International Journal of Biochemistry & Cell Biology最新文献_第9页

Influence of the ERK/CHGB pathway in breast cancer progression under chronic stress 慢性应激下ERK/CHGB通路对乳腺癌进展的影响

IF 3.4 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

International Journal of Biochemistry & Cell Biology

Pub Date : 2025-02-01 DOI: 10.1016/j.biocel.2024.106733

Yue Wang , Xi Hou , Zijing Wu , Junyu Ren , Yanfang Zhao

Background

Breast cancer is one of the most common malignancies among women, and its development involves a variety of complex molecular mechanisms. Extracellular signal-regulated kinase (ERK) and Chromogranin B (CHGB) are known to play key roles in various cancers. This study aims to explore the impact of the ERK/CHGB pathway in a chronic stress environment simulated by salbutamol on the development of breast cancer.

Methods

This study utilized female BALB/c mice to establish a breast cancer model, dividing them into control, salbutamol-treated, and salbutamol-inhibitor-treated groups. Cell culture, immunohistochemistry, Western Blot, real-time fluorescent quantitative PCR, and Transwell migration assays were employed to assess the effects of salbutamol and the ERK/CHGB pathway.

Results

Salbutamol treatment significantly enhanced the proliferation, migration, and invasiveness of breast cancer cells, associated with the activation of the ERK pathway and the inhibition of CHGB. The salbutamol-inhibitor-treated group exhibited a marked suppression of these effects. Additionally, the interaction of the ERK/CHGB pathway in an extracellular stress environment provided advantages for the survival and proliferation of breast cancer cells.

Conclusion

This study demonstrates that a chronic stress environment simulated by salbutamol can promote malignant behaviors in breast cancer cells through the ERK/CHGB pathway. These findings offer new molecular targets for breast cancer treatment and highlight the potential importance of managing chronic stress and blocking specific molecular pathways in cancer therapy.

背景：乳腺癌是女性最常见的恶性肿瘤之一，其发展涉及多种复杂的分子机制。已知细胞外信号调节激酶（ERK）和嗜铬颗粒蛋白B （CHGB）在多种癌症中起关键作用。本研究旨在探讨沙丁胺醇模拟慢性应激环境下ERK/CHGB通路对乳腺癌发生发展的影响。方法：采用雌性BALB/c小鼠建立乳腺癌模型，将其分为对照组、沙丁胺醇治疗组和沙丁胺醇抑制剂治疗组。采用细胞培养、免疫组织化学、Western Blot、实时荧光定量PCR和Transwell迁移实验来评估沙丁胺醇和ERK/CHGB通路的影响。结果：沙丁胺醇治疗可显著增强乳腺癌细胞的增殖、迁移和侵袭性，与ERK通路激活和CHGB表达增加有关。沙丁胺醇抑制剂治疗组对这些作用有明显的抑制作用。此外，ERK/CHGB通路在细胞外应激环境下的相互作用为乳腺癌细胞的存活和增殖提供了有利条件。结论：本研究表明沙丁胺醇模拟的慢性应激环境可通过ERK/CHGB通路促进乳腺癌细胞的恶性行为。这些发现为乳腺癌治疗提供了新的分子靶点，并强调了在癌症治疗中控制慢性应激和阻断特定分子途径的潜在重要性。

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引用次数: 0

A testis-specific long non-coding RNA, 1700052I22Rik, regulates spermatid chromatin condensation in mice 睾丸特异性长非编码 RNA 1700052I22Rik 可调节小鼠精子染色质凝聚。

IF 3.4 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

International Journal of Biochemistry & Cell Biology

Pub Date : 2025-02-01 DOI: 10.1016/j.biocel.2024.106725

Mengzhen Li , Zexuan Zhang , Qi Geng , Yan Lu , Shiying Miao , Xingguang Zhang , Wei Song , Kai Li

