出免疫细胞在非梗死（对侧）半球血管中的浸润增加，梗死（同侧）半球的炎症标志物增加。NOX5促进内皮细胞EJs的失调和细胞骨架的变化，从而导致促炎情况下免疫细胞在大脑中的浸润增加。

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引用次数: 0

Leveraging macrophage plasticity for precision-targeted tumor immunotherapy 利用巨噬细胞可塑性进行精确靶向肿瘤免疫治疗。

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: 2026-01-29 DOI: 10.1016/j.bbadis.2026.168176

Shu-Jin Li , Xiao-He Wang , Ling-Rui Li , Lei Chen , Zhi-Jun Sun

While immunotherapy has demonstrated remarkable therapeutic potential in certain malignancies, its overall clinical efficacy remains suboptimal. Emerging evidence indicates that the tumor microenvironment (TME) plays a pivotal role in determining immunotherapy response, with tumor-associated macrophages (TAMs) – the predominant immune cell population within TME – being closely associated with poor prognosis, metastatic progression, and therapeutic resistance. Traditionally, macrophages are classified into two primary activation states: the pro-inflammatory M1 (classically activated) phenotype and the anti-inflammatory M2 (alternatively activated) phenotype. However, this binary classification system fails to fully capture the functional complexity and phenotypic plasticity of TAMs. This comprehensive review critically examines TAM heterogeneity and explores emerging subtyping paradigms beyond conventional M1/M2 dichotomization. Furthermore, we systematically examine three principal therapeutic strategies: recruitment inhibition, TAM depletion, and phenotypic reprogramming, emphasizing their synergistic potential with existing immunotherapies. These multifaceted approaches provide novel insights for developing combination therapies to overcome current limitations in cancer treatment.

虽然免疫疗法在某些恶性肿瘤中显示出显著的治疗潜力，但其总体临床疗效仍不理想。新出现的证据表明，肿瘤微环境（TME）在决定免疫治疗反应性方面起着关键作用，肿瘤相关巨噬细胞（TME中主要的免疫细胞群）与预后不良、转移进展和治疗耐药性密切相关。传统上，巨噬细胞被分为两种主要的激活状态：促炎M1（经典激活）表型和抗炎M2（交替激活）表型。然而，这种二元分类系统未能充分反映tam的功能复杂性和表型可塑性。这篇综合综述批判性地考察了TAM的异质性，并探索了超越传统M1/M2二分法的新兴亚型范式。此外，我们系统地研究了三种主要的治疗策略：招募抑制、TAM耗竭和表型重编程，强调了它们与现有免疫疗法的协同潜力。这些多方面的方法为开发联合疗法提供了新的见解，以克服目前癌症治疗的局限性。

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引用次数: 0

Adipose-derived mesenchymal stem cell exosomes enhance diabetic wound healing via the amelioration of fibroblast senescence through the SMARCAL1-Drp1 signaling pathway 脂肪源性间充质干细胞外泌体通过SMARCAL1-Drp1信号通路改善成纤维细胞衰老，从而促进糖尿病伤口愈合。

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.2026.168187

Hang Wu , Xuan Jiang , Jieyun Cai , Changhong Li , Xihang Yuan , Yifeng Huang , Yang Xiong , Xiangdong Qi , Chiyang Li

Delayed healing of diabetic wounds (DW) represents a significant complication among diabetic patients, for which current therapeutic approaches remain suboptimal. Accumulating evidence indicates that fibroblast senescence plays a critical role in the impaired healing of diabetic wounds. Abnormal mitochondrial morphology has long been associated with cellular senescence and age-related pathologies, suggesting that mitochondrial dynamics are compromised during senescence. In this study, we explored the potential mechanisms through which adipose-derived mesenchymal stem cell-derived exosomes (ADSC-Exos) facilitate diabetic wound repair. We initially confirmed the presence of a substantial number of senescent fibroblasts in diabetic wound tissues. Subsequent investigations demonstrated that exosomes derived from adipose-derived stem cells can effectively alleviate fibroblast senescence. In-depth mechanistic analyses revealed that these exosomes suppress the expression of SMARCAL1, a chromatin remodeling protein, thereby enhancing the transcription of mitochondrial dynamin-related protein 1 (Drp1), and ultimately restoring mitochondrial dynamics and alleviating senescence in human dermal fibroblasts (HDFs). In vivo experiments further demonstrated that exosome administration significantly reduced HDFs senescence and accelerated wound healing in a diabetic mouse model. Collectively, our findings suggest that ADSC-Exos promote diabetic wound healing by mitigating HDFs senescence via the SMARCAL1-Drp1-mitochondrial dynamics pathway. This study elucidated the molecular mechanisms underlying exosome-mediated fibroblast senescence rescue and proposed a novel therapeutic strategy for diabetes-related wound management through targeted clearance of senescent cells.

