Chronic stress accelerates ligature-induced periodontitis by suppressing glucocorticoid receptor-α signaling.

Periodontitis is a common chronic inflammatory disease. Recent studies have shown that chronic stress (CS) might modulate periodontal disease, but there are few models of CS-induced periodontitis, and the underlying mechanisms are unclear. The present study established a rat model of periodontitis associated with CS induced by nylon thread ligatures. The severity of periodontitis was evaluated in this model by radiographic and pathological examination. The inflammatory reaction indicated by the elevated serum levels of interleukin (IL)-1ß, IL-6 and IL-8 was assessed by enzyme-linked immunosorbent assay. Toll-like receptor-4 (TLR4) and glucocorticoid receptor-α (GR-α) expressions were detected by reverse transcriptase-PCR and western blotting. Open-field tests and serum corticosterone were used to evaluate CS. The results showed that CS induced behavioral changes and increased corticosterone levels of the animals with periodontitis. CS stimulation markedly increased alveolar bone loss, periodontal pocket depth and the number of plaques. It also enhanced the inflammatory reaction. These results suggest that CS accelerated the ligature-induced pathological changes associated with periodontitis. Further analysis of the mechanisms involved showed that GR-α expression was significantly downregulated in periodontal tissues of the animals undergoing CS. Blocking GR-α signaling in lipopolysaccharide and corticosteroid-treated human periodontal ligament fibroblast cells in vitro significantly upregulated the expression of p-Akt (protein kinase B) and TLR4, promoted nuclear factor-κB activity and increased levels of IL-1ß, IL-6 and IL-8. This research suggests that CS might accelerate the pathological progression of periodontitis by a GR-α signaling-mediated inflammatory response and that this may be a potential therapeutic target for the treatment of periodontal disease, particularly in patients with CS.

Chronic stress enhances progression of periodontitis via α1-adrenergic signaling: a potential target for periodontal disease therapy.

This study assessed the roles of chronic stress (CS) in the stimulation of the sympathetic nervous system and explored the underlying mechanisms of periodontitis. Using an animal model of periodontitis and CS, the expression of tyrosine hydroxylase (TH) and the protein levels of the α1-adrenergic receptor (α1-AR) and ß2-adrenergic receptor (ß2-AR) were assessed. Furthermore, human periodontal ligament fibroblasts (HPDLFs) were stimulated with lipopolysaccharide (LPS) to mimic the process of inflammation. The proliferation of the HPDLFs and the expression of α1-AR and ß2-AR were assessed. The inflammatory-related cytokines interleukin (IL)-1ß, IL-6 and IL-8 were detected after pretreatment with the α1/ß2-AR blockers phentolamine/propranolol, both in vitro and in vivo. Results show that periodontitis under CS conditions enhanced the expression of TH, α1-AR and ß2-AR. Phentolamine significantly reduced the inflammatory cytokine levels. Furthermore, we observed a marked decrease in HPDLF proliferation and the increased expression of α1-ARfollowing LPS pretreatment. Pretreatment with phentolamine dramatically ameliorated LPS-inhibited cell proliferation. In addition, the blocking of α1-ARsignaling also hindered the upregulation of the inflammatory-related cytokines IL-1ß, IL-6 and IL-8. These results suggest that CS can significantly enhance the pathological progression of periodontitis by an α1-adrenergic signaling-mediated inflammatory response. We have identified a potential therapeutic target for the treatment of periodontal disease, particularly in those patients suffering from concurrent CS.

Overexpression of FOXM1 predicts poor prognosis and promotes cancer cell proliferation, migration and invasion in epithelial ovarian cancer.

