Prostaglandin E2 (PGE2), an eicosane, regulates the physiological activity of inflammatory cells and represents a potential therapeutic target for facilitating tissue repair in vivo. In our work, an electrochemical immunosensor employing Ketjen black-Au nanoparticles (KB-Au) and poly tannic acid nanospheres conjugated with anti-PGE2 polyclonal antibody (PTAN-Ab) was designed to ultra-sensitively analyze PGE2 levels secreted by living cells and tissues. Antibody assembly strategies were explored to achieve signal amplification. Moreover, we studied the therapy effects of docosahexaenoic acid (DHA), arachidonic acid (AA), hyaluronic acid (HA), and small molecule 15-hydroxyprostaglandin dehydrogenase inhibitor (SW033291) on inflammation and evaluated the protective functions of HA and SW033291 in a murine model subjected to colitis induced by dextran sulfate sodium (DSS) using the developed sensor. The sensor exhibited a linear range of 10^-5-10⁶ fg/mL and a detection limit (LOD) of 10^-5 fg/mL. Fetal bovine serum (FBS) samples were used to achieve high recovery of target analytes. This study not only presents an effective strategy for ultra-sensitively monitoring PGE2 but also provides valuable insights into assessing the degree of inflammation and the therapeutic effect of related drugs. Research on human health monitoring and regenerative medicine could greatly benefit from the findings.

2024-03-01·PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS

Inhibition of 15-prostaglandin dehydrogenase attenuates acetaminophen-induced liver injury via suppression of apoptosis in liver endothelial cells

Article

作者: Iwaki, Masahiro ; Yamamoto, Nonoka ; Yokotobi, Akito ; Kawase, Atsushi ; Nakanishi, Takeo ; Takada, Mao ; Shimada, Hiroaki

Hepatic microvascular disruption caused by injury to liver sinusoidal endothelial cells (LSECs) is an aggravating factor for drug-induced liver injury (DILI). It is suggested that prostaglandin E₂ (PGE₂) may be able to attenuate LSEC injury. However, it is also known that 15-keto PGE₂, a metabolite of PGE₂ produced by 15-prostaglandin dehydrogenase (15-PGDH) that is not a ligand of PGE₂ receptors, suppresses inflammatory acute liver injury as a ligand of peroxisome proliferator-activated receptor γ. In this study, we aimed to understand whether 15-PGDH activity is essential for preventing DILI by suppressing hepatic microvascular disruption in a mouse model of acetaminophen (APAP)-induced liver injury. To inhibit 15-PGDH activity prior to APAP-induced LSEC injury, we administered the 15-PGDH inhibitor, SW033291, 1 h before and 3 h after APAP treatment. We observed that LSEC injury preceded hepatocellular injury in APAP administered mice. Hepatic endogenous PGE₂ levels did not increase up till the initiation of LSEC injury but rather increased after hepatocellular injury. Moreover, hepatic 15-PGDH activity was downregulated in APAP-induced liver injury. The inhibition of 15-PGDH attenuated LSEC injury and subsequently hepatic injury by inhibiting apoptosis in APAP administered mice. Our in vitro studies also suggested that PGE₂ inhibited APAP-induced apoptosis via the EP4/PI3K pathway in endothelial cells. Therefore, a decrease in 15-PGDH activity would be beneficial for preventing APAP-induced liver injury by attenuating LSEC injury.

2023-12-01·Lung

Inhibition of Prostaglandin-Degrading Enzyme 15-PGDH Mitigates Acute Murine Lung Allograft Rejection

Article

作者: Yang, Zeran ; Lv, Zhe ; Lei, Jianfeng ; Cui, Ye

PURPOSE:

Acute rejection is a frequent complication among lung transplant recipients and poses substantial therapeutic challenges. 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme responsible for the inactivation of prostaglandin E2 (PGE2), has recently been implicated in inflammatory lung diseases. However, the role of 15-PGDH in lung transplantation rejection remains elusive. The present study was undertaken to examine the expression of 15-PGDH in rejected lung allografts and whether inhibition of 15-PGDH ameliorates acute lung allograft rejection.

METHODS:

Orthotopic mouse lung transplantations were performed between donor and recipient mice of the same strain or allogeneic mismatched pairs. The expression of 15-PGDH in mouse lung grafts was measured. The efficacy of a selective 15-PGDH inhibitor (SW033291) in ameliorating acute rejection was assessed through histopathological examination, micro-CT imaging, and pulmonary function tests. Additionally, the mechanism underlying the effects of SW033291 treatment was explored using CD8⁺ T cells isolated from mouse lung allografts.

