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The PIN1-YTHDF1 axis promotes breast tumorigenesis via the m6A-dependent stabilization of AURKA mRNA PIN1-YTHDF1 轴通过 m6A 依赖性稳定 AURKA mRNA 促进乳腺肿瘤发生。
IF 6.9 3区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2023-12-26 DOI: 10.1007/s12272-023-01480-z
Pratikshya Shrestha, Garam Kim, Hyelim Kang, Poshan Yugal Bhattarai, Hong Seok Choi

The post-transcriptional processing of N6-methyladenosine (m6A)-modified mRNA by YTH domain-containing family protein 1 (YTHDF1) plays a crucial role in the regulation of gene expression. Although YTHDF1 expression is frequently upregulated in breast cancer, the regulatory mechanisms for this remain unclear. In this study, we examined the role of peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) in regulating YTHDF1 stability in breast cancer cells. The WW domain of PIN1 interacted with YTHDF1 in a phosphorylation-dependent manner. Additionally, PIN1 overexpression increased YTHDF1 stability by preventing ubiquitin-dependent proteasomal degradation. Furthermore, using the MS2-tagged RNA pull-down assay, we identified Aurora kinase A (AURKA) mRNA as a bona fide substrate of YTHDF1. PIN1-mediated YTHDF1 stabilization increased the stability of AURKA mRNA in an m6A-dependent manner. Furthermore, YTHDF1 knockout reduced AURKA protein expression levels, resulting in anticancer effects in breast cancer cells, including decreased cell proliferation, cell cycle arrest at the G0/G1 phase, apoptotic cell death, and decreased spheroid formation. The anticancer effects induced by YTHDF1 knockout were reversed by AURKA overexpression. Similarly, the knockout of PIN1 produced comparable anticancer effects to those observed in YTHDF1-knockout cells, and these effects were reversed upon overexpression of YTHDF1. In conclusion, the findings of our study suggest that increased YTHDF1 stability induced by PIN1 promotes breast tumorigenesis via the stabilization of AURKA mRNA. Targeting the PIN1/YTHDF1 axis may represent a novel therapeutic strategy for breast cancer.

含YTH结构域的家族蛋白1(YTHDF1)对N6-甲基腺苷(m6A)修饰的mRNA进行转录后处理在基因表达调控中起着至关重要的作用。虽然 YTHDF1 的表达在乳腺癌中经常上调,但其调控机制仍不清楚。在这项研究中,我们研究了肽基-脯氨酰-顺反异构酶 NIMA-interacting 1(PIN1)在乳腺癌细胞中调控 YTHDF1 稳定性的作用。PIN1的WW结构域以磷酸化依赖的方式与YTHDF1相互作用。此外,PIN1的过表达可阻止泛素依赖性蛋白酶体降解,从而增加YTHDF1的稳定性。此外,利用MS2标记的RNA牵引试验,我们发现极光激酶A(AURKA)mRNA是YTHDF1的真正底物。PIN1 介导的 YTHDF1 稳定化以 m6A 依赖性方式增加了 AURKA mRNA 的稳定性。此外,YTHDF1基因敲除降低了AURKA蛋白的表达水平,从而对乳腺癌细胞产生抗癌作用,包括细胞增殖减少、细胞周期停滞在G0/G1期、细胞凋亡和球形体形成减少。AURKA 的过表达逆转了 YTHDF1 基因敲除诱导的抗癌效应。同样,PIN1基因敲除产生的抗癌效应与YTHDF1基因敲除细胞中观察到的抗癌效应相当,而过表达YTHDF1可逆转这些效应。总之,我们的研究结果表明,PIN1诱导的YTHDF1稳定性增加会通过稳定AURKA mRNA促进乳腺癌的发生。靶向 PIN1/YTHDF1 轴可能是治疗乳腺癌的一种新策略。
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引用次数: 0
Arsenic trioxide: applications, mechanisms of action, toxicity and rescue strategies to date 三氧化二砷:迄今为止的应用、作用机制、毒性和救治策略。
IF 6.9 3区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2023-12-26 DOI: 10.1007/s12272-023-01481-y
Meng Yan, Hao Wang, Rui Wei, Wenwen Li

Arsenical medicine has obtained its status in traditional Chinese medicine for more than 2,000 years. In the 1970s, arsenic trioxide was identified to have high efficacy and potency for the treatment of acute promyelocytic leukemia, which promoted many studies on the therapeutic effects of arsenic trioxide. Currently, arsenic trioxide is widely used to treat acute promyelocytic leukemia and various solid tumors through various mechanisms of action in clinical practice; however, it is accompanied by a series of adverse reactions, especially cardiac toxicity. This review presents a comprehensive overview of arsenic trioxide from preclinical and clinical efficacy, potential mechanisms of action, toxicities, and rescue strategies for toxicities to provide guidance or assistance for the clinical application of arsenic trioxide.

