Chrysosplenetin acts as a homeostasis stabilizer with dual-function in shattering Plasmodium berghei K173 resistance to artemisinin driven by both ABC transporters and heme-ROS/GSH axis.
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Abstract
Background: Chrysosplenetin (CHR), a polymethoxy flavonol co-occurring with artemisinin (ART) in Artemisia annua L., reverses ART resistance in Plasmodium berghei K173 potentially by downregulating intestinal P-glycoprotein (P-gp, encoded by Mdr1a) expression. In the present study, we further elaborated on the mechanism by comparing differences in antimalarial activity and resistance-associated molecular expression profiles between ART alone and combination therapy in blood and tissues of Mdr1a wild-type (WT) and knockout (KO) mice infected with either sensitive or resistant malarial parasites.
Methods: We evaluated the effects of monotherapy and combination therapy in WT and KO mice infected with sensitive and resistant P. berghei K173 strains. The mRNA expressions of multi-resistance proteins (Mrp1, 2, 4, 5) and breast cancer resistance proteins (Bcrp) were detected. Hemoglobin levels, mRNA expressions of cytokines including tumor necrosis factor-α (IFN-α), interferon-α (IFN-α), and interleukin (IL-1β) in blood and tissues, and redox balance (ROS/GSH levels), as well as gene or protein expression of signaling pathway (PI3K/AKT-mTOR and MAPK) were investigated.
Results: In drug-resistant mice, combination therapy maintained the highest survival (100%) and inhibition (30%) rates and the lowest parasitaemia percentage (approximately 20.0%), irrespective of Mdr1a gene status. Furthermore, combination reshaped the spatial and ART resistance-phenotypic disparities in Mrps and Bcrp mRNA expressions (with a fold change ranging from 1.35 to 38.03), ROS/GSH balance (ranging from 1.02-fold to 10.18-fold), hemoglobin levels (ranging from 1.04-fold to 1.20-fold), and cytokine profiles (ranging from 1.14-fold to 37.79-fold) induced by ART alone, which were partially dysregulated by Mdr1a deficiency. Monotherapy and combination exert oppositely regulatory effects on the PI3K/AKT-mTOR pathway in a tissue-, Mdr1a genotype-, and parasite sensitivity/resistance-dependent manner (ranging from 1.52-fold to 84.00-fold). Specifically, CHR reversed ART-induced changes via PI3K/AKT protein inhibition (ranging from 1.20-fold to 63.00-fold), which was contingent on P-gp functionality. Finally, mitogen-activated protein kinase (MAPK) pathway was involved in the antagonistic regulation between ART alone and combination therapy in a P-gp-independent manner (ranging from 1.39-fold to 16.69-fold).
Conclusions: The efflux pump function of P-gp is probably not a critical factor in the mechanism by which CHR reverses ART resistance. Instead, CHR acts as a homeostasis stabilizer with dual functions: it disrupts Plasmodium berghei K173 resistance to ART driven by both ABC transporters and the heme-ROS/GSH axis, in which the non-transport function of P-gp on ART is involved.
期刊介绍：
Parasites & Vectors is an open access, peer-reviewed online journal dealing with the biology of parasites, parasitic diseases, intermediate hosts, vectors and vector-borne pathogens. Manuscripts published in this journal will be available to all worldwide, with no barriers to access, immediately following acceptance. However, authors retain the copyright of their material and may use it, or distribute it, as they wish.
Manuscripts on all aspects of the basic and applied biology of parasites, intermediate hosts, vectors and vector-borne pathogens will be considered. In addition to the traditional and well-established areas of science in these fields, we also aim to provide a vehicle for publication of the rapidly developing resources and technology in parasite, intermediate host and vector genomics and their impacts on biological research. We are able to publish large datasets and extensive results, frequently associated with genomic and post-genomic technologies, which are not readily accommodated in traditional journals. Manuscripts addressing broader issues, for example economics, social sciences and global climate change in relation to parasites, vectors and disease control, are also welcomed.
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