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1.
J Innate Immun ; 16(1): 397-412, 2024.
Article de Anglais | MEDLINE | ID: mdl-39134014

RÉSUMÉ

INTRODUCTION: MDM2 is known as the primary negative regulator of p53, and MDM2 promotes lung cancer fibrosis and lung injury through p53-dependent and p53-independent pathways. However, the mechanism by which MDM2 influences the pathogenesis of asthma is unknown. In this study, we investigated the function of MDM2 in lung epithelial cells in type 2 lung inflammation. METHODS: We used type II alveolar epithelial cell-specific heterozygous knockout of Mdm2 mice to validate its function. Then papain-induced asthma model was established, and changes in inflammation were observed by measuring immunohistochemistry and flow cytometry analysis. RESULTS: In this study, we knockdown the mouse Mdm2 gene in type 2 alveolar epithelial cells. We demonstrated that heterozygous Mdm2 gene-deleted mice were highly susceptible to protease allergen papain-induced pulmonary inflammation characterized by increased ILC2 numbers, IL-5 and IL-13 cytokine levels, and lung pathology. A mechanistic study showed that following the decreased expression of Mdm2 in lung epithelial cells and A549 cell line, p53 was overactivated, and the expression of its downstream genes p21, Puma, and Noxa was elevated, which resulted in apoptosis. After Mdm2 knockdown, the mRNA expression of inflammation-related gene IL-25, HMGB1, and TNF-α were increased, which further amplified the downstream ILC2 response and lung inflammation. CONCLUSION: These results indicate that Mdm2 maintains the homeostasis of lung epithelial cells by targeting P53 and regulates the function of lung epithelial cells under type 2 lung inflammation.


Sujet(s)
Asthme , Homéostasie , Souris knockout , Protéines proto-oncogènes c-mdm2 , Protéine p53 suppresseur de tumeur , Animaux , Protéines proto-oncogènes c-mdm2/métabolisme , Protéines proto-oncogènes c-mdm2/génétique , Protéine p53 suppresseur de tumeur/métabolisme , Protéine p53 suppresseur de tumeur/génétique , Souris , Humains , Asthme/immunologie , Asthme/métabolisme , Asthme/induit chimiquement , Asthme/génétique , Cellules A549 , Modèles animaux de maladie humaine , Apoptose , Cellules épithéliales/métabolisme , Pneumocytes/métabolisme , Papaïne , Souris de lignée C57BL , Pneumopathie infectieuse/immunologie , Pneumopathie infectieuse/métabolisme
2.
Cell Mol Immunol ; 20(7): 794-807, 2023 07.
Article de Anglais | MEDLINE | ID: mdl-37217797

RÉSUMÉ

Interleukin-33 (IL-33) is a crucial nuclear cytokine that induces the type 2 immune response and maintains immune homeostasis. The fine-tuned regulation of IL-33 in tissue cells is critical to control of the type 2 immune response in airway inflammation, but the mechanism is still unclear. Here, we found that healthy individuals had higher phosphate-pyridoxal (PLP, an active form of vitamin B6) concentrations in the serum than asthma patients. Lower serum PLP concentrations in asthma patients were strongly associated with worse lung function and inflammation. In a mouse model of lung inflammation, we revealed that PLP alleviated the type 2 immune response and that this inhibitory effect relied on the activity of IL-33. A mechanistic study showed that in vivo, pyridoxal (PL) needed to be converted into PLP, which inhibited the type 2 response by regulating IL-33 stability. In mice heterozygous for pyridoxal kinase (PDXK), the conversion of PL to PLP was limited, and IL-33 levels were increased in the lungs, aggravating type 2 inflammation. Furthermore, we found that the mouse double minute 2 homolog (MDM2) protein, an E3 ubiquitin-protein ligase, could ubiquitinate the N-terminus of IL-33 and sustain IL-33 stability in epithelial cells. PLP reduced MDM2-mediated IL-33 polyubiquitination and decreased the level of IL-33 through the proteasome pathway. In addition, inhalation of PLP alleviated asthma-related effects in mouse models. In summary, our data indicate that vitamin B6 regulates MDM2-mediated IL-33 stability to constrain the type 2 response, which might help develop a potential preventive and therapeutic agent for allergy-related diseases.


