Endoplasmic reticulum stress is a target for therapy in Waldenstrom macroglobulinemia

Waldenstrom macroglobulinemia (WM) is an incurable low-grade lymphoma characterized by bone marrow (BM) involvement of IgM secreting lymphoplasmacytic cells. The induction of unfolded protein response (UPR) genes ("physiologic" UPR) enables cells to differentiate into professional secretory cells capable of production of high amounts of endoplasmic reticulum (ER)-processed proteins, such as immunoglobulins. Ultimately, the initially cytoprotective UPR triggers an apoptotic cascade if ER stress is not corrected, called proapoptotic/terminal UPR. We show that WM cells inherently express the physiologic UPR machinery compared with normal BM cells, and that increased ER stress leads to proapoptotic/terminal UPR in WM cells. We therefore examined tunicamycin, ER stress inducer, for potential antitumor effects in WM. Tunicamycin induced significant cytotoxicity, apoptosis and cell-cycle arrest, and inhibited DNA synthesis in WM cell lines and primary BM CD19(+) cells from patients with WM with an inhibitory concentration (IC(50)) of 0.5 microg/mL to 1 microg/mL, but not in healthy donor cells. Importantly, coculture of WM cells in the context of the BM microenvironment did not inhibit tunicamycin-induced cytotoxicity. Finally, we demonstrate that ER stress inducer synergizes with other agents used in the treatment of WM. These preclinical studies provide a framework for further evaluation of ER stress inducing agents as therapeutic agents in WM.     

Molecular docking to Toxoplasma gondii thymidylate synthase-dihydrofolate reductase and efficacy of raltitrexed in infected mice

Parasitology Research - Toxoplasmosis is a zoonosis of worldwide distribution. Currently, two drugs, pyrimethamine and sulfadiazine, are used as a reference in the treatment of toxoplasmosis, but...     

Simultaneous detection of West Nile and Japanese encephalitis virus RNA by duplex TaqMan RT-PCR

West Nile virus (WNV) and Japanese encephalitis virus (JEV) are important mosquito-borne viruses of the Flaviviridae family, associated with encephalitis, mainly in humans and horses. WNV is also pathogen for many bird species. The incidence of human and animal WNV infections in Europe has risen, mostly in recent years, and JEV was detected in 2011 in mosquitoes collected in Italy and may emerge in Europe in the same way as other flaviviruses had emerged recently (USUTU and Bagaza virus) and should be regarded as a potential threat to public health.     

Intermediate expression of CCRL1 reveals novel subpopulations of medullary thymic epithelial cells that emerge in the postnatal thymus

Cortical and medullary thymic epithelial cells (cTECs and mTECs, respectively) provide inductive microenvironments for T‐cell development and selection. The differentiation pathway of cTEC/mTEC lineages downstream of common bipotent progenitors at discrete stages of development remains unresolved. Using IL‐7/CCRL1 dual reporter mice that identify specialized TEC subsets, we show that the stepwise acquisition of chemokine (C–C motif) receptor‐like 1 (CCRL1) is a late determinant of cTEC differentiation. Although cTECs expressing high CCRL1 levels (CCRL1^hi) develop normally in immunocompetent and Rag2^?/?thymi, their differentiation is partially blocked in Rag2^?/?Il2rg^?/? counterparts. These results unravel a novel checkpoint in cTEC maturation that is regulated by the cross‐talk between TECs and immature thymocytes. Additionally, we identify new Ulex europaeus agglutinin 1 (UEA)⁺ mTEC subtypes expressing intermediate CCRL1 levels (CCRL1^int) that conspicuously emerge in the postnatal thymus and differentially express Tnfrsf11a, Ccl21, and Aire. While rare in fetal and in Rag2^?/? thymi, CCRL1^int mTECs are restored in Rag2^?/?Marilyn TCR‐Tg mice, indicating that the appearance of postnatal‐restricted mTECs is closely linked with T‐cell selection. Our findings suggest that alternative temporally restricted routes of new mTEC differentiation contribute to the establishment of the medullary niche in the postnatal thymus.     

