PT  - JOURNAL ARTICLE
AU  - Xuesong Zhao
AU  - Shanhong Ni
AU  - Yuanyuan Zhang
AU  - Xiuli Wu
AU  - Ying Yao
AU  - Jing Chen
TI  - Sensitization of Chrysosplenetin against Artemisinin Resistant <em>Plasmodium berghei</em> K173 via Blocking Host ABC Transporters Potentially Mediated by NF-κB p52 or PXR/CAR Signaling Pathway
AID  - 10.1101/2022.01.10.475770
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.01.10.475770
4099  - http://biorxiv.org/content/early/2022/01/11/2022.01.10.475770.short
4100  - http://biorxiv.org/content/early/2022/01/11/2022.01.10.475770.full
AB  - This study investigated if artemisinin-chrysosplenetin combination (ART-CHR) improved ART antimalarial efficacy against resistant Plasmodium berghei K173 via depressing host ABC transporter and potential molecular mechanism. Parasitaemia% and inhibition% were calculated and gene/protein expressions of ABC transporters or PXR/CAR/NF-κB p52 were detected by Western-blot and RT-qPCR. In vitro transcription of PXR/CAR was studied by dual-luciferase reporter assay. Our data indicated that ART-CHR improved ART efficacy against resistant parasites. P-gp inhibitor verapamil and CHR showed a stronger effect in killing resistant parasites while vehicle and Bcrp inhibitor novobiocin did not. ART activated intestinal ABCB1/ABCG2 and CHR inhibited them. ART decreased Bcrp protein whereas CHR increased it. ART ascended ABCC1/ABCC4/ABCC5 mRNA but ART-CHR descended them. CHR as well as rifampin (RIF) or 5-fluorouracil (5-FU) increased transcription levels of PXR/CAR while showed a versatile regulation on in vivo hepatic and enternal PXR/CAR in Mdr1a+/+ (WT) or Mdr1a-/- (KO) mice infected with sensitive or resistant parasites. Oppositely, hepatic and enteric N-κB p52 mRNA was conformably decreased in WT but increased in KO-resistant mice. NF-κB pathway should potentially involved in the mechanism of CHR on inhibiting ABC transporters and ART resistance while PXR/CAR play a more complicated role in this mechanism.MDRmulti-drug resistanceABC transportersATP binding cassette transportersP-gpP-glycoproteinBcrpbreast cancer resistance proteinMRPsmulti-drug resistance proteinsACTsartemisinin based combination treatmentsARTartemisininCHRchrysosplenetin5-FU5-fluorouracilRFP or RIFrifampinNOVnovobiocinVERverapamil hydrochlorideCMC-Nasodium carboxymethyl celluloseCCK8cell counting kitNCnormal controlDMSOdimethyl sulfoxideRBCred blood cellPXRpregnane X receptorCARconstitutive androstane receptorNF-κBnuclear factor kappa-B