Sujet(s)
Asthme , Vitamine B6 , Souris , Animaux , Vitamine B6/pharmacologie , Vitamine B6/métabolisme , Interleukine-33 , Pyridoxal , Inflammation , Modèles animaux de maladie humaine , Homéostasie
3.
Nat Immunol ; 23(7): 1021-1030, 2022 07.
Article de Anglais | MEDLINE | ID: mdl-35794369

RÉSUMÉ

Interleukin-33 (IL-33), an epithelial cell-derived cytokine that responds rapidly to environmental insult, has a critical role in initiating airway inflammatory diseases. However, the molecular mechanism underlying IL-33 secretion following allergen exposure is not clear. Here, we found that two cell events were fundamental for IL-33 secretion after exposure to allergens. First, stress granule assembly activated by allergens licensed the nuclear-cytoplasmic transport of IL-33, but not the secretion of IL-33. Second, a neo-form murine amino-terminal p40 fragment gasdermin D (Gsdmd), whose generation was independent of inflammatory caspase-1 and caspase-11, dominated cytosolic secretion of IL-33 by forming pores in the cell membrane. Either the blockade of stress granule assembly or the abolishment of p40 production through amino acid mutation of residues 309-313 (ELRQQ) could efficiently prevent the release of IL-33 in murine epithelial cells. Our findings indicated that targeting stress granule disassembly and Gsdmd fragmentation could reduce IL-33-dependent allergic airway inflammation.


Sujet(s)
Allergènes , Interleukine-33 , Protéines de liaison aux phosphates/métabolisme , Perforines/métabolisme , Animaux , Caspase-1/métabolisme , Inflammation , Interleukine-1 bêta/métabolisme , Interleukine-33/génétique , Interleukine-33/métabolisme , Protéines et peptides de signalisation intracellulaire/génétique , Protéines et peptides de signalisation intracellulaire/métabolisme , Souris , Peptide hydrolases/métabolisme , Granules de stress
4.
Int J Syst Evol Microbiol ; 69(5): 1390-1397, 2019 May.
Article de Anglais | MEDLINE | ID: mdl-30816842

RÉSUMÉ

Two Gram-stain-negative, aerobic, non-spore forming and rod-shaped bacterial strains, designated DHOM06T and 7MK8-2T, were isolated from forest soil sampled at Dinghushan Biosphere Reserve, Guangdong Province, PR China. Strain DHOM06T grew at 12-37 °C (optimum, 28-33 °C), pH 4.5-7.5 (pH 5.5) and in the presence of 0-0.5 % NaCl (w/v); while strain 7MK8-2T grew at 12-42 °C (28-33 °C), pH 4.0-8.5 (pH 4.5-5.5) and in the presence of 0-1.0 % NaCl (w/v). Strains DHOM06T and 7MK8-2T each has a 16S rRNA gene sequence similarity of 97.1-98.9 % as well as 97.4-97.9 % to Trinickia strains, respectively. In the 16S rRNA gene sequence phylogram, both strains and all five currently described Trinickia species formed a clade but they were all distinct from each other. The average nucleotide identity and digital DNA-DNA hybridization values for strains DHOM06T and 7MK8-2T and all Trinickia species were in the range of 77.4-82.6 % and 21.7-26.2 %, respectively. The DNA G+C content of DHOM06T and 7MK8-2T was 63.2 and 63.5 mol%, respectively, based on total genome calculations. These two strains contained ubiquinone 8 as the major respiratory quinone and C16 : 0, C17 : 0cyclo, C19 : 0cyclo ω8c, summed feature 3 (C16 : 1ω7c/C16 : 1ω6c) and summed feature 8 (C18 : 1ω7c/C18 : 1ω6c) as the major cellular fatty acids. The major polar lipids of DHOM06T and 7MK8-2T were phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol. On the basis of phenotypic, chemotaxonomic, phylogenetic and genomic analysis data, strains DHOM06T and 7MK8-2T represent two novel species of the genus Trinickia, for which the names Trinickia dinghuensis sp. nov. (type strain DHOM06T=GDMCC 1.1280T=LMG 30259T) and Trinickia fusca sp. nov. (type strain 7MK8-2T=GDMCC 1.1449T=KCTC 62469T) are proposed.


