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N-Acetylcysteine Alleviates Depressive-Like Behaviors in Adolescent EAAC1-/- Mice and Early Life Stress Model Rats. N-乙酰半胱氨酸能缓解青少年 EAAC1-/- 小鼠和早期生活压力模型大鼠的抑郁行为
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-07 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.97723
Han-Byeol Kim, Yu-Jin Kim, Ye-Ji Lee, Ji-Young Yoo, Yoori Choi, Eun-Mee Kim, Sang Won Suh, Ran-Sook Woo

Exposure to adverse experiences during early life is associated with an increased risk of psychopathology during adolescence. In a previous study, we demonstrated that neonatal maternal separation (NMS) combined with social isolation led to impulsive and depressive-like behaviors in male adolescents. Additionally, it significantly reduced the expression of excitatory amino acid carrier 1 (EAAC1) in the hippocampus. Building upon this work, we investigated the effects of N-acetylcysteine (NAC), a precursor to glutathione, in early-life stress (ELS) model rats and in EAAC1-/- mice. EAAC1 plays a dual role in transporting both glutamate and cysteine into neurons. Our findings revealed that female adolescents subjected to in the ELS model also exhibited behavioral defects similar to those of males. NAC injection rescued depressive-like behaviors in both male and female NMS models, but it improved impulsive behavior only in males. Furthermore, we observed increased reactive oxidative stress (ROS) and neuroinflammation in the ventral hippocampus (vHPC) and prefrontal cortex of NMS model rats, which were mitigated by NAC treatment. Notably, NAC reversed the reduced expression of EAAC1 in the vHPC of NMS model rats. In EAAC1-/- mice, severe impulsive and depressive-like behaviors were evident, and the NAC intervention improved only depressive-like behaviors. Collectively, our results suggest that ELS contributes to depression and impulsive behaviors during adolescence. Moreover, the cysteine uptake function of EAAC1 in neurons may be specifically related to depression rather than impulsive behavior.

早年的不良经历与青春期精神病理学风险的增加有关。在之前的一项研究中,我们证实了新生儿母体分离(NMS)与社会隔离会导致男性青少年出现冲动和抑郁样行为。此外,它还会显著降低兴奋性氨基酸载体 1(EAAC1)在海马中的表达。在此基础上,我们研究了谷胱甘肽的前体--N-乙酰半胱氨酸(NAC)对早期生活压力(ELS)模型大鼠和 EAAC1-/- 小鼠的影响。EAAC1 在向神经元转运谷氨酸和半胱氨酸方面发挥着双重作用。我们的研究结果表明,在 ELS 模型中,女性青少年也表现出与男性类似的行为缺陷。注射 NAC 可挽救男性和女性 NMS 模型中的抑郁样行为,但只改善了男性的冲动行为。此外,我们还观察到 NMS 模型大鼠腹侧海马(vHPC)和前额叶皮层中活性氧化应激(ROS)和神经炎症的增加,NAC 治疗可减轻这些症状。值得注意的是,NAC逆转了EAAC1在NMS模型大鼠vHPC中的表达减少。在EAAC1-/-小鼠中,明显存在严重的冲动和抑郁样行为,而NAC干预只改善了抑郁样行为。总之,我们的研究结果表明,ELS 是青春期抑郁和冲动行为的诱因。此外,EAAC1在神经元中的半胱氨酸摄取功能可能特别与抑郁而非冲动行为有关。
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引用次数: 0
SIRT1 Mediates the Antagonism of Wnt/β-Catenin Pathway by Vitamin D in Colon Carcinoma Cells. 维生素 D 在结肠癌细胞中调解 SIRT1 对 Wnt/β-Catenin 通路的拮抗作用
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-07 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.95875
José Manuel García-Martínez, Ana Chocarro-Calvo, Javier Martínez-Useros, Nerea Regueira-Acebedo, María Jesús Fernández-Aceñero, Alberto Muñoz, María Jesús Larriba, Custodia García-Jiménez

