ABSTRACT
An antimalarial screen for plants collected from Papua New Guinea identified an extract of Horsfieldia spicata as having activity. Isolation of the active constituents led to the identification of two new compounds: myristicyclins A (1) and B (2). Both compounds are procyanidin-like congeners of myristinins lacking a pendant aromatic ring. Myristicyclin A was found to inhibit the ring, trophozoite, and schizont stages of Plasmodium falciparum at similar concentrations in the mid-µM range.
Subject(s)
Antimalarials/isolation & purification , Antimalarials/pharmacology , Biflavonoids/isolation & purification , Biflavonoids/pharmacology , Catechin/isolation & purification , Catechin/pharmacology , Plasmodium falciparum/drug effects , Proanthocyanidins/isolation & purification , Proanthocyanidins/pharmacology , Antimalarials/chemistry , Biflavonoids/chemistry , Catechin/chemistry , Malaria, Falciparum/drug therapy , Molecular Structure , Papua New Guinea , Plasmodium falciparum/growth & development , Proanthocyanidins/chemistry , StereoisomerismABSTRACT
Nitric oxide (NO) mediates host resistance to severe malaria and other infectious diseases. NO production and mononuclear cell expression of the NO producing enzyme-inducible nitric oxide synthase (NOS2) have been associated with protection from severe falciparum malaria. The purpose of this study was to identify single nucleotide polymorphisms (SNPs) and haplotypes in the NOS2 promoter, to identify associations of these haplotypes with malaria severity and to test the effects of these polymorphisms on promoter activity. We identified 34 SNPs in the proximal 7.3 kb region of the NOS2 promoter and inferred NOS2 promoter haplotypes based on genotyping 24 of these SNPs in a population of Tanzanian children with and without cerebral malaria. We identified 71 haplotypes; 24 of these haplotypes comprised 82% of the alleles. We determined whether NOS2 promoter haplotypes were associated with malaria severity in two groups of subjects from Dar es Salaam (N = 185 and N = 250) and in an inception cohort of children from Muheza-Tanga, Tanzania (N = 883). We did not find consistent associations of NOS2 promoter haplotypes with malaria severity or malarial anemia, although interpretation of these results was potentially limited by the sample size of each group. Furthermore, cytokine-induced NOS2 promoter activity determined using luciferase reporter constructs containing the proximal 7.3 kb region of the NOS2 promoter and the G-954C or C-1173T SNPs did not differ from NOS2 promoter constructs that lacked these polymorphisms. Taken together, these studies suggest that the relationship between NOS2 promoter polymorphisms and malaria severity is more complex than previously described.
Subject(s)
Haplotypes/genetics , Malaria/genetics , Nitric Oxide Synthase Type II/genetics , Polymorphism, Single Nucleotide , Promoter Regions, Genetic/genetics , Alleles , Base Sequence , Cell Line, Tumor , Child , Child, Preschool , Gene Frequency , Genetic Heterogeneity , Genotype , Humans , Infant , Kenya , Linkage Disequilibrium , Malaria/pathology , Molecular Sequence Data , Mutation , Sequence Analysis, DNA , Sequence Homology, Nucleic Acid , Severity of Illness Index , TanzaniaABSTRACT
A traditional preparation of Parmotrema saccatilobum (Taylor) Hale (Family: Parmeliaceae) is being considered for inclusion into the PNG national drug formulary by the Ministry of Health Taskforce on Traditional Medicines. The lichen preparation is traditionally used in the Milne Bay province of Papua New Guinea for analgesic and anti-inflammatory activities. A hexane extract of P. saccatilobum yielded the principle components atranorin and chloroatranorin. Atranorin and chloroatranorin were tested in a COX-1 and -2 enzyme inhibition assay, which showed that atranorin inhibited COX-1 in a dose dependent manner and suggests partial inhibition by atranorin and chloroatranorin of COX-2 and COX-1, respectively.