[leish-l] Fwd: Articles found by RefScout 04/05/05 - 18/2005

[jeffreyj at usp.br]

    Date: Wed, 4 May 2005 07:18:55
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This is RefScout-Newsletter 18/2005






REQUEST: [ leishmaniasis ]

(12 articles match this request)



PMID: 15858151
 

TITLE: A novel semiquantitative fluorescence-based multiplex polymerase chain
reaction assay for rapid simultaneous detection of bacterial and parasitic
pathogens from blood.

AUTHORS: Angamuthu Selvapandiyan, Katie Stabler, Nasim A Ansari, Stephen Kerby,
Jenny Riemenschneider, Poonam Salotra, Robert Duncan, Hira L Nakhasi

AFFILIATION: DETTD/OBRR/CBER/FDA, Bldg. 29, Rm 425, 8800 Rockville Pike,
Bethesda, MD 20892. selvapandiyan at cber.fda.gov.

REFERENCE: J Mol Diagn 2005 May 7(2):268-75

A multiplex polymerase chain reaction assay was developed for the rapid 
simultaneous detection of category A select bacterial agents (Bacillus 
anthracis and Yersinia pestis) and parasitic pathogens (Leishmania 
species) in blood using the Cepheid Smart Cycler platform. B. anthracis
 (Sterne) and Yersinia. pseudotuberculosis were used in the assay for 
optimization for B. anthracis and Y. pestis, respectively. The 
specificity of the target amplicons [protective antigen gene of B. 
anthracis and rRNA genes of other pathogens or human (internal control
)] was evaluated by staining the amplicons with SYBR Green I and 
determining their individual melting temperatures (T(m)). As a novel 
approach for pathogen semiquantitation, the Tm peak height of the 
amplicon was correlated with a known standard curve of pathogen-spiked 
samples. This assay was able to detect DNA in blood spiked with less 
than 50 target cells/ml for all of the pathogens. The sensitivity of 
this assay in blood was 100% for the detection of Leishmania donovani 
from leishmaniasis patients and B. anthracis (Sterne) from symptomatic 
mice. The time necessary for performing this assay including sample 
preparation was less than 1.5 hours, making this a potentially useful 
method for rapidly diagnosing and monitoring the efficacy of drugs or 
vaccines in infected individuals.








PMID: 15851441
 

TITLE: Old world cutaneous leishmaniasis infection in children: a case series.

AUTHORS: J Jones, J Bowling, J Watson, F Vega-Lopez, J White, E Higgins

AFFILIATION: Department of Dermatology, The Middlesex Hospital and Hospital for
Tropical Diseases, University College London Hospitals, NHS Trust, London, UK.
docjenj at aol.com

REFERENCE: Arch Dis Child 2005 May 90(5):530-1




PMID: 15860091
 

TITLE: The burden of the Leishmania chagasi/infantum infection in a closed
rural
focus of visceral leishmaniasis in Lara state, west-central Venezuela.

AUTHORS: M Dora Feliciangeli, Olinda Delgado, Benny Suarez, Miguel Angel
Chiurillo

AFFILIATION: Universidad de Carabobo, CNRFV, Núcleo Aragua, Maracay,
Venezuela.

REFERENCE: Trop Med Int Health 2005 May 10(5):444-9

Summary A prospective study was conducted in El Brazilar, Curarigua, 
Lara State, Venezuela, a small rural focus of visceral leishmaniasis (VL
) to investigate the burden and the evolution of Leishmania infection in
 the human and canine population. The incidence of the disease from 
February 1998 to February 2002 was recorded and two cross-sectional 
surveys using the leishmanin skin test (LST) and immunofluorescent 
antibody test (IFAT) were carried out. The dipstick test with 
recombinant r-K39 antigen was also applied in 2002. The incidence of the
 disease per year among the population (n = 118) during the period of 
study was 0.004. The rate of new infections per year was 0.07 [95% 
confidence interval (95% CI): 0.15-1.09]. The overall prevalence of 
infection measured by LST was not significantly higher in 2002 (43.2%) 
than in 1998 (28.3%), but it was with IFAT [16.3%vs. 4.6%; odds ratio (
OR): 4.01; 95% CI: 1.03-22.78; P = 0.022] which would indicate an 
increasing transmission. The dipstick test only detected infection in 
children up to 10 years (19.4%). Prevalence in dogs was not 
significantly different in 2002 (57%) vs. 1998 (33%). The parasite was 
isolated from dogs and identified by a polymerase chain reaction based 
on telomeric sequences as Leishmania chagasi/infantum.




PMID: 15862577
 

TITLE: Differential effects of polyamine derivative compounds against
Leishmania
infantum promastigotes and axenic amastigotes.

AUTHORS: J Tavares, A Ouaissi, P K T Lin, A Tomás, A Cordeiro-da-Silva

AFFILIATION: Laboratório de Bioquímica, Faculdade de Farmácia da
Universidade
do Porto, Rua Anibal Cunha, 164, 4050-047 Porto, Portugal; Instituto de
Biologia
Molecular e Celular, Universidade do Porto, Porto, Portugal.

