更新于：2024-11-01

NOS x PGF2α

更新于：2024-11-01

基本信息

关联

项与 NOS x PGF2α 相关的药物

GUR-1001

地诺前列素(Gurus)

靶点

NOS x PGF2α

作用机制

NOS调节剂 [+1]

在研机构

Gurus Biopharm, Inc.

原研机构

Gurus Biopharm, Inc.

在研适应症

青光眼 [+1]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 NOS x PGF2α 相关的临床结果

登录后查看更多信息

100 项与 NOS x PGF2α 相关的转化医学

登录后查看更多信息

0 项与 NOS x PGF2α 相关的专利（医药）

登录后查看更多信息

项与 NOS x PGF2α 相关的文献（医药）

2020-04-01·Reproduction3区 · 生物学

The enrichment of maternal environment prevents pre-term birth in a mice model

3区 · 生物学

Article

作者: Juriol, Lorena ; Franchi, Ana María ; Schander, Julieta Aylen ; Wolfson, Manuel Luis ; Aisemberg, Julieta ; Cymeryng, Cora ; Correa, Fernando ; Jensen, Federico

Maternal lifestyle affects both mother health and pregnancy outcome in humans. Several studies have demonstrated that interventions oriented toward reducing stress and anxiety have positive effects on pregnancy complications such as preeclampsia, excessive gestational weight, gestational diabetes and preterm birth. In this work, we showed that the environmental enrichment (EE), defined as a noninvasive and biologically significant stimulus of the sensory pathway combined with voluntary physical activity, prevented preterm birth (PTB) rate by 40% in an inflammatory mouse model induced by the systemic administration of bacterial lipopolysaccharide (LPS). Furthermore, we found that EE modulates maternal metabolism and produces an anti-inflammatory environment that contributes to pregnancy maintenance. In pregnant mice uterus, EE reduces the expression of TLR4 and CD14 (the LPS receptor and its coactivator protein), preventing the LPS-induced increase in PGE2 and PGF2α release and nitric oxide synthase (NOS) activity. In cervical tissue, EE inhibits cervical ripening events, such as PGE2 release, matrix metalloproteinase (MMP)-9 increased activity and neutrophil recruitment, therefore conserving cervical function. It seems that EE exposure could mimic the stress and anxiety-reducing techniques mentioned above, explaining, at least partially, the beneficial effects of having a healthy lifestyle before and during gestation. Furthermore, we propose that designing an EE protocol for humans could be a noninvasive and preventive therapy for pregnancy complications, averting pre-term birth occurrence and dreaded sequelae that are present in the offspring born too soon.

2020-03-31·Neurospine3区 · 医学

Actions of Prostaglandins on Human Nucleus Pulposus Metabolism Inferred by Cyclooxygenase 2 Inhibition of Cytokine Activated Cells

3区 · 医学

ArticleOA

作者: Sowa, Gwendolyn ; Lee, Joon ; Kang, James ; Vo, Nam ; Couch, Brandon ; Rebecca, Studer

OBJECTIVELow back pain is frequently treated with nonsteroidal anti-inflammatory drugs (NSAIDs), but little is known about intervertebral disc metabolism of the prostaglandins that are diminished by these drugs. Hence, this study aimed at delineating prostaglandin actions in cytokine activated disc cells by comparing the response of nucleus pulposus (NP) cells to the pro-inflammatory cytokine interleukin (IL)-1β with and without cyclooxygenase 2 (COX-2) inhibition.METHODSNP cells cultured in alginate beads were activated with IL-1β ± the COX-2 inhibitor Sc-58125. Media harvested from cultured cells were analyzed for prostaglandin E2 (PGE2), prostaglandin F2 alpha (PGF2α), IL-6, and matrix metalloproteinase (MMP)-3 by enzymelinked immunosorbent assay and nitric oxide by Griess Reaction. Gene expression along with proteoglycan, collagen, and total protein synthesis were also measured.RESULTSIL-1β increased culture media PGE2 and PGF2α, but decreased proteoglycan and collagen syntheses as well as mRNA expression of the matrix genes aggrecan, versican, collagen I, and collagen II. COX-2 inhibition partially rescued proteoglycan and collagen syntheses and collagen I mRNA, but decreased collagen II mRNA IL-1β activated NP cells. COX-2 inhibition initially enhanced and subsequently reduced IL-1β induced inducible nitric oxide synthase, without altering medium nitrite. IL-1β induction of MMP-3 mRNA was increased by COX-2 inhibition at 24 and 48 hours.CONCLUSIONCOX-2 inhibition alters the response of NP cells to IL-1β, suggesting IL-1β action on disc cells is mediated at least in part through COX-2 and its prostaglandins. COX-2 inhibition produces minimal effects on several key catabolic mediators, with the exception of MMP-3. Blocking COX-2 might be beneficial for maintaining disc matrix since it provides an overall rescue of IL-1 induced loss of matrix protein synthesis.

