No increase of OT in the mPFC was observed in RAGE knockout male mice. First, we found that, after intranasal OT administration, the OT concentration increased in the extracellular space of the medial prefrontal cortex (mPFC) of wild-type male mice, as measured by push-pull microperfusion. Here, we address some unanswered questions on RAGE-dependent OT transport. Recently, it was found that the receptor for advanced glycation end-products (RAGE) is an OT-binding protein and plays a critical role in the uptake of OT to the brain after peripheral OT administration. Single and repetitive administration of OT increases social interaction and maternal behaviour in humans and mammals. doi: 10.1371/ (OT) is a neuropeptide hormone. Characterization of the ubiquitylating components of the human malaria parasite’s protein degradation pathway. Unraveling the ubiquitome of the human malaria parasite. Ponts N, Saraf A, Chung DW, Harris A, Prudhomme J, Washburn MP, Florens L, Le Roch KG. Deciphering the ubiquitin-mediated pathway in apicomplexan parasites: a potential strategy to interfere with parasite virulence.
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Ponts N, Yang J, Chung DW, Prudhomme J, Girke T, Horrocks P, Le Roch KG. The change in differential parasite counts in inhibitor treated cells at 48 hors post-treatment were statistically not significant ( P values >0.5) compared to controls and CQ treated PfD6 cultures due to large individual variations falciparum cultures were analyzed for statistical comparisons. The results on differential parasite stage counts in control, CQ and inhibitors treated P. falciparum D6 strain ( Pf D6) culture with high parasitemia (~6%) was treated with the lead E3 ligase inhibitors and differential parasite stages were monitored at 0, 8, 16, 24, 32, 40 and 48 h as indicated. The ring stage synchronized CQ-sensitive P.
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Chloroquine (CQ) and DMSO were tested as positive, and vehicle control respectively. Minimum one thousand erythrocytes were counted for each observation. Each bar represents the mean ± SEM of three observations. a Control b Chloroquine c JNJ 26854165 d HLI 373 e Nutlin-3 at 0, 8, 16, 24, 32, 40 and 48 h post-treatment. Further investigations on the lead E3 ligase inhibitors shall provide better understanding regarding the importance of E3 ligase functions in the malaria parasite as a potential new antimalarial drug target and a new class of antimalarial drug leads.Īntimalarial Malaria Plasmodium falciparum Proteasome Ubiquitine Ubiquitine E3 ligase.Įffect of selected E3 ligase inhibitors on cellular development of Plasmodium falciparum in vitro.
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The ubiquitin/proteasome functions may be critical for schizont maturation. Interruption of trophozoites and schizont maturation by the antimalarial E3 ligase inhibitors suggest the role of ubiquitin/proteasome functions in the intraerythrocytic development of malaria parasite. falciparum parasite at the trophozoite and schizont stages, resulting in accumulation of distorted trophozoites and immature schizonts.
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JNJ 26854165, HLI 373 and Nutlin 3 blocked the development of P. These inhibitors were considerably less cytotoxic to mammalian Vero cells. Statistics analysis was done by two-way ANOVA followed by Tukey and Sidak multiple comparison test using GraphPad Prism 6.Į3 ligase inhibitors namely, JNJ 26854165, HLI 373 and Nutlin 3 showed prominent antimalarial activity against PfD6 and PfW2. The lead antimalarial E3 ubiquitin ligase inhibitors were further evaluated for the stage-specific antimalarial action and effects on cellular development of P. The inhibitors were also tested against Vero and transformed THP1 cells for cytotoxicity. falciparum D6 strain (PfD6) and a chloroquine-resistant P. falciparum E3 ligase is substantially variable and divergent compared to the homologs from other eukaryotes, which make the E3 ligase a parasite-specific target.Ī set of selected E3 ubiquitin ligase inhibitors was tested in vitro against a chloroquine-sensitive P. Ubiquitin E1 and E2 are highly conserved within eukaryotes. Ubiquitin is a highly conserved 76 amino acid polypeptide, which attaches covalently to target proteins through combined action of three classes of enzymes namely, the ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2) and ubiquitin-protein ligase (E3). Protein ubiquitylation is an important post-translational regulation, which has been shown to be necessary for life cycle progression and survival of Plasmodium falciparum.