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Complex Interplay between Sphingolipid and Sterol Metabolism Revealed by Perturbations to the Leishmania Metabolome Caused by Miltefosine

With the World Health Organization reporting over 30,000 deaths and 200,000 to 400,000 new cases annually, visceral leishmaniasis is a serious disease affecting some of the world's poorest people. As drug resistance continues to rise, there is a huge unmet need to improve treatment. Miltefosine remains one of the main treatments for leishmaniasis, yet its mode of action (MoA) is still unknown. Understanding the MoA of this drug and parasite response to treatment could help pave the way for new and more successful treatments for leishmaniasis. A novel method has been devised to study the metabolome and lipidome ofLeishmania donovaniaxenic amastigotes treated with miltefosine. Miltefosine caused a dramatic decrease in many membrane phospholipids (PLs), in addition to amino acid pools, while sphingolipids (SLs) and sterols increased.Leishmania majorpromastigotes devoid of SL biosynthesis through loss of the serine palmitoyl transferase gene (ΔLCB2) were 3-fold less sensitive to miltefosine than wild-type (WT) parasites. Changes in the metabolome and lipidome of miltefosine-treatedL. majormirrored those ofL. donovani. A lack of SLs in the ΔLCB2 mutant was matched by substantial alterations in sterol content. Together, these data indicate that SLs and ergosterol are important for miltefosine sensitivity and, perhaps, MoA.

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Publication Date
Wed Feb 22 2023
Journal Name
Iraqi Journal Of Science
Miltefosine Efficacy on Leishmania Donovani Promastigote

In the current study, different concentrations of miltefosine drug, which is the first effective and safe oral treatment for visceral leishmaniasis, was evaluated against L. donovani promastigotes in comparison with pentosam drug. Direct counting microscopic assay was used to find 50% inhibitory concentration (IC50) of miltefosine and pentostam against L. donovani promastigotes. The IC50 of miltefosine drug was 45.42μg/ml, 46.76μg/ml and 36.68μg/ml after 24 hr, 48hr and 72hr respectively, In comparison with IC 50 of pentostam drug was 75.39 μg/ml after 72hr. There were significant differences (P˂0.05) between IC50 values of miltefosine and pentostam drugs from first day to third day.

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Publication Date
Sat Dec 01 2012
Journal Name
Advances In Bioresearch
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Publication Date
Sun Jan 01 2012
Journal Name
Biochemistry Research International
Endocytosis and Sphingolipid Scavenging in Leishmania mexicana Amastigotes

Leishmaniaspecies are the causative agents of the leishmaniases, a spectrum of neglected tropical diseases. Amastigote stage parasites exist within macrophages and scavenge host factors for survival, for example,Leishmaniaspecies utilise host sphingolipid for synthesis of complex sphingolipid. In this studyL. mexicanaendocytosis was shown to be significantly upregulated in amastigotes, indicating that sphingolipid scavenging may be enhanced. However, inhibition of host sphingolipid biosynthesis had no significant effect on amastigote proliferation within a macrophage cell line. In addition, infection itself did not directly influence host biosynthesis.

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Publication Date
Sat Mar 01 2014
Journal Name
International Journal Of Advanced Research
Ex vivo study of the importance of sphingolipid in Leishmania amastigote

Leishmania is the causative agent of leishmaniasis, a widely distributed disease. Amastigote forms of Leishmania are intracellular and reside within the macrophage of the vertebrate host. Previous studies showed that certain Leishmania species may scavenge host factors for survival, specially sphingolipids, the key element of the eukaryotic membranes. In this study we have investigated the survival of new world L. mexicana amastigotes in murine macrophage cell-line in the presence and absence of foetal bovine serum (FBS). Results showed that there was no significance in the infectivity of amastigotes and also the number of parasite per cell; such findings suggest that L. mexicana amastigotes have its own pathway of sphingolipid intake and c

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Publication Date
Thu Dec 31 2020
Journal Name
Iraqi Journal Of Market Research And Consumer Protection
SIMULATION AND MODELING OF HYDRO CRACKING REACTR TO REDUCE POLLUTION CAUSED BY REFINERIES: SIMULATION AND MODELING OF HYDRO CRACKING REACTR TO REDUCE POLLUTION CAUSED BY REFINERIES

