DHEA effects on myocardial Akt signaling modulation and oxidative stress changes in aged rats

The secretion of DHEA-synthesized mainly in the adrenal cortex-increases in the postnatal aging, peaks in the twenties and decreases with age afterwards. Exogenous DHEA can exert a dual effect depending on dose and on tissue. Akt is a serine/threonine kinase whose activity has been seen as an interventional approach for cardiomyopathic damage resulting from aging changes. In order to evaluate DHEA effects over myocardial Akt protein expression associated to oxidative stress markers during aging, male Wistar rats (3 and 18 months) were assigned into two groups: control or DHEA (10 mg/kg, subcutaneously, for 5 weeks). In the aged group, we found increased lipid peroxidation and glutathione-S-transferase activity. DHEA produced an increase in p-Akt protein expression and a decrease in SOD activity in both ages. Akt pathway activation might be related to changes in oxidative stress parameters according to age.     

Two- and three-dimensional quantitative structure-activity relationships for a series of purine nucleoside phosphorylase inhibitors

Comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis, and hologram quantitative structure-activity relationship (HQSAR) studies were conducted on a series of 52 training set inhibitors of calf spleen purine nucleoside phosphorylase (PNP). Significant cross-validated correlation coefficients (CoMFA, q(2)=0.68; CoMSIA, q(2)=0.66; and HQSAR, q(2)=0.70) were obtained, indicating the potential of the models for untested compounds. The models were then used to predict the inhibitory potency of 16 test set compounds that were not included in the training set, and the predicted values were in good agreement with the experimental results. The final QSAR models along with the information gathered from 3D contour and 2D contribution maps should be useful for the design of novel inhibitors of PNP having improved potency.     

Low and high-dose intradermal infection with Leishmania major and Leishmania amazonensis in C57BL/6 mice

A model of skin infection with Leishmania amazonensis with low doses of parasites is compared to infection with high doses of L. amazonensis and low and high doses of Leishmania major. C57BL/6 mice were infected with 103 or 10(6) parasites in the ear and the outcome of infection was assessed. The appearance of lesions in mice infected with 103 parasites was delayed compared to mice infected with 10(6) Leishmania and parasites were detectable at the infection site before lesions became apparent. Mice infected with L. amazonensis displayed persistent lesions, whereas infection with L. major spontaneously healed in all groups, although lymphocytes persisted at the site of infection after healing. Macrophages persisted only in L. amazonensis-infected mice. High-dose L. amazonensis-infected mice produced lower levels of IFN-γ and TNF than mice infected with L. major. No correlation between the persistence of parasites and IL-10 levels and the production of nitric oxide or urea by macrophages was found. We conclude that infection with low doses of L. amazonensis in the dermis changes the course of infection by delaying the appearance of lesions. However, low-dose infection does not change the outcomes of susceptibility and cytokine production described for subcutaneous infection with high numbers of parasites.     

Active immunization combined with cisplatin confers enhanced therapeutic protection and prevents relapses of HPV-induced tumors at different anatomical sites

The active immunotherapy concept relies on the use of vaccines that are capable of inducing antitumor immunity, reversion of the suppressive immunological environment, and long-term memory responses. Previously, antitumor vaccines based on a recombinant plasmid (pgDE7h) or a purified protein (gDE7) led to regression of early-established human papillomavirus (HPV)-associated tumors in a preclinical model. In this work, the anticancer vaccines were combined with cisplatin to treat HPV-induced tumors at advanced growth stages. The antitumor effects were evaluated in terms of tumor regression, induction of specific CD8⁺ T cells, and immune modulation of the tumor microenvironment. Acute toxicity induced by the treatment was measured by weight loss and histological alterations in the liver and kidneys. Our results revealed that the combination of cisplatin with either one of the tested immunotherapies (pgDE7h or gDE7) led to complete tumor regression in mice. Also, the combined treatment resulted in synergistic effects, particularly among mice immunized with gDE7, including activation of systemic and tumor-infiltrating E7-specific CD8⁺ T cells, tumor infiltration of macrophages and dendritic cells, and prevention of tumor relapses at different anatomical sites. Furthermore, the protocol allowed the reduction of cisplatin dosage and its intrinsic toxic effects, without reducing antitumor outcomes. These results expand our knowledge of active immunotherapy protocols and open perspectives for alternative treatments of HPV-associated tumors.     

