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Targeting ferroptosis opens new avenues in gliomas 靶向铁突变为胶质瘤开辟新途径
IF 9.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-03 DOI: 10.7150/ijbs.96476
Yuxin Wei, Yang Xu, Qian Sun, Yu Hong, Shanwen Liang, Hongxiang Jiang, Xinyi Zhang, Shenqi Zhang, Qianxue Chen
Gliomas are one of the most challenging tumors to treat due to their malignant phenotype, brain parenchymal infiltration, intratumoral heterogeneity, and immunosuppressive microenvironment, resulting in a high recurrence rate and dismal five-year survival rate. The current standard therapies, including maximum tumor resection, chemotherapy with temozolomide, and radiotherapy, have exhibited limited efficacy, which is caused partially by the resistance of tumor cell death. Recent studies have revealed that ferroptosis, a newly defined programmed cell death (PCD), plays a crucial role in the occurrence and progression of gliomas and significantly affects the efficacy of various treatments, representing a promising therapeutic strategy. In this review, we provide a comprehensive overview of the latest progress in ferroptosis, its involvement and regulation in the pathophysiological process of gliomas, various treatment hotspots, the existing obstacles, and future directions worth investigating. Our review sheds light on providing novel insights into manipulating ferroptosis to provide potential targets and strategies of glioma treatment.
胶质瘤是最难治疗的肿瘤之一,因为其恶性表型、脑实质浸润、瘤内异质性和免疫抑制微环境,导致复发率高和五年生存率低。目前的标准疗法包括最大限度切除肿瘤、替莫唑胺化疗和放疗,但疗效有限,部分原因在于肿瘤细胞死亡的抵抗性。最近的研究发现,新定义的程序性细胞死亡(PCD)(ferroptosis)在胶质瘤的发生和发展中起着至关重要的作用,并显著影响各种治疗方法的疗效,是一种很有前景的治疗策略。在这篇综述中,我们全面概述了铁突变的最新进展、铁突变在胶质瘤病理生理过程中的参与和调控、各种治疗热点、现有障碍以及未来值得研究的方向。我们的综述揭示了操纵铁蛋白沉积的新见解,为胶质瘤治疗提供了潜在靶点和策略。
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引用次数: 0
Genome-wide binding analysis unveils critical implication of B-Myb-mediated transactivation in cancers 全基因组结合分析揭示了 B-Myb 介导的转录激活在癌症中的重要作用
IF 9.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-03 DOI: 10.7150/ijbs.92607
Chuntao Tao, Tao Liu, Zongrong Zhao, Xuanqi Dou, Xing Xia, Kailong Du, Xiaofeng Zuo, Yitao Wang, Tingting Wang, Youquan Bu
B-Myb, also known as MYB proto-oncogene like 2 (MYBL2), is an important transcription factor implicated in transcription regulation, cell cycle and tumorigenesis. However, the molecular mechanism underlying B-Myb-controlled transactivation in different cell contexts as well as its functional implication in cancers remains elusive. In this study, we have conducted a comprehensive genome-wide analysis of B-Myb binding sites in multiple immortalized or cancer cell lines and identified its critical target genes. The results revealed that B-Myb regulates a common set of core cell cycle genes and cell type-specific genes through collaboration with other important transcription factors (e.g. NFY and MuvB complex) and binding to cell type-invariant promoters and cell type-specific enhancers and super-enhancers. KIF2C, UBE2C and MYC were further validated as B-Myb target genes. Loss-of-function analysis demonstrated that KIF2C knockdown inhibited tumor cell growth both in vitro and in vivo, suppressed cell motility and cell cycle progression, accompanied with defects in microtubule organization and mitosis, strongly suggesting that KIF2C is a critical regulator of cancer cell growth and mitosis, and maintains high cancer cell motility ability and microtubule dynamics. Pan-cancer transcriptomic analysis revealed that the overexpression of both B-Myb and KIF2C presents as independent prognostic markers in various types of cancer. Notably, B-Myb associates with NFYB, binds to target gene promoters, enhancers and super-enhancers, and provokes a cascade of oncogenic gene expression profiles in cancers. Overall, our results highly suggest the critical implication of B-Myb-mediated gene regulation in cancers, and the promising therapeutic and prognostic potentials of B-Myb and KIF2C for cancer diagnosis and treatment.