REFERENCE: Int J Parasitol 2005 May 35(6):637-46

The natural polyamines are ubiquitous polycationic compounds that play 
important biological functions in cell growth and differentiation. In 
the case of protozoan species that are causative agents of important 
human diseases such as Leishmaniasis, an exogenous supply of polyamines 
supports parasite proliferation. In the present study, we have 
investigated the effect of three polyamine derivatives, (namely bis-
naphthalimidopropyl putrescine (BNIPPut), spermidine (BNIPSpd) and 
spermine (BNIPSpm)), on the proliferative stages of Leishmania infantum
, the causative agent of visceral leishmaniasis in the Mediterranean 
basin. A significant reduction of promastigotes and axenic amastigotes 
growth was observed in the presence of increasing concentrations of the 
drugs, although the mechanisms leading to the parasite growth arrest 
seems to be different. Indeed, by using a number of biochemical 
approaches to analyse the alterations that occurred during early stages 
of parasite-drug interaction (i.e. membrane phosphatidylserine exposure 
measured by annexin V binding, DNA fragmentation, 
deoxynucleotidyltranferase-mediated dUTP end labelin (TUNEL), 
mitochondrial transmembrane potential loss), we showed that the drugs 
had the capacity to induce the death of promastigotes by a mechanism 
that shares many features with metazoan apoptosis. Surprisingly, the 
amastigotes did not behave in a similar way to promastigotes. The drug 
inhibitory effect on amastigotes growth and the absence of propidium 
iodide labelling may suggest that the compounds are acting as cytostatic
 substances. Although, the mechanisms of action of these compounds have 
yet to be elucidated, the above data show for the first time that 
polyamine derivatives may act differentially on the Leishmania parasite 
stages. Further chemical modifications are needed to make the polyamine 
derivatives as well as other analogues able to target the amastigote 
stage of the parasite.




PMID: 15855481
 

TITLE: Antileishmanial activity of the terpene nerolidol.

AUTHORS: Denise C Arruda, Fabio Luiz D'Alexandri, Alejandro M Katzin, Silvia R
B
Uliana

AFFILIATION: Universidade de São Paulo, Av. Professor Lineu Prestes, 1374, CEP
05508-900, São Paulo, SP, Brazil. srbulian at icb.usp.br.

REFERENCE: Antimicrob Agents Chemother 2005 May 49(5):1679-87

The activity of nerolidol, a sesquiterpene used as a food-flavoring 
agent and currently under testing as a skin penetration enhancer for the
 transdermal delivery of therapeutic drugs, was evaluated against 
Leishmania species. Nerolidol inhibited the growth of Leishmania 
amazonensis, L. braziliensis, and L. chagasi promastigotes and L. 
amazonensis amastigotes with in vitro 50% inhibitory concentrations of 
85, 74, 75, and 67 muM, respectively. The treatment of L. amazonensis-
infected macrophages with 100 muM nerolidol resulted in 95% reduction in
 infection rates. Inhibition of isoprenoid biosynthesis, as shown by 
reduced incorporation of [2-(14)C]mevalonic acid (MVA) or [1-(14)C]
acetic acid precursors into dolichol, ergosterol, and ubiquinone, was 
observed in nerolidol-treated promastigotes. This drug effect can be 
attributed to the blockage of an early step in the mevalonate pathway, 
since incorporation of the precursor [1(n)-(3)H]farnesyl pyrophosphate 
in polyisoprenoids is not inhibited by nerolidol. L. amazonensis-
infected BALB/c mice were treated with intraperitoneal doses of 100 mg/
kg/day for 12 days or topically with 5 or 10% ointments for 4 weeks. 
Significant reduction of lesion sizes in nerolidol treated mice was 
observed for both treatment routes. However, long-term follow up 
indicated that the disease was not cured in this highly susceptible 
animal model. Nonetheless, the in vitro activity of nerolidol against 
these parasites may prove a useful tool for the development of new drugs
 for the treatment of leishmaniasis. In addition, biosynthesis of 
dolichols with 11 and 12 isoprene units was identified in Leishmania, as
 described for other trypanosomatids and Apicomplexa.




PMID: 15734543
 

TITLE: Cellular immunophenotyping of exfoliative dermatitis in canine
leishmaniosis (Leishmania infantum).

AUTHORS: E I Papadogiannakis, A F Koutinas, M N Saridomichelakis, J Vlemmas, S
Lekkas, A Karameris, A Fytianou

AFFILIATION: Clinic of Companion Animal Medicine, School of Veterinary
Medicine,
Aristotles University of Thessaloniki, 11 Stavrou Voutyra, GR-54627
Thessaloniki, Greece.

REFERENCE: Vet Immunol Immunopathol 2005 Apr 104(3-4):227-37

Lymphocyte subsets, major histocompatibility complex (MHC)-II expressing
 cells and number of amastigotes in the epidermis and dermis were 
investigated immunohistochemically in 48 dogs with patent leishmaniosis
, with or without exfoliative dermatitis (ED) to study the 
immunopathogenesis of this common cutaneous form of the disease. Skin 
biopsies were obtained and compared for ED sites (group A, n = 26), 
normal-appearing skin from the same animals (group B, n = 24), and 
leishmanial dogs not exhibiting ED (group C, n = 22), and normal 
controls (group D, n = 22). The CD3+, CD45RA+, CD4+, CD8+ (CD8a+), CD21
+, and MHC-II+ cells and leishmania amastigotes were identified 
immunohistochemically and counted with the aid of an image analysis 
system. Pyogranulomatous to granulomatous dermatitis, expressed in 
various histopathological patterns, was noticed in all groups A and B 
and in half of group C dogs. In the epidermis, the low number of T-cells
 and their subsets did not differ significantly between groups A and B, 
but CD8+ outnumbered CD4+ lymphocytes in both groups. MHC-II+ expression
 on epidermal keratinocytes was intense in the skin with and without 
lesions from dogs with ED but not in group C dogs. CD3+, CD8+ and MHC-II
+ cells were fewer in group C compared to group A and B dogs. In the 
dermis, CD3+ cells in group A animals were mainly represented by the CD8
+. CD45RA+ and CD21+ cells were also seen in high numbers. MHC-II 
expression, potentially in lymphocytes, fibroblasts, dendritic cells, 
and macrophages was intense. The numbers of all cellular subpopulations 
in the dermis were significantly different between the groups, being 
highest in group A and lowest in group D. In sebaceous adenitis sites, 
CD4+ outnumbered CD8+ cells in contrast to the neighbouring dermis and 
the epidermis. The number of CD21+ and CD45RA+ cells was much lower in 
the inflamed sebaceous glands compared to the dermis. Finally, the 
number of amastigotes in the normal-appearing skin was significantly 
higher in the ED dogs (group B) than in those not exhibiting this 
cutaneous form of the disease (group C).




