title: Deprivation of L-Arginine Induces Oxidative Stress Mediated Apoptosis in Leishmania donovani Promastigotes: Contribution of the Polyamine Pathway.
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.
authors.affiliation: Department of Molecular Biology, Rajendra Memorial Research Institute of Medical Sciences (ICMR), Patna, India.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Mandal
authors.affiliation: Department of Microbiology, All India Institute of Medical Sciences (AIIMS), Patna, India.
authors.forename: Sushmita
authors.initials: S
authors.lastname: Das
authors.affiliation: Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Saptarshi
authors.initials: S
authors.lastname: Roy
authors.affiliation: Department of Molecular Biology, Rajendra Memorial Research Institute of Medical Sciences (ICMR), Patna, India.
authors.forename: Ayan Kumar
authors.initials: AK
authors.lastname: Ghosh
authors.affiliation: Department of Molecular Biology, Rajendra Memorial Research Institute of Medical Sciences (ICMR), Patna, India.
authors.forename: Abul Hasan
authors.initials: AH
authors.lastname: Sardar
authors.affiliation: Department of Molecular Biology, Rajendra Memorial Research Institute of Medical Sciences (ICMR), Patna, India.
authors.forename: Sudha
authors.initials: S
authors.lastname: Verma
authors.affiliation: Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Hajipur, India.
authors.forename: Savita
authors.initials: S
authors.lastname: Saini
authors.affiliation: Department of Molecular Biology, Rajendra Memorial Research Institute of Medical Sciences (ICMR), Patna, India.
authors.forename: Ruby
authors.initials: R
authors.lastname: Singh
authors.affiliation: Department of Molecular Biology, Rajendra Memorial Research Institute of Medical Sciences (ICMR), Patna, India.
authors.forename: Kumar
authors.initials: K
authors.lastname: Abhishek
authors.affiliation: Department of Molecular Biology, Rajendra Memorial Research Institute of Medical Sciences (ICMR), Patna, India.
authors.forename: Ajay
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Chitra
authors.initials: C
authors.lastname: Mandal
authors.affiliation: Department of Molecular Biology, Rajendra Memorial Research Institute of Medical Sciences (ICMR), Patna, India.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Das
mesh_terms: D000818:Animals; D017209:Apoptosis; D001120:Arginine / Q000378:metabolism*; D006224:Cricetinae; D006801:Humans; D007893:Leishmania donovani / Q000254:growth & development* / Q000378:metabolism*; D007898:Leishmaniasis, Visceral / Q000378:metabolism* / Q000469:parasitology / Q000503:physiopathology; D008018:Life Cycle Stages; D015227:Lipid Peroxidation; D008647:Mesocricetus; D018384:Oxidative Stress; D011073:Polyamines / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D011073:Polyamines; D017382:Reactive Oxygen Species; D001120:Arginine