Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malaria results in >1,000,000 deaths per year worldwide. Although no licensed vaccine exists, much effort is currently focused on subunit vaccines that elicit CD8 T cell responses directed against Plasmodium parasite liver stage Ags. Multiple immune-effector molecules play a role in antimicrobial immunity mediated by memory CD8 T cells, including IFN-gamma, perforin, TRAIL, Fas ligand, and TNF-alpha. However, it is not known which pathways are required for memory CD8 T cell-mediated immunity against liver stage Plasmodium infection. In this study, we used a novel immunization strategy to generate memory CD8 T cells in the BALB/c mouse model of P. berghei or P. yoelii sporozoite infection to examine the role of immune-effector molecules in resistance to the liver stage infection. Our studies reveal that endogenous memory CD8 T cell-mediated protection against both parasite species is, in part, dependent on IFN-gamma, whereas perforin was only critical in protection against P. yoelii. We further show that neutralization of TNF-alpha in immunized mice markedly reduces memory CD8 T cell-mediated protection against both parasite species. Thus, our studies identify IFN-gamma and TNF-alpha as important components of the noncytolytic pathways that underlie memory CD8 T cell-mediated immunity against liver stage Plasmodium infection. Our studies also show that the effector pathways that memory CD8 T cells use to eliminate liver stage infection are, in part, Plasmodium species specific.
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PMID:Differential effector pathways regulate memory CD8 T cell immunity against Plasmodium berghei versus P. yoelii sporozoites. 2009 64

Dihydroartemisinin (DHA) is a derivative of artemisinin and is an effective anti-malaria therapeutic used worldwide. In this paper, we report that DHA is as a potential anticancer drug for prostate cancer. Our data indicate that DHA suppresses the PI3-K/Akt and ERK cell survival pathways and triggers the induction of death receptor DR5 and activation of extrinsic and intrinsic cell death signaling. DHA-mediated DR5 induction appears to occur via increased transcriptional activity of DR5 promoter. Our data also show that, while DHA has strong cytotoxicity in tumor cells, it exhibits minimal cytotoxic effects on normal prostate epithelial cells. Our studies also demonstrate that DHA worked cooperatively with death ligand TRAIL. Combination of DHA and TRAIL significantly enhanced cell killing above that noted with a single agent alone. Based on these results, we propose a novel idea of developing DHA alone and/or in combination with TRAIL for the treatment of prostate cancer.
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PMID:Dihydroartemisinin upregulates death receptor 5 expression and cooperates with TRAIL to induce apoptosis in human prostate cancer cells. 2022 97

Quinacrine has been widely explored in treatment of malaria, giardiasis, and rheumatic diseases. We find that quinacrine stabilizes p53 and induces p53-dependent and independent cell death. Treatment by quinacrine alone at concentrations of 10-20 mM for 1-2 d cannot kill hepatocellular carcinoma cells, such as HepG2, Hep3B, Huh7, which are also resistant to TRAIL. However, quinacrine renders these cells sensitive to treatment by TRAIL. Co-treatment of these cells with quinacrine and TRAIL induces overwhelming cell death within 3-4 h. Levels of DR5, a pro-apoptotic death receptor of TRAIL, are increased upon treatment with quinacrine, while levels of Mcl-1, an anti-apoptotic member of the Bcl-2 family, are decreased. While the synergistic effect of quinacrine with TRAIL appears to be in part independent of p53, knockdown of p53 in HepG2 cells by siRNA results in more cell death after treatment by quinacrine and TRAIL. The mechanism by which quinacrine sensitizes hepatocellular carcinoma cells to TRAIL and chemotherapies, and the potential for clinical application currently are being further explored. Lastly, quinacrine synergizes with chemotherapeutics, such as adriamycin, 5-FU, etoposide, CPT11, sorafenib, and gemcitabine, in killing hepatocellular carcinoma cells in vitro and the drug enhances the activity of sorafenib to delay tumor growth in vivo.
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PMID:Quinacrine sensitizes hepatocellular carcinoma cells to TRAIL and chemotherapeutic agents. 2172 12

Malaria parasites, though widespread among wild chimpanzees and gorillas, have not been detected in bonobos. Here, we show that wild-living bonobos are endemically Plasmodium infected in the eastern-most part of their range. Testing 1556 faecal samples from 11 field sites, we identify high prevalence Laverania infections in the Tshuapa-Lomami-Lualaba (TL2) area, but not at other locations across the Congo. TL2 bonobos harbour P. gaboni, formerly only found in chimpanzees, as well as a potential new species, Plasmodium lomamiensis sp. nov. Rare co-infections with non-Laverania parasites were also observed. Phylogenetic relationships among Laverania species are consistent with co-divergence with their gorilla, chimpanzee and bonobo hosts, suggesting a timescale for their evolution. The absence of Plasmodium from most field sites could not be explained by parasite seasonality, nor by bonobo population structure, diet or gut microbiota. Thus, the geographic restriction of bonobo Plasmodium reflects still unidentified factors that likely influence parasite transmission.
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PMID:Wild bonobos host geographically restricted malaria parasites including a putative new Laverania species. 2915 12