2016-07-01·Domestic Animal Endocrinology2区 · 农林科学

Expression of nerve growth factor and its receptors in the uterus of rabbits: functional involvement in prostaglandin synthesis

2区 · 农林科学

Article

作者: Maranesi, M ; Boiti, C ; Petrucci, L ; Gobbetti, A ; Zerani, M ; Rebollar, P G ; Leonardi, L ; Parillo, F ; Arruda-Alencar, J ; Moura, A ; Alonso, B

The aim of the present study was to evaluate: (1) the presence of nerve growth factor (NGF), neurotrophic tyrosine kinase receptor 1 (NTRK1), and nerve growth factor receptor (NGFR) in the rabbit uterus; and (2) the in vitro effects of NGF on PGF2α and PGE2 synthesis and on the PGE2-9-ketoreductase (PGE2-9-K) activity by the rabbit uterus. Nerve growth factor, NTRK1, and NGFR were immunolocalized in the luminal and glandular epithelium and stroma cells of the endometrium. reverse transcriptase polymerase chain reaction indicated the presence of messenger RNA for NGF, NTRK1, and NGFR in the uterus. Nerve growth factor increased (P < 0.01) in vitro secretions of PGF2α and PGE2 but coincubation with either NTRK1 or oxide nitric synthase (NOS) inhibitors reduced (P < 0.01) PGF2α production and blocked (P < 0.01) PGE2 secretion. Prostaglandins releases were lower (P < 0.01) than control when uterine samples were treated with NGF plus cyclooxygenase inhibitor. However, addition of NGFR inhibitor reduced (P < 0.01) PGF2α secretion less efficiently than NTRK1 or NOS inhibitors but had no effect on PGE2 yield. Nerve growth factor increased (P < 0.01) the activity of PGE2-9-K, whereas coincubation with NTRK1 or NOS inhibitors abolished (P < 0.01) this increase in PGE2-9-K activity. However, cotreatment with either cyclooxygenase or NGFR inhibitors had no effect on PGE2-9-K activity. This is the first study to document the distribution of NGF/NTRK1 and NGFR systems and their effects on prostaglandin synthesis in the rabbit uterus. NGF/NTRK1 increases PGF2α and PGE2 productions by upregulating NOS and PGE2-9-K activities, whereas NGF/NGFR augments only PGF2α secretion, through an intracellular mechanism that is still unknown.