PMID: 15853916
 

TITLE: Effect of LACK and KMP11 on IFN-gamma Production by Peripheral Blood
Mononuclear Cells from Cutaneous and Mucosal Leishmaniasis Patients.

AUTHORS: L P Carvalho, S Passos, W O Dutra, M Soto, C Alonso, K J Gollob, E M
Carvalho, A Ribeiro de Jesus

AFFILIATION: Serviço de Imunologia, Hospital Universitário Prof Edgard
Santos,
Universidade Federal da Bahia, Salvador, BA, Brazil.

REFERENCE: Scand J Immunol 2005 Apr 61(4):337-42

Abstract The immune modulatory properties of recombinant antigens 
Kinetoplasmid membrane protein-11 (KMP11) and Leishmania homologue of 
receptors for activated C kinase (LACK) in cutaneous leishmaniasis (CL) 
and mucosal leishmaniasis (ML) patients were evaluated. The mean levels 
of interferon-gamma (IFN-gamma) in soluble leishmania antigen (SLA) 
stimulated peripheral blood mononuclear cells (PBMC) of ML and CL 
patients were 5625 +/- 2333 pg/ml and 4422 +/- 3665 pg/ml, respectively
. IFN-gamma was not detected in cultures stimulated with KMP11 or LACK. 
Interleukin-10 (IL-10) concentration in SLA, KMP11 and LACK-stimulated 
PBMC of ML patients was 13 +/- 12 pg/ml, 285 +/- 388 pg/ml and 802 +/- 
483 pg/ml, respectively. Addition of KMP11 or LACK to SLA-stimulated 
PBMC of CL and ML patients enhanced IL-10 production (P < 0.05). 
Addition of KMP11 decreased IFN-gamma levels by 52% in CL patients and 
by 19% in ML patients. Addition of LACK to SLA-stimulated cultures 
decreased IFN-gamma levels by 58% in CL patients and by 30% in ML 
patients. Neutralization of IL-10 abrogated the downregulatory effect of
 LACK and KMP11. The modulatory properties of LACK and KMP11 are due to 
induction of IL-10 production and may be helpful for attenuating chronic
 inflammatory diseases. However, in some clinical conditions, as 
demonstrated for ML, these molecules are not able to suppress the IFN-
gamma response, even inducing IL-10 production.








PMID: 15784182
 

TITLE: Specific human antibodies do not inhibit Trypanosoma cruzi
oligopeptidase
B and cathepsin B, and immunoglobulin G enhances the activity of
trypomastigote-secreted oligopeptidase B.

AUTHORS: Luciana C Fernandes, Izabela M D Bastos, Liana Lauria-Pires, Ana C O
Rosa, Antonio R L Teixeira, Philippe Grellier, Joseph Schrével, Jaime M
Santana

AFFILIATION: Laboratório Multidisciplinar de Pesquisa em Doença de Chagas (CP
04536), Universidade de Brasília, 70919-970 Brasília, DF, Brazil.

REFERENCE: Microbes Infect 2005 Mar 7(3):375-84

Trypanosoma cruzi expresses oligopeptidase B and cathepsin B that have 
important functions in the interaction with mammalian host cells. In 
this study, we demonstrated that sera from both chagasic rabbits and 
humans have specific antibodies to highly purified native oligopeptidase
 B and cathepsin B. Levels of antibodies to cathepsin B were higher than
 those observed to oligopeptidase B by absorbance values recorded upon 
ELISA. We next showed that 90% and 30% of sera from individuals with 
mucocutaneous leishmaniasis have antibodies that recognize 
oligopeptidase B and cathepsin B as antigens, respectively. In addition
, 55% and 40% of sera from kala-azar patients have antibodies to 
oligopeptidase B and cathepsin B, respectively. Sera from malaria 
patients did not recognize the proteases as antigens. Despite high 
levels of specific antibodies, sera from T. cruzi-infected patients did 
not inhibit the activities of either oligopeptidase B or cathepsin B. 
Furthermore, sera or IgG purified from either infected or non-infected 
individuals enhanced the enzymatic activity of the secreted 
oligopeptidase B. Oligopeptidase B secreted by trypomastigotes and 
cathepsin B released upon parasite lysis retain their enzymatic 
activities and may be associated with Chagas' disease pathogenesis by 
hydrolyzing host proteins and inducing host immune responses.




PMID: 15749897
 

TITLE: Mechanisms of the natural reactivity of lymphocytes from noninfected
individuals to membrane-associated Leishmania infantum antigens.

AUTHORS: Atfa Sassi, Beya Larguèche-Darwaz, Alexis Collette, Adrien Six,
Dhafer
Laouini, Pierre André Cazenave, Koussay Dellagi

AFFILIATION: Laboratoire d'Immunopathologie, Vaccinologie et Génétique
Moléculaire, Laboratoire International Associé Bioingénierie Moléculaire,
Institut Pasteur de Tunis, Tunis, Tunisia.