B-Myb又称MYB原癌基因2(MYBL2),是一种重要的转录因子,与转录调控、细胞周期和肿瘤发生有关。然而,B-Myb 在不同细胞环境中控制转录活化的分子机制及其在癌症中的功能性影响仍未确定。在这项研究中,我们对多个永生细胞系或癌细胞系中的 B-Myb 结合位点进行了全面的全基因组分析,并确定了其关键靶基因。结果发现,B-Myb通过与其他重要转录因子(如NFY和MuvB复合物)合作,并与细胞类型不变的启动子和细胞类型特异的增强子和超级增强子结合,调控一组常见的核心细胞周期基因和细胞类型特异基因。KIF2C、UBE2C 和 MYC 进一步被验证为 B-Myb 的靶基因。功能缺失分析表明,KIF2C敲除可抑制体外和体内肿瘤细胞的生长,抑制细胞运动和细胞周期的进展,并伴有微管组织和有丝分裂的缺陷。泛癌症转录组学分析表明,B-Myb和KIF2C的过表达是各类癌症的独立预后标志。值得注意的是,B-Myb与NFYB结合,与靶基因启动子、增强子和超增强子结合,并在癌症中引发一连串的致癌基因表达谱。总之,我们的研究结果高度揭示了 B-Myb 介导的基因调控在癌症中的关键作用,以及 B-Myb 和 KIF2C 在癌症诊断和治疗中的治疗和预后潜力。
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引用次数: 0
Targeting METTL3 enhances the chemosensitivity of non-small cell lung cancer cells by decreasing ABCC2 expression in an m6A-YTHDF1-dependent manner 通过以 m6A-YTHDF1 依赖性方式降低 ABCC2 的表达,靶向 METTL3 可增强非小细胞肺癌细胞的化疗敏感性
IF 9.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-03 DOI: 10.7150/ijbs.97425
Rui Zhang, Pu Chen, Yubo Wang, Zekun Zeng, Huini Yang, Mengdan Li, Xi Liu, Wei Yu, Peng Hou
Patients with non-small cell lung cancer (NSCLC) are easily resistant to first-line chemotherapy with paclitaxel (PTX) or carboplatin (CBP). N6-methyladenosine (m6A) methyltransferase-like 3 (METTL3) has crucial functions in m6A modification and tumorigenesis. However, its role in chemoresistance of NSCLC is still elusive. Here, we demonstrated that METTL3 inhibitor STM2457 significantly reduced the IC50 values of PTX or CBP in NSCLC cells, and they showed a synergistic effect. Comparing with monotherapy, a combination of STM2457 and PTX or CBP exhibited more potent in vitro and in vivo anti-tumor efficacy. In addition, we found that ATP binding cassette subfamily C member 2 (ABCC2) was responsively elevated in cytomembrane after PTX or CBP treatment, and targeting METTL3 could reverse this effect. Mechanistically, targeting METTL3 decreased the m6A modification of ABCC2 mRNA and accelerated its mRNA degradation. Further studies revealed that YTHDF1 could bind and stabilize the m6A-modified mRNA of ABCC2, while YTHDF1 knockdown promoted it mRNA degradation. These results, taken together, demonstrate that targeting METTL3 enhances the sensitivity of NSCLC cells to PTX or CBP by decreasing the cytomembrane-localized ABCC2 in an m6A-YTHDF1-dependent manner, and suggest that METTL3 may be a potential therapeutic target for acquired resistance to PTX or CBP in NSCLC.
