Gastric cancer is malignant cancer with high morbidity and mortality worldwide. Milk fat globule EGF and factor V/VIII domain containing (MFGE8) was involved in many cancers. Nevertheless, the role of MFGE8 in gastric cancer remained indistinct. To probe the role of MFGE8 in gastric cancer and further explore the regulating mechanism.

METHODS:

GEPIA was employed for analysis of MFGE8 expression and survival of gastric cancer patients. MFGE8 expression in gastric cancer was determined by immunohistochemistry, PCR, and western blot. The effect of MFGE8 on gastric cancer cells were evaluated by a series of cell function experiments. The mechanism of MFGE8 on gastric cancer was analyzed by GSEA and verified by in vitro and in vivo experiments.

RESULTS:

MFGE8 was over-expressed in gastric cancer. Silence of MFGE8 suppressed cell viability, proliferated ability, migrated and invasive ability, and EMT, but accelerated cell apoptosis. The opposite results were obtained in MFGE8-overexpressed gastric cancer cells. Zinc finger and BTB domain containing 7 A (ZBTB7A) was a transcription factor of MFGE8. ZBTB7A overexpression eliminated the effect of MFGE8 on gastric cancer cells. MFGE8 activated the IL-6/JAK/STAT3 signaling. Inhibition of IL-6/JAK/STAT3 signaling by Stattic (pathway inhibitor) could eliminate the promoting effect of MFGE8 on IL-6/JAK/STAT3 signaling. In addition, MFGE8 shRNA inhibited tumor growth.

CONCLUSION:

MFGE8 promoted cell proliferation, EMT progress, and tumor growth of gastric cancer by activating the IL-6/JAK/STAT3 signaling.

2025-01-01·CHEMICO-BIOLOGICAL INTERACTIONS

Sevoflurane postconditioning mitigates neuronal hypoxic-ischemic injury via regulating reactive astrocytic STAT3 protein modification

Article

作者: Li, Xingyue ; Song, Yanhong ; Zhao, Ping ; Fan, Shiyue ; Xue, Hang ; Wu, Ziyi ; Qiu, Yue ; Yang, Xu ; Zhang, Yinong ; Jia, Yufei ; Ding, Zixuan

Astrocyte activation plays a pivotal role in accelerating the cascade of neuroinflammation associated with the development of hypoxic-ischemic brain injury. This study aimed to investigate the mechanism by which sevoflurane postconditioning mitigates neuronal damage through astrocytes by regulating reactive astrocytic Signal Transducer and Activator of Transcription 3 (STAT3) modifications. A modified Rice‒Vannucci model in rats and a conditioned culture system established by subjecting primary astrocytes to oxygen glucose deprivation, followed by using the conditioned medium to culture the neuron cell line SH-SY5Y were used to simulate HI insult in vivo and in vitro, respectively. These models were followed by 30 min of 2.5 % sevoflurane treatment. Stattic was used to inhibit STAT3 phosphorylation, and (Z)-PUGNAc or OSMI-1 was added to regulate O-linked-β-N-acetylglucosamine modification (O-GlcNAcylation) in primary astrocytes in vitro. Neurobehavioral tests, Nissl staining, CCK8 assay, and flow cytometry for apoptosis were used to assess neuronal function. Immunofluorescence staining was used to detect astrocyte reactivity and the intracellular distribution of STAT3. Immunoprecipitation combined with Western blotting was used to evaluate the O-GlcNAcylation of STAT3. Protein expression and phosphorylation levels were detected by Western blotting. ELISA was conducted to detect the detrimental cytokines IL-6 and IL-1β in astrocyte-conditioned medium. Sevoflurane postconditioning enhanced the O-GlcNAcylation of astrocytic STAT3 following HI insult via the manner of OGT. Crosstalk between O-GlcNAcylation and phosphorylation of STAT3 showed that O-GlcNAcylation inhibited STAT3 phosphorylation. The inhibitory effect on astrocytes suppressed STAT3 nuclear translocation, reduced astrocyte reactivity, decreased the release of the inflammatory cytokines IL6 and IL-1β, attenuated neuronal apoptosis following HI insult, and improved neuron viability. Sevoflurane postconditioning increased astrocytic STAT3 O-GlcNAcylation level to competitively inhibit STAT3 phosphorylation. This deactivated downstream inflammation pathways and reduced astrocyte reactivity, thereby mitigating HI insult in neurons both in vivo and in vitro.