Sujet(s)
Burkholderiaceae/classification , Forêts , Phylogenèse , Microbiologie du sol , Techniques de typage bactérien , Composition en bases nucléiques , Burkholderiaceae/isolement et purification , Chine , ADN bactérien/génétique , Acides gras/composition chimique , Hybridation d'acides nucléiques , Phospholipides/composition chimique , ARN ribosomique 16S/génétique , Analyse de séquence d'ADN , Ubiquinones/composition chimique
5.
Int J Syst Evol Microbiol ; 68(6): 1963-1968, 2018 Jun.
Article de Anglais | MEDLINE | ID: mdl-29676723

RÉSUMÉ

A novel Gram-stain-negative, aerobic, non-spore-forming, motile and rod-shaped bacterial strain, designated HM451T, was isolated from forest soil sampled at the Dinghushan Biosphere Reserve, Guangdong Province, PR China (112° 31' E 23° 10' N). It grew optimally at 28 °C, pH 5.0-6.0 and in the presence of 0-2.5 % (w/v) NaCl on R2A medium. Strain HM451T was closely related to Paraburkholderia mimosarum NBRC 106338T (98.6 % 16S rRNA gene sequence similarity), Paraburkholderia heleia NBRC 101817T (98.4 %) and Paraburkholderia silvatlantica SRMrh-20T (98.0 %). The 16S rRNA gene sequence analysis showed that strain HM451T and the three closely related strains formed a clade within the genus Paraburkholderia, but was clearly separated from the established species. The DNA-DNA relatedness value between strain HM451T and its phylogenetically closest relative, P. mimosarum NBRC 106338T, was much lower than 70 %. Strain HM451T contained ubiquinone 8 as the major respiratory quinone. Major fatty acids were C16 : 0, C17 : 0cyclo and summed feature 8 (C18 : 1ω7c and/or C18 : 1ω6c). The DNA G+C content of strain HM451T was 65.4 mol%. The major polar lipids were phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, two unidentified aminophospholipids, one unidentified aminolipid and a polar lipid. The phenotypic, chemotaxonomic and phylogenetic data showed that strain HM451T represents a novel species of the genus Paraburkholderia, for which the name Paraburkholderia caseinilytica sp. nov. is proposed. The type strain is HM451T (=GDMCC 1.1190T=LMG 30092T).


Sujet(s)
Burkholderiaceae/classification , Forêts , Phylogenèse , Microbiologie du sol , Techniques de typage bactérien , Composition en bases nucléiques , Burkholderiaceae/génétique , Burkholderiaceae/isolement et purification , Chine , ADN bactérien/génétique , Acides gras/composition chimique , Hybridation d'acides nucléiques , ARN ribosomique 16S/génétique , Analyse de séquence d'ADN , Ubiquinones/composition chimique
6.
Drug Dev Ind Pharm ; 39(11): 1638-43, 2013 Nov.
Article de Anglais | MEDLINE | ID: mdl-24087855

RÉSUMÉ

The solid state properties and dissolution behavior of binary systems of cefdinir (CEF) with hydroxypropyl-ß-cyclodextrin (HP-ß-CD) were investigated. CEF-HP-ß-CD interaction in the solution state was studied by phase-solubility analysis and demonstrates the ability of HP-ß-CD to complex with CEF giving A(L) type profile with 65.28 ± 1.3 M⁻¹ stability constant. The freeze drying technique was adopted to prepare binary systems of CEF with HP-ß-CD in 1:1 molar ratio. The solid inclusion was characterized by fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X-ray powder diffractometry (XRD), and scanning electron microscopy (SEM). Aqueous solubility of CEF-HP-ß-CD inclusion complex was 2.36-fold of pure CEF. The dissolution profiles of inclusion complexes were determined and compared with those of CEF alone and their physical mixtures. The dissolution rate of inclusion complex was superior than the CEF alone. These approaches indicated that CEF was able to form an inclusion complex with HP-ß-CD, and the inclusion compounds exhibited different spectroscopic features and properties.


Sujet(s)
Antibactériens/composition chimique , Céphalosporines/composition chimique , Excipients/composition chimique , Cyclodextrines bêta/composition chimique , 2-Hydroxypropyl-beta-cyclodextrin , Calorimétrie différentielle à balayage , Cefdinir , Phénomènes chimiques , Préparation de médicament , Stabilité de médicament , Lyophilisation , Interactions hydrophobes et hydrophiles , Cinétique , Microscopie électronique à balayage , Taille de particule , Transition de phase , Diffraction sur poudre , Agents séquestrants/composition chimique , Solubilité , Spectroscopie infrarouge à transformée de Fourier , Propriétés de surface
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