Tamoxifen Ameliorates Peritoneal Membrane Damage by Blocking Mesothelial to Mesenchymal Transition in Peritoneal Dialysis

Mesothelial-to-mesenchymal transition (MMT) is an auto-regulated physiological process of tissue repair that in uncontrolled conditions such as peritoneal dialysis (PD) can lead to peritoneal fibrosis. The maximum expression of peritoneal fibrosis induced by PD fluids and other peritoneal processes is the encapsulating peritoneal sclerosis (EPS) for which no specific treatment exists. Tamoxifen, a synthetic estrogen, has successfully been used to treat retroperitoneal fibrosis and EPS associated with PD. Hence, we used in vitro and animal model approaches to evaluate the efficacy of Tamoxifen to inhibit the MMT as a trigger of peritoneal fibrosis. In vitro studies were carried out using omentum-derived mesothelial cells (MCs) and effluent-derived MCs. Tamoxifen blocked the MMT induced by transforming growth factor (TGF)-β1, as it preserved the expression of E-cadherin and reduced the expression of mesenchymal-associated molecules such as snail, fibronectin, collagen-I, α-smooth muscle actin, and matrix metalloproteinse-2. Tamoxifen-treatment preserved the fibrinolytic capacity of MCs treated with TGF-β1 and decreased their migration capacity. Tamoxifen did not reverse the MMT of non-epitheliod MCs from effluents, but it reduced the expression of some mesenchymal molecules. In mice PD model, we demonstrated that MMT progressed in parallel with peritoneal membrane thickness. In addition, we observed that Tamoxifen significantly reduced peritoneal thickness, angiogenesis, invasion of the compact zone by mesenchymal MCs and improved peritoneal function. Tamoxifen also reduced the effluent levels of vascular endothelial growth factor and leptin. These results demonstrate that Tamoxifen is a therapeutic option to treat peritoneal fibrosis, and that its protective effect is mediated via modulation of the MMT process.     

Renewed hope for a vaccine against the intestinal adult Taenia solium

Review of experimental and observational evidence about various cestode infections of mammalian hosts revives hope for the development of an effective vaccine against adult intestinal tapeworms, the central protagonists in their transmission dynamics. As for Taenia solium, there are abundant immunological data regarding cysticercosis in humans and pigs, but information about human taeniasis is scarce. A single publication reporting protection against T. solium taeniasis by experimental primo infection and by vaccination of an experimental foster host, the immunocompetent female hamster, kindles the hope of a vaccine against the tapeworm to be used in humans, its only natural definitive host.     

Immunoprotection of Mice against Schistosomiasis Mansoni Using Solubilized Membrane Antigens

Background

Schistosomiasis continues to be one of the most prevalent parasitic diseases in the world. Despite the existence of a highly effective antischistosome drug, the disease is spreading into new areas, and national control programs do not arrive to complete their tasks particularly in low endemic areas. The availability of a vaccine could represent an additional component to chemotherapy. Experimental vaccination studies are however necessary to identify parasite molecules that would serve as vaccine candidates. In the present work, C57BL/6 female mice were subcutaneously immunized with an n-butanol extract of the adult worm particulate membranous fraction (AWBE) and its protective effect against a S. mansoni challenge infection was evaluated.

Methodology and Findings

Water-saturated n-butanol release into the aqueous phase a set of membrane-associated (glyco)proteins that are variably recognized by antibodies in schistosome-infected patients; among the previously identified AWBE antigens there is Alkaline Phosphatase (SmAP) which has been associated with resistance to the infection in mice. As compared to control, a significantly lower number of perfuse parasites was obtained in the immunized/challenged mouse group (P<0.05, t test); and consequently, a lower number of eggs and granulomas (with reduced sizes), overall decreasing pathology. Immunized mice produced high levels of sera anti-AWBE IgG recognizing antigens of ∼190-, 130-, 98-, 47-, 28-23, 14-, and 9-kDa. The ∼130-kDa band (the AP dimer) exhibited in situ SmAP activity after addition of AP substrate and the activity was not apparently inhibited by host antibodies. A preliminary proteomic analysis of the 25-, 27-, and 28-kDa bands in the immunodominant 28–23 kDa region suggested that they are composed of actin.

Conclusions

Immunization with AWBE induced the production of specific antibodies to various adult worm membrane molecules (including AP) and a partial (43%) protection against a challenging S. mansoni infection by mechanism(s) that still has to be elucidated.     

Pollen movement by the bat <Emphasis Type="Italic">Artibeus jamaicensis</Emphasis> (Chiroptera) in an agricultural landscape in the Yucatan Peninsula,Mexico

Artibeus jamaicensis is a medium-sized frugivorous microchiropteran bat that complements its diet with nectar and pollen during the dry season. We investigated which species of pollen are carried by A. jamaicensis in order to determine its potential role as a plant pollinator in the northern Yucatan Peninsula. We collected pollen from the fur of 192 individuals throughout the year from April 2004 to March 2005. We recorded pollen from nine plant species of eight families and found five unidentified pollen types, with the highest pollen species richness recorded in June. A. jamaicensis moved pollen of Erythrina standleyana and Mimosa bahamensis, which have not hitherto been reported as visited by this species. The most abundant pollen in the samples was found to be that of three tree species: Ceiba pentandra, C. aesculifolia and Lysiloma latisiliquum. Very few samples contained pollen in the rainy season, when the bats fed mainly on fruits. A. jamaicensis can fly several kilometres among foraging locations and dispersed large amounts of pollen from tree species growing near cenotes as well as those not present at cenotes but occurring in other forest fragments, highlighting its importance as a pollen vector among forest fragments in the largely deforested landscape of the Yucatan Peninsula, helping to reduce the negative effects of forest fragmentation. Ceiba appears to benefit from the role of A. jamaicensis as a pollen vector, and the species play an important ecological role in the Yucatán landscape, supplying shade, nectar and fruit for wildlife.     

