%0 Journal Article
%~ PubMed
%A Hackett, Mark J
%A Lee, Joonsup
%A El-Assaad, Fatima
%A McQuillan, James A
%A Carter, Elizabeth A
%A Grau, Georges E
%A Hunt, Nicholas H
%A Lay, Peter A
%T FTIR Imaging of Brain Tissue Reveals Crystalline Creatine Deposits Are an ex Vivo Marker of Localized Ischemia during Murine Cerebral Malaria: General Implications for Disease Neurochemistry.
%B ACS Chemical Neuroscience
%D 2012
%C United States
%I American Chemical Society
%V 3
%N 12
%P 1017-1024
%@ 1948-7193
%X 
%Z FOR Codes: 60104 60502 110903


%0 Journal Article
%~ PubMed
%A Bakmiwewa, Supun M
%A Fatokun, Amos A
%A Tran, Anh
%A Payne, Richard J
%A Hunt, Nicholas H
%A Ball, Helen J
%T Identification of selective inhibitors of indoleamine 2,3-dioxygenase 2.
%B Bioorganic & Medicinal Chemistry Letters
%D 2012
%C United Kingdom
%I Pergamon
%V 22
%N 24
%P 7641-7346
%@ 1464-3405
%X 
%Z FOR Codes: 60104 110101 110106


%0 Journal Article
%~ PubMed
%A Lam, Yan Y
%A Ha, Connie W Y
%A Campbell, Craig R
%A Mitchell, Andrew J
%A Dinudom, Anuwat
%A Oscarsson, Jan
%A Cook, David I
%A Hunt, Nicholas H
%A Caterson, Ian D
%A Holmes, Andrew J
%A Storlien, Len H
%T Increased gut permeability and microbiota change associate with mesenteric fat inflammation and metabolic dysfunction in diet-induced obese mice.
%B PLoS One
%D 2012
%C United States
%I Public Library of Science
%V 7
%N 3
%P e34233
%@ 1932-6203
%X We investigated the relationship between gut health, visceral fat dysfunction and metabolic disorders in diet-induced obesity. C57BL/6J mice were fed control or high saturated fat diet (HFD). Circulating glucose, insulin and inflammatory markers were measured. Proximal colon barrier function was assessed by measuring transepithelial resistance and mRNA expression of tight-junction proteins. Gut microbiota profile was determined by 16S rDNA pyrosequencing. Tumor necrosis factor (TNF)-? and interleukin (IL)-6 mRNA levels were measured in proximal colon, adipose tissue and liver using RT-qPCR. Adipose macrophage infiltration (F4/80(+)) was assessed using immunohistochemical staining. HFD mice had a higher insulin/glucose ratio (P?=?0.020) and serum levels of serum amyloid A3 (131%; P?=?0.008) but reduced circulating adiponectin (64%; P?=?0.011). In proximal colon of HFD mice compared to mice fed the control diet, transepithelial resistance and mRNA expression of zona occludens 1 were reduced by 38% (P<0.001) and 40% (P?=?0.025) respectively and TNF-? mRNA level was 6.6-fold higher (P?=?0.037). HFD reduced Lactobacillus (75%; P<0.001) but increased Oscillibacter (279%; P?=?0.004) in fecal microbiota. Correlations were found between abundances of Lactobacillus (r?=?0.52; P?=?0.013) and Oscillibacter (r?=?-0.55; P?=?0.007) with transepithelial resistance of the proximal colon. HFD increased macrophage infiltration (58%; P?=?0.020), TNF-? (2.5-fold, P<0.001) and IL-6 mRNA levels (2.5-fold; P?=?0.008) in mesenteric fat. Increased macrophage infiltration in epididymal fat was also observed with HFD feeding (71%; P?=?0.006) but neither TNF-? nor IL-6 was altered. Perirenal and subcutaneous adipose tissue showed no signs of inflammation in HFD mice. The current results implicate gut dysfunction, and attendant inflammation of contiguous adipose, as salient features of the metabolic dysregulation of diet-induced obesity.
%Z FOR Codes: 60602 60106


%0 Journal Article
%~ PubMed
%A Mitchell, Andrew J
%A Yau, Belinda
%A McQuillan, James A
%A Ball, Helen J
%A Too, Lay Khoon
%A Abtin, Arby
%A Hertzog, Paul
%A Leib, Stephen L
%A Jones, Cheryl A
%A Gerega, Sebastien K
%A Weninger, Wolfgang
%A Hunt, Nicholas H
%T Inflammasome-Dependent IFN-γ Drives Pathogenesis in Streptococcus pneumoniae Meningitis.
%B Journal of Immunology
%D 2012
%C United States
%I American Association of Immunologists
%V 189
%N 10
%P 4970-4980
%@ 1550-6606
%X 
%Z FOR Codes: 110801


%0 Journal Article
%~ PubMed
%A Guo, Jin
%A Guiguemde, Armand W
%A Bentura-Marciano, Annael
%A Clark, Julie
%A Haynes, Richard K
%A Chan, Wing-Chi
%A Wong, Ho-Ning
%A Hunt, Nicholas
%A Guy, R Kiplin
%A Golenser, Jacob
%T Synthesis of Artemiside and Its Effects in Combination with Conventional Drugs, Against Severe Murine Malaria.
%B Antimicrobial agents and chemotherapy
%D 2012
%C United States
%I American Society for Microbiology
%V 56
%N 1
%P 163-73
%@ 1098-6596
%X This research describes the use of novel antimalarial combinations of the new artemisinin derivative artemiside, a 10-alkylamino artemisinin. It is a stable, highly crystalline compound that is economically prepared from dihydroartemisinin in a one-step process. Artemiside activity was more pronounced than that of any antimalarial drug in use, both in Plasmodium falciparum culture and in vivo in a murine malaria model depicting cerebral malaria (CM). In vitro high-throughput testing of artemiside combinations revealed a large number of conventional antimalarial drugs with which it was additive. Following monotherapy in mice, individual drugs reduced parasitemias to nondetectable levels. However, after a period of latency, parasites again were seen and eventually all mice became terminally ill. Treatment with individual drugs did not prevent CM in mice with recrudescent malaria, except for piperaquine at high concentrations. Even when CM was prevented, the mice developed later of severe anemia. In contrast, most of the mice treated with drug combinations survived. A combination of artemiside and mefloquine or piperaquine may confer an optimal result because of the longer half life of both conventional drugs. The use of artemiside combinations revealed a significant safety margin of the effective artemiside doses. Likewise, a combination of 1.3 mg/kg of body weight artemiside and 10 mg/kg piperaquine administered for 3 days from the seventh day postinfection was completely curative. It appears possible to increase drug concentrations in the combination therapy without reaching toxic levels. Using the drug combinations as little as 1 day before the expected death of control animals, we could prevent further parasite development and death due to CM or anemic malaria. Earlier treatment may prevent cognitive dysfunctions which might occur after recovery from CM.
%Z FOR Codes: 60502


%0 Journal Article
%~ PubMed
%A Combes, Val??ry
%A Guillemin, Gilles J
%A Chan-Ling, Tailoi
%A Hunt, Nicholas H
%A Grau, Georges E R
%T The crossroads of neuroinflammation in infectious diseases: endothelial cells and astrocytes.
%B Trends in Parasitology
%D 2012
%C United Kingdom
%I Elsevier Ltd
%V 28
%N 8
%P 311-319
%@ 1471-5007
%X Homeostasis implies constant operational defence mechanisms, against both external and internal threats. Infectious agents are prominent among such threats. During infection, the host elicits the release of a vast array of molecules and numerous cell-cell interactions are triggered. These pleiomorphic mediators and cellular effects are of prime importance in the defence of the host, both in the systemic circulation and at sites of tissue injury, for example, the blood-brain barrier (BBB). Here, we focus on the interactions between the endothelium, astrocytes, and the molecules they release. Our review addresses these interactions during infectious neurological diseases of various origins, especially cerebral malaria (CM). Two novel elements of the interplay between endothelium and astrocytes, microparticles and the kynurenine pathway, will also be discussed.
%Z FOR Codes: 1107


%0 Journal Article
%~ PubMed
%A Hempel, Casper
%A Combes, Valery
%A Hunt, Nicholas Henry
%A Lindholm Kurtzhals, J??rgen Anders
%A Raymond Grau, Georges Emile
%T CNS Hypoxia Is More Pronounced in Murine Cerebral than Noncerebral Malaria and Reversed by Erythropoietin.
%B American Journal of Pathology
%D 2011
%C United States
%I American Society for Investigative Pathology
%V 179
%N 4
%P 1939-1950
%@ 0002-9440
%X Cerebral malaria (CM) is associated with high mortality and risk of sequelae, and development of adjunct therapies is hampered by limited knowledge of its pathogenesis. To assess the role of cerebral hypoxia, we used two experimental models of CM, Plasmodium berghei ANKA in CBA and C57BL/6 mice, and two models of malaria without neurologic signs, P. berghei K173 in CBA mice and P. berghei ANKA in BALB/c mice. Hypoxia was demonstrated in brain sections using intravenous pimonidazole and staining with hypoxia-inducible factor-1??-specific antibody. Cytopathic hypoxia was studied using poly (ADP-ribose) polymerase-1 (PARP-1) gene knockout mice. The effect of erythropoietin, an oxygen-sensitive cytokine that mediates protection against CM, on cerebral hypoxia was studied in C57BL/6 mice. Numerous hypoxic foci of neurons and glial cells were observed in mice with CM. Substantially fewer and smaller foci were observed in mice without CM, and hypoxia seemed to be confined to neuronal cell somas. PARP-1-deficient mice were not protected against CM, which argues against a role for cytopathic hypoxia. Erythropoietin therapy reversed the development of CM and substantially reduced the degree of neural hypoxia. These findings demonstrate cerebral hypoxia in malaria, strongly associated with cerebral dysfunction and a possible target for adjunctive therapy.
%Z FOR Codes: 110803 110903


