Ultrastructural and Biochemical Alterations Induced by 22,26-Azasterol, a Δ
            <sup>24(25)</sup>
            -Sterol Methyltransferase Inhibitor, on Promastigote and Amastigote Forms of
            <i>Leishmania amazonensis</i>

Rodrigues, Juliany Cola Fernandes; Attias, Márcia; Rodríguez, C. O.; Urbina, Julio A.; Souza, Wanderley de

doi:10.1128/aac.46.2.487-499.2002

Cited by 114 publications

(134 citation statements)

References 66 publications

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“…2D). The same effects were observed after treatment of T. cruzi and Leishmania with SMT inhibitors [43][44][45][46] (Fig. 2A).…”

Section: Mitochondriasupporting

confidence: 64%

“…The authors described a change in electron density of the cytoplasm, an increase in volume and in the number of the organelles, and the presence of acidocalcisome cores inside large vacuoles presenting characteristic autophagic-like structures. This last feature was also observed after incubation of Leishmania with the SBI 22, 26-azasterol [44]. An increase in acidocalcisome volume was also observed after incubation of L chagasi promastigotes in the presence of essential oil from C. citratus, Lippia sidoides, and Ocimum gratissimum [122].…”

Section: Acidocalcisomessupporting

confidence: 52%

“…The flagellar pockets were frequently dilated and filled with double membrane-bound bodies that budded from the flagellar pocket membrane. The same phenomenon was also observed in promastigotes of L. amazonensis after incubation in the presence of azasterol and squalene synthase inhibitors, suggesting alterations in the secretory pathway [41,44]. The lysophospholipid analogues (LPAs) edelfosine, miltefosine and ilmofosine, in addition to inducing the formation of vesicles and myelin-like figures in the flagellar pocket of L. amazonensis promastigotes [50], also induce morphological alterations in the reservosomes in epimastigotes of T. cruzi, which are characterized by swelling and the concentration of several reservosomes near the nucleus [51].…”

Section: Endocytic/ Exocytic Related Organellesmentioning

confidence: 61%

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Contributions of Ultrastructural Studies to the Cell Biology of Trypanosmatids: Targets for Anti-Parasitic Drugs

Almeida¹,

Souto-Padrón

2010

TOPARAJ

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Protozoan parasites cause disease in humans worldwide, and many fall into the genera Trypanosoma and Leishmania; these parasites are responsible for African trypanosomiasis, Chagas disease and the different forms of Leishmaniasis. Strategies for the development of new drugs against these protozoans have been based on their cell biology and biochemistry complemented by the use of electron microscopy. Trypanosoma and Leishmania have special organelles that are involved in metabolic pathways, which are very distinct from those in mammalian cells; these organelles are potential drug targets. Scanning and transmission electron microscopy can identify not only the target organelles but also alterations to the cell surface and ultrastructural changes that characterize distinct forms of programmed cell death.

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“…2D). The same effects were observed after treatment of T. cruzi and Leishmania with SMT inhibitors [43][44][45][46] (Fig. 2A).…”

Section: Mitochondriasupporting

confidence: 64%

Section: Acidocalcisomessupporting

confidence: 52%

Section: Endocytic/ Exocytic Related Organellesmentioning

confidence: 61%

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Contributions of Ultrastructural Studies to the Cell Biology of Trypanosmatids: Targets for Anti-Parasitic Drugs

Almeida¹,

Souto-Padrón

2010

TOPARAJ

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“…In addition, the compound also affects amastigotes (13) (the intracellular form of the parasite) and has been shown to have antiproliferative effects in vitro and in vivo (31). Similarly, the compound is active against Leishmania amazonensis promastigotes and amastigotes (24) and Leishmania donovani promastigotes (8).…”

mentioning

confidence: 99%

Novel Azasterols as Potential Agents for Treatment of Leishmaniasis and Trypanosomiasis

Lorente

Rodrigues

Jimenez

et al. 2004

Antimicrob Agents Chemother

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This paper describes the design and evaluation of novel azasterols as potential compounds for the treatment of leishmaniasis and other diseases caused by trypanosomatid parasites. Azasterols are a known class of (S)-adenosyl-L-methionine: ⌬ 24 -sterol methyltransferase(24-SMT) inhibitors in fungi, plants, and some parasitic protozoa. The compounds prepared showed activity at micromolar and nanomolar concentrations when tested against Leishmania spp. and Trypanosoma spp. The enzymatic and sterol composition studies indicated that the most active compounds acted by inhibiting 24-SMT. The role of the free hydroxyl group at position 3 of the sterol nucleus was also probed. When an acetate was attached to the 3␤-OH, the compounds did not inhibit the enzyme but had an effect on parasite growth and the levels of sterols in the parasite, suggesting that the acetate group was removed in the organism. Thus, an acetate group on the 3␤-OH may have application as a prodrug. However, there may be an additional mode(s) of action for these acetate derivatives. These compounds were shown to have ultrastructural effects on Leishmania amazonensis promastigote membranes, including the plasma membrane, the mitochondrial membrane, and the endoplasmic reticulum. The compounds were also found to be active against the bloodstream form (trypomastigotes) of Trypanosoma brucei rhodesiense, a causative agent of African trypanosomiasis.

