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Establishment and characterization of two novel patient-derived cell lines from myxofibrosarcoma: NCC-MFS7-C1 and NCC-MFS8-C1. 两种新型肌纤维肉瘤患者衍生细胞系的建立和特征描述:NCC-MFS7-C1和NCC-MFS8-C1。
IF 3.4 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-11-01 Epub Date: 2024-08-31 DOI: 10.1007/s13577-024-01124-4
Yuki Adachi, Rei Noguchi, Julia Osaki, Takuya Ono, Shuhei Iwata, Taro Akiyama, Ryuto Tsuchiya, Yu Toda, Sekita Tetsuya, Shintaro Iwata, Eisuke Kobayashi, Naoki Kojima, Akihiko Yoshida, Hideki Yokoo, Akira Kawai, Tadashi Kondo

Myxofibrosarcoma (MFS), an aggressive soft tissue sarcoma, presents a significant challenge because of its high recurrence rate, distal metastasis, and complex genetic background. Although surgical resection is the standard treatment for MFS, the outcomes are unsatisfactory and effective non-surgical treatment strategies, including drug therapy, are urgently warranted. MFS is a rare tumor that requires comprehensive preclinical research to develop promising drug therapies; however, only two MFS cell lines are publicly available worldwide. The present study reports two novel patient-derived MFS cell lines, NCC-MFS7-C1 and NCC-MFS8-C1. These cell lines have been extensively characterized for their genetic profile, proliferation, spheroid-forming capacity, and invasive behavior, confirming that they retain MFS hallmarks. Furthermore, we conducted comprehensive drug screening against these cell lines and six others previously established in our laboratory to identify potential therapeutic candidates for MFS. Among the screened agents, actinomycin D, bortezomib, and romidepsin demonstrated considerable antiproliferative effects that were superior to those of doxorubicin, a standard drug, highlighting their potential as novel drugs. In conclusion, NCC-MFS7-C1 and NCC-MFS8-C1 are valuable research resources that contribute to the understanding of the pathogenesis and development of novel therapies for MFS.

肌纤维肉瘤(MFS)是一种侵袭性软组织肉瘤,因其复发率高、远端转移和复杂的遗传背景而成为一项重大挑战。虽然手术切除是 MFS 的标准治疗方法,但疗效并不令人满意,因此迫切需要有效的非手术治疗策略,包括药物治疗。MFS 是一种罕见的肿瘤,需要进行全面的临床前研究,以开发出有前景的药物疗法;然而,全球仅有两种 MFS 细胞系可公开获得。本研究报告了两种新型患者来源 MFS 细胞系:NCC-MFS7-C1 和 NCC-MFS8-C1。我们对这些细胞系的遗传特征、增殖、球形细胞形成能力和侵袭行为进行了广泛鉴定,证实它们保留了 MFS 的特征。此外,我们还针对这些细胞系和我们实验室以前建立的其他六个细胞系进行了全面的药物筛选,以确定潜在的 MFS 候选疗法。在筛选出的药物中,放线菌素 D、硼替佐米和罗米地平显示出相当大的抗增殖作用,其效果优于标准药物多柔比星,凸显了它们作为新型药物的潜力。总之,NCC-MFS7-C1 和 NCC-MFS8-C1 是宝贵的研究资源,有助于了解 MFS 的发病机制和开发新型疗法。
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引用次数: 0
Inhibition of the AP-1/TFPI2 axis contributes to alleviating cerebral ischemia/reperfusion injury by improving blood-brain barrier integrity. 抑制 AP-1/TFPI2 轴有助于改善血脑屏障的完整性,从而减轻脑缺血/再灌注损伤。
IF 3.4 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-11-01 Epub Date: 2024-09-04 DOI: 10.1007/s13577-024-01125-3
Yue Cao, Ruixian Xing, Qiushi Li, Yang Bai, Xuewen Liu, Buxian Tian, Xin Li