%0 Journal Article
%~ PubMed
%A Hackett, Mark J
%A McQuillan, James A
%A El-Assaad, Fatima
%A Aitken, Jade B
%A Levina, Aviva
%A Cohen, David D
%A Siegele, Rainer
%A Carter, Elizabeth A
%A Grau, Georges E
%A Hunt, Nicholas H
%A Lay, Peter A
%T Chemical alterations to murine brain tissue induced by formalin fixation: implications for biospectroscopic imaging and mapping studies of disease pathogenesis.
%B The Analyst
%D 2011
%C United Kingdom
%I Royal Society of Chemistry
%V 136
%N 14
%P 2941-2952
%@ 1364-5528
%X Understanding biochemical mechanisms and changes associated with disease conditions and, therefore, development of improved clinical treatments, is relying increasingly on various biochemical mapping and imaging techniques on tissue sections. However, it is essential to be able to ascertain whether the sampling used provides the full biochemical information relevant to the disease and is free from artefacts. A multi-modal micro-spectroscopic approach, including FTIR imaging and PIXE elemental mapping, has been used to study the molecular and elemental profile within cryofixed and formalin-fixed murine brain tissue sections. The results provide strong evidence that amino acids, carbohydrates, lipids, phosphates, proteins and ions, such as Cl(-) and K(+), leach from tissue sections into the aqueous fixative medium during formalin fixation of the sections. Large changes in the concentrations and distributions of most of these components are also observed by washing in PBS even for short periods. The most likely source of the chemical species lost during fixation is the extra-cellular and intra-cellular fluid of tissues. The results highlight that, at best, analysis of formalin-fixed tissues gives only part of the complete biochemical "picture" of a tissue sample. Further, this investigation has highlighted that significant lipid peroxidation/oxidation may occur during formalin fixation and that the use of standard histological fixation reagents can result in significant and differential metal contamination of different regions of tissue sections. While a consistent and reproducible fixation method may be suitable for diagnostic purposes, the findings of this study strongly question the use of formalin fixation prior to spectroscopic studies of the molecular and elemental composition of biological samples, if the primary purpose is mechanistic studies of disease pathogenesis.
%Z FOR Codes: 110803


%0 Journal Article
%~ PubMed
%A McQuillan, James A
%A Mitchell, Andrew J
%A Ho, Yuen Fern
%A Combes, Valéry
%A Ball, Helen J
%A Golenser, Jacob
%A Grau, Georges E
%A Hunt, Nicholas H
%T Coincident parasite and CD8 T cell sequestration is required for development of experimental cerebral malaria.
%B International Journal for Parasitology
%D 2011
%C United Kingdom, Australia
%I Elsevier Ltd
%V 41
%N 2
%P 155-163
%@ 0020-7519
%X Cerebral malaria (CM) is a fatal complication of Plasmodium falciparum infection. Using a well defined murine model, we observed the effect on disease outcome of temporarily reducing parasite burden by anti-malarial drug treatment. The anti-malarial treatment regime chosen decreased parasitaemia but did not cure the mice, allowing recrudescence of parasites. These mice were protected against CM, despite their parasitaemia having increased, following treatment cessation, to levels surpassing that associated with CM in mice not treated with the drug. The protection was associated with reduced levels of cytokines, chemokines, CD8(+) T cells and parasites in the brain. The results suggest that the development of the immunopathological response that causes CM depends on a continuous stimulus provided by parasitised red blood cells, either circulating or sequestered in small vessels.
%Z FOR Codes: 110803 110799 110903


%0 Journal Article
%~ PubMed
%A El-Assaad, Fatima
%A Hempel, Casper
%A Combes, Valery
%A Mitchell, Andrew J
%A Ball, Helen J
%A Kurtzhals, Jørgen A L
%A Hunt, Nicholas H
%A Mathys, Jean Marie
%A Grau, Georges E R
%T Differential microRNA expression in experimental cerebral and non-cerebral malaria.
%B Infection and Immunity
%D 2011
%C United States
%I American Society of Microbiology
%V 79
%N 6
%P 2379-2384
%@ 0019-9567
%X MicroRNAs (miRNAs) are posttranscriptional regulatory molecules that have been implicated in the regulation of immune responses, but their role in the immune response to Plasmodium infection is unknown. We studied the expression of selected miRNAs following infection of CBA mice with Plasmodium berghei ANKA (PbA), which causes cerebral malaria (CM), or Plasmodium berghei K173 (PbK), which causes severe malaria but without cerebral complications, termed non-CM. The differential expression profiles of selected miRNAs (let-7i, miR-27a, miR-150, miR-126, miR-210, and miR-155) were analyzed in mouse brain and heart tissue by quantitative reverse transcription-PCR (qRT-PCR). We identified three miRNAs that were differentially expressed in the brain of PbA-infected CBA mice: let7i, miR-27a, and miR-150. In contrast, no miRNA changes were detected in the heart, an organ with no known pathology during acute malaria. To investigate the involvement of let-7i, miR-27a, and miR-150 in CM-resistant mice, we assessed the expression levels in gamma interferon knockout (IFN-??(-/-)) mice on a C57BL/6 genetic background. The expression of let-7i, miR-27a, and miR-150 was unchanged in both wild-type (WT) and IFN-??(-/-) mice following infection. Overexpression of these three miRNAs during PbA, but not PbK, infection in WT mice may be critical for the triggering of the neurological syndrome via regulation of their potential downstream targets. Our data suggest that in the CBA mouse at least, miRNA may have a regulatory role in the pathogenesis of severe malaria.
%Z FOR Codes: 60502 110704 110803


%0 Journal Article
%~ PubMed
%A Bao, Shisan
%A Carr, Emma Dj
%A Xu, Ying-Hua
%A Hunt, Nicholas H
%T Gp91(phox) contributes to the development of experimental inflammatory bowel disease.
%B Immunology and cell biology
%D 2011
%C United Kingdom, Australia
%I Nature Publishing Group
%V 89
%N 8
%P 853-60
%@ 0818-9641
%X Inflammatory bowel disease (IBD) is related to dysfunction of intestinal immunity. Neutrophils have an important role in innate immunity via the oxidative burst, using the p47phox- and gp91(phox)-containing NAD(P)H oxidase known as Nox2. In dextran sulphate sodium (DSS)-induced colitis, no significant difference in inflammation between p47(phox-/-) and wild-type (WT) mice was reported, but there was improved endothelium-dependent arteriolar dilation in gp91(phox-/-) mice, compared with that in WT mice. Gp91(phox) and p47 (phox) are not only essential components of phagocyte Nox2, but also have roles in other enzymes. Thus the differences in response of their respective gene knockout mice to DSS challenge are not completely unexpected, but need further investigation. The clinicopathological changes and immunological responses to DSS challenge have not been fully described in gp91(phox-/-) mice. Thus we treated WT and gp91(phox-/-) mice with 2.5% DSS for 7 days. The gp91(phox-/-) mice developed less severe colitis than WT mice following DSS treatment, reflected by a smaller body weight loss, less rectal bleeding and fewer histopathological changes. Less colonic myeloperoxidase was observed in gp91(phox-/-), compared with WT mice, following DSS challenge, correlating with interleukin (IL)-6 production. IL-10 was upregulated in both gp91(phox-/-) and WT mice, but was significantly higher in the latter, following 7 days DSS challenge. These results suggest that gp91(phox-/-) mice are less susceptible to acute DSS-induced colitis, possibly because of a reduced oxidative burst in the intestine and, consequently, less tissue damage.
%Z FOR Codes: 60105 110704


%0 Journal Article
%A Hackett, Maree
%A Siegele, R.
%A El-Assaad, F.
%A McQuillan, James
%A Aitken, J.B.
%A Carter, E.A.
%A Grau, Georges
%A Hunt, Nicholas
%A Cohen, D.
%A Lay, P.A.
%T Investigation of the mouse cerebellum using STIM and l-PIXE spectrometric and FTIR spectroscopic mapping and imaging
%B Nuclear Instruments and Methods in Physics Research B
%D 2011
%C Netherlands
%I Elsevier
%V 269
%N 20
%P 2260-2263
%@ 0168-583X
%X 
%Z FOR Codes: 60101


