Ammonium trichloro [1,2-ethanediolato-O,O′]-tellurate cures experimental visceral leishmaniasis by redox modulation of Leishmania donovani trypanothione reductase and inhibiting host integrin linked ... View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2017-09-12

AUTHORS

Preeti Vishwakarma, Naveen Parmar, Pragya Chandrakar, Tanuj Sharma, Manoj Kathuria, Pramod K. Agnihotri, Mohammad Imran Siddiqi, Kalyan Mitra, Susanta Kar

ABSTRACT

In an endeavor to search for affordable and safer therapeutics against debilitating visceral leishmaniasis, we examined antileishmanial potential of ammonium trichloro [1,2-ethanediolato-O,O′]-tellurate (AS101); a tellurium based non toxic immunomodulator. AS101 showed significant in vitro efficacy against both Leishmania donovani promastigotes and amastigotes at sub-micromolar concentrations. AS101 could also completely eliminate organ parasite load from L. donovani infected Balb/c mice along with significant efficacy against infected hamsters (˃93% inhibition). Analyzing mechanistic details revealed that the double edged AS101 could directly induce apoptosis in promastigotes along with indirectly activating host by reversing T-cell anergy to protective Th1 mode, increased ROS generation and anti-leishmanial IgG production. AS101 could inhibit IL-10/STAT3 pathway in L. donovani infected macrophages via blocking α4β7 integrin dependent PI3K/Akt signaling and activate host MAPKs and NF-κB for Th1 response. In silico docking and biochemical assays revealed AS101’s affinity to form thiol bond with cysteine residues of trypanothione reductase in Leishmania promastigotes leading to its inactivation and inducing ROS-mediated apoptosis of the parasite via increased Ca2+ level, loss of ATP and mitochondrial membrane potential along with metacaspase activation. Our findings provide the first evidence for the mechanism of action of AS101 with excellent safety profile and suggest its promising therapeutic potential against experimental visceral leishmaniasis. More... »

PAGES

563-588

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s00018-017-2653-3

DOI

http://dx.doi.org/10.1007/s00018-017-2653-3

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1091600856

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/28900667


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71 docking
72 donovani
73 donovani promastigotes
74 efficacy
75 endeavor
76 evidence
77 excellent safety profile
78 experimental visceral leishmaniasis
79 findings
80 first evidence
81 generation
82 hamsters
83 host
84 host integrins
85 immunomodulators
86 inactivation
87 infected hamsters
88 integrins
89 leishmaniasis
90 levels
91 load
92 loss
93 loss of ATP
94 macrophages
95 mechanism
96 mechanism of action
97 mechanistic details
98 membrane
99 metacaspase activation
100 mice
101 mitochondrial membrane
102 mode
103 modulation
104 non toxic immunomodulator
105 parasite load
106 parasites
107 pathway
108 potential
109 production
110 profile
111 promastigotes
112 promising therapeutic potential
113 redox modulation
114 reductase
115 residues
116 response
117 safe therapeutics
118 safety profile
119 signaling
120 significant efficacy
121 silico docking
122 sub-micromolar concentrations
123 tellurate
124 tellurium
125 therapeutic potential
126 therapeutics
127 thiol bond
128 trichloro
129 trypanothione reductase
130 visceral leishmaniasis
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