Age-related changes in brain mitochondrial DNA deletion and oxidative stress are differentially modulated by dietary fat type and coenzyme Q₁₀

Mitochondria-related oxidative damage is a primary event in aging and age-related neurodegenerative disorders. Some dietary treatments, such as antioxidant supplementation or the enrichment of mitochondrial membranes with less oxidizable fatty acids, reduce lipid peroxidation and lengthen life span in rodents. This study compares life-long feeding on monounsaturated fatty acids (MUFAs), such as virgin olive oil, and n-6 polyunsaturated fatty acids, such as sunflower oil, with or without coenzyme Q₁₀ supplementation, with respect to age-related molecular changes in rat brain mitochondria. The MUFA diet led to diminished age-related phenotypic changes, with lipoxidation-derived protein markers being higher among the older animals, whereas protein carbonyl compounds were lower. It is noteworthy that the MUFA diet prevented the age-related increase in levels of mitochondrial DNA deletions in the brain mitochondria from aged animals. The findings of this study suggest that age-related oxidative stress is related, at the mitochondrial level, to other age-related features such as mitochondrial electron transport and mtDNA alterations, and it can be modulated by selecting an appropriate dietary fat type and/or by suitable supplementation with low levels of the antioxidant/electron carrier molecule coenzyme Q.     

Gene expression analysis of host innate immune responses during Lethal H5N1 infection in ferrets

How viral and host factors contribute to the severe pathogenicity of the H5N1 subtype of avian influenza virus infection in humans is poorly understood. We identified three clusters of differentially expressed innate immune response genes in lungs from H5N1 (A/Vietnam/1203/04) influenza virus-infected ferrets by oligonucleotide microarray analysis. Interferon response genes were more strongly expressed in H5N1-infected ferret lungs than in lungs from ferrets infected with the less pathogenic H3N2 subtype. In particular, robust CXCL10 gene expression in H5N1-infected ferrets led us to test the pathogenic role of signaling via CXCL10's cognate receptor, CXCR3, during H5N1 influenza virus infection. Treatment of H5N1-infected ferrets with the drug AMG487, a CXCR3 antagonist, resulted in a reduction of symptom severity and delayed mortality compared to vehicle treatment. We contend that unregulated host interferon responses are at least partially responsible for the severity of H5N1 infection and provide evidence that attenuating the CXCR3 signaling pathway improves the clinical course of H5N1 infection in ferrets.     

Spatial Analysis of Pulmonary Tuberculosis in Antananarivo Madagascar: Tuberculosis-Related Knowledge,Attitude and Practice

Introduction

Tuberculosis infection may remain latent, but the disease is nevertheless a serious public health issue. Various epidemiological studies on pulmonary tuberculosis have considered the spatial component and taken it into account, revealing the tendency of this disease to cluster in particular locations. The aim was to assess the contribution of Knowledge Attitude and Practice (KAP) to the distribution of tuberculosis and to provide information for the improvement of the National Tuberculosis Program.

Methods

We investigated the role of KAP to distribution patterns of pulmonary tuberculosis in Antananarivo. First, we performed spatial scanning of tuberculosis aggregation among permanent cases resident in Antananarivo Urban Township using the Kulldorff method, and then we carried out a quantitative study on KAP, involving TB patients. The KAP study in the population was based on qualitative methods with focus groups.

Results

The disease still clusters in the same districts identified in the previous study. The principal cluster covered 22 neighborhoods. Most of them are part of the first district. A secondary cluster was found, involving 18 neighborhoods in the sixth district and two neighborhoods in the fifth. The relative risk was respectively 1.7 (p<10⁻⁶) in the principal cluster and 1.6 (p<10⁻³) in the secondary cluster. Our study showed that more was known about TB symptoms than about the duration of the disease or free treatment. Knowledge about TB was limited to that acquired at school or from relatives with TB. The attitude and practices of patients and the population in general indicated that there is still a stigma attached to tuberculosis.

Conclusion

This type of survey can be conducted in remote zones where the tuberculosis-related KAP of the TB patients and the general population is less known or not documented; the findings could be used to adapt control measures to the local particularities.     

Antitumor efficacy,pharmacokinetic and biodistribution studies of the anticancer peptide CIGB‐552 in mouse models

Accumulation of the COMMD1 protein as a druggable pharmacology event to target cancer cells has not been evaluated so far in cancer animal models. We have previously demonstrated that a second‐generation peptide, with cell‐penetrating capacity, termed CIGB‐552, was able to induce apoptosis mediated by stabilization of COMMD1. Here, we explore the antitumor effect by subcutaneous administration of CIGB‐552 in a therapeutic schedule. Outstandingly, a significant delay of tumor growth was observed at 0.2 and 0.7 mg/kg (p < 0.01) or 1.4 mg/kg (p < 0.001) after CIGB‐552 administration in both syngeneic murine tumors and patient‐derived xenograft models. Furthermore, we evidenced that ¹³¹I‐CIGB‐552 peptide was actually accumulated in the tumors after administration by subcutaneous route. A typical serine‐proteases degradation pattern for CIGB‐552 in BALB/c mice serum was identified. Further, biological characterization of the main metabolites of the peptide CIGB‐552 suggests that the cell‐penetrating capacity plays an important role in the cytotoxic activity. This report is the first in describing the antitumor effect induced by systemic administration of a peptide that targets COMMD1 for stabilization. Moreover, our data reinforce the perspectives of CIGB‐552 for cancer targeted therapy. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd.     

Synthesis of proteins by native chemical ligation using Fmoc-based chemistry

C-terminal peptide alpha-thioesters are valuable intermediates in the synthesis/semisynthesis of proteins by native chemical ligation. They are prepared either by solid-phase peptide synthesis (SPPS) or biosynthetically by protein splicing techniques. The present paper reviews the different methods available for the chemical synthesis of peptide alpha-thioesters using Fmoc-based SPPS.     

Coinoculation with hepatitis B surface and core antigen promotes a Th1 immune response to a multiepitopic protein of HIV-1

It has been defined that strong and multispecific cellular immune responses correlate with a better prognosis during the course of chronic diseases. A cross-enhancing effect on the resulting immune response obtained by the coadministration of recombinant hepatitis B virus (HBV) surface and core Ag was recently observed. With the objective of studying the effect of such Ag on the immune response to coinoculated heterologous Ag and vice versa, several formulations containing the recombinant HBV Ag and a multiepitopic protein (CR3) composed by CTL and Th epitopes from HIV-1 were evaluated by s.c. and mucosal administration. Combinations of two and three Ag were evaluated for cellular and humoral immune responses. The results showed that the best Ag combination for nasal immunization was the mixture comprising the CR3 recombinant HIV protein and both HBV Ag. Similarly, it was also the best formulation for s.c. immunization in aluminium phosphate adjuvant. In conclusion, it is possible to induce a Th1 stimulation of the cellular immune response specific for a HIV-based recombinant protein by formulating this Ag with the recombinant HBV Ag.     

Properties of soft X-ray emission from a fast capillary discharge

Results are presented from experimental studies of the time resolved, spatially resolved, and spectrally resolved soft X rays emitted along the axis of a fast capillary discharge.