Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three cecropin genes (AgCecA-C) were identified from Anopheles gambiae, a major vector for malaria in sub-Saharan Africa. These genes form a cluster with AgCecA and AgCecB positioned in opposite orientation, while AgCecC is downstream of AgCecA in the same direction. One intron is present in each of these three genes. Motif searches of promoter regions revealed elements that could be regulated by the NF-kappaB family of transcriptional regulators. The divergent promoter (1186 nucleotides in length) between CecA and CecB and the promoter for CecC were analysed by transfection in An. gambiae cell lines. Results showed that these promoters were up-regulated by lipopolysaccharide. The activity was further elevated when heat-inactivated microbes were used to challenge the cell line. At least one NF-kappaB site was required for inducible expression of both CecA and CecB.
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PMID:Genomic organization and regulation of three cecropin genes in Anopheles gambiae. 1242 9

This pharmacological investigation sought to determine whether nitric oxide (NO) had an antiparasitic effect and/or mediated pathology in mice infected with nonlethal P. chabaudi or lethal P. berghei. Nitric oxide synthase (NOS) inhibitors were evaluated for their ability to inhibit the rise in reactive nitrogen intermediates (RNI) induced by bacterial lipopolysaccharide (LPS) in mice. The more effective compound, aminoguanidine (AG) inhibited the rise in RNI induced by P. chabaudi and increased mortality, but had no effect on parasitaemia. Inducers and donors of NO were screened for their ability to increase RNI and the most effective agents evaluated for their ability to modify P. berghei infection. S-Nitrosoglutathione had little effect, but LPS decreased parasitaemia and mortality. An inconsistent relationship is evident between the abilities of these agents to modify NO activity and their effects on malaria in mice. Increased mortality in mice with P. chabaudi treated with AG indicates a reduction in resistance. The absence of an effect on parasitaemia by a NOS inhibitor or NO donor indicates either RNI have insignificant antimalarial action in vivo or the efficacy of the compounds is inadequade. Resistance to P. berghei in LPS-treated mice demonstrates an antiparasitic effect, but this may be attributable to factors other than NO.
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PMID:Pharmacological assessment of the role of nitric oxide in mice infected with lethal and nonlethal species of malaria. 1291 23

The effects of exposure to placental malaria infection on newborn immunological responses, in particular Th1/Th2 cytokines and antigen-presenting cell (APC) function, were compared between cord blood mononuclear cells (CBMC) from parasitized and non-parasitized placentas of Gambian women. Cells were analysed in vitro for their ability to respond to mitogens [phorbol myristate acetate (PMA)/ionomycin, phytohaemagglutinin (PHA)], a malaria-unrelated test antigen [purified protein derivative of Mycobacterium tuberculin[purified protein derivative (PPD)] and Plasmodium falciparum schizont extracts. Mitogens induced strong proliferation and secretion of high concentrations of both IL-13 and sCD30 in CBMC from both groups. Conversely, significantly lower amounts of IFN-gamma were induced in the parasitized group in response to low doses of PHA. Protein antigens induced very low amounts of all tested cytokines, in particular IFN-gamma. However, a significantly higher release of sCD30 was observed in response to schizont extracts in the parasitized group. Addition of LPS to activate APC to low doses of PHA or schizont extracts increased the IFN-gamma production in both groups but levels remained lower in CBMC from the parasitized group. This result correlates with the lower production of IL-12 found following lipopolysaccharide (LPS) stimulation in this group. Taken together, these data show that placental infection with P. falciparum affects Th1 differentiation and sCD30 priming of neonatal lymphocytes and that the probable mode of action is via APC.
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PMID:Plasmodium falciparum infection of the placenta affects newborn immune responses. 1293 Mar 69