Reperfusion after cerebral ischemia leads to secondary damage to the nervous system, called cerebral ischemia/reperfusion injury (CIRI). The blood-brain barrier (BBB) consists of endothelial cells and tight junction (TJ) proteins, and its disruption aggravates CIRI. Two GSE datasets identified Tissue Factor Pathway Inhibitor 2 (TFPI2) as a differentially upregulated gene (Log2FC > 1, p < 0.01) in the cerebral cortex of ischemic rats, and TFPI2 affects angiogenesis of endothelial cells. Moreover, genes (c-Jun, c-Fos, FosL1) encoding subunits of Activator Protein-1 (AP-1), a transcription factor involved in IRI, were highly expressed in ischemic samples. Thus, the effects of the AP-1/TFPI2 axis on CIRI were explored. We determined increased TFPI2 expression in the cerebral cortex of rats receiving middle cerebral artery occlusion (MCAO) for 90 min and reperfusion (R) for 48 h. Then AAV2-shTFPI2 particles (5 × 1010 vg) were injected into the right lateral ventricle of rats 3 weeks before MCAO/R. TFPI2 knockdown decreased infarct size and neuronal injury in ischemic rats. It improved BBB integrity, demonstrated by reduced FITC-dextran leakage in brain tissues of MCAO/R-operated rats. Furthermore, it increased the expression of TJ proteins (Occludin, Claudin-5, TJP-1) in the cerebral cortex of rats with CIRI. Consistently, we found that TFPI2 knockdown mitigated cell damage in mouse endothelial bEND.3 cells with oxygen and glucose deprivation (ODG) for 6 h and reoxygenation (R) for 18 h (OGD/R) treatment. High co-expression of c-Jun and c-Fos significantly elevated TFPI2 promoter activity. c-Jun knockdown inhibited TFPI2 expression in OGD/R-treated bEND.3 cell. Collectively, our findings demonstrate that inhibition of the AP-1/TFPI2 axis alleviates CIRI.

脑缺血后的再灌注会导致神经系统的二次损伤,称为脑缺血再灌注损伤(CIRI)。血脑屏障(BBB)由内皮细胞和紧密连接(TJ)蛋白组成,其破坏会加重 CIRI。在大鼠右心室注射组织因子通路抑制因子 2(TFPI2)作为差异上调基因(Log2FC > 1, p 10 vg)的两个 GSE 数据集后,大鼠的右心室在 MCAO/R 前 3 周发生了损伤。敲除 TFPI2 能缩小缺血大鼠的梗死面积并减轻神经元损伤。MCAO/R手术大鼠脑组织中FITC-葡聚糖渗漏的减少证明TFPI2敲除改善了BBB的完整性。此外,它还能增加 CIRI 大鼠大脑皮层中 TJ 蛋白(Occludin、Claudin-5、TJP-1)的表达。同样,我们发现敲除 TFPI2 可减轻小鼠内皮细胞 bEND.3 在缺氧和缺糖(ODG)6 小时和复氧(R)18 小时(OGD/R)处理下的细胞损伤。c-Jun和c-Fos的高共表达显著提高了TFPI2启动子的活性,敲除c-Jun可抑制TFPI2在OGD/R处理的bEND.3细胞中的表达。总之,我们的研究结果表明,抑制 AP-1/TFPI2 轴可减轻 CIRI。
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引用次数: 0
The role of monoglyceride lipase gene in promoting proliferation, metastasis, and free fatty acid accumulation in uveal melanoma cells. 单甘酯脂肪酶基因在促进葡萄膜黑色素瘤细胞增殖、转移和游离脂肪酸积累中的作用
IF 3.4 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-11-01 Epub Date: 2024-08-24 DOI: 10.1007/s13577-024-01120-8
Yanan Xu, Jiangming Zhong, Zhenhua Liu, Deyu Li

Uveal melanoma is a malignant tumor originating from melanocytes in the eye's uvea, often detected during routine ophthalmic examinations due to its typically asymptomatic nature. Despite effective local treatments, up to 50% of patients develop hematogenous metastases, highlighting the need for better prognostic markers and therapeutic targets. In this study, we developed an innovative Metastasis-Related Gene Signature (MERGS) score to classify patients from various cohorts. By establishing this scoring method, we discovered underlying mechanisms responsible for significant differences between samples with high and low MERGS scores. We identified a set of ten genes to construct MERGS, which showed a high predictive accuracy for patient survival. Further, Monoglyceride Lipase (MGLL) emerged as the most important gene in distinguishing uveal melanoma metastasis. Functional studies demonstrated that knocking down MGLL significantly inhibited proliferation, invasion, and migration of uveal melanoma cells in vitro and in vivo, while overexpression of MGLL enhanced these malignant behaviors. Additionally, MGLL modulated free fatty acid (FFA) levels within these cells. Our findings reveal MGLL as a crucial player in uveal melanoma progression and propose it as a novel therapeutic target, potentially leading to improved management and outcomes for patients with this disease.