项与 NOS x PGF2α 相关的新闻（医药）

2024-06-27

·生物探索

Nat Metab | 艾玎/朱毅/孙金鹏发现多不饱和脂肪酸对动脉粥样硬化保护作用的潜在机理

引言 Omega-3多不饱和脂肪酸(ω-3 PUFAs)与潜在的心血管益处有关，部分归因于其生物活性代谢物。然而，造成这些优势的潜在机制还没有被完全理解。之前报道了来自二十碳五烯酸(EPA)的细胞色素P450途径的代谢物介导ω-3 PUFAs的动脉粥样硬化保护作用。 2024年6月21日，天津医科大学艾玎、朱毅及山东大学孙金鹏共同通讯在Nature Metabolism 在线发表题为“The sphingosine-1-phosphate receptor 1 mediates the atheroprotective effect of eicosapentaenoic acid”的研究论文，该研究发现内皮细胞(ECs)中的17,18-环氧二碳四烯酸(17,18-EEQ)及其受体鞘氨醇-1-磷酸受体1 (S1PR1)可以抑制振荡剪切应力或肿瘤坏死因子-α诱导的内皮细胞活化。值得注意的是，在内皮细胞S1PR1缺乏的雄性小鼠中，17,18-EEQ和纯化EPA的动脉粥样硬化保护作用被绕过。在机制上，17,18-EEQ的抗炎作用依赖于钙释放介导的内皮型一氧化氮合酶(eNOS)的激活，而eNOS的激活在抑制S1PR1或Gq信号传导时被消除。此外，17,18-EEQ通过与Lys34Nter的极性相互作用变构调节S1PR1的构象。最后，含有高纯度和稳定的EPA乙酯的处方药Vascepa通过17,18-EEQ-S1PR1途径在雄性和雌性小鼠中发挥心血管保护作用。总之，该研究结果表明，17,18-EEQ的抗炎作用涉及激活ECs中的S1PR1-Gq-Ca2+ -eNOS轴，为动脉粥样硬化提供了潜在的治疗靶点。心血管疾病仍然是一个主要的全球健康问题，促使对潜在的预防和治疗战略进行广泛的研究。ω-3 PUFAs，特别是EPA和二十二碳六烯酸(DHA)，因其潜在的心血管益处而受到相当多的关注。食用深海鱼或鱼油，已知是ω-3 PUFAs的丰富来源，与降低心血管终点事件的发生率有很强的相关性。然而，研究ω-3 PUFAs对心血管结果影响的临床试验结果相互矛盾，导致其真正功效的不确定性。ω-3 PUFAs发挥其心血管作用的潜在机制尚未完全解决。 G蛋白偶联受体(GPCRs)是人体组织中表达的最大的膜受体家族，通过检测细胞外配体和启动细胞内信号级联反应，在调节广泛的生理反应中发挥关键作用。近年来，作为人类疾病的潜在治疗靶点，GPCRs引起了越来越多的关注。值得注意的是，一个显著的发现是通过特定的脂肪酸代谢物识别和激活许多GPCRs，从而通过第二信使或阻滞蛋白介导的机制调节细胞内信号通路。例如，包括GPR41、GPR43、GPR84、GPR40和GPR120在内的几种GPCRs已显示出对脂肪酸刺激的反应性。此外，ARA衍生的代谢物，如前列腺素，通过环加氧酶途径产生，导致多种脂质介质的产生，包括PGE2、PGF2α和PGD2。这些代谢物依次选择性地激活特定受体，如EP、FP和PGD受体。然而，EPA和DHA及其各自的代谢物通过与细胞特异性GPCRs结合而作为信号分子发挥作用的程度仍有待充分阐明。 17,18-EEQ介导的抗炎作用机制（Credit: Nature Metabolism）该研究发现S1PR1是17,18-EEQ的受体，并证明17,18-EEQ通过偏向的S1PR1-Gq-Ca2+-eNOS信号抑制内皮活化和动脉粥样硬化。分子对接证实，17,18-EEQ通过与Lys34Nter形成极性相互作用，正极激活S1PR1。S1PR1缺陷小鼠没有表现出17,18-EEQ介导的动脉粥样硬化进展的减少。此外，我们还通过实验验证了Vascepa的心血管保护作用，Vascepa是一种含有高纯度和稳定的EPA乙酯的处方药，已被FDA批准用于降低心血管风险。总之，该研究揭示了S1PR1作为一种新发现的17,18-EEQ受体，选择性激活Gq-Ca2+ -eNOS信号以抑制血管内皮的激活。这些发现有助于更好地理解17,18-EEQ对血管内皮细胞保护作用的分子机制。参考文献 https://www.nature.com/articles/s42255-024-01070-3 责编|探索君排版|探索君文章来源|“iNature” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