Variations in the expressed antimicrobial peptide repertoire of northern leopard frog (Rana pipiens) populations suggest intraspecies differences in resistance to pathogens

The northern leopard frog (Rana pipiens or Lithobates pipiens) is historically found in most of the provinces of Canada and the northern and southwest states of the United States. In the last 50 years, populations have suffered significant losses, especially in the western regions of the species range. Using a peptidomics approach, we show that the pattern of expressed antimicrobial skin peptides of frogs from three geographically separated populations are distinct, and we report the presence of four peptides (brevinin-1Pg, brevinin-1Pl, ranatuerin-2Pb, and ranatuerin-2Pc) that have not previously been found in skin secretions. The differences in expressed peptides reflect differences in the distribution of alleles for the newly described Brevinin1.1 locus in the three populations. When enriched peptide mixtures were tested for their ability to inhibit growth of the pathogenic amphibian chytrid (Batrachochytrium dendrobatidis), peptides from Minnesota or Vermont frogs were more effective that peptides from Michigan frogs. Four of the purified peptides were tested for their ability to inhibit growth of two bacterial pathogens (Aeromonas hydrophila and Staphylococcus epidermidis) and B. dendrobatidis. Three of the four were effective inhibitors of B. dendrobatidis and S. epidermidis, but none inhibited A. hydrophila. We interpret these differences in expression and activity of antimicrobial peptides as evidence to suggest that each population may have been selected to express a suite of peptides that reflects current and past encounters with skin microbes.     

Topographic distribution of Thy-1 positive cells in epithelial tissues of BALB/c mice

Epithelial sheets prepared from murine oral epithelia (palate, lining mucosa, gingiva) and oesophagus contained dendritic and round Thy-1 positive (+) cells similar to those observed in epidermis by immunofluorescence microscopy. Bladder, intestine and tracheal epithelium did not contain such cells. Thus, cells bearing the cells-surface glycoprotein Thy-1, like Ia-antigen-bearing Langerhans cells, may be restricted to stratified squamous epithelia.     

Antibiofilm Effects of Endodontic Sealers Containing Quaternary Ammonium Polyethylenimine Nanoparticles

Introduction

This study evaluated the antibiofilm effects of 2 endodontic sealers incorporated with quaternary ammonium polyethylenimine (QPEI) nanoparticles at a 2% concentration (w/w).

Methods

The materials tested were AH Plus and Pulp Canal Sealer EWT (PCS) in the commercial unmodified form or containing 2% QPEI. Antibiofilm assays were conducted by using direct-contact and membrane-restricted tests for evaluation of bacterial viability in biofilms grown onto membranes or paper disks and the crystal violet microtiter-plate assay to evaluate the effects of sealer extracts on the biofilm biomass. Two Enterococcus faecalis strains (ATCC and an endodontic isolate) were used.

Results

Direct contact and membrane-restricted antibiofilm tests revealed that PCS 2% was the only material to promote total killing of E. faecalis ATCC biofilms. All the materials significantly reduced bacterial counts in E. faecalis ATCC biofilms when compared with the positive control in both tests (P < .05). In the direct test against E. faecalis RW35, PCS 2% was significantly more effective than the other materials and was the only one that showed significantly lower counts than the positive control (P < .05). In the crystal violet assay, only AH Plus 2% presented optical density readings significantly lower than the positive control of the ATCC strain (P < .05). No other significant effects on the biofilm biomass of the 2 E. faecalis strains were observed for any of the sealers tested (P > .05).

Conclusions

Addition of QPEI nanoparticles improved the killing ability of PCS against biofilms of both E. faecalis strains and the effects of AH Plus on the biomass of biofilms from the ATCC strain.     

Is the body fat of the lizard Tupinambis merianae effective against bacterial infections?

Aim of the study

Tupinambis merianae is one of the animals that is most frequently used for medicinal purposes in Brazil as its body fat has many therapeutic indications in local folk medicine. This work presents the chemical compositions of the body fat of Tupinambis merianae and evaluates the antibacterial activity of the body fat as well as the ecological implications of its use in traditional medicine.

Materials and methods

Oil (OTM) was extracted from body fat located in the ventral region of Tupinambis merianae using hexane as a solvent. Fatty acids were determined indirectly using their corresponding methyl esters. The antibacterial activity of OTM was tested against standard as well as multi-resistant lines of Escherichia coli and Staphylococcus aureus, either alone or in combination with antibiotics and UV-A light.

Results

Body fat of Tupinambis merianae presents 57% and 43% of unsaturated and saturated fatty acids respectively. Our results indicated that OTM did not demonstrate relevant antibacterial activity against any of the lines of Escherichia coli or Staphylococcus aureus, nor when combined with antibiotics or with UV-A light.

Conclusions

In light of these results, we recommend (i) development of management plans for a sustainable and rational use of Tupinambis merianae reducing the possible pressure on this species; and (ii) more studies be focused on the use of OTM and other natural products derived from animals that are used to treat other illnesses.