非小细胞肺癌(NSCLC)患者很容易对紫杉醇(PTX)或卡铂(CBP)一线化疗产生耐药性。N6-甲基腺苷(m6A)甲基转移酶样3(METTL3)在m6A修饰和肿瘤发生中具有重要功能。然而,它在 NSCLC 化疗耐药性中的作用仍然难以捉摸。在这里,我们证实了METTL3抑制剂STM2457能显著降低PTX或CBP在NSCLC细胞中的IC50值,并且它们表现出协同作用。与单药治疗相比,STM2457与PTX或CBP联合治疗在体外和体内均表现出更强的抗肿瘤疗效。此外,我们还发现 PTX 或 CBP 治疗后,细胞膜中的 ATP 结合盒 C 亚家族成员 2(ABCC2)呈反应性升高,而靶向 METTL3 可以逆转这种效应。从机制上讲,靶向METTL3可减少ABCC2 mRNA的m6A修饰并加速其mRNA降解。进一步的研究发现,YTHDF1能结合并稳定ABCC2的m6A修饰mRNA,而YTHDF1的敲除能促进其mRNA降解。这些结果表明,靶向METTL3能以m6A-YTHDF1依赖的方式降低胞膜定位的ABCC2,从而增强NSCLC细胞对PTX或CBP的敏感性,并表明METTL3可能是NSCLC对PTX或CBP获得性耐药的潜在治疗靶点。
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引用次数: 0
Versatility of the Zinc-Finger Antiviral Protein (ZAP) As a Modulator of Viral Infections 锌指抗病毒蛋白 (ZAP) 作为病毒感染调节剂的多功能性
IF 9.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-26 DOI: 10.7150/ijbs.98029
Ran Shao, Imke Visser, Jelke J. Fros, Xin Yin
The zinc-finger antiviral protein (ZAP) is a restriction factor that proficiently impedes the replication of a variety of RNA and DNA viruses. In recent years, the affinity of ZAP's zinc-fingers for single-stranded RNA (ssRNA) rich in CpG dinucleotides was uncovered. High frequencies of CpGs in RNA may suggest a non-self origin, which underscores the importance of ZAP as a potential cellular sensor of (viral) RNA. Upon binding viral RNA, ZAP recruits cellular cofactors to orchestrate a finely tuned antiviral response that limits virus replication via distinct mechanisms. These include promoting degradation of viral RNA, inhibiting RNA translation, and synergizing with other immune pathways. Depending on the viral species and experimental set-up, different isoforms and cellular cofactors have been reported to be dominant in shaping the ZAP-mediated antiviral response. Here we review how ZAP differentially affects viral replication depending on distinct interactions with RNA, cellular cofactors, and viral proteins to discuss how these interactions shape the antiviral mechanisms that have thus far been reported for ZAP. Importantly, we zoom in on the unknown aspects of ZAP's antiviral system and its therapeutic potential to be employed in vaccine design.
锌指抗病毒蛋白(ZAP)是一种限制因子,能有效阻碍多种 RNA 和 DNA 病毒的复制。近年来,ZAP 的锌指对富含 CpG 二核苷酸的单链 RNA(ssRNA)的亲和力被发现。RNA 中 CpGs 的高频率可能表明 RNA 并非来自自身,这突出了 ZAP 作为(病毒)RNA 潜在细胞传感器的重要性。在与病毒 RNA 结合后,ZAP 会招募细胞辅助因子来协调微调的抗病毒反应,通过不同的机制限制病毒的复制。这些机制包括促进病毒 RNA 降解、抑制 RNA 翻译以及与其他免疫途径协同作用。据报道,根据病毒种类和实验装置的不同,不同的同工酶和细胞辅助因子在形成 ZAP 介导的抗病毒反应中起主导作用。在此,我们回顾了 ZAP 是如何通过与 RNA、细胞辅助因子和病毒蛋白的不同相互作用对病毒复制产生不同影响的,并讨论了这些相互作用是如何形成迄今已报道的 ZAP 抗病毒机制的。重要的是,我们放大了 ZAP 抗病毒系统的未知方面及其在疫苗设计中的治疗潜力。
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引用次数: 0
SIX4 Activation in Inflammatory Response Drives the Transformation of Colorectal Epithelium into Inflammation and Tumor via Feedback-Enhancing Inflammatory Signaling to Induce Tumor Stemness Signaling 炎症反应中的 SIX4 激活通过反馈增强炎症信号转导肿瘤干性信号转导,驱动结直肠上皮细胞向炎症和肿瘤转化
IF 9.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-26 DOI: 10.7150/ijbs.93411
Ziyan Zhang, Huang Huang, Lanzhu Peng, Beixian Zhou, Huiling Yang, Zibo Tang, Weiwei Yan, Weifeng Chen, Zhen Liu, Dayong Zheng, Peng Shen, Weiyi Fang
