Acta histochemica最新文献_第2页

S100A8 and S100A9-mediated keratinocyte affecting T lymphocyte immune imbalance through TLR4/NF-κ B in psoriasis 银屑病中S100A8和s100a9介导的角化细胞通过TLR4/NF-κ B影响T淋巴细胞免疫失衡。

IF 2.4 4区生物学 Q4 CELL BIOLOGY

Acta histochemica

Pub Date : 2025-11-17 DOI: 10.1016/j.acthis.2025.152297

Yali He , Jianxiao Xing , Junqin Li , Kaiming Zhang , Xinhua Li

Psoriasis is a chronic,immune-mediated inflammatory skin disorder characterized by recurrent thick plaque. As an alarmin of inflammation, the importance of S100A8 and S100A9 have already been confirmed to be associated with the development of chronic inflammation in diseases. However, the precise mechanisms of S100A8 and S100A9 in psoriasis remain unclear. Therefore,the aim of this study was to elucidate the effects and underlying mechanisms of S100A8 and S100A9 in psoriasis. In this study, we found that both S100A8 and S100A9 were highly expressed in cells treated with M5—a cytokine mixture containing IL-1α, IL-17A, IL-22, oncostatin M, and TNF-α—as well as in a mouse model of imiquimod (IMQ)-induced psoriasis. Meanwhile, S100A8 and S100A9 knockdown in normal human epidermal keratinocytes (NHEK) inhibited the proliferation of NHEK cells in psoriasis. To further investigate the effects of S100A8 and S100A9 on psoriatic inflammation, T cells were co-cultured with S100A8 and S100A9 knockdown NHEK cells, and S100A8 and S100A9 promoted the production of pro-inflammatory cytokines by T cells through activation of Toll-like receptor 4 (TLR4)/NF-κB signaling pathway. In particular, when the S100A8 and S100A9 inhibitor paquinimod was added to a mouse model of imiquimot-induced psoriasis, psoriatic dermatitis and inflammatory factors were reduced, and the expression of TLR4/NF-κB was also significantly reduced. In conclusion, this study illustrated that S100A8 and S100A9 participates in the pathogenesis of psoriasis by activating TLR4/NF-κB signaling pathways, thereby promoting psoriasis-associated skin inflammation, which suggested the potential role of S100A8 and S100A9 in the development of psoriasis and provided new insight into targeted therapies.

银屑病是一种慢性的、免疫介导的炎症性皮肤疾病，以复发性厚斑块为特征。作为炎症的警示因子，S100A8和S100A9的重要性已被证实与疾病中慢性炎症的发生发展有关。然而，S100A8和S100A9在银屑病中的确切机制尚不清楚。因此，本研究的目的是阐明S100A8和S100A9在银屑病中的作用及其机制。在本研究中，我们发现S100A8和S100A9在含有IL-1α、IL-17A、IL-22、癌抑素M和TNF-α-的细胞因子混合物m5处理后的细胞以及咪喹莫特（IMQ）诱导的银屑病小鼠模型中均高表达。同时，在正常人表皮角质形成细胞（NHEK）中敲低S100A8和S100A9可抑制银屑病中NHEK细胞的增殖。为了进一步研究S100A8和S100A9对银屑病炎症的影响，我们将T细胞与S100A8和S100A9敲低的NHEK细胞共培养，发现S100A8和S100A9通过激活toll样受体4 (TLR4)/NF-κB信号通路，促进T细胞产生促炎细胞因子。特别是在吡喹莫特诱导的银屑病小鼠模型中加入S100A8和S100A9抑制剂帕喹莫德后，银屑病皮炎和炎症因子减少，TLR4/NF-κB的表达也明显降低。综上所述，本研究提示S100A8和S100A9通过激活TLR4/NF-κB信号通路参与银屑病的发病，从而促进银屑病相关的皮肤炎症，提示S100A8和S100A9在银屑病发生发展中的潜在作用，并为靶向治疗提供新的思路。

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引用次数: 0

Immunofluorescent characterization of Klotho and FGF23 in clear cell renal cell carcinoma: A pilot study Klotho和FGF23在透明细胞肾细胞癌中的免疫荧光特性：一项初步研究

IF 2.4 4区生物学 Q4 CELL BIOLOGY

Acta histochemica

Pub Date : 2025-11-14 DOI: 10.1016/j.acthis.2025.152298

Anita Racetin , Nela Kelam , Merica Glavina Durdov , Katarina Vukojević

Background/objectives

Clear cell renal cell carcinoma (ccRCC) is the most prevalent histological subtype of renal malignancy, associated with poor prognosis in advanced stages. Emerging evidence highlights the potential tumor-suppressive role of the anti-aging protein Klotho (KL) and its cofactor, fibroblast growth factor 23 (FGF23), both of which are implicated in phosphate metabolism and cellular homeostasis.

