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SHED-derived exosomes ameliorate hyposalivation caused by Sjögren’s syndrome via Akt/GSK-3β/Slug-mediated ZO-1 expression

SHED-derived exosomes ameliorate hyposalivation caused by Sj?gren’s syndrome via Akt/GSK-3β/Slug-mediated ZO-1 expression

摘要:

Background::Sj?gren’s syndrome (SS) is an autoimmune disorder characterized by sicca syndrome and/or systemic manifestations. The treatment is still challenging. This study aimed to explore the therapeutic role and mechanism of exosomes obtained from the supernatant of stem cells derived from human exfoliated deciduous teeth (SHED-exos) in sialadenitis caused by SS.Methods::SHED-exos were administered to the submandibular glands (SMGs) of 14-week-old non-obese diabetic (NOD) mice, an animal model of the clinical phase of SS, by local injection or intraductal infusion. The saliva flow rate was measured after pilocarpine intraperitoneal injection in 21-week-old NOD mice. Protein expression was examined by western blot analysis. Exosomal microRNA (miRNAs) were identified by microarray analysis. Paracellular permeability was evaluated by transepithelial electrical resistance measurement.Results::SHED-exos were injected into the SMG of NOD mice and increased saliva secretion. The injected SHED-exos were taken up by glandular epithelial cells, and further increased paracellular permeability mediated by zonula occluden-1 (ZO-1). A total of 180 exosomal miRNAs were identified from SHED-exos, and Kyoto Encyclopedia of Genes and Genomes analysis suggested that the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) pathway might play an important role. SHED-exos treatment down-regulated phospho-Akt (p-Akt)/Akt, phospho-glycogen synthase kinase 3β (p-GSK-3β)/GSK-3β, and Slug expressions and up-regulated ZO-1 expression in SMGs and SMG-C6 cells. Both the increased ZO-1 expression and paracellular permeability induced by SHED-exos were abolished by insulin-like growth factor 1, a PI3K agonist. Slug bound to the ZO-1 promoter and suppressed its expression. For safer and more effective clinical application, SHED-exos were intraductally infused into the SMGs of NOD mice, and saliva secretion was increased and accompanied by decreased levels of p-Akt/Akt, p-GSK-3β/GSK-3β, and Slug and increased ZO-1 expression.Conclusion::Local application of SHED-exos in SMGs can ameliorate Sj?gren syndrome-induced hyposalivation by increasing the paracellular permeability of glandular epithelial cells through Akt/GSK-3β/Slug pathway-mediated ZO-1 expression.

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abstracts:

Background::Sj?gren’s syndrome (SS) is an autoimmune disorder characterized by sicca syndrome and/or systemic manifestations. The treatment is still challenging. This study aimed to explore the therapeutic role and mechanism of exosomes obtained from the supernatant of stem cells derived from human exfoliated deciduous teeth (SHED-exos) in sialadenitis caused by SS.Methods::SHED-exos were administered to the submandibular glands (SMGs) of 14-week-old non-obese diabetic (NOD) mice, an animal model of the clinical phase of SS, by local injection or intraductal infusion. The saliva flow rate was measured after pilocarpine intraperitoneal injection in 21-week-old NOD mice. Protein expression was examined by western blot analysis. Exosomal microRNA (miRNAs) were identified by microarray analysis. Paracellular permeability was evaluated by transepithelial electrical resistance measurement.Results::SHED-exos were injected into the SMG of NOD mice and increased saliva secretion. The injected SHED-exos were taken up by glandular epithelial cells, and further increased paracellular permeability mediated by zonula occluden-1 (ZO-1). A total of 180 exosomal miRNAs were identified from SHED-exos, and Kyoto Encyclopedia of Genes and Genomes analysis suggested that the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) pathway might play an important role. SHED-exos treatment down-regulated phospho-Akt (p-Akt)/Akt, phospho-glycogen synthase kinase 3β (p-GSK-3β)/GSK-3β, and Slug expressions and up-regulated ZO-1 expression in SMGs and SMG-C6 cells. Both the increased ZO-1 expression and paracellular permeability induced by SHED-exos were abolished by insulin-like growth factor 1, a PI3K agonist. Slug bound to the ZO-1 promoter and suppressed its expression. For safer and more effective clinical application, SHED-exos were intraductally infused into the SMGs of NOD mice, and saliva secretion was increased and accompanied by decreased levels of p-Akt/Akt, p-GSK-3β/GSK-3β, and Slug and increased ZO-1 expression.Conclusion::Local application of SHED-exos in SMGs can ameliorate Sj?gren syndrome-induced hyposalivation by increasing the paracellular permeability of glandular epithelial cells through Akt/GSK-3β/Slug pathway-mediated ZO-1 expression.

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作者: Du Zhihao [1] Wei Pan [2] Jiang Nan [3] Wu Liling [4] Ding Chong [3] Yu Guangyan [1]
作者单位: Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology amp; National Center of Stomatology amp; National Clinical Research Center for Oral Diseases amp; National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, China [1] Department of Oral Medicine, Peking University School and Hospital of Stomatology amp; National Center of Stomatology amp; National Clinical Research Center for Oral Diseases amp; National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, China [2] Center Laboratory, Peking University School and Hospital of Stomatology amp; National Center of Stomatology amp; National Clinical Research Center for Oral Diseases amp; National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, China [3] Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China [4]
期刊: 《中华医学杂志英文版》2023年136卷21期 2596-2608页 SCIMEDLINEISTICCSCDBP
栏目名称: Original Article
DOI: 10.1097/CM9.0000000000002610
发布时间: 2025-01-14
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