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Search Results: 1 - 10 of 148524 matches for " Jonathan K. Stiles "
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Plasmodium berghei ANKA infection increases Foxp3, IL-10 and IL-2 in CXCL-10 deficient C57BL/6 mice
Bismark Y Sarfo, Nana O Wilson, Vincent C Bond, Jonathan K Stiles
Malaria Journal , 2011, DOI: 10.1186/1475-2875-10-69
Abstract: The hypothesis that resistance of CXCL-10-/- mice to murine CM may be due to enhanced expression of Foxp3 in concert with IL-10 and IL-2 was tested. CXCL-10-/- and WT C57BL/6 mice were infected with Plasmodium berghei ANKA and evaluated for CM symptoms. Brain, peripheral blood mononuclear cells (PBMCs) and plasma were harvested from infected and uninfected mice at days 2, 4 and 8. Regulatory T cells (CD4+CD25+) and non-T regs (CD4+CD25-) were isolated from PBMCs and cultured with P. berghei antigens in vitro with dendritic cells as antigen presenting cells. Regulatory T cell transcription and specific factor Foxp3, was evaluated in mouse brain and PBMCs by realtime-PCR and Western blots while IL-10, and IL-2 were evaluated in plasma and cultured supernatants by ELISA.Wild type mice exhibited severe murine CM symptoms compared with CXCL-10-/- mice. Foxp3 mRNA and protein in brain and PBMC's of CXCL-10-/- mice was significantly up-regulated (p < 0.05) by day 4 post-infection (p.i) compared with WT. Plasma levels of IL-10 and IL-2 in infected CXCL-10-/- were higher than in WT mice (p < 0.05) at days 2 and 4 p.i. Ex-vivo CD4+CD25+ T cells from CXCL-10-/- re-stimulated with P. berghei antigens produced more IL-10 than WT CD4+CD25+ T cells.The results indicate that in the absence of CXCL-10, the resulting up-regulation of Foxp3, IL-10 and IL-2 may be involved in attenuating fatal murine CM.Cerebral malaria (CM) is a major cause of malaria mortality in endemic countries. The current paradigm of CM pathogenesis suggests that parasite proliferation activates endothelial cells to produce adhesion molecules that enable sequestration of infected and uninfected red blood cells (RBCs) in brain capillaries which obstruct brain microvessels which results in severe inflammatory processes that lead to CM syndrome. Recently it has been reported that regulatory inflammatory responses are associated with CM but the mechanism by which they regulate CM pathogenesis is unclear. For example
STAT3 Regulates MMP3 in Heme-Induced Endothelial Cell Apoptosis
Mingli Liu, Nana O. Wilson, Jacqueline M. Hibbert, Jonathan K. Stiles
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0071366
Abstract: Background We have previously reported that free Heme generated during experimental cerebral malaria (ECM) in mice, is central to the pathogenesis of fatal ECM. Heme-induced up-regulation of STAT3 and CXCL10 promotes whereas up-regulation of HO-1 prevents brain tissue damage in ECM. We have previously demonstrated that Heme is involved in the induction of apoptosis in vascular endothelial cells. In the present study, we further tested the hypothesis that Heme reduces blood-brain barrier integrity during ECM by induction of apoptosis of brain vascular endothelial cells through STAT3 and its target gene matrix metalloproteinase three (MMP3) signaling. Methods Genes associated with the JAK/STAT3 signaling pathway induced upon stimulation by Heme treatment, were assessed using real time RT2 Profile PCR arrays. A human MMP3 promoter was cloned into a luciferase reporter plasmid, pMMP3, and its activity was examined following exposure to Heme treatment by a luciferase reporter gene assay. In order to determine whether activated nuclear protein STAT3 binds to the MMP3 promoter and regulates MMP3 gene, we conducted a ChIP analysis using Heme-treated and untreated human brain microvascular endothelial cells (HBVEC), and determined mRNA and protein expression levels of MMP3 using qRT-PCR and Western blot. Apoptosis in HBVEC treated with Heme was evaluated by MTT and TUNEL assay. Results The results show that (1) Heme activates a variety of JAK/STAT3 downstream pathways in HBVEC. STAT3 targeted genes such as MMP3 and C/EBPb (Apoptosis-related genes), are up regulated in HBVEC treated with Heme. (2) Heme-induced HBVEC apoptosis via activation of STAT3 as well as its downstream signaling molecule MMP3 and upregulation of CXCL10 and HO-1 expressions. (3) Phosphorylated STAT3 binds to the MMP3 promoter in HBVEC cells, STAT3 transcribed MMP3 and induced MMP3 protein expression in HBVEC cells. Conclusions Activated STAT3 binds to the MMP3 promoter region and regulates MMP3 in Heme-induced endothelial cell apoptosis.
