Role of cathepsin B of Naegleria fowleri during primary amebic meningoencephalitis.

Naegleria fowleri causes primary amoebic meningoencephalitis in humans and experimental animals. It has been suggested that cysteine proteases of parasites play key roles in metabolism, nutrient uptake, host tissue invasion, and immune evasion. The aim of this work was to evaluate the presence, expression, and role of cathepsin B from N. fowleri in vitro and during PAM. Rabbit-specific polyclonal antibodies against cathepsin B were obtained from rabbit immunization with a synthetic peptide obtained by bioinformatic design. In addition, a probe was designed from mRNA for N. fowleri cathepsin B. Both protein and messenger were detected in fixed trophozoites, trophozoites interacted with polymorphonuclear and histological sections of infected mice. The main cathepsin B distribution was observed in cytoplasm or membrane mainly pseudopods and food-cups while messenger was in nucleus and cytoplasm. Surprisingly, both the messenger and enzyme were observed in extracellular medium. To determine cathepsin B release, we used trophozoites supernatant recovered from nasal passages or brain of infected mice. We observed the highest release in supernatant from recovered brain amoebae, and when we analyzed molecular weight of secreted proteins by immunoblot, we found 30 and 37 kDa bands which were highly immunogenic. Finally, role of cathepsin B during N. fowleri infection was determined; we preincubated trophozoites with E-64, pHMB or antibodies with which we obtained 60%, 100%, and 60% of survival, respectively, in infected mice. These results suggest that cathepsin B plays a role during pathogenesis caused by N. fowleri mainly in adhesion and contributes to nervous tissue damage.

El ácido valproico como agente sensibilizador al tratamiento anticáncer.

Valproic acid is an antiepileptic drug with more than 50 years of clinical use. In the past decade, its anticancer effects were discovered. Analyses in groups of patients who used this drug for years have shown that it decreases the frequency of head and neck cancer. Recent studies show the anticancer effect of combining valproic acid with chemotherapy, biological therapy and antioxidant systems inhibitors, with exceptional results. In this review, we analyze the metabolism of valproic acid and its application against cancer.

El ácido valproico es un fármaco antiepiléptico con más de 50 años de uso clínico. En la década pasada se descubrieron sus efectos anticancerígenos. El análisis de grupos de pacientes que utilizaron este fármaco durante años ha mostrado que disminuye la frecuencia de cáncer de cabeza y cuello. Estudios recientes evidencian el efecto anticáncer al combinar el ácido valproico con la quimioterapia, terapia biológica e inhibidores de sistemas antioxidantes, con resultados excepcionales. En esta revisión se analiza el metabolismo del ácido valproico y su aplicación contra el cáncer.

El ácido valproico como agente sensibilizador al tratamiento anticáncer / Valproic acid as a sensitizing agent in anticancer treatment

Resumen El ácido valproico es un fármaco antiepiléptico con más de 50 años de uso clínico. En la década pasada se descubrieron sus efectos anticancerígenos. El análisis de grupos de pacientes que utilizaron este fármaco durante años ha mostrado que disminuye la frecuencia de cáncer de cabeza y cuello. Estudios recientes evidencian el efecto anticáncer al combinar el ácido valproico con la quimioterapia, terapia biológica e inhibidores de sistemas antioxidantes, con resultados excepcionales. En esta revisión se analiza el metabolismo del ácido valproico y su aplicación contra el cáncer.

Abstract Valproic acid is an antiepileptic drug with more than 50 years of clinical use. In the past decade, its anticancer effects were discovered. Analyses in groups of patients who used this drug for years have shown that it decreases the frequency of head and neck cancer. Recent studies show the anticancer effect of combining valproic acid with chemotherapy, biological therapy and antioxidant systems inhibitors, with exceptional results. In this review, we analyze the metabolism of valproic acid and its application against cancer.

Three amino acid derivatives of valproic acid: design, synthesis, theoretical and experimental evaluation as anticancer agents.

Valproic acid (VPA) is extensively used as an anticonvulsive agent and as a treatment for other neurological disorders. It has been shown that VPA exerts an anti-proliferative effect on several types of cancer cells by inhibiting the activity of histone deacetylases (HDACs), which are involved in replication and differentiation processes. However, VPA has some disadvantages, among which are poor water solubility and hepatotoxicity. Therefore, the aim of the present study was to design and synthesize three derivatives of VPA to improve its physicochemical properties and anti-proliferative effects. For this purpose, the amino acids aspartic acid, glutamic acid and proline were added to the molecular structure of VPA. Docking and molecular dynamics simulations were used to determine the mode of recognition of these three derivatives by different conformations of HDAC8. This receptor was used as the specific target because of its high affinity for this type of substrate. The results demonstrate that, compared to VPA, the test compounds bind to different sites on the enzyme and that hydrogen bonds and hydrophobic interactions play key roles in this difference. The IC50 values of the VPA derivatives, experimentally determined using HeLa cells, were in the mM range. This result indicates that the derivatives have greater antiproliferative effects than the parent compound. Hence, these results suggest that these amino acid derivatives may represent a good alternative for anticancer treatment.

[Transfer factors in medical therapy]. / Factores de transferencia en la terapéutica médica.

Transfer factor (TF) consists of messenger peptides produced by activated T lymphocytes as part of cellular immunity, and it acts in virgin lymphocytes through TF inducers, suppressors and specific antigens. TF is not immunogenic because it is not species-specific, since it contains a consensus sequence of amino acids LLYAQDL/VEDN. TF extracted from leukocytes can transfer immunity from a human to another species. TF extracts are complex, containing more than 200 molecules with molecular weights ranging from 1 to 20 kDa. The antigen specific transfer factors (STF) have molecular weights between 3,5 and 5 kDa. TF is easy to prepare and well tolerated. It does not contain HL-A antigens against potential receptors and it can used as adjuvant therapy in several diseases.