DETC Induces Leishmania Parasite Killing in Human In Vitro and Murine In Vivo Models: A Promising Therapeutic Alternative in Leishmaniasis

Background: Chemotherapy remains the primary tool for treatment and control of human leishmaniasis. However, currently available drugs present serious problems regarding side-effects, variable efficacy, and cost. Affordable and less toxic drugs are urgently needed for leishmaniasis. Methodology/Principal Findings: We demonstrate, by microscopy and viability assays, that superoxide dismutase inhibitor diethyldithiocarbamate (DETC) dose-dependently induces parasite killing (p,0.001) and is able to ??????sterilize?????? Leishmania amazonensis infection at 2 mM in human macrophages in vitro. We also show that DETC-induced superoxide production (p,0.001) and parasite destruction (p,0.05) were reverted by the addition of the antioxidant N-acetylcysteine, indicating that DETC-induced killing occurs through oxidative damage. Furthermore, ultrastructural analysis by electron microscopy demonstrates a rapid and highly selective destruction of amastigotes in the phagosome upon DETC treatment, without any apparent damage to the host cell, including its mitochondria. In addition, DETC significantly induced parasite killing in Leishmania promastigotes in axenic culture. In murine macrophages infected with Leishmania braziliensis, DETC significantly induced in vitro superoxide production (p = 0.0049) and parasite killing (p = 0.0043). In vivo treatment with DETC in BALB/C mice infected with Leishmania braziliensis caused a significant decrease in lesion size (p,0.0001), paralleled by a 100-fold decrease (p = 0.0087) in parasite burden. Conclusions/Significance: Due to its strong leishmanicidal effect in human macrophages in vitro, its in vivo effectiveness in a murine model, and its previously demonstrated in vivo safety profile in HIV treatment, DETC treatment might be considered as a valuable therapeutic option in human leishmaniasis, including HIV/Leishmania co-infection

Assesment of Interregional Cooperation in the Implementation of Infrastructure Projects (an Example of HSH «Moscow - Kazan»)

ВСМ «Москва – Казань» пройдет по территории 7 субъектов РФ и является одним из самых капиталоемких инфраструктурных проектов РФ до 2030 г. В работе с использованием авторской им итационной модели осуществляется расчет прогнозных эффектов проекта, обоснование инстит уционального механизма межрегионального сотрудничества при его реализации, проведена оценка чувствительности проекта к изменению производительности, объема инвестиций, тарифов.The HSH "Moscow-Kazan" which will pass through the territory of seven subjects of the Russian Federation is one of the most capital-intensive infrastructure projects of the Russian Federation until 2030. In this paper, using the author's simulation model the project's effects are calculated, justification of the i nstitutional mechanism for interregional cooperation in its implementation is conducted, the assessment of the project's sensitivity to changes in productivity, investment volume and tariffs is done