INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
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2019
·Vol. 43
·期 5
·2103-2117
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IF 2.928
Nan Miao,Yuanbo Zhan,Yingying Xu,Haoze Yuan,Chunlin Qin,Feng Lin,Xiaohua Xie,Sen Mu,Mengtong Yuan,Haibin Mu,Shouli Guo,Ying Li,Bin Zhang
Family with sequence similarity 20‑member C (FAM20C), a recently characterized Golgi kinase, performs numerous biological functions by phosphorylating more than 100 secreted proteins. However, the role of FAM20C in the salivary glands remains undefined. The present study demonstrated that FAM20C is mainly located in the cytoplasm of duct epithelial cells in the salivary glands. Fam20cf/f; Mmtv‑Cre mice were created in which Fam20c was inactivated in the salivary gland cells and observed that the number of ducts and the ductal cross‑sectional area increased significantly, while the number of acinar cells was reduced. The granular convoluted tubules (GCTs) exhibited an accumulation of aberrant secretory granules, along with a reduced expression and altered distribution patterns of β nerve growth factor, α‑amylase and bone morphogenetic protein (BMP) 4. This abnormality suggested that the GCT cells were immature and exhibited defects in developmental and secretory functions. In accordance with the morphological alterations and the reduced number of acinar cells, FAM20C deficiency in the salivary glands significantly decreased the salivary flow rate. The Na+, Cl– and K+ concentrations in the saliva were all significantly increased due to dysfunction of the ducts. Furthermore, Fam20c deficiency significantly increased BMP2 and BMP7 expression, decreased BMP4 expression, and attenuated the canonical and noncanonical BMP signaling pathways in the salivary glands. Collectively, the results of the present study demonstrate that FAM20C is a key regulator of acinar and duct structure and duct maturation and provide a novel avenue for investigating novel therapeutic targets for oral diseases including xerostomia.
研究领域:
分子生物学
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发育生物学
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口腔疾病
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DOI
PubMed
高影响因子
INFLAMMATION RESEARCH
·
2025
·Vol. 74
·期 1
·1-19
·
IF 5.4
Weng Xiuhong,Wang Simin,Wang Qing,Wei Mingbo,Cheng Bo
Background Primary Sjögren’s syndrome (pSS) is an autoimmune disease characterized by xerostomia and autoimmune sialadenitis. Interferon-γ (IFN-γ) induces ferroptosis in salivary gland epithelial cells (SGECs), leading to salivary gland (SG) hypofunction. We previously demonstrated the beneficial effects of melatonin (MLT) in alleviating SG dysfunction and inflammation in a pSS animal model. However, the precise underlying mechanism remains unclear. Methods Female NOD/ltj and ICR mice were used as the pSS mouse model and control group, respectively. MLT was administered via intraperitoneal injection to NOD/ltj mice to detect its effect on ferroptosis in SGs. Primary human SGECs and A253 cells were treated with IFN-γand ferroptosis inducers, with or without MLT. Results Exogenous MLT alleviated pathological SG alterations and promoted saliva production through inhibiting SGEC ferroptosis. MLT inhibited SGEC ferroptosis induced by IFN-γ and ferroptosis inducers via nuclear factor erythroid 2-related factor 2/heme oxygenase-1/glutathione peroxidase 4 (NRF2/HO-1/GPX4) pathway activation. Moreover, MLT suppressed the nuclear factor-kappa B (NF-κB) pathway, which is triggered by ferroptosis in SGECs. Nevertheless, ML385-mediated NRF2 inhibition abrogated the antiferroptotic protective effects of MLT on SGECs. Conclusions MLT inhibits SGEC ferroptosis through NRF2/HO-1/GPX4 pathway activation and thus attenuates ferroptosis-triggered NF-κB activity. Melatonin represents a potential therapeutic approach for pSS owing to its capacity to regulate ferroptosis.
研究领域:
免疫学
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细胞生物学
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医学
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PubMed
高影响因子
JOURNAL OF ORAL PATHOLOGY & MEDICINE
·
2017
·Vol. 47
·期 2
·144-151
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IF 2.043
Jin Hou,Fangyuan Wang,Xiaohao Liu,Mengyang Song,Xuemin Yin
Objectives Tumor-derived exosomes (TDE) have been shown to participate in different steps of the dissemination of cancer cells. However, the role of salivary adenoid cystic carcinoma-derived (SACC-derived) exosomes had not been documented in SACC. The study aims to explore the functions of SACC-derived TDE in SACC progression and investigate potential mechanisms. Methods Salivary adenoid cystic carcinoma cell line SACC-83 was used to generate TDE. Afterward, SACC-83 or HUVECs were cocultured with or without TDE. Tumor migration, tumor invasion, and endothelial permeability were examined by wound healing assay, tumor invasion assay, endothelial permeability assay, and tumor cell transendothelial migration assay, respectively. Moreover, the expression levels of cell junction-related proteins were examined by qRT-PCR and Western blot. Results Salivary adenoid cystic carcinoma -83-derived exosomes were taken up by their host cells. Meanwhile, TDE increased migration and invasion capacity of SACC-83 cells and enhanced endothelial cell permeability. Furthermore, we demonstrated that the expression of cell junction-related proteins (Claudins and ZO-1) was downregulated, which is presumably involved in the TDE-mediated promotion of migration, invasion, and metastasis. Conclusion The results suggested that SACC cell-derived exosomes were loaded with individual components that could enhance invasiveness and induce microenvironment changes, thus promoting SACC aggression.