Cancer initiation and progression result from genetic and epigenetic alterations caused by interactions between environmental and endogenous factors leading to aberrant cell signalling. Colorectal cancers (CRC) are linked to abnormal activation of the Wnt/β-catenin pathway, whose key feature is the nuclear accumulation of acetylated β-catenin in colon epithelial cells. Nuclear β-catenin acts as a transcriptional co-activator, targeting genes involved in cell proliferation and invasion. 1α,25-Dihydroxyvitamin D3 (1,25(OH)2D3 or calcitriol), the active form of vitamin D, antagonizes Wnt/β-catenin over-activation by engaging its high affinity receptor, VDR. Here we unveil that 1,25(OH)2D3-bound VDR activates Silent Information Regulator of Transcription, sirtuin 1 (SIRT1), leading to β-catenin deacetylation and nuclear exclusion, downregulation of its pro-tumourigenic target genes and inhibition of human colon carcinoma cell proliferation. Notably, orthogonal SIRT1 activation mimics nuclear exclusion of β-catenin while SIRT1 inhibition blocks the effects of 1,25(OH)2D3. Thus, SIRT1 emerges as a crucial mediator in the protective action of vitamin D against CRC. The mutual negative feedback loop unveiled here between Wnt and SIRT1 represents an important surrogate target in CRC. Since nuclear localisation of β-catenin is a critical driver of CRC that requires its acetylation, we provide a mechanistic foundation for the epidemiological evidence linking vitamin D deficiency and increased CRC risk and mortality.

癌症的发生和发展源于环境因素和内源性因素相互作用引起的遗传和表观遗传学改变,从而导致细胞信号异常。结肠直肠癌(CRC)与 Wnt/β-catenin 通路的异常激活有关,其主要特征是乙酰化的 β-catenin 在结肠上皮细胞核内聚集。核β-catenin作为一种转录共激活因子,靶向参与细胞增殖和侵袭的基因。1α,25-二羟维生素 D3(1,25(OH)2D3 或钙三醇)是维生素 D 的活性形式,它通过与高亲和力受体 VDR 结合来拮抗 Wnt/β-catenin 的过度激活。在这里,我们揭示了与 1,25(OH)2D3 结合的 VDR 可激活沉默信息转录调节因子 sirtuin 1(SIRT1),从而导致 β-catenin 去乙酰化和核排斥,下调其促肿瘤靶基因,抑制人类结肠癌细胞增殖。值得注意的是,正交 SIRT1 激活可模拟 β-catenin 的核排斥,而抑制 SIRT1 则可阻断 1,25(OH)2D3 的作用。因此,SIRT1 成为维生素 D 对 CRC 起保护作用的关键介质。本文揭示的 Wnt 与 SIRT1 之间的相互负反馈回路代表了 CRC 的一个重要替代靶点。由于β-catenin的核定位是CRC的一个关键驱动因素,需要其乙酰化,因此我们为维生素D缺乏与CRC风险和死亡率增加之间的流行病学证据提供了一个机理基础。
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引用次数: 0
Three-Dimensional In Vitro Cell Cultures as a Feasible and Promising Alternative to Two-Dimensional and Animal Models in Cancer Research. 三维体外细胞培养是癌症研究中二维模型和动物模型的可行且前景广阔的替代方案。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-30 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.96469
Andrea Esposito, Alessandra Ferraresi, Letizia Vallino, Beatrice Garavaglia, Danny N Dhanasekaran, Ciro Isidoro

Cancer represents one of the diseases with the highest mortality rate worldwide. The burden of cancer continues to increase, not only affecting the health-related quality of life of patients but also causing an elevated global financial impact. The complexity and heterogeneity of cancer pose significant challenges in research and clinical practice, contributing to increase the failure rate of clinical trials for antitumoral drugs. This is partially due to the fact that preclinical models still present important limitations in faithfully recapitulating human tumors to serve as reliable indicators of drug effectiveness. Up to now, research and development strategies employ expensive animal models (including the so-called "humanized mice") that not only raise ethical concerns, but also frequently fail to accurately predict responses to anticancer drugs because they do not faithfully replicate human physiology as well as the patient's tumor microenvironment. On the other side, traditional two-dimensional (2D) cell cultures fail to adequately reproduce the structural organization of tumor and the cellular heterogeneity found in vivo. The growing necessity to develop more accurate cancer models has increasingly emphasized the importance of three-dimensional (3D) in vitro cell cultures, such as cancer-derived spheroids and organoids, as promising alternatives to bridge the gap between 2D and animal models. In this review, we provide a brief overview focusing on 3D in vitro cell cultures as preclinical models capable of properly reproducing the tissue organization, biological composition, and complexity of in vivo tumors in a fine-tuned microenvironment. Despite their limitations, these models collectively enhance our understanding of the mechanisms underlying cancer and may offer the potential for a more reliable assessment of drug efficacy before clinical testing and, consequently, improve therapeutic outcomes for cancer patients.