%0 Journal Article
%~ PubMed
%A Ampawong, Sumate
%A Combes, Valéry
%A Hunt, Nicholas H
%A Radford, Jane
%A Chan-Ling, Tailoi
%A Pongponratn, Emsri
%A Grau, Georges E R
%T Quantitation of brain edema and localisation of aquaporin 4 expression in relation to susceptibility to experimental cerebral malaria.
%B International Journal of Clinical and Experimental Pathology
%D 2011
%C United States
%I E-Century Publishing Corporation
%V 4
%N 6
%P 566-574
%@ 1936-2625
%X The pathogenic mechanisms underlying the occurrence of cerebral malaria (CM) are still incompletely understood but, clearly, cerebral complications may result from concomitant microvessel obstruction and inflammation. The extent to which brain edema contributes to pathology has not been investigated. Using the model of P. berghei ANKA infection, we compared brain microvessel morphology of CM-susceptible and CM-resistant mice. By quantitative planimetry, we provide evidence that CM is characterized by enlarged perivascular spaces (PVS). We show a dramatic aquaporin 4 (AQP4) upregulation, selectively at the level of astrocytic foot processes, in both CM and non-CM disease, but significantly more pronounced in mice with malarial-induced neurological syndrome. This suggests that a threshold of AQP4 expression is needed to lead to neurovascular pathology, a view that is supported by significantly higher levels in mice with clinically overt CM. Numbers of intravascular leukocytes significantly correlated with both PVS enlargement and AQP4 overexpression. Thus, brain edema could be a contributing factor in CM pathogenesis and AQP4, specifically in its astrocytic location, a key molecule in this mechanism. Since experimental CM is associated with substantial brain edema, it models paediatric CM better than the adult syndrome and it is tempting to evaluate AQP4 in the former context. If AQP4 changes are confirmed in human CM, it may represent a novel target for therapeutic intervention.
%Z FOR Codes: 60502


%0 Journal Article
%~ PubMed
%A Hunt, Nicholas H
%T Redox Pioneer: Professor Roland Stocker.
%B Antioxidants & redox signaling
%D 2011
%C United States
%I Mary Ann Liebert, Inc. Publishers
%V 15
%N 12
%P 3101-5
%@ 1557-7716
%X Dr. Roland Stocker (Ph.D. 1985) is recognized here as a Redox Pioneer, because he has published one article on antioxidant/redox biology as first author that has been cited over 1000 times and has published another 32 articles, each cited over 100 times. Dr. Stocker received his undergraduate education at the Federal Institute of Technology Z??rich, Switzerland (1975-1981), followed by postgraduate training at the Australian National University Canberra, Australia (1982-1985) and postdoctoral training at the University of California, Berkeley (1986-1987), and the University of Berne, Switzerland (1987-1988). Dr. Stocker''s top scientific contributions are in the following areas: (i) molecular action and interaction of nonproteinaceous antioxidants, particularly bilirubin, ??-tocopherol, and ubiquinol-10; (ii) lipoprotein lipid oxidation and its inhibition, with a particular focus on how ??-tocopherol affects these processes; (iii) the role of arterial lipoprotein lipid oxidation in atherosclerosis and related diseases; (iv) modes of antiatherosclerotic action of probucol and the involvement of heme oxygenase-1 in vascular protection; and (v) the regulation of indoleamine 2,3-dioxygenase and its contribution to vascular tone and blood pressure in inflammatory diseases.
%Z FOR Codes: 110201


%0 Journal Article
%~ PubMed
%A Hee, Leia
%A Dinudom, Anuwat
%A Mitchell, Andrew J
%A Grau, Georges E
%A Cook, David I
%A Hunt, Nicholas H
%A Ball, Helen J
%T Reduced activity of the epithelial sodium channel in malaria-induced pulmonary edema in mice.
%B International Journal for Parasitology
%D 2011
%C United Kingdom, Australia
%I Elsevier Ltd
%V 41
%N 1
%P 81-88
%@ 0020-7519
%X Lung complications during malaria infection can range from coughs and impairments in gas transfer to the development of acute respiratory distress syndrome (ARDS). Infecting C57BL/6 mice with Plasmodium berghei K173 strain (PbK) resulted in pulmonary oedema, capillaries congested with leukocytes and infected red blood cells (iRBCs), and leukocyte infiltration into the lungs. This new model of malaria-associated lung pathology, without any accompanying cerebral complications, allows the investigation of mechanisms leading to the lung disease. The activity of the amiloride-sensitive epithelial sodium channel (ENaC) in alveolar epithelial cells is decreased by several respiratory tract pathogens and this is suggested to contribute to pulmonary oedema. We show that PbK, a pathogen that remains in the circulation, also decreased the activity and expression of ENaC, suggesting that infectious agents can have indirect effects on ENaC activity in lung epithelial cells. The reduced ENaC activity may contribute to the pulmonary oedema induced by PbK malaria.
%Z FOR Codes: 110803 110707 111699


%0 Journal Article
%~ PubMed
%A Lam, Yan Y
%A Mitchell, Andrew J
%A Holmes, Andrew J
%A Denyer, Gareth S
%A Gummesson, Anders
%A Caterson, Ian D
%A Hunt, Nicholas H
%A Storlien, Len H
%T Role of the Gut in Visceral Fat Inflammation and Metabolic Disorders.
%B Obesity (Silver Spring, Md.)
%D 2011
%C United States
%I Nature Publishing Group
%V 19
%N 11
%P 2113-20
%@ 1930-7381
%X 
%Z FOR Codes: 60199


%0 Journal Article
%~ PubMed
%A Conroy, Trent
%A Guo, Jin T
%A Linington, Roger G
%A Hunt, Nicholas H
%A Payne, Richard J
%T Total synthesis, stereochemical assignment, and antimalarial activity of gallinamide A.
%B Chemistry (Weinheim an der Bergstrasse, Germany)
%D 2011
%C Germany
%I Wiley-VCH
%V 17
%N 48
%P 13544-52
%@ 1521-3765
%X The total synthesis and stereochemical assignment of gallinamide A, an antimalarial depsipeptide of cyanobacterial origin, is described. Synthesis of the four possible N-terminal diastereoisomers of gallinamide A (including the natural product symplostatin 4) was achieved using a divergent strategy from a common imide fragment. The natural product and corresponding diastereoisomers were synthesized in 30-33% overall yield in a longest linear sequence of 8 steps. Comparative NMR spectroscopic studies of the four synthetic diastereoisomers with the isolated natural product demonstrated that gallinamide A possesses a dimethylated L-isoleucyl residue at the N-terminus. As such, we have shown that gallinamide A is structurally and stereochemically identical to symplostatin 4. Gallinamide A and its N-terminal diastereoisomers were also shown to possess significant antimalarial activity with IC(50) values in the nanomolar range against the 3D7 strain of Plasmodium falciparum.
%Z FOR Codes: 30403


%0 Journal Article
%~ PubMed
%A Yuasa, Hajime J
%A Ball, Helen J
%A Austin, Christopher J D
%A Hunt, Nicholas H
%T 1-l-methyltryptophan is a more effective inhibitor of vertebrate IDO2 enzymes than 1-d-methyltryptophan.
%B Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology
%D 2010
%C United States
%I Elsevier Inc.
%V 157
%N 1
%P 10-5
%@ 1879-1107
%X 1-D-methyltryptophan (D-1MT) is an effective anti-cancer agent in mouse tumour models. It has been suggested to be a selective inhibitor of the recently described tryptophan-degrading enzyme indoleamine 2,3-dioxygenase 2 (IDO2) rather than the closely related enzyme IDO1. We found that mammalian (mouse, opossum and platypus), chicken, frog, and fish IDO2 could be functional tryptophan-catabolising enzymes. The characteristics of pH-dependent activity and inhibitor selectivity were conserved amongst the vertebrate IDO2 proteins tested. Like IDO1 enzymes, the enzymatic activity of all IDO2s was inhibited by L-1MT but not by D-1MT in a cell-free assay. When IDO2s were expressed in mammalian cells, L-1MT was also a better inhibitor than D-1MT.
%Z FOR Codes: 30406 60107 30404


%0 Journal Article
%~ PubMed
%A Waknine-Grinberg, Judith H
%A Hunt, Nicholas
%A Bentura-Marciano, Annael
%A McQuillan, James A
%A Chan, Ho-Wai
%A Chan, Wing-Chi
%A Barenholz, Yechezkel
%A Haynes, Richard K
%A Golenser, Jacob
%T Artemisone effective against murine cerebral malaria.
%B Malaria Journal
%D 2010
%C United Kingdom
%I BioMed Central Ltd.
%V 9
%N 
%P 227
%@ 1475-2875
%X Artemisinins are the newest class of drug approved for malaria treatment. Due to their unique mechanism of action, rapid effect on Plasmodium, and high efficacy in vivo, artemisinins have become essential components of malaria treatment. Administration of artemisinin derivatives in combination with other anti-plasmodials has become the first-line treatment for uncomplicated falciparum malaria. However, their efficiency in cases of cerebral malaria (CM) remains to be determined.
%Z FOR Codes: 60502


%0 Journal Article
%~ PubMed
%A Austin, Christopher Jonathan Daraius
%A Mailu, B M
%A Maghzal, G J
%A Sanchez-Perez, A
%A Rahlfs, S
%A Zocher, K
%A Yuasa, H J
%A Arthur, J W
%A Becker, K
%A Stocker, R
%A Hunt, N H
%A Ball, H J
%T Biochemical characteristics and inhibitor selectivity of mouse indoleamine 2,3-dioxygenase-2.
%B Amino acids
%D 2010
%C Austria
%I Springer Wien
%V 39
%N 2
%P 565-78
%@ 1438-2199
%X The first step in the kynurenine pathway of tryptophan catabolism is the cleavage of the 2,3-double bond of the indole ring of tryptophan. In mammals, this reaction is performed independently by indoleamine 2,3-dioxygenase-1 (IDO1), tryptophan 2,3-dioxygenase (TDO) and the recently discovered indoleamine 2,3-dioxygenase-2 (IDO2). Here we describe characteristics of a purified recombinant mouse IDO2 enzyme, including its pH stability, thermal stability and structural features. An improved assay system for future studies of recombinant/isolated IDO2 has been developed using cytochrome b (5) as an electron donor. This, the first description of the interaction between IDO2 and cytochrome b (5), provides further evidence of the presence of a physiological electron carrier necessary for activity of enzymes in the "IDO family". Using this assay, the kinetic activity and substrate range of IDO2 were shown to be different to those of IDO1. 1-Methyl-D-tryptophan, a current lead IDO inhibitor used in clinical trials, was a poor inhibitor of both IDO1 and IDO2 activity. This suggests that its immunosuppressive effect may be independent of pharmacological inhibition of IDO enzymes, in the mouse at least. The different biochemical characteristics of the mouse IDO proteins suggest that they have evolved to have distinct biological roles.
%Z FOR Codes: 60107