Methods

Using immunofluorescence and quantitative image analysis, we assessed KL and FGF23 protein levels in 20 ccRCC specimens stratified by tumor grade, alongside adjacent normal tissue. Publicly available RNA-seq and survival data from the TCGA-KIRC cohort were analyzed to complement our findings.

Results

Immunofluorescence analysis of 20 ccRCC samples and matched normal tissues revealed consistently low Klotho expression with no significant differences across tumor grades. However, Kaplan–Meier survival analysis revealed that high KL mRNA expression was significantly associated with improved overall survival and disease-free survival, highlighting its role as a protective prognostic biomarker. Multivariate Cox regression confirmed KL as an independent predictor of better overall survival. In contrast, FGF23 protein levels were significantly elevated in ccRCC samples, particularly in high-grade tumors, despite minimal expression in control tissue and no significant differences at the mRNA level in the TCGA cohort. Notably, patients with detectable FGF23 expression had significantly worse survival outcomes, and multivariate analysis identified elevated FGF23 as an independent risk factor for poor prognosis. Age and tumor stage also remain strong prognostic determinants in our models.

Conclusions

These findings suggest a dichotomous role for KL and FGF23 in ccRCC, with KL functioning as a favorable prognostic factor and FGF23 potentially contributing to disease progression and early relapse. Further mechanistic studies are warranted to elucidate their interplay and evaluate their utility as biomarkers or therapeutic targets in renal cancer.

背景/目的透明细胞肾细胞癌（ccRCC）是肾脏恶性肿瘤中最常见的组织学亚型，晚期预后较差。新出现的证据强调了抗衰老蛋白Klotho （KL）及其辅助因子成纤维细胞生长因子23 （FGF23）的潜在肿瘤抑制作用，这两者都与磷酸盐代谢和细胞稳态有关。方法采用免疫荧光和定量图像分析方法，对20例按肿瘤分级的ccRCC标本及邻近正常组织的KL和FGF23蛋白水平进行了评估。我们分析了来自TCGA-KIRC队列的公开可用RNA-seq和生存数据，以补充我们的发现。结果20例ccRCC样本和匹配的正常组织的免疫荧光分析显示，Klotho的表达持续较低，不同肿瘤级别间无显著差异。然而，Kaplan-Meier生存分析显示，高KL mRNA表达与总生存期和无病生存期显著相关，突出了其作为保护性预后生物标志物的作用。多变量Cox回归证实KL是更好的总生存的独立预测因子。相比之下，FGF23蛋白水平在ccRCC样本中显著升高，特别是在高级别肿瘤中，尽管在对照组织中表达极低，并且在TCGA队列中mRNA水平无显著差异。值得注意的是，FGF23表达可检测的患者生存结果明显较差，多变量分析发现FGF23升高是预后不良的独立危险因素。在我们的模型中，年龄和肿瘤分期仍然是重要的预后决定因素。这些发现提示KL和FGF23在ccRCC中的双重作用，KL是一个有利的预后因素，而FGF23可能有助于疾病进展和早期复发。需要进一步的机制研究来阐明它们的相互作用，并评估它们作为肾癌生物标志物或治疗靶点的效用。

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引用次数: 0

POSTN promotes ferroptosis and contributes to the pathogenesis of IgA nephropathy via GPX4 downregulation POSTN促进铁下垂，并通过GPX4下调参与IgA肾病的发病机制