Inflammatory responses of human peripheral blood monocytes to the Gram-negative endotoxin lipopolysaccharide (LPS) are enhanced by structurally diverse substances, such as anionic polysaccharides or cationic polypeptides. Only a few substances are known to effectively blunt LPS-induced monocyte activation. We now show that synthetic poly-L-histidine (Hn) binds to LPS and abrogates the release of the proinflammatory cytokine interleukin-8 (IL-8) in LPS-stimulated human whole blood. LPS-induced stimulation of monocytes was strictly pH-dependent with only minor amounts of IL-8 secreted in acidic blood. Maximum levels of IL-8 secretion occurred at a strongly basic pH. Hn inhibition of the release of IL-8 from LPS-stimulated monocytes was observed under acidic, neutral and physiological conditions. With increasing alkalosis, the effectiveness of Hn was gradually lost, suggesting that protonated, but not deprotonated, Hn was effective in inhibiting LPS-induced monocyte responses. Histidine-rich protein 2 from the malaria parasite, Plasmodium falciparum, inhibited the ability of LPS to evoke an inflammatory response in CD14-transfected THP-1 cells. Further, a short synthetic peptide derived from human histidine- and proline-rich glycoprotein also exhibited LPS-inhibitory effects in CD14 transfectants. Taken together, these observations demonstrate the capacity of histidine-rich peptides, irrespective of their origin, to neutralize LPS-induced proinflammatory host responses.
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PMID:Endotoxin-neutralizing effects of histidine-rich peptides. 1455 May 61

Bacterial DNA (bDNA) and lipopolysaccharide (LPS) are potent activators of immune cells such as monocytes and macrophages, which contribute to systemic inflammatory response syndrome (SIRS) and sepsis. To date, no effective anti-sepsis drugs have been developed for clinical use. Chloroquine (CQ), a diprotic weak base traditionally used for treating malaria, was recently shown to decrease cytokine release from macrophages induced by LPS and CpG oligonucleotide (CpG ODN). In the present study, Escherichia coli DNA (EC DNA), CpG ODN and LPS were used to induce SIRS/sepsis in animal models. We found that 30 mg/kg of CQ could protect mice from lethal challenge by CpG ODN and LPS, and 25 mg/kg of CQ could decrease serum TNF-alpha and IL-6 in rats injected with sublethal doses of CpG ODN and LPS. In addition, treatment of murine macrophage ANA-1 cells with 2 mM CQ potently inhibited the release of TNF-alpha, IL-6 and IL-12 induced by CpG ODN and LPS. In human peripheral blood mononuclear cells (hPBMC), 100-200 microM CQ almost completely abrogated release of both TNF-alpha and IL-6 induced by CpG ODN and LPS, whereas IL-6 release induced by EC DNA was not significantly affected by 50 microM CQ. Furthermore, CQ reduced the expression of TLR9 and TLR4 mRNA and the activation of NFkappaB and AP-1 stimulated by CpG ODN and LPS in ANA-1 cells. Flow cytometry and confocal microscopy revealed that CQ increased the accumulation of CpG ODN within ANA-1 cells without influence on its uptake, suggesting that the delayed degradation of CpG ODN was associated with the reduction of proinflammatory cytokine release from the cells. Our results demonstrated that CQ-mediated protection of lethal challenge by CpG ODN and LPS was associated with the reduction of proinflammatory cytokine release.
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PMID:Chloroquine protects mice from challenge with CpG ODN and LPS by decreasing proinflammatory cytokine release. 1499 14