%0 Journal Article
%~ PubMed
%A Wang, Yutang
%A Liu, Hanzhong
%A McKenzie, Gavin
%A Witting, Paul K
%A Stasch, Johannes-Peter
%A Hahn, Michael
%A Changsirivathanathamrong, Dechaboon
%A Wu, Ben J
%A Ball, Helen J
%A Thomas, Shane R
%A Kapoor, Vimal
%A Celermajer, David S
%A Mellor, Andrew L
%A Keaney, John F
%A Hunt, Nicholas H
%A Stocker, Roland
%T Kynurenine is an endothelium-derived relaxing factor produced during inflammation.
%B Nature Medicine
%D 2010
%C United States
%I Nature Publishing Group
%V 16
%N 3
%P 279-285
%@ 1078-8956
%X Control of blood vessel tone is central to vascular homeostasis. Here we show that metabolism of tryptophan to kynurenine by indoleamine 2,3-dioxygenase (Ido) expressed in endothelial cells contributes to arterial vessel relaxation and the control of blood pressure. Infection of mice with malarial parasites (Plasmodium berghei) or induction of endotoxemia in mice led to endothelial expression of Ido, decreased plasma tryptophan concentration, increased kynurenine concentration and hypotension. Pharmacological inhibition of Ido increased blood pressure in systemically inflamed mice but not in mice deficient in Ido or interferon-gamma, which is required for Ido induction. Both tryptophan and kynurenine dilated preconstricted porcine coronary arteries; the dilating effect of tryptophan required the presence of active Ido and an intact endothelium, whereas the effect of kynurenine was endothelium independent. The arterial relaxation induced by kynurenine was mediated by activation of the adenylate and soluble guanylate cyclase pathways. Kynurenine administration decreased blood pressure in a dose-dependent manner in spontaneously hypertensive rats. Our results identify tryptophan metabolism by Ido as a new pathway contributing to the regulation of vascular tone.
%Z FOR Codes: 110201


%0 Journal Article
%~ PubMed
%A Combes, Valéry
%A El-Assaad, Fatima
%A Faille, Dorothée
%A Jambou, Ronan
%A Hunt, Nicholas H
%A Grau, Georges E R
%T Microvesiculation and cell interactions at the brain-endothelial interface in cerebral malaria pathogenesis.
%B Progress in Neurobiology
%D 2010
%C United Kingdom
%I Pergamon
%V 91
%N 2
%P 140-151
%@ 1873-5118
%X Cerebral malaria (CM) is still a major world health problem whose pathogenic mechanisms remain incompletely understood. After reviewing some particularities of anti-malarial immunity, we focus here on the neurovascular aspects of CM. We specifically address the central role of endothelial activation and alteration in disease pathogenesis. We discuss the respective roles of "mediator-induced" versus "host cell-induced" mechanisms of endothelial alteration. The former include cytokines, chemokines and their receptors, while the latter encompass cells located inside and outside the vessel, notably glial cells. We also present evidence for a pathogenic role for membrane microparticles (MP) in CM, based on studies in African patients and in a recognised mouse model. Intervention studies on MP production, via either gene knockout or pharmacological inhibition, can prevent the neurological syndrome and its associated mortality, suggesting potential new therapeutic avenues.
%Z FOR Codes: 1106


%0 Journal Article
%~ PubMed
%A Waknine-Grinberg, Judith H
%A McQuillan, James A
%A Hunt, Nicholas
%A Ginsburg, Hagai
%A Golenser, Jacob
%T Modulation of cerebral malaria by fasudil and other immune-modifying compounds.
%B Experimental Parasitology
%D 2010
%C United States
%I Academic Press
%V 125
%N 2
%P 141-146
%@ 1090-2449
%X Malaria continues to cause millions of deaths annually. No specific effective treatment has yet been found for cerebral malaria, one of the most severe complications of the disease. The pathology of cerebral malaria is considered to be primarily immunological. We examined a number of compounds with known effects on the immune system, in a murine model of cerebral malaria. Of the compounds tested, only fasudil and curcumin had significant effects on the progression of the disease. Although neither drug caused a reduction in parasitemia, survival of the treated mice was significantly increased, and the development of cerebral malaria was either delayed or prevented. Our results support the hypothesis that an immunomodulator efficient in preventing CM should be administered together with anti-plasmodial drugs to prevent severe malaria disease; curcumin and fasudil should be further investigated to determine efficiency and feasibility of treatment.
%Z FOR Codes: 60502


%0 Journal Article
%~ PubMed
%A Hunt, Nicholas H
%A Grau, Georges E
%A Engwerda, Christian
%A Barnum, Scott R
%A van der Heyde, Henri
%A Hansen, Diana S
%A Schofield, Louis
%A Golenser, Jacob
%T Murine cerebral malaria: the whole story.
%B Trends in parasitology
%D 2010
%C United Kingdom
%I Elsevier Ltd.
%V 26
%N 6
%P 272-4
%@ 1471-5007
%X 
%Z FOR Codes: 60502


%0 Journal Article
%~ PubMed
%A Mitchell, Andrew J
%A Pradel, Lydie C
%A Chasson, Lionel
%A Van Rooijen, Nico
%A Grau, Georges E
%A Hunt, Nicholas H
%A Chimini, Giovanna
%T Technical Advance: Autofluorescence as a tool for myeloid cell analysis.
%B Journal of leukocyte biology
%D 2010
%C United States
%I Federation of American Societies for Experimental
%V 88
%N 3
%P 597-603
%@ 1938-3673
%X Cellular AF is usually considered a hindrance to flow cytometric analysis. Here, we incorporate AF into analysis of complex mixtures of leukocytes. Using a mouse model, we examined cellular AF at multiple excitation and emission wavelengths, and populations with discrete patterns were gated and examined for surface marker expression. In the spleen, all major myeloid populations were identified. In particular, the approach allowed simultaneous characterization of RPM and resident monocytes. When monocytes and RPM were compared, RPM exhibited a phenotype that was consistent with involvement in physiological processes, including expression of genes involved in lipid and iron metabolism. The presence of large amounts of stored ferric iron within RPM enabled purification of these cells using a magnetic-based approach. When adapted for use on leukocytes isolated from a range of other organs, incorporation of AF into analysis allowed identification and isolation of biologically important myeloid populations, including subsets that were not readily identifiable by conventional cytometric analysis.
%Z FOR Codes: 110701


%0 Journal Article
%~ PubMed
%A Conroy, Trent
%A Guo, Jin T
%A Hunt, Nicholas H
%A Payne, Richard J
%T Total Synthesis and Antimalarial Activity of Symplostatin 4.
%B Organic letters
%D 2010
%C United States
%I American Chemical Society
%V 12
%N 23
%P 5576-9
%@ 1523-7060
%X The first total synthesis of symplostatin 4, a marine cyanobacterium-derived natural product, is described. Notable features of the route include the efficient preparation of three key fragments and final assembly to the natural product via sequential imide and amide couplings. Symplostatin 4 was also demonstrated to possess significant antimalarial activity (ED(50) of 74 nM against Plasmodium falciparum, strain 3D7).
%Z FOR Codes: 110803


%0 Journal Article
%~ PubMed
%A Krimmer, D I
%A Loseli, M
%A Hughes, J M
%A Oliver, B G G
%A Moir, L M
%A Hunt, N H
%A Black, J L
%A Burgess, J K
%T CD40 and OX40 ligand are differentially regulated on asthmatic airway smooth muscle.
%B Allergy
%D 2009
%C United Kingdom, Swit
%I Wiley-Blackwell Publishing Ltd.
%V 64
%N 7
%P 1074-82
%@ 0105-4538
%X CD40 and OX40 Ligand (OX40L) are cell-surface molecules expressed on airway smooth muscle (ASM) that can enhance inflammatory cell activation and survival. The aim of this study was to examine the effect of tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) on ASM CD40 and OX40L expression.
%Z FOR Codes: 110701