Development of an Indirect ELISA for Serological Diagnosis of Bovine herpesvirus 5

Bovine herpesviruses 1 and 5 (BoHV-1 and BoHV-5) are economically important pathogens, associated with a variety of clinical syndromes, including respiratory and genital disease, reproductive failure and meningoencephalitis. The standard serological assay to diagnose BoHV-1 and BoHV-5 infections is the virus neutralization test (VNT), a time consuming procedure that requires manipulation of infectious virus. In the present study a highly sensitive and specific single dilution indirect ELISA was developed using recombinant glycoprotein D from BoHV-5 as antigen (rgD5ELISA). Bovine serum samples (n = 450) were screened by VNT against BoHV-5a and by rgD5ELISA. Compared with the VNT, the rgD5ELISA demonstrated accuracy of 99.8%, with 100% sensitivity, 96.7% specificity and coefficient of agreement between the tests of 0.954. The rgD5ELISA described here shows excellent agreement with the VNT and is shown to be a simple, convenient, specific and highly sensitive virus-free assay for detection of serum antibodies to BoHV-5.     

(+/-)-cis-(6-Ethyl-tetrahydropyran-2-yl)-formic acid: a novel substance with antinociceptive properties

We described in this paper the first synthesis to the (+/-) cis (6-ethyl-tetrahydropyran-2-yl) formic acid (1) using the very efficient Prins cyclization reaction as strategy to construction of its tetrahydropyran skeleton. This new compound presented a significant antinociceptive property by the tail-flick model.     

Carbohydrate-binding agents cause deletions of highly conserved glycosylation sites in HIV GP120: a new therapeutic concept to hit the achilles heel of HIV

Mannose-binding proteins derived from several plants (i.e. Hippeastrum hybrid and Galanthus nivalis agglutinin) or prokaryotes (i.e. cyanovirin-N) inhibit human immunodeficiency virus (HIV) replication and select for drug-resistant viruses that show profound deletion of N-glycosylation sites in the GP120 envelope (Balzarini, J., Van Laethem, K., Hatse, S., Vermeire, K., De Clercq, E., Peumans, W., Van Damme, E., Vandamme, A.-M., Bolmstedt, A., and Schols, D. (2004) J. Virol. 78, 10617-10627; Balzarini, J., Van Laethem, K., Hatse, S., Froeyen, M., Van Damme, E., Bolmstedt, A., Peumans, W., De Clercq, E., and Schols, D. (2005) Mol. Pharmacol. 67, 1556-1565). Here we demonstrated that the N-acetylglucosamine-binding protein from Urtica dioica (UDA) prevents HIV entry and eventually selects for viruses in which conserved N-glycosylation sites in GP120 were deleted. In contrast to the mannose-binding proteins, which have a 50-100-fold decreased antiviral activity against the UDA-exposed mutant viruses, UDA has decreased anti-HIV activity to a very limited extent, even against those mutant virus strains that lack at least 9 of 22 ( approximately 40%) glycosylation sites in their GP120 envelope. Therefore, UDA represents the prototype of a new conceptual class of carbohydrate-binding agents with an unusually specific and targeted drug resistance profile. It forces HIV to escape drug pressure by deleting the indispensable glycans on its GP120, thereby obligatorily exposing previously hidden immunogenic epitopes on its envelope.     

A comparison of morphometric characteristics of sperm from fertile Bos taurus and Bos indicus bulls in Brazil

The current work has as main objective the systematic investigation of sperm morphometric characteristics of fertile Bos taurus and Bos indicus bulls living in Brazil by using several traditional as well as more modern and advanced computer vision concepts and methodologies. Ten smears of B. taurus semen and ten smears of B. indicus semen have been evaluated. Sperm morphology was quantified in terms of the following morphological features: head area, perimeter, width, length, width:length ratio, ellipticity, shape factor, width of sperm basis, the three first Fourier values, symmetry and hydrodynamics. Morphometric differences have been observed between the sperm cell of B. taurus and B. indicus bulls. The sperm cells of Zebu bulls tend to be smaller and less elliptic, however without modifying hydrodynamic, side symmetry and width of sperm head base. These differences clearly indicate that the geometrical characterization of bull sperm cells should take into account morphological peculiarities that are specific to each subspecies. Another important contribution is the identification that morphological differences implied by bulls of different fertility, as characterized by other authors, were found to be less as compared with those obtained in the current study where highly fertile animals from the two subspecies were studied.     

Genetically identified neurons in avian auditory pallium mirror core principles of their mammalian counterparts

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