葡萄膜黑色素瘤是一种起源于眼葡萄膜黑色素细胞的恶性肿瘤,由于通常无症状,常在常规眼科检查中被发现。尽管局部治疗有效,但仍有多达 50% 的患者会发生血行转移,因此需要更好的预后指标和治疗靶点。在这项研究中,我们开发了一种创新的转移相关基因特征(MERGS)评分法,用于对不同组群的患者进行分类。通过建立这种评分方法,我们发现了造成 MERGS 高分和低分样本之间显著差异的潜在机制。我们确定了一组十个基因来构建 MERGS,这组基因对患者生存的预测准确率很高。此外,单甘油脂酶(MGLL)成为区分葡萄膜黑色素瘤转移的最重要基因。功能研究表明,敲除 MGLL 能显著抑制葡萄膜黑色素瘤细胞在体外和体内的增殖、侵袭和迁移,而过表达 MGLL 则会增强这些恶性行为。此外,MGLL 还能调节这些细胞内的游离脂肪酸(FFA)水平。我们的研究结果揭示了 MGLL 在葡萄膜黑色素瘤发展过程中的关键作用,并提出将其作为一种新的治疗靶点,从而有可能改善这种疾病患者的管理和治疗效果。
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引用次数: 0
Osteoarthritis rat serum-derived extracellular vesicles aggravate osteoarthritis development by inducing NLRP3-mediated pyroptotic cell death and cellular inflammation. 骨关节炎大鼠血清衍生的细胞外囊泡通过诱导 NLRP3 介导的细胞凋亡和细胞炎症加剧了骨关节炎的发展。
IF 3.4 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-11-01 Epub Date: 2024-08-14 DOI: 10.1007/s13577-024-01119-1
Zhifang Tang, Longjun Shu, Zijian Cao, Yongqing Xu, Chuan Li

Osteoarthritis (OA), degenerative joint disease, is the most prevalent form of arthritis worldwide. Besides its substantial burden on society, the high OA morbidity greatly diminishes patients' quality of life. According to recent research, patients-derived serum extracellular vesicles (EVs) are critically involved in sustaining the corresponding disease progression. However, limited research has fully explored the specific functions and molecular mechanisms of OA serum-derived EVs in disease progression. Consequently, we aimed to investigate the underlying mechanism of OA rats-derived serum EVs in regulating OA progression. Before constructing the exosome-cell co-culture system, EVs were extracted from OA and control rat serum and co-cultured with bone marrow mesenchymal stem cells (BM-MSCs). Western blotting (WB), RT-qPCR, and enzyme-linked immunosorbent assay (ELISA) results revealed that OA rat serum-derived EVs upregulated cell pyroptosis-related markers, including nod-Like receptor protein-3 (NLRP3), apoptosis-associated speck-like protein (ASC), gasdermin D (GSDMD), and cleaved caspase-1. The OA rat-EVs also induced the release of LDH and inflammatory cytokines, including interleukin (IL)-1β, IL-18, IL-6, and TNF-α. Additional experiments revealed that OA rat-EVs delivered miR-133a-3p to BM-MSCs and upregulated miR-133a-3p to degrade sirtuin 1 (SIRT1), and activating the downstream NF-κB signaling pathway. Furthermore, the rescuing experiments confirmed that silencing SIRT1 abrogated the miR-133a-3p-induced protective effects in OA-EVs-treated BM-MSCs. In conclusion, OA rats-derived miR-133a-3p-containing EVs modulated the downstream SIRT1/NF-κB pathway-mediated pyroptotic cell death and inflammation in OA. In other words, this study confirmed the role and underlying mechanisms by which OA-associated serum EVs regulate pyroptosis and inflammation response in OA development.