REFERENCE: J Immunol 2005 Mar 174(6):3598-607

Membrane-associated Leishmania Ags (MLA) or soluble Leishmania Ags were 
used in vitro to stimulate cord blood or PBMC from healthy donors 
noninfected by Leishmania parasites. MLA, but not soluble Leishmania Ags
, constantly induce strong proliferation of cord blood mononuclear cells
 and PBMC from noninfected individuals. Responding cells are CD3+, CD4
+, TCRalphabeta+, CD45RO+, and CD45RA+ and secrete IFN-gamma and IL-10, 
but not IL-4. MLA do not activate NK cells nor NKT cells. Membrane Ags 
also induce purified macrophages from noninfected individuals to secrete
 IL-10 and TNF-alpha, but have no effect on IL-1alpha or IL-12 secretion
. The effects of MLA are proteinase K-sensitive and resistant to lipid 
extraction. The lymphoproliferative responses are inhibited by anti-HLA-
DR Abs and require Ag processing by APCs, excluding that the biological 
effect of MLA could be attributed to a superantigen. Finally, TCR 
repertoire analysis shows that the T cell expansion induced by MLA uses 
TCR with various variable beta segment rearrangements and CDR3 lengths, 
features much more characteristic to those observed with a polyclonal 
activator than with a conventional Ag. These results suggest a 
particular mechanism developed during the host's natural response to 
Leishmania parasites that allows direct activation of naive CD4 
lymphocytes by parasite membrane-associated Ags.




PMID: 15859939
 

TITLE: Parasitic infections in organ transplantation.

AUTHORS: Rashad S Barsoum

AFFILIATION: Cairo University, Egypt.

REFERENCE: Exp Clin Transplant 2004 Dec 2(2):258-67

More than 340 parasitic species infect more than 3 billion people 
worldwide with varying morbidity and mortality. The Tropics constitute 
the main reservoir of infection with the highest clinical impact, owing 
to favorable ecological factors. Acquisition of infection, clinical 
severity, and outcome of a parasitic disease depend on innate and 
acquired host immunity as well as the parasite's own immune response 
against the host when infection is established. Organ transplant 
recipients may acquire significant parasitic disease in 3 ways: 
transmission with the graft, de novo infection, or activation of dormant
 infection as a consequence of immunosuppression. Malaria, Trypanosoma, 
Toxoplasma, and Leishmania are the principal parasites that may be 
transmitted with bone marrow, kidney, or liver homografts, and 
microsporidia with xenotransplants. De novo infection with malaria and 
kala-azar may occur in immunocompromised travelers visiting in endemic 
areas, while immunocompromised natives are subject to superinfection 
with different strains of endemic parasites, reinfection with 
schistosomiasis, or rarely, with primary infections such as acanthamoeba
. The list of parasites that may be reactivated in the immunocompromised
 host includes giardiasis, balantidiasis, strongyloidiasis, 
capillariasis, malaria, Chagas' disease, and kalaazar. The broad 
clinical syndromes of parasitic infection in transplant recipients 
include prolonged pyrexia, lower gastrointestinal symptoms, 
bronchopneumonia, and meningoencephalitis. Specific syndromes include 
the hematologic manifestations of malaria, myocarditis in Chagas' 
disease, acute renal failure in malaria and leishmaniasis, and the 
typical skin lesions of Chagas' and cutaneous leishmaniasis. Many 
antiparasitic drugs have the potential for gastrointestinal, hepatic, 
renal, and hematologic toxicity, and may interact with the metabolism of
 immunosuppressive agents. It is recommended that transplant clinicians 
have a high index of suspicion of parasitic infections as an important 
transmission threat, as well as a potential cause of significant 
posttransplant morbidity.




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PMID: 12435061
 

TITLE: NADH-oxidase, NADPH-oxidase and myeloperoxidase activity of visceral
leishmaniasis patients.

AUTHORS: Promod Kumar, Kalpana Pai, Haushila P Pandey, Shyam Sundar

AFFILIATION: Department of Biochemistry, Faculty of Science, Banaras Hindu
University, Varanasi, India.

REFERENCE: J Med Microbiol 2002 Oct 51(10):832-6

It is believed that the enhanced capability of activated macrophages to 
resist infection is related to the remarkable increase in the production
 of oxygen metabolites in response to phagocytosis. Both the production 
of H2O2 and the oxidation of NAD(P)H are directly dependent upon NAD(P)H
-oxidase. It has been established that the respiratory burst is due to 
activation of NAD(P)H-oxidase localised in the plasmalemma. 
Myeloperoxidase is believed to be involved in augmenting the cytotoxic 
activity of H2O2. Low NADH-oxidase, NADPH-oxidase and myeloperoxidase 
activity were observed in monocytes of patients with active visceral 
leishmaniasis as compared with healthy controls. These results suggest 
that low NADH-oxidase, NADPH-oxidase and myeloperoxidase activities may 
account for persistence of Leishmania parasites in visceral 
leishmaniasis.




PMID: 14762559
 

TITLE: [Representations, attitudes, and practices related to Cutaneous
Leishmaniasis in people from Acosta County, San Jose province, Costa Rica. An
exploratory anthropological study]

AUTHORS: A Dobles-Ulloa, C Perriard

AFFILIATION: Unidad de Epidemiolog a, Facultad de Ciencias de la Salud,
Universidad Nacional 'Campus Omar Dengo', Heredia, 304-3000, Costa Rica.

REFERENCE: Cad Saude Publica 1994 Apr-Jun 10(2):181-9

An exploratory anthropological study on representations, attitudes, and 
practices related to Cutaneous Leishmaniasis (CL) among the rural 
population of Acosta County, Costa Rica, aimed to estimate the 
applicability of epidemiologically-based control measures. Open 
interviews with a small sample of individuals from both case and control
 households provided the basic for a Propositional Discourse Analysis (
PDA). Results are that Acosta people consider CL a distinct nosologic 
entity, but they are mainly interested in its clinical manifestations in
 children (who are mainly affected), as well as in their own capacity to
 act on the disease using folk remedies. The idea of control measures on
 reservoirs, on vectors, or on the spatial and temporal context of 
contact does not arise spontaneously in people's thinking. Nevertheless
, CL is perceived as a disruption in the safe domiciliary and 
peridomiciliary space, so that control measures intervening there could 
have a chance for success.




