Salivary trefoil factor 3 enhances migration of oral keratinocytes

Trefoil factor 3 (TFF3) is a member of the mammalian TFF family. Trefoil factors are secreted onto mucosal surfaces of the entire body and exert different effects according to tissue location. Trefoil factors may enhance mucosal healing by modulating motogenic activity, inhibiting apoptosis, and promoting angiogenesis. Trefoil factor 3 is secreted from the submandibular gland and is present in whole saliva. The aim of this study was to assess the migratory and proliferative effects of TFF3 on primary oral human keratinocytes and oral cancer cell lines. The addition of TFF3 increased the migration of both normal oral keratinocytes and the cancer cell line D12, as evaluated by a two-dimensional scratch assay. By contrast, no increase in proliferation or energy metabolism was observed after stimulation with TFF3. Trefoil factor 3-enhanced migration was found to be driven partly by the extracellular signal-related kinase (Erk1/2) pathway, as shown by addition of the mitogen-activated protein kinase (MAPK) inhibitor PD 98059. Previous functional studies on trefoil peptides have all been based on cells from monolayered epithelium like the intestinal mucosa; this is the first report to show that normal and cancerous keratinocytes from stratified epithelium respond to TFF stimuli. Taken together, salivary TFF3 is likely to contribute to oral wound healing.     

Nerve growth factor concentration in human saliva

OBJECTIVE: The aims of this study were to measure the normal concentration of nerve growth factor (NGF) in healthy human saliva and to investigate the effects of age and gender differences on saliva NGF level. MATERIALS AND METHODS: Resting whole, stimulated parotid, and stimulated submandibular/sublingual saliva were collected from 127 healthy volunteers with ages ranging from 20 to 81 years. The saliva NGF concentration was measured by enzyme immunoassay. RESULTS AND CONCLUSIONS: The mean concentrations of NGF were 901.4 +/- 75.6 pg ml(-1) in resting whole saliva, 885.9 +/- 79.9 pg ml(-1) in stimulated parotid saliva, and 1066.1 +/- 88.1 pg ml(-1) in stimulated submandibular/sublingual saliva. The stimulated submandibular saliva showed lower NGF concentrations with increasing age (rho = -0.296, P = 0.001). The NGF concentrations of resting whole saliva (P = 0.025) and stimulated parotid saliva (P = 0.005) were significantly higher in women than men. The NGF concentration of stimulated submandibular saliva was significantly higher than stimulated parotid saliva (P = 0.005) and significantly correlated with stimulated parotid saliva NGF level (rho = -0.244, P = 0.008). We found measurable concentrations of NGF in all three sources of saliva; the concentration was affected by the source for the stimulated parotid and submandibular saliva, age for stimulated submandibular saliva, and gender difference for resting whole saliva and stimulated parotid saliva.     

Keratinocyte growth factor colocalized with perlecan at the site of capsular invasion and vascular involvement in salivary pleomorphic adenomas

Background:  Capsular invasion is often observed in daily pathologic diagnosis of pleomorphic adenomas, although neither actual information about its occurrence nor molecular mechanisms leading to their invasive activities have been reported. In this study, our aim was to elucidate the mode and the frequency of capsular invasion in this tumor and to characterize the tumor cell arrangement at the site of capsular invasion.
Methods:  The mode and frequency of capsular invasion of salivary pleomorphic adenomas were histopathologically examined in 104 surgical specimens of pleomorphic adenoma, and stromal characteristics, and tumor cell arrangements at the sites of capsular invasion were immunohistochemically investigated.
Results:  A total of 353 areas with capsular invasive changes were collected from 104 cases. The mode of capsular invasion was classified into two types: type I: intracapsular invasion (247 areas, 70%) and type II: capsular penetration (106 areas, 30%). Myxoid stroma, which was perlecan-immunopositive (+), was shared by both type I and type II sites, while tumor cell foci containing ductal structures were predominant in type II sites. These foci were composed of KGF⁺ and FGFR2⁺ cells. In addition, apparent vascular involvement was recognized in 31 tumors (29.8%).
Conclusion:  The results suggest that pleomorphic adenoma cells are able to invade into the capsule and involve blood vessels when they are situated in perlecan-rich milieu, which accelerate KGF signaling.     

