Head and neck squamous cell carcinomas (HNSCC) are one of the leading causes of cancer deaths world wide. Up-regulation of the epidermal growth factor receptor (EGFR) and BCL-2 family anti-apoptosis proteins in these cancers is linked to aggressive tumor growth, metastasis and chemoresistance. Infection of two HNSCC cell lines, SCC25 and CAL27 by an Ad5 mutant (lp11w) defective in coding for the viral anti-apoptosis protein, E1B-19K efficiently induced apoptotic cell death. In cells infected with lp11w there was a dramatic down-regulation of EGFR by apoptosis-dependent and -independent mechanisms. The levels of the anti-apoptotic proteins BCL-2, BCL-xL and MCL-1 were also down-regulated in lp11w-infected cells compared to uninfected or Ad5-RM infected cells. Infection with lp11w also enhanced sensitivity of the HNSCC cells to the chemotherapeutic drug cisplatin. Our results suggest that adenoviral vectors defective in E1B-19K would be valuable for efficient down-regulation of cell survival proteins and EGFR in epithelial cancers and could be exploited as oncolytic agents to treat HNSCCs.

Protein arginine N-methyltransferase 1 (PRMT1) is an important epigenetic regulation factor in eukaryotic genomes. PRMT1 is involved in histone arginine loci methylation modification, changes in eukaryotic genomes' chromatin structure, and gene expression regulation. In the present paper, the full-length 1201-bp cDNA sequence of the PRMT1 homolog of Artemia sinica (As-PRMT1) was cloned for the first time. The putative As-PRMT1 protein comprises 346 amino acids with a SAM domain and a PRMT5 domain. Multiple sequence alignments revealed that the putative sequence of As-PRMT1 protein was relatively conserved across species, especially in the SAM domain. As-PRMT1 is widely expressed during embryo development of A. sinica. This is followed by a dramatic upregulation after diapause termination and then downregulation from the nauplius stage. Furthermore, As-PRMT1 transcripts are highly upregulated under conditions of high salinity and low temperature stress. These findings suggested that As-PRMT1 is a stress-related factor that might promote or inhibit the expression of certain genes, play a critical role in embryonic development and in resistance to low temperature and high salinity stress.

The gut microbiota is central to human health, but its establishment in early life has not been quantitatively and functionally examined. Applying metagenomic analysis on fecal samples from a large cohort of Swedish infants and their mothers, we characterized the gut microbiome during the first year of life and assessed the impact of mode of delivery and feeding on its establishment. In contrast to vaginally delivered infants, the gut microbiota of infants delivered by C-section showed significantly less resemblance to their mothers. Nutrition had a major impact on early microbiota composition and function, with cessation of breast-feeding, rather than introduction of solid food, being required for maturation into an adult-like microbiota. Microbiota composition and ecological network had distinctive features at each sampled stage, in accordance with functional maturation of the microbiome. Our findings establish a framework for understanding the interplay between the gut microbiome and the human body in early life.

We aimed to investigate the associations of polymorphisms in Canonical Wnt/β-catenin pathway (WNT) signaling genes (including low-density lipoprotein-related protein 5 [LRP5] and transcription factor 7-like 2 [TCF7L2] gene) and the downstream gene glucagon (GCG) and risk of type 2 diabetes mellitus (T2DM) in a Han Chinese population. We genotyped the single nucleotide polymorphisms (SNPs) for LRP5, TCF7L2 and GCG gene were genotyped in 1842 patients with T2DM and 7777 normal glucose-tolerant healthy subjects. We used multifactor dimensionality reduction (MDR) and multiplicative logistic regression adjusting for sex, age, anthropometric measurements and lipid levels to investigate the gene-gene interactions for the risk of T2DM. Among the five SNPs in LRP5, the recessive model of rs7102273 and the haplotype GCTCC were associated with T2DM risk; the haplotype GCTTC was associated with decreased risk. For TCF7L2, the rs11196218 genotype GA and the haplotype CCG, TTG, TTA were associated with T2DM risk; whereas, the haplotype CTG and TCG were associated with decreased risk. Both MDR and multiplicative logistic regression revealed potential gene-gene interactions among LRP5, TCF7L2, and GCG associated with T2DM. The WNT signaling pathway may play a significant role in risk of T2DM in Han Chinese people.

