The Leishmania mexicana proteasome

Robertson, Colin D.

doi:10.1016/s0166-6851(99)00110-3

Cited by 66 publications

(50 citation statements)

References 53 publications

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“…The inhibition of leishmanial growth produced by these com- pounds may be due to their effects on proteasome activity. As observed on L. mexicana [13], these effects may depend on the stage of the parasite; for example, amastigotes developing within macrophages during human infection are more sensitive to lactacystin than promastigotes developing in culture medium. If the same applies to indinavir and saquinavir, their leishmanicidal effects should be higher in vivo than in vitro.…”

Section: Resultsmentioning

confidence: 92%

“…They are characterised by evolutionarily conserved proteins and are present in Trypanosoma brucei [8], Trypanosoma cruzi [9], Toxoplasma gondii [10], Plasmodium spp. [11], Entamoeba histolytica and Entamoeba invadens [12], as well as in Leishmania mexicana [13]. A molecular similarity was found between the human 20S proteasome ␣-type subunit and a Leishmania donovani cDNA clone [14] and between a gene encoding a 20S proteasome ␤ subunit in Plasmodium falciparum [15].…”

Section: Introductionmentioning

confidence: 99%

“…A molecular similarity was found between the human 20S proteasome ␣-type subunit and a Leishmania donovani cDNA clone [14] and between a gene encoding a 20S proteasome ␤ subunit in Plasmodium falciparum [15]. Proteasomes play a key role in differentiation and replication of protozoa, and lactacystin, a specific inhibitor of proteasomes, has a negative impact on the replication of L. mexicana promastigotes, although only at a high concentration [13].…”

Section: Introductionmentioning

confidence: 99%

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Antileishmanial activity of HIV protease inhibitors

Savoia

Allice

Tovo

2005

International Journal of Antimicrobial Agents

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The proteasomes of some protozoa are possible targets for chemotherapy. Leishmaniasis is a major health problem in human immunodeficiency virus (HIV) co-infected subjects. Two HIV protease inhibitors (PI), indinavir and saquinavir, have been shown to block proteasome functions; we therefore investigated their effects on the growth of two Leishmania spp. (Leishmania major and Leishmania infantum). After 24 h of treatment, both drugs exhibited a dose-dependent antileishmanial activity, with 50% lethal dose (LD 50 ) values of, respectively, 8.3 M and 7 M on L. major; minor activity was observed on L. infantum. These results add new in vitro insights into the wide-spectrum efficacy of PI and suggest studying their action on amastigote forms of leishmania within macrophages in order to validate their potential contribution against opportunistic infections in treated seropositive patients.

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Section: Resultsmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Antileishmanial activity of HIV protease inhibitors

Savoia

Allice

Tovo

2005

International Journal of Antimicrobial Agents

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“…Moreover, evidence is now accumulating that noncaspases, including cathepsins, calpains, granzymes, and the proteasome complex, also have roles in mediating and promoting cell death (27,43). Recent studies have otherwise pointed out in two Leishmania species the existence of an active proteasome, one similar to the proteasomes of other eukaryotes (10,49). This potent proteasome might be involved in the NO-mediated apoptosis-like process.…”

Section: Discussionmentioning

confidence: 99%

Nitric Oxide-Mediated Proteasome-Dependent Oligonucleosomal DNA Fragmentation inLeishmania amazonensisAmastigotes