RESULTS:

Increased 15-PGDH expression was observed in rejected allografts and allogeneic CD8⁺ T cells. Treatment with SW033291 led to an accumulation of PGE2, modulation of CD8⁺ T-cell responses and mitochondrial activity, and improved allograft function and survival.

CONCLUSION:

Our study provides new insights into the role of 15-PGDH in acute lung rejection and highlights the therapeutic potential of inhibiting 15-PGDH for enhancing graft survival. The accumulation of PGE2 and modulation of CD8⁺ T-cell responses represent potential mechanisms underlying the benefits of 15-PGDH inhibition in this model. Our findings provide impetus for further exploring 15-PGDH as a target for improving lung transplantation outcomes.

项与 SW-033291 相关的新闻（医药）

2023-02-22

·生物谷

Circ Res：抑制15-PGDH可减缓心脏纤维化

在一项新的研究中，来自美国科罗拉多大学医学院的研究人员发现了一种减缓心脏形成瘢痕组织---心脏纤维化（cardiac fibrosis）---的新机制。在一项新的研究中，来自美国科罗拉多大学医学院的研究人员发现了一种减缓心脏形成瘢痕组织---心脏纤维化（cardiac fibrosis）---的新机制。相关研究结果发表在2023年1月6日的Circulation Research期刊上，论文标题为“Inhibition of Eicosanoid Degradation Mitigates Fibrosis of the Heart”。论文通讯作者、科罗拉多大学医学院心脏科医学教授Timothy McKinsey博士说，“心脏的纤维化是对多种应激的反应。这可能是好事。例如，如果你遭受心脏病发作，你的心肌大量死亡，你需要用一些东西来替代心肌。在这种情况下，纤维化的瘢痕使心脏不会破裂，防止人们死亡。但是，我们对病理性纤维化---一种发生在长期高血压或其他合并症患者身上的不受控制的纤维化---更感兴趣。这可能会导致心脏僵化，并导致所谓的舒张功能障碍（diastolic dysfunction）。” 一种独特的抑制剂这项新的研究显示化合物SW033291通过抑制15-羟基前列腺素脱氢酶（15-hydroxyprostaglandin dehydrogenase, 15-PGDH）的作用减缓了心脏纤维化。15-PGDH能降解类花生酸（eicosanoids），而类花生酸是有助于防止纤维化的脂质信号分子。图片来自Circulation Research, 2023, doi:10.1161/CIRCRESAHA.122.321475。 McKinsey说，“慢性纤维化被认为是心力衰竭发病机制中的一个主要角色。心力衰竭影响着全世界数百万人，而且没有任何好的疗法来预防或逆转心脏纤维化。这就是我们发起这类研究的原因。” 在人体样本中显示出有效性 McKinsey和他的研究团队开始了他们的研究，用一些化合物进行表型高通量筛选，寻找阻断负责推动纤维化的成纤维细胞的激活。他们找到了九种小分子，它们具有阻断心脏、肺部和肾脏成纤维细胞激活的共同能力。在这九种化合物中，SW033291似乎是最有希望的。除了实验室测试和动物模型外，这些作者利用从接受心脏移植的患者中提取的衰竭的人类心脏成纤维细胞，以及未衰竭的供体对照心脏成纤维细胞，创建了一个新的生物库。McKinsey说，SW033291表现出了逆转衰竭的人类心脏成纤维细胞的激活状态的显著能力，这支持了15-PGDH抑制可能有助于改善患者现有的心脏纤维化的观点。接下来的步骤随着他们的研究的继续，McKinsey和他的团队计划重点研究15-PGDH在不同细胞群体（包括成纤维细胞、免疫细胞和心肌细胞）中的作用。他们还希望对SW033291进行额外的疗效研究，在更严重的心脏纤维化和舒张功能障碍模型中进行测试。 McKinsey说，他的还计划更仔细地研究不同的类花生酸在抑制成纤维细胞激活方面的功能，以及它们如何激活信号通路以防止成纤维细胞导致纤维化。他说，“这项新的研究确定了一种调节心脏纤维化的新途径。没有人研究过心脏中的15-PGDH。这开辟了一条全新的研究途径，并提出了靶向心脏纤维化的方法来治疗大量的心脏疾病，包括心力衰竭。”（生物谷 Bioon.com）参考资料： Marcello Rubino et al. Inhibition of Eicosanoid Degradation Mitigates Fibrosis of the Heart. Circulation Research, 2023, doi:10.1161/CIRCRESAHA.122.321475.