Long non-coding RNAs (lncRNAs), serving as diverse functional regulators, are abundantly expressed in the testis. However, many testis-specific or preferentially expressed lncRNAs remain uncharacterized. Here, we report a testis-specific lncRNA, 1700052I22Rik, which exhibits a dynamic expression pattern during spermatogenesis. Our findings demonstrate that knockout of 1700052I22Rik in mice leads to reduced sperm counts and subfertility in males, as well as defective spermatid chromatin condensation. We further elucidate the underlying mechanism by which 1700052I22Rik modulates the translation of protamine 1 (PRM1) through interaction with Y-box binding protein 2 (YBX2). Collectively, our results uncover a crucial role for the testis-specific lncRNA 1700052I22Rik in regulating spermatid chromatin condensation in mice, providing novel insights into the functions of lncRNAs in spermatogenesis and potential targets for the diagnosis and treatment of male infertility.

长链非编码rna （lncRNAs）作为多种功能调节剂在睾丸中大量表达。然而，许多睾丸特异性或优先表达的lncrna仍未被表征。在这里，我们报道了睾丸特异性lncRNA 1700052I22Rik，它在精子发生过程中表现出动态表达模式。我们的研究结果表明，在小鼠中敲除1700052I22Rik会导致雄性精子数量减少和生育能力低下，以及精子染色质凝结缺陷。我们进一步阐明了1700052I22Rik通过与Y-box结合蛋白2 （YBX2）相互作用调节鱼精蛋白1 （PRM1）翻译的潜在机制。总之，我们的研究结果揭示了睾丸特异性lncRNA 1700052I22Rik在调节小鼠精细胞染色质凝聚中的关键作用，为lncRNA在精子发生中的功能和诊断和治疗男性不孕症的潜在靶点提供了新的见解。

引用次数: 0

GABPα targeted by miR-378a-5p inhibits the growth and angiogenesis of colorectal carcinoma miR-378a-5p靶向GABPα抑制结直肠癌的生长和血管生成。

IF 3.4 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

International Journal of Biochemistry & Cell Biology

Pub Date : 2025-02-01 DOI: 10.1016/j.biocel.2024.106729

Mengyi Wang , Jiangfa Qi , Zhenlin Tan , Runlong Zhou , Qing Zhuo , Xiaotong Deng , Zhenrong Wang , Ruijie Zhou , Fan Li , Yao Xu

Considering the high degree of malignancy, recurrence rate and poor prognosis, exploring promising targets is an imperious strategy for colorectal carcinoma therapy. Recent studies have indicated that GABPα plays a role in cancer aggressiveness, but its exact function and regulatory mechanisms in colorectal cancer progression remain unclear. This study aims to explore the biological role of GABPα and its upstream regulator, miR-378a-5p, in modulating cancer progression. The expression levels of GABPα and miR-378a-5p were analyzed through comprehensive data mining and qPCR assays. The functional effects of GABPα were assessed using CCK-8, wound healing, transwell invasion assay, tube formation and xenograft model in nude mice. A co-transfection assay was also performed to investigate the regulatory relationship between miR-378a-5p and GABPα. We found that GABPα expression was significantly downregulated in human colorectal cancer tissues and cell lines. Functional assays revealed that GABPα overexpression suppressed the proliferation, migration, invasion and angiogenesis of colorectal cancer cells, and in vivo experiments further confirmed the inhibitory role of GABPα. Additionally, miR-378a-5p was upregulated in colorectal cancer, and GABPα was identified as a direct target of miR-378a-5p, as confirmed by luciferase reporter assays. Furthermore, overexpression of GABPα partially counteracted the enhanced malignant behaviors of cancer cells induced by miR-378a-5p. Our findings suggest that miR-378a-5p promotes the aggressive progression of colorectal cancer by directly targeting GABPα, highlighting this regulatory axis as a potential therapeutic target for colorectal carcinoma.