Some colorectal cancer patients have experienced normal epithelial transformation into inflammatory and tumor states, but the molecular basis still needs to be further determined. The expression levels of SIX4 are gradually increased in dextran sodium sulfate (DSS) and azoxymethane (AOM)/DSS-induced colonic epithelial inflammation and tumors, respectively, in mice. Targeting SIX4 alleviates intestinal inflammation occurrence and reduces adenoma formation in mice. Clinical sample assays indicated that SIX4 is upregulated in inflammatory bowel disease (IBD) and colorectal cancer (CRC) tissues compared to normal colorectal tissues. In a subsequent study, we found that SIX4, transcriptionally activated by the proinflammatory IL-6/STAT3 signal, binds to c-Jun to transcribe IL-6, thus forming a positive IL-6/STAT3/SIX4/c-Jun feedback loop, which further induces intestinal inflammation occurrence. In addition, elevated SIX4 also induces the expression of DeltaNp63, rather than wild-type p63, by binding to its promoter and thus facilitates the activation of tumor stemness signals, which ultimately leads to the formation of colorectal cancer. Our study first observes that activated SIX4 in inflammation induction drives the transformation of colorectal epithelium into inflammation and tumor, which demonstrates SIX4 as a significant therapeutic target in IBD and colitis-associated colorectal cancer (CAC) and CRC pathogenesis./n/n
一些结直肠癌患者的正常上皮会转变为炎症和肿瘤状态,但其分子基础仍有待进一步确定。在右旋糖酐硫酸钠(DSS)和偶氮甲烷(AOM)/DSS诱导的小鼠结肠上皮炎症和肿瘤中,SIX4的表达水平分别逐渐升高。靶向 SIX4 可减轻小鼠肠道炎症的发生并减少腺瘤的形成。临床样本检测表明,与正常结直肠组织相比,SIX4在炎症性肠病(IBD)和结直肠癌(CRC)组织中上调。在随后的研究中,我们发现 SIX4 被促炎性 IL-6/STAT3 信号转录激活,与 c-Jun 结合转录 IL-6,从而形成 IL-6/STAT3/SIX4/c-Jun 正反馈环,进一步诱导肠道炎症的发生。此外,升高的 SIX4 还会通过与其启动子结合,诱导 DeltaNp63(而非野生型 p63)的表达,从而促进肿瘤干性信号的激活,最终导致结直肠癌的形成。我们的研究首次发现,在炎症诱导过程中活化的 SIX4 会驱动结直肠上皮细胞向炎症和肿瘤转化,这表明 SIX4 是 IBD 和结肠炎相关性结直肠癌(CAC)及 CRC 发病机制中的一个重要治疗靶点。
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引用次数: 0
Dissection of Targeting Molecular Mechanisms of Celastrol-induced Nephrotoxicity via A Combined Deconvolution Strategy of Chemoproteomics and Metabolomics 通过化学蛋白组学和代谢组学的联合解旋策略剖析 Celastrol 诱导肾毒性的靶向分子机制
IF 9.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-26 DOI: 10.7150/ijbs.91751
Xueying Liu, Qian Zhang, Peili Wang, Xin Peng, Yehai An, Junhui Chen, Jingnan Huang, Shuanglin Qin, Hengkai He, Mingjing Hao, Jiahang Tian, Letai Yi, Ming Lei, Piao Luo, Jigang Wang, Xinzhou Zhang
Celastrol (Cel), derived from the traditional herb Tripterygium wilfordii Hook. f., has anti-inflammatory, anti-tumor, and immunoregulatory activities. Renal dysfunction, including acute renal failure, has been reported in patients following the administration of Cel-relative medications. However, the functional mechanism of nephrotoxicity caused by Cel is unknown. This study featured combined use of activity-based protein profiling and metabolomics analysis to distinguish the targets of the nephrotoxic effects of Cel. Results suggest that Cel may bind directly to several critical enzymes participating in metabolism and mitochondrial functions. These enzymes include voltage-dependent anion-selective channel protein 1 (essential for maintaining mitochondrial configurational and functional stability), pyruvate carboxylase (involved in sugar isomerization and the tricarboxylic acid cycle), fatty acid synthase (related to β-oxidation of fatty acids), and pyruvate kinase M2 (associated with aerobic respiration). Proteomics and metabolomics analysis confirmed that Cel-targeted proteins disrupt some metabolic biosynthetic processes and promote mitochondrial dysfunction. Ultimately, Cel aggravated kidney cell apoptosis. These cumulative results deliver an insight into the potential mechanisms of Cel-caused nephrotoxicity. They may also facilitate development of antagonistic drugs to mitigate the harmful effects of Cel on the kidneys and improve its clinical applications.