2025-01-01·INTERNATIONAL IMMUNOPHARMACOLOGY

IL-1β-induced pericyte dysfunction with a secretory phenotype exacerbates retinal microenvironment inflammation via Hes1/STAT3 signaling pathway

Article

作者: Liu, Suhuan ; Wu, Menghua ; Li, Xuejun ; Yang, Chen ; Zhang, Xiaofang ; Chen, Wenting ; Ge, Xilin ; Huang, Caoxin ; Yang, Shuyu

Retinal pericytes are mural cells surrounding capillaries to maintain the integrity of blood-retina barrier and regulate vascular behaviors. Pericyte loss has been considered as the hallmark of diabetic retinopathy (DR), which is a major complication of diabetes and the leading cause of blindness in adults. However, the precise function of pericytes in regulating the retinal microenvironment and the underlying mechanism remains largely unknown. In this study, we observed a secretory phenotype of pericytes with elevated inflammatory cytokines in response to Interleukin-1β (IL-1β), a canonical inflammatory cytokine which significantly increases during the initial stages of diabetic retinopathy. This phenotype is also accompanied by reduced expression of adherent junction proteins and contractile proteins. Paracrine cytokines derived from pericytes further induce the chemotaxis of microglia cells and trigger detrimental changes in endothelial cells, including reduced expression of tight junction protein Occludin and increased apoptosis. Mechanically, the secretion potential in pericytes is partially mediated by Hes1/STAT3 signaling pathway. Moreover, co-injection of stattic, an inhibitor targeting STAT3 activation, could effectively attenuate IL-1β-induced retinal inflammation and microglial activation in retina tissues. Collectively, these findings demonstrate the potential of retinal pericytes as an initial inflammatory sensor prior to their anatomical pathological loss, via undergoing phenotypic changes and secreting paracrine factors to amplify local inflammation and damage endothelial cells in vitro. Furthermore, inhibition of STAT3 activation by inhibitors significantly ameliorates IL-1β-induced retinal inflammation, suggesting STAT3 in retinal pericytes as a promising target for alleviating DR and other IL-1β-induced ocular diseases.

