Efeito de proteínas terapeuticas do látex de Calotropis procera em animais hiperglicêmicos infectados com Salmonella: modulação da resposta inflamatória e propriedades reológicas do sangue

Abstract

Diabetes mellitus (DM), a chronic disease that affects millions of people globally, is characterized by the prevalence of high blood glucose levels (hyperglycemia) and is associated with an increased risk of various complications, including infections. The search for new therapeutic approaches to diabetes and its complications is constant. Latex proteins from the plant Calotropis procera (CpLP), with various reported pharmacological activities and modulations, could be a promising potential agent in this adverse physiological condition. Hyperglycemia was induced in mice using streptozotocin (i.p). In the first stage of the study, in order to assess the impact of CpLP on survival and the inflammatory response, the hyperglycemic animals (blood glucose greater than 220 mg/ dL) were challenged with a lethal bacterial infection of Salmonella Typhimurium, which was defined for the hyperglycemic mouse model as 104 CFU/ mL. The survival of the animals was monitored daily for 7 days to determine any significant differences between the groups. Blood and peritoneal fluid samples were collected 24 and 72 hours after infection for detailed analysis of the levels of the cytokines TNF-α, IL-1β and IL-10. Liver, kidneys and pancreas were collected for histopathological evaluation related to inflammation and hyperglycemia. In the second stage of the study, the rheology and hematology of the mice's blood were analyzed. Blood viscosity, an important indicator of blood fluidity, was measured using rotational rheometry and analyzed using a mathematical Bingham fluid model. Hematological parameters, such as red blood cell, white blood cell and platelet counts, hematocrit and hemoglobin, were evaluated in a complete blood count. Treatment with CpLP at doses of 30 and 60 mg/ kg resulted in an increase in the survival of infected hyperglycemic mice compared to the control group. However, CpLP was unable to prevent the death of the infected mice. Cytokine analysis revealed that CpLP modulated the inflammatory response, reducing the levels of the pro-inflammatory cytokines TNF-α and IL-1β in the peritoneal fluid and plasma after infection. Treatment also raised levels of the anti-inflammatory cytokine IL-10, suggesting an anti-inflammatory effect, even in the hyperglycemic condition. In plasma, CpLP showed a similar effect on TNF-α, but did not affect IL-1β or IL-10 levels. In blood rheology, hyperglycemia increased blood viscosity, but treatment with

CpLP made the blood less viscous and facilitated its flow, both in infected and non- infected animals, reverting fluid behavior to parameters similar to those of non- hyperglycemic animals. These results suggest that treatment with CpLP balanced the

pro-inflammatory and anti-inflammatory responses and reduced the inflammatory damage caused by the infection, even though it did not prevent death. Furthermore, these results demonstrate the therapeutic potential of CpLP in reversing rheological changes in the blood caused by hyperglycemia.