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Leishmaniasis caused by the intracellular protozoan parasite of mononuclear phagocytes Leishmania is endemic in 88 countries [1]. Leishmania amazonensis, a species transmitted mainly in the Amazon region, has been associated with localized cutaneous lesions, diffuse cutaneous disease, and mucosal infection [1,2]. The disease is neglected by the pharmaceutical industry, even though no vaccine exists, and significant side effects and signs of increasing resistance continue to occur with the use of the few effective drugs available [3,4].More recently, the pharmaceutical proprieties of tellurane compounds were investigated [5,6]. Several tellurides show antioxidative and immunomodulating proprieties and antitumor activities [5][6][7][8][9][10][11][12]. Clinical trials with a tellurane compound are presently underway [13,14]. The synthetic organotellurane compound RT-01 ( Fig. 1) has been previously shown to inhibit cathepsin B, a cysteine protease involved in tumor invasion, and presents a cytotoxic effect on cancer cells [7]. In an attempt to find new leishmanial drugs, RT-01 was tested both in vitro and in vivo against L. amazonensis. The results reported here suggest that RT-01 is effective against the flagellate and nonflagellate parasitic forms and in L. amazonensis-infected BALB/c mice. MATERIALS AND METHODS Organotellurane compound (RT-01)The organotellurane RT-01 used to evaluate the effects in vitro against L. amazonensis and in vivo in L. amazonensis-infected mice was prepared by the reaction of tellurium tetrachloride with propargyl alcohol in benzene followed by complexation with triethylbenzylammonium chloride, as described previously [7,15] (Fig. 1). The compound was dissolved in DMSO and diluted in phosphate buffer pH 7.4, medium or saline. The final concentration of DMSO in vitro and in vivo experiments was 0.1%. A Novel Organotellurium Compound (RT-01) as a New Antileishmanial AgentKorean J Parasitol. Vol. 47, No. 3: 213-218, September 2009 DOI: 10.3347/kjp.2009 213 Abstract: Leishmaniasis is a neglected disease and endemic in developing countries. A lack of adequate and definitive chemotherapeutic agents to fight against this infection has led to the investigation of numerous compounds. The aim of this study was to investigate the effect of RT-01, an organotellurane compound presenting biological activities, in 2 experimental systems against Leishmania amazonensis. The in vitro system consisted of promastigotes and amastigotes forms of the parasite, and the in vivo system consisted of L. amazonensis infected BALB/c mice, an extremely susceptible mouse strain. The compound proved to be toxic against promastigotes and amastigotes. The study also showed that treatment with RT-01 produces an effect similar to that treatment with the reference antimonial drug, Glucantime, in L. amazonensis infected mice. The best results were obtained following RT-01 intralesional administration (720 μ g/kg/day); mice showed significant delay in the development of cutaneous lesions and decreased numbers of parasites ob...

SUMMARYInflammation due to Shigella flexneri can cause damage to the colonic mucosa and cell death by necrosis and apoptosis. This bacteria can reach the bloodstream in this way, and the liver through portal veins. Hypoxia is a condition present in many human diseases, and it may induce bacterial translocation from intestinal lumen. We studied the ability of S. flexneri to invade rat hepatocytes and Caco-2 cells both in normoxic and hypoxic microenvironments, as well as morphological and physiological alterations in these cells after infection under hypoxia. We used the primary culture of rat hepatocytes as a model of study. We analyzed the following parameters in normoxic and hypoxic conditions: morphology, cell viability, bacterial recovery and lactate dehydrogenase (LDH) released. The results showed that there were fewer bacteria within the Caco-2 cells than in hepatocytes in normoxic and hypoxic conditions. We observed that the higher the multiplicity of infection (MOI) the greater the bacterial recovery in hepatocytes. The hypoxic condition decreased the bacterial recovery in hepatocytes. The cytotoxicity evaluated by LDH released by cells was significantly higher in cells submitted to hypoxia than normoxia. Caco-2 cells in normoxia released 63% more LDH than hepatocytes. LDH increased 164% when hepatocytes were submitted to hypoxia and just 21% when Caco-2 cells were in the same condition. The apoptosis evaluated by Tunel was significantly higher in cells submitted to hypoxia than normoxia. When comparing hypoxic cells, we obtained more apoptotic hepatocytes than apoptotic Caco-2 cells. Concluding our results contribute to a better knowledge of interactions between studied cells and Shigella flexneri. These data may be useful in the future to define strategies to combat this virulent pathogen.

Aim: Shigella flexneri (S. flexneri) is a gram-negative enterobacterium responsible for severe intestinal end systemic infection in humans. The bacteria can reach the liver due to degeneration of the colonic epithelium. Hypoxia is present in many human diseases and can induce the expression of the transcription factor HIF-1alpha that may have a cell protective role. The influence of hypoxia and HIF-1alpha on bacterial infection, studied in this work, is unclear. Hypoxia inducible factor1alpha (HIF-1alpha) is a transcription factor that acts as a master regulator of gene expression induced by hypoxia. Methods: We compared the ability of S. flexneri to invade rat hepatocytes in primary culture both in normoxic and hypoxic conditions. We evaluated TNF-alpha released by hepatocytes, apoptosis rate and HIF-1alpha expression by confocal microscopy as well as real time PCR technique. Results: We showed that S. flexneri invaded less hepatocytes previously submitted to 24 h hypoxia (6.5% O2) than those cultivated in normoxia (21% O2). S. flexneri also induced HIF-1α expression in hepatocytes, TNF-α secretion and apoptosis. Conclusion: a) Hypoxia alone was not a stimulus to TNF-α secretion, but induced cell apoptosis and HIF-1α expression; b) S. flexneri was able to invade rat hepatocytes and hypoxia apparently influenced significantly bacterial cell invasiveness; c) HIF-1α was expressed in hypoxic conditions, and it was also stimulated by S. flexneri.

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