考虑到结直肠癌的恶性程度高、复发率高、预后差，探索有前景的靶点是结直肠癌治疗的迫切策略。最近的研究表明，GABPα在癌症侵袭性中起作用，但其在结直肠癌进展中的确切功能和调节机制尚不清楚。本研究旨在探讨GABPα及其上游调节因子miR-378a-5p在调节癌症进展中的生物学作用。通过综合数据挖掘和qPCR分析GABPα和miR-378a-5p的表达水平。采用CCK-8法、创面愈合法、跨井侵入法、成管法和裸鼠异种移植模型评价GABPα的功能作用。我们还进行了共转染实验来研究miR-378a-5p和GABPα之间的调控关系。我们发现GABPα在人结直肠癌组织和细胞系中表达显著下调。功能实验显示，GABPα过表达可抑制结直肠癌细胞的增殖、迁移、侵袭和血管生成，体内实验进一步证实了GABPα的抑制作用。此外，miR-378a-5p在结直肠癌中表达上调，GABPα被确定为miR-378a-5p的直接靶点，荧光素酶报告基因检测证实了这一点。此外，GABPα的过表达部分抵消了miR-378a-5p诱导的癌细胞恶性行为的增强。我们的研究结果表明，miR-378a-5p通过直接靶向GABPα促进结直肠癌的侵袭性进展，突出了这一调节轴作为结直肠癌的潜在治疗靶点。

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引用次数: 0

Priming human bone marrow-derived mesenchymal stromal cells with signaling modifiers boosts their functionality: Potential application in regenerative therapies 用信号调节剂诱导人骨髓间充质间质细胞增强其功能：在再生治疗中的潜在应用。

IF 3.4 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

International Journal of Biochemistry & Cell Biology

Pub Date : 2025-02-01 DOI: 10.1016/j.biocel.2025.106734

Vaijayanti Kale

Mesenchymal stromal cells (MSCs) isolated from tissues such as bone marrow, cord, cord blood, etc., are frequently used as feeder layers to expand hematopoietic stem/ progenitor cells (HSCs/HSPCs) in vitro. They are also co-infused with the HSCs to improve the efficacy of transplantation. However, the MSCs sourced from non-hematopoietic tissues could have suboptimal hematopoiesis-supportive ability. Likewise, the functionality of the MSCs is known to decline after continuous in vitro culture – an unavoidable manipulation to get clinically relevant cell numbers. Hence, it may be necessary to boost the hematopoiesis-supportive ability of the long-term cultured MSCs so that they can, in turn, be used to prime the HSCs before their clinical applications. Here, I show that priming human bone marrow-derived MSCs (BMSCs) with appropriately selected signaling modifiers and integrin-activating bioactive peptides boosts their hematopoiesis-supportive ability, as seen by the formation of a significantly higher number of colonies from the bone marrow-derived mononuclear cells (MNCs) and extensive proliferation of CD34⁺ HSCS briefly interacted with them. Priming the BMSCs with signaling modifiers is a cost-effective and time-efficient process as synthesizing these small molecule compounds is relatively inexpensive – an advantage in clinical settings. The approach of briefly interacting the donor HSCs/HSPCs with the primed BMSCs just before their infusion into the recipients' bodies could save the cost of long-term ex vivo expansion of HSCs. This concept could also find applications in other regenerative medicine protocols after identifying suitable pharmacological modulators that have the desired effects on the target cells.

从骨髓、脐带、脐带血等组织中分离的间充质间质细胞（MSCs）常被用作体外扩增造血干细胞/祖细胞（hsc /HSPCs）的饲养层。它们也与造血干细胞共输注以提高移植疗效。然而，来自非造血组织的间充质干细胞可能具有次优的造血支持能力。同样，已知MSCs的功能在连续体外培养后会下降-这是一种不可避免的操作，以获得临床相关的细胞数量。因此，有必要增强长期培养的间充质干细胞的造血支持能力，以便在临床应用前用于造血干细胞。在这里，我展示了用适当选择的信号调节剂和整合素激活生物活性肽引发人骨髓源性间充质干细胞（BMSCs）增强其造血支持能力，从骨髓源性单核细胞（MNCs）形成的大量菌落以及CD34+ hsc的广泛增殖与它们短暂相互作用可见一斑。在骨髓间充质干细胞中注入信号调节剂是一种具有成本效益和时间效率的过程，因为合成这些小分子化合物相对便宜，这在临床环境中具有优势。在供体造血干细胞/造血干细胞与引物骨髓间充质干细胞输注到受体体内之前短暂相互作用的方法可以节省造血干细胞长期体外扩增的成本。在确定合适的药理学调节剂对靶细胞有预期的作用后，这一概念也可以在其他再生医学方案中找到应用。