Celastrol (Cel) 提取自传统草药 Tripterygium wilfordii Hook.f.,具有抗炎、抗肿瘤和免疫调节活性。有报告称,服用 Cel 相关药物的患者会出现肾功能障碍,包括急性肾衰竭。然而,Cel 引起肾毒性的功能机制尚不清楚。本研究结合使用基于活性的蛋白质分析和代谢组学分析来区分 Cel 肾毒性作用的靶点。结果表明,Cel 可能直接与参与新陈代谢和线粒体功能的几种关键酶结合。这些酶包括电压依赖性阴离子选择性通道蛋白1(对维持线粒体构型和功能稳定性至关重要)、丙酮酸羧化酶(参与糖异构化和三羧酸循环)、脂肪酸合成酶(与脂肪酸的β-氧化有关)和丙酮酸激酶M2(与有氧呼吸有关)。蛋白质组学和代谢组学分析证实,Cel靶向蛋白破坏了一些代谢生物合成过程,并促进线粒体功能障碍。最终,Cel 加剧了肾细胞凋亡。这些累积的结果使人们对 Cel 导致肾毒性的潜在机制有了深入的了解。它们还有助于开发拮抗药物,以减轻 Cel 对肾脏的有害影响并改善其临床应用。
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引用次数: 0
The Essential Role of Angiogenesis in Adenosine 2A Receptor Deficiency-mediated Impairment of Wound Healing Involving c-Ski via the ERK/CREB Pathways. 血管生成在腺苷 2A 受体缺陷介导的伤口愈合障碍中的重要作用,涉及 c-Ski 通过 ERK/CREB 通路的作用。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-19 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.98856
Yan Peng, Renping Xiong, Bo Wang, Xing Chen, Yalei Ning, Yan Zhao, Nan Yang, Jing Zhang, Changhong Li, Yuanguo Zhou, Ping Li

Adenosine receptor-mediated signaling, especially adenosine A2A receptor (A2AR) signaling, has been implicated in wound healing. However, the role of endothelial cells (ECs) in A2AR-mediated wound healing and the mechanism underlying this effect are still unclear. Here, we showed that the expression of A2AR substantially increased after wounding and was especially prominent in granulation tissue. The delaying effects of A2AR knockout (KO) on wound healing are due mainly to the effect of A2AR on endothelial cells, as shown with A2AR-KO and EC-A2AR-KO mice. Moreover, the expression of c-Ski, which is especially prominent in CD31-positive cells in granulation tissue, increased after wounding and was decreased by both EC-A2AR KO and A2AR KO. In human microvascular ECs (HMECs), A2AR activation induced EC proliferation, migration, tubule formation and c-Ski expression, whereas c-Ski depletion by RNAi abolished these effects. Mechanistically, A2AR activation promotes the expression of c-Ski through an ERK/CREB-dependent pathway. Thus, A2AR-mediated angiogenesis plays a critical role in wound healing, and c-Ski is involved mainly in the regulation of angiogenesis by A2AR via the ERK/CREB pathway. These findings identify A2AR as a therapeutic target in wound repair and other angiogenesis-dependent tissue repair processes.

腺苷受体介导的信号转导,尤其是腺苷 A2A 受体(A2AR)信号转导,已被认为与伤口愈合有关。然而,内皮细胞(ECs)在 A2AR 介导的伤口愈合中的作用及其机制仍不清楚。在这里,我们发现 A2AR 的表达在伤口愈合后大幅增加,在肉芽组织中尤为突出。如 A2AR-KO 和 EC-A2AR-KO 小鼠所示,A2AR 基因敲除(KO)对伤口愈合的延迟作用主要是由于 A2AR 对内皮细胞的影响。此外,肉芽组织中 CD31 阳性细胞中的 c-Ski 表达量在伤口愈合后增加,EC-A2AR KO 和 A2AR KO 均使其表达量减少。在人微血管内皮细胞(HMECs)中,A2AR 激活可诱导内皮细胞增殖、迁移、小管形成和 c-Ski 表达,而通过 RNAi 去除 c-Ski 则可消除这些效应。从机制上讲,A2AR 激活通过 ERK/CREB 依赖性途径促进 c-Ski 的表达。因此,A2AR介导的血管生成在伤口愈合中起着关键作用,而c-Ski主要通过ERK/CREB途径参与A2AR对血管生成的调控。这些发现确定了 A2AR 是伤口修复和其他依赖血管生成的组织修复过程中的治疗靶点。
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引用次数: 0
Nuclear receptor subfamily 4 group A member 1 promotes myocardial ischemia/reperfusion injury through inducing mitochondrial fission factor-mediated mitochondrial fragmentation and inhibiting FUN14 domain containing 1-depedent mitophagy. 核受体 4 亚家族 A 组 1 通过诱导线粒体分裂因子介导的线粒体破碎和抑制含 FUN14 结构域 1 的有丝分裂,促进心肌缺血/再灌注损伤。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-19 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.95853
Junyan Wang, Haowen Zhuang, Lianqun Jia, Xinyong He, Sicheng Zheng, Kangshou Ji, Kang Xie, Tong Ying, Ying Zhang, Chun Li, Xing Chang