砒霜在中国传统医学中的地位已有两千多年的历史。20 世纪 70 年代,三氧化二砷被发现对治疗急性早幼粒细胞白血病有很高的疗效和效力,从而促进了许多关于三氧化二砷治疗作用的研究。目前,三氧化二砷在临床上通过各种作用机制被广泛用于治疗急性早幼粒细胞白血病和各种实体瘤,但同时也伴随着一系列不良反应,尤其是心脏毒性。本综述从临床前和临床疗效、潜在作用机制、毒性以及毒性救治策略等方面对三氧化二砷进行了全面概述,以期为三氧化二砷的临床应用提供指导或帮助。
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引用次数: 0
Physiologically based pharmacokinetic (PBPK) modeling to predict the pharmacokinetics of irbesartan in different CYP2C9 genotypes 基于生理学的药代动力学(PBPK)模型预测不同 CYP2C9 基因型的厄贝沙坦药代动力学
IF 6.9 3区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2023-12-08 DOI: 10.1007/s12272-023-01472-z
Chang-Keun Cho, Pureum Kang, Choon-Gon Jang, Seok-Yong Lee, Yun Jeong Lee, Chang-Ik Choi

Irbesartan, a potent and selective angiotensin II type-1 (AT1) receptor blocker (ARB), is one of the representative medications for the treatment of hypertension. Cytochrome P450 (CYP) 2C9 is primarily involved in the oxidation of irbesartan. CYP2C9 is highly polymorphic, and genetic polymorphism of this enzyme is the leading cause of significant alterations in the pharmacokinetics of irbesartan. This study aimed to establish the physiologically based pharmacokinetic (PBPK) model to predict the pharmacokinetics of irbesartan in different CYP2C9 genotypes. The irbesartan PBPK model was established using the PK-Sim® software. Our previously reported pharmacogenomic data for irbesartan was leveraged in the development of the PBPK model and collected clinical pharmacokinetic data for irbesartan was used for the validation of the model. Physicochemical and ADME properties of irbesartan were obtained from previously reported data, predicted by the modeling software, or optimized to fit the observed plasma concentration–time profiles. Model evaluation was performed by comparing the predicted plasma concentration–time profiles and pharmacokinetic parameters to the observed results. Predicted plasma concentration–time profiles were visually similar to observed profiles. Predicted AUCinf in CYP2C9*1/*3 and CYP2C9*1/*13 genotypes were increased by 1.54- and 1.62-fold compared to CYP2C9*1/*1 genotype, respectively. All fold error values for AUC and Cmax in non-genotyped and CYP2C9 genotyped models were within the two-fold error criterion. We properly established the PBPK model of irbesartan in different CYP2C9 genotypes. It can be used to predict the pharmacokinetics of irbesartan for personalized pharmacotherapy in individuals of various races, ages, and CYP2C9 genotypes.