调控涎腺细胞分泌的受体及其信号转导的研究进展

涎腺细胞膜表面的受体及其所介导的信号转导通路是调控涎腺分泌的重要途径。本文概要介绍了毒蕈碱型胆碱受体、α1-肾上腺素受体、β-肾上腺素受体及辣椒素受体在正常颌下腺的表达及其对唾液分泌的调控作用,重点介绍了作者所进行的涎腺细胞受体对失神经支配的移植颌下腺分泌调控作用的研究结果。     

Sclerosing mucoepidermoid carcinoma of the oral cavity

Sclerosing mucoepidermoid carcinoma (SMEC) with eosinophilia is a rare but distinctive tumor usually affecting the thyroid. SMEC involvement of salivary gland is exceptional, with only six cases in the literature. We present here the first case of an intermediate-grade SMEC, arising from the intraoral minor salivary glands. A particularly interesting finding is the cytoplasmic accumulation of eosinophilic hyaline granules in carcinoma cells, similar to aberrant zymogen-like granules previously described in salivary sclerosing polycystic adenosis.     

Low-grade adenocarcinoma of the oral cavity: polymorphous or papillary?

Polymorphous low-grade adenocarcinomas are low-grade malignant salivary-gland neoplasms with a broad variety of architectural patterns. Whether papillary structures fall within this spectrum or whether they should lead to a diagnosis of papillary low-grade adenocarcinoma is a subject of debate. This problem was investigated by analyzing a series of 22 salivary gland neoplasms. It was concluded that papillary structures form part of the histologic spectrum of polymorphous low-grade adenocarcinoma but that there are also tumors with papillary structures as a single component. In most instances these are more properly classified as papillary cystadenocarcinomas. As the designation papillary low-grade adenocarcinoma has been used for polymorphous low-grade adenocarcinomas with papillary structures as well as for papillary cystadenocarcinoma, it is advocated that the diagnosis of papillary low-grade adenocarcinoma should be discontinued.     

Autonomic nervous system in individuals with cerebral palsy: a controlled study

J Oral Pathol Med (2011) 40 : 576–581 Background: Disturbances in homeostatic functions have been observed in individuals with cerebral palsy (CP), possibly resulting from autonomic dysfunction. Salivary flow rate and saliva composition are controlled by the autonomic nervous system, and CP individuals exhibit alterations in salivary parameters that suggest autonomic impairment. This study aimed to investigate cardiac parameters as indicative of autonomic disturbances, possibly associated with salivary changes observed in CP individuals. Methods: Ninety individuals with CP were compared with 35 sibling volunteers with no neurological damage (CG). Twenty‐four‐hour ECG/Holter monitoring (SEER^® Light; GE Medical Systems, Milwaukee, WI, USA) and 12‐lead electrocardiographic recordings were performed on the CP and control groups. Total saliva was collected, and the salivary flow rate and total protein concentration were determined. Results: Cerebral palsy (CP) individuals presented a significant reduction in salivary flow rate (P < 0.01) and increased protein concentrations (P < 0.01) compared to CG. Twenty‐four‐hour Holter ECG analysis showed differences for high frequency (HF), low frequency (LF) and LF/HF ratio between the groups, with the CP group presenting higher HF and LF values and lower LF/HF. Electrocardiographic parameters showed a statistically significant difference for heart rate, and its correlates, and mean corrected QT interval between the groups studied (P < 0.05). Snoring was frequent among CP patients. ECG and autonomic changes were independently associated with CP. Conclusion: Individuals with cerebral palsy present cardiovascular changes principally manifested as disturbed sympathovagal balance. These autonomic dysfunctions could contribute to the salivary changes observed.     

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涎腺疾病包括涎腺肿瘤及非肿瘤性涎腺疾病.涎腺主要依靠其分泌液--唾液发挥功能.近些年来,涎腺疾病和唾液的研究方面取得了明显的进展,本文对其中部分进展作一概述.     