Molecular immunologic determinants of disease severity during Plasmodium falciparum malaria are largely undetermined. Our recent investigations showed that peripheral blood mononuclear cell (PBMC) cyclooxygenase-2 (COX-2) gene expression and plasma prostaglandin E(2) (PGE(2)) production are suppressed in children with falciparum malaria relative to healthy, malaria-exposed children with partial immunity. Furthermore, decreased COX-2/PGE(2) levels were significantly associated with increased plasma interleukin-10 (IL-10), an anti-inflammatory cytokine that inhibits the expression of COX-2 gene products. To determine the mechanism(s) responsible for COX-2-derived PGE(2) suppression, PBMCs were cultured from children with falciparum malaria. PGE(2) production was suppressed under baseline and COX-2-promoting conditions (stimulation with lipopolysaccharide [LPS] and interferon [IFN]-gamma) over prolonged periods, suggesting that an in vivo-derived product(s) was responsible for reduced PGE(2) biosynthesis. Ingestion of hemozoin (malarial pigment) by PBMC was investigated as a source of COX-2/PGE(2) suppression in PBMCs from healthy, malaria-naive adults. In addition, synthetically prepared hemozoin, beta-hematin, was used to investigate the effects of the core iron component of hemozoin, ferriprotoporphyrin-IX (FPIX). Physiologic concentrations of hemozoin or b-hematin suppressed LPS- and IFN-gamma-induced COX-2 mRNA in a time- and dose-dependent manner, resulting in decreased COX-2 protein and PGE(2) production. Suppression of COX-2/PGE(2) by hemozoin was not due to decreased cell viability as evidenced by examination of mitochondrial bioactivity. These data illustrate that ingestion of FPIX by blood mononuclear cells is responsible for suppression of COX-2/PGE(2). Although hemozoin induced overproduction of IL-10, neutralizing IL-10 antibodies failed to restore PGE(2) production. Thus, acquisition of hemozoin by blood mononuclear cells is responsible for suppression of PGE(2) in malaria through inhibition of de novo COX-2 transcripts via molecular mechanisms independent of increased IL-10 production.
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PMID:Reduced peripheral PGE2 biosynthesis in Plasmodium falciparum malaria occurs through hemozoin-induced suppression of blood mononuclear cell cyclooxygenase-2 gene expression via an interleukin-10-independent mechanism. 1550 82

Chloroquine, a well-known lysosomotropic agent, has long been used for the treatment of malaria and rheumatologic disorders. However, therapeutic doses of chloroquine are known to cause behavioral side effects. In the present study, we investigated whether chloroquine stimulates inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) synthesis in C6 glioma cells. Chloroquine caused dose-dependent increase in iNOS protein expression and NO production in C6 glioma cells. A tyrosine kinase inhibitor (genistein), a protein kinase C (PKC) inhibitor (Ro 31-8220), and a p38 mitogen-activated protein kinase (MAPK) inhibitor (SB 203580) all respectively suppressed chloroquine-induced iNOS expression and NO release from C6 glioma cells. Chloroquine activates p38 MAPK and stimulates PKC-alpha and -delta translocation from the cytosol to the membrane in C6 glioma cells. Chloroquine-stimulated p38 MAPK activation was blocked by genistein (20 microM), Ro 31-8220 (3 microM), and SB 203580 (10 microM). Incubation of lipopolysaccharide (LPS)-stimulated cells with chloroquine at non-toxic concentrations (10-100 microM) for 48 h increased iNOS expression, and led to a significant loss of adherent cells. Induction of DNA fragmentation in floating cells indicated that the C6 glioma cells were undergoing apoptosis. Taken together, our data suggest that chloroquine may activate tyrosine kinase and/or PKC to induce p38 MAPK activation, which in turn induces iNOS expression and NO production.
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PMID:Chloroquine induces the expression of inducible nitric oxide synthase in C6 glioma cells. 1568 46

Severe malaria is associated with the failure of host defenses to control parasite replication, with the excessive secretion of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), and with the sequestration of parasitized erythrocytes (PEs) in the microcirculation of vital organs. The scavenger receptor CD36, known as a major sequestration receptor, has also been identified as an important factor in mediating nonopsonic phagocytosis of PEs by monocytes and macrophages. The specific consequence of this phagocytosis is a decrease in parasite-induced TNF-alpha secretion. We evaluated the variations in CD36 level and in lipopolysaccharide (LPS)-induced TNF-alpha production in monocytes from Plasmodium falciparum-infected patients and in vitro in the presence of PEs. Both the monocytes from infected patients and from in vitro culture showed a decrease of CD36 expression and a reduced production of TNF-alpha induced by LPS. Using incubation assays with no contact between monocytes and PEs, or in the presence of a soluble supernatant obtained from the incubation of monocytes and PEs, this study shows that decreased CD36 expression was posttranscriptional and not directly related to PEs phagocytosis. In addition, these culture models suggest that the reduced capacity of TNF-alpha production occurred in 2 phases. The early phase (24 hr) appeared to be CD36 dependent and the second phase (48 hr) was due to a soluble factor produced by PEs. These observations suggest that the control of the TNF-alpha production in malaria by monocytes was not entirely dependent on the phagocytosis of PEs by CD36 and that soluble factors produced by PEs could play a role in this process.
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PMID:Ex vivo and in vitro impairment of CD36 expression and tumor necrosis factor-alpha production in human monocytes in response to Plasmodium falciparum-parasitized erythrocytes. 1598 6