Macrophage migration inhibitory factor is associated with mortality in cerebral malaria patients in India
Vidhan Jain, Shannon McClintock, Avinash C Nagpal, Aditya P Dash, Jonathan K Stiles, Venkatachalam Udhayakumar, Neeru Singh, Naomi W Lucchi
BMC Research Notes , 2009, DOI: 10.1186/1756-0500-2-36
Abstract: Three categories of subjects contributed to this study: healthy controls subjects, mild malaria patients, and cerebral malaria patients. The cerebral malaria patients were further grouped into cerebral malaria survivors and cerebral malaria non-survivors. MIF levels in the peripheral blood plasma, obtained at the time of enrollment, were measured using standard ELISA methods. In logistic regression on cerebral malaria patients, log MIF levels were found to be significantly associated with fatal outcome (odds ratio 4.0; 95%CI 1.6, 9.8; p = 0.003). In multinomial logistic regression log MIF levels were found to be significantly associated with patient category (p = 0.004).This study suggests that elevated levels of MIF in the peripheral blood of cerebral malaria patients may be associated with fatal outcomes.Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine whose role as an important regulator of immune and inflammatory responses in a number of human diseases, such as sepsis, rheumatoid arthritis, cancer and inflammatory neurological diseases, has been confirmed (reviewed in [1]). Its role in the pathogenesis of malaria has only begun to be investigated. The potential role of MIF in the pathogenesis of malaria anemia was evident from an experimental study using a mouse model in which high MIF levels were associated with malaria anemia [2]. However, most human studies conducted with African children have reported lower levels of MIF in malaria infected children compared to healthy asymptomatic children [3]. In addition, a recent study demonstrated a decline in MIF levels during an experimental malaria infection using healthy European volunteers [4]. These studies have suggested a protective role for MIF during malaria. However, a few studies have reported an increase in MIF levels during malaria infections [2,5,6]. Elevated MIF levels were observed in malaria infected Zambian children compared to uninfected children [2]. Pregnant women with pla
Genetic polymorphisms linked to susceptibility to malaria
Adel Driss, Jacqueline M Hibbert, Nana O Wilson, Shareen A Iqbal, Thomas V Adamkiewicz, Jonathan K Stiles
Malaria Journal , 2011, DOI: 10.1186/1475-2875-10-271
Abstract: Recent advances in human genome research technologies such as genome-wide association studies (GWAS) and fine genotyping tools have enabled the discovery of several genetic polymorphisms and biomarkers that warrant further study in host-parasite interactions. This review describes and discusses human gene polymorphisms identified thus far that have been shown to be associated with susceptibility or resistance to P. falciparum malaria. Although some polymorphisms play significant roles in susceptibility to malaria, several findings are inconclusive and contradictory and must be considered with caution. The discovery of genetic markers associated with different malaria phenotypes will help elucidate the pathophysiology of malaria and enable development of interventions or cures. Diversity in human populations as well as environmental effects can influence the clinical heterogeneity of malaria, thus warranting further investigations with a goal of developing new interventions, therapies and better management against malaria.Plasmodium falciparum malaria is a major cause of mortality and morbidity, particularly in endemic areas of sub-Saharan Africa [1]. The disease aetiology is variable and is attributable to environmental factors, host genetics and parasite virulence [2]. Variations in severity of P. falciparum infections considered as different phenotypes include hyper or asymptomatic parasitaemia (proportion of red blood cells that are parasitized), severe malaria anaemia (SMA) and cerebral malaria (CM). Host genetic factors contribute to the variability of malaria phenotypes [3] and thus, should help to determine some of the mechanisms involved in susceptibility to P. falciparum infection. The knowledge gained since 1980s using molecular genetics approaches has produced undisputed evidence about polymorphisms associated with malaria resistance and their complex interactions. Indeed, several gene mutations and polymorphisms in the human hosts confer survival advanta
Pharmacologic Inhibition of CXCL10 in Combination with Anti-malarial Therapy Eliminates Mortality Associated with Murine Model of Cerebral Malaria
Nana O. Wilson, Wesley Solomon, Leonard Anderson, John Patrickson, Sidney Pitts, Vincent Bond, Mingli Liu, Jonathan K. Stiles
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0060898