REQUEST: [ leishmania ]

(21 articles match this request. 7 articles matching other requests removed)



PMID: 15850702
 

TITLE: Overexpression of AP endonuclease protects Leishmaniamajor cells against
methotrexate induced DNA fragmentation and hydrogen peroxide.

AUTHORS: Cláribel Gallego, Antonio M Estévez, Esther Fárez, Luis M
Ruiz-Pérez, Dolores González-Pacanowska

AFFILIATION: Instituto de Parasitología y Biomedicina "López-Neyra", CSIC.
Avda. del Conocimiento s/n Parque Tecnológico de Ciencias de la Salud, 18100
Armilla, Granada, Spain.

REFERENCE: Mol Biochem Parasitol 2005 Jun 141(2):191-7

Generation of abasic (AP) sites is one of the main anomalies to arise in
 cellular DNA. These lesions are highly mutagenic, and need to be 
repaired by the base-excision repair (BER) system. Oxidative stress and 
misincorporation of dUTP are important sources of mutation load trough 
generation of AP sites. Kinetoplastid protozoa are able to survive in a 
highly oxidative environment within the host macrophages and between the
 different strategies used for survival, active DNA repair mechanisms 
must exist. In order to assess the role of BER in protecting parasites 
against DNA damage, we have overexpressed one enzyme of the pathway, AP 
endonuclease, in Leishmania major. Parasites overproducing AP 
endonuclease of L. major (APLM) showed an increased resistance to 
hydrogen peroxide, a mutagen that produces oxidative stress, and also to
 methotrexate (MTX), an inhibitor of thymidylate biosynthesis which 
causes a massive incorporation of dUTP into DNA, when compared to 
control cells. Moreover, DNA fragmentation caused by MTX was prevented 
in cells overexpressing APLM. Our results suggest that APLM is a key 
enzyme in mediating repair of AP sites in these pathogens.








PMID: 15606359
 

TITLE: Mutational analysis of the active-site residues crucial for catalytic
activity of adenosine kinase from Leishmania donovani.

AUTHORS: Rupak Datta, Ishita Das, Banibrata Sen, Anutosh Chakraborty, Subrata
Adak, Chhabinath Mandal, Alok K Datta

AFFILIATION: Division of Infectious Diseases, Leishmania Group, Indian
Institute
of Chemical Biology, 4, Raja S.C. Mullick Road, Kolkata 700 032, India.

REFERENCE: Biochem J 2005 May 387(Pt 3):591-600

Leishmania donovani adenosine kinase (LdAdK) plays a pivotal role in 
scavenging of purines from the host. Exploiting interspecies homology 
and structural co-ordinates of the enzyme from other sources, we 
generated a model of LdAdK that led us to target several amino acid 
residues (namely Gly-62, Arg-69, Arg-131 and Asp-299). Replacement of 
Gly-62 with aspartate caused a drastic reduction in catalytic activity, 
with decreased affinity for either substrate. Asp-299 was found to be 
catalytically indispensable. Mutation of either Arg-131 or Arg-69 caused
 a significant reduction in kcat. R69A (Arg-69-->Ala) and R131A mutants 
exhibited unaltered K(m) for either substrate, whereas ATP K(m) for R69K
 increased 6-fold. Importance of both of the arginine residues was 
reaffirmed by the R69K/R131A double mutant, which exhibited approx. 0.5
% residual activity with a large increase in ATP K(m). Phenylglyoxal, 
which inhibits the wild-type enzyme, also inactivated the arginine 
mutants to different extents. Adenosine protected both of the Arg-69 
mutants, but not the R131A variant, from inactivation. Binding 
experiments revealed that the AMP-binding property of R69K or R69A and 
D299A mutants remained largely unaltered, but R131A and R69K/R131A 
mutants lost their AMP binding ability significantly. The G62D mutant 
did not bind AMP at all. Free energy calculations indicated that Arg-69 
and Arg-131 are functionally independent. Thus, apart from the mandatory
 requirement of flexibility around the diglycyl (Gly-61-Gly-62) motif, 
our results identified Asp-299 and Arg-131 as key catalytic residues, 
with the former functioning as the proton abstractor from the 5'-OH of 
adenosine, while the latter acts as a bidentate electrophile to 
stabilize the negative charge on the leaving group during the phosphate 
transfer. Moreover, the positive charge distribution of Arg-69 probably 
helps in maintaining the flexibility of the alpha-3 helix needed for 
proper domain movement. These findings provide the first comprehensive 
biochemical evidence implicating the mechanistic roles of the 
functionally important residues of this chemotherapeutically exploitable
 enzyme.




PMID: 15855523
 

TITLE: Role of the ABC Transporter MRPA (PGPA) in Antimony Resistance in
Leishmania infantum Axenic and Intracellular Amastigotes.

AUTHORS: Karima El Fadili, Nadine Messier, Philippe Leprohon, Gaétan Roy,
Chantal Guimond, Nathalie Trudel, Nancy G Saravia, Barbara Papadopoulou,
Danielle Légaré, Marc Ouellette

AFFILIATION: Centre de Recherche en Infectiologie, CHUQ, pavillon CHUL, 2705
boul. Laurier, Ste-Foy, Québec, Canada G1V 4G2.
marc.ouellette at crchul.ulaval.ca.