%0 Journal Article
%~ PubMed
%A Yuasa, Hajime J
%A Ball, Helen J
%A Ho, Yuen Fern
%A Austin, Christopher J D
%A Whittington, Camilla M
%A Belov, Katherine
%A Maghzal, Ghassan J
%A Jermiin, Lars S
%A Hunt, Nicholas H
%T Characterization and evolution of vertebrate indoleamine 2, 3-dioxygenases IDOs from monotremes and marsupials.
%B Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology
%D 2009
%C United States
%I Elsevier
%V 153
%N 2
%P 137-144
%@ 1879-1107
%X Indoleamine 2,3-dioxygenase (IDO1) and tryptophan 2,3-dioxygenase (TDO) are tryptophan-degrading enzymes that catalyze the first step in tryptophan catabolism via the kynurenine pathway. TDO is widely distributed in both eukaryotes and bacteria. In contrast, IDO has been found only in mammals and yeast. In 2007, a third enzyme, indoleamine 2,3-dioxygenase-2 (IDO2), was discovered. IDO2 is found not only in mammals but also in lower vertebrates. Interestingly, the K(m) value of IDO2 for L-Trp was 500-1000 fold higher than that of IDO1. In this study, we isolated both IDO1 and IDO2 cDNA from a monotreme, the platypus (Ornithorhynchus anatinus), and a marsupial, the gray short-tailed opossum (Monodelphis domestica). We characterized the recombinant proteins and those of other known IDO1/IDO2 in intact cells and a cell-free system. It was found that methylene blue may not be suitable reductant for IDO2, hence resulting in an underestimation of recombinant IDO2 activity. In intact cells, the K(m) value of IDO2 for L-Trp was estimated to be much higher than that of IDO1 and this high K(m) value appears to have been conserved during the evolution of IDO2. The protein encoded by the ancestor gene of IDO1 and IDO2 is likely to have had properties more similar to present day IDO2 than to IDO1.
%Z FOR Codes: 110199


%0 Journal Article
%~ PubMed
%A Miu, Jenny
%A Ball, Helen J
%A Mellor, Andrew L
%A Hunt, Nicholas H
%T Effect of indoleamine dioxygenase-1 deficiency and kynurenine pathway inhibition on murine cerebral malaria.
%B International journal for parasitology
%D 2009
%C United Kingdom
%I Elsevier
%V 39
%N 0
%P 363-70
%@ 0020-7519
%X Cerebral malaria (CM) can be a fatal manifestation of Plasmodium falciparum infection. In this study, two different approaches were used to examine the role of indoleamine 2,3-dioxygenase-1 (IDO-1) and its metabolites in the development of murine CM. Mice genetically deficient in IDO-1 were not protected against CM, but partial protection was observed in C57BL/6 mice treated with Ro 61-8048, an inhibitor of kynurenine-3-hydroxylase. This protection was associated with suppressed levels of picolinic acid (PA) within the brain, but not with changes in the levels of kynurenic acid (KA) or quinolinic acid (QA). These data suggest that although IDO-1 is not directly involved in the pathogenesis of CM in C57BL/6 mice, the production of the kynurenine pathway metabolite PA may contribute to the development of murine CM.
%Z FOR Codes: 110704 110803 110101


%0 Journal Article
%~ PubMed
%A Togbe, Dieudonnée
%A de Sousa, Paulo Loureiro
%A Fauconnier, Mathilde
%A Boissay, Victorine
%A Fick, Lizette
%A Scheu, Stefanie
%A Pfeffer, Klaus
%A Menard, Robert
%A Grau, Georges E
%A Doan, Bich-Thuy
%A Beloeil, Jean Claude
%A Renia, Laurent
%A Hansen, Anna M
%A Ball, Helen J
%A Hunt, Nicholas H
%A Ryffel, Bernhard
%A Quesniaux, Valerie F J
%T Both functional LTbeta receptor and TNF receptor 2 are required for the development of experimental cerebral malaria.
%B PloS one
%D 2008
%C United States
%I Public Library of Science
%V 3
%N 7
%P e2608
%@ 1932-6203
%X TNF-related lymphotoxin alpha (LTalpha) is essential for the development of Plasmodium berghei ANKA (PbA)-induced experimental cerebral malaria (ECM). The pathway involved has been attributed to TNFR2. Here we show a second arm of LTalpha-signaling essential for ECM development through LTbeta-R, receptor of LTalpha1beta2 heterotrimer.
%Z FOR Codes: 60502 110902


%0 Journal Article
%~ PubMed
%A Miu, Jenny
%A Mitchell, Andrew J
%A Müller, Marcus
%A Carter, Sally L
%A Manders, Peter M
%A McQuillan, James A
%A Saunders, Bernadette M
%A Ball, Helen J
%A Lu, Bao
%A Campbell, Iain L
%A Hunt, Nicholas H
%T Chemokine gene expression during fatal murine cerebral malaria and protection due to CXCR3 deficiency.
%B Journal of immunology
%D 2008
%C United States
%I American Association of Immunologists
%V 180
%N 2
%P 1217-30
%@ 0022-1767
%X Cerebral malaria (CM) can be a fatal manifestation of Plasmodium falciparum infection. Using murine models of malaria, we found much greater up-regulation of a number of chemokine mRNAs, including those for CXCR3 and its ligands, in the brain during fatal murine CM (FMCM) than in a model of non-CM. Expression of CXCL9 and CXCL10 RNA was localized predominantly to the cerebral microvessels and in adjacent glial cells, while expression of CCL5 was restricted mainly to infiltrating lymphocytes. The majority of mice deficient in CXCR3 were found to be protected from FMCM, and this protection was associated with a reduction in the number of CD8+ T cells in brain vessels as well as reduced expression of perforin and FasL mRNA. Adoptive transfer of CD8+ cells from C57BL/6 mice with FMCM abrogated this protection in CXCR3-/- mice. Moreover, there were decreased mRNA levels for the proinflammatory cytokines IFN-gamma and lymphotoxin-alpha in the brains of mice protected from FMCM. These data suggest a role for CXCR3 in the pathogenesis of FMCM through the recruitment and activation of pathogenic CD8+ T cells.
%Z FOR Codes: 110704 110803


%0 Journal Article
%~ PubMed
%A Belnoue, E
%A Potter, S M
%A Rosa, D S
%A Mauduit, M
%A Grüner, A C
%A Kayibanda, M
%A Mitchell, A J
%A Hunt, N H
%A Rénia, L
%T Control of pathogenic CD8+ T cell migration to the brain by IFN-gamma during experimental cerebral malaria.
%B Parasite Immunology
%D 2008
%C United Kingdom
%I Wiley-Blackwell Publishing Ltd.
%V 30
%N 10
%P 544-553
%@ 1365-3024
%X 
%Z FOR Codes: 110803


%0 Journal Article
%~ PubMed
%A Maghzal, Ghassan J
%A Thomas, Shane R
%A Hunt, Nicholas H
%A Stocker, Roland
%T Cytochrome b5, not superoxide anion radical, is a major reductant of indoleamine 2,3-dioxygenase in human cells.
%B Journal of Biological Chemistry
%D 2008
%C United States
%I American Society for Biochemistry and Molecular Bi
%V 283
%N 18
%P 12014-12025
%@ 1083-351X
%X The heme protein indoleamine 2,3-dioxygenase (IDO) initiates oxidative metabolism of tryptophan along the kynurenine pathway, and this requires reductive activation of Fe(3+)-IDO. The current dogma is that superoxide anion radical (O(2)(*-)) is responsible for this activation, based largely on previous work employing purified rabbit IDO and rabbit enterocytes. We have re-investigated this role of O(2)(*-) using purified recombinant human IDO (rhIDO), rabbit enterocytes that constitutively express IDO, human endothelial cells, and monocyte-derived macrophages treated with interferon-gamma to induce IDO expression, and two cell lines transfected with the human IDO gene. Both potassium superoxide and O(2)(*-) generated by xanthine oxidase modestly activated rhIDO, in reactions that were prevented completely by superoxide dismutase (SOD). In contrast, SOD mimetics had no effect on IDO activity in enterocytes and interferon-gamma-treated human cells, despite significantly decreasing cellular O(2)(*-) Similarly, cellular IDO activity was unaffected by increasing SOD activity via co-expression of Cu,Zn-SOD or by increasing cellular O(2)(*-) via treatment of cells with menadione. Other reductants, such as tetrahydrobiopterin, ascorbate, and cytochrome P450 reductase, were ineffective in activating cellular IDO. However, recombinant human cytochrome b(5) plus cytochrome P450 reductase and NADPH reduced Fe(3+)-IDO to Fe(2+)-IDO and activated rhIDO in a reconstituted system, a reaction inhibited marginally by SOD. Additionally, short interfering RNA-mediated knockdown of microsomal cytochrome b(5) significantly decreased IDO activity in IDO-transfected cells. Together, our data show that cytochrome b(5) rather than O(2)(*-) plays a major role in the activation of IDO in human cells.
%Z FOR Codes: 111601 110106


%0 Journal Article
%~ PubMed
%A Burgess, Janette K
%A Lee, Jin Hee
%A Ge, Qi
%A Ramsay, Emma E
%A Poniris, Maree H
%A Parmentier, Johannes
%A Roth, Michael
%A Johnson, Peter R A
%A Hunt, Nicholas H
%A Black, Judith L
%A Ammit, Alaina J
%T Dual ERK and phosphatidylinositol 3-kinase pathways control airway smooth muscle proliferation: Differences in asthma.
%B Journal of cellular physiology
%D 2008
%C United States
%I John Wiley & Sons
%V 216
%N 3
%P 673-9
%@ 1097-4652
%X Hyperplasia of airway smooth muscle (ASM) within the bronchial wall of asthmatic patients has been well documented and is likely due to increased muscle proliferation. We have shown that ASM cells obtained from asthmatic patients proliferate faster than those obtained from non-asthmatic patients. In ASM from non-asthmatics, mitogens act via dual signaling pathways (both ERK- and PI 3-kinase-dependent) to control growth. In this study we are the first to examine whether dual pathways control the enhanced proliferation of ASM from asthmatics. When cells were incubated with 0.1% or 1% FBS, ERK activation was significantly greater in cells from asthmatic subjects (P < 0.05). In contrast, when cells were stimulated with 10% FBS, ERK activity was significantly greater in the non-asthmatic cells. However, cell proliferation in asthmatic cells was still significantly higher in cells stimulated by both 1% and 10% FBS. Pharmacological inhibition revealed that although dual proliferative pathways control ASM growth in cells from non-asthmatics stimulated with 10% FBS to an equal extent ([(3)H]-thymidine incorporation reduced to 57.2 +/- 6.9% by the PI 3-kinase inhibitor LY294002 and 57.8 +/- 1.1% by the ERK-pathway inhibitor U0126); in asthmatics, the presence of a strong proliferative stimulus (10% FBS) reduces ERK activation resulting in a shift to the PI 3-kinase pathway. The underlying mechanism appears to be upregulation of an endogenous MAPK inhibitor--MKP-1--that constrains ERK signaling in asthmatic cells under strong mitogenic stimulation. This study suggests that the PI 3-kinase pathway may be an attractive target for reversing hyperplasia in asthma.
%Z FOR Codes: 111601


