Publications by authors named "Lizheng Qin"

33 Publications

Circulating Natural Autoantibodies to HER2-Derived Peptides Performed Antitumor Effects on Oral Squamous Cell Carcinoma.

Front Pharmacol 2021 5;12:693989. Epub 2021 Nov 5.

Beijing Institute of Dental Research, Beijing Stomatological Hospital, Capital Medical University, Beijing, China.

Natural autoantibodies play a crucial role in destruction of malignant tumors due to immune surveillance function. Epidermal growth factor receptor 2 (HER2) has been found to be highly expressed in a variety of epithelial tumors including oral squamous cell carcinoma (OSCC). The present study was thus undertaken to investigate the effect of anti-HER2 natural autoantibodies on OSCC. Compared with cancer-adjacent tissues, cancer tissues from OSCC patients exhibited higher HER2 expression especially in those with middle & advanced stage OSCC. Plasma anti-HER2 IgG levels examined with an enzyme-linked immunosorbent assay (ELISA) developed in-house showed differences between control subjects, individuals with oral benign tumor and patients with OSCC. In addition, anti-HER2 IgG-abundant plasma was screened from healthy donors to treat OSCC cells and to prepare for anti-HER2 intravenous immunoglobulin (IVIg). Both anti-HER2 IgG-abundant plasma and anti-HER2 IVIg could significantly inhibit proliferation and invasion of OSCC cells by inducing the apoptosis, and also regulate apoptosis-associated factors and epithelial-mesenchymal transition (EMT), respectively. Besides, the complement-dependent cytotoxicity (CDC) pathway was likely to contribute to the anti-HER2 IgG mediated inhibition of OSCC cells. After the HER2 gene was knocked down with HER2-specific siRNAs, the inhibitory effects on OSCC cell proliferation and apoptotic induction faded away. In conclusion, human plasma IgG, or IVIg against HER2 may be a promising agent for anti-OSCC therapy.
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http://dx.doi.org/10.3389/fphar.2021.693989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8602057PMC
November 2021

Inorganic nitrate alleviates irradiation-induced salivary gland damage by inhibiting pyroptosis.

Free Radic Biol Med 2021 11 26;175:130-140. Epub 2021 Aug 26.

Department of Oral and Maxillofacial & Head and Neck Oncology, Beijing Stomatological Hospital, Capital Medical University, Beijing, 100050, China; Beijing Laboratory of Oral Helath, Capital Medical University, Beijing 100069, China. Electronic address:

Over 80% of patients undergoing radiotherapy (RT) for head and neck cancer (HNC) suffer reduced saliva secretion and dry mouth symptoms due to salivary gland damage. Although therapeutic interventions to alleviate such RT-induced damage are available, long-term hypofunction remains a significant issue. Therefore, novel therapeutic solutions to prevent irradiation (IR)-induced salivary gland damage are required. This study explored the protective effect of inorganic nitrate in preventing IR-induced salivary gland injury via pyroptosis suppression, both in vivo and in vitro. In the treatment group, C57BL/6 mice were pretreated with 2 mmol/L NaNO supplied in drinking water one week before a single-dose of 15 Gy IR in the submandibular gland (SMG) region. Human vein endothelial cells (HUVECs) and mice SMG cells were treated with 10 μmol/L or 100 μmol/L NaNO 2 h before a single-dose of 8 Gy IR. In vivo, IR-induced decreased saliva flow rate and body weight loss could be alleviated by nitrate supplementation. Nitrate prevented acinar and microvascular endothelial cell loss. Moreover, nitrate improved mitochondrial function and significantly decreased pyroptosis-related indexes. In vitro, nitrate supplementation reduced reactive oxygen species (ROS) generation by preserving mitochondrial homeostasis to inhibit NLPR3 inflammasome-mediated pyroptosis both in HUVECs and SMG cells. Nitrate showed potential as an oral protective agent to prevent IR-induced salivary gland damage; prospective insight into the underlying molecular mechanisms is presented.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.08.227DOI Listing
November 2021

Accuracy of Magnetic Resonance Imaging in Evaluating the Depth and Level of Invasion of Buccal Carcinoma: A Prospective Cohort Study.

