Allergiccontact dermatitis (AcD) is a prevalent and poorly controlled inflammatory disease caused by skin infiltration of T cells and granulocytes. The beta common (beta(c)) cytokines GM-cSF, IL-3, and IL-5 are power...
详细信息
Allergiccontact dermatitis (AcD) is a prevalent and poorly controlled inflammatory disease caused by skin infiltration of T cells and granulocytes. The beta common (beta(c)) cytokines GM-cSF, IL-3, and IL-5 are powerful regulators of granulocyte function that signal through their common receptor subunit beta(c), a property that has made beta(c) an attractive target to simultaneously inhibit these cytokines. However, the species specificity of beta(c) has precluded testing of inhibitors of human beta(c) in mouse models. To overcome this problem, we developed a human beta(c) receptor transgenic mouse strain with a hematopoieticcell-specific expression of human beta(c) instead of mouse beta(c). Human beta(c) receptor transgeniccells responded to mouse GM-cSF and IL-5 but not to IL-3 in vitro and developed tissue pathology and cellular inflammation comparable with those in wild-type mice in a model of AcD. Similarly, Il3(-/-) mice developed AcD pathology comparable with that of wild-type mice. Importantly, the blocking anti-human beta(c) antibody cSL311 strongly suppressed ear pinna thickening and histopathological changes typical of AcD and reduced accumulation of neutrophils, mast cells, and eosinophils in the skin. These results show that GM-cSF and IL-5 but not IL-3 are major mediators of AcD and define the human beta(c) receptor transgenic mouse as a unique platform to test the inhibitors of beta(c) in vivo.
Background As a fatal interstitial lung disease, idiopathic pulmonary fibrosis (IPF) was characterized by the insidious proliferation of extracellular matrix (EcM)-producing mesenchymal cells. Recent studies have demo...
详细信息
Background As a fatal interstitial lung disease, idiopathic pulmonary fibrosis (IPF) was characterized by the insidious proliferation of extracellular matrix (EcM)-producing mesenchymal cells. Recent studies have demonstrated that lung resident mesenchymal/stromal cells (LR-MSc) are the source of myofibroblasts. Endoplasmic reticulum (ER) stress is prominent in IPF lung. This study sought to investigate the effects of ER stress on the behavior of LR-MSc during pulmonary fibrosis. Methods ER stress and myofibroblast differentiation of LR-MSc in patients with IPF were evaluated. Primary mouse LR-MSc was harvested and used in vitro for testing the effects of ER stress and c/EBP homologous protein (cHOP) on LR-MSc. Adoptive transplantation of LR-MSc to bleomycin-induced pulmonary fibrosis was done to test the in vivo behavior of LR-MSc and its influence on pulmonary fibrosis. Results We found that myofibroblast differentiation of LR-MSc is associated with ER stress in IPF and bleomycin-induced mouse fibrotic lung. Tunicamycin-induced ER stress impairs the paracrine, migration, and reparative function of mouse LR-MSc to injured type 2 alveolar epithelial cells MLE-12. Overexpression of the ER stress responder c/EBP homologous protein (cHOP) facilitates the TGF beta 1-induced myofibroblast transformation of LR-MSc via boosting the TGF beta/SMAD signaling pathway. cHOP knockdown facilitates engraftment and inhibits the myofibroblast transformation of LR-MSc during bleomycin-induced pulmonary fibrosis, thus promoting the efficacy of adopted LR-MSc in alleviating pulmonary fibrosis. conclusion Our work revealed a novel role that ER stress involved in pulmonary fibrosis by influencing the fate of LR-MSc and transformed to "crime factor" myofibroblast, during which cHOP acts as the key modulator. These results indicate that pharmacies targeting cHOP or therapies based on cHOP knockdown LR-MSc may be promising ways to treat pulmonary fibrosis.
Purpose In women under the age of 40, primary ovarian insufficiency (POI) is a devastating diagnosis with significant prevalence of 1-4% (Rajkovic and Pangas, Semin Reprod Med. 35(3):231-40, 2017). POI is characterize...
详细信息
Purpose In women under the age of 40, primary ovarian insufficiency (POI) is a devastating diagnosis with significant prevalence of 1-4% (Rajkovic and Pangas, Semin Reprod Med. 35(3):231-40, 2017). POI is characterized by amenorrhea with elevated levels of follicle stimulating hormone (FSH) and reduced estrogen levels, mimicking the menopausal state. Genetic determinants account for just over 10% of POI cases, yet determining whether particular single nucleotide polymorphisms (SNPs) are pathogenic is challenging. Methods We performed exome sequencing on a cohort of women with POI. cRISPR mutagenesis was employed to create a mutation in a conserved amino acid in the nematode protein. Functional relevance was assessed by analysis of bivalents and aberrant DNA morphologies in diakinesis nuclei. Results We identified a nonsynonymous c.c1051G;p.R351G variant, in a conserved region of the MSH5 protein. Mutation of this conserved amino acid in the c. elegans homolog, msh-5, revealed defective crossover outcomes in the homozygous and hemizygous states. conclusions These studies further implicate MSH5 as a POI gene and c.c1051G;p.R351G variant as likely playing a functional role in mammalian meiosis. This approach also highlights the ability of model organisms, such as c. elegans, to rapidly and inexpensively identify alleles of interest for further studies in mammalian models.
