Fused Enzyme Glucose-6-Phosphate Dehydrogenase::6-Phosphogluconolactonase (G6PD::6PGL) as a Potential Drug Target in Giardia lamblia, Trichomonas vaginalis, and Plasmodium falciparum.

Several microaerophilic parasites such as Giardia lamblia, Trichomonas vaginalis, and Plasmodium falciparum are major disease-causing organisms and are responsible for spreading infections worldwide. Despite significant progress made in understanding the metabolism and molecular biology of microaerophilic parasites, chemotherapeutic treatment to control it has seen limited progress. A current proposed strategy for drug discovery against parasitic diseases is the identification of essential key enzymes of metabolic pathways associated with the parasite's survival. In these organisms, glucose-6-phosphate dehydrogenase::6-phosphogluconolactonase (G6PD:: 6PGL), the first enzyme of the pentose phosphate pathway (PPP), is essential for its metabolism. Since G6PD:: 6PGL provides substrates for nucleotides synthesis and NADPH as a source of reducing equivalents, it could be considered an anti-parasite drug target. This review analyzes the anaerobic energy metabolism of G. lamblia, T. vaginalis, and P. falciparum, with a focus on glucose metabolism through the pentose phosphate pathway and the significance of the fused G6PD:: 6PGL enzyme as a therapeutic target in the search for new drugs.

A significant therapeutic effect of silymarin administered alone, or in combination with chemotherapy, in experimental pulmonary tuberculosis caused by drug-sensitive or drug-resistant strains: In vitro and in vivo studies.

For many years, tuberculosis (TB) has been a major public health problem worldwide. Advances for treatment and eradication have been very limited. Silymarin (Sm) is a natural product with antioxidant and hepatoprotective activities that has been proposed as a complementary medicine to reduce the liver injury produced by the conventional anti-TB chemotherapy. Sm also has immunoregulatory and microbicide properties. In this study, we determined the effect of Sm on the growth control of mycobacteria. In vitro studies showed that Sm and Silibinin (the principal active compound of Sm) have microbicidal activity against drug-sensitive and multidrug-resistant (MDR) mycobacteria, induce the production of protective cytokines from infected macrophages, and improve the growth control of mycobacteria (p ≤ 0.0001). Studies in vivo using a model of progressive pulmonary TB in BALB/c mice infected with drug-sensitive or MDR mycobacteria have shown that Sm induces significant expression of Th-1 cytokines such as IFN-γ and IL-12 as well as TNFα, which produce significant therapeutic activity when administered alone and apparently have a synergistic effect with chemotherapy. These results suggest that Sm has a bactericidal effect and can contribute to the control and establishment of a TH1 protective immune response against mycobacterial infection. Thus, it seems that this flavonoid has a promising potential as adjuvant therapy in the treatment of TB.

The response of the fibrinolytic system to mycobacteria infection.

The human pathogen Mycobacterium tuberculosis binds to a variety of host cell proteins, including those of the fibrinolytic system. These observations prompted us to study the expression of components of this system in an animal model of progressive pulmonary tuberculosis. Lung homogenates from BALB/c mice infected with M. tuberculosis H37Rv were analyzed to determine the expression and enzymatic activity of plasmin/plasminogen and tissue plasminogen activator, as well as the mRNA levels for plasminogen, tissue and urokinase plasminogen activators. Plasminogen was also detected in infected lungs with immunohistochemistry. The results show that the expression of molecules of the fibrinolytic system increased gradually over the course of the infection, peaking during the chronic phase of the disease. Furthermore, in vitro experiments showed that both plasminogen activators were specifically induced after the stimulation of spleen cells from BCG-immunized mice with M. tuberculosis proteins. Together, these results show that molecules of the fibrinolytic system are up-regulated in the chronic phase of experimental tuberculosis and suggest that the mycobacterium itself could play an important role in the overexpression of molecules of the fibrinolytic system, contributing to chronic inflammation in tuberculosis.