IF 2.4 4区生物学 Q4 CELL BIOLOGY

Acta histochemica

Pub Date : 2025-11-06 DOI: 10.1016/j.acthis.2025.152296

Wang Jia , Yonggui Wu

IgA nephropathy (IgAN) is a prevalent glomerular disease characterized by mesangial deposition of IgA1-containing immune complexes, yet its underlying molecular mechanisms remain incompletely understood. In this study, we integrated bioinformatics analyses of two public datasets (GSE104948 and GSE93798) to identify key differentially expressed genes (DEGs) associated with IgAN. Periostin (POSTN) emerged as a hub gene, exhibiting significant upregulation in IgAN samples and correlating with histopathological severity. Functional enrichment revealed that overlapping DEGs are involved in extracellular matrix organization, immune response, and signaling pathways relevant to renal pathology. Immunohistochemical and immunofluorescence analyses confirmed increased POSTN and decreased GPX4 expression in renal biopsies from IgAN patients, indicating enhanced ferroptosis. In vitro, IgA1 stimulation of human mesangial cells (HMCs) elevated POSTN expression and induced ferroptosis, evidenced by increased oxidative stress, mitochondrial damage, and reduced cell viability. Knockdown of POSTN ameliorated these effects by restoring glutathione levels and reducing lipid peroxidation, while POSTN overexpression exacerbated ferroptosis. Notably, treatment with the ferroptosis inhibitor ferrostatin-1 reversed POSTN-induced cellular damage. Our findings suggest that POSTN promotes IgAN progression by facilitating ferroptosis through GPX4 downregulation, highlighting a novel pathogenic mechanism. Targeting POSTN-mediated ferroptosis may provide promising therapeutic strategies for IgAN. This study advances our understanding of IgAN molecular pathology and offers potential biomarkers and intervention targets to improve patient outcomes.

IgA肾病（IgAN）是一种常见的肾小球疾病，其特征是含iga1免疫复合物的肾小球系膜沉积，但其潜在的分子机制仍不完全清楚。在这项研究中，我们整合了两个公共数据集（GSE104948和GSE93798）的生物信息学分析，以确定与IgAN相关的关键差异表达基因（DEGs）。骨膜蛋白（POSTN）作为枢纽基因出现，在IgAN样本中表现出显著的上调，并与组织病理严重程度相关。功能富集显示重叠的deg参与细胞外基质组织、免疫反应和与肾脏病理相关的信号通路。免疫组织化学和免疫荧光分析证实，在IgAN患者的肾活检中，POSTN升高，GPX4表达降低，表明铁下垂增强。体外，IgA1刺激人系膜细胞（HMCs）可提高POSTN表达并诱导铁上吊，表现为氧化应激增加、线粒体损伤和细胞活力降低。下调POSTN可通过恢复谷胱甘肽水平和减少脂质过氧化来改善这些影响，而过表达POSTN则会加剧铁下垂。值得注意的是，用铁下垂抑制剂铁抑素-1治疗可以逆转postn诱导的细胞损伤。我们的研究结果表明，POSTN通过GPX4下调促进铁下垂，从而促进IgAN的进展，强调了一种新的致病机制。靶向后n介导的铁下垂可能为IgAN提供有希望的治疗策略。这项研究促进了我们对IgAN分子病理学的理解，并提供了潜在的生物标志物和干预靶点，以改善患者的预后。

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引用次数: 0

Retraction notice to " Paeonol antagonizes oncogenesis of osteosarcoma by inhibiting the function of TLR4/MAPK/NF-?B pathway" [Acta Histochem. 122 (2020) 151455] “丹皮酚通过抑制TLR4/MAPK/NF-？B通路”[组织化学学报，122(2020)151455]。

IF 2.4 4区生物学 Q4 CELL BIOLOGY

Acta histochemica

Pub Date : 2025-10-01 DOI: 10.1016/j.acthis.2025.152295

Jianguo Zhou , Qinglin Liu , Rui Qian, Shiwei Liu, Weiquan Hu, Zhenyu Liu

引用次数: 0

FoxO1 in skeletal muscle atrophy: Multifaceted regulatory mechanisms and therapeutic opportunities fox01在骨骼肌萎缩中的作用：多方面的调控机制和治疗机会

IF 2.4 4区生物学 Q4 CELL BIOLOGY

Acta histochemica

Pub Date : 2025-09-23 DOI: 10.1016/j.acthis.2025.152293

Cheng-Ya Song , Tian-Yi Zhou , Han-Bo Shi , Xin-Yi Li , Kan Hong

Skeletal muscle, which accounts for nearly 40 % of total body mass, serves as the primary effector organ for locomotion, metabolism, and thermoregulation. Skeletal muscle atrophy, a common condition associated with aging, disease, and disability, significantly compromises patients’ quality of life. This review focuses on the occurrence and progression of skeletal muscle atrophy. Forkhead box protein O1 (FoxO1) is a key regulatory factor that mediates pathological mechanisms through multidimensional molecular networks. It influences skeletal muscle metabolism via post-translational modifications (PTMs), dysregulated autophagy, an imbalanced inflammatory microenvironment, and the regulation of satellite cell function. Therapeutic strategies targeting FoxO1, such as resveratrol-induced SIRT1 activation and miR-486 mimics, have shown promising results in preclinical models. This review highlights the central role of FoxO1 in molecular pathways, proposes a potential framework for addressing muscle atrophy, and offers new insights into the treatment of sarcopenia and related diseases.