研究领域:
肿瘤学
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细胞生物学
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癌症研究
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PubMed
高影响因子
Experimental and Therapeutic Medicine
·
2021
·Vol. 22
·期 2
·1-11
·
IF 2.447
Jingli Zhang,Lingling Zhu,Hong Shi,Huizhe Zheng
Previous studies have demonstrated that microRNAs (miRNAs/miRs) serve a vital role in the pathogenesis of Sjögren's syndrome (SS). The present study aimed to investigate the role of miR‑155‑5p in SS and determine its underlying molecular mechanism. An inflammatory lesion model was established by stimulating salivary gland epithelial cells (SGECs) with interferon‑γ (IFN‑γ). The apoptosis of SGECs was measured by using flow cytometry. Levels of proinflammatory factors were detected by reverse transcription‑quantitative PCR and ELISA, respectively. Immunofluorescence was used for p65 staining. Dual‑luciferase reporter assay was performed to verify the interaction between miR‑155‑5p and arrestin β2 (ARRB2). The protein levels in the NF‑κB signaling pathway were assessed by western blotting. The results of the present study demonstrated that treatment with IFN‑γ increased miR‑155‑5p expression, in addition to inducing apoptosis and inflammation in SGECs. Furthermore, overexpression of miR‑155‑5p promoted IFN‑γ‑induced apoptosis and inflammation in SGECs. Overexpression of miR‑155‑5p also increased Bax protein expression, enzyme activities of caspase 3 and caspase 9, release of inflammatory cytokines interleukin‑6 and tumor necrosis factor‑α, and decreased Bcl‑2 protein expression in IFN‑γ‑treated SGECs. By contrast, all of the effects aforementioned were reversed following miR‑155‑5p knockdown. These results demonstrated that miR‑155‑5p activated the NF‑κB signaling pathway, where treatment with the NF‑κB inhibitor, pyrrolidine dithiocarbamate, reversed the effects of miR‑155‑5p overexpression on the inflammatory factors in IFN‑γ‑induced SGECs. miR‑155‑5p was demonstrated to target ARRB2 and negatively regulated its expression levels, such that overexpression of ARRB2 reversed the effects of miR‑155‑5p overexpression on the inflammatory response, apoptosis and the NF‑κB signaling pathway in IFN‑γ‑treated SGECs. Collectively, results from the present study suggest that miR‑155‑5p may activate the NF‑κB signaling pathway by negatively regulating ARRB2 to promote salivary gland damage during SS pathogenesis. This suggests that miR‑155‑5p may serve to be a potential target for the treatment of SS.
研究领域:
免疫学
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分子生物学
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细胞生物学
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病理学
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PubMed
高影响因子
OncoTargets and Therapy
·
2019
·
IF 3.046
Chao Ma,Tao Gao,Jun Ju,Yi Zhang,Qianwei Ni,Yun Li,Zhenyan Zhao,Juan Chai,Xiangming Yang,Moyi Sun
Purpose Perineural invasion (PNI) is reported to correlate with local recurrence and poor prognosis of salivary adenoid cystic carcinoma (SACC). However, the pathogenesis of PNI remains unclear. The aims of this study were to investigate the correlation between sympathetic innervation and SACC PNI and to elucidate how the sympathetic neurotransmitter norepinephrine (NE) regulates the PNI process. Materials and methods Sympathetic innervation and β2-adrenergic receptor (β2-AR) expression in SACC tissues were evaluated by immunohistochemistry. The NE concentrations in SACC tissues and dorsal root ganglia (DRG) coculture models were measured by ELISA. β2-AR expression in SACC cells was detected by performing quantitative real-time polymerase chain reaction (qRT-PCR) and immunofluorescence assay. SACC cells were treated with NE, the nonselective α-AR blocker phentolamine, the β2-AR antagonist ICI118,551, or were transfected with β2-AR small interfering RNA (siRNA). Proliferation was evaluated in methyl thiazolyl tetrazolium assay, and migration was evaluated in Transwell assay and wound-healing assay. PNI was tested through both Transwell assay and a DRG coculture model. The expressions of epithelial–mesenchymal transition (EMT) markers and matrix metalloproteinases (MMPs) were measured by performing qRT-PCR and Western blot assay. Results Sympathetic innervation and β2-AR were highly distributed in SACC tissues and correlated positively with PNI ( P =0.035 and P =0.003, respectively). The sympathetic neurotransmitter NE was overexpressed in SACC tissues and DRG coculture models. Exogenously added NE promoted proliferation, migration, and PNI of SACC cells via β2-AR activation. NE/β2-AR signaling may promote proliferation, migration, and PNI by inducing EMT and upregulating MMPs. However, β2-AR inhibition with either an antagonist or siRNA abrogated NE-induced PNI. Conclusion Collectively, our findings reveal the supportive role of sympathetic innervation in the pathogenesis of SACC PNI and suggest β2-AR as a potential therapeutic target for treating PNI in SACC.
研究领域:
肿瘤学
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神经科学
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分子生物学
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PubMed
高影响因子
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