Research LettersInducible nitric oxide synthase polymorphism and fatal cerebral malaria
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Possible central role of nitric oxide in conditions clinically similar to cerebral malaria
Lancet
(1992) - JFJ Kun et al.
Polymorphism in promoter region of inducible nitric oxide synthase and protection against malaria
Lancet
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Cited by (115)
Unravelling the influence of host genetic factors on malaria susceptibility in Asian populations
2024, Acta TropicaMalaria is a deadly blood-borne disease caused by a Plasmodium parasite. Infection results in various forms of malaria, including an asymptomatic state, uncomplicated disease, or severe disease. Severe malaria (SM) is particularly prevalent among young children and is a significant cause of mortality. SM is associated with the sequestration of parasitized erythrocytes in the microvasculature of vital host organs, disrupting the normal functioning of the immune system. Although the exact mechanisms of malaria pathogenesis are yet to be fully understood, researchers have been investigating the role of host genetics in determining the severity of the disease and the outcome of infection. The objective of this study is to identify specific host genes that have been examined for their association with malaria in Asian populations and pinpoint those most likely to influence susceptibility. Through an extensive screening process, a total of 982 articles were initially identified, and after careful review, 40 articles discussing 68 genes were included in this review. By constructing a network of protein-protein interactions (PPIs), we identified six key proteins (TNF, IL6, TLR4, IL1β, IL10, and IL8) that exhibited substantial interactions (more than 30 edges), suggesting their potential as significant targets for influencing malaria susceptibility. Notably, these six proteins have been previously identified as crucial components of the immune response, associated with malaria susceptibility, and capable of affecting different clinical forms of the disease. Identifying genes that contribute to malaria susceptibility or resistance holds the promise of enhancing the diagnosis and treatment of this debilitating illness. Such knowledge has the potential to pave the way for more targeted and effective strategies in combating malaria, particularly in Asian populations where controlling Plasmodium vivax is challenging, and India contributes the highest number of cases. By understanding the genetic factors underlying malaria vulnerability, we can develop interventions that are tailored to the specific needs of Asian populations, ultimately leading to better outcomes in the fight against this disease.
Overview of human genetic susceptibility to malaria: From parasitemia control to severe disease
2018, Infection, Genetics and EvolutionMalaria is a life-threatening blood disease caused by the protozoan Plasmodium. Infection may lead to several different patterns of symptoms in the host: asymptomatic state, uncomplicated disease or severe disease. Severe malaria occurs mostly in young children and is a major cause of death. Disease is thought to result from the sequestration of parasites in the small blood vessels of the brain and the deregulation of key immune system elements. The cellular and molecular regulatory mechanisms underlying the pathogenesis of disease are however not fully understood. What is known it is that the genetic determinants of the host play an important role in the severity of the disease and the outcome of infection. Here we review the most convincing results obtained through genetic epidemiology studies concerning the genetic control of malaria in human caused by Plasmodium falciparum infection. The identification of genes conferring susceptibility or resistance to malaria might improve diagnosis and treatment.
iNOS polymorphism modulates iNOS/NO expression via impaired antioxidant and ROS content in P. vivax and P. falciparum infection
2018, Redox BiologyNitric oxide (NO) has dicotomic influence on modulating host-parasite interplay, synchronizing physiological orchestrations and diagnostic potential; instigated us to investigate the plausible association and genetic regulation among NO level, components of oxidative stress, iNOS polymorphisms and risk of malaria. Here, we experimentally elucidate that iNOS promoter polymorphisms are associated with risk of malaria; employing mutation specific genotyping, functional interplay using western blot and RT-PCR, quantitative estimation of NO, total antioxidant content (TAC) and reactive oxygen species (ROS).
Genotyping revealed significantly associated risk of P. vivax (adjusted OR = 1.92 and 1.72) and P. falciparum (adjusted OR = 1.68 and 1.75) infection with SNP at iNOS-954G/C and iNOS-1173C/T positions, respectively; though vivax showed higher risk of infection. Intriguingly, mutation and infection specific differential upregulation of iNOS expression/NO level was observed and found to be significantly associated with mutant genotypes. Moreover, P. vivax showed pronounced iNOS protein (2.4 fold) and mRNA (2.5 fold) expression relative to healthy subjects. Furthermore, TAC and ROS were significantly decreased in infection; and differentially decreased in mutant genotypes.