癌症是全球死亡率最高的疾病之一。癌症造成的负担不断加重,不仅影响了患者与健康相关的生活质量,还造成了巨大的全球经济影响。癌症的复杂性和异质性给研究和临床实践带来了巨大挑战,导致抗肿瘤药物临床试验的失败率上升。这部分是由于临床前模型在忠实再现人类肿瘤以作为药物疗效的可靠指标方面仍存在重大局限性。迄今为止,研发策略采用的昂贵动物模型(包括所谓的 "人源化小鼠")不仅会引发伦理问题,而且由于不能忠实再现人体生理以及患者的肿瘤微环境,往往无法准确预测对抗癌药物的反应。另一方面,传统的二维(2D)细胞培养无法充分再现肿瘤的结构组织和体内的细胞异质性。开发更精确癌症模型的必要性日益凸显,三维(3D)体外细胞培养(如癌源球形细胞和有机体)作为弥合 2D 模型和动物模型之间差距的有前途的替代方法,其重要性日益凸显。在这篇综述中,我们将简要概述三维体外细胞培养物作为临床前模型,能够在微调的微环境中正确再现体内肿瘤的组织结构、生物成分和复杂性。尽管这些模型有其局限性,但它们共同增进了我们对癌症发病机制的了解,并有可能在临床试验前对药物疗效进行更可靠的评估,从而改善癌症患者的治疗效果。
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引用次数: 0
Unveiling the Role of Mechanical Microenvironment in Hepatocellular Carcinoma: Molecular Mechanisms and Implications for Therapeutic Strategies. 揭示机械微环境在肝细胞癌中的作用:分子机制及对治疗策略的影响
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-30 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.102706
Jiachen Hong, Jiongjie Yu, Damiano Buratto, Wei Chen, Ruhong Zhou, Sunbin Ling, Xiao Xu

Hepatocellular carcinoma (HCC) is the sixth most common cancer in the world and the third leading cause of cancer deaths globally. More than 80% of HCC patients have a background of fibrosis or cirrhosis, which leads to changes in physical factors in tumor microenvironment (TME), such as increased stiffness, solid stress, fluid stresses and structural alterations in the extracellular matrix (ECM). In the past, the focus of cancer research has predominantly been on genetic and biochemical factors in the TME, and the critical role of physical factors has often been overlooked. Recent discoveries suggest these unique physical signals are converted into biochemical signals through a mechanotransduction process that influences the biological behavior of tumor cells and stromal cells. This process facilitates the occurrence and progression of tumors. This review delves into the alterations in the mechanical microenvironment during the progression of liver fibrosis to HCC, the signaling pathways activated by physical signals, and the effects on both tumor and mesenchymal stromal cells. Furthermore, this paper summarizes and discusses the therapeutic options for targeting the mechanical aspects of the TME, offering valuable insights for future research into novel therapeutic avenues against HCC and other solid tumors.

肝细胞癌(HCC)是全球第六大常见癌症,也是全球第三大癌症死亡原因。80%以上的肝细胞癌患者都有纤维化或肝硬化的背景,这导致肿瘤微环境(TME)中的物理因素发生变化,如硬度增加、固体应力、流体应力和细胞外基质(ECM)的结构改变。过去,癌症研究的重点主要是肿瘤微环境中的遗传和生化因素,而物理因素的关键作用往往被忽视。最新发现表明,这些独特的物理信号通过机械传导过程转化为生化信号,从而影响肿瘤细胞和基质细胞的生物学行为。这一过程促进了肿瘤的发生和发展。本综述深入探讨了肝纤维化向 HCC 进展过程中机械微环境的改变、物理信号激活的信号通路以及对肿瘤细胞和间质基质细胞的影响。此外,本文还总结并讨论了针对TME机械方面的治疗方案,为今后研究针对HCC和其他实体瘤的新型治疗途径提供了宝贵的见解。
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引用次数: 0
Amlexanox Enforces Osteogenic Differentiation and Bone Homeostasis Through Inhibiting Ubiquitin-Dependent Degradation of β-Catenin. Amlexanox通过抑制β-Catenin的泛素依赖性降解促进成骨分化和骨稳态
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-30 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.101507
Qian He, Zhouboran Liu, Xuan Xia, Jun Zeng, Yuling Liu, Jingqiong Xun, Meilu Liu, Yueming Mei, Ruchun Dai