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引用次数: 0

Bemcentinib enhances sensitivity to estrogen receptor inhibitors in breast cancer cells 贝美替尼增强乳腺癌细胞对雌激素受体抑制剂的敏感性

IF 3.4 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

International Journal of Biochemistry & Cell Biology

Pub Date : 2025-02-01 DOI: 10.1016/j.biocel.2025.106750

Gyeongmi Kim , Se Hee Ahn , Se-Kyeong Jang , Selim Kim , Hyunggee Kim , Ki Soo Park , Hyeon-Ok Jin , Chan Sub Park , Min-Ki Seong , Hyun-Ah Kim , In-Chul Park

Estrogen receptor (ER)-positive breast cancer accounts for a substantial proportion of breast cancer cases and is typically managed using ER inhibitors, such as tamoxifen and fulvestrant. However, the development of resistance to these therapies is a significant clinical challenge, and the improvement of therapeutic strategies is crucial. This study aimed to investigate the potential of bemcentinib, a well-known AXL inhibitor, to enhance the sensitivity of MCF7 breast cancer cells to 4-hydroxytamoxifen (4-OHT) and fulvestrant. Our findings revealed that bemcentinib effectively decreased S6K1 phosphorylation and synergistically induced cell death when used in combination with ER inhibitors. Bemcentinib treatment also unexpectedly activated STAT3, and inhibition of STAT3 enhanced cell death induced by bemcentinib and 4-OHT. Notably, the combination of bemcentinib and 4-OHT effectively induced cell death even in tamoxifen-resistant MCF7 cells (MCF7-TR), highlighting its potential to overcome tamoxifen resistance. Interestingly, AXL knockdown did not enhance the sensitivity to 4-OHT or affect S6K1 signaling in either MCF7 or MCF7-TR cells, suggesting that the sensitizing effect of bemcentinib through S6K1 inhibition may be independent of AXL expression. Our findings suggest that bemcentinib treatment, particularly in combination therapy, could be a promising strategy for improving treatment efficacy and overcoming tamoxifen resistance in ER-positive breast cancer.

雌激素受体（ER）阳性乳腺癌占乳腺癌病例的很大比例，通常使用雌激素受体抑制剂，如他莫昔芬和氟维司汀。然而，对这些疗法的耐药性的发展是一个重大的临床挑战，改进治疗策略至关重要。本研究旨在探讨bemcentinib（一种众所周知的AXL抑制剂）增强MCF7乳腺癌细胞对4-羟基他莫昔芬（4-OHT）和氟维司汀敏感性的潜力。我们的研究结果表明，当与内质网抑制剂联合使用时，贝肯替尼可以有效地降低S6K1磷酸化并协同诱导细胞死亡。贝伐替尼治疗也意外激活了STAT3， STAT3的抑制增强了贝伐替尼和4-OHT诱导的细胞死亡。值得注意的是，即使在他莫昔芬耐药的MCF7细胞（MCF7- tr）中，贝伐替尼和4-OHT联合使用也能有效诱导细胞死亡，这突出了其克服他莫昔芬耐药的潜力。有趣的是，在MCF7或MCF7- tr细胞中，AXL敲低并没有增强对4-OHT的敏感性或影响S6K1信号传导，这表明本生替尼通过抑制S6K1的增敏作用可能与AXL的表达无关。我们的研究结果表明，在er阳性乳腺癌中，贝伐替尼治疗，特别是联合治疗，可能是提高治疗效果和克服他莫昔芬耐药性的一种有希望的策略。

