ABC transporters are important for excretion of xenobiotics and metabolites into urine. They are sensitive to metallic pollutants like cadmium, mercury, zinc, or arsenic. Here, we show that copper (Cu(ATSM)) stimulates ABC transporter-mediated export in isolated renal proximal tubules from Atlantic killifish (Fundulus heteroclitus) with main focus on Mrp2. Transporter stimulation was reduced by cycloheximide (CHX), an inhibitor of translation, suggesting that it is partially caused by induced expression. Functional activation was reversed by modulators of the endothelin receptor (ET_B)/nitric oxide synthase/protein kinase C signaling pathway. Transporter activating effects were reversed by Gö6976 and peptide C2-4, both being PKCα inhibitors. Cu(ATSM)-induced activation was further suppressed by phosphatidylinositol 3-kinase inhibitor LY-294002 and mTOR inhibitor rapamycin. Activation was also inhibited by GSK650394, an inhibitor of serum-and-glucocorticoid-inducible-kinase-1 being a subsequent target. Given the parallelism with other metals, this ABC transporter regulation appears to be a general defense mechanism of teleosts to react on metallic pollutants.

2025-02-01·Arteriosclerosis, Thrombosis, and Vascular Biology

SGK1-Mediated Vascular Smooth Muscle Cell Phenotypic Transformation Promotes Thoracic Aortic Dissection Progression

Article

作者: Zhang, Leilei ; Leng, Shuai ; Dang, Zhiqiao ; Ning, Yansong ; Xue, Shishan ; Wang, Honglu ; Teng, Xilong ; Zhang, Fengquan ; Li, Haijie ; Li, Na ; Shao, Baowei ; Zhang, Pengfei ; Yu, Wenqian

BACKGROUND:The occurrence of thoracic aortic dissection (TAD) is closely related to the transformation of vascular smooth muscle cells (VSMCs) from a contractile to a synthetic phenotype. The role of SGK1 (serum- and glucocorticoid-regulated kinase 1) in VSMC phenotypic transformation and TAD occurrence is unclear.METHODS: Four-week-old male Sgk1 F/F ( Sgk1 floxed) and Sgk1 F/F ;Tagln Cre (smooth muscle cell–specific Sgk1 knockout) mice were administered β-aminopropionitrile monofumarate for 4 weeks to model TAD. The SGK1 inhibitor GSK650394 was administered daily via intraperitoneal injection to treat the mouse model of TAD. Immunopurification and mass spectrometry were used to identify proteins that interact with SGK1. Immunoprecipitation, immunofluorescence colocalization, and GST (glutathione S-transferase) pull-down were used to detect molecular interactions between SGK1 and SIRT6 (sirtuin 6). RNA-sequencing analysis was performed to evaluate changes in the SIRT6 transcriptome. Quantitative chromatin immunoprecipitation was used to determine the target genes regulated by SIRT6. Functional experiments were also conducted to investigate the role of SGK1-SIRT6-MMP9 (matrix metalloproteinase 9) in VSMC phenotypic transformation. The effect of SGK1 regulation on target genes was evaluated in human and mouse TAD samples. RESULTS: Sgk1 F/F ;Tagln Cre or pharmacological blockade of Sgk1 inhibited the formation and rupture of β-aminopropionitrile monofumarate–induced TADs in mice and reduced the degradation of the ECM (extracellular matrix) in vessels. Mechanistically, SGK1 promoted the ubiquitination and degradation of SIRT6 by phosphorylating SIRT6 at Ser338, thereby reducing the expression of the SIRT6 protein. Furthermore, SIRT6 transcriptionally inhibits the expression of MMP9 through epigenetic modification, forming the SGK1-SIRT6-MMP9 regulatory axis, which participates in the ECM signaling pathway. Additionally, our data showed that the lack of SGK1-mediated inhibition of ECM degradation and VSMC phenotypic transformation is partially dependent on the regulatory effect of SIRT6-MMP9. CONCLUSIONS:These findings highlight the key role of SGK1 in the pathogenesis of TAD. A lack of SGK1 inhibits VSMC phenotypic transformation by regulating the SIRT6-MMP9 axis, providing insights into potential epigenetic strategies for TAD treatment.

2025-01-01·Molecular Pain

SGK1-HDAC4-HMGB1 signaling pathway in the spinal cord dorsal horn participates in diabetic neuropathic pain

Article

作者: Chen, Jia-Li ; Cao, Hong ; Li, Jun ; Zhang, Mao-Biao ; Jia, Gai-Li ; Lu, Jia-Hui

Purpose: This study aimed to determine whether serum-and glucocorticoid-inducible kinase1 (SGK1) activation-dependent histone deacetylase 4 (HDAC4) phosphorylation, nucleocytoplasmic trafficking, and subsequent regulation of high-mobility group protein box 1 (HMGB1) expression are involved in type 2 diabetic neuropathic pain (DNP). Methods: The type 2 diabetic neuropathic pain model was established in rats by feeding them with a high-fat and high-sugar diet for 8 weeks and then fasting them for 12 h, followed by a single intraperitoneal injection of streptozotocin (STZ, 35 mg/kg). SGK1 was inhibited in the spinal cord by intrathecal administration of the SGK1 inhibitor GSK-650394. Results: The present study revealed that pSGK1/tSGK1 was persistently upregulated in the spinal cord of rats with type-2 DNP. The downregulation of pSGK1/tSGK1 through the intrathecal injection of the SGK1 inhibitor GSK-650394 significantly ameliorated the pain hypersensitivity, relieved the abnormal expression of pHDAC4/tHDAC4 and HMGB1, and affected HDAC4 nucleocytoplasmic trafficking in DNP rats. Conclusion: Our data suggest that SGK1 in the spinal cord modulates type-2 DNP by regulating the HDAC4/HMGB1 pathway.