There was arising osteoporosis from an imbalance in bone remodeling, with excessive differentiation of bone marrow mesenchymal stem cells (BMSCs) into adipocytes instead of osteoblasts. In this study, we found IKKε was upregulated in osteoporotic bone and Ikbke knockdown promoted osteoblast differentiation. We explored amlexanox (AM), a novel IKKε inhibitor, for its effects on osteogenic differentiation and bone homeostasis. AM treatment in mice decreased bone loss, reduced marrow fat, and improved bone microarchitecture, leading to enhanced bone strength. In vitro, AM promoted osteogenesis and suppressed adipogenesis of BMSCs in a dose-dependent manner. Moreover, AM controlled RANKL/OPG expression of BMSC which regulated osteoclast differentiation. Mechanistic explorations revealed AM reinforced Wnt/β-catenin pathway by suppressing ubiquitin-proteasome-dependent degradation of β-catenin. Importantly, AM stimulated osteogenesis in human BMSCs. By promoting osteogenesis at the expense of adipogenesis and hindering osteoclastogenesis, AM offers a promising therapeutic strategy for osteoporosis due to its established safety profile.

由于骨髓间充质干细胞(BMSCs)过度分化为脂肪细胞而非成骨细胞,导致骨重塑失衡,从而引发骨质疏松症。本研究发现,IKKε在骨质疏松症骨中上调,Ikbke敲除可促进成骨细胞分化。我们探索了一种新型 IKKε 抑制剂--氨来呫诺(AM)对成骨分化和骨稳态的影响。AM治疗小鼠可减少骨质流失、减少骨髓脂肪、改善骨的微结构,从而增强骨强度。在体外,AM 能以剂量依赖的方式促进 BMSCs 的成骨和抑制脂肪生成。此外,AM 还能控制 BMSC 的 RANKL/OPG 表达,从而调节破骨细胞的分化。机理研究发现,AM通过抑制泛素蛋白酶体依赖的β-catenin降解,强化了Wnt/β-catenin通路。重要的是,AM能刺激人类BMSCs的成骨。AM以脂肪生成为代价促进骨生成,并阻碍破骨细胞生成,其安全性已得到证实,为骨质疏松症提供了一种有前景的治疗策略。
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引用次数: 0
USP10 promotes pancreatic ductal adenocarcinoma progression by attenuating FOXC1 protein degradation to activate the WNT signaling pathway. USP10 通过抑制 FOXC1 蛋白降解来激活 WNT 信号通路,从而促进胰腺导管腺癌的进展。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-30 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.92278
Jie Wang, Lang Gan, Fenghao Liu, Qin Yang, Qingsong Deng, Di Jiang, Chengcheng Zhang, LeiDa Zhang, XiaoJun Wang

Increasing evidence has suggested that ubiquitin-specific protease 10 (USP10), a deubiquitinating enzyme, plays an essential role in targeted protein degradation and participates in cancer progression. However, the relationship between USP10 and pancreatic ductal adenocarcinoma (PDAC) is poorly understood. Here, we developed a USP-targeting siRNA library, combining a loss-of-function experimental screen in patient-derived PDAC cells. This approach identified USP10 as a master regulator of PDAC cell migration. High USP10 expression levels were observed in PDAC patient tissues, which were associated with poor prognosis. Furthermore, knockdown of USP10 expression inhibited PDAC cell proliferation and migration in vivo and in vitro. Mechanistically, USP10 increased FOXC1 protein stability via deubiquitination. The phosphorylation of FOXC1 at S272A was dependent on USP10-mediated deubiquitination of FOXC1. Additionally, USP10 promoted FOXC1 protein localization in the nucleus. Interestingly, FOXC1 could increase USP10 mRNA expression levels by transcriptional activation. Our data suggest that a positive feedback loop exists between USP10 and FOXC1 that can activate WNT signaling, thus facilitating PDAC malignant progression. Therefore, USP10 represents an exciting therapeutic target that could support new strategies for treating PDAC.