The type I interferon (IFN) signaling response limits infection of many RNA and DNA viruses. To define key cell types that require type I IFN signaling to orchestrate immunity against West Nile virus (WNV), we infected mice with conditional deletions of the type I IFN receptor (IFNAR) gene. Deletion of the Ifnar gene in subsets of myeloid cells resulted in uncontrolled WNV replication, vasoactive cytokine production, sepsis, organ damage, and death that were remarkably similar to infection of Ifnar-/- mice completely lacking type I IFN signaling. In Mavs-/-×Ifnar-/- myeloid cells and mice lacking both Ifnar and the RIG-I-like receptor adaptor gene Mavs, cytokine production was muted despite high levels of WNV infection. Thus, in myeloid cells, viral infection triggers signaling through MAVS to induce proinflammatory cytokines that can result in sepsis and organ damage. Viral pathogenesis was caused in part by massive complement activation, as liver damage was minimized in animals lacking complement components C3 or factor B or treated with neutralizing anti-C5 antibodies. Disease in Ifnar-/- and CD11c Cre+Ifnarf/f mice also was facilitated by the proinflammatory cytokine TNF-α, as blocking antibodies diminished complement activation and prolonged survival without altering viral burden. Collectively, our findings establish the dominant role of type I IFN signaling in myeloid cells in restricting virus infection and controlling pathological inflammation and tissue injury.

Autophagy is a protective mechanism in normal cartilage. The present study aimed to investigate the synergistic therapeutic effect of promotion of chondrocyte autophagy via exposure to cordycepin encapsulated by chitosan microspheres (CM-cordycepin) and photo-crosslinked hyaluronic acid methacrylate (HAMA) hydrogel, with the goal of evaluating CM-cordycepin as a treatment for patients with osteoarthritis. First, we developed and evaluated the characteristics of HAMA hydrogels and chitosan microspheres. Next, we measured the effect of cordycepin on cartilage matrix degradation induced by IL1-β in chondrocytes and an ex vivo model. Cordycepin protects cartilage from degradation partly by activation of autophagy. Moreover, we surgically induced osteoarthritis in mice, which were injected intra-articularly with CM-cordycepin and HAMA. The combination of CM-cordycepin and HAMA hydrogel retarded the progression of surgically induced OA. Cordycepin ameliorated cartilage matrix degradation at least partially by inducing autophagy in vivo. Our results demonstrate that the combination of cordycepin encapsulated by CMs and photo-crosslinked HAMA hydrogel could be a promising strategy for treating patients with osteoarthritis.

Antigen specific B cells undergo a process termed affinity maturation in the germinal centers of secondary lymphoid organs where B cells with high affinity receptors are selected to mature into antibody-producing cells or to the memory B cell pool. It is known that B cell antigen receptor (BCR) signaling plays pivotal role in this selection process. Calcium influx is an essential component of BCR signaling. The current report is to determine the effect of calcium influx on antibody affinity maturation. In our studies, mice deficient for both endoplasmic reticulum calciumsensor Stim1 and Stim2 was immunized with T-cell dependent and independent antigens. Antibody affinity was measured by ELISA. We demonstrated that Stim1 &Stim2 deficient B cells exhibit accelerated pace of affinity maturation compared to wild type controls while the overall antibody production was not dramatically impaired to T-independent antigen immunization. In conclusion, calcium influx plays an important role in antibody affinity maturation in humoral immune responses. The knowledge can be used in manipulate humoral immune response for the design of effective vaccines.

Glomus intraradices is a species of arbuscular mycorrhizal fungi that, as an obligate endomycorrhiza, can form mutually beneficial associations with plants. Panax ginseng is a popular traditional Chinese medicine; however, problems associated with ginseng planting, such as pesticide residues, reduce the ginseng quality.

This study examined whether the neuroprotective drug, 3-n-butylphthalide (NBP), which is used to treat ischemic stroke, prevents mitochondrial dysfunction.

Rheumatoid arthritis (RA), a disease that causes joint destruction and bone erosion, is related to osteoclast activity. RA is generally treated with methotrexate (MTX). In this study, a MTX-Alendronate (ALN) conjugate was synthesized and characterized. The conjugate dramatically inhibited osteoclast formation and bone resorption compared with MTX and ALN used alone or in combination. Due to the characteristics of ALN, the MTX-ALN conjugate can adhere to the exposed bone surface and enhance drug accumulation in the pathological region for targeted therapy against osteoclastogenesis. Additionally, MTX was rapidly released in the presence of lysozyme under mildly acidic conditions, similar to inflammatory tissue and osteoclast-surviving conditions, which contributes to inflammatory inhibition; this was confirmed by the presence of pro-inflammatory cytokines. Our study highlights the use of the MTX-ALN conjugate as a potential therapeutic approach for RA by targeting osteoclastogenesis.