项与 Stattic 相关的新闻（医药）

2023-11-24

·生物制品圈

联合疗法！哈医大金焰教授团队发文：胶质母细胞瘤最新进展机制

导读：胶质母细胞瘤（GBM）的侵袭性和耐药性是临床治疗中的主要挑战。近日，哈尔滨医科大学金焰、吴楠共同通讯在期刊《Cell Death & Disease》上在线发表题为“RPL22L1, a novel candidate oncogene promotes temozolomide resistance by activating STAT3 in glioblastoma”的研究论文，研究人员证实了RPL22L1通过激活EGFR/STAT3途径促进了GBM的间质性表型、侵袭性和进展。它可以作为GBM的STAT3抑制联合治疗的一个有前途的指标，高表达RPL22L1的患者可以从联合治疗中获益。https://www-nature-com.libproxy1.nus.edu.sg/articles/s41419-023-06156-6研究背景 01 胶质母细胞瘤（GBM）是成人中最常见的侵袭性原发性脑癌，中位生存期仅为14.6个月。目前，GBM主要采用手术切除、放射治疗和替莫唑胺（TMZ）化疗作为一线治疗。由于快速发展、肿瘤异质性强、治疗抵抗和复发，GBM患者的预后非常惨淡。目前，GBM仍需要更多有效的靶点和生物标志物来进行精准治疗。因此，迫切需要揭示GBM发病和发展的分子机制，并确定有效的生物标志物，为治疗提供理论依据。表皮生长因子受体（EGFR）是GBM的主要治疗靶点之一。大约60%的GBM中发现了EGFR的变化，这会引发肿瘤的发生、发展和对TMZ的抵抗。然而，由于GBM的异质性，靶向EGFR的治疗是无效的，部分原因是由于上皮间质转化（EMT）的增加。除了EGFR之外，还有许多其他分子调节因子对GBM的恶性程度和治疗抵抗有贡献，需要进一步探索。例如，信号转导与转录激活因子3（STAT3）是GBM的重要致病因素，并且可以被Stattic特异性抑制。STAT3的激活与GBM的恶性程度和不良预后密切相关。但是，STAT3在GBM治疗中的应用仍需要进一步探索。研究发现 02 研究人员进行了细胞功能实验、原位和皮下异种移植肿瘤模型，以评估RPL22L1对GBM的影响和分子机制。结果显示，RPL22L1在GBM中表达显著上调，并与较差的预后相关。RPL22L1过表达增强了GBM细胞的增殖、迁移、侵袭、TMZ耐药性和肿瘤形成能力，而RPL22L1敲降可以减少这些影响。研究人员发现RPL22L1促进了GBM的间充质表型，并且这些效应的影响与EGFR / STAT3途径密切相关。研究人员观察到STAT3特异性抑制剂（Stattic）显著抑制了RPL22L1的恶性功能，特别是在TMZ耐药性方面。RPL22L1过表达增加了体内外Stattic和TMZ联合用药的敏感性。此外，Stattic有效地恢复了RPL22L1诱导的体内外TMZ耐药性的敏感性。研究确定了一种新的候选癌基因RPL22L1，通过STAT3途径促进了GBM的恶性程度。Stattic结合TMZ疗法可能是RPL22L1高表达的GBM患者的有效治疗策略。RPL22L1激活EGFR/STAT3途径以促进GBM的恶性程度 03 激活EGFR/STAT3途径在GBM的进展中发挥重要作用。通过检测过表达RPL22L1的GBM细胞的Western Blot，发现p-EGFR和p-STAT3明显升高。相反，在敲降RPL22L1的GBM细胞中，它们显著减弱。为了检测EGFR、STAT3蛋白磷酸化水平与RPL22L1在GBM中的关系，进行了TMA的免疫组织化学分析。研究人员观察到p-EGFR和RPL22L1（R=0.2914，P=0.0343）、p-STAT3和RPL22L1（R=0.5501，P=1e-04）之间呈正相关。此外，这些相关性也在移植瘤中得到检测。为了进一步确认RPL22L1是否直接调节EGFR/STAT3途径参与GBM的进展，使用EGFR抑制剂Gefitinib和STAT3抑制剂Stattic处理细胞模型。采用Western Blot验证抑制效果。在功能实验中，Stattic能够显著降低过表达RPL22L1的细胞的存活率，但Gefitinib不能。无论是Gefitinib还是Stattic都能显著降低过表达RPL22L1的细胞的迁移能力和侵袭能力。由RPL22L1引起的EMT相关因子N-钙粘蛋白、Vimentin、α-SMA、Snail2和Twist1的增加以及E-钙粘蛋白和β-连环蛋白的减少被这两种抑制剂所抑制。免疫荧光染色也证实了这两种抑制剂抑制了RPL22L1诱导的N-钙粘蛋白和Vimentin的增加。这些结果表明，RPL22L1通过激活EGFR/STAT3途径增强间质型表型并促进GBM的进展。研究结果 04 综上所述，研究人员证实了RPL22L1通过激活EGFR/STAT3途径促进了GBM的间质性表型、侵袭性和进展。它可以作为GBM的STAT3抑制联合治疗的一个有前途的指标，高表达RPL22L1的患者可以从联合治疗中获益。参考资料：https://www-nature-com.libproxy1.nus.edu.sg/articles/s41419-023-06156-6识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

放射疗法临床结果临床终止

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