Dinoflagellates are amongst the most abundant and diverse groups of plankton in surface waters and contribute to food web productivity and c:N:P biogeochemistry. Here we analyse the c:N:P of marine, autotrophic, plank...
详细信息
Dinoflagellates are amongst the most abundant and diverse groups of plankton in surface waters and contribute to food web productivity and c:N:P biogeochemistry. Here we analyse the c:N:P of marine, autotrophic, planktonic dinoflagellates compiled from culture data from the scientific literature and test if dinoflagellate c:N:P differs from the Redfield ratio, and whether variability in c:N:P is associated with three traits: cell size, wall structure and toxin production. We find the average c:N:P of dinoflagellates is 90:12:1;higher in c:N, and lower in c:P and N:P than the canonical Redfield ratio. In aggregate the three traits examined here account for between 20-31% while taxonomic order accounts for between 37-38% of the variance in c:N:P. Smaller-sized and thecate taxa are higher in c:N, c:P and N:P than larger-size and athecate taxa. Species known to be able to produce c-rich toxins tend to be higher in c:P and N:P while species known to be able to produce N-rich toxins are lower in c:N, c:P and N:P relative to non-toxic species. These results indicate that any average estimate of dinoflagellate c:N:P will be influenced by the relative number of taxa with these traits.
Riboflavin (Rf), or vitamin B2, is the precursor of FMN and FAD, redox cofactors of several dehydrogenases involved in energy metabolism, redox balance and other cell regulatory processes. FAD synthase, coded by FLAD1...
详细信息
Riboflavin (Rf), or vitamin B2, is the precursor of FMN and FAD, redox cofactors of several dehydrogenases involved in energy metabolism, redox balance and other cell regulatory processes. FAD synthase, coded by FLAD1 gene in humans, is the last enzyme in the pathway converting Rf into FAD. Mutations in FLAD1 gene are responsible for neuromuscular disorders, in some cases treatable with Rf. In order to mimic these disorders, the caenorhabditis elegans (c. elegans) gene orthologue of FLAD1 (flad-1) was silenced in a model strain hypersensitive to RNA interference in nervous system. Silencing flad-1 resulted in a significant decrease in total flavin content, paralleled by a decrease in the level of the FAD-dependent ETFDH protein and by a secondary transcriptional down-regulation of the Rf transporter 1 (rft-1) possibly responsible for the total flavin content decrease. conversely an increased ETFDH mRNA content was found. These biochemical changes were accompanied by significant phenotypical changes, including impairments of fertility and locomotion due to altered cholinergic transmission, as indicated by the increased sensitivity to aldicarb. A proposal is made that neuronal acetylcholine production/release is affected by alteration of Rf homeostasis. Rf supplementation restored flavin content, increased rft-1 transcript levels and eliminated locomotion defects. In this aspect, c. elegans could provide a low-cost animal model to elucidate the molecular rationale for Rf therapy in human Rf responsive neuromuscular disorders and to screen other molecules with therapeutic potential.
Polyinosinic-polycytidylic acid (poly I:c) is a synthetic analog of double-stranded RNA (dsRNA) that activates anti-infective innate immunity. The underlying mechanisms are identified as targeting pattern recognition ...
详细信息
Polyinosinic-polycytidylic acid (poly I:c) is a synthetic analog of double-stranded RNA (dsRNA) that activates anti-infective innate immunity. The underlying mechanisms are identified as targeting pattern recognition receptors and Th1-inducing. However, whether poly I:c manipulates metabolism to implement this anti-infective function is unknown. Here, Gc-MS based metabolomics was used to characterize metabolic profiles induced by different doses of poly I:c. Analysis on the dose-dependent metabolomes shows that elevation of the TcA cycle and malate with the increasing dose of ploy I:c forms the most characteristic feature of the poly I:c stimulation. Exogenous malate activates the TcA cycle and elevates survival of zebrafish infected with Vibrio alginolyticus, which is related to the elevated expression of il-1b, il-6, il-8, tnf-a, and c3b. These results reveal a previously unknown regulation of poly I:c that boosts the TcA cycle to enhance innate immunity against bacterial infection.
Parkinson's disease (PD) is a common neurodegenerative disease. The main pathological feature is the degeneration and loss of dopaminergic neurons in the substantia nigra, which leads to the significant decrease o...