J Oral Maxillofac Surg 2021 May 18. Epub 2021 May 18.

Department Head, Department of Oral and Maxillofacial-Head and Neck Oncology, Beijing Stomatological Hospital, Capital Medical University, Beijing, China. Electronic address:

Purpose: This study evaluated the accuracy of magnetic resonance imaging (MRI) in determining the depth and level of invasion of buccal carcinoma.

Methods: Patients with buccal squamous cell carcinoma diagnosed pathologically from July 2016 to December 2019 were included. The depth of invasion (DOI) and level of invasion (LOI) were evaluated by MRI, intraoperative specimens and pathological sections. Statistical analyses were performed using IBM SPSS software version 25.0 (IBM Corp., Armonk, NY).

Results: Forty-nine patients were ultimately included. The overall difference in DOI between MRI and pathological sections (DMP) was 5.55 ± 2.40 mm, and T category correlated with the differences in DOI measurement and LOI assessment. The threshold value of DOI by MRI to identify lymph node metastasis was 8.5 mm, and that for overall survival (OS) and disease-specific survival (DSS) was 14.1 mm for both. Buccinator invasion on MRI correlated with OS and DSS.

Conclusion: Tumors with MRI-derived DOI larger than 8.5 mm deserve simultaneous neck dissection at initial surgery. Buccinator invasion was found to be an independent prognostic factor for buccal carcinoma patients.
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http://dx.doi.org/10.1016/j.joms.2021.05.008DOI Listing
May 2021

The intact parasympathetic nerve promotes submandibular gland regeneration through ductal cell proliferation.

Cell Prolif 2021 Jul 7;54(7):e13078. Epub 2021 Jun 7.

Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China.

Objectives: Salivary gland regeneration is closely related to the parasympathetic nerve; however, the mechanism behind this relationship is still unclear. The aim of this study was to evaluate the relationship between the parasympathetic nerve and morphological differences during salivary gland regeneration.

Materials And Methods: We used a duct ligation/deligation-induced submandibular gland regeneration model of Sprague-Dawley (SD) rats. The regenerated submandibular gland with or without chorda lingual (CL) innervation was detected by haematoxylin-eosin staining, real-time PCR (RT-PCR), immunohistochemistry and Western blotting. We counted the number of Ki67-positive cells to reveal the proliferation process that occurs during gland regeneration. Finally, we examined the expression of the following markers: aquaporin 5, cytokeratin 7, neural cell adhesion molecule (NCAM) and polysialyltransferases.

Results: Intact parasympathetic innervation promoted submandibular gland regeneration. The process of gland regeneration was significantly repressed by cutting off the CL nerve. During gland regeneration, Ki67-positive cells were mainly found in the ductal structures. Moreover, the expression of NCAM and polysialyltransferases-1 (PST) expression in the innervation group was significantly increased during early regeneration and decreased in the late stages. In the denervated submandibular glands, the expression of NCAM decreased during regeneration.

Conclusions: Our findings revealed that the regeneration of submandibular glands with intact parasympathetic innervation was associated with duct cell proliferation and the increased expression of PST and NCAM.
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http://dx.doi.org/10.1111/cpr.13078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249781PMC
July 2021

Inhibitory effects of circulating natural autoantibodies to CD47-derived peptides on OSCC cells.

Oral Dis 2021 May 24. Epub 2021 May 24.

Beijing Institute of Dental Research, Beijing Stomatological Hospital, Capital Medical University, Beijing, China.

Objectives: Natural autoantibodies serve as an important anti-tumorigenic component in the body. This study was thus designed to investigate whether circulating natural IgG autoantibodies against a cluster of differentiation 47 (CD47) could exert inhibitory effects on oral squamous cell carcinoma (OSCC).