厄贝沙坦是一种强效、选择性血管紧张素 II 1 型(AT1)受体阻断剂(ARB),是治疗高血压的代表性药物之一。细胞色素 P450(CYP)2C9 主要参与厄贝沙坦的氧化。CYP2C9 具有高度多态性,该酶的遗传多态性是导致厄贝沙坦药代动力学显著改变的主要原因。本研究旨在建立基于生理学的药代动力学(PBPK)模型,以预测不同 CYP2C9 基因型的厄贝沙坦药代动力学。厄贝沙坦 PBPK 模型是利用 PK-Sim® 软件建立的。在建立 PBPK 模型的过程中,利用了我们先前报告的厄贝沙坦药物基因组学数据,并利用收集的厄贝沙坦临床药代动力学数据对模型进行了验证。厄贝沙坦的理化和 ADME 特性来自于先前报告的数据、建模软件的预测或优化,以适应观察到的血浆浓度-时间曲线。通过比较预测的血浆浓度-时间曲线和药代动力学参数与观察结果,对模型进行评估。预测的血浆浓度-时间曲线与观察到的曲线直观相似。与 CYP2C9*1/*1 基因型相比,CYP2C9*1/*3 和 CYP2C9*1/*13 基因型的预测 AUCinf 分别增加了 1.54 倍和 1.62 倍。在非基因分型和 CYP2C9 基因分型模型中,AUC 和 Cmax 的所有折合误差值均在两倍误差标准之内。我们正确地建立了不同 CYP2C9 基因型厄贝沙坦的 PBPK 模型。该模型可用于预测不同种族、年龄和 CYP2C9 基因型个体的厄贝沙坦药代动力学,以实现个性化药物治疗。
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引用次数: 0
Phytochemistry and pharmacology of plants in the genus Chaenomeles Chaenomeles属植物的植物化学和药理学
IF 6.9 3区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2023-12-07 DOI: 10.1007/s12272-023-01475-w
Ruoling Xu, Mengting Kuang, Ning Li

Chaenomeles plants belong to the Rosaceae family and include five species, Chaenomeles speciosa (Sweet) Nakai, Chaenomeles sinensis (Thouin) Koehne, Chaenomeles japonica (Thunb.) Lindl, Chaenomeles cathayensis (Hemsl.) Schneid and Chaenomeles thibetica Yu. Chaenomeles plants are found and cultivated in nearly every country worldwide. China serves as both the origin and distribution hub for the plants in the Chaenomeles genus, and all Chaenomeles species except for C. japonica are indigenous to China. Chaenomeles spp. is a type of edible medicinal plant that has been traditionally used in China to treat various ailments, such as rheumatism, cholera, dysentery, enteritis, beriberi, and scurvy. A variety of chemical constituents have been extracted from this genus, including terpenoids, phenolics, flavonoids, phenylpropanoids and their derivatives, benzoic acid derivatives, biphenyls, oxylipins, and alkaloids. The biological activity of some of these constituents has already been evaluated. Pharmacological investigations have demonstrated that the plants in the genus Chaenomeles exhibit anti-inflammatory, analgesic, antioxidant, antihyperglycemic, antihyperlipidemic, gastrointestinal protective, antitumor, immunomodulatory, antibacterial, antiviral, hepatoprotective, neuroprotective and other pharmacological activities. The objective of this review is to provide a comprehensive and up-to-date summary of the available information on the genus Chaenomeles to serve as a valuable reference for further investigations.

Chaenomeles 植物属于蔷薇科,包括五个品种:Chaenomeles speciosa (Sweet) Nakai、Chaenomeles sinensis (Thouin) Koehne、Chaenomeles japonica (Thunb.) Lindl、Chaenomeles cathayensis (Hemsl.) Schneid 和 Chaenomeles thibetica Yu。Chaenomeles植物在全世界几乎每个国家都有发现和栽培。中国既是Chaenomeles属植物的原产地,也是其分布中心,除C. japonica外,所有Chaenomeles种均为中国原产。柴胡是一种可食用的药用植物,在中国传统上用于治疗各种疾病,如风湿、霍乱、痢疾、肠炎、脚气病和坏血病。从该属植物中提取了多种化学成分,包括萜类化合物、酚类化合物、黄酮类化合物、苯丙类化合物及其衍生物、苯甲酸衍生物、联苯类化合物、氧脂类化合物和生物碱。其中一些成分的生物活性已经过评估。药理研究表明,柴诺木属植物具有抗炎、镇痛、抗氧化、降血糖、降血脂、胃肠道保护、抗肿瘤、免疫调节、抗菌、抗病毒、保肝、神经保护等药理活性。本综述旨在全面总结有关柴诺木属的最新信息,为进一步研究提供有价值的参考。
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引用次数: 0
Targeting dysregulated lipid metabolism in the tumor microenvironment 靶向肿瘤微环境中脂质代谢失调。
IF 6.9 3区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2023-12-07 DOI: 10.1007/s12272-023-01473-y
Do-Hee Kim, Na-Young Song, Hyungshin Yim