%0 Journal Article
%~ PubMed
%A Ball, Helen J
%A Yuasa, Hajime J
%A Austin, Christopher J D
%A Weiser, Silvia
%A Hunt, Nicholas H
%T Indoleamine 2,3-dioxygenase-2; a new enzyme in the kynurenine pathway.
%B The international journal of biochemistry & cell biology
%D 2008
%C United Kingdom
%I Pergamon
%V 41
%N 0
%P 467-71
%@ 1357-2725
%X The kynurenine pathway of tryptophan metabolism converts the amino acid tryptophan into a number of biologically active metabolites. The first and rate-limiting step in this pathway is the conversion of tryptophan to N-formylkynurenine and until recently this reaction was thought to be performed by either of two enzymes, tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase. A third enzyme, indoleamine 2,3-dioxygenase-2, indoleamine 2,3-dioxygenase-like protein or proto-indoleamine 2,3-dioxygenase (IDO2, IDO-2, INDOL1 or proto-IDO), with this activity recently has been described. The gene encoding IDO2 is adjacent and structurally similar to the indoleamine 2,3-dioxygenase gene and both mouse genes use multiple promoters to express transcripts with alternate 5'' exons. The IDO2 protein is expressed in the murine kidney, liver, male and female reproductive system. The two IDO enzymes can utilise a similar range of substrates, however they differ in their selectivity for some inhibitors. The selective inhibition of IDO2 by 1-methyl-D-tryptophan suggests that IDO2 activity may have a role in the inhibition of immune responses to tumours.
%Z FOR Codes: 111603


%0 Journal Article
%~ PubMed
%A Austin, Christopher
%A Astelbauer, Florian
%A Kosim-Satyaputra, Priambudi
%A Ball, Helen
%A Willows, Robert
%A Jamie, Joanne
%A Hunt, Nicholas
%T Mouse and human indoleamine 2,3-dioxygenase display some distinct biochemical and structural properties.
%B Amino acids
%D 2008
%C Austria
%I Springer Wien
%V 36
%N 0
%P 99-106
%@ 1438-2199
%X The hemoprotein indoleamine 2,3-dioxygenase (IDO) is the first and rate-limiting enzyme in the most significant pathway for mammalian tryptophan metabolism. It has received considerable attention in recent years, particularly due to its dual role in immunity and the pathogenesis of many diseases. Reported here are differences and similarities between biochemical behaviour and structural features of recombinant human IDO and recombinant mouse IDO. Significant differences were observed in the conversion of substrates and pH stability. Differences in inhibitor potency and thermal stability were also noted. Secondary structural features were broadly similar but variation between species was apparent, particularly in the alpha-helix portion of the enzymes. With mouse models substituting for human diseases, the differences between mouse and human IDO must be recognised before applying experimental findings from one system to the next.
%Z FOR Codes: 111601


%0 Journal Article
%~ PubMed
%A Boeuf, Philippe
%A Tan, Aimee
%A Romagosa, Cleofe
%A Radford, Jane
%A Mwapasa, Victor
%A Molyneux, Malcolm E
%A Meshnick, Steven R
%A Hunt, Nicholas H
%A Rogerson, Stephen J
%T Placental hypoxia during placental malaria.
%B The Journal of Infectious Diseases
%D 2008
%C United States
%I University of Chicago Press
%V 197
%N 5
%P 757-765
%@ 0022-1899
%X Placental malaria causes fetal growth retardation (FGR), which has been linked epidemiologically to placental monocyte infiltrates. We investigated whether parasite or monocyte infiltrates were associated with placental hypoxia, as a potential mechanism underlying malarial FGR.
%Z FOR Codes: 111401 110309


%0 Journal Article
%~ PubMed
%A Miu, Jenny
%A Hunt, Nicholas H
%A Ball, Helen J
%T Predominance of interferon-related responses in the brain during murine malaria, as identified by microarray analysis.
%B Infection and Immunity
%D 2008
%C United States
%I American Society for Microbiology
%V 76
%N 5
%P 1812-1824
%@ 1098-5522
%X Cerebral malaria (CM) can be a fatal manifestation of Plasmodium falciparum infection. We examined global gene expression patterns during fatal murine CM (FMCM) and noncerebral malaria (NCM) by microarray analysis. There was differential expression of a number of genes, including some not yet characterized in the pathogenesis of FMCM. Some gene induction was observed during Plasmodium berghei infection regardless of the development of CM, and there was a predominance of genes linked to interferon responses, even in NCM. However, upon real-time PCR validation and quantitation, these genes were much more highly expressed in FMCM than in NCM. The observed changes included genes belonging to pathways such as interferon signaling, major histocompatibility complex processing and presentation, apoptosis, and immunomodulatory and antimicrobial processes. We further characterized differentially expressed genes by examining the cellular source of their expression as well as their temporal expression patterns during the course of malaria infection. These data identify a number of novel genes that represent interesting candidates for further investigation in FMCM.
%Z FOR Codes: 110704 110803


%0 Journal Article
%~ PubMed
%A Xu, Yinghua
%A Hunt, Nicholas H
%A Bao, Shisan
%T The effect of restraint stress on experimental colitis is IFN-gamma independent.
%B Journal of neuroimmunology
%D 2008
%C Netherlands
%I Elsevier BV
%V 200
%N 0
%P 53-61
%@ 0165-5728
%X Stress, a protective reaction to external threats, may be deleterious if linked to an inflammatory stimulus. Stress may influence intestinal immunity, thereby contributing to the development of colitis. Less severe histological abnormalities and clinical scores were detected in dextran sulphate sodium (DSS)-induced colitis in IFN-gamma(-/-), compared to Wt, mice. Disease severity was increased by restraint stress in DSS-treated IFN-gamma(-/-) and Wt mice, accompanied by suppressed colonic pro and anti inflammatory cytokine responses. Our data suggest that IFN-gamma is important in the development of acute colitis. Stress increases the severity of colitis, but is independent of the IFN-gamma pathway.
%Z FOR Codes: 110704


%0 Journal Article
%~ PubMed
%A Xu, Yinghua
%A Hunt, Nicholas H
%A Bao, Shisan
%T The role of granulocyte macrophage-colony-stimulating factor in acute intestinal inflammation.
%B Cell research
%D 2008
%C United Kingdom
%I Nature Publishing Group
%V 18
%N 0
%P 1220-9
%@ 1748-7838
%X An imbalance of mucosal pro- and anti-inflammatory cytokines is crucial in the pathogenesis of inflammatory bowel disease (IBD). GM-CSF influences the development of hemopoietic cells. The precise role of GM-CSF in IBD remains to be elucidated. GM-CSF gene knockout (GM-CSF(-/-)) and wild-type (Wt) mice were challenged with 2.5% dextran sulfate sodium (DSS) for 7 days. The ensued clinical and pathological changes, macrophage infiltration, colonic cytokine production, and bacterial counts were examined. DSS-treated GM-CSF(-/-) mice developed more severe acute colitis than DSS-treated Wt mice, reflected by a greater body weight loss, more rectal bleeding, and aggravated histopathological changes. More infiltrating macrophages were observed in GM-CSF(-/-), compared with Wt mice following DSS challenge, correlating with monocyte chemoattractant protein-1 (MCP-1) production. The levels of colonic IL-17 and TNF-alpha were increased significantly in GM-CSF(-/-) mice, but not in Wt mice, following DSS administration. The level of IL-6 was increased by 1.5- and 2-fold in the colon of GM-CSF(-/-) and Wt mice, respectively, following DSS challenge. No significant changes in IL-4 and IFN-gamma were detected in Wt and GM-CSF(-/-) mice following DSS treatment. The bacteria recovery from colon was increased about 15- and 5-fold, respectively, in Wt mice and GM-CSF(-/-) mice following DSS challenge. These results suggest that GM-CSF(-/-) mice are more susceptible to acute DSS-induced colitis, possibly because of an impaired gut innate immune response as a result of diminished GM-CSF.
%Z FOR Codes: 110701