骨关节炎(OA)是一种退行性关节疾病,是全球最常见的关节炎。除了给社会带来沉重负担外,骨关节炎的高发病率还大大降低了患者的生活质量。最近的研究表明,患者血清中的细胞外囊泡(EVs)在维持相应的疾病进展中起着至关重要的作用。然而,对 OA 血清衍生的 EVs 在疾病进展中的特定功能和分子机制的全面探索还很有限。因此,我们旨在研究OA大鼠血清衍生EVs调控OA进展的内在机制。在构建外泌体-细胞共培养系统之前,先从 OA 大鼠和对照组大鼠血清中提取 EVs,然后与骨髓间充质干细胞(BM-MSCs)共培养。Western印迹(WB)、RT-qPCR和酶联免疫吸附试验(ELISA)结果显示,OA大鼠血清衍生的EVs能上调细胞凋亡相关标记物,包括NLRP3受体蛋白(Nod-Like receptor protein-3)、凋亡相关斑点样蛋白(ASC)、gasdermin D(GSDMD)和裂解的caspase-1。OA 大鼠-EV 还诱导释放 LDH 和炎性细胞因子,包括白细胞介素(IL)-1β、IL-18、IL-6 和 TNF-α。其他实验显示,OA大鼠EV将miR-133a-3p传递给BM-间充质干细胞,并上调miR-133a-3p以降解sirtuin 1(SIRT1),激活下游NF-κB信号通路。此外,抢救实验证实,沉默 SIRT1 会减弱 miR-133a-3p 在 OA-EVs 处理的 BM-MSCs 中诱导的保护作用。总之,OA 大鼠衍生的含 miR-133a-3p 的 EVs 调节了下游 SIRT1/NF-κB 通路介导的 OA 热休克细胞死亡和炎症。换句话说,这项研究证实了OA相关血清EVs在OA发展过程中调控热噬和炎症反应的作用和潜在机制。
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引用次数: 0
Exploring the relationship between ulcerative colitis, colorectal cancer, and prostate cancer. 探索溃疡性结肠炎、结肠直肠癌和前列腺癌之间的关系。
IF 3.4 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-11-01 Epub Date: 2024-08-20 DOI: 10.1007/s13577-024-01118-2
Yurie Kura, Marco A De Velasco, Kazuko Sakai, Hirotsugu Uemura, Kazutoshi Fujita, Kazuto Nishio

Chronic systemic inflammation caused by diseases such as ulcerative colitis (UC) and Crohn's disease (CD) increases the risk of developing colorectal cancer (CRC). Recent evidence indicates that patients with UC are more susceptible to prostate cancer (PCa), and individuals with PCa may also be at a higher risk of developing CRC. However, these relationships are not well defined. A better understanding of this phenomenon could improve the identification of high-risk populations. In this study, we characterized these relationships with experiments using preclinical mouse models of dextran sulfate sodium (DSS)-induced colitis (DSS-UC) and DSS/azoxymethane (AOM)-induced CRC (DSS/AOM-CRC) in wild-type and conditional transgenic mice of PCa. We showed that DSS-induced UC was more severe in mice with PCa and resulted in the development of CRC in the absence of AOM. We further showed that PCa-free mice that developed DSS-induced UC also showed histological changes in the normal prostate that resembled proliferative inflammatory atrophy. Finally, we used immunohistochemical immune profiling to show that mice with PCa-induced chronic systemic inflammation accumulated Gr1+ myeloid cells in the normal colon and exposure to DSS further enriched these cells in active colitis regions and colon tumors. Our study provides evidence to support a link between systemic chronic inflammation and cancer.

溃疡性结肠炎(UC)和克罗恩病(CD)等疾病引起的慢性全身性炎症会增加罹患结直肠癌(CRC)的风险。最近的证据表明,溃疡性结肠炎(UC)患者更容易患前列腺癌(PCa),而 PCa 患者患 CRC 的风险也可能更高。然而,这些关系并没有得到很好的界定。如果能更好地了解这一现象,就能更好地识别高危人群。在本研究中,我们利用野生型和条件性转基因 PCa 小鼠的右旋糖酐硫酸钠(DSS)诱导的结肠炎(DSS-UC)和右旋糖酐硫酸钠/氮氧甲烷(AOM)诱导的 CRC(DSS/AOM-CRC)临床前小鼠模型进行了实验,从而确定了这些关系的特征。我们发现,DSS诱导的UC在患有PCa的小鼠中更为严重,并且在没有AOM的情况下会导致CRC的发生。我们还进一步发现,无 PCa 的小鼠在发生 DSS 诱导的 UC 后,正常前列腺也出现了类似增殖性炎症萎缩的组织学变化。最后,我们利用免疫组化免疫图谱分析表明,PCa诱导的慢性全身性炎症小鼠在正常结肠中积累了Gr1+髓系细胞,而暴露于DSS会进一步在活动性结肠炎区域和结肠肿瘤中富集这些细胞。我们的研究为全身慢性炎症与癌症之间的联系提供了证据。
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引用次数: 0
Transcription repression of estrogen receptor alpha by ghrelin/Gq/11/YAP signaling in granulosa cells promotes polycystic ovary syndrome. 颗粒细胞中的ghrelin/Gq/11/YAP信号对雌激素受体α的转录抑制促进了多囊卵巢综合征的发生。
IF 3.4 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-11-01 Epub Date: 2024-09-03 DOI: 10.1007/s13577-024-01127-1
Pengfei Zhu, Xingyu Bi, Dan Su, Xiaoling Li, Yanhua Chen, Zhijiao Song, Lijiang Zhao, Yaoqing Wang, Suming Xu, Xueqing Wu