骨骼肌占人体总质量的近40% %，是运动、代谢和体温调节的主要效应器。骨骼肌萎缩是一种与衰老、疾病和残疾相关的常见疾病，严重影响患者的生活质量。本文就骨骼肌萎缩的发生与进展作一综述。叉头盒蛋白O1 （FoxO1）是通过多维分子网络介导病理机制的关键调控因子。它通过翻译后修饰（PTMs）、失调的自噬、不平衡的炎症微环境和卫星细胞功能的调节来影响骨骼肌代谢。针对fox01的治疗策略，如白藜芦醇诱导的SIRT1激活和miR-486模拟，在临床前模型中显示出有希望的结果。这篇综述强调了fox01在分子通路中的核心作用，提出了解决肌肉萎缩的潜在框架，并为肌肉减少症和相关疾病的治疗提供了新的见解。

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引用次数: 0

Cancer-associated fibroblast-derived CCL5 enhanced aerobic glycolysis through upregulation of IP3R to promote breast cancer cell metastasis 癌症相关成纤维细胞衍生的CCL5通过上调IP3R增强有氧糖酵解，促进乳腺癌细胞转移

IF 2.4 4区生物学 Q4 CELL BIOLOGY

Acta histochemica

Pub Date : 2025-09-23 DOI: 10.1016/j.acthis.2025.152292

Mingxiang Zhang , Zhengzhi Zhu , Guang Yang , Yongyun Zhu

Background

This study aimed to investigate whether cancer-associated fibroblast (CAF)-derived chemokine C-C motif ligand 5 (CCL5) promotes breast cancer (BC) cell metastasis by enhancing aerobic glycolysis via upregulation of IP3R.

Methods

Lentiviral vectors for CCL5 overexpression or knockdown were constructed, transfected into CAFs, and co-cultured with ZR-75–30 cells CCL5. Cell proliferation and apoptosis were assessed by CCK-8, cloning assay and flow cytometry. Cell migration and invasion were verified by scratch assay and Transwell assay. Co-IP verified the interactions between CCL5 and IP3R. The kit detects aerobic glycolysis-related indexes. western bloting detects CCL5, IP3R, glycolysis-related proteins, EMT-related proteins and metastasis-related proteins.

Results

Knockdown of CCL5 in CAFs and co-culture with breast cancer cells resulted in decreased cell proliferation, migration, and invasionCCL5, increased apoptosis, and attenuated aerobic glycolysis. Co-immunoprecipitation (Co-IP) assays revealed direct protein-protein interactions between CCL5 and IP3RCCL5. IP3R overexpression following CCL5 knockdown rescued breast cancer cell proliferative viability CCL5, restoration of migration and invasion abilities, and enhanced aerobic glycolysis.

Conclusion

CAF-derived CCL5 enhanced aerobic glycolysis in breast cancer cells by up-regulating IP3R expression, which in turn promoted their metastasis.

Data Availability

The data used to support the findings of this study are available from the corresponding author upon request.

本研究旨在探讨癌症相关成纤维细胞（CAF）衍生的趋化因子C-C基序配体5 （CCL5）是否通过上调IP3R来促进有氧糖酵解，从而促进乳腺癌（BC）细胞转移。方法构建CCL5过表达或低表达的慢病毒载体，转染到CAFs中，与ZR-75-30细胞CCL5共培养。采用CCK-8、克隆实验和流式细胞术检测细胞增殖和凋亡情况。通过划痕实验和Transwell实验验证了细胞的迁移和侵袭。Co-IP验证了CCL5和IP3R之间的相互作用。该试剂盒检测有氧糖酵解相关指标。western blotting检测CCL5、IP3R、糖酵解相关蛋白、emt相关蛋白和转移相关蛋白。结果caf中CCL5的下调和与乳腺癌细胞的共培养导致CCL5细胞增殖、迁移和侵袭减少，凋亡增加，有氧糖酵解减弱。共免疫沉淀（Co-IP）实验揭示了CCL5和IP3RCCL5之间的直接蛋白相互作用。CCL5敲低后IP3R过表达挽救了乳腺癌细胞的增殖活力，恢复了CCL5的迁移和侵袭能力，并增强了有氧糖酵解。结论caf衍生的CCL5通过上调IP3R表达，促进乳腺癌细胞的有氧糖酵解，从而促进乳腺癌细胞的转移。数据可获得性用于支持本研究结果的数据可应要求从通讯作者处获得。

