Zhongguo Yao Li Xue Bao = Acta Pharmacologica Sinica
Immunoregulatory properties of a novel antimalarial drug dihydroartemisinin (DHA) were investigated in vitro. DHA 0.5-5 mumol.L-1 enhanced the lymphocyte proliferation induced by Con A. Interleukin 2 (IL-2) production and its mRNA expression by both Con A-stimulated mouse splenocytes and a T cell line LBRM-33-1A5 were also augmented by DHA. In contrast, DHA 0.5-5 mumol.L-1 did not show any effect on the lipopolysaccharides (LPS)-induced lymphocyte proliferation and the spontaneous and mitogen-induced proliferation of transformed T cells.
A cell-free system from Plasmodium falciparum able to translate endogenous mRNA was used to determine the effect of artemisinin, chloroquine and primaquine on the protein synthesis mechanism of the parasite. The antimalarial drugs did not inhibit the incorporation of [3H] methionine into parasite proteins even at concentrations higher than the ones found to strongly inhibit the parasite growth. Results clearly indicate that these compounds do not have a direct effect on protein synthesis activity of P. falciparum coded by endogenous mRNA.
Drug resistance in Plasmodium falciparum is a serious problem in most endemic areas. Recent studies have suggested the potential involvement of genes in the MDR gene family in resistance to quinoline-containing compounds in P. falciparum. In our present studies, a molecular analysis of pfmdr 1 in isolate strain of P. falciparum, 523a R, from Japanese mefloquine-resistant patient was done to determine the reported association of pfmdr 1 intragenic alleles and mefloquine resistance, and to examine the antimalarial activities of several antimalarial agents against the P. falciparum strain.
A profound cytotoxic action of the antimalarial, artesunate (ART), was identified against 55 cancer cell lines of the U.S. National Cancer Institute (NCI). The 50% inhibition concentrations (IC50 values) for ART correlated significantly to the cell doubling times (P = 0.00132) and the portion of cells in the G0/G1 (P = 0.02244) or S cell cycle phases (P = 0.03567). We selected mRNA expression data of 465 genes obtained by microarray hybridization from the NCI data base.
We studied sequence polymorphism, expression level of pfmdr1 gene and drug sensitivity in mefloquine sensitive-strain as well as mefloquine-resistant clone/24 to understand underlying drug resistance mechanism. Mefloquine-resistant clone/24 exhibited decreased susceptibility to mefloquine, quinine, halofantrine and artemisinin and increased susceptibility to chloroquine. We analyzed sequence of pfmdr1 gene and found mutation in pfmdr1 on clone/24. Moreover, overexpression of mRNA level of pfmdr1 has been observed in mefloquine-resistant clone/24.
The anti-malarial artesunate (ART) also inhibits the growth of cancer cells. The active moiety is an endoperoxide bridge whose cleavage generates reactive oxygen species and free radicals. We analyzed whether glutathione-related enzymes contribute to tumor resistance to ART and to the low toxicity of ART towards normal organs.
We studied DNA sequence polymorphism, expression level of pfmdr1 gene and sensitivity of major antimalarial drugs in both mefloquine sensitive and resistant strains to elucidate mechanism of mefloquine resistance. Mefloquine-resistant 523a R/24 strain exhibited decreased susceptibility to mefloquine, artemisinin and halofantrine whereas increased susceptibility to chloroquine. We found a novel point mutation in pfmdr1 gene of 523a R/24 strain. Moreover, overexpression of mRNA of pfmdr1 has been observed in this strain.
BACKGROUND AND PURPOSE: Our previous study showed that SM905, a novel artemisinin derivative, exhibited potent immunosuppressive activity. In this study, we evaluate preventive and therapeutic effect of SM905 on collagen-induced arthritis (CIA) in DBA/1 mice, and investigate its mechanisms both in inflammatory and autoimmune aspects of the disease. EXPERIMENTAL APPROACH: CIA was induced by type II bovine collagen (CII) in DBA/1 mice.
Dehydroartemisinin (DHA) is an effective anti-malaria agent. Fortilin is an anti-apoptotic molecule overexpressed in many human cancers. Here, we show that DHA binds human fortilin, increases the ubiquitination of fortilin, shortens fortilin's half-life in a proteasome-dependent fashion, and reduces cellular levels of fortilin in varieties of cells. DHA induced DNA fragmentation in U2OS cells in a fortilin-dependent manner.
Drug Metabolism and Disposition: The Biological Fate of Chemicals
Fa2N-4 cells have been proposed as a tool to identify CYP3A4 inducers. To evaluate whether Fa2N-4 cells are a reliable surrogate for cryopreserved human hepatocytes, we assessed the basal mRNA expression of 64 drug disposition genes in Fa2N-4 cells. Significant differences were found in the expression of major drug-metabolizing enzymes, nuclear receptors, and transporters between both cell types.