REFERENCE: Antimicrob Agents Chemother 2005 May 49(5):1988-93

Antimonial compounds are the mainstay for the treatment of infections 
with the protozoan parasite Leishmania. We present our studies on 
Leishmania infantum amastigote parasites selected for resistance to 
potassium antimonyl tartrate [Sb(III)]. Inside macrophages, the Sb(III)-
selected cells are cross-resistant to sodium stibogluconate (Pentostam
), the main drug used against Leishmania. Putative alterations in the 
level of expression of more than 40 genes were compared between 
susceptible and resistant axenic amastigotes using customized DNA 
microarrays. The expression of three genes coding for the ABC 
transporter MRPA (PGPA), S-adenosylhomocysteine hydrolase, and 
folylpolyglutamate synthase was found to be consistently increased. The 
levels of cysteine were found to be increased in the mutant. 
Transfection of the MRPA gene was shown to confer sodium stibogluconate 
resistance in intracellular parasites. This MRPA-mediated resistance 
could be reverted by using the glutathione biosynthesis-specific 
inhibitor buthionine sulfoximine. These results highlight for the first 
time the role of MRPA in antimony resistance in the amastigote stage of 
the parasite and suggest a strategy for reversing resistance.




PMID: 15856417
 

TITLE: In Vitro Antileishmanial Activity of Diphyllin Isolated from
Haplophyllum
bucharicum.

AUTHORS: Carole Di Giorgio, Florence Delmas, Valentina Akhmedjanova, Evelyne
Ollivier, Iraida Bessonova, Elias Riad, Pierre Timon-David

AFFILIATION: Laboratoire de Parasitologie Hygiène et Zoologie, Faculté de
Pharmacie, Marseille, France.

REFERENCE: Planta Med 2005 Apr 71(4):366-9

Diphyllin isolated from Haplophyllum bucharicum Litv. (Rutaceae), an 
endemic plant of Uzbekistan, displayed a moderate antiproliferative 
activity towards human monocytes (IC (50) = 35.2 muM) and Leishmania 
promastigotes (IC (50) = 14.4 muM), by a mechanism of action that 
involved interaction with macromolecules and resulted in cell cycle 
arrest in the S-phase and inhibition of protein synthesis. In the 
intracellular amastigote form of the parasite, diphyllin exerted a 
strong specific inhibitory activity (IC (50) = 0.2 muM) resulting from 
the inhibition of parasite internalization within macrophages. This 
property was mainly due to modulation of macrophage phagocytosis and, to
 a lesser extent, it also involved interference with surface molecules 
of the promastigote membrane.




PMID: 15856892
 

TITLE: The effect of amphotericin b derivatives on Leishmania and immune
functions.

AUTHORS: Tirtsa Ehrenfreund-Kleinman, Abraham J Domb, Charles L Jaffe, Abed
Nasereddin, Benni Leshem, Jacob Golenser

AFFILIATION: Department of Medicinal Chemistry, School of Pharmacy, Hebrew
University of Jerusalem, Jerusalem 91120, Israel.

REFERENCE: J Parasitol 2005 Feb 91(1):158-63

The effects of a water-soluble amphotericin B (AmB)-arabinogalactan (AG
) conjugate on several immune functions were investigated. The 
experiments measured the effects of AmB-AG on (1) release of tumor 
necrosis factor-alpha (TNF-alpha), nitric oxide (NO), and interferon-
gamma (IFN-gamma) from phagocytic cells and (2) cell-mediated immune 
responses. AmB-AG increased TNF-alpha release from mouse peritoneal 
macrophages and human monocytes but had no effect on IFN-gamma and NO 
release. A commercial preparation of nonconjugated AmB (Fungizone) also 
increased TNF-alpha production, but to a lesser extent than AmB-AG. AG 
alone had no effect on TNF-alpha production, proving that AmB caused the
 increased TNF-alpha production. AmB-AG and Fungizone were also tested 
for their effect on B- and T-cell proliferation. Neither compound 
altered T-lymphocyte responses to concanavalin A, but both inhibited the
 stimulation of B lymphocytes by lipopolysaccharides. However, Fungizone
 showed a stronger inhibitory effect on B cells. Allocytotoxicity was 
also inhibited by AmB-AG and more strongly by Fungizone. The increased 
production of TNF-alpha by cells treated with AmB-AG and the lower 
inhibitory effect of AmB-AG on lymphocyte stimulation and 
allocytotoxicity, as compared with Fungizone, explain the better 
therapeutic efficacy of the AmB-polysaccharide conjugate. AmB is active 
because of its preferential binding to ergosterol rather than 
cholesterol, the former sterol preferentially present in parasite 
surface membranes. This is also valid for the axenic amastigotes, which 
were sensitive to the AmB-AG. Overall, our results suggest that the 
antileishmanial activity of AmB-AG is mediated both directly and via 
modulation of immune functions.




PMID: 15856912
 

TITLE: Late cutaneous metastases in C3H SCID mice infected with Leishmania
amazonensis.

AUTHORS: Y Vanloubbeeck, M R Ackermann, D E Jones

AFFILIATION: Department of Veterinary Pathology, College of Veterinary
Medicine,
Iowa State University, Ames, Iowa 50011, USA.

REFERENCE: J Parasitol 2005 Feb 91(1):226-8

The biological behavior of Leishmania amazonensis in the mammalian host 
is highly variable, resulting in local to diffuse cutaneous lesions that
 sometimes metastasize. Inflammation and, more specifically, CD4+ T 
cells have been shown to enhance metastases in mice infected with L. 
amazonensis, suggesting that the process may be lymphocyte mediated. 
However, we document, in this study, the development of multiple 
cutaneous metastases in C3H SCID mice infected with L. amazonensis. This
 shows that functional T and B cells are not required for metastases to 
occur.