Abstract: Despite appropriate anti-malarial treatment, cerebral malaria (CM)-associated mortalities remain as high as 30%. Thus, adjunctive therapies are urgently needed to prevent or reduce such mortalities. Overproduction of CXCL10 in a subset of CM patients has been shown to be tightly associated with fatal human CM. Mice with deleted CXCL10 gene are partially protected against experimental cerebral malaria (ECM) mortality indicating the importance of CXCL10 in the pathogenesis of CM. However, the direct effect of increased CXCL10 production on brain cells is unknown. We assessed apoptotic effects of CXCL10 on human brain microvascular endothelial cells (HBVECs) and neuroglia cells in vitro. We tested the hypothesis that reducing overexpression of CXCL10 with a synthetic drug during CM pathogenesis will increase survival and reduce mortality. We utilized atorvastatin, a widely used synthetic blood cholesterol-lowering drug that specifically targets and reduces plasma CXCL10 levels in humans, to determine the effects of atorvastatin and artemether combination therapy on murine ECM outcome. We assessed effects of atorvastatin treatment on immune determinants of severity, survival, and parasitemia in ECM mice receiving a combination therapy from onset of ECM (day 6 through 9 post-infection) and compared results with controls. The results indicate that CXCL10 induces apoptosis in HBVECs and neuroglia cells in a dose-dependent manner suggesting that increased levels of CXCL10 in CM patients may play a role in vasculopathy, neuropathogenesis, and brain injury during CM pathogenesis. Treatment of ECM in mice with atorvastatin significantly reduced systemic and brain inflammation by reducing the levels of the anti-angiogenic and apoptotic factor (CXCL10) and increasing angiogenic factor (VEGF) production. Treatment with a combination of atorvastatin and artemether improved survival (100%) when compared with artemether monotherapy (70%), p<0.05. Thus, adjunctively reducing CXCL10 levels and inflammation by atorvastatin treatment during anti-malarial therapy may represent a novel approach to treating CM patients.
Plasma levels of angiopoietin-1 and -2 predict cerebral malaria outcome in Central India
Vidhan Jain, Naomi W Lucchi, Nana O Wilson, Anna J Blackstock, Avinash C Nagpal, Pradeep K Joel, Mrigendra P Singh, Venkatachalam Udhayakumar, Jonathan K Stiles, Neeru Singh
Malaria Journal , 2011, DOI: 10.1186/1475-2875-10-383
Abstract: Patients enrolled in the study were clinically characterized as healthy controls (HC), mild malaria (MM), CM survivors (CMS) and CM non-survivors (CMNS) based on their malaria status and hospital treatment outcome. Plasma ANG-1 and ANG-2 levels were assessed using sandwich ELISA. Receiver operating characteristic (ROC) curve analysis was used to calculate area under the curve (AUC) for each biomarker in order to assess predictive accuracy of individual biomarkers.The plasma levels of ANG-1 were lower in CMS and CMNS compared to control groups (mild malaria and healthy controls) at the time of hospital admission. On the contrary, ANG-2 levels positively correlated with malaria severity and were significantly higher in CMNS. The ratio of ANG-2/ANG-1 was highest in CMNS compared to other groups. Receiver operating characteristic curves revealed that compared to ANG-1 (AUC = 0.35), ANG-2 (AUC = 0.95) and ratio of ANG-2/ANG-1 (AUC = 0.90) were better markers to discriminate CMNS from MM cases. However, they were less specific in predicting fatal outcome amongst CM cases at the time of hospital admission.These results suggest that at the time of admission plasma levels of ANG-2 and ratio of ANG-2/ANG-1 are clinically informative biomarkers to predict fatal CM from MM cases while they have limited usefulness in discriminating fatal CM outcomes in a pool of CM cases in endemic settings of Central India.Cerebral malaria (CM) is a severe form of central nervous system (CNS) pathology associated with Plasmodium falciparum infection. It is characterized by unarousable coma that often begins with seizures among children but coma in adults is less frequently associated with seizures [1]. Despite treatment, mortality due to CM can be as high as 30%, while neurological sequelae that are uncommon in adults occurred among 10% of children recovering from CM [1-3]. Further CM is also associated with cognitive deficit [4,5]. Early diagnosis and prompt treatment can minimize or avert mor
Elevated Levels of IL-10 and G-CSF Associated with Asymptomatic Malaria in Pregnant Women
Nana O. Wilson,Tameka Bythwood,Wesley Solomon,Pauline Jolly,Nelly Yatich,Yi Jiang,Faisal Shuaib,Andrew A. Adjei,Winston Anderson,Jonathan K. Stiles
Infectious Diseases in Obstetrics and Gynecology , 2010, DOI: 10.1155/2010/317430