糖尿病伤口延迟愈合（DW）是糖尿病患者的一个重要并发症，目前的治疗方法仍不理想。越来越多的证据表明，成纤维细胞衰老在糖尿病伤口愈合受损中起着关键作用。线粒体形态异常长期以来与细胞衰老和年龄相关的病理有关，这表明线粒体动力学在衰老过程中受到损害。在这项研究中，我们探索了脂肪源性间充质干细胞源性外泌体（ADSC-Exos）促进糖尿病伤口修复的潜在机制。我们最初证实了糖尿病伤口组织中存在大量衰老成纤维细胞。随后的研究表明，来自脂肪来源的干细胞的外泌体可以有效地缓解成纤维细胞衰老。深入的机制分析表明，这些外泌体抑制染色质重塑蛋白SMARCAL1的表达，从而增强线粒体动力蛋白相关蛋白1 （Drp1）的转录，最终恢复线粒体动力学并缓解人类真皮成纤维细胞（HDFs）的衰老。体内实验进一步证明，在糖尿病小鼠模型中，外泌体可显著减少HDFs衰老并加速伤口愈合。总之，我们的研究结果表明，ADSC-Exos通过smarcal1 - drp1 -线粒体动力学途径减缓HDFs衰老，从而促进糖尿病伤口愈合。本研究阐明了外泌体介导的成纤维细胞衰老修复的分子机制，并提出了一种通过靶向清除衰老细胞来治疗糖尿病相关伤口的新治疗策略。

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引用次数: 0

Multifaceted role of primary cilia and ciliary proteins: A potential nexus for hedgehog signaling and prostate cancer 原发性纤毛和纤毛蛋白的多方面作用：刺猬信号和前列腺癌的潜在联系。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-03-01 Epub Date: 2025-11-14 DOI: 10.1016/j.bbadis.2025.168120

Jyoti B. Kaushal , Parthasarathy Seshacharyulu , Surinder K. Batra , Sakthivel Muniyan

The primary cilium is a solitary, non-motile, microtubule-based organelle that extends from the cell membrane and functions as a critical coordinator of multiple signaling pathways. Despite its association with hundreds of proteins, only a subset is essential for its biogenesis and signal transmission. Malfunctions in primary cilia are associated with developmental disorders and various malignancies, including prostate cancer (PCa). Recent studies highlight the regulation of ciliogenesis, cilia length, and interaction among cilia-resident proteins, particularly within the ciliary hedgehog (Hh) signaling axis in oncogenesis, thereby positioning primary cilia as potential therapeutic targets. Nevertheless, the precise contribution of ciliary components to Hh pathway modulation in PCa remains poorly defined. This review integrates emerging evidence to elucidate the current state of knowledge on the structural and functional attributes of primary cilia, cilia-mediated molecular dynamics with Hh signaling, and their intersection in the context of PCa progression, including prostate development, carcinogenesis, and tumor microenvironment dynamics. Particular emphasis is placed on cilia-associated proteins, such as SCL/TAL1 interrupting locus (STIL), intraflagellar transport (IFT) family proteins, ADP-ribosylation factor (Arf) family proteins, transforming acidic coiled-coil protein-3 (TACC3), mitotic kinase Aurora A, and dual-specificity tyrosine-regulated kinase (DYRK), which have been mechanistically linked to PCa and modulate Hh signaling. However, their detailed contributions remain insufficiently characterized and warrant further investigation. This review underscores the role of primary cilia in PCa progression, highlights unresolved mechanistic gaps in their regulation, and proposes future directions for targeted molecular and therapeutic research.