越来越多的证据表明,泛素特异性蛋白酶 10(USP10)是一种去泛素化酶,在有针对性的蛋白质降解过程中发挥着重要作用,并参与癌症进展。然而,人们对 USP10 与胰腺导管腺癌(PDAC)之间的关系知之甚少。在这里,我们开发了一个 USP 靶向 siRNA 文库,并结合了在源自患者的 PDAC 细胞中进行的功能缺失实验筛选。这种方法确定了 USP10 是 PDAC 细胞迁移的主调控因子。在 PDAC 患者组织中观察到 USP10 的高表达水平,这与预后不良有关。此外,敲除 USP10 的表达抑制了 PDAC 细胞在体内和体外的增殖和迁移。从机制上讲,USP10 通过去泛素化增加了 FOXC1 蛋白的稳定性。FOXC1 在 S272A 处的磷酸化依赖于 USP10 介导的 FOXC1 去泛素化。此外,USP10 还促进了 FOXC1 蛋白在细胞核中的定位。有趣的是,FOXC1 可以通过转录激活提高 USP10 mRNA 的表达水平。我们的数据表明,USP10 和 FOXC1 之间存在正反馈回路,可以激活 WNT 信号,从而促进 PDAC 的恶性进展。因此,USP10 是一个令人兴奋的治疗靶点,可支持治疗 PDAC 的新策略。
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引用次数: 0
Theophylline derivatives promote primordial follicle activation via cAMP-PI3K/Akt pathway and ameliorate fertility deficits in naturally aged mice. 茶碱衍生物通过cAMP-PI3K/Akt途径促进原始卵泡活化,改善自然老龄小鼠的生育能力缺陷。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-30 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.99936
Wenbo Zhang, Longwei Gao, Xiaodan Zhang, Yashuang Weng, Yan Du, Yan-Li Sun, Hongwei Wei, Tiantian Hao, Yuezhou Chen, Xiaoyan Liang, Meijia Zhang

In elderly women and patients with premature ovarian insufficiency (POI), activating their remaining dormant primordial follicles in vivo is challenging. In this study, we found that phosphodiesterase (PDE) subtypes were expressed mainly in primordial follicle oocytes. The specific PDE inhibitors and theophylline derivatives (aminophylline, dyphylline, and enprofylline) activated primordial follicles in neonatal mice by ovary culture and intraperitoneal injection. These inhibitors also increased the levels of ovarian cyclic adenosine monophosphate (cAMP) and oocyte phosphorylated protein kinase B (p-Akt). The blockade of gap junctions using carbenoxolone (CBX) increased the levels of ovarian cAMP and pre-granulosa cell phosphorylated mammalian target of rapamycin (p-mTOR), suggesting that oocyte PDEs hydrolyze cAMP from pre-granulosa cells through gap junctions to maintain primordial follicle dormancy. Importantly, oral aminophylline improved ovulated oocyte quantity and quality, and increased offspring numbers in naturally aged mice. In addition, theophylline derivatives also activated human primordial follicles and increased p-Akt levels. Thus, theophylline derivatives activate primordial follicles by accumulating cAMP levels and activating phosphatidylinositol 3-kinase (PI3K)/Akt pathway in oocytes, and oral aminophylline increased fertility in naturally aged female mice by improving ovulated oocyte quantity and quality. As oral medications, theophylline derivatives may be used to improve fertility in elderly women and patients with POI.