{"title":"Cancer-associated fibroblast-derived CCL5 enhanced aerobic glycolysis through upregulation of IP3R to promote breast cancer cell metastasis","authors":"Mingxiang Zhang , Zhengzhi Zhu , Guang Yang , Yongyun Zhu","doi":"10.1016/j.acthis.2025.152292","DOIUrl":"10.1016/j.acthis.2025.152292","url":null,"abstract":"<div><h3>Background</h3><div>This study aimed to investigate whether cancer-associated fibroblast (CAF)-derived chemokine C-C motif ligand 5 (CCL5) promotes breast cancer (BC) cell metastasis by enhancing aerobic glycolysis via upregulation of IP3R.</div></div><div><h3>Methods</h3><div>Lentiviral vectors for CCL5 overexpression or knockdown were constructed, transfected into CAFs, and co-cultured with ZR-75–30 cells CCL5. Cell proliferation and apoptosis were assessed by CCK-8, cloning assay and flow cytometry. Cell migration and invasion were verified by scratch assay and Transwell assay. Co-IP verified the interactions between CCL5 and IP3R. The kit detects aerobic glycolysis-related indexes. western bloting detects CCL5, IP3R, glycolysis-related proteins, EMT-related proteins and metastasis-related proteins.</div></div><div><h3>Results</h3><div>Knockdown of CCL5 in CAFs and co-culture with breast cancer cells resulted in decreased cell proliferation, migration, and invasionCCL5, increased apoptosis, and attenuated aerobic glycolysis. Co-immunoprecipitation (Co-IP) assays revealed direct protein-protein interactions between CCL5 and IP3RCCL5. IP3R overexpression following CCL5 knockdown rescued breast cancer cell proliferative viability CCL5, restoration of migration and invasion abilities, and enhanced aerobic glycolysis.</div></div><div><h3>Conclusion</h3><div>CAF-derived CCL5 enhanced aerobic glycolysis in breast cancer cells by up-regulating IP3R expression, which in turn promoted their metastasis.</div></div><div><h3>Data Availability</h3><div>The data used to support the findings of this study are available from the corresponding author upon request.</div></div>","PeriodicalId":6961,"journal":{"name":"Acta histochemica","volume":"127 4","pages":"Article 152292"},"PeriodicalIF":2.4,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145118326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Neurochemical heterogeneity of ChAT-immunoreactive neurons in the basal forebrain cholinergic nuclei and striatum in reference to CGRP, CCK, and calcium-binding proteins 基底前脑胆碱能核和纹状体中chat免疫反应神经元的神经化学异质性与CGRP、CCK和钙结合蛋白相关

IF 2.4 4区生物学 Q4 CELL BIOLOGY

Acta histochemica

Pub Date : 2025-09-08 DOI: 10.1016/j.acthis.2025.152291

Mirza Mienur Meher , Marya Afrin , Mir Rubayet Jahan , Kanako Nozaki , Koh-hei Masumoto , Akie Yanai , Md Nabiul Islam

Cholinergic neurons in the basal forebrain cholinergic nuclei (BFCN) and neostriatum (CPu) play key roles in learning, attention, and motor control. The loss of cholinergic neurons causes major neurodegenerative diseases such as Alzheimer’s disease. This study aimed to elucidate the molecular diversity of choline acetyltransferase immunoreactive (ChAT-ir) neurons in these brain regions. We performed immunohistochemistry to determine the co-expression of ChAT-ir neurons with two neuropeptides, calcitonin gene-related peptide (CGRP) and cholecystokinin (CCK), as well as three calcium-binding proteins, such as calbindin, calretinin, and parvalbumin, in the adult mouse brain. The results showed that ChAT, calbindin, CGRP and CCK were strongly expressed in the BFCN, including medial septal nucleus (MS), nucleus of vertical limb and horizontal limb of the diagonal band of Broca (VDB and HDB), substantia innominata basal part (SIB), and in the caudate putamen (CPu). CGRP and CCK showed a high immunoreactive co-expression with ChAT, especially in the HDB and CPu. Calbindin immunoreactivity was widely present and coincided with ChAT in the VDB, HDB, and CPu. However, calretinin immunoreactivity showed a selective co-expression with ChAT in the VDB, SIB, and CPu. Although parvalbumin immunoreactivity was observed throughout the BFCN and CPu, but there was no co-expression between ChAT and parvalbumin. The neurochemical diversity of ChAT-ir neurons in the BFCN and neostriatum suggests the specialized functions of cholinergic neurons across different circuits, especially by modulating CGRP, CCK, or calbindin. These results could provide new insight into cholinergic modulation throughout the BFCN and striatum.