Abstract: In sub-Saharan Africa, approximately 30 million pregnant women are at risk of contracting malaria annually. Nearly 36% of healthy pregnant women receiving routine antenatal care tested positive for Plasmodium falciparum HRP-II antigen in Ghana. We tested the hypothesis that asymptomatic HRP II positive pregnant women expressed a unique Th1 and Th2 phenotype that differs from healthy controls. Plasma from healthy ( ) and asymptomatic ( ) pregnant women were evaluated for 27 biomarkers (IL-1b, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL- 17, Eotaxin, bFGF-2, G-CSF, GM-CSF, IFN- , IP-10, MCP-1, MIP-1 , MIP-1 , PDGF-bb, RANTES, TNF, and VEGF) associated with Th1 and Th2 cytokine homeostasis. IL-10 and G-CSF levels were elevated in the asymptomatic group when compared with the healthy group ( and .041, resp.). The median ratios of IL-1 :5, IL-1 :10, IL-1 :G-CSF, IL-1 :Eotaxin, IL-12:G-CSF, IL-15:10, IL-17:G-CSF, IL-17:Eotaxin, TNF:IL-4, TNF:IL-5, and TNF:G-CSF were significantly different among the two groups. Thus, asymptomatic malaria carriage may be linked to circulating levels of IL-10 and G-CSF. 1. Introduction The World Health Organization estimates that around 250 million cases of malaria infections and 1–3 million associated deaths globally are reported annually [1]. Infection with Plasmodium falciparum has a wide spectrum of manifestations that are classified into three main clinical groups: asymptomatic (presence of malaria parasite without malaria symptoms), mild, and severe malaria. In malaria-endemic areas, a significant proportion of individuals considered asymptomatic, harbor parasites without presenting signs of clinical malaria [2]. The significance of such asymptomatic infections in the broader context of malaria transmission has been evaluated in diverse situations using complementary approaches [3–6]. Variant-specific immunity has been used to explain the low-grade infection during extended periods without clinical symptoms [7]. Studies suggest that long-term asymptomatic carriage may represent a form of tolerance to parasites in individuals such that asymptomatic carriage may protect these individuals from developing severe malaria [3–5]. Older individuals are more likely to develop uncomplicated malaria or asymptomatic parasitemia [8]. In high malaria endemic areas, protection from severe malaria is acquired early during childhood, although it takes longer to be protected from less severe disease [9]. Although immunoprotective mechanisms clear a large proportion of infected erythrocytes, a subset
Heme Mediated STAT3 Activation in Severe Malaria
Mingli Liu, Audu S. Amodu, Sidney Pitts, John Patrickson, Jacqueline M. Hibbert, Monica Battle, Solomon F. Ofori-Acquah, Jonathan K. Stiles
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0034280
Abstract: Background The mortality of severe malaria [cerebral malaria (CM), severe malaria anemia (SMA), acute lung injury (ALI) and acute respiratory distress syndrome (ARDS)] remains high despite the availability associated with adequate treatments. Recent studies in our laboratory and others have revealed a hitherto unknown correlation between chemokine CXCL10/CXCR3, Heme/HO-1 and STAT3 and cerebral malaria severity and mortality. Although Heme/HO-1 and CXCL10/CXCR3 interactions are directly involved in the pathogenesis of CM and fatal disease, the mechanism dictating how Heme/HO-1 and CXCL10/CXCR3 are expressed and regulated under these conditions is still unknown. We therefore tested the hypothesis that these factors share common signaling pathways and may be mutually regulated. Methods We first clarified the roles of Heme/HO-1, CXCL10/CXCR3 and STAT3 in CM pathogenesis utilizing a well established experimental cerebral malaria mouse (ECM, P. berghei ANKA) model. Then, we further determined the mechanisms how STAT3 regulates HO-1 and CXCL10 as well as mutual regulation among them in CRL-2581, a murine endothelial cell line. Results The results demonstrate that (1) STAT3 is activated by P. berghei ANKA (PBA) infection in vivo and Heme in vitro. (2) Heme up-regulates HO-1 and CXCL10 production through STAT3 pathway, and regulates CXCL10 at the transcriptional level in vitro. (3) HO-1 transcription is positively regulated by CXCL10. (4) HO-1 regulates STAT3 signaling. Conclusion Our data indicate that Heme/HO-1, CXCL10/CXCR3 and STAT3 molecules as well as related signaling pathways play very important roles in the pathogenesis of severe malaria. We conclude that these factors are mutually regulated and provide new opportunities to develop potential novel therapeutic targets that could be used to supplement traditional prophylactics and treatments for malaria and improve clinical outcomes while reducing malaria mortality. Our ultimate goal is to develop novel therapies targeting Heme or CXCL10-related biological signaling molecules associated with development of fatal malaria.