对于老年妇女和早衰性卵巢功能不全(POI)患者来说,在体内激活其剩余的休眠原始卵泡是一项挑战。在这项研究中,我们发现磷酸二酯酶(PDE)亚型主要在原始卵泡卵母细胞中表达。通过卵巢培养和腹腔注射,特异性 PDE 抑制剂和茶碱衍生物(氨茶碱、二茶碱和恩丙茶碱)激活了新生小鼠的原始卵泡。这些抑制剂还能提高卵巢环磷酸腺苷(cAMP)和卵母细胞磷酸化蛋白激酶 B(p-Akt)的水平。使用羧甲唑龙(CBX)阻断间隙连接可提高卵巢cAMP和前颗粒细胞磷酸化哺乳动物雷帕霉素靶标(p-mTOR)的水平,这表明卵母细胞PDE通过间隙连接水解前颗粒细胞的cAMP,以维持原始卵泡休眠。重要的是,口服氨茶碱可改善排卵卵母细胞的数量和质量,并增加自然衰老小鼠的后代数量。此外,茶碱衍生物还能激活人类原始卵泡,提高p-Akt水平。因此,茶碱衍生物通过积累cAMP水平和激活卵母细胞中的磷脂酰肌醇3-激酶(PI3K)/Akt通路来激活原始卵泡,而口服氨茶碱通过改善排卵卵母细胞的数量和质量来提高自然老龄雌性小鼠的生育能力。作为口服药物,茶碱衍生物可用于改善老年妇女和 POI 患者的生育能力。
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引用次数: 0
Identification of miR-6794-3p as a suppressor in pancreatic cancer metastasis. 鉴定 miR-6794-3p 是胰腺癌转移的抑制因子。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-30 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.98490
Ha Gyeong Kim, Yunmi Cho, Jae-Seon Lee, Eun-Taex Oh, Heon Joo Park

Metastasis is a major cause of treatment failure in patients with pancreatic cancer, highlighting the urgent need for effective therapeutic strategies. Here, we focused on identifying novel miRNAs with key roles in metastasis of pancreatic cancer. Microarray analysis of miRNA expression in metastatic and non-metastatic pancreatic cancer samples revealed significantly lower expression of miR-6794-3p in the metastatic tumor group. Gain- and loss-of-function approaches using the pancreatic cancer cell lines MIA-PaCa-2 and HPAF-II expressing low and high levels of miR-6794-3p, respectively, indicated a role of miR-6794-3p in suppression of cell invasion, migration, and EMT signaling. Importantly, our results showed that miR-6794-3p exerts its effects by inhibiting expression of the chromatin remodeling factor, RBBP4. The resulting suppression of RBBP4 induced an increase in the levels of GRHL2 involved in regulating invasion, migration, and EMT signaling in metastatic pancreatic cancer cells. Consistent with these findings, low miR-6794-3p expression levels correlate with poor pancreatic cancer patient survival. Additional preclinical experiments on nude mice clearly demonstrated inhibitory effects of miR-6794-3p on pancreatic cancer cell metastasis. The collective results highlight the functional significance of miR-6794-3p as a suppressor of metastasis and support its predictive utility as a prognostic biomarker and therapeutic target in pancreatic cancer.

转移是胰腺癌患者治疗失败的一个主要原因,因此迫切需要有效的治疗策略。在此,我们重点研究了在胰腺癌转移中起关键作用的新型 miRNA。对转移性和非转移性胰腺癌样本中 miRNA 表达的芯片分析表明,miR-6794-3p 在转移性肿瘤组中的表达明显较低。利用分别表达低水平和高水平 miR-6794-3p 的胰腺癌细胞系 MIA-PaCa-2 和 HPAF-II 进行的功能增益和功能缺失分析表明,miR-6794-3p 在抑制细胞侵袭、迁移和 EMT 信号传导中发挥作用。重要的是,我们的研究结果表明,miR-6794-3p 是通过抑制染色质重塑因子 RBBP4 的表达来发挥其作用的。RBBP4 的抑制导致转移性胰腺癌细胞中参与调控侵袭、迁移和 EMT 信号转导的 GRHL2 水平升高。与这些发现一致的是,miR-6794-3p 的低表达水平与胰腺癌患者的不良生存率相关。在裸鼠身上进行的其他临床前实验清楚地证明了 miR-6794-3p 对胰腺癌细胞转移的抑制作用。这些研究结果凸显了 miR-6794-3p 作为转移抑制因子的功能意义,并支持其作为胰腺癌预后生物标志物和治疗靶点的预测作用。
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引用次数: 0
Molecular changes in intraocular fluid: implications for myopia. 眼内液的分子变化:对近视的影响。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-30 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.101438
Zewei Zhang, Lingfeng Lv, Dongmei Chen, Fang Li, Jibo Zhou

Myopia is the most common eye disease in the world which is caused by a mismatch between the optical power of the eye and its excessive axial length. Scleral remodeling, oxidative stress, inflammation, pathological states of angiogenesis and fibrosis and metabolism are closely associated with the onset and progression of myopia and the pathological changes that may ultimately result. Intraocular fluid is a collective term for the fluid within the eye, and changes in its composition can reflect the physiological and pathological status within the eye, with aqueous humor and vitreous being the commonly tested specimens. Recent studies have revealed potential changes in a variety of molecules in intraocular fluid during myopia progression. Abnormal expression of these molecules may reflect different stages of myopia and provide new perspectives for disease monitoring and treatment. Therefore, in this review, we systematically review the molecular changes in intraocular fluid associated with myopia, as well as the possible mechanisms, with a view to informing basic myopia research and clinical work.