基底前脑胆碱能核（BFCN）和新纹状体（CPu）中的胆碱能神经元在学习、注意和运动控制中起关键作用。胆碱能神经元的丧失会导致主要的神经退行性疾病，如阿尔茨海默病。本研究旨在阐明这些脑区胆碱乙酰转移酶免疫反应（ChAT-ir）神经元的分子多样性。我们采用免疫组织化学方法测定了ChAT-ir神经元与两种神经肽（降钙素基因相关肽（CGRP）和胆囊收缩素（CCK））以及三种钙结合蛋白（calbindin， calretinin和parvalbumin）在成年小鼠脑中的共表达。结果显示，ChAT、calbindin、CGRP和CCK在BFCN中，包括中隔核（MS）、Broca斜带纵肢和水平肢核（VDB和HDB）、基底基底物质（SIB）和尾状壳核（CPu）中均有强烈表达。CGRP和CCK与ChAT具有较高的免疫反应性共表达，特别是在HDB和CPu中。Calbindin免疫反应性广泛存在，并与VDB、HDB和CPu的ChAT一致。然而，calretinin的免疫反应性与ChAT在VDB、SIB和CPu中选择性共表达。虽然在BFCN和CPu中观察到细小蛋白的免疫反应性，但ChAT与细小蛋白之间没有共表达。BFCN和新纹状体中ChAT-ir神经元的神经化学多样性表明胆碱能神经元在不同回路中的特殊功能，特别是通过调节CGRP， CCK或calbindin。这些结果可以为胆碱能在BFCN和纹状体中的调节提供新的见解。

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引用次数: 0

Neuroprotective effect of Urolithin A via downregulating VDAC1-mediated autophagy in Alzheimer's disease 尿素A通过下调vdac1介导的自噬在阿尔茨海默病中的神经保护作用

IF 2.4 4区生物学 Q4 CELL BIOLOGY

Acta histochemica

Pub Date : 2025-09-01 DOI: 10.1016/j.acthis.2025.152290

Bensi Zhang , Xiujun Zhang , Waleephan Treebupachatsakul , Rungusa Pantan , Natnicha Kampan , Manussabhorn Phatsara , Chun Shi , Suteera Narakornsak

Background

Amyloid β (Aβ) accumulation in the brains of patients with Alzheimer's disease (AD) contributes to cognitive impairment and neuronal damage. Urolithin A (UA), a gut microbiota–derived metabolite of ellagic acid, has been reported to cross the blood-brain barrier to exert anti-inflammatory and anti-oxidation effects in the brain. However, the molecular mechanisms of UA in AD were still unclear. This study aims to explore the neuroprotective effect and mechanism of UA on APP/PS1 mice and Aβ_1–42-injured N2a and PC12 cells.

Methods

In this study, Morris water maze was used to detect the cognitive function. Immunofluorescence was used to detect the deposition of Aβ and the expression of voltage-dependent anion channel 1 (VDAC1) in the brains of APP/PS1 mice. Western blotting was used to detect the expression of VDAC1, AMPK pathway, PI3K pathway and autophagy-related proteins. CCK8 was used to detect the viability of Aβ_1–42-injured cells.

Results

In this research, we found that UA improved cognitive dysfunction and reduced Aβ deposition in APP/PS1 mice. Furthermore, UA activated autophagy and upregulated the levels of autophagy-related proteins in both APP/PS1 mice and Aβ_1–42-injured N2a and PC12 cells. At the same time, UA down-regulated the phosphorylation level of PI3K/AKT/mTOR and up-regulated the phosphorylation level of AMPK in APP/PS1 mice and Aβ_1–42-injured N2a cells and PC12 cells. In addition, UA down-regulated VDAC1, consistent with the effect of VDAC1 antagonist DIDS (4′-diisothiocyano-2,2′-disulfonic acid stilbene). Importantly, the UA-induced activation of autophagy and modulation of the PI3K and AMPK pathways were reversed by VDAC1 overexpression.