The reprogramming of lipid metabolism and its association with oncogenic signaling pathways within the tumor microenvironment (TME) have emerged as significant hallmarks of cancer. Lipid metabolism is defined as a complex set of molecular processes including lipid uptake, synthesis, transport, and degradation. The dysregulation of lipid metabolism is affected by enzymes and signaling molecules directly or indirectly involved in the lipid metabolic process. Regulation of lipid metabolizing enzymes has been shown to modulate cancer development and to avoid resistance to anticancer drugs in tumors and the TME. Because of this, understanding the metabolic reprogramming associated with oncogenic progression is important to develop strategies for cancer treatment. Recent advances provide insight into fundamental mechanisms and the connections between altered lipid metabolism and tumorigenesis. In this review, we explore alterations to lipid metabolism and the pivotal factors driving lipid metabolic reprogramming, which exacerbate cancer progression. We also shed light on the latest insights and current therapeutic approaches based on small molecular inhibitors and phytochemicals targeting lipid metabolism for cancer treatment. Further investigations are worthwhile to fully understand the underlying mechanisms and the correlation between altered lipid metabolism and carcinogenesis.

脂质代谢的重编程及其与肿瘤微环境(TME)中致癌信号通路的关联已成为癌症的重要标志。脂质代谢被定义为一系列复杂的分子过程,包括脂质摄取、合成、转运和降解。脂质代谢的失调受直接或间接参与脂质代谢过程的酶和信号分子的影响。脂质代谢酶的调节已被证明可以调节肿瘤的发展并避免肿瘤和TME对抗癌药物的耐药性。正因为如此,了解与致癌进展相关的代谢重编程对于制定癌症治疗策略非常重要。最近的进展提供了洞察基本机制和改变脂质代谢和肿瘤发生之间的联系。在这篇综述中,我们探讨了脂质代谢的改变和驱动脂质代谢重编程的关键因素,这些因素加剧了癌症的进展。我们还阐明了基于靶向脂质代谢的小分子抑制剂和植物化学物质的最新见解和当前治疗方法。为了充分了解脂质代谢改变与癌变之间的潜在机制和相关性,进一步的研究是值得的。
{"title":"Targeting dysregulated lipid metabolism in the tumor microenvironment","authors":"Do-Hee Kim,&nbsp;Na-Young Song,&nbsp;Hyungshin Yim","doi":"10.1007/s12272-023-01473-y","DOIUrl":"10.1007/s12272-023-01473-y","url":null,"abstract":"<div><p>The reprogramming of lipid metabolism and its association with oncogenic signaling pathways within the tumor microenvironment (TME) have emerged as significant hallmarks of cancer. Lipid metabolism is defined as a complex set of molecular processes including lipid uptake, synthesis, transport, and degradation. The dysregulation of lipid metabolism is affected by enzymes and signaling molecules directly or indirectly involved in the lipid metabolic process. Regulation of lipid metabolizing enzymes has been shown to modulate cancer development and to avoid resistance to anticancer drugs in tumors and the TME. Because of this, understanding the metabolic reprogramming associated with oncogenic progression is important to develop strategies for cancer treatment. Recent advances provide insight into fundamental mechanisms and the connections between altered lipid metabolism and tumorigenesis. In this review, we explore alterations to lipid metabolism and the pivotal factors driving lipid metabolic reprogramming, which exacerbate cancer progression. We also shed light on the latest insights and current therapeutic approaches based on small molecular inhibitors and phytochemicals targeting lipid metabolism for cancer treatment. Further investigations are worthwhile to fully understand the underlying mechanisms and the correlation between altered lipid metabolism and carcinogenesis.</p></div>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":"46 11-12","pages":"855 - 881"},"PeriodicalIF":6.9,"publicationDate":"2023-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10725365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138497686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Role of monocarboxylate transporter I/lactate dehydrogenase B-mediated lactate recycling in tamoxifen-resistant breast cancer cells 单羧酸转运体I/乳酸脱氢酶b介导的乳酸循环在他莫昔芬耐药乳腺癌细胞中的作用。
IF 6.9 3区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2023-12-04 DOI: 10.1007/s12272-023-01474-x
Min Chang Choi, Sang Kyum Kim, Young Jae Choi, Yong June Choi, Suntae Kim, Kyung Hwan Jegal, Sung Chul Lim, Keon Wook Kang