Our findings endorse polymorphic regulation of iNOS expression, altered oxidant-antioxidant components and evidences of risk association as the hallmark of malaria pathogenesis. iNOS/NO may serve as potential diagnostic marker in assessing clinical malaria.
Exhaled nitric oxide and inducible nitric oxide synthase gene polymorphism in Japanese asthmatics
2016, Allergology InternationalInducible nitric oxide synthase (iNOS) induced by inflammatory cytokines and iNOS activity in bronchial epithelial cells is a major determinant of fractional exhaled nitric oxide (FeNO) levels. The aim of this study was to investigate the association of iNOS promoter gene polymorphisms and FeNO levels in Japanese asthmatics before the introduction of asthma treatment.
Asthmatics were recruited from Fukushima Medical University Hospital. Genotyping of the pentanucleotide repeat (CCTTT)n and seven previously detected single nucleotide polymorphisms (SNPs) in the iNOS promoter lesion was performed. The relationships between the genotypes and FeNO levels before the introduction of asthma treatment were compared.
In 91 asthmatics, the number of microsatellite repeats ranged from 9 to 20 and showed a bimodal distribution. According to this distribution, asthmatics were divided into two groups: genotypes with at least one long allele with more than 14 repeats (L/s or L/L) and genotypes with both short alleles with 14 or fewer repeats (s/s). No significant differences were observed in each parameter between the two groups. The mean FeNO level before treatment was significantly higher in the L/s or L/L subjects than in the s/s subjects. After treatment, the lowest FeNO level did not differ between the two groups. Three SNPs detected in the Japanese subjects were not associated with FeNO levels.
The number of CCTTT repeats in the iNOS promoter region was associated with FeNO levels in asthmatics before treatment, suggesting the importance of iNOS genotype in the clinical application of FeNO for asthmatics.
Influence of Intron II microsatellite polymorphism in human toll-like receptor 2 gene in leprosy
2013, Human ImmunologyLeprosy is a chronic granulomatous infection caused by the obligate intracellular organism Mycobacterium leprae. TLR2 plays a key role when activated by M. leprae lipoproteins initiating protective responses which induce bacterial killing and therefore control of disease spread. Microsatellite polymorphisms in intron2 of TLR2 gene have been reported to be associated with development of clinical features of several infectious diseases. The study aims to evaluate the influence of GT microsatellite on the expression of TLR2 which could make humans prone to M. leprae infections. A total of 279 individuals were enrolled in the study, 88 were leprosy patients, 95 were house hold contacts (HHC) and 96 were healthy controls (HC). Genotyping was done using PCR-Sequencing method. TLR2 mRNA expression was analyzed by RT-PCR. IL-10 and IFN-γ levels were measured using ELISA in MLSA stimulated cell culture supernatants. Statistical analysis was performed using Chi-Square (χ2) test and t-tests. Allele/genotype of TLR2 microsatellite which includes longer GT repeats was associated with low TLR2 mRNA expression and high IL-10 production while that including shorter GT repeats was associated with high TLR2 mRNA expression and low IL-10 production. High IL10 producing allele of TLR2 microsatellite might predispose house hold contacts to leprosy.
Nitric oxide for the adjunctive treatment of severe malaria: Hypothesis and rationale
2011, Medical HypothesesWe hypothesize that supplemental inhaled nitric oxide (iNO) will improve outcomes in children with severe malaria receiving standard antimalarial therapy. The rationale for the hypothesized efficacy of iNO rests on: (1) biological plausibility, based on known actions of NO in modulating endothelial activation; (2) pre-clinical efficacy data from animal models of experimental cerebral malaria; and (3) a human trial of the NO precursor l-arginine, which improved endothelial function in adults with severe malaria. iNO is an attractive new candidate for the adjunctive treatment of severe malaria, given its proven therapeutic efficacy in animal studies, track record of safety in clinical practice and numerous clinical trials, inexpensive manufacturing costs, and ease of administration in settings with limited healthcare infrastructure. We plan to test this hypothesis in a randomized controlled trial (ClinicalTrials.gov Identifier: NCT01255215).