Polycystic ovarian syndrome (PCOS) is a prevalent endocrinological disorder affected by ghrelin. This study aimed to investigate the molecular mechanisms underlying the effects of ghrelin on PCOS manifestations in mice and to assess the therapeutic potential of ghrelin. Female C57BL/6 mice were subcutaneously injected with 6 mg/100 g dehydroepiandrosterone (DHEA) for 20 days to induce PCOS. Alterations in reproductive cycles, ovarian morphology, serum sex hormone levels, and related signaling markers were examined. Furthermore, ghrelin-induced effects on granulosa cells and the role of ghrelin/Gq/11/ Yes-associated protein (YAP) signaling were studied by silencing Gαq/11 or YAP using si-RNAs. Finally, we evaluated the therapeutic potential of anti-ghrelin antibodies in DHEA-induced PCOS mice. DHEA administration led to significant PCOS-associated changes including weight gain, disrupted estrous cycles, ovarian morphological alterations, and hormonal imbalances in mice, with elevated Gαq/11 and acylated ghrelin expression, which was also noted in PCOS patients. However, treatment with anti-ghrelin antibodies effectively managed DHEA-induced damage in PCOS mice. In vitro, ghrelin exposure resulted in granulosa cell injury and modulated estrogen receptors alpha (ERα) and YAP protein levels, whereas silencing YAP and Gαq/11 reversed ghrelin-induced detrimental effects and up-regulated ERα expression. This study revealed that DHEA-induced PCOS traits in mice could be improved by anti-ghrelin antibodies, with the ghrelin/Gq/11/YAP signaling pathway identified as a crucial mediator in granulosa cells, affecting ERα transcription to regulate PCOS. These findings suggest a potential therapeutic strategy for the treatment of PCOS.

多囊卵巢综合征(PCOS)是一种受胃泌素影响的常见内分泌疾病。本研究旨在探讨胃泌素影响小鼠多囊卵巢综合征表现的分子机制,并评估胃泌素的治疗潜力。雌性C57BL/6小鼠皮下注射6毫克/100克脱氢表雄酮(DHEA)20天,诱导多囊卵巢综合征。实验研究了生殖周期、卵巢形态、血清性激素水平和相关信号标记物的变化。此外,通过使用si-RNAs沉默Gαq/11或YAP,研究了胃泌素诱导对颗粒细胞的影响以及胃泌素/Gq/11/Yes相关蛋白(YAP)信号转导的作用。最后,我们评估了抗ghrelin抗体在DHEA诱导的多囊卵巢综合征小鼠中的治疗潜力。服用DHEA会导致小鼠体重增加、发情周期紊乱、卵巢形态改变和内分泌失调等与多囊卵巢综合征相关的显著变化,Gαq/11和酰化胃泌素表达升高,这在多囊卵巢综合征患者中也有发现。然而,使用抗胃泌素抗体治疗可有效控制多囊卵巢综合征小鼠体内由 DHEA 引起的损伤。在体外,格列林暴露导致颗粒细胞损伤,并调节雌激素受体α(ERα)和YAP蛋白水平,而沉默YAP和Gαq/11可逆转格列林诱导的有害影响,并上调ERα的表达。这项研究揭示了抗胃泌素抗体可改善DHEA诱导的小鼠多囊卵巢综合征性状,并确定胃泌素/Gq/11/YAP信号通路是颗粒细胞中的关键介质,可影响ERα转录,从而调节多囊卵巢综合征。这些发现为治疗多囊卵巢综合症提供了一种潜在的治疗策略。
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引用次数: 0
Establishment and characterization of a patient-derived metastatic extraskeletal Ewing sarcoma cell line ES-ZSS-1. 来源于患者的骨外转移性尤文肉瘤细胞系 ES-ZSS-1 的建立和特征描述。
IF 3.4 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-10-30 DOI: 10.1007/s13577-024-01133-3
Chenlu Zhang, Mengling Liu, Lijuan Luan, Xi Guo, Yang You, Zhiming Wang, Wei Li, Nanhang Lu, Yingyong Hou, Lili Lu, Weiqi Lu, Yuhong Zhou

