A Novel Antioxidant Multitarget Iron Chelator M30 Protects Hepatocytes against Ethanol-Induced Injury

published_or_final_versio

Antioxidant treatment enhances human mesenchymal stem cell anti-stress ability and therapeutic efficacy in an acute liver failure model

published_or_final_versio

The role of secretory leukocyte proteinase inhibitor and elafin (elastase-specific inhibitor/skin-derived antileukoprotease) as alarm antiproteinases in inflammatory lung disease

Secretory leukocyte proteinase inhibitor and elafin are two low-molecular-mass elastase inhibitors that are mainly synthesized locally at mucosal sites. It is thought that their physicochemical properties allow them to efficiently inhibit target enzymes, such as neutrophil elastase, released into the interstitium. Historically, in the lung, these inhibitors were first purified from secretions of patients with chronic obstructive pulmonary disease and cystic fibrosis. This suggested that they might be important in controlling excessive neutrophil elastase release in these pathologies. They are upregulated by 'alarm signals' such as bacterial lipopolysaccharides, and cytokines such as interleukin-1 and tumor necrosis factor and have been shown to be active against Gram-positive and Gram-negative bacteria, so that they have joined the growing list of antimicrobial 'defensin-like' peptides produced by the lung. Their site of synthesis and presumed functions make them very attractive candidates as potential therapeutic agents under conditions in which the excessive release of elastase by neutrophils might be detrimental. Because of its natural tropism for the lung, the use of adenovirus-mediated gene transfer is extremely promising in such applications

Comparison of immature and mature bone marrow-derived dendritic cells by atomic force microscopy

A comparative study of immature and mature bone marrow-derived dendritic cells (BMDCs) was first performed through an atomic force microscope (AFM) to clarify differences of their nanostructure and adhesion force. AFM images revealed that the immature BMDCs treated by granulocyte macrophage-colony stimulating factor plus IL-4 mainly appeared round with smooth surface, whereas the mature BMDCs induced by lipopolysaccharide displayed an irregular shape with numerous pseudopodia or lamellapodia and ruffles on the cell membrane besides becoming larger, flatter, and longer. AFM quantitative analysis further showed that the surface roughness of the mature BMDCs greatly increased and that the adhesion force of them was fourfold more than that of the immature BMDCs. The nano-features of the mature BMDCs were supported by a high level of IL-12 produced from the mature BMDCs and high expression of MHC-II on the surface of them. These findings provide a new insight into the nanostructure of the immature and mature BMDCs

H5N1 Vaccine-Specific B Cell Responses in Ferrets Primed with Live Attenuated Seasonal Influenza Vaccines

Live attenuated influenza H5N1 vaccines have been produced and evaluated in mice and ferrets that were never exposed to influenza A virus infection (Suguitan et al., Plos Medicine, e360:1541, 2006). However, the preexisting influenza heterosubtypic immunity on live attenuated H5N1 vaccine induced immune response has not been evaluated.Primary and recall B cell responses to live attenuated H5N1 vaccine viruses were examined using a sensitive antigen-specific B cell ELISpot assay to investigate the effect of preexisting heterosubtypic influenza immunity on the development of H5N1-specific B cell immune responses in ferrets. Live attenuated H5N1 A/Hong Kong/213/03 and A/Vietnam/1203/04 vaccine viruses induced measurable H5-specific IgM and IgG secreting B cells after intranasal vaccination. However, H5-specific IgG secreting cells were detected significantly earlier and at a greater frequency after H5N1 inoculation in ferrets previously primed with trivalent live attenuated influenza (H1N1, H3N2 and B) vaccine. Priming studies further revealed that the more rapid B cell responses to H5 resulted from cross-reactive B cell immunity to the hemagglutinin H1 protein. Moreover, vaccination with the H1N1 vaccine virus was able to induce protective responses capable of limiting replication of the H5N1 vaccine virus to a level comparable with prior vaccination with the H5N1 vaccine virus without affecting H5N1 vaccine virus induced antibody response. vaccine and the heterosubtypic immunity may be beneficial for pandemic preparedness

Ionic immune suppression within the tumour microenvironment limits T cell effector function.

Tumours progress despite being infiltrated by tumour-specific effector T cells. Tumours contain areas of cellular necrosis, which are associated with poor survival in a variety of cancers. Here, we show that necrosis releases intracellular potassium ions into the extracellular fluid of mouse and human tumours, causing profound suppression of T cell effector function. Elevation of the extracellular potassium concentration ([K+]e) impairs T cell receptor (TCR)-driven Akt-mTOR phosphorylation and effector programmes. Potassium-mediated suppression of Akt-mTOR signalling and T cell function is dependent upon the activity of the serine/threonine phosphatase PP2A. Although the suppressive effect mediated by elevated [K+]e is independent of changes in plasma membrane potential (Vm), it requires an increase in intracellular potassium ([K+]i). Accordingly, augmenting potassium efflux in tumour-specific T cells by overexpressing the potassium channel Kv1.3 lowers [K+]i and improves effector functions in vitro and in vivo and enhances tumour clearance and survival in melanoma-bearing mice. These results uncover an ionic checkpoint that blocks T cell function in tumours and identify potential new strategies for cancer immunotherapy

Androgen Receptor Variants Mediate DNA Repair after Prostate Cancer Irradiation.