详细信息
Parkinson's disease (PD) is a common neurodegenerative disease. The main pathological feature is the degeneration and loss of dopaminergic neurons in the substantia nigra, which leads to the significant decrease of dopamine content in the striatum. Our recent studies have shown that scorpion venom heat-resistant synthetic peptide (SVHRSP) have protective effects on neuroinflammation. In this study, using c. elegans induced by 6hydroxydopamine (6-OHDA) as neurodegenerative model, we investigated the effect of SVHRSP on dopaminergic neurons neurotoxicity. Our results implied that SVHRSP treatment could improve the motor capacity in 6OHDA-induced c. elegans and improve dopaminergic neuron mediated food sensitivity behavior. After SVHRSP treatment, dopaminergic neuron degeneration induced by 6-OHDA was significantly prevented along with a decreased alpha-synuclein aggregation and restored lipid deposition in c. elegans induced by 6-OHDA. We also observed the reduced levels of reactive oxygen species (ROS) after SVHRSP treatment in model-building c. elegans. In addition, the genes related to apoptosis, oxidative stress, like ctl-1, egl-1and cat-2 in c. elegans induced by 6-OHDA upregulated after treatment with SVHRSP. In conclusion, SVHRSP may impose anti-PD effect through its neuroprotective action on dopaminergic neurons. This study elucidates the effect and related mechanism of SVHRSP on PD and provides evidences for the therapeutic treatment of PD.
Introduction Diffuse midline gliomas (DMGs) are infiltrative midline gliomas harboring H3K27M mutations and are generally associated with poor outcomes. H3K27M mutations include mutations in HIST1H3B/c (H3.1), HIST2H3...
详细信息
Introduction Diffuse midline gliomas (DMGs) are infiltrative midline gliomas harboring H3K27M mutations and are generally associated with poor outcomes. H3K27M mutations include mutations in HIST1H3B/c (H3.1), HIST2H3B/D (H3.2), or H3F3A (H3.3) genes. It is still unclear whether these mutations each portend a universally poor prognosis, or if there are any factors which modulate outcome. The main objective of this study was to study overall survival (OS) of H3.1 versus H3.3 K27M-mutant DMGs in pediatric and adult patients. Methods PubMed and Web of Science were searched, and we included studies if they have individual patient data of DMGs with available H3K27M genotype. Kaplan-Meier analysis and cox regression models were used to analyze the survival of H3.1 and H3.3 mutations in each subgroup. Results We included 26 studies with 102 and 529 H3.1 and H3.3-mutant DMGs, respectively. The H3.1 mutation was more commonly seen in younger age. In pediatric population, H3.3 mutation conferred a shorter survival (median OS of 10.1 vs 14.2 months;p < 0.001) in comparison to H3.1-positive patients, which was further confirmed in the multivariate cox analysis. conversely, H3.3 was associated with a prolonged survival in adult patients as compared with H3.1 mutation (median OS of 14.4 vs 1.7 months;p = 0.019). conclusion We demonstrated that the prognosis of H3.1 and H3.3 K27M mutation in DMG patients is modulated by patient age. Routine H3K27M mutation genotyping in newly diagnosed DMGs may further stratify patients with these difficult tumors.
Background Protein-protein interactions form the basis of every organism and thus, investigating their dynamics, intracellular protein localization, trafficking and interactions of distinct proteins such as receptors ...
详细信息
Background Protein-protein interactions form the basis of every organism and thus, investigating their dynamics, intracellular protein localization, trafficking and interactions of distinct proteins such as receptors and their ligand-binding are of general interest. Bioluminescence resonance energy transfer (BRET) is a powerful tool to investigate these aspects in vitro. Since in vitro approaches mostly neglect the more complex in vivo situation, we established BRET as an in vivo tool for studying protein interactions in the nematode c. elegans. Results We generated worms expressing NanoBRET sensors and elucidated the interaction of two ligand-G protein-coupled receptor (GPcR) pairs, the neuropeptide receptor NPR-11 and the Adhesion GPcR LAT-1. Furthermore, we adapted the enhanced bystander BRET technology to measure subcellular protein localization. Using this approach, we traced ligand-induced internalization of NPR-11 in vivo. conclusions Our results indicate that in vivo NanoBRET is a tool to investigate specific protein interactions and localization in a physiological setting in real time in the living organism c. elegans.
ceRNA effect was an important regulation mode of miRNA mediated bio-activities, however, most of the researches of ceRNA were on ncRNAs synergetic with mRNAs, the exploration of ceRNA effect regulated mRNA interaction...
详细信息
ceRNA effect was an important regulation mode of miRNA mediated bio-activities, however, most of the researches of ceRNA were on ncRNAs synergetic with mRNAs, the exploration of ceRNA effect regulated mRNA interaction was still lack of. Besides, c/EBPa was one of the most crucial adipogenic regulators, which has been demonstrated to form a protein complex with FOXO1 to mediate AdipoQ expression. So that, we try to explore whether the ceRNA effect mediated the interaction of c/EBPa and FOXO1, and identified the key miRNAs of their ceRNA effect. In this paper, we found the ceRNA effect of c/EBPa and FOXO1 mediated their protein complex formation, furthermore regulated its transcriptional role for AdipoQ, thereby influencing pre-adipocytes adipogenesis. More importantly, we demonstrated that the miR-144 was the decisive factor that mediated the ceRNA effect of c/EBPa and FOXO1 to influence AdipoQ, thus regulated pre-adipocytes adipogenesis. This research will provide a new supplementary idea of the miRNA role in mediating coding RNA interaction that regulates pre-adipocyte adipogenesis. (c) 2022 Elsevier Inc. All rights reserved.
暂无评论