项与 GSK-650394 相关的新闻（医药）

2025-02-24

·今日头条

胰腺癌预后新突破：广州医科大学揭秘肿瘤膜基因的预测力量

点击蓝字关注我们【导读】胰腺癌是导致肿瘤相关死亡的主要原因之一，其特点是患者存活时间短，治疗方案有限。一些靶向疗法未能成功改善患者的预后。肿瘤膜具有潜在的靶向特异性，为提高免疫疗法和药物治疗的疗效带来了希望。 2025年2月19日，广州医科大学第一附属医院的研究团队在期刊《Heliyon》上发表了题为“A novel signature predicts prognosis in pancreatic cancer based on tumor membrane-associated genes”的研究论文。这项研究通过scRNA-seq技术揭示了PDAC的瘤内异质性，构建了一个新的预后风险模型（MaGPS），并鉴定了6个与预后相关的膜相关基因，为PDAC的诊断和治疗提供了新的见解和潜在靶点。 https://www.cell.com/heliyon/fulltext/S2405-8440(25)01172-7 01 研究背景 Deng等人在PDAC小鼠模型中证实，糖皮质激素受体（GR）的表达与PD-L1呈正相关，抑制GR会导致肿瘤细胞上的PD-L1下调，从而促进T细胞浸润，增强抗肿瘤免疫力。表皮生长因子受体抑制剂已被批准用于肺腺癌患者的表皮生长因子受体靶向治疗。Alan团队报告称，靶向表皮生长因子受体的多克隆T细胞能有效引导PDAC肿瘤细胞，从而增加T细胞浸润和T细胞介导的抗肿瘤效应。靶向治疗与免疫治疗的结合，主要集中在黑色素瘤和非小细胞肺癌。目前，靶向治疗、化疗或免疫疗法的联合应用在癌症治疗中可能更具潜力。PDAC急需找到新的有效靶点或生物标志物。 02 MaGPS预测PDAC抗肿瘤治疗的潜在益处为了探索MaGPS相关基因的潜在靶向药物，团队们利用癌症基因组计划（CGP 2014）数据集分析了MaGPS风险组与抗肿瘤药物敏感性之间的相关性。基于TCGA-PAAD数据，团队使用pRRophetic软件包预测了138种药物对PDAC患者的IC50值。样本被分为MaGPS评分高和低两组，并比较了两组之间的差异。两组间有38种药物的IC50值存在显著差异。低风险组中有7种药物的IC50值较低，而高风险组中有31种药物的IC50值较低。低风险组IC50值明显较低的药物包括ATRA、AICAR、EHT-1864、BX-795和CCT007093。MaGPS评分较低的PDAC患者可能对这些药物更敏感。此外，高风险组中IC50值较低的药物包括Tipifarnib、GSK-650394、VX-680、Thapsigargin和Epothilone-B，这些药物可能对MaGPS特征评分较高的PDAC患者更有效。这些结果表明， MaGPS相关基因在指导抗肿瘤药物的选择以及为PDAC患者制定更有针对性、更有效的治疗策略方面具有潜力。与PDAC药物敏感性相关的MaGPS。 03 总结 1. 关键基因的发现：研究确定了6个与预后相关的膜相关基因（LMO7、APOL1、SLC2A1、C15orf48、FXYD3和CLDN18），这些基因在PDAC的诊断和治疗中具有潜在价值。 2. 临床潜力： MaGPS模型在预测PDAC患者生存率方面表现出色，并且这些基因的高表达可能为PDAC的诊断和治疗提供新的靶点。例如，Tipifarnib可能对MaGPS评分高的患者有治疗益处。 3. 未来方向：研究结果为PDAC患者的预后评估和治疗提供了新的生物标志物和潜在治疗靶点，未来的研究应进一步验证这些特征并探索其在联合疗法中的应用。参考资料： 1.Huang, J. ∙ Lok, V. ∙ Ngai, C.H. ... Worldwide Burden of, Risk Factors for, and Trends in Pancreatic Cancer Gastroenterology. 2021; 160:744-754 2.Siegel, R.L. ∙ Miller, K.D. ∙ Fuchs, H.E. ... Cancer Statistics CA Cancer J Clin. 2021; 71:7-33 2021 【关于投稿】转化医学网（360zhyx.com）是转化医学核心门户，旨在推动基础研究、临床诊疗和产业的发展，核心内容涵盖组学、检验、免疫、肿瘤、心血管、糖尿病等。如您有最新的研究内容发表，欢迎联系我们进行免费报道（公众号菜单栏-在线客服联系），我们的理念：内容创造价值，转化铸就未来！转化医学网（360zhyx.com）发布的文章旨在介绍前沿医学研究进展，不能作为治疗方案使用；如需获得健康指导，请至正规医院就诊。热门推荐活动点击免费报名 🕓 全国｜2024年12月-2025年03月 ▶ 中国转化医学产业大会 🕓 上海｜2025年02月28日-03月01日 ▶ 第四届长三角单细胞组学技术应用论坛暨空间组学前沿论坛点击对应文字查看详情

免疫疗法

100 项与 GSK-650394 相关的药物交易

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