Although tamoxifen (TAM) is widely used in patients with estrogen receptor-positive breast cancer, the development of tamoxifen resistance is common. The previous finding suggests that the development of tamoxifen resistance is driven by epiregulin or hypoxia-inducible factor-1α-dependent glycolysis activation. Nonetheless, the mechanisms responsible for cancer cell survival and growth in a lactic acid-rich environment remain elusive. We found that the growth and survival of tamoxifen-resistant MCF-7 cells (TAMR-MCF-7) depend on glycolysis rather than oxidative phosphorylation. The levels of the glycolytic enzymes were higher in TAMR-MCF-7 cells than in parental MCF-7 cells, whereas the mitochondrial number and complex I level were decreased. Importantly, TAMR-MCF-7 cells were more resistant to low glucose and high lactate growth conditions. Isotope tracing analysis using 13C-lactate confirmed that lactate conversion to pyruvate was enhanced in TAMR-MCF-7 cells. We identified monocarboxylate transporter1 (MCT1) and lactate dehydrogenase B (LDHB) as important mediators of lactate influx and its conversion to pyruvate, respectively. Consistently, AR-C155858 (MCT1 inhibitor) inhibited the proliferation, migration, spheroid formation, and in vivo tumor growth of TAMR-MCF-7 cells. Our findings suggest that TAMR-MCF-7 cells depend on glycolysis and glutaminolysis for energy and support that targeting MCT1- and LDHB-dependent lactate recycling may be a promising strategy to treat patients with TAM-resistant breast cancer.

虽然他莫昔芬(TAM)被广泛用于雌激素受体阳性乳腺癌患者,但他莫昔芬耐药性的发展是常见的。先前的研究结果表明,他莫昔芬耐药的发生是由表调节蛋白或缺氧诱导因子-1α-依赖性糖酵解激活驱动的。尽管如此,癌细胞在富含乳酸的环境中存活和生长的机制仍然难以捉摸。我们发现耐他莫昔芬MCF-7细胞(TAMR-MCF-7)的生长和存活依赖于糖酵解而不是氧化磷酸化。与亲代MCF-7细胞相比,TAMR-MCF-7细胞中糖酵解酶水平较高,而线粒体数量和复合体I水平降低。重要的是,TAMR-MCF-7细胞对低葡萄糖和高乳酸的生长条件更有抵抗力。13c -乳酸同位素示踪分析证实,TAMR-MCF-7细胞中乳酸转化为丙酮酸的能力增强。我们发现单羧酸转运体1 (MCT1)和乳酸脱氢酶B (LDHB)分别是乳酸内流及其转化为丙酮酸的重要介质。同样,AR-C155858 (MCT1抑制剂)抑制TAMR-MCF-7细胞的增殖、迁移、球体形成和体内肿瘤生长。我们的研究结果表明TAMR-MCF-7细胞依赖糖酵解和谷氨酰胺解来获取能量,并支持靶向MCT1和ldhb依赖性乳酸再循环可能是治疗tam耐药乳腺癌患者的一种有希望的策略。
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引用次数: 0
Selumetinib overcomes gefitinib primary and acquired resistance by regulating MIG6/STAT3 in NSCLC Selumetinib通过调节MIG6/STAT3在NSCLC中克服吉非替尼的原发性和获得性耐药。
IF 6.9 3区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2023-11-30 DOI: 10.1007/s12272-023-01471-0
Xiaoping Song, Lina Wang, Wei Tang, Luyao Yuan, Qingchao Liu, Jing Li, Daidi Fan

Gefitinib, as the first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has achieved great advances in the treatment of non-small cell lung cancer (NSCLC), but drug resistance will inevitably occur. Therefore, exploring the resistance mechanism of gefitinib and developing new combination treatment strategies are of great importance. In our study, the results showed that selumetinib (AZD6244) synergistically inhibited the proliferation of NSCLC with gefitinib. Selumetinib also enhanced gefitinib-induced apoptosis and migration inhibition ability in gefitinib-resistant lung cancer cell lines. Subsequently, the negative regulation between MIG6 and STAT3 was observed and verified through the STRING database and western blotting assays. Sustained activation of STAT3 was significantly downregulated when co-treatment with selumetinib in gefitinib-resistant cells. However, the downregulation of p-STAT3, resulting from the combination of selumetinib and gefitinib was counteracted by the deletion of MIG6, suggesting that selumetinib enhanced gefitinib sensitivity by regulating MIG6/STAT3 in NSCLC. In contrast, p-STAT3 was further inhibited after treatment with gefitinib and selumetinib when MIG6 was overexpressed. Furthermore, the combined administration of selumetinib and gefitinib effectively promoted the sensitivity of lung cancer xenografts to gefitinib in vivo, and the tumor inhibition rate reached 81.49%, while the tumor inhibition rate of the gefitinib monotherapy group was only 31.95%. Overall, MIG6/STAT3 negative regulation plays an important role in the sustained activation of STAT3 and the resistance to EGFR-TKIs. Our study also suggests that EGFR-TKIs combined with MEK1/2 inhibitors, such as selumetinib, may be beneficial to those NSCLC patients who develop a primary or acquired resistance to EGFR-TKIs, providing theoretical support for combining TKIs and selumetinib in clinical cancer treatment.