PMID: 15852483
 

TITLE: Evaluation of antiprotozoal and plasmodial enoyl-ACP reductase
inhibition
potential of turkish medicinal plants.

AUTHORS: D Tasdemir, R Brun, R Perozzo, A A Dönmez

AFFILIATION: Institute of Organic Chemistry, University of Zurich,
Winterthurerstrasse 190, CH-8057, Zürich, Switzerland.

REFERENCE: Phytother Res 2005 Feb 19(2):162-6

A total of 58 extracts of different polarity were prepared from various 
organs of 16 species of Turkish plants and screened for their 
antitrypanosomal, antileishmanial and antiplasmodial activities. No 
significant activity was observed against Trypanosoma cruzi, whereas 
many extracts showed appreciable trypanocidal potential against T. 
brucei rhodesiense, with the CHCl(3)-soluble portion of Phlomis kurdica 
being the most active (IC(50) 2.7 microg[sol ]mL). Almost all extracts, 
particularly the CHCl(3) phases, exhibited growth inhibition activity 
against Leishmania donovani amastigotes. The CHCl(3)-solubles of Putoria
 calabrica roots (IC(50) 1.9 microg[sol ]mL), Wendlandia ligustroides 
leaves (IC(50) 2.1 microg[sol ]mL) and Rhododendron luteum leaves (IC(50
) 2.3 microg[sol ]mL) displayed the highest leishmanicidal potential. 
The majority of the extracts also possessed antiplasmodial activity 
against the multi-drug resistant K1 Plasmodium falciparum strain. The 
most potent antiplasmodial activity was observed with the CHCl(3) 
extracts of Phlomis kurdica (IC(50) 1.5 microg[sol ]mL), P. leucophracta
 (IC(50) 1.6 microg[sol ]mL), Scrophularia cryptophila (IC(50) 1.8 
microg[sol ]mL), Morina persica (IC(50) 1.9 microg[sol ]mL) and the 
aqueous root extract of Asperula nitida subsp. subcapitellata (IC(50) 1.
6 microg[sol ]mL). Twenty-one extracts with significant antimalarial 
activity (IC(50) < 5 microg[sol ]mL) were also tested for their 
ability to inhibit the purified enoyl-ACP reductase (FabI), a crucial 
enzyme in the fatty acid biosynthesis of P. falciparum. The CHCl(3) 
extract of Rhododendron ungernii leaves (IC(50) 10 microg[sol ]mL) and 
the H(2)O-soluble portion of Rhododendron smirnovii leaves (IC(50) 0.4 
microg[sol ]mL) strongly inhibited the FabI enzyme. The preliminary data
 indicate that some (poly)phenolic compounds are responsible for the 
FabI inhibition potential of these extracts. The presented work reports 
for the first time the antiprotozoal activity of nine different genera 
as well as a target specific antimalarial screening for the 
identification of P. falciparum FabI inhibitors from medicinal plant 
extracts. Copyright (c) 2005 John Wiley & Sons, Ltd.








PMID: 15860773
 

TITLE: Characterization of the DNA-binding domain and identification of the
active site residue in the 'Gyr A' half of Leishmania donovani topoisomerase
II.

AUTHORS: Tanushri Sengupta, Mandira Mukherjee, Rakhee Das, Aditi Das, Hemanta K
Majumder

AFFILIATION: Molecular Parasitology Laboratory, Indian Institute of Chemical
Biology 4 Raja S.C. Mullick Road, Kolkata-700032, India.

REFERENCE: Nucleic Acids Res 2005  33(8):2364-73

DNA topoisomerase II is a multidomain homodimeric enzyme that changes 
DNA topology by coupling ATP hydrolysis to the transport of one DNA 
helix through a transient double-stranded break in another. To 
investigate the biochemical properties of the individual domains of 
Leishmania donovani topoisomerase II, four truncation mutants were 
generated. Deletion of 178 aminoacids from the C-terminus (core and 
LdDeltaC1058) had no apparent effect on the DNA-binding or cleavage 
activities of the enzymes. However, when 429 aminoacids from the N-
terminus and 451 aminoacids from the C-terminus were removed (
LdDeltaNDeltaC), the enzyme was no longer active. Moreover, the removal 
of 429 aminoacids from the N-terminus (LdDeltaNDeltaC, core and 
LdDeltaN429) render the mutant proteins incapable of performing ATP 
hydrolysis. The mutant proteins show cleavage activities at wide range 
of KCl concentrations (25-350 mM). In addition, the mutant proteins, 
excepting LdDeltaNDeltaC, can also act on kDNA and linearize the 
minicircles. Surprisingly, the mutant proteins fail to show the 
formation of the enhanced cleavable complex in the presence of etoposide
. Our findings suggest that the conformation required for interaction 
with the drug is absent in the mutant proteins. Here, we have also 
identified Tyr(775) through direct sequencing of the DNA linked peptide 
as the catalytic residue implicated in DNA-breakage and rejoining. Taken
 together, our results demonstrate that topoisomerase II are 
functionally and mechanistically conserved enzymes and the variations in
 activity seem to reflect functional optimization for its physiological 
role during parasite genome replication.




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PMID: 11421285
 

TITLE: Fungal ABC proteins: pleiotropic drug resistance, stress response and
cellular detoxification.

AUTHORS: H Wolfger, Y M Mamnun, K Kuchler

AFFILIATION: Institute of Medical Biochemistry, Department of Molecular
Genetics, University and Biocenter of Vienna, Austria.