BACKGROUND: The Forkhead box M1 (FOXM1), an important regulator of cell differentiation and proliferation, is overexpressed in a number of aggressive human carcinomas. The purpose of this study was to examine the expression levels of FOXM1 in epithelial ovarian cancer (EOC), to identify the relationship between FOXM1 expression and patient survival, and to investigate the role of FOXM1 in human ovarian cancer development. METHODS: Immunohistochemical analysis for FOXM1 was performed in a total of 158 ovarian tissue specimens, all with linked clinical outcome data. Kaplan-Meier method and Cox proportional hazards analysis were used to relate FOXM1 expression to clinicopathological variables and to progression-free survival (PFS) and overall survival (OS). In vitro studies were performed to determine the function of FOXM1 in cell proliferation, migration and invasion in EOC cells using pcDNA3.1-FOXM1 and FOXM1 shRNA. RESULTS: Elevated FOXM1 levels were associated with lymph node metastasis (P = 0.009), but not with age, FIGO stage, histological grade and histological type. Patients with high expression of FOXM1 had poorer PFS (P = 0.0001) and OS (P < 0.0001) than patients with low expression of FOXM1. Furthermore, multivariate analyses indicated that FOXM1 positivity was an independent prognostic factor for PFS (P = 0.046) and OS (P = 0.022), respectively. Overexpression of FOXM1 increased expression and activity of matrix metalloproteinase-2 (MMP-2), MMP-9 and vascular endothelial growth factor-A (VEGF-A), and cancer cell proliferation, migration and invasion of HO-8910 cells, whereas knockdown of FOXM1 reduced expression and activity of MMP-2, MMP-9 and VEGF-A, and cancer cell proliferation, migration and invasion of HO-8910 PM cells. CONCLUSIONS: Our results suggest that FOXM1 expression is likely to play important roles in EOC development and progression. FOXM1 expression is a potential prognostic factor for PFS and OS, and it could be a novel treatment target in EOC patients.

Icariin enhances the healing of rapid palatal expansion induced root resorption in rats.

Icariin has been reported to enhance bone healing and treat osteoporosis. In this study, we examined the effect of Icariin on rapid palatal expansion induced root resorption in rats. Our hypothesis is that Icariin can enhance the healing of rapid palatal expansion induced root resorption. Forty-eight male Wistar rats were divided randomly and equally into three groups (n=16 rats each). The rats were untreated (negative control) or treated with rapid palatal expansion without (positive control) or with Icariin at 2.5 mg/kg day (Icariin-treated groups). An initial force of 50×g was applied to the areas between the right and left upper first molars of the rats for 21 days. Eight rats were randomly chosen from each group, and the root resorption index (RRI) was determined with scanning electron microscopy (SEM). Upper first molar-centered buccal- lingual tissue slices were generated from the upper first molars and peridentium of the remaining eight rats from each group. Specimen slices were analyzed with HE and tararate-resistant acid phosphatase staining, osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-B ligand (RANKL) immunohistochemistry, and optical microscopy. Analyses of cell number, densitometry, and one-way analysis of variance were performed. The Icariin-treated groups displayed decreased RRI values, decreased osteoclast numbers and activity levels, and increased OPG/RANKL expression ratios. High-power SEM revealed reparative cementum in the Icariin-treated samples. Icariin regulates osteoclast differentiation via the OPG/RANKL ratio, evoking a reparative effect on rapid palatal expansion induced root resorption in rats.

[Protective effect of resveratrol on apoptosis of human periodontal ligament cells in vitro].

OBJECTIVE: To investigate the effects of resveratrol (RES) on apoptosis of human periodontal ligament cells (HPLC). METHODS: HPLC were subjected to oxidative injury induced by H2O2 for 24 h after pretreatment with different concentration of RES. HPLC were then divided into the control, model, vector, RES 1, 10, 30, 50 micromol/L treatment group. The viability of the HPLC was determined by methyl thiazolyl tetrazolium (MTT) method. Lactate dehydrogenase (LDH) rate and malondialdehyde (MDA) in the culture medium, superoxide dismutase (SOD) in the HPLC homogenate were evaluated by spectrophotometry. The apoptotic HPLC was detected by flow cytometry (FCM) and calculated by relative apoptosis rate. Bax and Bcl-2 protein levels were detected by Western blotting. RESULTS: RES increased the cell survival rate after H2O2 injury. The survival rate of RES 30 micromol/L group was (86.1 +/- 4.1)% and the model group was (54.6 +/- 4.0)%, which was significantly different between the two groups (P < 0.01). The LDH leakage rate and MDA content of the RES 30 micromol/L group were (32.6 +/- 2.0)% and (1.70 +/- 0.21) micromol/L, which were significantly different with that in the model group (P < 0.01). At the same time RES could remarkably restore the vitality of SOD in the HPLC. RES increased Bcl-2 and reduced the expression of Bax protein. The apoptosis rate of the RES 30 micromol/L group and model group was (14.84 +/- 1.36)% and (64.37 +/- 2.34)%, respectively (P < 0.01). The protective effect of RES on the cell apoptosis was in a dose-dependent manner, reaching peak at a concentration of 30 micromol/L (P < 0.01). CONCLUSIONS: RES reduced oxidative stress and apoptosis in an experimental HPLC injury model induced by H2O2. RES plays a key role in the HPLC protection against oxidative injury.