02901nas a2200349   4500008004100000022001400041245017200055210006900227260000800296300001400304490000700318520169700325653002202022653001102044653003402055653000802089653001702097653002502114653002602139653001402165653003002179100002402209700002402233700002702257700001602284700002502300700002002325700001902345700002802364700002902392856013002421       2020                        eng d  a0066-480400aWhole-cell phenotypic screening of medicines for malaria venture pathogen box identifies specific inhibitors of plasmodium falciparum late-stage development and egress0 aWholecell phenotypic screening of medicines for malaria venture   cMAY  ae01802-190 v643 a<p>We report a systematic, cellular phenotype-based antimalarial screening of the Medicines for Malaria Venture Pathogen Box collection, which facilitated the identification of specific blockers of late-stage intraerythrocytic development of Plasmodium falciparum. First, from standard growth inhibition assays, we identified 173 molecules with antimalarial activity (50% effective concentration [EC50] &lt;= 10 mu M), which included 62 additional molecules over previously known antimalarial candidates from the Pathogen Box. We identified 90 molecules with EC50 of &lt;= 1 mu M, which had significant effect on the ring-trophozoite transition, while 9 molecules inhibited the trophozoite-schizont transition and 21 molecules inhibited the schizontring transition (with &gt;= 50% parasites failing to proceed to the next stage) at 1 mu M. We therefore rescreened all 173 molecules and validated hits in microscopy to prioritize 12 hits as selective blockers of the schizont-ring transition. Seven of these molecules inhibited the calcium ionophore-induced egress of Toxoplasma gondii, a related apicomplexan parasite, suggesting that the inhibitors may be acting via a conserved mechanism which could be further exploited for target identification studies. We demonstrate that two molecules, MMV020670 and MMV026356, identified as schizont inhibitors in our screens, induce the fragmentation of DNA in merozoites, thereby impairing their ability to egress and invade. Further mechanistic studies would facilitate the therapeutic exploitation of these molecules as broadly active inhibitors targeting late-stage development and egress of apicomplexan parasites relevant to human health.</p>
10aDNA fragmentation10aegress10aMedicines for Malaria Venture10aMMV10aPathogen Box10aphenotypic screening10aPlasmodium falciparum10aschizonts10astage-specific inhibition1 aPatra, Alok, Tanala1 aHingamire, Tejashri1 aBelekar, Meenakshi, A.1 aXiong, Aoli1 aSubramanian, Gowtham1 aBozdech, Zbynek1 aPreiser, Peter1 aShanmugam, Dhanasekaran1 aChandramohanadas, Rajesh  uhttps://library.ncl.res.in/content/whole-cell-phenotypic-screening-medicines-malaria-venture-pathogen-box-identifies-specific03191nas a2200313   4500008004100000022001400041245011700055210006900172260000800241300001200249490000700261520213700268653002902405653002602434653001202460653002602472653001802498100002302516700002502539700002802564700002402592700002802616700002202644700002402666700001902690700001802709700002202727856012802749       2023                        eng d  a1230-282100aAntimalarial activity of anacardium occidentale leaf extracts against plasmodium falciparum transketolase (PfTK)0 aAntimalarial activity of anacardium occidentale leaf extracts ag  cDEC  a832-8410 v683 a<p>
	BackgroundAs per estimates by WHO in 2021 almost half of the world's population was at risk of malaria and &gt; 0.6 million deaths were attributed to malaria. Therefore, the present study was aimed to explore the antimalarial activity of extracts derived from the leaves of the plant Anacardium occidentale L., which has been used traditionally for the treatment of malaria. Different extracts of A.occidentale leaves were prepared and tested for their inhibitory activity against recombinant P. falciparum transketolase (rPfTK) enzyme, in vitro. Further, growth inhibitory activity against cultivated blood stage P. falciparum parasites (3D7 strain), was studied using SYBR Green fluorescence-based in vitro assays. Acute toxicity of the hydro alcoholic extracts of leaves of A. occidentale (HELA) at different concentrations was evaluated on mice and Zebra fish embryos. HELA showed 75.45 +/- 0.35% inhibitory activity against the recombinant PfTk and 99.31 +/- 0.08% growth inhibition against intra-erythrocytic stages of P. falciparum at the maximum concentration (50 mu g/ml) with IC50 of 4.17 +/- 0.22 mu g/ml. The toxicity test results showed that the heartbeat, somite formation, tail detachment and hatching of embryos were not affected when Zebra fish embryos were treated with 0.1 to 10 mu g/ml of the extract. However, at higher concentrations of the extract, at 48 h (1000 mu g/ml) and 96 h (100 mu g/ml and 1000 mu g/ml, respectively) there was no heartbeat in the fish embryos. In the acute oral toxicity tests performed on mice, the extract showed no toxicity up to 300 mg/kg body weight in mice.ConclusionThe hydro-alcoholic extract of leaves of A. occidentale L. showed potent antimalarial activity against blood stage P. falciparum. Based on the observed inhibitory activity on the transketolase enzyme of P. falciparum it is likely that this enzyme is the target for the development of bioactive molecules present in the plant extracts. The promising anti-malarial activity of purified compounds from leaves of A. occidentale needs to be further explored for development of new anti-malarial therapy.</p>
10aAnacardium occidentale L10aAntimalarial activity10amalaria10aPlasmodium falciparum10aTransketolase1 aKaushik, Meenakshi1 aHoti, Sugeerappa, L.1 aSaxena, Jitendra, Kumar1 aHingamire, Tejashri1 aShanmugam, Dhanasekaran1 aJoshi, Rajesh, K.1 aMetgud, Sharada, C.1 aUngar, Banappa1 aSingh, Ishwar1 aHegde, Harsha, V.  uhttps://library.ncl.res.in/content/antimalarial-activity-anacardium-occidentale-leaf-extracts-against-plasmodium-falciparum