Although typhoid fever is confirmed by culture of Salmonella enterica serotype Typhi, rapid and simple diagnostic serologic tests would be useful in developing countries. We examined the performance of Widal test in a community field site and compared it with Typhidot and Tubex tests for diagnosis of typhoid fever. Blood samples were collected from 6697 patients with fever for > or =3 days for microscopy, culture, and serologic testing and from randomly selected 172 consenting healthy individuals to assess the baseline Widal anti-Typhi O lipopolysaccharide antibody (anti-TO) and anti-Typhi H flagellar antibody (anti-TH) titers. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the 3 serologic tests were calculated using culture-confirmed typhoid fever cases as "true positives" and paratyphoid fever and malaria cases as "true negatives". Comparing cutoff values for the Widal test, an anti-TO titer of 1/80 was optimal with 58% sensitivity, 85% specificity, 69% PPV, and 77% NPV. Sensitivity was increased to 67% when the Widal test was done on the 5th day of illness and thereafter. The sensitivity, specificity, PPV, and NPV of Typhidot and Tubex were not better than Widal test. There is a need for more efficient rapid diagnostic test for typhoid fever especially during the acute stage of the disease. Until then, culture remains the method of choice.
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PMID:Evaluation of new-generation serologic tests for the diagnosis of typhoid fever: data from a community-based surveillance in Calcutta, India. 1693 21

Placental Plasmodium falciparum sequestration is associated with dysregulated immune function. Placental inflammatory responses via IFN-gamma and TNF-alpha are implicated in functional damage. However, they are needed during placental infection to control asexual stage parasites. To test the hypothesis that placental immunomodulation associated with malaria disturbs cytokine secretion differently in monocytes and lymphocytes, we have determined the proportion of monocytes and/or lymphocytes secreting IFN-gamma, TNF-alpha, IL-10 and IL-12. Intervillous and peripheral blood monocyte (CD14+) and lymphocyte (CD3/CD4+; CD3/CD8+) cytokine production was compared between 17 P. falciparum-infected and 12 non-infected Senegalese women. After culture with phorbolmyristate acetate/ionomycin (PMA/iono), lipopolysaccharide (LPS) or P. falciparum-infected erythrocytes (IE), the intracellular expression of cytokines in lymphocytes (IFN-gamma, TNF-alpha) and monocytes (IL-10, IL-12, TNF-alpha), was detected. In response to IE, CD4+ and CD8+ T-cells produced IFN-gamma and TNF-alpha at similar rates in both compartments. In response to PMA/iono, the frequencies of CD4+ and CD8+ T-cells producing IFN-gamma and TNF-alpha were similar in both compartments, but increased in P. falciparum-infected placentas. In response to LPS or IE, IL-12 secreting monocytes were increased in infected women, while the frequency of TNF-alpha secreting monocytes was decreased compared to that in non-infected placenta. The monocyte IL-12 response is not impaired in infected women. IL-12 is an important factor for inducing IFN-gamma in T-cells. Thus, IL-12 and IFN-alpha responses may synergistically allow a protective immune response in placental malaria. TNF-alpha production by CD4+ and CD8+ T-cells is up-regulated in P. falciparum-infected placentas, suggesting that T-cells actively participate to inflammatory responses.
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PMID:IL-12 producing monocytes and IFN-gamma and TNF-alpha producing T-lymphocytes are increased in placentas infected by Plasmodium falciparum. 1719 81


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