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“…Fungicidal chemicals such as ketoconazole, azasterol, and 2=,6=-dihydrooxy-4=methoxychalcone that target the ergosterol biosynthesis pathway have been shown to cause a depletion of normal sterol and an accumulation of abnormal sterol precursors in L. donovani, L. infantum, L. major, and L. amazonensis (31,47,(66)(67)(68)(69)(70). It was further shown that depletion of membrane sterols by M␤CD impaired action of the antileishmanial drug miltefosine on L. donovani promastigotes (71).…”

Section: Discussionmentioning

confidence: 99%

Attenuation of Leishmania infantum chagasi Metacyclic Promastigotes by Sterol Depletion

et al. 2013

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The infectious metacyclic promastigotes of Leishmania protozoa establish infection in a mammalian host after they are deposited into the dermis by a sand fly vector. Several Leishmania virulence factors promote infection, including the glycosylphosphatidylinositol membrane-anchored major surface protease (MSP). Metacyclic Leishmania infantum chagasi promastigotes were treated with methyl-beta-cyclodextrin (M␤CD), a sterol-chelating reagent, causing a 3-fold reduction in total cellular sterols as well as enhancing MSP release without affecting parasite viability in vitro. M␤CD-treated promastigotes were more susceptible to complement-mediated lysis than untreated controls and reduced the parasite load 3-fold when inoculated into BALB/c mice. Paradoxically, M␤CD-treated promastigotes caused a higher initial in vitro infection rate in human or murine macrophages than untreated controls, although their intracellular multiplication was hindered upon infection establishment. There was a corresponding larger amount of covalently bound C3b than iC3b on the parasite surfaces of M␤CD-treated promastigotes exposed to healthy human serum in vitro, as well as loss of MSP, a protease that enhances C3b cleavage to iC3b. Mass spectrometry showed that M␤CD promotes the release of proteins into the extracellular medium, including both MSP and MSPlike protein (MLP), from virulent metacyclic promastigotes. These data support the hypothesis that plasma membrane sterols are important for the virulence of Leishmania protozoa at least in part through retention of membrane virulence proteins. Leishmania protozoa shuttle between a mammalian host as intracellular amastigotes and a sand fly vector as flagellated promastigotes. The sand fly acquires amastigote-laden cells during a blood meal. In the sand fly midgut, procyclic promastigotes derived from transformation of amastigotes undergo multiplication and development via intermediate stages, eventually yielding metacyclic promastigotes (1). The infectious metacyclic promastigote is inoculated into a pool of blood in the dermis of a mammalian host formed during a sand fly bite. Parasites are phagocytized by host macrophages, where they transform to amastigotes and multiply in parasitophorous vacuoles. Amastigotes spread to new macrophages at local or disseminated sites, perpetuating the infection and ultimately resulting in asymptomatic infections or symptomatic leishmaniasis (2). Various forms of leishmaniasis are endemic in 88 countries on four continents, leading to approximately two million new cases and 59,000 deaths annually (3).Both host and parasite factors contribute to the success of infection. On one hand, mammalian host environmental risk factors and genetic background influence the clinical manifestations of infection (4). On the other hand, parasite virulence determinants required for disease development include, but are not limited to, the major surface protease (MSP) (also called GP63 or leishmanolysin) and lipophosphoglycan (LPG) (5-8). These two molecules play both overl...

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Ultrastructural and Biochemical Alterations Induced by 22,26-Azasterol, a Δ ²⁴⁽²⁵⁾ -Sterol Methyltransferase Inhibitor, on Promastigote and Amastigote Forms of Leishmania amazonensis

Cited by 114 publications

References 66 publications

Contributions of Ultrastructural Studies to the Cell Biology of Trypanosmatids: Targets for Anti-Parasitic Drugs

Contributions of Ultrastructural Studies to the Cell Biology of Trypanosmatids: Targets for Anti-Parasitic Drugs

Novel Azasterols as Potential Agents for Treatment of Leishmaniasis and Trypanosomiasis

Attenuation of Leishmania infantum chagasi Metacyclic Promastigotes by Sterol Depletion

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Ultrastructural and Biochemical Alterations Induced by 22,26-Azasterol, a Δ 24(25) -Sterol Methyltransferase Inhibitor, on Promastigote and Amastigote Forms of Leishmania amazonensis

Cited by 114 publications

References 66 publications

Contributions of Ultrastructural Studies to the Cell Biology of Trypanosmatids: Targets for Anti-Parasitic Drugs

Contributions of Ultrastructural Studies to the Cell Biology of Trypanosmatids: Targets for Anti-Parasitic Drugs

Novel Azasterols as Potential Agents for Treatment of Leishmaniasis and Trypanosomiasis

Attenuation of Leishmania infantum chagasi Metacyclic Promastigotes by Sterol Depletion

Contact Info

Product

Resources

About

Ultrastructural and Biochemical Alterations Induced by 22,26-Azasterol, a Δ ²⁴⁽²⁵⁾ -Sterol Methyltransferase Inhibitor, on Promastigote and Amastigote Forms of Leishmania amazonensis