Melatonin in diseases of the oral cavity

Oral Diseases (2010) 16 , 242–247 Background: Melatonin is the principal secretory product of the pineal gland. It has immunomodulatory and antioxidant activities, stimulates the proliferation of collagen and osseous tissue and acts as a protector against cellular degeneration associated with aging and toxin exposure. Arising out of its antioxidant actions, melatonin protects against inflammatory processes and cellular damage caused by the toxic derivates of oxygen. As a result of these actions, melatonin may be useful as a co‐adjuvant in the treatment of certain conditions of the oral cavity. Methods:  An extensive review of the scientific literature was carried out using PubMed, Science Direct, ISI Web of Knowledge and the Cochrane base. Results: Melatonin, which is released into the saliva, may have important implications for oral diseases. Melatonin may have beneficial effects in certain oral pathologies including periodontal diseases, herpes viral infections and Candida, local inflammatory rocesses, xerostomia, oral ulcers and oral cancer. Conclusions: Melatonin may play a role in protecting the oral cavity from tissue damage caused by oxidative stress. The experimental evidence suggests that melatonin may have utility in the treatment of several common diseases of the oral cavity. However, more specific studies are necessary to extend the therapeutic possibilities to other oral diseases.     

唾液腺良性肿瘤患者唾液中CA125的表达及临床意义

目的:探讨唾液腺良性肿瘤患者唾液中CA125的表达及其临床意义。方法:采集30例唾液腺良性肿瘤患者和30例健康对照者的唾液,采用酶联免疫吸附分析法(ELISA)检测唾液中CA125的含量,通过统计学软件进行比较分析。结果:唾液腺良性肿瘤患者唾液中CA125的含量为506.4±75.0U/L;显著高于健康对照者唾液中CA125的含量306.0±50.1U/L(P<0.05)。结论:唾液中CA125的检测对于判断唾液腺良性肿瘤具有一定的临床应用价值。     

Metalloproteinase expression in normal and malignant oral keratinocytes: stimulation of MMP-2 and -9 by scatter factor

Matrix metalloproteinases (MMPs) are Zn2+ dependent proteases produced by a variety of cell types. They have a fundamental role in tissue remodelling, tumour invasion and metastasis. Scatter factor (SF), secreted by fibroblasts, has a paracrine action on epithelial cells and binds the trans-membrane c-met receptor inducing loss of adhesion, cell motility and invasiveness in vitro. The purpose of this study was to test if SF can regulate the production of MMPs by epithelial cells. Supernatants from oral squamous cell carcinoma-derived cells (H375 and H376), a human keratinocyte line (UP), and primary cultures of oral mucosal keratinocytes, grown in the presence or absence of SF, were analysed using 0.1% gelatin zymography. MMPs were characterised by comparison with human recombinant enzymes and by the use of specific inhibitors. Oral mucosal keratinocytes, UP, and H357 cells expressed MMP-2 and MMP-9, whilst H376 cells only expressed MMP-2. SF increased the expression of MMP-9 in UP and MMP-2 in H376 supernatants. Both MMP-2 and MMP-9 activity were increased in H357 and normal keratinocyte supernatants. This could be blocked using a human recombinant anti-SF antibody. In all epithelial lines tested, c-Met, the cell surface receptor for SF, could be detected. The results indicate that SF stimulates MMP expression in UP, H376, H357, and normal oral mucosal cells and points to a role for SF in the regulation of oral keratinocyte behaviour in wound healing and neoplasia.     

A method of measuring salivary flow rate in the lower labial mucosal region

To measure resting whole saliva, draining and spitting methods have been commonly used. However, these methods require the patients' understanding and cooperation. The aim of this study was to establish a method for measuring the salivary flow rate that does not rely on patient's cooperation or the state of the mouth and does not cause any discomfort to patients when performing the measurements. The salivary flow rate in the lower labial mucosal region was measured by means of strips that incorporated the iodo-starch reaction. The salivary flow rate was then calculated on the basis of the number of spots and area of discoloration on the strip. In order to test the validity of these methods, the correlation between these results and resting whole saliva measured by the draining method was also investigated. A positive correlation was found between the salivary flow rate estimated from the area of discoloration on the strip and the resting whole saliva (r=0.678, P=0.01). Therefore, these findings indicate that this is a valid method of measuring the salivary flow rate in the lower labial mucosal region.     