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引用次数: 0

Ethacrynic acid inhibits the growth and proliferation of prostate cancer cells by targeting GSTP1 and regulating the PI3K-AKT signaling pathway 乙丙酸通过靶向GSTP1，调控PI3K-AKT信号通路抑制前列腺癌细胞的生长和增殖。

IF 3.4 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

International Journal of Biochemistry & Cell Biology

Pub Date : 2025-02-01 DOI: 10.1016/j.biocel.2025.106740

Bin Zhao , Bingfeng Zhang , Minhao Chenzhang , Kangxian Jiang , Dianyu Wang , Junyi Chen

Background

As a diuretic, ethacrynic acid (EA) has been shown to play a suppressive role in cancers, including prostate cancer (PC). However, its molecular regulatory mechanism is still unclear. Therefore, our study is centered on investigating the effect of EA on PC development and its mechanism.

Methods

To verify the binding relationship between EA and GSTP1, molecular docking and cellular thermal shift assay (CETSA) were conducted. To examine how EA affects PC cell proliferation, cell cycle, and apoptosis, cell function assays were performed. qRT-PCR was used to detect GSTP1 mRNA expression. The expression of GSTP1 protein and PI3K-AKT signaling pathway-related proteins in cells was detected by western blot (WB). To verify how EA and GSTP1 influence cell growth in PC, in vivo experiments were conducted.

Results

The binding relationship between GSTP1 and EA was confirmed by molecular docking and CETSA results. Cell experiments showed that EA could hinder PI3K/AKT pathway and PC cell proliferation, arrest the cell cycle in G0/G1 phase, and facilitate apoptosis by binding to GSTP1. In vivo experiments in nude mice verified that the interaction between EA and GSTP1 reduced PI3K and AKT phosphorylation and inhibited the growth of PC cells.

Conclusion

EA inhibits PC progression by binding to GSTP1 to downregulate the activity of PI3K/AKT pathway, and this result suggests the potential of EA to be an anticancer agent for PC therapy.

背景：作为一种利尿剂，乙酸（EA）已被证明在包括前列腺癌（PC）在内的癌症中发挥抑制作用。然而，其分子调控机制尚不清楚。因此，我们的研究重点是探讨EA对PC开发的影响及其机制。方法：通过分子对接和细胞热移实验（CETSA）验证EA与GSTP1的结合关系。为了研究EA如何影响PC细胞增殖、细胞周期和凋亡，进行了细胞功能测定。采用qRT-PCR检测GSTP1 mRNA的表达。western blot （WB）检测细胞中GSTP1蛋白和PI3K-AKT信号通路相关蛋白的表达。为了验证EA和GSTP1如何影响PC细胞生长，我们进行了体内实验。结果：通过分子对接和CETSA结果证实了GSTP1与EA的结合关系。细胞实验表明，EA可抑制PI3K/AKT通路，抑制PC细胞增殖，使细胞周期停留在G0/G1期，并通过与GSTP1结合促进细胞凋亡。裸鼠体内实验证实EA与GSTP1的相互作用降低了PI3K和AKT的磷酸化，抑制了PC细胞的生长。结论：EA通过与GSTP1结合，下调PI3K/AKT通路活性，抑制PC的进展，提示EA可能是一种用于PC治疗的抗癌药物。

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引用次数: 0

Transcription factors, nucleotide excision repair, and cancer: A review of molecular interplay 转录因子、核苷酸切除修复与癌症：分子相互作用综述》。

