Deprivation of L-Arginine Induces Oxidative Stress Mediated Apoptosis in Leishmania donovani Promastigotes: Contribution of the Polyamine Pathway
Authors: Ruby Singh
Ajay Kumar
Pradeep Das
Abhishek Mandal
Sudha Verma
Ayan Kumar Ghosh
Saptarshi Roy
Abul Hasan Sardar
Sushmita Das
Kumar Abhishek
Savita Saini
Chitra Mandal
Journal: PLoS Neglected Tropical Diseases (2016)
Discipline: IMMUNOLOGY
Keywords: intracellular parasites; nutrients; redox balance; L-arginine; Leishmania donovani
Affiliations: Department of Molecular Biology, Rajendra Memorial Research Institute of Medical Sciences (ICMR), Patna, India., Department of Microbiology, All India Institute of Medical Sciences (AIIMS), Patna, India., Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India., Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Hajipur, India.

Abstract:  The growth and survival of intracellular parasites depends on the availability of extracellular nutrients. Deprivation of nutrients viz glucose or amino acid alters redox balance in mammalian cells as well as some lower organisms. To further understand the relationship, the mechanistic role of L-arginine in regulation of redox mediated survival of Leishmania donovani promastigotes was investigated. L-arginine deprivation from the culture medium was found to inhibit cell growth, reduce proliferation and increase L-arginine uptake. Relative expression of enzymes, involved in L-arginine metabolism, which leads to polyamine and trypanothione biosynthesis, were downregulated causing decreased production of polyamines in L-arginine deprived parasites and cell death. The resultant increase in reactive oxygen species (ROS), due to L-arginine deprivation, correlated with increased NADP+/NADPH ratio, decreased superoxide dismutase (SOD) level, increased lipid peroxidation and reduced thiol content. A deficiency of L-arginine triggered phosphatidyl serine externalization, a change in mitochondrial membrane potential, release of intracellular calcium and cytochrome-c. This finally led to DNA damage in Leishmania promastigotes. In summary, the growth and survival of Leishmania depends on the availability of extracellular L-arginine. In its absence the parasite undergoes ROS mediated, caspase-independent apoptosis-like cell death. Therefore, L-arginine metabolism pathway could be a probable target for controlling the growth of Leishmania parasites and disease pathogenesis. 

Retracted: No

PubPeer comments:
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 #4 1. Re: yellow plots in comment #1. Signal inside the green boxes very similar. 2. How to explain the high degree of similarity between the signal inside the green rectangles in figure 6, comment #1 , 
 Copy pasted from https: doi.org 10.1371 journal.pntd.0009580 :  Expression of Concern: Deprivation of L-Arginine Induces Oxidative Stress Mediated Apoptosis in Leishmania donovani Promastigotes: Contribution of the Polyamine Pathway. Following the publication of this article, concerns were raised regarding results presented in Fig 6. Specifically, (a) The results presented for the 72 hr AD-Ld Orn+, 72 hr AD-Ld Put+, 72 hr AD-Ld NAC+, and 96 hr AD-Ld NAC+ appear similar but not quite identical, (b) the results presented for the 120 hr AD-Ld Orn+ and 120 AD-Ld Put+ results appear similar but not quite identical. The authors submitted higher resolution versions of the panels presented in Fig 6, provided in the S1 File below. A member of the PLOS Neglected Tropical Diseases board assessed the concerns and the data provided by the author and indicated that the higher resolution images highlight minor differences between the 72 hr AD-Ld Orn+, 72 hr AD-Ld Put+, 72 hr AD-Ld NAC+, and 96 hr AD-Ld NAC+ panels, but that the 120 hr AD-Ld Orn+ and 120 AD-Ld Put+ panels appear more similar than would be expected from independent samples. The raw flow cytometry data underlying the panels presented in Fig 6 are no longer available. In the absence of the original data underlying Fig 6, PLOS Neglected Tropical Diseases cannot confirm the reliability of the results presented in this figure. The raw data and individual level data underlying the other results presented in this article are no longer available. The PLOS Neglected Tropical Diseases Editors issue this Expression of Concern to notify readers of the above concerns and relay the higher resolution figures provided by the corresponding author. Supporting information. Higher resolution copies of the panels presented in Fig 6. Published: July 8, 2021. See also https: retractionwatch.com 2021 07 21 two-years-thats-how-long-it-took-a-plos-journal-to-flag-a-paper-after-a-sleuth-raised-concerns Comments above were posted two years ago. ,