Targeting of apicoplast replication and protein synthesis in the apicomplexan Toxoplasma gondii has conventionally been associated with the typical "delayed death" phenotype, characterized by the death of parasites only in the generation following drug intervention. We demonstrate that antibiotics like clindamycin, chloramphenicol, and tetracycline, inhibitors of prokaryotic protein synthesis, invoke the delayed death phenotype in Plasmodium falciparum, too, as evident from a specific reduction of apicoplast genome copy number. Interestingly, however, molecules like triclosan, cerulenin, fops, and NAS-91, inhibitors of the recently discovered fatty acid synthesis pathway, and succinyl acetone, an inhibitor of heme biosynthesis that operates in the apicoplast of the parasite, display rapid and striking parasiticidal effects. Our results draw a clear distinction between apicoplast functions per se and the apicoplast as the site of metabolic pathways, which are required for parasite survival, and thus subserve the development of novel antimalarial therapy.
We
theoretically propose a surface-plasmon-based fiber optic biosensor
in metal/graphene/MoS2 configuration with molybdenum disulfide
(MoS2) as a bio recognition layer. The proposed configuration
works in the visible region of the electromagnetic spectrum with a
very high sensitivity. A comparative theoretical study of the sensors
with different metallic layers of gold (Au), copper (Cu), and aluminum
(Al) has been performed. The sensor has been found to be the most
sensitive in both Cu/graphene/MoS2 and Al/graphene/MoS2 configurations with sensitivity of 6.2 μm/RIU. In both
of the configurations the thicknesses of Cu and Al layers is 50 nm
and the number of layers of graphene is 16 and 27, respectively, while
only a single layer of MoS2 has been used. The sensitivity
of the sensor in the Au/graphene/MoS2 configuration is
5.0 μm/RIU with comparatively high depth of resonance.
Accumulating evidence suggests that deposition of neurotoxic α-synuclein
aggregates in the brain during the development of neurodegenerative diseases like
Parkinson’s disease can be curbed by anti-aggregation strategies that
either disrupt or eliminate toxic aggregates. Curcumin, a dietary polyphenol
exhibits anti-amyloid activity but the use of this polyphenol is limited owing to
its instability. As chemical modifications in curcumin confiscate this limitation,
such efforts are intensively performed to discover molecules with similar but
enhanced stability and superior properties. This study focuses on the inhibitory
effect of two stable analogs of curcumin viz. curcumin pyrazole and curcumin
isoxazole and their derivatives against α-synuclein aggregation,
fibrillization and toxicity. Employing biochemical, biophysical and cell based
assays we discovered that curcumin pyrazole (3) and its derivative
N-(3-Nitrophenylpyrazole) curcumin (15) exhibit remarkable potency in not only
arresting fibrillization and disrupting preformed fibrils but also preventing
formation of A11 conformation in the protein that imparts toxic effects. Compounds 3
and 15 also decreased neurotoxicity associated with fast aggregating A53T mutant
form of α-synuclein. These two analogues of curcumin described here may
therefore be useful therapeutic inhibitors for the treatment of
α-synuclein amyloidosis and toxicity in Parkinson’s disease
and other synucleinopathies.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.