Subjects And Methods: The expression levels of 13 tumor-targeted genes in three OSCC cell lines were analyzed by qPCR, and CD47 expression in OSCC tissues was also verified with IHC staining. An in-house ELISA was performed to analyze circulating anti-CD47 IgG levels in control subjects, oral benign tumor, and OSCC patients, and to detect anti-CD47 IgG-abundant plasma. Three OSCC cell lines were treated with anti-CD47 IgG-abundant and -deficient plasma, respectively, followed by the analysis of cell proliferation, apoptosis, and invasion/metastasis.

Results: The CD47 gene showed the highest expression among 13 genes detected in three OSCC cell lines; its expression was significantly higher in OSCC tissues than adjacent tissues. Plasma anti-CD47 IgG levels showed the differences between control subjects, oral benign tumor, and OSCC patients. Anti-CD47 IgG-abundant plasma could evidently reduce cell viability via suppressing p-AKT expression and inducing cell apoptosis and inhibit the invasion of all three OSCC cell lines.

Conclusions: Natural autoantibodies against CD47 may be a potential agent for OSCC immunotherapy.
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http://dx.doi.org/10.1111/odi.13922DOI Listing
May 2021

Role of honey in preventing radiation-induced oral mucositis: a meta-analysis of randomized controlled trials.

Food Funct 2021 Apr 31;12(8):3352-3365. Epub 2021 Mar 31.

Department of Oral and Maxillofacial & Head and Neck Oncology, Beijing Stomatological Hospital, Capital Medical University, Tian Tan Xi Li No.4, Beijing, 100050, China.

Background: Radiotherapy-induced mucositis easily arouses oral ulceration, pain and xerostomia. Intense pain, difficulty swallowing and speaking greatly affect the quality of life and the treatment process.

Objective: This study aimed to examine the effects of honey in preventing and treating radiotherapy-induced mucositis in patients with head and neck cancer using a different analytical strategy.

Methods: Articles published until July 2020 were searched across PubMed, Embase, and Cochrane Library databases. Randomized controlled trials that evaluated honey were assessed by two reviewers. The number of mucositis incidences was the primary outcome. Weight loss, pain scale and incidence of severe pain were pooled to be calculated as secondary outcomes. Statistical analyses were conducted using RevMan5.3 software. The funnel plot was used to detect publication bias.

Results: Overall, 11/179 records with 715 patients who received radiotherapy were included. Honey significantly reduced the incidence of grade 2 (OR: 0.43, 95%CI: 0.54-0.98, P = 0.03), grade 3 (odds ratio [OR]: 0.24, 95% confidence interval [CI]: 0.16-0.35, P < 0.001) and grade 4 mucositis (OR: 0.17, 95%CI: 0.08-0.36, P < 0.001). In grade 1 (OR: 1.54, 95%CI: 1.15-2.06, P = 0.003), and honey was not significant in preventing radiation-induced mucositis. The incidence of unbearable pain was lower in the honey group at all grades (OR: -0.20, 95%CI: -0.33 to -0.07). The effect of honey on weight loss and pain score was not statistically significant.

Conclusion: Honey can prevent and alleviate grade 2-4 mucositis, especially in high grade mucositis. Honey also provides some relief from severe pain. But, more evidence is required to prove that honey is an effective substance for relieving pain or minimizing weight loss.
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http://dx.doi.org/10.1039/d0fo02808hDOI Listing
April 2021

Knowledge of Chinese dentists on HPV, their willingness and barriers to recommend HPV vaccination to patients.

Hum Vaccin Immunother 2021 08 9;17(8):2728-2735. Epub 2021 Mar 9.

Department of Oral and Maxillofacial & Head and Neck Oncology, Beijing Stomatological Hospital, Capital Medical University, Beijing, P.R. China.