This study investigated the mechanism by which NR4A1 regulates mitochondrial fission factor (Mff)-related mitochondrial fission and FUN14 domain 1 (FUNDC1)-mediated mitophagy following cardiac ischemia-reperfusion injury(I/R). Our findings showed that the damage regulation was positively correlated with the pathological fission and pan-apoptosis of myocardial cell mitochondria. Compared with wild-type mice (WT), NR4A1-knockout mice exhibited resistance to myocardial ischemia-reperfusion injury and mitochondrial pathological fission, characterized by mitophagy activation. Results showed that ischemia-reperfusion injury increased NR4A1 expression level, activating mitochondrial fission mediated by Mff and restoring the mitophagy phenotype mediated by FUNDC1. The inactivation of FUNDC1 phosphorylation could not mediate the normalization of mitophagy in a timely manner, leading to an excessive stress response of unfolded mitochondrial proteins and an imbalance in mitochondrial homeostasis. This process disrupted the normalization of the mitochondrial quality control network, leading to accumulation of damaged mitochondria and the activation of pan-apoptotic programs. Our data indicate that NR4A1 is a novel and critical target in myocardial I/R injury that exertsand negative regulatory effects by activating Mff-mediated mito-fission and inhibiting FUNDC1-mediated mitophagy. Targeting the crosstalk balance between NR4A1-Mff-FUNDC1 is a potential approach for treating I/R.

本研究探讨了心脏缺血再灌注损伤(I/R)后,NR4A1调控线粒体裂变因子(Mff)相关线粒体裂变和FUN14结构域1(FUNDC1)介导的有丝分裂的机制。我们的研究结果表明,损伤调控与心肌细胞线粒体的病理性裂变和泛凋亡呈正相关。与野生型小鼠(WT)相比,NR4A1基因敲除小鼠表现出对心肌缺血再灌注损伤和线粒体病理性裂变的抵抗力,线粒体病理性裂变的特征是有丝分裂活化。结果显示,缺血再灌注损伤增加了 NR4A1 的表达水平,激活了由 Mff 介导的线粒体裂变,恢复了由 FUNDC1 介导的有丝分裂表型。FUNDC1 磷酸化失活不能及时介导有丝分裂的正常化,导致线粒体未折叠蛋白的过度应激反应和线粒体平衡失衡。这一过程破坏了线粒体质量控制网络的正常化,导致受损线粒体的积累和泛凋亡程序的激活。我们的数据表明,在心肌I/R损伤中,NR4A1是一个新的关键靶点,它通过激活Mff介导的线粒体裂变和抑制FUNDC1介导的有丝分裂来发挥负调控作用。针对 NR4A1-Mff-FUNDC1 之间的串扰平衡是治疗 I/R 的一种潜在方法。
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引用次数: 0
Integrative alternative splicing analysis reveals new prognosis signature in B-cell acute lymphoblastic leukemia. 替代剪接整合分析揭示了 B 细胞急性淋巴细胞白血病新的预后特征。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-19 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.98899
Zhiyi Zhuo, Junfei Wang, Yonglei Zhang, Guoyu Meng

The dysregulation of alternative splicing (AS) is increasingly recognized as a pivotal player in the pathogenesis, progression, and treatment resistance of B-cell acute lymphoblastic leukemia (B-ALL). Despite its significance, the clinical implications of AS events in B-ALL remain largely unexplored. This study developed a prognostic model based on 18 AS events (18-AS), derived from a meticulous integration of bioinformatics methodologies and advanced machine learning algorithms. The 18-AS signature observed in B-ALL distinctly categorized patients into different groups with significant differences in immune infiltration, V(D)J rearrangement, drug sensitivity, and immunotherapy outcomes. Patients classified within the high 18-AS group exhibited lower immune infiltration scores, poorer chemo- and immune-therapy responses, and worse overall survival, underscoring the model's potential in refining therapeutic strategies. To validate the clinical applicability of the 18-AS, we established an SF-AS regulatory network and identified candidate drugs. More importantly, we conducted in vitro cell proliferation assays to confirm our analysis, demonstrating that the High-18AS cell line (SUP-B15) exhibited significantly enhanced sensitivity to Dasatinib, Dovitinib, and Midostaurin compared to the Low-18AS cell line (REH). These findings reveal AS events as novel prognostic biomarkers and therapeutic targets, advancing personalized treatment strategies in B-ALL management.