Conclusion

These findings demonstrated that UA down-regulated VDAC1 played a key neuroprotective role on AD by inhibiting the PI3K/AKT/mTOR pathway and activating the AMPK pathway to promote autophagy.

阿尔茨海默病（AD）患者大脑中淀粉样蛋白β (Aβ)的积累有助于认知障碍和神经元损伤。尿素A （UA）是一种肠道微生物衍生的鞣花酸代谢物，据报道可以穿过血脑屏障，在大脑中发挥抗炎和抗氧化作用。然而，UA在AD中的分子机制尚不清楚。本研究旨在探讨UA对APP/PS1小鼠及a β1 - 42损伤的N2a和PC12细胞的神经保护作用及其机制。方法采用Morris水迷宫法检测大鼠认知功能。应用免疫荧光法检测APP/PS1小鼠脑内Aβ的沉积及电压依赖性阴离子通道1 （VDAC1）的表达。Western blotting检测VDAC1、AMPK通路、PI3K通路及自噬相关蛋白的表达。CCK8检测a β1 - 42损伤细胞的活力。结果本研究发现UA可改善APP/PS1小鼠的认知功能障碍，减少Aβ沉积。此外，UA在APP/PS1小鼠和a β1 - 42损伤的N2a和PC12细胞中激活自噬并上调自噬相关蛋白的水平。同时，UA下调APP/PS1小鼠及a β1 - 42损伤的N2a细胞和PC12细胞中PI3K/AKT/mTOR的磷酸化水平，上调AMPK的磷酸化水平。此外，UA下调VDAC1，与VDAC1拮抗剂DIDS（4′-二异硫氰酸-2,2′-二磺酸二苯乙烯）的作用一致。重要的是，uva诱导的自噬激活和PI3K和AMPK通路的调节被VDAC1过表达逆转。结论UA下调VDAC1通过抑制PI3K/AKT/mTOR通路，激活AMPK通路促进自噬，在AD中发挥关键的神经保护作用。

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引用次数: 0

USP22-mediated PNMA5 deubiquitination promotes proliferation, migration and invasion of prostate cancer cells. usp22介导的PNMA5去泛素化促进前列腺癌细胞的增殖、迁移和侵袭。

IF 2.4 4区生物学 Q4 CELL BIOLOGY

Acta histochemica

Pub Date : 2025-09-01 Epub Date: 2025-08-09 DOI: 10.1016/j.acthis.2025.152279

Hong Zhi, Tana, Nigemutu Bai, Wuenbilige Bai, Bowen Bai, Suo Liu

Background: Prostate cancer (PCa) stands as one of the primary contributors to cancer-related mortality among men globally. It is reported that USP22 functions as an oncogene, while PNMA5 exhibits a significant pro-metastatic effect. This research investigation centered on examining the interplay between USP22 and PNMA5 and their collaborative role in enhancing PCa progression.

Methods: The expression of USP22 and PNMA5 in tissue was determined by IHC. The differential expression of cellular USP22 and PNMA5 were detected using qPCR and immunoblotting, respectively. Cell viability and proliferation were assessed by MTT and sphere-formation assay. Transwell and wound-healing assay were conducted to evaluate the metastatic ability. The interaction between USP22 and PNMA5 was detected by Co-IP and IP. A tumor-bearing mice model was established for in vivo detection.

Results: USP22 and PNMA5 were highly expressed in both PCa tumor tissues and cells. Knocking down USP22 or PNMA5 inhibited the migration and invasion of PCa cells. USP22 mediated the deubiquitination of PNMA5. PNMA5 overexpression reversed the decrease in cell viability and proliferation rate, as well as the diminished migration and invasion ability induced by USP22 knockdown.

Conclusion: USP22 promotes migration and invasion of PCa cells by regulating PNMA5 deubiquitination.