吉非替尼作为第一代表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI),在治疗非小细胞肺癌(NSCLC)方面取得了很大进展,但不可避免地会出现耐药性。因此,探索吉非替尼耐药机制,开发新的联合治疗策略具有重要意义。在我们的研究中,结果显示selumetinib (AZD6244)与吉非替尼协同抑制NSCLC的增殖。Selumetinib还增强了吉非替尼耐药肺癌细胞系中吉非替尼诱导的细胞凋亡和迁移抑制能力。随后,通过STRING数据库和western blotting实验观察并验证了MIG6和STAT3之间的负调控。在吉非替尼耐药细胞中,与selumetinib共处理时,STAT3的持续激活显著下调。然而,塞鲁美替尼和吉非替尼联合导致的p-STAT3的下调被MIG6的缺失所抵消,这表明塞鲁美替尼通过调节非小细胞肺癌中MIG6/STAT3来增强吉非替尼的敏感性。相比之下,当MIG6过表达时,吉非替尼和塞鲁美替尼治疗后p-STAT3进一步受到抑制。此外,塞鲁美替尼与吉非替尼联用有效促进了肺癌异种移植物体内对吉非替尼的敏感性,肿瘤抑制率达到81.49%,而吉非替尼单药组的肿瘤抑制率仅为31.95%。综上所述,MIG6/STAT3负调控在STAT3的持续激活和对EGFR-TKIs的抗性中起着重要作用。我们的研究还提示,EGFR-TKIs联合MEK1/2抑制剂(如selumetinib)可能有利于那些对EGFR-TKIs产生原发性或获得性耐药的NSCLC患者,为TKIs联合selumetinib在临床癌症治疗中的应用提供理论支持。
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引用次数: 0
Human milk oligosaccharides 3′-sialyllactose and 6′-sialyllactose attenuate LPS-induced lung injury by inhibiting STAT1 and NF-κB signaling pathways 母乳低聚糖3'-唾液乳糖和6'-唾液乳糖通过抑制STAT1和NF-κB信号通路来减轻LPS诱导的肺损伤。
IF 6.9 3区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2023-11-09 DOI: 10.1007/s12272-023-01470-1
Yujin Jin, Hyesu Jeon, Thuy Le Lam Nguyen, Lila Kim, Kyung-Sun Heo

Acute lung injury (ALI) is the leading cause of respiratory diseases induced by uncontrolled inflammation and cell death. Lipopolysaccharide (LPS) is a major trigger of ALI in the progression through macrophage differentiation and the accelerated release of pro-inflammatory cytokines. The present study aimed to investigate the protective effects of human milk oligosaccharides, specifically 3′-sialyllactose (3′-SL) and 6′-sialyllactose (6′-SL), on LPS-induced ALI and elucidate their underlying signaling pathways. The inhibitory effects of 3′-SL and 6′-SL on inflammation were evaluated using LPS-treated RAW 264.7 macrophages. To establish the ALI model, mice were treated with 10 mg/kg LPS for 24 h. Histological changes in the lung tissues were assessed using hematoxylin and eosin staining and immunofluorescence. LPS causes thickening of the alveolar wall infiltration of immune cells in lung tissues and increased serum levels of TNF-α, IL-1β, and GM-CSF. However, these effects were significantly alleviated by 100 mg/kg of 3′-SL and 6′-SL. Consistent with the inhibitory effects of 3′-SL and 6′-SL on LPS-induced pro-inflammatory cytokine secretion in serum, 3′-SL and 6′-SL suppressed mRNA expression of TNF-α, IL-1β, MCP-1, iNOS, and COX2 in LPS-induced RAW 264.7 cells. Mechanistically, 3′-SL and 6′-SL abolished LPS-mediated phosphorylation of NF-κB and STAT1. Interestingly, fludarabine treatment, a STAT1 inhibitor, did not affect LPS-mediated NF-κB phosphorylation. In summary, 3′-SL and 6′-SL protect LPS-induced macrophage activation and ALI through the STAT1 and NF-κB signaling pathways.