人们越来越认识到,替代剪接(AS)失调是 B 细胞急性淋巴细胞白血病(B-ALL)发病、进展和耐药性的关键因素。尽管其意义重大,但B-ALL中AS事件的临床影响在很大程度上仍未得到探讨。本研究基于18个AS事件(18-AS)建立了一个预后模型,该模型是通过对生物信息学方法和先进的机器学习算法进行细致整合而得出的。在B-ALL中观察到的18-AS特征将患者分为不同的组别,这些组别在免疫浸润、V(D)J重排、药物敏感性和免疫治疗结果方面存在显著差异。被归入高18-AS组的患者免疫浸润评分较低,化疗和免疫治疗反应较差,总生存率较低,这凸显了该模型在完善治疗策略方面的潜力。为了验证18-AS的临床适用性,我们建立了一个SF-AS调控网络,并确定了候选药物。更重要的是,我们进行了体外细胞增殖试验来证实我们的分析,结果表明与低18-AS细胞系(REH)相比,高18-AS细胞系(SUP-B15)对达沙替尼、多韦替尼和米多司林的敏感性明显增强。这些发现揭示了作为新型预后生物标志物和治疗靶点的AS事件,从而推进了B-ALL管理中的个性化治疗策略。
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引用次数: 0
Mitochondrial pyruvate carrier 2 mitigates acute kidney injury via sustaining mitochondrial metabolism. 线粒体丙酮酸载体 2 通过维持线粒体代谢减轻急性肾损伤。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-19 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.98627
Lin Wu, Qing Li, Fang Lu, Li Qian, Ying Pan, Chen Chen, Zhimin Huang, Suyan Duan, Bo Zhang, Hongwei Liang, Changying Xing, Huijuan Mao, Yanggang Yuan

Cisplatin, a chemotherapeutic drug, can result in acute kidney injury (AKI). Currently, there are no effective prevention methods. An incomplete understanding of the pathogenesis of AKI is a major barrier to the development of effective therapies. Metabolism reprogramming shift to glycolysis was involved in AKI pathogenesis. Glycolysis results in the pyruvate production. The mitochondrial pyruvate carrier (MPC) conveys cytosol pyruvate into mitochondria, promoting the tricarboxylic acid cycle. In this current study, we found a reduction in MPC2 expression in mice and cultured HK2 cells with cisplatin-induced AKI. MPC2 overexpression attenuated cisplatin-mediated nephrotoxicity both in vitro and in vivo via restoring pyruvate metabolism and mitochondrial function. Knockdown of MPC2 reversed this effect. Furthermore, artemether, an MPC2 potential activator, could mitigate AKI via regulating MPC2-mediated pyruvate metabolism. Our findings revealed that MPC2-pyruvate metabolism axis was a promising strategy to alleviate AKI induced by cisplatin.

顺铂是一种化疗药物,可导致急性肾损伤(AKI)。目前,还没有有效的预防方法。对急性肾损伤发病机制的不完全了解是开发有效疗法的主要障碍。代谢重编程转向糖酵解与 AKI 的发病机制有关。糖酵解产生丙酮酸。线粒体丙酮酸载体(MPC)将细胞膜丙酮酸输送到线粒体,促进三羧酸循环。在本研究中,我们发现在顺铂诱导的 AKI 小鼠和培养的 HK2 细胞中,MPC2 的表达量减少。MPC2 的过表达通过恢复丙酮酸代谢和线粒体功能,减轻了顺铂介导的体外和体内肾毒性。敲除 MPC2 可逆转这种效应。此外,MPC2潜在激活剂蒿甲醚可通过调节MPC2介导的丙酮酸代谢缓解AKI。我们的研究结果表明,MPC2-丙酮酸代谢轴是缓解顺铂诱导的AKI的一种有前途的策略。
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International Journal of Biological Sciences
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