IF 3.4 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

International Journal of Biochemistry & Cell Biology

Pub Date : 2025-02-01 DOI: 10.1016/j.biocel.2024.106724

Perihan Yagmur Guneri-Sozeri, Ogün Adebali

Bulky DNA adducts are mostly formed by external factors such as UV irradiation, smoking or treatment with DNA crosslinking agents. If such DNA adducts are not removed by nucleotide excision repair, they can lead to formation of driver mutations that contribute to cancer formation. Transcription factors (TFs) may critically affect both DNA adduct formation and repair efficiency at the binding site to DNA. For example, "hotspot" mutations in melanoma coincide with UV-induced accumulated cyclobutane pyrimidine dimer (CPD) adducts and/or inhibited repair at the binding sites of some TFs. Similarly, anticancer treatment with DNA cross-linkers may additionally generate DNA adducts leading to secondary mutations and the formation of malignant subclones. In addition, some TFs are overexpressed in response to UV irradiation or chemotherapeutic treatment, activating oncogenic and anti-oncogenic pathways independently of nucleotide excision repair itself. This review focuses on the interplay between TFs and nucleotide excision repair during cancer development and progression.

大块的DNA加合物大多是由外部因素形成的，如紫外线照射、吸烟或DNA交联剂处理。如果这些DNA加合物没有通过核苷酸切除修复去除，它们可能导致驱动突变的形成，从而导致癌症的形成。转录因子可能对DNA加合物的形成和DNA结合位点的修复效率产生关键影响。例如，黑色素瘤中的“热点”突变与紫外线诱导的累积环丁烷嘧啶二聚体（CPD）加合物和/或某些tf结合位点的抑制修复相吻合。同样，用DNA交联剂进行抗癌治疗也可能产生DNA加合物，导致继发性突变和恶性亚克隆的形成。此外，一些tf在紫外线照射或化疗的反应中过度表达，独立于核苷酸切除修复本身激活致癌和抗致癌途径。本文综述了肿瘤发生和发展过程中tf与核苷酸切除修复之间的相互作用。

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引用次数: 0

Prevention of fenitrothion induced hepatic toxicity by saponarin via modulating TLR4/MYD88, JAK1/STAT3 and NF-κB signaling pathways 皂苷通过调控TLR4/MYD88、JAK1/STAT3和NF-κB信号通路预防菲诺硫磷诱导的肝毒性

IF 3.4 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

International Journal of Biochemistry & Cell Biology

Pub Date : 2025-02-01 DOI: 10.1016/j.biocel.2024.106716

Hesham M. Hassan , Mahmoud El Safadi , Muhammad Faisal Hayat , Ahmed Al-Emam

Fenitrothion (FEN) is an organophosphate insecticidal agent that is considered as major source of organs toxicity. Saponarin (SAP) is a naturally occurring novel flavone that exhibits a wide range of medicinal properties. The current trial was conducted to evaluate the ameliorative potential of SAP against FEN instigated liver toxicity in rats. Thirty-two male albino rats were apportioned into four groups including control, FEN (10 mg/kg), FEN (10 mg/kg) + SAP (80 mg/kg), and SAP (80 mg/kg) alone treated group. It was revealed that FEN administration upregulated the gene expression of TNF-α, TLR4, IL-1β, MYD88, IL-6, TRAF6, COX-2, NF-κB, JAK1 and STAT3 while reducing the gene expression of IκB. Moreover, the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) were increased while the activities of catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), heme-oxygenase-1 (HO-1) and glutathione reductase (GSR) were decreased after FEN exposure. Furthermore, FEN administration notably escalated the levels of hepatic enzymes including alanine transaminase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT) and alkaline phosphatase (ALP) whereas reduced the levels of total proteins and albumin. Besides, FEN intake upregulated the levels of Caspase-9, Bax and Caspase-3 while reducing the levels of Bcl-2. Hepatic histology was impaired after FEN intoxication. Nonetheless, SAP treatment remarkably protected the normal state of liver via regulating abovementioned irregularities. Our in-silico analysis confirmed that SAP hold that potential to interact with binding pocket of these proteins, highlighting its ability as a therapeutic compound to alleviate FEN-induced liver damage.

