scholarly journals Experimental Selection of Paromomycin Resistance in Leishmania donovani Amastigotes Induces Variable Genomic Polymorphisms

2021 ◽  
Vol 9 (8) ◽  
pp. 1546
Author(s):  
Sarah Hendrickx ◽  
João Luís Reis-Cunha ◽  
Sarah Forrester ◽  
Daniel C. Jeffares ◽  
Guy Caljon
Keyword(s):  
Ribosomal Protein ◽  
Protein Tyrosine Phosphatase ◽  
Copy Number ◽  
Leishmania Donovani ◽  
Rna Binding ◽  
Tyrosine Phosphatase ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Gene Copy ◽  
Protein Tyrosine

The relatively high post-treatment relapse rates of paromomycin (PMM) in visceral leishmaniasis treatment and the swift emergence of experimental drug resistance challenge its broad application and urge for rational use and monitoring of resistance. However, no causal molecular mechanisms to Leishmania PMM resistance have been identified so far. To gain insights into potential resistance mechanisms, twelve experimentally selected Leishmania donovani clonal lines and the non-cloned preselection population, with variable degrees of PMM resistance, were subjected to whole genome sequencing. To identify genomic variations potentially associated with resistance, SNPs, Indels, chromosomal somy and gene copy number variations were compared between the different parasite lines. A total of 11 short nucleotide variations and the copy number alterations in 39 genes were correlated to PMM resistance. Some of the identified genes are involved in transcription, translation and protein turn-over (transcription elongation factor-like protein, RNA-binding protein, ribosomal protein L1a, 60S ribosomal protein L6, eukaryotic translation initiation factor 4E-1, proteasome regulatory non-ATP-ase subunit 3), virulence (major surface protease gp63, protein-tyrosine phosphatase 1-like protein), mitochondrial function (ADP/ATP mitochondrial carrier-like protein), signaling (phosphatidylinositol 3-related kinase, protein kinase putative and protein-tyrosine phosphatase 1-like protein) and vesicular trafficking (ras-related protein RAB1). These results indicate that, in Leishmania, the aminoglycoside PMM affects protein translational processes and underlines the complex and probably multifactorial origin of resistance.

Copy number alterations of chromosomal regions enclosing protein tyrosine phosphatase receptor-like genes in colorectal cancer

2014 ◽  
Vol 210 (12) ◽  
pp. 893-896 ◽  
Author(s):  
Izabela Laczmanska ◽  
Pawel Karpinski ◽  
Joanna Kozlowska ◽  
Marek Bebenek ◽  
David Ramsey ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Protein Tyrosine Phosphatase ◽  
Copy Number ◽  
Tyrosine Phosphatase ◽  
Copy Number Alterations ◽  
Protein Tyrosine

scholarly journals Role of Host Protein Tyrosine Phosphatase SHP-1 in Leishmania donovani-Induced Inhibition of Nitric Oxide Production

2006 ◽  
Vol 74 (11) ◽  
pp. 6272-6279 ◽  
Author(s):  
Geneviève Forget ◽  
David J. Gregory ◽  
Lorie A. Whitcombe ◽  
Martin Olivier
Keyword(s):  
Nitric Oxide ◽  
Transcription Factors ◽  
Protein Tyrosine Phosphatase ◽  
Leishmania Donovani ◽  
Tyrosine Phosphatase ◽  
Host Protein ◽  
Nitric Oxide Production ◽  
Protein Tyrosine ◽  
Oxide Production ◽  
Ifn Γ

ABSTRACT In order to survive within the macrophages of its host organism, the protozoan parasite Leishmania inhibits a number of critical, gamma interferon (IFN-γ)-inducible, macrophage functions, including the generation of nitric oxide. We have previously shown that the protein tyrosine phosphatase SHP-1 (Src-homology 2 domain containing phosphatase-1) is activated during Leishmania infection and plays an important role in both the survival of Leishmania within cultured macrophages and disease progression in vivo by inhibiting nitric oxide production. Here we use a SHP-1−/− macrophage cell line derived from motheaten mice to address the mechanisms by which SHP-1 prevents IFN-γ-dependent nitric oxide production during Leishmania donovani infection. We show that Leishmania inhibits nitric oxide production in response to IFN-γ poorly in SHP-1-deficient macrophages. This correlates with the inability of Leishmania to alter JAK2 and mitogen-activated protein kinase extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation and to prevent nuclear translocation of transcription factors NF-κB and AP-1, although the latter two to a lesser extent. Surprisingly, Leishmania inactivated the transcription factor STAT1 to a similar extent in SHP-1-deficient and wild-type macrophages, so STAT1 is not necessary for nitric oxide production by infected macrophages. Overall, this study demonstrates that induction of SHP-1 by Leishmania is vital for inhibition of nitric oxide generation and that this inhibition occurs through the inactivation of JAK2 and ERK1/2, and transcription factors NF-κB and AP-1.

1742-P: Targeting the Low Molecular Weight Protein Tyrosine Phosphatase for Obesity-Associated Diabetes Therapy

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 1742-P
Author(s):  
STEPHANIE M. STANFORD ◽  
MICHAEL A. DIAZ ◽  
JIWEN J. ZOU ◽  
ROBERT J. ARDECKY ◽  
ANTHONY PINKERTON ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Low Molecular Weight ◽  
Molecular Weight Protein ◽  
Diabetes Therapy ◽  
Protein Tyrosine ◽  
Weight Protein ◽  
Low Molecular Weight Protein

Inhibition of Protein Tyrosine Phosphatase 1B by Lutein Derivatives isolated from Mexican Oregano (Lippia graveolens)

2018 ◽  
Vol 17 (3) ◽  
pp. 134-139
Author(s):  
R.M. Perez-Gutierrez
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Inhibitory Activity ◽  
Spectroscopic Data ◽  
Methanol Extract ◽  
Tyrosine Phosphatase ◽  
Positive Control ◽  
Protein Tyrosine Phosphatase 1B ◽  
Protein Tyrosine ◽  
Ic50 Value ◽  
Ic50 Values

Methanol extract from Lippia graveolens (Mexican oregano) was studied in order to identify inhibitory bioactives for protein tyrosine phosphatase 1B (PTP1B). Known flavone as lutein (1), and another flavone glycoside such as lutein-7-o-glucoside (2), 6-hydroxy-lutein-7-ohexoside (3) and lutein-7-o-ramnoide (4) were isolated from methanol extract of aerial parts of the Lippia graveolens. All isolates were identified based on extensive spectroscopic data analysis, including UV, IR, NMR, MS and compared with spectroscopic data previously reported. These flavones were evaluated for PTP1B inhibitory activity. Among them, compounds 1 and 3 displayed potential inhibitory activity against PTP1B with IC50 values of 7.01 ± 1.25 μg/ml and 18.4 μg/ml, respectively. In addition, compound 2 and 4 showed moderate inhibitory activity with an IC50 value of 23.8 ± 6.21 and 67.8 ± 5.80 μg/ml respectively. Among the four compounds, luteolin was found to be the most potent PTP1B inhibitor compared to the positive control ursolic acid, with an IC50 value of 8.12 ± 1.06 μg/ml. These results indicate that flavonoids constituents contained in Lippia graveolens can be considered as a natural source for the treatment of type 2 diabetes.

Sign in / Sign up

Export Citation Format

Share Document