急性肺损伤(ALI)是由失控的炎症和细胞死亡引起的呼吸道疾病的主要原因。脂多糖(LPS)是ALI通过巨噬细胞分化和促炎细胞因子加速释放进展的主要触发因素。本研究旨在研究母乳低聚糖,特别是3'-唾液乳糖(3'-SL)和6'-唾液乳糖(6'-SL)对LPS诱导的ALI的保护作用,并阐明其潜在的信号通路。使用LPS处理的RAW 264.7巨噬细胞评估3'-SL和6'-SL对炎症的抑制作用。为了建立ALI模型,用10mg/kg LPS处理小鼠24小时。使用苏木精和伊红染色以及免疫荧光评估肺组织的组织学变化。LPS导致肺组织中免疫细胞的肺泡壁浸润增厚,并增加血清TNF-α、IL-1β和GM-CSF水平。然而,100 mg/kg的3'-SL和6'-SL显著减轻了这些影响。与3'-SL和6'-SL对LPS诱导的血清促炎细胞因子分泌的抑制作用一致,3'-SL、6'-SL抑制LPS诱导的RAW 264.7细胞中TNF-α、IL-1β、MCP-1、iNOS和COX2的mRNA表达。从机制上讲,3'-SL和6'-SL消除了LPS介导的NF-κB和STAT1的磷酸化。有趣的是,作为STAT1抑制剂的氟达拉滨治疗并不影响LPS介导的NF-κB磷酸化。总之,3'-SL和6'-SL通过STAT1和NF-κB信号通路保护LPS诱导的巨噬细胞活化和ALI。
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引用次数: 0
Death-associated protein kinase 1 phosphorylates MDM2 and inhibits its protein stability and function 死亡相关蛋白激酶1磷酸化MDM2并抑制其蛋白质稳定性和功能。
IF 6.9 3区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2023-10-07 DOI: 10.1007/s12272-023-01469-8
Mi Zhang, Xindong Shui, Xiaoqing Zheng, Jong Eun Lee, Yingxue Mei, Ruomeng Li, Yuan Tian, Xiuzhi Zheng, Quling Wang, Long Wang, Dongmei Chen, Tao Zhang, Byeong Mo Kim, Jungho Kim, Tae Ho Lee

Breast cancer is one of the major malignancies in women, and most related deaths are due to recurrence, drug resistance, and metastasis. The expression of the mouse double minute 2 (MDM2) oncogene is upregulated in breast cancer; however, its regulatory mechanism has yet to be fully elucidated. Herein, we identified the tumor suppressor death-associated protein kinase 1 (DAPK1) as a novel MDM2 regulator by unbiased peptide library screening. DAPK1 is directly bound to MDM2 and phosphorylates it at Thr419. DAPK1-mediated MDM2 phosphorylation promoted its protein degradation via the ubiquitin–proteasome pathway, resulting in upregulated p53 expression. DAPK1 overexpression, but not its kinase activity-deficient form, decreased colony formation and increased doxorubicin-induced cell death; however, DAPK1 knockdown produced the opposite effects in human breast cancer cells. In a xenograft tumorigenesis assay, DAPK1 overexpression significantly reduced tumor formation, whereas inhibition of DAPK1 kinase activity reduced its antitumorigenic effect. Finally, DAPK1 expression was negatively correlated with MDM2 levels in human breast cancer tissues. Thus, these results suggest that DAPK1-mediated MDM2 phosphorylation and its protein degradation may contribute to its antitumorigenic function in breast cancer.