%0 Journal Article
%~ PubMed
%A Ball, Helen J
%A Sanchez-Perez, Angeles
%A Weiser, Silvia
%A Austin, Christopher J D
%A Astelbauer, Florian
%A Miu, Jenny
%A McQuillan, James A
%A Stocker, Roland
%A Jermiin, Lars S
%A Hunt, Nicholas H
%T Characterization of an indoleamine 2,3-dioxygenase-like protein found in humans and mice.
%B Gene
%D 2007
%C Netherlands
%I Elsevier BV
%V 396
%N 1
%P 203-213
%@ 0378-1119
%X Indoleamine 2,3-dioxygenase (INDO) and tryptophan 2,3-dioxygenase (TDO) each catalyze the first step in the kynurenine pathway of tryptophan metabolism. We describe the discovery of another enzyme with this activity, indoleamine 2,3-dioxygenase-like protein (INDOL1), which is closely related to INDO and is expressed in mice and humans. The corresponding genes have a similar genomic structure and are situated adjacent to each other on human and mouse chromosome 8. They are likely to have arisen by gene duplication before the origin of the tetrapods. The expression of INDOL1 is highest in the mouse kidney, followed by epididymis, and liver. Expression of mouse INDOL1 was further localized to the tubular cells in the kidney and the spermatozoa. INDOL1 was assigned its name because of its structural similarity to INDO. We demonstrate that INDOL1 catalyses the conversion of tryptophan to kynurenine therefore a more appropriate nomenclature for the enzymes might be INDO-1 and INDO-2, or the more commonly-used abbreviations, IDO-1 and IDO-2. Although the two proteins have similar enzymatic activities, their different expression patterns within tissues and during malaria infection, suggests a distinct role for each protein. This identification of INDOL1 may help to explain the regulation of the diversity of physiological and patho-physiological processes in which the kynurenine pathway is involved.
%Z FOR Codes: 110106


%0 Journal Article
%~ PubMed
%A Hunt, Nicholas H
%A Stocker, Roland
%T Heme moves to center stage in cerebral malaria.
%B Nature medicine
%D 2007
%C United States
%I Nature Publishing Group
%V 13
%N 6
%P 667-669
%@ 1078-8956
%X 
%Z FOR Codes: 110803 110101


%0 Journal Article
%~ PubMed
%A Weiser, Silvia
%A Miu, Jenny
%A Ball, Helen J
%A Hunt, Nicholas H
%T Interferon-gamma synergises with tumour necrosis factor and lymphotoxin-alpha to enhance the mRNA and protein expression of adhesion molecules in mouse brain endothelial cells.
%B Cytokine
%D 2007
%C United Kingdom
%I Academic Press
%V 37
%N 1
%P 84-91
%@ 1043-4666
%X Changes to the cerebral microvasculature are evident during cerebral malaria (CM). Activation of the endothelium is likely to be due to the actions of cytokines, circulating levels of which are elevated during CM. Endothelial cells are known to up-regulate the expression of cellular adhesion molecules, which can lead to cellular sequestration and obstruction of vessels. However, it is unknown whether cytokines synergise in the up-regulation of the adhesion molecules involved in CM. In this study, the mRNA and/or protein expression of the adhesion molecules vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), P-selectin and E-Selectin were examined in a mouse brain endothelial cell line. Endothelial cells were stimulated with interferon-gamma (IFN-gamma), tumour necrosis factor (TNF) and lymphotoxin-alpha (LT-alpha), alone or in combination. The expression of ICAM-1, VCAM-1, P-selectin and E-Selectin mRNA in mouse brain endothelial cells by TNF and/or LT-alpha was found to be significantly enhanced in the presence of IFN-gamma. The same synergistic effect was found when analyzing ICAM-1 protein expression in cytokine stimulated mouse brain endothelial cells. The findings show that cytokines can synergise to influence gene expression and protein expression in a mouse brain endothelial cell line.
%Z FOR Codes: 110704 110903


%0 Journal Article
%~ PubMed
%A Xu, Yinghua
%A Hunt, Nicholas H
%A Bao, Shisan
%T The correlation between proinflammatory cytokines, MAdCAM-1 and cellular infiltration in the inflamed colon from TNF-alpha gene knockout mice.
%B Immunology and cell biology
%D 2007
%C UK, Australia
%I Nature Publishing Group
%V 85
%N 8
%P 633-9
%@ 1440-1711
%X Tumour necrosis factor (TNF) is important in the development of inflammatory bowel disease. TNF-alpha-deficient mice show more severe colonic inflammation than wild-type (Wt) mice, but the underlying mechanism remains unclear. Using immunohistochemistry, enzyme-linked-immunosorbent assay and histopathology, we found that there was a higher level of macrophage infiltration in TNF-alpha(-/-) compared to Wt mice. This is consistent with higher levels of monocyte chemotactic protein-1, interleukin (IL)-6 and granulocyte monocyte colony-stimulating factor (GM-CSF) in the inflamed colon from the TNF-alpha(-/-) mice, compared to the Wt mice, following dextran sulphate sodium (DSS) challenge. There was close correlation between clinical observations and histopathological findings in both Wt and TNF-alpha(-/-) mice. The expression of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) was upregulated in the colon of Wt and TNF-alpha(-/-) mice following DSS challenge. Interestingly, the induction of MAdCAM-1 was relatively lower in the inflamed colon of TNF-alpha(-/-) mice, despite the higher inflammatory cell infiltrate, compared to their Wt counterparts. On the other hand, TNF-alpha(-/-) mice had significantly lower baseline levels of colonic IL-4, IL-6 and GM-CSF. Furthermore, there was a reduction of both immunoglobulin A (IgA) and IgG in the gut from TNF-alpha(-/-) mice following DSS challenge. These data indicate that TNF-alpha deficiency alters homoeostasis of the colonic chemokine/cytokine environment and humoral immune response, resulting in an exacerbation of acute DSS-induced colitis in TNF-alpha(-/-) mice. These findings support the idea that TNF-alpha plays a role in the acute stage of intestinal inflammation.
%Z FOR Codes: 110316


%0 Journal Article
%~ PubMed
%A Potter, Sarah M
%A Chan-Ling, Tailoi
%A Rosinova, Emilia
%A Ball, Helen J
%A Mitchell, Andrew J
%A Hunt, Nicholas H
%T A role for Fas-Fas ligand interactions during the late-stage neuropathological processes of experimental cerebral malaria.
%B Journal of Neuroimmunology
%D 2006
%C Netherlands
%I Elsevier BV
%V 173
%N 1-2
%P 96-107
%@ 0165-5728
%X Cerebral malaria (CM) kills more than 1 million children each year. Using a murine model of CM, we investigated the role of Fas-Fas ligand interactions in the neuropathogenesis of this disease. Lpr and Gld mice, deficient in Fas and Fas ligand, respectively, were protected from fatal CM, although they demonstrated some pathological features associated with CM in the wild type mouse. Fas-Fas ligand mRNA and protein expression were increased in the brain in mice with CM, and activated caspase-3-positive apoptotic astrocytes were observed. We suggest that Fas-mediated apoptosis of astrocytes is likely to be a critical factor in late-stage murine CM pathogenesis.
%Z FOR Codes: 110799


%0 Journal Article
%~ PubMed
%A Hunt, Nicholas
%A Grau, Georges
%T Blood-brain barrier in parasitic disease.
%B International journal for parasitology
%D 2006
%C United Kingdom
%I Elsevier Ltd.
%V 36
%N 5
%P 503-4
%@ 0020-7519
%X 
%Z FOR Codes:


%0 Journal Article
%~ PubMed
%A Parekh, Sapan B
%A Bubb, William A
%A Hunt, Nicholas H
%A Rae, Caroline
%T Brain metabolic markers reflect susceptibility status in cytokine gene knockout mice with murine cerebral malaria.
%B International journal for parasitology
%D 2006
%C UK
%I Elsevier Ltd.
%V 36
%N 13
%P 1409-18
%@ 0020-7519
%X Treatment of cerebral malaria, a complication of the world''s most significant parasitic disease, remains problematic due to lack of understanding of its pathogenesis. Metabolic changes, along with cytokine expression alterations and blood cell sequestration in the brain, have previously been reported during severe disease in human infection and mouse models leading to the "cytopathic hypoxia" and "sequestration" theories of pathogenesis. Here, to determine the robustness of the metabolic changes and their relationship to disease development, we investigated changes in cerebral metabolic markers in a mouse model of cerebral malaria (CM) in wildtype (C57BL/6) and cytokine knockout (TNF(-/-), IFNgamma(-/-) and LTalpha(-/-)) mice using multinuclear magnetic resonance spectroscopy. Mice susceptible to CM (wildtype, TNF(-/-)) showed decreased cerebral glucose use, decreased Krebs cycle metabolism and decreased high-energy phosphates. Conversely, mice resistant to CM (IFNgamma(-/-), LTalpha(-/-)) showed little sign of these effects, despite identical levels of parasitemia. Previously reported changes in lactate were shown to be strain dependent. Elevated glutamine and decreased phosphorylation potential emerged as robust metabolic markers of susceptibility, further implicating the trytophan/NAD(+) pathway in disease development. Thus these metabolic changes are firmly linked both to the immune system response to malaria and to the occurrence of pathogenic changes in experimental CM.
%Z FOR Codes: 110101 110803 110902


%0 Journal Article
%A Miu, Jenny
%A Mitchell, Andrew
%A Ball, Helen
%A Hunt, Nicholas
%T Chemokines and malarial infection
%B Current Immunology Reviews
%D 2006
%C United Kingdom
%I Bentham Science Publishers Ltd.
%V 2
%N 
%P 331-334
%@ 1573-3955
%X 
%Z FOR Codes: 110704