The methods available for treating metastatic Ewing sarcoma (ES) are inadequate; thus, innovative therapeutic approaches need to be developed. However, the lack of clinically relevant ES models has hindered the discovery of drugs for this disease. In this study, we established and characterized a patient-derived xenograft (PDX) cell line model, which was constructed using tumor tissue from a patient with metastatic extraskeletal ES. The cells were found to recapitulate the morphological and histopathological features of the patient tumor and were designated as ES-ZSS-1. The cells harbor the characteristic EWSR1-FLI1 infusion and underwent successive passages in vitro. By performing gene expression profiling, we found that the mutation in STAG2 was the most frequent. An increase in Twist1 and epithelial-to-mesenchymal transition (EMT) was recorded. These genetic features might be relevant to metastasis and resistance to chemotherapy. To summarize, the novel patient-derived ES cell line we developed closely mimics the phenotype and genotype of patient tumors, making it a reliable tool for research on metastatic ES.

治疗转移性尤文肉瘤(ES)的现有方法并不完善,因此需要开发创新的治疗方法。然而,由于缺乏与临床相关的ES模型,阻碍了该疾病药物的发现。在这项研究中,我们利用一名转移性骨骼外骨肉瘤患者的肿瘤组织,建立了患者衍生异种移植(PDX)细胞系模型,并对其进行了表征。我们发现该细胞再现了患者肿瘤的形态学和组织病理学特征,并将其命名为 ES-ZSS-1。这些细胞携带特征性的 EWSR1-FLI1 输注,并在体外进行了连续传代。通过基因表达谱分析,我们发现 STAG2 突变最为常见。我们还记录到 Twist1 和上皮细胞向间质转化(EMT)的增加。这些遗传特征可能与转移和化疗耐药有关。总之,我们开发的新型患者来源ES细胞系密切模拟了患者肿瘤的表型和基因型,使其成为研究转移性ES的可靠工具。
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引用次数: 0
Emodin regulated lactate metabolism by inhibiting MCT1 to delay non-small cell lung cancer progression. 大黄素通过抑制 MCT1 来调节乳酸代谢,从而延缓非小细胞肺癌的进展。
IF 3.4 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-10-28 DOI: 10.1007/s13577-024-01140-4
Fei Zhang, Tian Gu, Jin Li, Yanqiu Zhu, Mingliang Chu, Qing Zhou, Jiemin Liu

Lung cancer is one of the most common malignant tumors in the world, with high incidence rate and mortality. Monocarboxylate transporter (MCT) 1 has been found to be widely expressed in various tumors and plays a crucial role in regulating energy metabolism. Emodin, as an important traditional Chinese medicine in China, has been reported to inhibit the progression of lung cancer. However, its potential mechanism has not been fully elucidated. The effects of emodin and MCT1 inhibitor AZD3965 on the proliferation, migration, and invasion of lung cancer cells were detected using cell counting kit-8 (CCK-8) assay, wound-healing assay, and transwell small chamber assay. The content of glucose, lactate, and pyruvate in the cell culture medium was detected using a glucose, lactate, and pyruvate detection kit, and also detected protein expression using western blotting. In addition, to investigate the effects of emodin and AZD3965 on lung cancer in vivo, we constructed nude mice subcutaneous transplant tumor model by subcutaneous injection of lung cancer cells. The results showed that emodin and AZD3965 could inhibit the proliferation, migration, and invasion of lung cancer cells. At the same time, they could inhibit the expression of MCT1 in lung cancer cells and promote the release of lactate, but did not affect the content of glucose and pyruvate. In vivo experiments had shown that emodin and AZD3965 could effectively inhibit the growth of lung cancer and inhibit the expression of MCT1. All in all, our data suggested that emodin inhibited the proliferation, migration, and invasion of lung cancer cells, possibly by inhibiting MCT1, providing important theoretical basis for elucidating the mechanism of emodin in treating lung cancer.

