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Chemometric studies on natural products as potential inhibitors of the NADH oxidase from Trypanosoma cruzi using the VolSurf approach.

ABSTRACT: Natural products have widespread biological activities, including inhibition of mitochondrial enzyme systems. Some of these activities, for example cytotoxicity, may be the result of alteration of cellular bioenergetics. Based on previous computer-aided drug design (CADD) studies and considering reported data on structure-activity relationships (SAR), an assumption regarding the mechanism of action of natural products against parasitic infections involves the NADH-oxidase inhibition. In this study, chemometric tools, such as: Principal Component Analysis (PCA), Consensus PCA (CPCA), and partial least squares regression (PLS), were applied to a set of forty natural compounds, acting as NADH-oxidase inhibitors. The calculations were performed using the VolSurf+ program. The formalisms employed generated good exploratory and predictive results. The independent variables or descriptors having a hydrophobic profile were strongly correlated to the biological data.

SUBMITTER: Scotti L

PROVIDER: S-EPMC6259467 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Chemometric studies on natural products as potential inhibitors of the NADH oxidase from Trypanosoma cruzi using the VolSurf approach.

Scotti Luciana L Ferreira Elizabeth Igne EI Silva Marcelo Sobral da MS Scotti Marcus Tullius MT

Molecules (Basel, Switzerland) 20101021 10

Natural products have widespread biological activities, including inhibition of mitochondrial enzyme systems. Some of these activities, for example cytotoxicity, may be the result of alteration of cellular bioenergetics. Based on previous computer-aided drug design (CADD) studies and considering reported data on structure-activity relationships (SAR), an assumption regarding the mechanism of action of natural products against parasitic infections involves the NADH-oxidase inhibition. In this stu ...[more]

PMID: 20966878

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Project description:BackgroundSexual reproduction provides an evolutionary advantageous mechanism that combines favorable mutations that have arisen in separate lineages into the same individual. This advantage is especially pronounced in microparasites as allelic reassortment among individuals caused by sexual reproduction promotes allelic diversity at immune evasion genes within individuals which is often essential to evade host immune systems. Despite these advantages, many eukaryotic microparasites exhibit highly-clonal population structures suggesting that genetic exchange through sexual reproduction is rare. Evidence supporting clonality is particularly convincing in the causative agent of Chagas disease, Trypanosoma cruzi, despite equally convincing evidence of the capacity to engage in sexual reproduction.Methodology/ principle findingsIn the present study, we investigated two hypotheses that can reconcile the apparent contradiction between the observed clonal population structure and the capacity to engage in sexual reproduction by analyzing the genome sequences of 123 T. cruzi isolates from a natural population in Arequipa, Peru. The distribution of polymorphic markers within and among isolates provides clear evidence of the occurrence of sexual reproduction. Large genetic segments are rearranged among chromosomes due to crossing over during meiosis leading to a decay in the genetic linkage among polymorphic markers compared to the expectations from a purely asexually-reproducing population. Nevertheless, the population structure appears clonal due to a high level of inbreeding during sexual reproduction which increases homozygosity, and thus reduces diversity, within each inbreeding lineage.Conclusions/ significanceThese results effectively reconcile the apparent contradiction by demonstrating that the clonal population structure is derived not from infrequent sex in natural populations but from high levels of inbreeding. We discuss epidemiological consequences of this reproductive strategy on genome evolution, population structure, and phenotypic diversity of this medically important parasite.

Project description:Trypanosoma cruzi, the aetiological agent of Chagas disease, invades nucleated mammalian cells including macrophages. In this study, we investigated the crosstalk between T. cruzi-induced immune activation of reactive oxygen species (ROS) and pro-inflammatory responses, and their role in myocardial pathology. Splenocytes of infected mice (C3H/HeN) responded to Tc-antigenic stimulus by more than a two-fold increase in NADPH oxidase (NOX) activity, ROS generation, cytokine production (IFN-? > IL-4 > TNF? > IL1-?? IL6), and predominant expansion of CD4(+) and CD8(+) T cells. Inhibition of NOX, but not of myeloperoxidase and xanthine oxidase, controlled the ROS (>98%) and cytokine (70-89%) release by Tc-stimulated splenocytes of infected mice. Treatment of infected mice with apocynin (NOX inhibitor) in drinking water resulted in a 50-90% decline in endogenous NOX/ROS and cytokine levels, and splenic phagocytes' proliferation. The splenic percentage of T cells was maintained, though more than a 40% decline in splenic index (spleen weight/body weight) indicated decreased T-cell proliferation in apocynin-treated/infected mice. The blood and tissue parasite burden were significantly increased in apocynin-treated/infected mice, yet acute myocarditis, ie inflammatory infiltrate consisting of macrophages, neutrophils, and CD8(+) T cells, and tissue oxidative adducts (eg 8-isoprostanes, 3-nitrotyrosine, and 4-hydroxynonenal) were diminished in apocynin-treated/infected mice. Consequently, hypertrophy (increased cardiomyocytes' size and ?-MHC, BNP, and ANP mRNA levels) and fibrosis (increased collagen, glycosaminoglycans, and lipid contents) of the heart during the chronic phase were controlled in apocynin-treated mice. We conclude that NOX/ROS is a critical regulator of the splenic response (phagocytes, T cells, and cytokines) to T. cruzi infection, and bystander effects of heart-infiltrating phagocytes and CD8(+) T cells resulting in cardiac remodelling in chagasic mice.

Dataset Information

Chemometric studies on natural products as potential inhibitors of the NADH oxidase from Trypanosoma cruzi using the VolSurf approach.

Publications

Chemometric studies on natural products as potential inhibitors of the NADH oxidase from Trypanosoma cruzi using the VolSurf approach.

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