Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, China.
Institute of Clinical Pharmacology, General Hospital of Ningxia Medical University, Yinchuan, China.
Phytother Res. 2023 Jul;37(7):2939-2956. doi: 10.1002/ptr.7789. Epub 2023 Mar 20.
This study investigated antimalarial efficacy and sensitization of chrysosplenetin against artemisinin-resistant Plasmodium berghei K173 and potential molecular mechanism. Our data indicated a risk of artemisinin resistance because a higher parasitaemia% and lower inhibition% under artemisinin treatment against resistant parasites than those in the sensitive groups were observed. Two non-antimalarial components, verapamil and chrysosplentin, being P-gp inhibitors, possessed a strong efficacy against resistant parasites but it was not the case for Bcrp inhibitor novobiocin. Artemisinin-chrysosplenetin combination improved artemisinin susceptibility of resistant P. berghei. Artemisinin activated intestinal P-gp and Abcb1/Abcg2 expressions and suppressed Bcrp whereas chrysosplenetin reversed them. Resistant parasite infection led to a decreased haemozoin in organs or an increased heme in peripheral bloods compared with the sensitives; however, that in Abcb1-deficient knockout (KO)-resistant mice reversely got increased or decreased versus wild type (WT)-resistant animals. Chrysosplenetin as well as rifampin (nuclear receptor agonist) increased the transcription levels of PXR/CAR while showed a versatile regulation on hepatic and enternal PXR/CAR in WT- or KO-sensitive or -resistant parasites. Oppositely, hepatic and enteric NF-κB p52 mRNA decreased conformably in WT but increased in KO-resistant mice. NF-κB pathway potentially involved in the mechanism of chrysosplenetin on inhibiting P-gp expressions while PXR/CAR play a more complicated role in this mechanism.
本研究调查了 chrysosplenetin 对青蒿素耐药疟原虫 Plasmodium berghei K173 的抗疟疗效和敏化作用及其潜在的分子机制。我们的数据表明存在青蒿素耐药风险，因为与敏感组相比，耐药寄生虫对青蒿素治疗的寄生虫血症%更高和抑制%更低。两种非抗疟成分维拉帕米和 chrysosplentin 作为 P-糖蛋白抑制剂，对耐药寄生虫具有很强的疗效，但 Bcrp 抑制剂诺氟沙星则不然。青蒿素- chrysosplenetin 联合用药提高了耐药 P. berghei 的青蒿素敏感性。青蒿素激活肠道 P-糖蛋白和 Abcb1/Abcg2 的表达，并抑制 Bcrp，而 chrysosplenetin 则逆转了这一作用。与敏感组相比，耐药寄生虫感染导致器官中的血色素减少或外周血中的血红素增加；然而，与野生型（WT）耐药动物相比，Abcb1 缺陷敲除（KO）耐药小鼠的血红素则相反增加或减少。chrysosplenetin 以及利福平（核受体激动剂）增加了 PXR/CAR 的转录水平，同时对 WT 或 KO 敏感或耐药寄生虫的肝内和肠内 PXR/CAR 表现出多种调节作用。相反，肝内和肠内 NF-κB p52 mRNA 在 WT 中一致减少，但在 KO 耐药小鼠中增加。NF-κB 途径可能参与了 chrysosplenetin 抑制 P-糖蛋白表达的机制，而 PXR/CAR 在该机制中发挥更复杂的作用。