初级纤毛是一个孤立的、不运动的、基于微管的细胞器，从细胞膜延伸出来，作为多种信号通路的关键协调者。尽管它与数百种蛋白质相关，但只有一个子集对其生物发生和信号传递至关重要。原发性纤毛功能障碍与发育障碍和各种恶性肿瘤，包括前列腺癌（PCa）有关。最近的研究强调了纤毛发生、纤毛长度和纤毛驻留蛋白之间的相互作用的调节，特别是在纤毛hedgehog （Hh）信号轴中，从而将初级纤毛定位为潜在的治疗靶点。然而，纤毛成分对PCa中Hh通路调节的精确贡献仍然不明确。这篇综述整合了新出现的证据来阐明初级纤毛的结构和功能属性、纤毛介导的Hh信号分子动力学以及它们在前列腺癌进展（包括前列腺发育、致癌和肿瘤微环境动力学）背景下的交叉知识的现状。特别强调的是纤毛相关蛋白，如SCL/TAL1中断位点（STIL），鞭毛内运输（IFT）家族蛋白，adp -核糖化因子（Arf）家族蛋白，转化酸性卷曲蛋白-3 (TACC3)，有丝分裂激酶Aurora A和双特异性酪氨酸调节激酶（DYRK），它们与PCa有机制联系并调节Hh信号。然而，他们的详细贡献仍然没有得到充分的描述，需要进一步调查。这篇综述强调了初级纤毛在前列腺癌进展中的作用，强调了其调控中尚未解决的机制空白，并提出了靶向分子和治疗研究的未来方向。

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引用次数: 0

Vimentin-targeting adaptogen withaferin A: Potential to selectively suppress cervical cancer – Single-cell microspectroscopic and molecular analysis 靶向vimentin的适应原与aferin A：选择性抑制宫颈癌的潜力-单细胞显微光谱和分子分析

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-03-01 Epub Date: 2025-11-25 DOI: 10.1016/j.bbadis.2025.168125

Ewa Pięta , Agnieszka Panek , Monika Szczepanek-Dulska , Katarzyna Pogoda

This study investigates the preferential anticancer effects of withaferin A, an adaptogenic compound, on primary and metastatic cervical cancer cells (C-33 A and CaSki, respectively) and non-cancerous skin fibroblast cells (Detroit-551). Employing a multi-modal approach, we combined biological assays with advanced vibrational spectroscopic imaging techniques, including Fourier-transform infrared (FT-IR), Raman (RS), and atomic force microscopy (AFM). The results revealed a dose-dependent reduction in cell viability, with a more pronounced effect observed in C-33 A cells compared to CaSki and fibroblasts, indicating a heightened sensitivity of C-33 A cells to withaferin A. The comet assay revealed significantly higher levels of DNA damage in primary tumor C-33A cells, whereas minimal DNA breaks were observed in fibroblasts and metastatic cells, further confirming the higher sensitivity of cancer cells compared to fibroblasts. Fluorescence staining and AFM topography imaging showed morphological alterations in cancer cells at higher withaferin A doses and longer incubation times. Flow cytometry analysis revealed significant apoptotic changes in primary C-33A cells due to withaferin A treatment, highlighting a large amount of cells undergoing late apoptosis, compared to a weaker apoptotic effect on metastatic CaSki cells and negligible effect for fibroblasts. Spectroscopic analyses revealed molecular alterations in lipid, protein, and nucleic acid composition, indicative of withaferin A's impact on cellular membranes and genetic material. These findings highlight withaferin A as a promising therapeutic agent with the potential to preferentially target primary cervical cancer cells, while minimizing toxicity to healthy cells.