Kidney fibrosis is the main pathologic change in diabetic nephropathy (DN), which is the major cause of end-stage renal disease. Current therapeutic strategies slow down but cannot reverse the progression of renal dysfunction in DN. Plant-derived bioactive peptides in foodstuffs are widely used in many fields because of their potential pharmaceutical and nutraceutical benefits. However, this type of peptide has not yet been studied in renal fibrosis of DN. Previous studies have indicated that the peptide YWDHNNPQIR (named RAP), a natural peptide derived from rapeseed protein, has an antioxidative stress effect. The oxidative stress is believed to be associated with DN. The aim of this study was to evaluate the pharmacologic effects of RAP against renal fibrosis of DN and high glucose (HG)-induced mesangial dysfunction.

The Pseudomonas syringae acetyltransferase HopZ1a is delivered into host cells by the type III secretion system to promote bacterial growth. However, in the model plant host Arabidopsis thaliana, HopZ1a activity results in an effector-triggered immune response (ETI) that limits bacterial proliferation. HopZ1a-triggered immunity requires the nucleotide-binding, leucine-rich repeat domain (NLR) protein, ZAR1, and the pseudokinase, ZED1. Here we demonstrate that HopZ1a can acetylate members of a family of 'receptor-like cytoplasmic kinases' (RLCK family VII; also known as PBS1-like kinases, or PBLs) and promote their interaction with ZED1 and ZAR1 to form a ZAR1-ZED1-PBL ternary complex. Interactions between ZED1 and PBL kinases are determined by the pseudokinase features of ZED1, and mutants designed to restore ZED1 kinase motifs can (1) bind to PBLs, (2) recruit ZAR1, and (3) trigger ZAR1-dependent immunity in planta, all independently of HopZ1a. A ZED1 mutant that mimics acetylation by HopZ1a also triggers immunity in planta, providing evidence that effector-induced perturbations of ZED1 also activate ZAR1. Overall, our results suggest that interactions between these two RLCK families are promoted by perturbations of structural features that distinguish active from inactive kinase domain conformations. We propose that effector-induced interactions between ZED1/ZRK pseudokinases (RLCK family XII) and PBL kinases (RLCK family VII) provide a sensitive mechanism for detecting perturbations of either kinase family to activate ZAR1-mediated ETI.

Malignant growth and chemotherapy resistance to 5-fluorouracil (5-FU) are the obstacles to the treatment of Colorectal cancer (CRC). There is need to develop effective therapeutic option. Demethylzeylasteral benefits to immune and anti-tumor function. However, the role demethylzeylasteral played in colorectal cancer remains unclear. Here, our study confirmed that demethylzeylasteral could inhibit the cell malignant capacity, such as proliferation, migration and invasion. And we also found demethylzeylasteral could cause cell cycle arrest and apoptosis. Followed we verified that combination demethylzeylasteral with 5-FU has a better curative effect in vitro. The two drugs function synergistically in SW480 and additionally in RKO. IC50 values of 5-FU decreased when combined with demethylzeylasteral. Next, we used the network pharmacology approach to explore the the potential molecular mechanism of demethylzeylasteral. We constructed the "Colorectal - targets - Demethylzeylasteral" and protein-protein interactions (PPI) networks. And 15 hub genes were found in PPI network. Then Gene Ontology (GO) enrichment analysis showed that demethylzeylasteral may affect cell cycle, apoptosis, invasion and response to chemotherapy drugs. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated demethylzeylasteral may be involved in many cancer-related pathways. Taken together, the network pharmacology approach provided a potential mechanism of demethylzeylasteral in colorectal cells. Our study indicated that demethylzeylasteral could exert anti-tumor effects and enhance the sensitivity of the Colorectal cells to 5-FU, suggesting a promising ability to serve as an anti-cancer agent in Colorectal cancer.

Peatlands in the Sanjiang Plain could be more vulnerable to global warming because they are located at the southernmost boundary of northern peatlands. Unlike bacteria, fungi are often overlooked, even though they play important roles in substance circulation in the peatland ecosystems. Accordingly, it is imperative that we deepen our understanding of fungal community structure and diversity in the peatlands. In this study, high-throughput Illumina sequencing was used to study the fungal communities in three fens in the Sanjiang Plain, located at the southern edge of northern peatlands. Peat soil was collected from the three fens which developed during different periods. A total of 463,198 fungal ITS sequences were obtained, and these sequences were classified into at least six phyla, 21 classes, more than 60 orders and over 200 genera. The fungal community structures were distinct in the three sites and were dominated by Ascomycota and Basidiomycota. However, there were no significant differences between these three fens in any α-diversity index (p > 0.05). Soil age and the carbon (C) accumulation rate, as well as total carbon (TC), total nitrogen (TN), C/N ratio, and bulk density were found to be closely related to the abundance of several dominant fungal taxa. We captured a rich fungal community and confirmed that the dominant taxa were those which were frequently detected in other northern peatlands. Soil age and the C accumulation rate were found to play important roles in shaping the fungal community structure.

