Citrinin derivatives have been found to have various pharmacological activities, such as anti-inflammatory, anti-tumor, and antioxidant effects. Dicitrinone G (DG) was a new citrinin dimer isolated from marine-derived fungus Penicillium sp. GGF 16-1-2 which has potential activity. Here, we aim to investigate whether DG has anti-pancreatic cancer activity. In xenograft tumor model, 2 × 10⁶ BXPC-3 cells were injected into the hind flank of NU/NU nude mice by subcutaneously for 2 weeks followed by treating with DG (0.25, 0.5, 1 mg/kg) and 5-FU (30 mg/kg) for 4 weeks. Tumor volume and weight were measured, and the expression of CD31, IL-18, NLRP3, and Caspase-1 in tumor tissue were detected. In vitro, HUVECs were treated with conditioned medium (CM) derived from BXPC-3 cells, the effects of DG on angiogenesis were detected by tube formation and western blot analysis. In vivo studies showed that the tumor growth and angiogenesis were greatly suppressed. The tumor weight inhibition rates of DG and 5-FU groups were about 42.36%, 38.94%, 43.80%, and 31.88%. Furthermore, the expression of CD31 and Caspase-1 were decreased. In vitro, CM derived from BXPC-3 cells which treated with DG could inhibit the tube formation and expression of pro-angiogenic NICD in HUVECs. Our study suggests that DG could suppress angiogenesis via the NLRP3/IL-18 pathway and may have the potential to inhibit tumor development.

Graphical abstract

中文翻译：

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海洋青霉菌 sp. GGF16-1-2代谢物双西三农G通过调节NLRP3炎症小体的激活抑制胰腺血管生成

橘霉素衍生物已被发现具有多种药理活性，如抗炎、抗肿瘤和抗氧化作用。Dicitrinone G (DG) 是从海洋来源的真菌青霉中分离出来的一种新的柠檬酸二聚体。GGF 16-1-2具有潜在的活性。在这里，我们的目的是研究 DG 是否具有抗胰腺癌活性。在异种移植肿瘤模型中，将2×10 ⁶ BXPC-3细胞皮下注射到NU/NU裸鼠后胁腹2周，然后用DG（0.25、0.5、1 mg/kg）和5-FU（ 30毫克/公斤）持续4周。测量肿瘤体积和重量，检测肿瘤组织中CD31、IL-18、NLRP3、Caspase-1的表达量。在体外，用 BXPC-3 细胞来源的条件培养基 (CM) 处理 HUVEC，通过管形成和蛋白质印迹分析检测 DG 对血管生成的影响。体内研究表明肿瘤生长和血管生成受到极大抑制。DG组和5-FU组的瘤重抑制率分别约为42.36%、38.94%、43.80%、31.88%。此外，CD31和Caspase-1的表达降低。在体外，用DG处理的BXPC-3细胞来源的CM可以抑制HUVEC中管的形成和促血管生成NICD的表达。我们的研究表明，DG 可以通过 NLRP3/IL-18 途径抑制血管生成，并可能具有抑制肿瘤发展的潜力。

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