Transient yellow colouration of the bat Artibeus jamaicensis coincides with pollen consumption

Atypical colouration of the fur is not commonly recorded in bats. Here we report a transient yellow colouration attributed to dietary components in Artibeus jamaicensis in 2004 and 2005 at two localities of Yucatan, Mexico. Change in colouration was recorded in January when 62% of A. jamaicensis captured (n = 50) appeared yellow. All faecal samples collected from atypically coloured individuals consisted mainly of Ceiba pentandra pollen, which was also recovered from the fur. Carotenoid pigments contained in pollen ingested during peak Ceiba flowering appear to be incorporated into the hairs of A. jamaicensis. Further investigations are required to understand how pigment is transferred between the pollen and the hairs of A. jamaicensis.     

Calmodulin is a selective modulator of estrogen receptors

In the search for differences between ERalpha and ERbeta, we analyzed the interaction of both receptors with calmodulin (CaM) and demonstrated that ERalpha but not ERbeta directly interacts with CaM. Using transiently transfected HeLa cells, we examined the effect of the CaM antagonist N-(6-aminohexyl)-5-chloro-naphthalene sulfonilamide hydrochloride (W7) on the transactivation properties of ERalpha and ERbeta in promoters containing either estrogen response elements or activator protein 1 elements. Transactivation by ERalpha was dose-dependently inhibited by W7, whereas that of ERbeta was not inhibited or even activated at low W7 concentrations. In agreement with these results, transactivation of an estrogen response element containing promoter in MCF-7 cells (which express a high ERalpha/ERbeta ratio) was also inhibited by W7. In contrast, transactivation in T47D cells (which express a low ERalpha/ERbeta ratio) was not affected by this CaM antagonist. The sensitivity of MCF-7 cells to W7 was abolished when cells were transfected with increasing amounts of ERbeta, indicating that the sensitivity to CaM antagonists of estrogen-responsive tissues correlates with a high ERalpha/ERbeta ratio. Finally, substitution of lysine residues 302 and 303 of ERalpha for glycine rendered a mutant ERalpha unable to interact with CaM whose transactivation activity became insensitive to W7. Our results indicate that CaM antagonists are selective modulators of ER able to inhibit ERalpha-mediated activity, whereas ERbeta actions were not affected or even potentiated by W7.     

A single amino acid substitution in the MurF UDP‐MurNAc‐pentapeptide synthetase renders Streptococcus pneumoniae dependent on CO2 and temperature

The respiratory tract pathogen Streptococcus pneumoniae encounters different levels of environmental CO₂ during transmission, host colonization and disease. About 8% of all pneumococcal isolates are capnophiles that require CO₂‐enriched growth conditions. The underlying molecular mechanism for caphnophilic behaviour, as well as its biological function is unknown. Here, we found that capnophilic S. pneumoniae isolates from clonal complex (CC) 156 (i.e. Spain^9V‐3 ancestry) and CC344 (i.e. Norway^NT‐42 ancestry) have a valine at position 179 in the MurF UDP‐MurNAc‐pentapeptide synthetase. At ≤ 30°C, the growth characteristics of capnophilic and non‐capnophilic CC156 strains were equal, but at > 30°C growth and survival of MurF^V179 strains was dependent on > 0.1% CO₂‐enriched conditions. Expression of MurF^V179 in S. pneumoniae R6 and G54 rendered these, otherwise non‐capnophilic strains, capnophilic. Time‐lapse microscopy revealed that a capnophilic CC156 strain undergoes rapid autolysis upon exposure to CO₂‐poor conditions at 37°C, and staining with fluorescently labelled vancomycin showed a defect in de novo cell wall synthesis. In summary, in capnophilic S. pneumoniae strains from CC156 and CC344 cell wall synthesis is placed under control of environmental CO₂ levels and temperature. This mechanism might represent a novel strategy of the pneumococcus to rapidly adapt and colonize its host under changing environmental conditions.     

alpha-MSH and gamma-MSH inhibit IL-1beta induced activation of the hypothalamic-pituitary-adrenal axis through central melanocortin receptors

Alpha-melanocyte-stimulating hormone (alpha-MSH) is a neuroimmunomodulatory peptide that is involved in the control of host responses trough modulation of production and action of proinflammatory cytokines in inflammatory cells in the periphery and within the central nervous system (CNS). However, little is known about the receptors that mediate the modulatory effects of alpha-MSH in the CNS. The objective of the present study was to establish the specific melanocortin receptors involved in the inhibition by MSH peptides of IL-1beta-induced activation of the HPA. i.c.v. injection of 12.5 ng of IL-1beta caused significant changes in plasma corticosterone, as compared to basal levels. The treatment with gamma-MSH (1 microg), an MC3 receptor agonist, resulted in significant reduction of the IL-1beta-induced plasma corticosterone levels. Administration of the MC3/MC4 receptor antagonist SHU9119 blocked this effect. Besides, treatment with a high dose of alpha-MSH (1 microg) increased plasma corticosterone. When alpha-MSH was given at a lower dose (0.1 microg), it did not modify corticosterone levels but caused an inhibitory effect on the corticosterone release induced by IL-1beta. The administration of SHU9119 or a more selective MC4 receptor antagonist like HS014 blocked the effects of alpha-MSH. In conclusion, our results suggest that both alpha-MSH and gamma-MSH are capable of inhibiting the effect of the IL-1beta on the activation of HPA axis acting at the CNS, and that this effect is mediated by specific central melanocortin receptors.