Composted sewage sludge (CS) is considered a rich source of soil nutrients and significantly affects the physical, chemical, and biological characteristics of soil, but its effect on specific enzyme activity in soil is disregarded. The present experiment examined the absolute and specific enzyme activity of the enzymes involved in carbon, nitrogen, and phosphorus cycles, the diversity of soil microbial functions, and soil community composition in a Fluventic Ustochrept under a maize-wheat rotation system in North China during 2012-2015. Application of CS led to increase in MBC and in its ratio to both total organic carbon (TOC) and microbial biomass nitrogen (MBN). Absolute enzyme activity, except that of phosphatase, increased in CS-treated soils, whereas specific activity of all the enzymes declined, especially at the highest dose of CS (45 t ha-1). The diversity of soil microbial community also increased in CS-treated soils, whereas its functional diversity declined at higher doses of CS owing to the lowered specific enzyme activity. These changes indicate that CS application induced the domination of microorganisms that are not metabolically active and those that use resources more efficiently, namely fungi. Redundancy analysis showed that fundamental alterations in soil enzyme activity depend on soil pH. Soil specific enzyme activity is affected more than absolute enzyme activity by changes in soil properties, especially soil microbial activity and composition of soil microflora (as judged by the following ratios: MBC/TOC, MBC/MBN, and TOC/LOC, that is labile organic carbon) through the Pearson Correlation Coefficient. Specific enzyme activity is thus a more accurate parameter than absolute enzyme activity for monitoring the effect of adding CS on the activities and structure of soil microbial community.

Decellularized tendon extracellular matrix (tECM) perfectly provides the natural environment and holds great potential for bone regeneration in Bone tissue engineering (BTE) area. However, its densifying fiber structure leads to reduced cell permeability. Our study aimed to combine tECM with polyethylene glycol diacrylate (PEGDA) to form a biological scaffold with appropriate porosity and strength using stereolithography (SLA) technology for bone defect repair.

Cancer-related depression (CRD) is the most common mood disorder in patients with malignant tumors, negatively influencing the patient's daily life. Traditional Chinese medicine, as an alternative CRD therapy, has shown good treatment performance in recently years. Soothing liver-qi stagnation, as a classic therapy for depression, is based on traditional Chinese medicine theory. However, there is no evidence-based medical confirmation for the soothing liver-qi stagnation method for CRD treatment.

Renal fibrosis is a progressive disease that leads to renal dysfunction and end-stage renal failure, and there is currently no specific treatment. Our previous study showed that the 8-residue peptide DR8 (DHNNPQIR) exhibits potent antioxidant and antifibrotic properties, and accumulating evidence suggests that oxidative stress contributes greatly to fibrosis. The effects and mechanisms of DR8 on renal fibrosis remain unknown.

This study was designed to investigate the mechanism by which miR-129-5p affects the biological function of liver cancer cells. The expression levels of miR-129-5p in liver cancer tissues and cells were, respectively, determined. Crystal violet staining and flow cytometry were used to detect cell proliferation and apoptosis. Wound healing assay and transwell assay were performed to test cell migration and invasion. The target gene of miR-129-5p was analyzed and verified by bioinformatics analysis and luciferase reporter assay. Tumorigenicity assays in nude mice were used to test the antitumor ability of calcium calmodulin-dependent protein kinase IV (CAMK4). miR-129-5p was found to be underexpressed in hepatocellular cancer tissues and cells and also to inhibit liver cells proliferation, migration, and invasion and promote apoptosis. CAMK4 was a direct target for miR-129-5p and was lowly expressed in liver cancer tissues and cells. CAMK4 was also found to inhibit liver cells proliferation, migration and invasion, and promote apoptosis. CAMK4 might exert an antitumor effect by inhibiting the activation of mitogen-activated protein kinase (MAPK). MiR-129-5p was a tumor suppressor with low expression in liver cancer tissues and cells. CAMK4, which is a direct target gene of miR-129-5p, could inhibit tumor by inhibiting the activation of MAPK signaling pathway.

In recent years, sepsis-induced acute respiratory distress syndrome (ARDS) has remained a major clinical challenge for patients in intensive care units. While some progress has been reported over the years, the pathogenesis of ARDS still needs to be further expounded.