2024-04-05

·佰傲谷BioValley

肿瘤中的关键炎症通路

J Hematol Oncol.(一) 类花生酸(Eicosanoid)信号通路：二十烷基硫酸酯信号通路在生理过程和病理过程中都起着关键作用，通过类花生酸将炎症与癌症联系起来。二十碳多不饱和脂肪酸(PUFAs)是由20碳多不饱和脂肪酸(PUFAs)氧化而成的具有高度生物活性的衍生物，可通过环氧合酶(COX)、脂氧合酶(LOX)和细胞色素P450途径产生。COX途径产生前列腺素(PGs)和血栓素A(TXs)，而LOX途径则产生白三烯(LTs)和脂氧素(LXs)。COX信号通路COX家族中，COX-2的表达会受到早期炎症(proinflammatory)的上调，并被发现和调控多种肿瘤的进展相关。在炎症反应的早期阶段，COX-2衍生的PG被认为具有促炎功能。前列腺素D2、前列腺素E2、前列腺素F2α、前列腺素I2和血栓素A2是通过COX通路衍生的五种关键 PG。COX/PEG2COX-2/CSK3β信号还和上皮-间充质转化有关，通过抑制GSK3β来促进E-钙粘蛋白、β-连环蛋白和p120连环蛋白的蛋白质稳定性。抑制COX-2可以下调E-钙黏蛋白导致细胞死亡。PGE2通过其两种E-前列腺素受体EP2和EP4提供信号传导来塑造DC功能。EP4调节CD80、CD86、CD83、MHC II等激活标志物上调以及IL-10和IL-23的产生，引导cDC2成熟，促进T细胞扩增，形成抑制性而非促炎性T细胞群富集。PGE2还可能通过E2调节NK细胞合成IFN-γ来诱导免疫抑制，从而促进肿瘤的发生。肿瘤来源的前列腺素E2(PGE2)介导MDSC分化和获得促肿瘤特征。在PGE2暴露期间，EP2/4联合阻断M-MDSCs可防止这些抑制特征的发生。双重 EP2/EP4 PGE2受体拮抗剂增加了肿瘤微环境淋巴细胞浸润，并显着降低了多种肿瘤模型中的疾病负担。前列腺素D2则是COX-2的另一种代谢物，可能在慢性炎症和癌症中发挥双重作用。PGD2与其受体PTGDR2之间的相互作用抑制了胃癌细胞的自我更新，并减弱了胃癌的生长和转移。脂氧合酶(LOX)信号通路LOX通路负责将花生四烯酸代谢为白三烯，包括白三烯A4(LTA4)、LTB4和LTD4等。炎症细胞(包括白细胞、巨噬细胞和肥大细胞)是白三烯的主要来源。抑制LTB4受体可抑制炎症相关肿瘤的进展，LTD4则在肝细胞癌和慢性乙型肝炎患者的循环中上调。LOX途径主要包括5-LOX、12-LOX和15-LOX。5-LOX在上皮性癌和淋巴瘤中高度表达，具有促血管生成和促肿瘤活性。12-LOX通过激活整合素连接的激酶/NF-κB途径来促进肿瘤的生长。而15-LOX的代谢产物被发现能增强肿瘤相关炎症，既有促肿瘤作用又有抗肿瘤作用。另一种由LOX衍生的类花生酸脂毒素(lipoxins， LXs)则具有抗肿瘤作用。在前列腺癌中，LXA4通过抑制METTL3和或FPR2/IRF4途径，以促进巨噬细胞M2样极化。LXA4对炎性巨噬细胞极化的抑制作用与p-NF-κB p65和IRF5活性的下调有关，从而降低了LPS诱导的M1巨噬细胞通过FPR2/IRF5信号通路的表型和功能极化。 J Hematol Oncol.(二)JAK/STAT信号通路STAT3在炎症反应和肿瘤进展中发挥着广泛的作用。多种生长因子和细胞因子参与典型的STAT3通路，调节细胞分化、血管生成和肿瘤形成。IL-6和STAT3是启动肿瘤的肠上皮细胞生存和增殖所必需的。此外，在设计肠道的肿瘤如前列腺癌中，肠道生物失调增加了肠道通透性，肿瘤内的内毒素通过NF-κB/IL 6/STAT3轴促进了肿瘤的进展。Int Immunopharmacol.影响JAK/STAT通路的药物种类复杂，包括植物化学物质、合成药物和生物分子等等。Int Immunopharmacol.(三)金属代谢铁和ROS氧化还原铁代谢失调是肿瘤细胞的一个重要标志，在肿瘤细胞中，恶性肿瘤细胞需要大量的铁来生存和增殖。细胞色素P450酶、一氧化氮合酶、NADPH氧化酶和脂氧合酶等铁依赖性酶参与ROS的产生。同时，谷胱甘肽过氧化物酶GPX4是一种铁死亡的中枢抑制剂，GPX4利用还原性谷胱甘肽将活性的PUFA-PL-OOH还原为非活性和非致死性的PUFA-PL-OH。抑制Gpx4可通过诱导铁性死亡而增强治疗的抗肿瘤效应。十年铁死亡：双向调控与药物开发锌和NF-κB通路锌与许多炎症性细胞因子的产生和信号传递有关。当对应激刺激做出急性反应时，血浆锌浓度迅速下降。人体的锌代谢与ZIP8等锌转运蛋白的活性密切相关。在感染过程中，激活的NF-κB增加ZIP8的表达，ZIP8定位于细胞膜并调节锌的摄取。锌抑制了IKKβ的活性，从而减弱了炎症反应。参考文献：1.Wang M, Chen S, He X, Yuan Y, Wei X. Targeting inflammation as cancer therapy. J Hematol Oncol. 2024 Mar 22;17(1):13. doi: 10.1186/s13045-024-01528-7.2.Balamurugan K,et al.Stabilization of E-cadherin adhesions by COX-2/GSK3β signaling is a targetable pathway in metastatic breast cancer. JCI Insight. 2023 Mar 22;8(6):e156057. doi: 10.1172/jci.insight.156057.3.Cuenca-Escalona J,et al.PGE2-EP4 signaling steers cDC2 maturation toward the induction of suppressive T-cell responses. Eur J Immunol. 2024 Mar;54(3):e2350770. doi: 10.1002/eji.202350770.4.Francica BJ,et al.Dual Blockade of EP2 and EP4 Signaling is Required for Optimal Immune Activation and Antitumor Activity Against Prostaglandin-Expressing Tumors. Cancer Res Commun. 2023 Aug 8;3(8):1486-1500. doi: 10.1158/2767-9764.CRC-23-0249.5.Yuan J, et al. Lipoxin A4 regulates M1/M2 macrophage polarization via FPR2-IRF pathway. Inflammopharmacology. 2022 Apr;30(2):487-498. doi: 10.1007/s10787-022-00942-y.6.Wang Y,et al. Deciphering JAK/STAT signaling pathway: A multifaceted approach to tumorigenesis, progression and therapeutic interventions. Int Immunopharmacol. 2024 Mar 22;131:111846. doi: 10.1016/j.intimp.2024.111846.·····

免疫疗法