Hydro cracking of heavy oil is used in refinery to produce invaluable products. In this research, a model of hydro cracking reactor has been used to study the behavior of heavy oil in hydro cracking under the conditions recommended by literature in terms lumping of feed and products. The lumping scheme is based on five lumps include: heavy oil, vacuum oil, distillates, naphtha and gases. The first order kinetics was assumed for the conversion in the model and the system is modeled as an isothermal tubular reactor. MATLAB 6.1 was used to solve the model for a five lump scheme for different values of feed velocity, and temperature.

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Publication Date
Wed Jan 19 2022
Journal Name
Iraqi Journal Of Science
In Vitro Assessment of Miltefosine Activity Against Promastigotes and Axenic Amastigotes of Leishmania tropica

Leishmaniasis is a worldwide disease still treated with expensive compounds that present severe side effects, and are frequently ineffective emphasizing the importance to search effective compounds against this disease. Miltefosine drug (HePC) that used as antitumor agent has been used against Leishmania tropica in two forms promastigote and axenic amastigote in vitro conditions. Different concentrations (5, 10, 15, 20, 25 and 30 μM) of HePC were performed and exposed to both parasite forms in comparison to sodium stibogluconate (Sb) drug. Parasites viability then was determined using MTT assay after 12, 24, and 48hr of exposure. DNA was extracted from treated and untreated parasites after 48hr of exposure and qualitative analysis of th

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Publication Date
Sat Jan 01 2011
Journal Name
North American Journal Of Medical Sciences
Urinary tract infections caused by staphylococcus aureus DNA in comparison to the candida albicans DNA

Background: Bacterial DNA released upon bacterial autolysis or killed by antibiotics, hence, many inflammatogenic reactions will be established leading to serious tissue damage. Aim: the present work aimed to elucidate the histopathological changes caused by prokaryotic (bacterial) DNA and eukaryotic (candidal) DNA. Materials and methods: twenty one Staphylococcus aureus and 36 Candida albicans isolates were isolated from UTI patients. Viable cells and DNA of the highest antibiotic sensitive isolates were injected, intraurethraly, in mice. Results were evaluated via histopathological examination. Results: Mildest reactions were obtained from mice challenged with viable C. albicans compared with those challenged with viable S. aureus. Dos

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Publication Date
Fri Dec 31 2021
Journal Name
Journal Of Legal Sciences
International responsibility for damage caused by cyber attacks

The research sheds light on a new topic of international law, the most important of which is, around which there are still question marks and differences in most of its aspects, especially with regard to international liability for damage caused by cyber attacks in the virtual space, the last is the fifth area that appeared alongside other area (Land, sea, air and outer space) and in addition to being a space on which states depend in the performance of their functions and international relations, it is a new arena for war and a source of danger to the security of states, As the security exposure to the secrets of states increased due to espionage and piracy, and the attacks on the infrastructure of countries increased, and the silence o

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Publication Date
Fri Jun 24 2022
Journal Name
Iraqi Journal Of Science
Preparation of Nanoliposomes by Size Exclusion Chromatography to Entrap Soluble Antigens from Leishmania Donovani

In this study, we investigated the ability of nanoliposomes preparation, as a nanoadjuvant, to entrap soluble Leismania donovani antigens (SLAs) and release in vitro. The parasite reactivation was carried out when inoculated into Rosewell park memorial institute media (RPMI) and incubated at 23 °C for 4 days. L. donovani promastigote inoculum (104 cell / ml) of 4 days was used to inoculate modified medium of Saline - Neopeptone and Blood agar 9 (SNB 9) to produce promastigote mass. SLAs were extracted from the promastigotes ghost membrane after fourth passages of subculturing in SNB. The membrane pellet obtained was suspended in 5 mM Tris buffer (pH 7.6) and sonicated three times at 4 °C and entrapped in freshly prepared nanoliposomes.

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Publication Date
Mon Sep 14 2020
Journal Name
British Journal Of Neurosurgery
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