背景：前列腺癌（PCa）是全球男性癌症相关死亡的主要原因之一。据报道，USP22作为癌基因起作用，而PNMA5表现出显著的促转移作用。本研究的重点是研究USP22和PNMA5之间的相互作用以及它们在促进前列腺癌进展中的协同作用。方法：采用免疫组化法检测组织中USP22和PNMA5的表达。分别采用qPCR和免疫印迹法检测细胞USP22和PNMA5的差异表达。MTT法和成球法检测细胞活力和增殖能力。采用Transwell法和创面愈合法评价转移能力。通过Co-IP和IP检测USP22与PNMA5的相互作用。建立荷瘤小鼠模型进行体内检测。结果：USP22和PNMA5在前列腺癌组织和细胞中均有高表达。敲低USP22或PNMA5可抑制PCa细胞的迁移和侵袭。USP22介导PNMA5的去泛素化。PNMA5过表达逆转了USP22敲低引起的细胞活力和增殖率的下降，以及迁移和侵袭能力的降低。结论：USP22通过调控PNMA5去泛素化促进PCa细胞的迁移和侵袭。

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引用次数: 0

Blood transfusion mediated tumor microenvironment remodeling in breast cancer 输血介导的乳腺癌肿瘤微环境重塑

IF 2.4 4区生物学 Q4 CELL BIOLOGY

Acta histochemica

Pub Date : 2025-08-23 DOI: 10.1016/j.acthis.2025.152289

Qinan Yin , Shunshun Zhang , Mouna Ouchari , Pei Wang , Anshun Zhao , Li Zeng , Jingjing Wang , Kaiyuan Yao , Siya Tang , Haodi Ma , Anne-Catherine Girondin , Hecai Yang , Xuewei Zheng , Zhifeng Qu

Blood transfusions play a critical role in breast cancer management, particularly in addressing perioperative blood loss and chemotherapy-induced anemia. However, emerging evidence suggests that transfusions may adversely affect oncologic outcomes by inducing transfusion-related immunomodulation (TRIM) and altering the tumor microenvironment (TME). TRIM suppresses cytotoxic immune responses, potentially facilitating tumor progression—especially in aggressive subtypes such as triple-negative breast cancer (TNBC) and HER2-positive cancers. Additionally, transfusions can paradoxically exacerbate tumor hypoxia by increasing blood viscosity and impairing microvascular perfusion, thereby reducing the effectiveness of chemotherapy, radiotherapy, and immunotherapy. This review examines the dual role of blood transfusions in breast cancer, emphasizing both their clinical benefits and potential risks. We analyze their impact on treatment resistance and tumor progression and discuss strategies to mitigate associated risks, including leukoreduction, erythropoiesis-stimulating agents (ESAs), intravenous iron supplementation, and blood conservation techniques. Furthermore, we highlight the importance of personalized transfusion approaches guided by tumor subtype, immune status, and relevant biomarkers such as tumor-infiltrating lymphocytes (TILs), PD-L1 expression, and circulating tumor DNA (ctDNA). Future research should focus on optimizing transfusion timing, implementing biomarker-driven protocols, and developing immune-modulating interventions to counteract TRIM. A personalized, evidence-based transfusion strategy may ultimately enhance treatment efficacy and improve long-term outcomes in breast cancer care.

输血在乳腺癌治疗中起着至关重要的作用，特别是在处理围手术期失血和化疗引起的贫血方面。然而，新出现的证据表明，输血可能通过诱导输血相关免疫调节（TRIM）和改变肿瘤微环境（TME）对肿瘤预后产生不利影响。TRIM抑制细胞毒性免疫反应，潜在地促进肿瘤进展-特别是在侵袭性亚型，如三阴性乳腺癌（TNBC）和her2阳性癌症中。此外，输血可能通过增加血液粘度和损害微血管灌注而矛盾地加剧肿瘤缺氧，从而降低化疗、放疗和免疫治疗的有效性。这篇综述探讨了输血在乳腺癌中的双重作用，强调了其临床益处和潜在风险。我们分析了它们对治疗耐药和肿瘤进展的影响，并讨论了减轻相关风险的策略，包括白细胞减少、促红细胞生成剂（esa）、静脉补铁和血液保存技术。此外，我们强调了根据肿瘤亚型、免疫状态和相关生物标志物（如肿瘤浸润淋巴细胞（TILs）、PD-L1表达和循环肿瘤DNA (ctDNA)）指导的个性化输血方法的重要性。未来的研究应侧重于优化输血时机，实施生物标志物驱动的方案，并开发免疫调节干预措施来抵消TRIM。个性化的、基于证据的输血策略可能最终提高治疗效果并改善乳腺癌护理的长期结果。

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