肺癌是世界上最常见的恶性肿瘤之一,发病率和死亡率都很高。研究发现,单羧酸盐转运体(MCT)1在多种肿瘤中广泛表达,并在调节能量代谢方面发挥着重要作用。大黄素是我国重要的传统中药,据报道可抑制肺癌的进展。然而,其潜在机制尚未完全阐明。本研究采用细胞计数试剂盒-8(CCK-8)检测法、伤口愈合检测法和Transwell小室检测法,检测大黄素和MCT1抑制剂AZD3965对肺癌细胞增殖、迁移和侵袭的影响。使用葡萄糖、乳酸和丙酮酸检测试剂盒检测细胞培养基中葡萄糖、乳酸和丙酮酸的含量,并使用 Western 印迹法检测蛋白质的表达。此外,为了研究大黄素和AZD3965对肺癌的体内作用,我们通过皮下注射肺癌细胞构建了裸鼠皮下移植肿瘤模型。结果表明,大黄素和 AZD3965 可抑制肺癌细胞的增殖、迁移和侵袭。同时,它们还能抑制肺癌细胞中 MCT1 的表达,促进乳酸的释放,但不影响葡萄糖和丙酮酸的含量。体内实验表明,大黄素和 AZD3965 能有效抑制肺癌的生长,并抑制 MCT1 的表达。总之,我们的研究数据表明,大黄素可能通过抑制MCT1来抑制肺癌细胞的增殖、迁移和侵袭,为阐明大黄素治疗肺癌的机制提供了重要的理论依据。
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引用次数: 0
Adiponectin-induced activation of ERK1/2 drives fibrosis in retinal pigment epithelial cells. 脂肪蛋白诱导的 ERK1/2 激活促使视网膜色素上皮细胞纤维化。
IF 3.4 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-10-26 DOI: 10.1007/s13577-024-01131-5
Karthikka Palanisamy, Muthuramalingam Karpagavalli, Ragavachetty Nagaraj Nareshkumar, Sharada Ramasubramanyan, Narayanasamy Angayarkanni, Rajiv Raman, Subbulakshmi Chidambaram

Adiponectin (APN), a vasoactive cytokine produced by adipocytes, has emerged as a critical player in retinal diseases. Renowned for its antioxidant, anti-angiogenic, and anti-inflammatory properties, APN levels are closely linked to metabolic disorders, such as insulin resistance, obesity, and diabetic retinopathy (DR). Our previous work demonstrated that APN is similar in efficiency as Avastin in limiting neovascularization in retinal endothelial cells. In this study, we analyzed the effect of APN on retinal epithelial cells to understand its potential impact on eye-related pathologies. Overexpression of APN in ARPE-19 cells predominantly yielded the MMW-APN form, accompanied by increased expression of pro-fibrotic markers and decreased levels of tight junction (TJ) proteins, ZO-1, and Occludin. Further, confocal imaging revealed impaired TJ assembly and the integrity of TJ was also compromised as evidenced by the higher paracellular permeability and lower TEER. Besides, rAPN treatment in ARPE-19 cells as well triggered increased expression of pro-fibrotic markers, pro-MMP2, and enhanced cell migration and proliferation. Mechanistically, these pro-fibrotic effects were mediated by APN-induced phosphorylation of ERK1/2, causing RPE cell transdifferentiation. Furthermore, we identified that MMW-APN was the most prevalent form detected in the vitreous humor of proliferative diabetic retinopathy (PDR) patients, emphasizing the clinical relevance of our findings. Overall, our data suggest that APN, particularly its MMW form, induces epithelial-mesenchymal transition (EMT) and fibrosis in RPE cells, potentially driving the angio-fibrotic shift observed in PDR via ERK1/2 activation.