: This study aimed to assess the knowledge of Chinese dentists on human papilloma virus (HPV), their willingness and factors prevention them from recommending patients for HPV vaccination, and to identify ways through which dentists can acquire HPV-related knowledge.: This was a cross-sectional study based on Chinese dentists. The anonymous self-filled questionnaire method was used to collect demographic information of participants, their knowledge of HPV, willingness and barriers to recommending HPV vaccines to patients, and the strategies they can adopt to obtain HPV-related knowledge.: A total of 517 dentists completed the questionnaire, and 89.94% of dentists were willing to recommend HPV vaccination to patients. Participants aged 30-39 years, male dentists and dentist-in-charge had relatively lower knowledge scores than other groups. Besides, participants aged 30-39 years, working in private hospitals, and practicing in Southern China had a lower willingness to recommend HPV vaccination to patients. Recommending HPV vaccination to patients is not within the scope of practicing dentists, and concerns about the safety of the HPV vaccine were found to be the main barriers preventing its recommendation. Notably, 97.87% of dentists were eager to acquire HPV-related knowledge, and agreed for the first time to enroll in relevant educational courses.: Chinese dentists had expressed a strong desire to recommend HPV vaccines to patients, even though their knowledge of HPV was scanty. Therefore, measures to improve their understanding of HPV vaccines and eliminate barriers suppressing their willingness to recommend HPV vaccines are urgently needed.
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http://dx.doi.org/10.1080/21645515.2021.1885967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475622PMC
August 2021

Prognostic value of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio and systemic immune-inflammation index in patients with laryngeal squamous cell carcinoma.

Clin Otolaryngol 2021 Mar 27;46(2):395-405. Epub 2020 Dec 27.

Department of Oral and Maxillofacial & Head and Neck Oncology, Beijing Stomatological Hospital, Capital Medical University, Beijing, China.

Objectives: We aimed to determine the prognostic value of the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII) in patients with laryngeal squamous cell carcinoma (LSCC).

Design And Setting: A retrospective analysis of patients with LSCC was conducted in our hospitals. Clinical information, including age, sex, TNM classification and other demographic and clinical data, was acquired and analysed. Progression-free survival (PFS) and overall survival (OS) were calculated and compared using the Kaplan-Meier method and log-rank test.

Participants: A total of 147 patients with LSCC were included.

Results: According to the receiver operating characteristic (ROC) curve, the optimal cut-off points for NLR, PLR and SII were 1.88, 117.36 and 517.64. The analysis revealed NLR, PLR and SII to be independent predictors for OS and PFS (P < .05).

Conclusions: Preoperative NLR, PLR and SII are promising prognostic predictors for patients with LSCC.
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http://dx.doi.org/10.1111/coa.13689DOI Listing
March 2021

Primary sialorrhea and its surgical treatment with denervation of the submandibular glands in combination with sublingual gland excision.

J Craniomaxillofac Surg 2021 Jan 21;49(1):47-51. Epub 2020 Nov 21.

Department of Oral and Maxillofacial & Head and Neck Oncology, Beijing Stomatological Hospital, Capital Medical University, Beijing, 100050, China. Electronic address:

Objectives: The purpose of this study was to evaluate the effectiveness of ablating postganglionic parasympathetic fibers of the submandibular ganglion in combination with sublingual gland excision in the treatment of primary sialorrhea.

Materials And Methods: Healthy volunteers were initially chosen to determine a basic saliva flow rate value by saliva collection. Next, unstimulated and stimulated saliva flow rates, and a visual analog scale index for sialorrhea were recorded in all the patients pre- and postoperatively. In addition, the generalized anxiety disorder scale was used to assess preoperative anxiety symptoms. The follow-up durations ranged from 24 to 36 months after surgery.

Results: A total of 10 patients were included in this study. Preoperatively, the mean unstimulated saliva flow rate for the 10 patients was 11.26 ± 4.19 ml/10 min, the stimulated saliva flow rate was 16.76 ± 3.49 ml/6 min, and the visual analog scale index was 66.29 ± 14.86. Postoperatively, the mean unstimulated and stimulated saliva flow rates were significantly reduced to 5.99 ± 1.33 ml/10 min (p = 0.001) and 13.28 ± 1.86 ml/6 min (p = 0.013), respectively, and the visual analog scale index was 25.41 ± 5.6 (p < 0.001). No complications were found after operation.