Antibody responses to the merozoite surface protein-1 complex in cerebral malaria patients in India
Naomi W Lucchi, Jon Tongren, Vidhan Jain, Avinash C Nagpal, Christian W Kauth, Ute Woehlbier, Hermann Bujard, Aditya P Dash, Neeru Singh, Jonathan K Stiles, Venkatachalam Udhayakumar
Malaria Journal , 2008, DOI: 10.1186/1475-2875-7-121
Abstract: Peripheral blood antibody responses to recombinant antigens of the two major allelic forms of MSP-1 complex, MSP-636 and MSP-722 were compared between healthy subjects, mild malaria patients (MM) and CM patients residing in a malaria endemic region of central India. Total IgG and IgG subclass antibody responses were determined using ELISA method.The prevalence and levels of IgG and its subclasses in the plasma varied for each antigen. In general, the prevalence of total IgG, IgG1 and IgG3 was higher in the MM patients and lower in CM patients compared to healthy controls. Significantly lower levels of total IgG antibodies to the MSP-1f38, IgG1 levels to MSP-1d83, MSP-119 and MSP-636 and IgG3 levels to MSP-1f42 and MSP-722 were observed in CM patients as compared to MM patients.These results suggest that there may be some dysregulation in the generation of antibody responses to some MSP antigens in CM patients and it is worth investigating further whether perturbations of antibody responses in CM patients contribute to pathogenesis.One life-threatening complication of Plasmodium falciparum infection is cerebral malaria (CM). This complex syndrome affects mainly young children (two to six years old) in sub-Saharan Africa with an estimated incidence of 1.12 cases per 1,000 children per year and an estimated mortality of 18.6% [1]. In addition, a subset of CM survivors have an increased risk of developing persistent neurocognitive sequelae post-recovery [2-4] and reviewed in [5]. In Asia and South America, where the intensity of P. falciparum is much lower than in Africa, all age groups are at risk for CM [1,6-9]. The pathogenesis of CM is complex and it is still poorly understood as to why only a subset of patients develop CM. Various factors, such as sequestration of infected erythrocytes, and inflammatory cytokines and chemokines, have been postulated to play major roles in CM pathogenesis [10-17]. The role of antibodies in CM pathogenesis or protection is not well u
Plasmodium yoelii 17XL infection up-regulates RANTES, CCR1, CCR3 and CCR5 expression, and induces ultrastructural changes in the cerebellum
Bismark Y Sarfo, Henry B Armah, Ikovwaiza Irune, Andrew A Adjei, Christine S Olver, Shailesh Singh, James W Lillard, Jonathan K Stiles
Malaria Journal , 2005, DOI: 10.1186/1475-2875-4-63
Abstract: The alterations in immunomodulator gene expression in brains of Plasmodium yoelii 17XL-infected mice was analysed using cDNA microarray screening, followed by a temporal comparison of mRNA and protein expression of RANTES and its corresponding receptors by qRT-PCR and Western blot analysis, respectively. Plasma RANTES levels was determined by ELISA and ultrastructural studies of brain sections from infected and uninfected mice was conducted.RANTES (p < 0.002), CCR1 (p < 0.036), CCR3 (p < 0.033), and CCR5 (p < 0.026) mRNA were significantly upregulated at peak parasitaemia and remained high thereafter in the experimental mouse model. RANTES protein in the brain of infected mice was upregulated (p < 0.034) compared with controls. RANTES plasma levels were significantly upregulated; two to three fold in infected mice compared with controls (p < 0.026). Some d istal microvascular endothelium in infected cerebellum appeared degraded, but remained intact in controls.The upregulation of RANTES, CCR1, CCR3, and CCR5 mRNA, and RANTES protein mediate inflammation and cellular degradation in the cerebellum during P. yoelii 17XL malaria.Malaria afflicts between 300–500 million people causing up to 2 million deaths globally per year [1]. Cerebral malaria (CM), characterized by seizures and loss of consciousness, is the most severe complication of Plasmodium falciparum infection with mortality rates ranging from 15 to 20% [2,3]. Malaria-induced brain inflammation is known to be mediated partly by complex cellular and immunomodulator interactions, involving co-regulators such as cytokines and adhesion molecules, resulting in the sequestration of parasite-infected erythrocytes in the brain in human CM. Apart from the sequestration of P. falciparum-infected erythrocytes, recent studies [4-7] have revealed significant accumulation of platelets and leukocytes in the distal microvasculature of the brains of human cases of CM, suggesting a role for platelet and leukocyte sequestration i
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