由脂肪细胞产生的血管活性细胞因子--脂肪连素(APN)已成为视网膜疾病的一个关键因素。APN具有抗氧化、抗血管生成和抗炎特性,其水平与胰岛素抵抗、肥胖和糖尿病视网膜病变(DR)等代谢性疾病密切相关。我们之前的研究表明,APN 在限制视网膜内皮细胞新生血管方面的功效与阿瓦斯汀相似。在本研究中,我们分析了 APN 对视网膜上皮细胞的影响,以了解其对眼部相关病症的潜在影响。APN 在 ARPE-19 细胞中的过表达主要产生 MMW-APN 形式,伴随着促纤维化标记物表达的增加和紧密连接(TJ)蛋白、ZO-1 和 Occludin 水平的降低。此外,共聚焦成像显示 TJ 组装受损,TJ 的完整性也受到损害,这一点从较高的细胞旁通透性和较低的 TEER 可以看出。此外,在 ARPE-19 细胞中处理 rAPN 还会引发促纤维化标志物、促 MMP2 的表达增加,并增强细胞的迁移和增殖。从机理上讲,这些促纤维化效应是由 APN 诱导的 ERK1/2 磷酸化介导的,从而导致 RPE 细胞的转分化。此外,我们还发现 MMW-APN 是在增殖性糖尿病视网膜病变(PDR)患者玻璃体内检测到的最常见形式,这强调了我们研究结果的临床意义。总之,我们的数据表明,APN,尤其是其 MMW 形式,可诱导上皮-间充质转化(EMT)和 RPE 细胞纤维化,有可能通过激活 ERK1/2 推动在 PDR 中观察到的血管-纤维化转变。
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引用次数: 0
Assessment of non-myelotoxic agents as a preparatory regimen for hematopoietic stem cell gene therapy. 将非骨髓毒性药物作为造血干细胞基因治疗的预备方案进行评估。
IF 3.4 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-10-26 DOI: 10.1007/s13577-024-01130-6
Mehmet Emin Şeker, Özgür Doğuş Erol, Burcu Pervin, Gerard Wagemaker, Niek P van Til, Fatima Aerts-Kaya

RAG2 deficiency is characterized by a lack of B and T lymphocytes, causing severe lethal infections. Currently, RAG2 deficiency is treated with a Hematopoietic Stem Cell transplantation (HSCT). Most conditioning regimens used before HSCT consist of alkylating myelotoxic agents with or without irradiation and affect growth and development of pediatric patients. Here, we developed a non-myelotoxic regimen using G-CSF, VLA-4I or AMD3100. These agents are known HSC mobilizers or affect bone marrow (BM) permeability and may support the homing of HSCs to the BM, without inducing major side effects. Female Rag2-/- mice were pre-treated with Busulfan (BU), G-CSF, VLA-4I or AMD3100 and transplanted with male BM cells transduced with a lentiviral vector carrying codon optimized human RAG2 (RAG2co). Peripheral blood cell counts increased significantly after G-CSF, VLA-4I and AMD3100 treatment, but not after BU. Reconstitution of PB lymphocytes was comparable for all groups with full immune reconstitution at 6 months post transplantation, despite different methods of conditioning. Survival of mice pre-treated with non-myelotoxic agents was significantly higher than after BU treatment. Here, we show that the non-myelotoxic agents G-CSF, VLA-4I, and AMD3100 are highly effective as conditioning regimen before HSC gene therapy and can be used as an alternative to BU.

RAG2 缺乏症的特征是缺乏 B 淋巴细胞和 T 淋巴细胞,从而导致严重的致命性感染。目前,治疗 RAG2 缺乏症的方法是进行造血干细胞移植(HSCT)。造血干细胞移植前使用的大多数调理方案包括烷基化骨髓毒性药物和或非辐照,会影响儿童患者的生长发育。在这里,我们开发了一种使用 G-CSF、VLA-4I 或 AMD3100 的非骨髓毒性方案。这些药物都是已知的造血干细胞动员剂或影响骨髓(BM)通透性的药物,可支持造血干细胞向BM归巢,且不会产生重大副作用。雌性Rag2-/-小鼠预先用布舒凡(BU)、G-CSF、VLA-4I或AMD3100处理,然后用携带密码子优化人RAG2(RAG2co)的慢病毒载体转导雄性BM细胞。经 G-CSF、VLA-4I 和 AMD3100 处理后,外周血细胞计数明显增加,而经 BU 处理后则没有增加。尽管调理方法不同,但各组小鼠移植后 6 个月的 PB 淋巴细胞重建与完全免疫重建相当。接受非骨髓毒性药物预处理的小鼠存活率明显高于接受 BU 治疗的小鼠。在此,我们证明了非骨髓毒性药物 G-CSF、VLA-4I 和 AMD3100 作为造血干细胞基因治疗前的调理方案非常有效,可作为 BU 的替代方案。
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引用次数: 0
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Human Cell
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