杀虫磷（FEN）是一种有机磷杀虫剂，被认为是器官毒性的主要来源。皂苷（Saponarin， SAP）是一种天然存在的新型黄酮，具有巨大的药用价值。目前的试验是为了评估SAP对FEN引起的肝毒性的治疗潜力。将32只雄性褐家鼠分为4组，分别为对照组、FEN （10mg/kg）组、FEN (10mg/kg) + SAP （80mg/kg）组和SAP （80mg/kg）单独处理组。结果表明，FEN可上调TNF-α、TLR4、IL-1β、MYD88、IL-6、TRAF6、COX-2、NF-κB、JAK1和STAT3基因的表达，抑制i -κB基因的表达。此外，添加FEN可提高活性氧（ROS）和丙二醛（MDA）水平，抑制过氧化氢酶（CAT）、谷胱甘肽过氧化物酶（GPx）、超氧化物歧化酶（SOD）、血红素加氧酶-1 （HO-1）和谷胱甘肽还原酶（GSR）活性。此外，FEN显著升高了肝酶的浓度，包括丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）、γ -谷氨酰转氨酶（GGT）和碱性磷酸酶（ALP），同时降低了总蛋白和白蛋白的浓度。此外，FEN摄入上调了Caspase-9、Bax和Caspase-3的水平，降低了Bcl-2的水平。给予FEN后肝脏组织学改变。尽管如此，SAP治疗通过调节上述不规则性显著保护了肝脏的正常状态。我们的计算机计算证实，SAP具有与这些蛋白质结合袋相互作用的潜力，突出了其作为一种治疗性化合物减轻fen诱导的肝损伤的能力。

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引用次数: 0

Disulfiram/copper induces BAK-mediated caspase-independent apoptosis in MCF-7 cells 双硫仑/铜诱导bac介导的MCF-7细胞非caspase依赖性凋亡。

IF 3.4 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

International Journal of Biochemistry & Cell Biology

Pub Date : 2025-02-01 DOI: 10.1016/j.biocel.2024.106731

Beini Sun , Yu Wang , Hongce Chen , Qialing Huang , Chunchun An , Qiuqiang Zhan , Xiaoping Wang , Tongsheng Chen

Disulfiram (DSF) and copper (Cu^2 +) in combination exhibit powerful anti-cancer effect on a variety of cancer cell lines. Here, we found that DSF/Cu²⁺ facilitated the accumulation of intracellular reactive oxygen species (ROS), and induced ROS-dependent apoptosis accompanied by chromatin condensation and phosphatidylserine externalization in MCF-7 cells. DSF/Cu²⁺ caused caspase-independent apoptosis by promoting the AIF translocation from mitochondria to nucleus. Most importantly, the cytotoxicity of DSF/Cu²⁺ was markedly inhibited by knocking out AIF, suggesting the indispensability of AIF in DSF/Cu²⁺-induced apoptosis. The pro-apoptotic protein BAK instead of BAX was upregulated and activated upon DSF/Cu²⁺ treatment, and the BAK knockout cells exhibited high resistance to DSF/Cu²⁺, indicating the importance of BAK in DSF/Cu²⁺-induced apoptosis. Additionally, both co-immunoprecipitation and live-cell quantitative fluorescence resonance energy transfer (FRET) analysis revealed that DSF/Cu²⁺ unlocked the binding of MCL-1 to BAK, which resulted in subsequent BAK homo-oligomerization. Overall, our data demonstrate for the first time that DSF/Cu²⁺ unlocks the binding of MCL-1 to BAK, thus leading BAK oligomerization and subsequent AIF nucleus translocation to mediate caspase-independent apoptosis in MCF-7 cells.

