CC-chemokine receptors: a potential therapeutic target for Trypanosoma cruzi-elicited myocarditis

The comprehension of the pathogenesis of Trypanosoma cruzi-elicited myocarditis is crucial to delineate new therapeutic strategies aiming to ameliorate the inflammation that leads to heart dysfunction, without hampering parasite control. The augmented expression of CCL5/RANTES and CCL3/MIP-1alpha, and their receptor CCR5, in the heart of T. cruzi-infected mice suggests a role for CC-chemokines and their receptors in the pathogenesis of T. cruzi-elicited myocarditis. Herein, we discuss our recent results using a CC-chemokine receptor inhibitor (Met-RANTES), showing the participation of CC-chemokines in T. cruzi infection and unraveling CC-chemokine receptors as an attractive therapeutic target for further evaluation in Chagas disease

Lipase production by solid-state fermentation in fixed-bed bioreactors

In the present work, packed bed bioreactors were employed with the aim of increasing productivity and scaling up of lipase production using Penicillium simplicissimum in solid-state fermentation. The influence of temperature and air flow rate on enzyme production was evaluated employing statistical experimental design, and an empirical model was adjusted to the experimental data. It was shown that higher lipase activities could be achieved at lower temperatures and higher air flow rates. The maximum lipase activity (26.4 U/g) was obtained at the temperature of 27&deg;C and air flow rate of 0.8 L/min.<br>O fungo Penicillium simplicissimum se mostrou, em trabalhos anteriores, um ótimo produtor de lipase por fermentação no estado sólido, quando cultivado em biorreatores do tipo bandeja, utilizando a torta de babaçu como meio de cultura. Com o objetivo de aumentar a produtividade e possibilitar uma ampliação de escala, foi investigado, no presente trabalho, o emprego de biorreatores de leito fixo com aeração forçada. Os biorreatores utilizados tinham 4 cm de diâmetro interno e 14 cm de altura útil. Empregando-se planejamento estatístico de experimentos como ferramenta, foram avaliadas as influências da temperatura e da vazão de ar sobre a produção de lipase nestes biorreatores. Os resultados obtidos permitiram ajustar um modelo empírico, o qual indicou que maiores atividades lipásicas são alcançadas para temperaturas mais baixas e vazões de ar mais altas. A atividade lipásica máxima (26,4 U/g) foi obtida para temperatura de 27&deg;C e vazão de ar de 0,8 L/min

Statins Decrease Neuroinflammation and Prevent Cognitive Impairment after Cerebral Malaria

<div><p>Cerebral malaria (CM) is the most severe manifestation of <em>Plasmodium falciparum</em> infection in children and non-immune adults. Previous work has documented a persistent cognitive impairment in children who survive an episode of CM that is mimicked in animal models of the disease. Potential therapeutic interventions for this complication have not been investigated, and are urgently needed. HMG-CoA reductase inhibitors (statins) are widely prescribed for cardiovascular diseases. In addition to their effects on the inhibition of cholesterol synthesis, statins have pleiotropic immunomodulatory activities. Here we tested if statins would prevent cognitive impairment in a murine model of cerebral malaria. Six days after infection with <em>Plasmodium berghei</em> ANKA (PbA) mice displayed clear signs of CM and were treated with chloroquine, or chloroquine and lovastatin. Intravital examination of pial vessels of infected animals demonstrated a decrease in functional capillary density and an increase in rolling and adhesion of leukocytes to inflamed endothelium that were reversed by treatment with lovastatin. In addition, oedema, ICAM-1, and CD11b mRNA levels were reduced in lovastatin-treated PbA-infected mice brains. Moreover, HMOX-1 mRNA levels are enhanced in lovastatin-treated healthy and infected brains. Oxidative stress and key inflammatory chemokines and cytokines were reduced to non-infected control levels in animals treated with lovastatin. Fifteen days post-infection cognitive dysfunction was detected by a battery of cognition tests in animals rescued from CM by chloroquine treatment. In contrast, it was absent in animals treated with lovastatin and chloroquine. The outcome was similar in experimental bacterial sepsis, suggesting that statins have neuroprotective effects in severe infectious syndromes in addition to CM. Statin treatment prevents neuroinflammation and blood brain barrier dysfunction in experimental CM and related conditions that are associated with cognitive sequelae, and may be a valuable adjuvant therapeutic agent for prevention of cognitive impairment in patients surviving an episode of CM.</p> </div

Lovastatin treatment prevents impairment of short and long-term aversive memory after sepsis.

<p>C57BL/6 mice (n = 5–10/group) were inoculated with fecal supernatant (2.5 mg/g b.w.). For control, one group was inoculated with saline (0.9%). Control and mice challenged with fecal supernatant were divided and one group was treated with lovastatin (20 mg/kg b.w.) 1 hour prior to feces or saline injection respectively, and every 24 h for 3 days. All the animals received imipenem (10 mg/kg b.w.) 6 hours after inoculation and every 24 h for 3 days. On day 15 all animals were subjected to a training session of inhibitory avoidance task, where the latency time on the platform is recorded and an electrical shock is given immediately after the mice step down onto the bars. (A) 1.5 (Short-term memory) and (B) 24 h (long-term memory) aversive memory was then tested by recording the latency time on the platform (with a cut-off of 180 sec). Data are expressed as individual values and horizontal lines represent the mean of latency, in seconds; significant difference compared between saline versus feces injected mice (comparisons among groups were performed by Mann-Whitney U test, *p<0.05).</p

Lovastatin treatment decreases ICAM-1 and CD11b expression and vascular permeability and induce HMOX-1 expression in the brains of mice with CM.

<p>Panels illustrate histological examinations of cerebral cortex on day 6 post-infection, immunostained for ICAM-1 (brown and arrow) and counterstained with hematoxylin-eosin. Brain histology was examined using tissue from the following groups of animals: uninfected (A), uninfected treated with lovastatin (B), PbA-infected (C), and PbA-infected treated with lovastatin (D). Vascular congestion and edema (*) were observed in all PbA-infected mice, but were not seen in controls or treated animals. Scale bar: 50 µm. E: Dose-response relationships for effects of lovastatin on edema formation measured by Evans Blue Dye accumulation in the brain tissue on day 7 post-infection. F–H: ICAM-1, CD11b, and HMOX-1 expression in brain samples evaluated by semi-quantitative PCR on day 6 post-infection; *p<0.05 by Tukey's Multiple Comparison Test (n = 3–5/group). I-representative macroscopic image of Evans blue dye extravasation in the brain, demonstrating a marked reduction in PbA mice treated with lovastatin (20 mg/kg) on day 7-post infection.</p