Conclusion: This study demonstrates that ablation of postganglionic parasympathetic fibers of the submandibular ganglion in combination with sublingual gland excision by an intraoral approach is a simple, safe, and efficient approach for treating primary sialorrhea.
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http://dx.doi.org/10.1016/j.jcms.2020.11.006DOI Listing
January 2021

Risk factors for surgical site infection after major oral oncological surgery: the experience of a tertiary referral hospital in China.

J Int Med Res 2020 Aug;48(8):300060520944072

Department of Oral Medicine, Beijing Stomatological Hospital & School of Stomatology, Capital Medical University, Beijing, China.

Objective: To identify risk factors associated with surgical site infection (SSI) after major oral oncological surgery.

Methods: This retrospective study reviewed data from patients that underwent major surgery for oral cancer at a tertiary referral hospital in China between January 2005 and July 2016. SSI was diagnosed within 30 days. Demographic, cancer-related, preoperative, perioperative and postoperative data were analysed using descriptive statistics and univariate and multivariate analyses of the risk factors for SSI.

Results: A total of 786 patients were enrolled, of whom 125 had SSI (15.9%), which were all incisional. Independent risk factors for SSI, identified by multivariate analysis, were diabetes mellitus (odds ratio [OR] 2.147, 95% confidence interval [CI] 1.240, 3.642), prior radiotherapy (OR 4.595, 95% CI 1.293, 17.317) and oral-neck communication (OR 2.838, 95% CI 1.263, 7.604); and factors reflecting large extent resections were tracheostomy (OR 2.235, 95% CI 1.435, 3.525), anterolateral thigh flap (OR 1.971, 95% CI 1.103, 3.448) and latissimus dorsi flap (OR 4.178, 95% CI 1.325, 13.189).

Conclusions: Multiple risk factors were associated with SSI after major oral oncological surgery. To minimize SSI risk, surgeons managing oral cancer patients should have a better understanding of the risk factors, including diabetes mellitus, prior radiotherapy, tracheostomy, oral-neck communication and flap reconstruction.
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http://dx.doi.org/10.1177/0300060520944072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463046PMC
August 2020

ALDH3A1 acts as a prognostic biomarker and inhibits the epithelial mesenchymal transition of oral squamous cell carcinoma through IL-6/STAT3 signaling pathway.

J Cancer 2020 19;11(9):2621-2631. Epub 2020 Feb 19.

Professor and Medical Doctor, Department of Oral and Maxillofacial & Head and Neck Oncology, Beijing Stomatological Hospital, Capital Medical University, Beijing, China, 100050.

Aldehyde dehydrogenase 3A1 (ALDH3A1) is a member of the ALDH superfamily and its relationship with oral squamous cell carcinoma (OSCC) still unknown. In our subject, we aimed to reveal the expression pattern and clinical value of ALDH3A1 in OSCC and its biological function in OSCC cell lines. The expression level of ALDH3A1 in paired OSCC tissues and adjacent noncancerous tissues were detected by quantitative real-time PCR, Western blot and immunohistochemistry. The relationship between ALDH3A1 expression and clinical characteristics was analyzed. Besides, cell-counting kit 8, colony formation, wound healing, transwell invasion, apoptosis and cell cycle assays were employed to assess the role of ALDH3A1 in OSCC cells. To explore the influence of ALDH3A1 on OSCC epithelial-to-mesenchymal transition (EMT), the expression of EMT markers (E-cadherin, vimentin, snail, MMP3) on OSCC cells were detected, and possible mechanisms were analyzed. In OSCC tissues, ALDH3A1 was significantly decreased compared to the adjacent normal tissues. Lower ALDH3A1 expression in OSCC tissues was associated with a higher incidence of lymph node metastasis (LNM). Moreover, the overall survival of OSCC with low ALDH3A1 expression was significantly worse compared to that of OSCC with high ALDH3A1 expression. Restored expression of ALDH3A1 suppressed cell proliferation, migration and invasion in OSCC cells. Further experiments showed that ALDH3A1 might inhibit EMT in OSCC via a regulation of the IL-6/STAT3 signal pathway. These data indicate that ALDH3A1 may serve as a biomarker and may be developed into a novel treatment for OSCC.
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http://dx.doi.org/10.7150/jca.40171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066020PMC
February 2020