癌症是女性的主要恶性肿瘤之一,大多数相关死亡是由于复发、耐药性和转移。小鼠双分钟2(MDM2)癌基因在癌症中的表达上调;然而,其调控机制尚未完全阐明。在此,我们通过无偏肽库筛选确定肿瘤抑制死亡相关蛋白激酶1(DAPK1)是一种新的MDM2调节因子。DAPK1直接与MDM2结合,并在Thr419处将其磷酸化。DAPK1介导的MDM2磷酸化通过泛素-蛋白酶体途径促进其蛋白质降解,导致p53表达上调。DAPK1过表达,但不是其激酶活性缺陷形式,减少了集落形成并增加了阿霉素诱导的细胞死亡;然而,DAPK1敲除在人类乳腺癌症细胞中产生相反的作用。在异种移植物肿瘤发生测定中,DAPK1过表达显著减少了肿瘤形成,而DAPK1激酶活性的抑制降低了其抗肿瘤作用。最后,DAPK1在人类癌症组织中的表达与MDM2水平呈负相关。因此,这些结果表明DAPK1介导的MDM2磷酸化及其蛋白质降解可能有助于其在癌症中的抗肿瘤功能。
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引用次数: 0
2-Geranyl-1-methoxyerythrabyssin II alleviates lipid accumulation and inflammation in hepatocytes through AMPK activation and AKT inhibition 2-杰拉尔基-1-甲氧基赤藓霉素II通过AMPK激活和AKT抑制减轻肝细胞中的脂质积聚和炎症。
IF 6.7 3区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2023-10-02 DOI: 10.1007/s12272-023-01464-z
Yiyuan Xi, Soeun Kim, Thi Thanh Thuy Nguyen, Phil Jun Lee, Jujia Zheng, Zhuofeng Lin, Namki Cho

A growing proportion of the global adult and pediatric populations are currently affected by nonalcoholic steatohepatitis (NASH), leading to rising rates of liver fibrosis and hepatocellular carcinoma without effective pharmacotherapy. Here, we investigated whether 2-geranyl-1-methoxyerythrabyssin II (GMET), isolated from Lespedeza bicolor, could alleviate lipid accumulation and inflammatory responses in a NASH model. GMET exhibited potent in vitro and in vivo effects against lipid accumulation and attenuated inflammatory responses without cytotoxicity. Mechanistically, GMET inhibits acetyl-CoA carboxylase (ACC), sterol regulatory element-binding proteins-1c (SREBP1), and mammalian target of rapamycin (mTOR), and activates PPARα by activating AMP-activated kinase (AMPK), leading to the alleviation of lipid accumulation. In addition, GMET suppresses the NF-κB pathway by activating AMPK and inhibiting the activated protein kinase B (AKT)/IκB-kinase (IKK) pathway, leading to the inhibition of the inflammatory response in hepatocytes. All these protective effects of GMET on lipid accumulation and inflammation in vivo and in vitro were largely abolished by co-treatment with dorsomorphin, an AMPK inhibitor. In conclusion, GMET alleviated lipid accumulation and inflammation to preserve normal hepatocyte function in steatohepatitis. Thus, GMET is a novel potential multi-targeting compound to improve steatohepatitis.

目前,全球越来越多的成人和儿童人群受到非酒精性脂肪性肝炎(NASH)的影响,导致在没有有效药物治疗的情况下肝纤维化和肝细胞癌的发病率上升。在这里,我们研究了从双色胡枝子中分离的2-香叶基-1-甲氧基赤藓霉素II(GMET)是否可以缓解NASH模型中的脂质积聚和炎症反应。GMET在体外和体内表现出强大的抗脂质积聚作用,并在没有细胞毒性的情况下减弱炎症反应。从机制上讲,GMET抑制乙酰辅酶A羧化酶(ACC)、甾醇调节元件结合蛋白-1c(SREBP1)和哺乳动物雷帕霉素靶点(mTOR),并通过激活AMP活化激酶(AMPK)激活PPARα,从而减缓脂质积聚。此外,GMET通过激活AMPK和抑制活化蛋白激酶B(AKT)/IκB激酶(IKK)途径来抑制NF-κB途径,从而抑制肝细胞的炎症反应。通过与AMPK抑制剂dorsomorphin共同治疗,GMET对体内外脂质积聚和炎症的所有这些保护作用基本上被消除。总之,在脂肪性肝炎中,GMET减轻了脂质积聚和炎症,以保持正常的肝细胞功能。因此,GMET是一种新的潜在的多靶向化合物,可以改善脂肪性肝炎。
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Archives of Pharmacal Research
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