双硫仑（DSF）和铜（Cu2+）联合使用对多种癌细胞具有强大的抗癌作用。在这里，我们发现DSF/Cu2+促进了细胞内活性氧（ROS）的积累，并诱导了MCF-7细胞中伴随着染色质浓缩和磷脂酰丝氨酸外化的ROS依赖性凋亡。DSF/Cu2+通过促进AIF从线粒体向细胞核的易位而引起caspase非依赖性凋亡。最重要的是，敲除AIF可以显著抑制DSF/Cu2+的细胞毒性，这表明AIF在DSF/Cu2+诱导的细胞凋亡中是不可或缺的。在DSF/Cu2+处理下，促凋亡蛋白BAK代替BAX被上调和激活，并且BAK敲除的细胞对DSF/Cu2+表现出高抗性，这表明BAK在DSF/Cu2+诱导的细胞凋亡中的重要作用。此外，共免疫沉淀和活细胞定量荧光共振能量转移（FRET）分析显示，DSF/Cu2+解锁了MCL-1与BAK的结合，导致随后的BAK同源寡聚。总体而言，我们的数据首次证明DSF/Cu2+解锁MCL-1与BAK的结合，从而导致BAK寡聚化和随后的AIF核易位介导MCF-7细胞中caspase非依赖性凋亡。

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引用次数: 0

SENP2 as a critical regulator in liver ischemia-reperfusion injury SENP2是肝脏缺血再灌注损伤的关键调节因子。

IF 3.4 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

International Journal of Biochemistry & Cell Biology

Pub Date : 2025-01-29 DOI: 10.1016/j.biocel.2025.106741

Lei Zheng , Shuling Han , Olivia M Martinez , Sheri M Krams

Background and Aims

Liver ischemia-reperfusion injury (LIRI) profoundly affects liver function and survival largely through activation of the innate immune system. In this study we sought to elucidate the underlying mechanisms by which the innate immune system impacts liver function and survival in LIRI.

Approach and Results

RNA-seq analyses, from existing datasets of liver from mice with LIRI, was performed to identify differentially expressed genes (DEGs) associated with LIRI. Protein-protein interaction analysis revealed clusters involved in signaling pathways with a cluster anchored by Senp2, acting as a central modulator. Macrophages and monocytes were determined to be the source of Senp2 with monocyte-derived macrophages expressing the highest levels of Senp2. Experiments in a mouse model of LIRI further elucidated the expression, function, and mechanism of Senp2. Overexpression of Senp2 suppressed both the polarization of M1 macrophages and the production of inflammatory mediators. Further, Senp2-overexpressing macrophages significantly ameliorated LIRI.

Conclusions

Our study suggests that SENP2 plays an important role in regulating LIRI by influencing macrophage polarization through the Dvl2/GSK-3β/β-catenin axis. While further validation is needed, these findings indicate that targeting SENP2-mediated pathways could be a promising approach for mitigating LIRI and enhancing therapeutic strategies.

背景与目的：肝缺血再灌注损伤（LIRI）主要通过激活先天免疫系统来影响肝功能和生存。在这项研究中，我们试图阐明先天免疫系统影响LIRI患者肝功能和生存的潜在机制。方法和结果：从现有的LIRI小鼠肝脏数据集中进行RNA-seq分析，以鉴定与LIRI相关的差异表达基因（DEGs）。蛋白质-蛋白质相互作用分析揭示了参与信号通路的簇，其中一个簇由Senp2锚定，作为中心调节剂。巨噬细胞和单核细胞被确定为Senp2的来源，单核细胞来源的巨噬细胞表达最高水平的Senp2。小鼠LIRI模型实验进一步阐明了Senp2的表达、功能和机制。Senp2的过表达抑制了M1巨噬细胞的极化和炎症介质的产生。此外，过表达senp2的巨噬细胞显著改善了LIRI。结论：本研究提示SENP2通过Dvl2/GSK-3β/β-catenin轴影响巨噬细胞极化，在LIRI调控中发挥重要作用。虽然需要进一步验证，但这些发现表明，靶向senp2介导的途径可能是缓解LIRI和增强治疗策略的有希望的方法。

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引用次数: 0