Nitrate partially inhibits lipopolysaccharide-induced inflammation by maintaining mitochondrial function.

J Int Med Res 2020 Feb;48(2):300060520902605

Department of Oral and Maxillofacial & Head and Neck Oncology, Beijing Stomatological Hospital, Capital Medical University, Beijing, China.

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http://dx.doi.org/10.1177/0300060520902605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7111041PMC
February 2020

Erratum: Histological characteristics following a long-term nitrate-rich diet in miniature pigs with parotid atrophy.

Int J Clin Exp Pathol 2019;12(12):4405-4406. Epub 2019 Dec 1.

Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology Beijing, China.

[This corrects the article on p. 6225 in vol. 8, PMID: 26261499.].
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949886PMC
December 2019

A pilot study of modified resection for anterior floor of the mouth squamous cell carcinoma without infiltration of the mandible.

J Craniomaxillofac Surg 2019 Mar 28;47(3):516-522. Epub 2018 Nov 28.

Department of Oral and Maxillofacial-Head and Neck Oncology, Beijing Stomatological Hospital, Capital Medical University, Beijing 100050, China. Electronic address:

Objective: To explore the application of modified resection compared with traditional segmental resection of the mandible for patients with anterior floor of the mouth and tongue squamous cell carcinoma (SCC) without infiltration of the mandible.

Subjects And Methods: This is a retrospective study including 36 eligible patients with anterior floor of the mouth SCC(9 patients received modified mandibulectomy, and 27 patients received segmental mandibulectomy).

Results: No patients in the modified mandibulectomy group developed recurrence in the floor of the mouth, and all of the patients survived. Only one patient developed osteoradionecrosis. When the modified mandibulectomy group was compared with the segmental mandibulectomy group, the former exhibited a lower recurrence rate in the floor of the mouth (0.0% vs. 14.8%), less blood loss (516.7 ± 70.7 ml vs. 533.3 ± 93.0 ml), shorter durations of gastric tube placement (11.4 ± 4.5 days vs. 20.7 ± 11.9 days) and tracheostomy (6.9 ± 0.6 days vs. 8.5 ± 1.6 days), a lower postoperative infection rate (11.1% vs. 18.5%), and a shorter postoperative hospital stay (13.7 ± 3.8 days vs. 15.9 ± 5.1 days).

Conclusion: This modified mandibulectomy method is safe and feasible and is recommended for further prospective study in a clinical setting.
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http://dx.doi.org/10.1016/j.jcms.2018.11.019DOI Listing
March 2019

The strategy on managing cervical lymph nodes of patients with maxillary gingival squamous cell carcinoma.

J Craniomaxillofac Surg 2019 Feb 13;47(2):300-304. Epub 2018 Dec 13.

Department of Oral and Maxillofacial & Head and Neck Oncology, Beijing Stomatological Hospital, Capital Medical University, Beijing, 100050, China. Electronic address:

Purpose: We aimed to determine the risk of occult cervical metastasis of maxillary gingival squamous cell carcinoma (SCC), the predisposing factors for occult cervical metastasis and the therapeutic value of elective neck dissection (END) in survival of clinically negative neck node (cN0) patients.

Methods: A retrospective study of patients with maxillary gingival SCC was conducted in our hospital. Clinical information including age, gender, TNM staging, pathological staging, as well as other demographic and clinical data was acquired and analyzed. The Kaplan-Meier method was used to evaluate overall survival rate. Descriptive and bivariate statistics were computed.