Vascular endothelial growth factor and thymidine phosphorylase expression in salivary gland tumors with distinct metastatic behavior

J Oral Pathol Med (2010) 40 : 456–459 Background: Metastasis of salivary gland tumors has a negative impact on survival. Angiogenesis and its factors are potential markers for predicting metastasis in different malignant tumors, but this is not the case for salivary gland tumors. Methods: Salivary gland tumors of distinct biologic behavior were analyzed according to the semiquantitative immunoexpression of vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP). Results: Vascular endothelial growth factor expression was predominantly weak in benign tumors. Weak TP expression was observed in 100% cases of benign tumors and in 74.3% of primary malignant tumors. High VEGF and TP expression levels were significantly associated with primary malignant tumors but not with primary non‐metastasizing and primary metastasizing malignant tumors or with subtypes of malignant tumors. Conclusions: Vascular endothelial growth factor and TP expression levels discriminate benign and malignant tumors but cannot predict metastasis from non‐metastasizing tumors.     

Comparison of antioxidant enzymes activity and the concentration of uric acid in the saliva of patients with oral cavity cancer,odontogenic cysts and healthy subjects

J Oral Pathol Med (2011) 40 : 726–730 Chronic inflammation is related to oxidative stress and is still believed to be the cause of carcinogenesis. Patients with oral cavity cancer (OCC) exhibited lower total antioxidant capacity, uric acid (UA) concentration, salivary peroxidise (SPO) and superoxide dismutase (SOD) activity in their saliva than did healthy subjects. This could be a risk factor for tumour induction. Odontogenic cysts also arise in response to locally acting proinflammatory factors, for example, a gangrenous tooth. Furthermore, cyst development is accompanied by chronic inflammation. There are some reports in the literature concerning primary tumours such as squamous cell carcinomas arising from odontogenic cysts. The reason for this transformation is still unknown. The aim of this study was to compare the status of the antioxidant defence system in the saliva of the group with odontogenic cysts and OCC with that of the healthy control. Saliva samples were collected in the morning. SOD, SPO activity and UA concentration were determined using standard methods. Patients with odontogenic cysts and OCC exhibited lower activity of major antioxidants in their saliva (SPO, UA) than did healthy people. SOD activity and age are the main factors that distinguish these diseases. Discriminant function analysis showed that once data such as antioxidant status of saliva, age and smoking status are known 80% cases can be correctly classified as healthy, 80% as having odontogenic cysts and 40% as cancerous. To conclude, the decrease in concentrations of major antioxidants in the saliva of patients with cysts may increase the risk of neoplastic transformation especially in advanced age.     

Acute salivary gland hypofunction in the duct ligation model in the absence of inflammation

Objective:  The commonly associated aetiology of salivary gland inflammation and salivary hypofunction has led to the widely held belief that inflammation causes salivary gland hypofunction. Indeed, our own recent study seemed to support this contention. Here, we tested the hypothesis that, in an acute duct ligation model, eliminating inflammation the submandibular gland would recover normal function.
Materials and methods:  Ligation of the rat submandibular gland excretory duct for 24 h was used to induce inflammation and salivary gland hypofunction. A group of duct ligated rats was compared with a second group given dexamethasone, on the day of duct ligation. Twenty-four hours later salivary gland function was assessed and salivary glands were collected.
Results:  Histology and myeloperoxidase activity assay revealed a profound decrease in inflammatory cell infiltration of ligated glands from rats given dexamethasone, compared with ligated glands in the absence of dexamethasone. Salivary flow rate evoked by methacholine was decreased ( P  < 0.01) by approximately 56% (ligated vs control, 79 ± 9  μ l min⁻¹ g⁻¹ vs 177 ± 11  μ l min⁻¹ g⁻¹) and salivary flow from ligated dexamethasone-treated and ligated glands was similar.
Conclusion:  Despite eliminating the inflammatory reaction in the ligated gland, salivary hypofunction was not reversed, suggesting that other mechanisms must be at work in the ligation-induced salivary hypofunction.     

涎石成因的研究进展

涎石的成因迄今为止尚未明确。目前研究认为,唾液有机成分和无机成分浓度的改变、细菌感染及炎症、导管解剖形态、全身性因素等均可影响涎石的形成,具体的涎石形成机制主要包括几个学说:矿物质核心学说、逆行性学说、微结石学说和变性细胞器学说等。本文就有关涎石形成机制的研究进展作一综述。