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Targeting the Human βc Receptor Inhibits contact Dermatitis in a Transgenic Mouse Model

JOURNAL OF INVESTIGATIVE DERMATOLOGY 2022年第4期142卷 1103-+页

作者： Yip, Kwok Ho McKenzie, Duncan Ramshaw, Hayley S. chao, Jessica Mcclure, Barbara J. Raquet, Elmar Kraushaar, Timo Roeder, Joachim Maxwell, Mhairi Alhamdoosh, Monther Hammet, Andrew Fong, Jia Hong Zeglinski, Kathleen Monaghan, Katherine Pant, Harshita Grimbaldeston, Michele A. Vairo, Gino Wilson, Nicholas J. Owczarek, catherine M. Hercus, Timothy R. Lopez, Angel F. Tumes, Damon J. SA Pathol Ctr Canc Biol Bradley BldgNorth Terrace Adelaide SA Australia Univ South Australia Bradley BldgNorth Terrace Adelaide SA Australia CSL Behring Res & Dev Marburg Germany CSL Ltd Mol Sci & Biotechnol Inst Bio21 Res & Dev Parkville Vic Australia Genentech Inc OMNI Biomarker Dev San Francisco CA 94080 USA Univ Adelaide Fac Hlth & Med Sci Adelaide Med Sch Adelaide SA Australia

Allergic contact 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 hematopoietic cell-specific expression of human beta(c) instead of mouse beta(c). Human beta(c) receptor transgenic cells 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.

关键词： AcD allergic contact dermatitis cHS contact hypersensitivity hβ c human β c hβ c Tg human βc receptor transgenic STAT5 signal transducer and activator of transcription 5 WT wild type β c beta common

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Endoplasmic reticulum stress modulates the fate of lung resident mesenchymal stem cell to myofibroblast via c/EBP homologous protein during pulmonary fibrosis

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STEM cELL RESEARcH & THERAPY 2022年第1期13卷 1页

作者： Yang, Xiaoyu Sun, Wei Jing, Xiaoyan Zhang, Qian Huang, Hui Xu, Zuojun Chinese Acad Med Sci & Peking Union Med Coll Dept Resp & Crit Care Med Peking Union Med Coll Hosp 1 Shuai Fu Yuan St Beijing 100730 Peoples R China Sichuan Acad Med Sci Dept Resp & Crit Care Med Sichuan Prov Peoples Hosp Chengdu Peoples R China

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.

关键词： Lung resident mesenchymal stem cell Endoplasmic reticulum stress c EBP homologous protein Pulmonary fibrosis

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Modeling primary ovarian insufficiency-associated loci in c. elegans identifies novel pathogenic allele of MSH5

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JOURNAL OF ASSISTED REPRODUcTION AND GENETIcS 2022年第6期39卷 1255-1260页

作者： Macaisne, Nicolas Sol Touzon, Maria Rajkovic, Aleksander Yanowitz, Judith L. Magee Womens Res Inst Pittsburgh PA 15217 USA Univ Paris Inst Jacques Monod CNRS F-75013 Paris France Hosp Pediatr Garrahan CONICET Res Unit Garrahan Endocrinol Dept RA-1245 Buenos Aires DF Argentina Univ Calif San Francisco Dept Pathol Obstet Gynecol & Reprod Sci San Francisco CA 94158 USA Univ Pittsburgh Dept Obstet Gynecol & Reprod Sci Pittsburgh PA 15213 USA Univ Pittsburgh Dept Dev Biol Pittsburgh PA 15213 USA Univ Pittsburgh Dept Microbiol & Mol Genet Pittsburgh PA 15213 USA Univ Pittsburgh Hillman Canc Ctr Pittsburgh PA 15213 USA Magee Womens Res Inst 204 Craft Ave Pittsburgh PA 15213 USA

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.

关键词： POI MSH5 crossover Infertility c elegans Meiosis

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Traits influence dinoflagellate c:N:P

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EUROPEAN JOURNAL OF PHYcOLOGY 2022年第2期57卷 154-165页

作者： carnicer, Olga Irwin, Andrew J. Finkel, Zoe V. Dalhousie Univ Dept Oceanog Halifax NS Canada Dalhousie Univ Dept Math & Stat Halifax NS Canada

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.