%0 Journal Article
%~ PubMed
%A Golenser, J
%A McQuillan, J
%A Hee, L
%A Mitchell, A J
%A Hunt, N H
%T Conventional and experimental treatment of cerebral malaria.
%B International journal for parasitology
%D 2006
%C UK
%I Elsevier Ltd.
%V 36
%N 5
%P 583-93
%@ 0020-7519
%X The most severe complication of Plasmodium falciparum infection is cerebral malaria (CM). Cerebral malaria implies the presence of neurological features, especially impaired consciousness. The treatment of CM is limited to: (i) a few conventional anti-malarial drugs (quinine or artemisinins), (ii) adjunctive treatments (initial stabilisation, blood exchange transfusion, osmotic diuretics and correction of hypoglycaemia, acidosis and hypovolaemia) and (iii) immunomodulation. There are clear procedures concerning treatment of CM, which include the use of the anti-plasmodial drugs. Adjunctive treatments are permissible but there is no single official guideline and immune intervention is a possibility currently being examined in rodent models only. The suggested immunomodulation approach is based on the strong likelihood that CM is the result of an immunopathological process. P. falciparum initiates the multifactorial chain of events leading to lethal CM and, after a certain stage, it is impossible to stop the progression even by using anti-malarial drugs. We present evidence that CM is a result of a dysregulated immune response. Therefore, it might be prevented by early modulation of discrete factors that participate in this process. In experimental systems, some immunomodulators delay or prevent CM without affecting the parasitaemia. Therefore, in the future the ultimate treatment of CM may be a combination of an anti-malarial and an immunomodulator. However, the overall effect of an immunomodulator would need to be carefully examined in view of concomitant infections, especially in malaria endemic areas.
%Z FOR Codes: 110502 110803


%0 Journal Article
%~ PubMed
%A Golenser, Jacob
%A Waknine, Judith H
%A Krugliak, Miriam
%A Hunt, Nicholas H
%A Grau, Georges E
%T Current perspectives on the mechanism of action of artemisinins.
%B International journal for parasitology
%D 2006
%C United Kingdom
%I Elsevier Ltd.
%V 36
%N 14
%P 1427-41
%@ 0020-7519
%X Artemisinin derivatives are the most recent single drugs approved and introduced for public antimalarial treatment. Although their recommended use is for treatment of Plasmodium falciparum infection, these drugs also act against other parasites, as well as against tumor cells. The mechanisms of action attributed to artemisinin include interference with parasite transport proteins, disruption of parasite mitochondrial function, modulation of host immune function and inhibition of angiogenesis. Artemisinin combination therapies are currently the preferred treatment for malaria. These combinations may prevent the induction of parasite drug resistance. However, in view of the multiple mechanisms involved, especially when additional drugs are used, the combined therapy should be carefully examined for antagonistic effects. It is now a general theory that the crucial mechanism is interference with plasmodial SERCA. Therefore, future development of resistance may be associated with overproduction or mutations of this transporter. However, a general mechanism, such as alterations in general drug transport pathways, is feasible. In this article, we review the evidence for each mechanism of action suggested.
%Z FOR Codes: 110803 110502


%0 Journal Article
%~ PubMed
%A Hunt, Nicholas H
%A Golenser, Jacob
%A Chan-Ling, Tailoi
%A Parekh, Sapan
%A Rae, Caroline
%A Potter, Sarah
%A Medana, Isabelle M
%A Miu, Jenny
%A Ball, Helen J
%T Immunopathogenesis of cerebral malaria.
%B International Journal for Parasitology
%D 2006
%C United Kingdom
%I Elsevier Ltd.
%V 36
%N 5
%P 569-582
%@ 0020-7519
%X Malaria is one of the most important global health problems, potentially affecting more than one third of the world''s population. Cerebral malaria (CM) is a deadly complication of Plasmodium falciparum infection, yet its pathogenesis remains incompletely understood. In this review, we discuss some of the principal pathogenic events that have been described in murine models of the disease and relate them to the human condition. One of the earliest events in CM pathogenesis appears to be a mild increase in the permeability to protein of the blood-brain barrier. Recent studies have shown a role for CD8+T cells in mediating damage to the microvascular endothelium and this damage can result in the leakage of cytokines, malaria antigens and other potentially harmful molecules across the blood-brain barrier into the cerebral parenchyma. We suggest that this, in turn, leads to the activation of microglia and the activation and apoptosis of astrocytes. The role of hypoxia in the pathogenesis of cerebral malaria is also discussed, with particular reference to the local reduction of oxygen consumption in the brain as a consequence of vascular obstruction, to cytokine-driven changes in glucose metabolism, and to cytopathic hypoxia. Interferon-gamma, a cytokine known to be produced in malaria infection, induces increased expression, by microvascular endothelial cells, of the haem enzyme indoleamine 2,3-dioxygenase, the first enzyme in the kynurenine pathway of tryptophan metabolism. Enhanced indoleamine 2,3-dioxygenase expression leads to increased production of a range of biologically active metabolites that may be part of a tissue protective response. Damage to astrocytes may result in reduced production of the neuroprotectant molecule kynurenic acid, leading to a decrease in its ratio relative to the neuroexcitotoxic molecule quinolinic acid, which might contribute to some of the neurological symptoms of cerebral malaria. Lastly, we discuss the role of other haem enzymes, cyclooxygenase-2, inducible nitric oxide synthase and haem oxygenase-1, as potentially being components of mechanisms that protect host tissue against the effects of cytokine- and leukocyte-mediated stress induced by malaria infection.
%Z FOR Codes: 110803


%0 Journal Article
%~ PubMed
%A Potter, Sarah
%A Chan-Ling, Tailoi
%A Ball, Helen J
%A Mansour, Hussein
%A Mitchell, Andrew
%A Maluish, Linda
%A Hunt, Nicholas H
%T Perforin mediated apoptosis of cerebral microvascular endothelial cells during experimental cerebral malaria.
%B International Journal for Parasitology
%D 2006
%C United Kingdom
%I Elsevier Ltd.
%V 36
%N 4
%P 485-496
%@ 0020-7519
%X Cerebral malaria is a serious complication of Plasmodium falciparum infection. We have investigated the role of perforin in the pathogenesis of cerebral malaria in a murine model (Plasmodium berghei ANKA (PbA) infection). C57BL/6 mice demonstrated the typical neuropathological symptoms of experimental cerebral malaria infection from day 5p.i. and became moribund on day 6p.i. This pathology was not seen in PbA-infected, perforin-deficient (pfp-/-) mice. From days 5-6p.i. onwards there was a significant increase in mRNA for granzyme B and CD8, but not CD4, in brain tissue from PbA-infected C57BL/6 and pfp-/- mouse brains. Perforin mRNA was strongly increased in the brains of PbA-infected C57BL/6 mice on day 6p.i. Immunohistochemistry revealed increased perforin staining and elevated numbers of CD8(+) cells within the cerebral microvessels in PbA-infected C57BL/6 at days 5 and 6p.i. compared with uninfected animals. At day 6p.i., there were TUNEL-positive cells and activated caspase-3 positive cells of endothelial morphology in the CNS of PbA-infected C57BL/6 mice. The TUNEL-positive cells were greatly reduced in pfp-/- mice. These results suggest that CD8(+)T lymphocytes induce apoptosis of endothelial cells via a perforin-dependent process, contributing to the fatal pathogenic process in murine cerebral malaria.
%Z FOR Codes: 110803


%0 Journal Article
%~ PubMed
%A Golenser, Jacob
%A Hunt, Nicholas H
%T Probing for antiparasitic drugs.
%B Mini reviews in medicinal chemistry
%D 2006
%C Netherlands
%I Bentham Science Publishers Ltd.
%V 6
%N 2
%P 121-2
%@ 1389-5575
%X 
%Z FOR Codes: 110502 110803


%0 Journal Article
%~ PubMed
%A Okada, Futoshi
%A Kobayashi, Masanobu
%A Tanaka, Hiroki
%A Kobayashi, Tokushige
%A Tazawa, Hiroshi
%A Iuchi, Yoshihito
%A Onuma, Kunishige
%A Hosokawa, Masuo
%A Dinauer, Mary C
%A Hunt, Nicholas H
%T The role of nicotinamide adenine dinucleotide phosphate oxidase-derived reactive oxygen species in the acquisition of metastatic ability of tumor cells.
%B American journal of pathology
%D 2006
%C United States
%I American Society for Investigative Pathology
%V 169
%N 1
%P 294-302
%@ 0002-9440
%X We examined the role of phagocyte-derived oxygen radicals in tumor cell acquisition of metastatic phenotype by comparing gp91(phox-/-) mice and C57BL/6J wild-type (WT) mice. The gp91(phox-/-) mouse is deficient in the gp91(phox) gene, an essential subunit of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase that generates superoxide anion. QR-32 fibrosarcoma cells are nonmetastatic but are converted into metastatic tumors once in contact with foreign body (gelatin sponge)-induced phagocytes in vivo. Compared to QR-32 cells co-implanted with the foreign body in WT mice, those in gp91(phox-/-) mice exhibited reduced metastasis. There was no difference in the incidence of primary tumors after injection of B16BL6 melanoma cells in WT and gp91(phox-/-) mice. However, after resection of the primary tumors, metastases were reduced in gp91(phox-/-) mice. Thymosin beta4 gene expression and cell motility/invasion were seen in the tumors from WT mice but not in those from gp91(phox-/-) mice. Adoptive transfer of phagocytes from WT mice, but not those from gp91(phox-/-) mice, restored the metastatic ability of tumors grown in gp91(phox-/-) mice. These findings show that tumor metastatic behavior can primarily be endowed by phagocyte-derived superoxide anion and its oxidative metabolites, which are generated through activation of nicotinamide adenine dinucleotide phosphate oxidase.
%Z FOR Codes: 110709