et al. 2002

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Resistance to leishmanial infections depends on intracellular parasite killing by activated host macrophages through the L-arginine-nitric oxide (NO) metabolic pathway. Here we investigate the cell death process induced by NO for the intracellular protozoan Leishmania amazonensis. Exposure of amastigotes to moderate concentrations of NO-donating compounds (acidified sodium nitrite NaNO 2 or nitrosylated albumin) or to endogenous NO produced by lipopolysaccharide or gamma interferon treatment of infected macrophages resulted in a dramatic time-dependent cell death. The combined use of several standard DNA status analysis techniques (including electrophoresis ladder banding patterns, YOPRO-1 staining in flow cytofluorometry, and in situ recognition of DNA strand breaks by TUNEL [terminal deoxynucleotidyltransferase-mediated dUTPbiotin nick end labeling] assay) revealed a rapid and extensive fragmentation of nuclear DNA in both axenic and intracellular NO-treated amastigotes of L. amazonensis. Despite some similarities to apoptosis, the nuclease activation responsible for characteristic DNA degradation was not under the control of caspase activity as indicated by the lack of involvement of cell-permeable inhibitors of caspases and cysteine proteases. In contrast, exposure of NO-treated amastigotes with specific proteasome inhibitors, such as lactacystin or calpain inhibitor I, markedly reduced the induction of the NO-mediated apoptosis-like process. These data strongly suggest that NO-induced oligonucleosomal DNA fragmentation in Leishmania amastigotes is, at least in part, regulated by noncaspase proteases of the proteasome. The determination of biochemical pathways leading up to cell death might ultimately allow the identification of new therapeutic targets.Leishmania spp. are obligate intracellular protozoan parasites of macrophages that are responsible for a wide range of human diseases, including self-healing skin lesions, diffuse cutaneous and mucosal lesions, or fatal visceral infections. In the Leishmania life cycle, two principal parasite forms exist: (i) the amastigote form that develops inside mononuclear phagocytes of a vertebrate host and (ii) the motile promastigote form that develops in the vector gut. The various possible outcomes of leishmanial infection have been associated with expansion of specific T helper lymphocyte populations (52). Immune control of leishmaniasis involves a dominant Th1 response, leading to macrophage activation and elimination of intracellular parasites through the induction of nitric oxide synthase (NOS II) and NO synthesis from L-arginine. This prototypical model has been largely evidenced in murine leishmaniasis (17,22,33). Human activated macrophages can also induce antileishmanial activity via the L-arginine NO pathway (44,58,60). Studies on human cutaneous leishmaniasis reveal that Leishmania killing is associated with NO production (40). Moreover, the capacity of canine macrophages to eliminate intracellular amastigotes through a NO-dependent mechanism has been docum...

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“…For instance, lactacystin and its active form clastolactacystin b-lactone blocked the in vitro growth and intracellular survival of L. chagasi promastigotes and arrested the intracellular development of the lactacystin-treated parasites during the infectivity of L. chagasi promastigotes in mouse peritoneal macrophages [199]. The involvement of the proteasome in the regulation of L. mexicana cell cycle progression was demonstrated by the addition of a peptide aldehydes inhibitor (MG132), since this drug caused an accumulation of promastigotes with 4n DNA content.…”

Section: Proteasomementioning

confidence: 99%

Biological Roles of Peptidases in Trypanosomatids~!2009-11-26~!2010-02-15~!2010-03-18~!

Vermelho

Branquinha²,

d’Avila-Levy³

et al. 2010

TOPARAJ

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Abstract:In this review, we report the recent developments in the characterization of peptidases and their possible biological functions in the Trypanosomatidae family. The focus will be on peptidases from Trypanosoma cruzi, Leishmania spp., African trypanosomes and plant and insect trypanosomatids. There are numerous events in parasite development where the involvement of peptidases has been established, and they will be approached in the present review. Also in this review we will discuss the central roles have been proposed for peptidases in diverse processes such as virulence, host cell interaction and invasion, catabolism of host proteins, differentiation, cell cycle progression and both stimulation and evasion of host immune responses.

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The Leishmania mexicana proteasome

Cited by 66 publications

References 53 publications

Antileishmanial activity of HIV protease inhibitors

Antileishmanial activity of HIV protease inhibitors

Nitric Oxide-Mediated Proteasome-Dependent Oligonucleosomal DNA Fragmentation inLeishmania amazonensisAmastigotes

Biological Roles of Peptidases in Trypanosomatids~!2009-11-26~!2010-02-15~!2010-03-18~!

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