关键词： c N P dinoflagellate size stoichiometry thecate toxins

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Mimicking human riboflavin responsive neuromuscular disorders by silencing flad-1 gene in c. elegans: Alteration of vitamin transport and cholinergic transmission

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IUBMB LIFE 2022年第7期74卷 672-683页

作者： Leone, Piero Tolomeo, Maria Piancone, Elisabetta Puzzovio, Pier Giorgio De Giorgi, carla Indiveri, cesare Di Schiavi, Elia Barile, Maria Univ Bari Dept Biosci Biotechnol & Biopharmaceut Bari Italy Hebrew Univ Jerusalem Fac Med Sch Pharm Inst Drug ResPharmacol & Expt Therapeut Unit Jerusalem Israel Univ Calabria Dept DiBEST Biol Ecol Sci Terra Unit Biochem & Mol Biotechnol Arcavacata Di Rende Italy CNR Inst Biosci & Bioresources IBBR Naples Italy

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.

关键词： c elegans ETFDH flad-1 LSMFLAD rft-1 riboflavin therapy RNA interference

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Poly I:c promotes malate to enhance innate immune response against bacterial infection

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FISH & SHELLFISH IMMUNOLOGY 2022年 131卷 172-180页

作者： Guo, chang Ye, Jing-zhou Song, Min Peng, Xuan-xian Li, Hui Sun Yat Sen Univ Sch Life Sci State Key Lab Biocontrol Southern Marine Sci & Engn Guangdong Lab Zhuhai Guangzhou 510006 Peoples R China Qingdao Natl Lab Marine Sci & Technol Lab Marine Fisheries Sci & Food Prod Proc Qingdao 266071 Peoples R China Longyan Univ Sch Life Sci Fujian Prov Key Lab Prevent & Control Anim Infect Key Lab Prevent Vet Med & Biotechnol Longyan 364012 Peoples R China

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.

关键词： Poly I c The TcA cycle Malate Innate immunity Bacteria Vibrio alginolyticus Infection

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Scorpion venom heat-resistant synthetic peptide protects dopamine neurons against 6-hydroxydopamine neurotoxicity in c. elegans

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BRAIN RESEARcH BULLETIN 2022年 190卷 195-203页

作者： Guo, Song-Yu Guan, Rong-Xiao chi, Xiao-Dong Yue-Zhang, Wei Sui, Ao-Ran Zhao, Wei Supratik, Kundu Yang, Jin-Yi Zhao, Jie Li, Shao Coll Basic Med Sci Dept Physiol Liaoning Prov Key Lab Cerebral Dis Dalian Peoples R China Dalian Med Univ Natl Local Joint Engn Res Ctr Drug Research& Dev R Dalian 116044 Liaoning Peoples R China Dalian Med Univ Affiliated Dalian Friendship Hosp Dept Neurol Dalian Peoples R China Dalian Med Univ Affiliated Dalian Friendship Hosp Dept Urol Dalian Peoples R China

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.

关键词： c elegans 1 SVHRSP 2 Parkinson&rsquo s disease3 6-hydroxydopamine4

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The prognostic significance of HIST1H3B/c and H3F3A K27M mutations in diffuse midline gliomas is influenced by patient age

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JOURNAL OF NEURO-ONcOLOGY 2022年第3期158卷 405-412页

作者： Vuong, Huy Gia Tam N M Ngo Hieu Trong Le Dunn, Ian F. Oklahoma Univ Dept Neurosurg Hlth Sci Ctr Oklahoma City OK 73104 USA Pham Ngoc Thach Univ Med Fac Med Ho Chi Minh City 700000 Vietnam Univ Med & Pharm Ho Chi Minh City Dept Pathol Ho Chi Minh City 700000 Vietnam

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.

关键词： Histone H3 c Midline glioma

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NanoBRET in c. elegans illuminates functional receptor interactions in real time

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BMc MOLEcULAR AND cELL BIOLOGY 2022年第1期23卷 1页

作者： Gross, Victoria Elisabeth Gershkovich, Miron Mikhailowitsch Schoeneberg, Torsten Kaiser, Anette Proemel, Simone Univ Leipzig Med Fac Rudolf Schonheimer Inst Biochem D-04103 Leipzig Germany Heinrich Heine Univ Dusseldorf Dept Biol Inst Cell Biol D-40225 Dusseldorf Germany Univ Leipzig Fac Life Sci Inst Biochem D-04103 Leipzig Germany

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.

关键词： NanoBRET c elegans Receptor-ligand interaction Enhanced bystander BRET

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MiR-144 regulates adipogenesis by mediating formation of c/EBPa-FOXO1 protein complex

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BIOcHEMIcAL AND BIOPHYSIcAL RESEARcH cOMMUNIcATIONS 2022年 612卷 126-133页

作者： Lin, Weimin Wen, Xianyu Li, Xuexin chen, Lei Wei, Wei Zhang, Lifan chen, Jie Nanjing Agr Univ Coll Anim Sci & Technol Nanjing 210095 Jiangsu Peoples R China

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.

关键词： c EBP a FOXO1 miR-144 AdipoQ Adipogenesis

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