近视是世界上最常见的眼病,是由于眼睛的光学能力与过长的轴长不匹配造成的。巩膜重塑、氧化应激、炎症、血管生成和纤维化的病理状态以及新陈代谢与近视的发生和发展以及最终可能导致的病理变化密切相关。眼内液是眼内液体的统称,其成分的变化可以反映眼内的生理和病理状态,其中房水和玻璃体是常用的检测标本。最近的研究揭示了近视发展过程中眼内液中各种分子的潜在变化。这些分子的异常表达可能反映了近视的不同阶段,并为疾病监测和治疗提供了新的视角。因此,在这篇综述中,我们系统回顾了与近视相关的眼内液分子变化以及可能的机制,以期为近视基础研究和临床工作提供参考。
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引用次数: 0
Deubiquitinases in Ovarian Cancer: Role in Drug Resistance and Tumor Aggressiveness. 卵巢癌中的去泛素酶:在抗药性和肿瘤侵袭性中的作用
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-23 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.100355
Giovanni Luca Beretta, Matteo Costantino, Luca Mirra, Pietro Pettinari, Paola Perego

Ovarian cancer is a lethal disease due to late diagnosis and occurrence of drug resistance that limits the efficacy of platinum-based therapy. Drug resistance mechanisms include both tumor intrinsic and tumor microenvironment-related factors. A role for deubiquitinases (DUBs) is starting to emerge in ovarian cancer. DUBs are a large family of enzymes that remove ubiquitin from target proteins and participate in processes affecting drug resistance such as DNA damage repair and apoptosis. Besides, DUBs modulate the functions of T cell populations favoring an immune suppressed microenvironment. Three DUBs are proteasome-associated, whereas the large majority are not. Among the former DUBs, USP14 has been proposed to modulate transcription factors such as Bcl6 and BACH1. In addition, RPN11/PSMD14 interferes with various processes including epithelial mesenchymal transition, also favored by non-proteasomal DUBs such as USP1 by acting on Snail. Besides, USP8 by stabilizing HER family receptors can confer drug resistance. Overall, DUBs appear to be druggable, with several inhibitors under development. Based on DUBs biological role, DUBs targeting appears promising in view of combination strategies involving different therapeutic approaches. Here, we summarize the relevance of DUBs in ovarian carcinoma and provide insights into future challenges for the treatment of this disease.

卵巢癌是一种致命性疾病,原因是诊断较晚和出现耐药性,从而限制了以铂为基础的疗法的疗效。耐药机制包括肿瘤内在因素和肿瘤微环境相关因素。去泛素酶(DUBs)在卵巢癌中的作用开始显现。DUBs是一个庞大的酶家族,能清除靶蛋白上的泛素,并参与DNA损伤修复和细胞凋亡等影响耐药性的过程。此外,DUBs 还能调节有利于免疫抑制微环境的 T 细胞群的功能。有三种 DUB 与蛋白酶体相关,而绝大多数不相关。在前一种 DUBs 中,USP14 被认为可调节 Bcl6 和 BACH1 等转录因子。此外,RPN11/PSD14 还能干扰包括上皮间质转化在内的各种过程,而 USP1 等非蛋白酶体 DUBs 也能通过作用于蜗牛(Snail)来实现上皮间质转化。此外,USP8 通过稳定 HER 家族受体可产生耐药性。总的来说,DUBs 似乎是可以药物治疗的,有几种抑制剂正在开发中。基于 DUBs 的生物学作用,DUBs 靶向似乎很有希望成为涉及不同治疗方法的组合策略。在此,我们总结了 DUBs 与卵巢癌的相关性,并深入探讨了治疗这种疾病的未来挑战。
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