本研究探讨了一种适应性化合物withaferin A对原发性和转移性宫颈癌细胞（分别为c - 33a和CaSki）和非癌性皮肤成纤维细胞（Detroit-551）的优先抗癌作用。采用多模态方法，我们将生物检测与先进的振动光谱成像技术相结合，包括傅里叶变换红外（FT-IR）、拉曼（RS）和原子力显微镜（AFM）。结果显示，与CaSki和成纤维细胞相比，在C-33A细胞中观察到的效果更明显，表明C-33A细胞对withaferin a的敏感性更高。彗星试验显示，原发肿瘤C-33A细胞的DNA损伤水平显著较高，而在成纤维细胞和转移细胞中观察到的DNA断裂最小，进一步证实了癌细胞比成纤维细胞更高的敏感性。荧光染色和AFM形貌成像显示，在高剂量和较长孵育时间下，癌细胞的形态发生了变化。流式细胞术分析显示，原代C-33A细胞由于withaferin A处理而发生了显著的凋亡变化，显示大量细胞发生了晚期凋亡，而对转移性CaSki细胞的凋亡作用较弱，对成纤维细胞的影响可以忽略不计。光谱分析揭示了脂质、蛋白质和核酸组成的分子改变，表明了withaferin A对细胞膜和遗传物质的影响。这些发现突出了withaferin A作为一种有前途的治疗药物，具有优先靶向原发性宫颈癌细胞的潜力，同时将对健康细胞的毒性降到最低。

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引用次数: 0

USP38 deficiency mitigates arrhythmogenic remodeling in obese mice by inhibiting TLR4/CaMKII signaling USP38缺乏通过抑制TLR4/CaMKII信号传导减轻肥胖小鼠的心律失常重塑。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-03-01 Epub Date: 2025-11-21 DOI: 10.1016/j.bbadis.2025.168122

Tao Chen , Hongjie Yang , Yang Gong , Jingjing Zhang , He Huang , Wei Shuai

Obesity-associated metabolic disturbances and cardiac remodeling significantly contribute to ventricular arrhythmias (VAs), a leading cause of sudden cardiac death. Although our previous studies have implicated the deubiquitinase USP38 in cardiovascular pathology, its precise role in obesity-related VAs remains unclear. Here, we aimed to elucidate the functional role and underlying mechanisms of USP38 in obesity-induced VAs.Cardiac-specific Usp38 knockout (CKO) mice were commercially generated. Obesity was induced by feeding mice a high-fat diet (HFD), while control mice received a normal diet (ND). We found the USP38 expression was significantly elevated in cardiac tissues of obese mice. Cardiac-specific deletion of USP38 markedly improved metabolic profiles and attenuated pathological remodeling, evidenced by reduced fibrosis markers (α-SMA, collagen I, collagen III), hypertrophy markers (ANP, BNP, β-MHC), and aberrant ion channel expression (Cav1.2, Kv1.5, Kv2.1, Kv4.2, Kv4.3). Correspondingly, the incidence of inducible VAs was significantly reduced. Co-immunoprecipitation confirmed a direct interaction between USP38 and the Toll-like receptor-4 (TLR4) signaling pathway. Further analyses demonstrated that USP38 knockout effectively blunted TLR4-mediated CaMKII activation both in vivo and in vitro. Cardiac-specific USP38 knockout effectively mitigates obesity-induced cardiac hypertrophy, fibrosis, and electrical remodeling, significantly reducing susceptibility to ventricular arrhythmias via inhibition of the TLR4/CaMKII signaling pathway. Mechanically, USP38 interacts with TLR4 and prevents the proteasomal degradation of TLR4, stabilizing TLR4 and promoting the activation of its downstream mediators. Therefore, targeted inhibition of USP38 may represent a promising therapeutic strategy for preventing obesity-associated ventricular arrhythmias.

肥胖相关的代谢紊乱和心脏重构显著导致室性心律失常（VAs），这是心源性猝死的主要原因。尽管我们之前的研究表明去泛素酶USP38与心血管病理有关，但其在肥胖相关VAs中的确切作用尚不清楚。在此，我们旨在阐明USP38在肥胖诱导的VAs中的功能作用及其潜在机制。心脏特异性Usp38基因敲除（CKO）小鼠被商业化生产。给小鼠喂食高脂肪饮食（HFD）诱导肥胖，而对照组小鼠喂食正常饮食（ND）。我们发现肥胖小鼠心脏组织中USP38的表达显著升高。心脏特异性缺失USP38显著改善了代谢谱，减轻了病理性重塑，纤维化标志物（α-SMA、胶原I、胶原III）、肥大标志物（ANP、BNP、β-MHC）和异常离子通道表达（Cav1.2、Kv1.5、Kv2.1、Kv4.2、Kv4.3）的减少证明了这一点。相应的，诱导性VAs的发生率显著降低。共免疫沉淀证实了USP38与toll样受体-4 （TLR4）信号通路之间的直接相互作用。进一步的分析表明，USP38敲除在体内和体外都能有效地减弱tlr4介导的CaMKII激活。心脏特异性USP38基因敲除可有效减轻肥胖引起的心脏肥大、纤维化和电重构，通过抑制TLR4/CaMKII信号通路显著降低室性心律失常的易感性。机械上，USP38与TLR4相互作用，阻止TLR4的蛋白酶体降解，稳定TLR4并促进其下游介质的激活。因此，靶向抑制USP38可能是预防肥胖相关室性心律失常的一种有前景的治疗策略。

