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The use of Doxorubicin (Dox), a frontline drug for many cancers, is often complicated by dose-limiting cardiotoxicity in approximately 20% of patients. The G-protein estrogen receptor GPER/GPR30 mediates estrogen action as the cardioprotection under certain stressful conditions. For instance, GPER activation by the selective agonist G-1 reduced myocardial inflammation, improved immunosuppression, triggered pro-survival signaling cascades, improved myocardial mechanical performance, and reduced infarct size after ischemia/reperfusion (I/R) injury. Hence, we evaluated whether ligand-activated GPER may exert cardioprotection in male rats chronically treated with Dox. 1 week of G-1 (50 μg/kg/day) intraperitoneal administration mitigated Dox (3 mg/kg/day) adverse effects, as revealed by reduced TNF-α, IL-1β, LDH, and ROS levels. Western blotting analysis of cardiac homogenates indicated that G-1 prevents the increase in p-c-jun, BAX, CTGF, iNOS, and COX2 expression induced by Dox. Moreover, the activation of GPER rescued the inhibitory action elicited by Dox on the expression of BCL2, pERK, and pAKT. TUNEL assay indicated that GPER activation may also attenuate the cardiomyocyte apoptosis upon Dox exposure. Using ex vivo Langendorff perfused heart technique, we also found an increased systolic recovery and a reduction of both infarct size and LDH levels in rats treated with G-1 in combination with Dox respect to animals treated with Dox alone. Accordingly, the beneficial effects induced by G-1 were abrogated in the presence of the GPER selective antagonist G15. These data suggest that GPER activation mitigates Dox-induced cardiotoxicity, thus proposing GPER as a novel pharmacological target to limit the detrimental cardiac effects of Dox treatment. J. Cell. Physiol. 232: 1640-1649, 2017. © 2016 Wiley Periodicals, Inc.

El objetivo de este estudio fue evaluar la actividad de cefalexina y la actividad bactericida intrínseca de suero y orina de canino sobre seis cepas de Escherichia coli, utilizando un modelo in vitro de dilución simulando las concentraciones de cefalexina en estos fluidos biológicos durante la fase de eliminación tras la administración de una dosis por vía intravenosa. La concentración inhibitoria mínima de cefalexina en todas las cepas fue de 16 μg/ml a pH estándar de 7,4 y a valores de 6,5 y 5,5. El valor de la CIM no se modificó en presencia de suero u orina. En el modelo dinámico in vitro, la eficacia de cefalexina en medio de cultivo estándar fue de 57,2 ± 3,95%, mientras que en presencia de suero ésta se incrementó a 74,3 ± 8,59%, aunque a concentraciones mayores a las presentes en suero, la eficacia de cefalexina en orina fue de 68,7 ± 4,19%. En conclusión, nuestro ensayo destaca el importante papel de la actividad bactericida de estos fluidos biológicos en el éxito de la terapéutica antibiótica y propone el concepto de efecto bactericida total o global. The aim of this study was to evaluate the activity of cephalexin and the intrinsic antibacterial activity of dog serum and urine on six strains of Escherichia coli, using a dynamic one step dilution in vitro one compartmental model, simulating cephalexin concentrations in these biological fluids during its elimination phase after the intravenous administration. The minimum inhibitory concentration of cephalexin for all strains was 16 µg/mL at standard pH value of 7.4 and at values of 6.5 and 5.5. The CIM was not modified by serum or urine. In the dynamic in vitro model, the efficacy of cephalexin in standard culture medium was 57.2 ± 3.95%, while in presence of serum this increased to 74.3 ± 8.59%, although at higher concentrations than those present in serum, the efficacy of cephalexin in urine was 68.7 ± 4.19%. In conclusion, our study emphasizes the important role of the antibacterial activity of these biological fluids in the success of the antibiotic therapy and proposes the concept of total or global bactericidal effect.

The importance of the pericardium and the pericardial fluid (PF) in the control of cardiac function has emerged over the past few years. Despite the acknowledgment that amphibians are exposed to both dehydration and excessive water accumulation, nothing is known about their pericardial structure and the morphological basis of the PF formation. We have studied the parietal pericardium (PP) morphology in Rana esculenta by electron microscopy. SEM images of the inner surface, which lines the pericardial cavity, revealed the presence of large vesicles and many small circular openings. TEM observations showed that the PP is made up of an inner mesothelial lining, often constituted by two layers of very flat cells lying on a basal membrane and of regularly oriented collagen bundles. The PP outer surface is lined by a layer of flat cells, without a basal membrane. The mesothelial cells had overlapping boundaries with complex intercellular connections and a rich pool of caveolae opened in the direction of both the pericardial cavity and intercellular spaces. These cells indicate an intense intracellular and/or intercellular transfer of fluids and substances. The intraperitoneal injection of the idromineral hormone, Val5-ANG II, induced PP modifications, particularly evident at the level of the structures involved in the transmesothelial traffic. These lymphatic-like traits suggest that the frog PP represents a large lymphatic sac, subject to paracrine-endocrine remodeling, which can actively adjust the PF, influencing the composition and volume of the myocardial interstitial fluid. © 2003 Wiley-Liss, Inc.