REFERENCE: Res Microbiol 2001 Apr-May 152(3-4):375-89

A number of prominent genetic diseases are caused by mutations in genes 
encoding ATP-binding cassette (ABC) proteins (Ambudkar, Gottesmann, 1998
). Moreover, several mammalian ABC proteins such as P-glycoprotein (P-gp
) (Gottesman et al., 1995) and multidrug-resistance-associated proteins
 (MRPs) (Cole, Deeley, 1998) have been implicated in multidrug 
resistance (MDR) phenotypes of tumor cells highly resistant to many 
different anticancer drugs. The characteristics of MDR phenomena include
 the initial resistance to a single anticancer drug, followed by the 
development of cross-resistance to many structurally and functionally 
unrelated drugs. Similar mechanisms of MDR exist in pathogenic fungi, 
including Candida and Aspergillus (Vanden Bossche et al., 1998), and 
also in parasites such as Plasmodium and Leishmania (Ambudkar, 
Gottesmann, 1998), as well as in many bacterial pathogens (Nikaido, 1998
). To dissect the mechanisms of MDR development and to elucidate the 
physiological functions of ABC proteins, many efforts have been made 
during the past decade. Importantly, yeast orthologues of mammalian 
disease genes made this unicellular eukaryote an invaluable model system
 for studies on the molecular mechanisms of ABC proteins, in order to 
better understand and perhaps improve treatment of ABC gene-related 
disease. In this review, we provide an overview of ABC proteins and 
pleiotropic drug resistance in the budding yeast Saccharomyces 
cerevisiae and the fission yeast Schizosaccharomyces pombe. Furthermore
, we discuss the role of ABC proteins in clinical drug resistance 
development of certain fungal pathogens.




PMID: 11716297
 

TITLE: Crowbars and ratchets: hsp100 chaperones as tools in reversing protein
aggregation.

AUTHORS: J R Glover, J M Tkach

AFFILIATION: Department of Biochemistry, University of Toronto, ON, Canada.
john.glover at utoronto.ca

REFERENCE: Biochem Cell Biol 2001  79(5):557-68

Molecular chaperones have the capacity to prevent inappropriate 
interactions between aggregation-prone folding or unfolding 
intermediates created in the cell during protein synthesis or in 
response to physical and chemical stress. What happens when surveillance
 by molecular chaperones is evaded or overwhelmed and aggregates 
accumulate? Recent progress in the elucidation of Hsp100/Clp function 
suggests that intracellular aggregates or stable complexes can be 
progressively dissolved by the action of chaperones that act as 
molecular crowbars or ratchets. These insights set the stage for new 
progress in the understanding and treatment of diseases of protein 
folding.




PMID: 9651675
 

TITLE: Molecular chaperones: clamps for the Clps?

AUTHORS: H P Feng, L M Gierasch

AFFILIATION: Department of Chemistry, University of Massachusetts, Amherst
01003, USA.

REFERENCE: Curr Biol 1998 Jun 8(13):R464-7

The Clp/Hsp100 molecular chaperones are unusual in their ability to 
tease apart protein aggregates and complexes. Recent results make a good
 case that these chaperones bind substrates via PDZ-like domains; this 
may reflect a general strategy for manipulating the] assembly state of 
substrate proteins.




PMID: 9428517
 

TITLE: PDZ-like domains mediate binding specificity in the Clp/Hsp100 family of
chaperones and protease regulatory subunits.

AUTHORS: I Levchenko, C K Smith, N P Walsh, R T Sauer, T A Baker

AFFILIATION: Department of Biology, Howard Hughes Medical Institute,
Massachusetts Institute of Technology, Cambridge 02139, USA.

REFERENCE: Cell 1997 Dec 91(7):939-47

ClpX, a molecular chaperone and the regulatory subunit of the ClpXP 
protease, is shown to contain tandem modular domains that bind to the C-
terminal sequences of target proteins in a manner that parallels 
functional specificity. Nuclear magnetic resonance studies show that 
these C-terminal sequences are displayed as disordered peptides on the 
surface of otherwise folded proteins. The ClpX substrate-binding domains
 are homologous to sequences in other Clp/Hsp100 proteins and are 
related more distantly to PDZ domains, which also mediate C-terminal 
specific protein-protein interactions. Conservation of these binding 
domains indicates that the mode of substrate recognition characterized 
here for ClpX will be a conserved feature among Clp/Hsp100 family 
members and a distinguishing characteristic between this chaperone 
family and the Hsp70 chaperones.




PMID: 9149530
 

TITLE: ATP-dependent proteases that also chaperone protein biogenesis.

AUTHORS: C K Suzuki, M Rep, J M van Dijl, K Suda, L A Grivell, G Schatz

AFFILIATION: Biozentrum, University of Basel, Switzerland.

REFERENCE: Trends Biochem Sci 1997 Apr 22(4):118-23

The ATP-dependent proteases Clp and FtsH from bacteria, as well as 
mitochondrial homologs of FtsH and Lon from yeast, may act as chaperones
; they mediate not only proteolysis, but also the insertion of proteins 
into membranes and the disassembly or oligomerization of protein 
complexes. The coordination of such processes with selective proteolysis
 may function in the quality control of protein biogenesis.




PMID: 8772382
 

TITLE: HSP100/Clp proteins: a common mechanism explains diverse functions.

AUTHORS: E C Schirmer, J R Glover, M A Singer, S Lindquist

AFFILIATION: Howard Hughes Medical Institute, Chicago, IL, USA.

REFERENCE: Trends Biochem Sci 1996 Aug 21(8):289-96

The HSP100/Clp proteins are a newly discovered family with a great 
diversity of functions, such as increased tolerance to high temperatures
, promotion of proteolysis of specific cellular substrates and 
regulation of transcription. HSP100/Clp proteins are also synthesized in
 a variety of specific patterns and, in eukaryotes, are localized to 
different subcellular compartments. Recent data suggest that a common 
ability to disassemble higher-order protein structures and aggregates 
unifies the molecular functions of this diverse family.




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