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引用次数: 0

Urolithin A protects against calcium oxalate-induced crystal formation and kidney injury by regulating PCK1 to restore mitophagy function in kidney stone disease 尿素A通过调节PCK1恢复肾结石的自噬功能，防止草酸钙诱导的晶体形成和肾损伤。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-03-01 Epub Date: 2025-11-19 DOI: 10.1016/j.bbadis.2025.168106

Xiaoyi Sun , Chunlin Gao , Pei Zhang , Yingchao Peng , Meiqiu Wang , Jiuyu Liu , Chenxi Ma , Shan Li , Zhengkun Xia

Kidney stone disease (KSD) is one of the most common urological disorders, and oxalate-induced tubular epithelial cell injury plays a crucial role in stone-related renal damage. However, the mechanisms linking oxalate exposure to mitochondrial dysfunction remain unclear.

Urolithin A (UA), a gut microbiota–derived metabolite of ellagitannins, is recognized for its antioxidant and mitophagy-promoting properties. This study investigated the renoprotective effects and mechanisms of UA in calcium oxalate (CaOx) crystal–induced renal injury. In mice, UA markedly reduced renal CaOx deposition, improved renal function, and alleviated kidney injury. Consistently, both in vivo and in vitro experiments demonstrated that UA restored oxalate-suppressed mitophagy while also alleviating oxidative stress, apoptosis, and mitochondrial dysfunction.

Transcriptomic and molecular docking analyses identified phosphoenolpyruvate carboxykinase 1 (PCK1) as a downstream target of UA. UA restored PCK1 expression under oxalate stress both in vivo and in vitro, whereas pharmacological inhibition of PCK1 weakened the renal protective and mitophagy-promoting effects. Conversely, PCK1 overexpression enhanced mitophagy under high-oxalate conditions.

These findings indicate that UA alleviates CaOx-induced renal injury by activating PCK1-dependent mitophagy and restoring mitochondrial homeostasis. Given its natural origin and favorable safety profile, UA represents a promising candidate for preventing or treating calcium oxalate–associated renal injury.

肾结石病（KSD）是最常见的泌尿系统疾病之一，草酸盐诱导的肾小管上皮细胞损伤在结石相关性肾损害中起着至关重要的作用。然而，草酸暴露与线粒体功能障碍之间的联系机制尚不清楚。尿素A （UA）是一种肠道微生物衍生的鞣花单宁代谢物，被认为具有抗氧化和促进线粒体自噬的特性。本研究探讨了UA对草酸钙（CaOx）晶体所致肾损伤的保护作用及其机制。在小鼠中，UA可显著减少肾CaOx沉积，改善肾功能，减轻肾损伤。体内和体外实验一致表明，UA可以恢复草酸抑制的线粒体自噬，同时减轻氧化应激、细胞凋亡和线粒体功能障碍。转录组学和分子对接分析发现，磷酸烯醇丙酮酸羧激酶1 （PCK1）是UA的下游靶点。UA在体内和体外均能恢复草酸应激下PCK1的表达，而PCK1的药理抑制则削弱了其对肾脏的保护和促进有丝分裂的作用。相反，在高草酸条件下，PCK1过表达增强了线粒体自噬。这些结果表明，UA通过激活pck1依赖性的线粒体自噬和恢复线粒体稳态来减轻caox诱导的肾损伤。鉴于其天然来源和良好的安全性，UA代表了预防或治疗草酸钙相关肾损伤的有希望的候选者。

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引用次数: 0