In prostate cancer, androgen deprivation therapy (ADT) enhances the cytotoxic effects of radiotherapy. This effect is associated with weakening of the DNA damage response (DDR) normally supported by the androgen receptor. As a significant number of patients will fail combined ADT and radiotherapy, we hypothesized that DDR may be driven by androgen receptor splice variants (ARV) induced by ADT. Investigating this hypothesis, we found that ARVs increase the clonogenic survival of prostate cancer cells after irradiation in an ADT-independent manner. Notably, prostate cancer cell irradiation triggers binding of ARV to the catalytic subunit of the critical DNA repair kinase DNA-PK. Pharmacologic inhibition of DNA-PKc blocked this interaction, increased DNA damage, and elevated prostate cancer cell death after irradiation. Our findings provide a mechanistic rationale for therapeutic targeting of DNA-PK in the context of combined ADT and radiotherapy as a strategy to radiosensitize clinically localized prostate cancer. Cancer Res; 77(18); 4745-54. ©2017 AACR

Enzymatic processing of protein-based fibers

Wool and silk are major protein fiber materials used by the textile industry. Fiber protein structure-function relationships are briefly described here, and the major enzymatic processing routes for textiles and other novel applications are deeply reviewed. Fiber biomodification is described here with various classes of enzymes such as protease, transglutaminase, tyrosinase, and laccase. It is expected that the reader will get a perspective on the research done as a basis for new applications in other areas such as cosmetics and pharma.This work was financially supported by the National Natural Science Foundation of China (21274055,51373071, 31201134 and 31470509), the Program for New Century Excellent Talents in University (NCET-12-0883), the Program for Changjiang Scholars and Innovative Research Team in University (IRT1135), the Jiangsu Provincial Natural Science Foundation of China (BK2012112), and the Fundamental Research Funds for the Central Universities (JUSRP51312B)

Fatty Acid Composition of Developing Sea Buckthorn (Hippophae rhamnoides L.) Berry and the Transcriptome of the Mature Seed

Background: Sea buckthorn (Hippophae rhamnoides L.) is a hardy, fruit-producing plant known historically for its medicinal and nutraceutical properties. The most recognized product of sea buckthorn is its fruit oil, composed of seed oil that is rich in essential fatty acids, linoleic (18:2\u3c9-6) and \u3b1-linolenic (18:3\u3c9-3) acids, and pulp oil that contains high levels of monounsaturated palmitoleic acid (16:1\u3c9-7). Sea buckthorn is fast gaining popularity as a source of functional food and nutraceuticals, but currently has few genomic resources; therefore, we explored the fatty acid composition of Canadian-grown cultivars (ssp. mongolica) and the sea buckthorn seed transcriptome using the 454 GS FLX sequencing technology. Results: GC-MS profiling of fatty acids in seeds and pulp of berries indicated that the seed oil contained linoleic and \u3b1-linolenic acids at 33-36% and 30-36%, respectively, while the pulp oil contained palmitoleic acid at 32-42%. 454 sequencing of sea buckthorn cDNA collections from mature seeds yielded 500,392 sequence reads, which identified 89,141 putative unigenes represented by 37,482 contigs and 51,659 singletons. Functional annotation by Gene Ontology and computational prediction of metabolic pathways indicated that primary metabolism (protein>nucleic acid>carbohydrate>lipid) and fatty acid and lipid biosynthesis pathways were highly represented categories. Sea buckthorn sequences related to fatty acid biosynthesis genes in Arabidopsis were identified, and a subset of these was examined for transcript expression at four developing stages of the berry. Conclusion: This study provides the first comprehensive genomic resources represented by expressed sequences for sea buckthorn, and demonstrates that the seed oil of Canadian-grown sea buckthorn cultivars contains high levels of linoleic acid and \u3b1-linolenic acid in a close to 1:1 ratio, which is beneficial for human health. These data provide the foundation for further studies on sea buckthorn oil, the enzymes involved in its biosynthesis, and the genes involved in the general hardiness of sea buckthorn against environmental conditions.Peer reviewed: YesNRC publication: Ye

Network Topologies and Dynamics Leading to Endotoxin Tolerance and Priming in Innate Immune Cells

The innate immune system, acting as the first line of host defense, senses and adapts to foreign challenges through complex intracellular and intercellular signaling networks. Endotoxin tolerance and priming elicited by macrophages are classic examples of the complex adaptation of innate immune cells. Upon repetitive exposures to different doses of bacterial endotoxin (lipopolysaccharide) or other stimulants, macrophages show either suppressed or augmented inflammatory responses compared to a single exposure to the stimulant. Endotoxin tolerance and priming are critically involved in both immune homeostasis and the pathogenesis of diverse inflammatory diseases. However, the underlying molecular mechanisms are not well understood. By means of a computational search through the parameter space of a coarse-grained three-node network with a two-stage Metropolis sampling approach, we enumerated all the network topologies that can generate priming or tolerance. We discovered three major mechanisms for priming (pathway synergy, suppressor deactivation, activator induction) and one for tolerance (inhibitor persistence). These results not only explain existing experimental observations, but also reveal intriguing test scenarios for future experimental studies to clarify mechanisms of endotoxin priming and tolerance.Comment: 15 pages, 8 figures, submitte