Results: The sample was composed of 107 patients (43 men, 64 women). The overall lymph node metastasis (LNM) rate was 28%. The LNM rates were 7.1%, 15%, 41.7% and 44.8% for T1 to T4 stage tumors, and were 9.3%, 46.8%, and 50% for pathological grades I to III. The tumor stage and pathological grade showed a significant relationship with cervical metastasis (P < 0.01). The 5-year survival rate was higher in those who had an END (76%) when compared to those who did not receive an END (46.4%; P < 0.05). With regard to the nodal status, pN0 group had a higher survival rate than pN + group (P < 0.01).

Conclusion: The results of this study suggest that the risk of LNM for SCC originating from the maxillary gingiva is higher than expected and comparable to that for other oral sites. We recommend END for T3 and T4 stage cN0 patients, especially for moderately and poorly-differentiated tumors.
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http://dx.doi.org/10.1016/j.jcms.2018.12.008DOI Listing
February 2019

The impact of age on oral squamous cell carcinoma: A longitudinal cohort study of 2,782 patients.

Oral Dis 2019 Apr 6;25(3):730-741. Epub 2019 Jan 6.

Department of Oral and Maxillofacial-Head and Neck Oncology, Beijing Stomatological Hospital, Capital Medical University, Beijing, China.

Background: The purposes of this study were to assess the influence of age on oral squamous cell carcinoma patients and sought to analyze the reasons that may contribute to this difference.

Methods: This study enrolled 2,782 patients included 2,443 patients in a retrospective cohort to find the influence of age and 339 patients in a prospective cohort to testify these findings. The patients were divided into young age-group (≤40 years old), moderate age-group (41-75 years old), and advanced age-group (>75 years old). All patients were diagnosed as oral squamous cell carcinoma and were surgically treated in our hospital. Chi-square test, Kaplan-Meier analysis, and Cox proportional-hazards regression model were performed for statistical analysis.

Results: Younger patients started smoking (p < 0.001) and drinking (p < 0.001) earlier than the older patients and consumed more tobacco (p = 0.005) and alcohol (p = 0.156). Patients with advanced age had worse outcomes in both recurrence (p = 0.002) and survival (p < 0.001). They also had more severe comorbidity (p < 0.001) and were more likely to receive conservative treatment (p = 0.011).

Conclusions: Compared with young patients, older patients had worse prognosis, and it was related with their more severe comorbidity and received more conservative treatment. Young adults smoking and drinking earlier and heavier than old patients, it may relate with their occurrence of oral squamous cell carcinoma.
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http://dx.doi.org/10.1111/odi.13015DOI Listing
April 2019

Intragland Shh gene delivery mitigated irradiation-induced hyposalivation in a miniature pig model.

Theranostics 2018 30;8(16):4321-4331. Epub 2018 Jul 30.

Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing 100050, PR China.

Irreversible hypofunction of salivary glands is common in head and neck cancer survivors treated with radiotherapy and can only be temporarily relieved with current treatments. We found recently in mouse models that transient activation of Hedgehog pathway following irradiation rescued salivary gland function by preserving salivary stem/progenitor cells, parasympathetic innervation and microvessels. Due to huge differences between salivary glands of rodents and humans, to examine the translational potential of this approach, we evaluated effects of Shh gene transfer in a miniature pig model of irradiation-induced hyposalivation. : The right parotid of each pig was irradiated with a single dose of 20 Gray. Shh and control GFP genes were delivered into irradiated parotid glands by noninvasive retrograde ductal instillation of corresponding adenoviral vectors 4 or 16 weeks after irradiation. Parotid saliva was collected every two weeks. Parotid glands were collected 5 or 20 weeks after irradiation for histology, Western blot and qRT-PCR assays. : Shh gene delivery 4 weeks after irradiation significantly improved stimulated saliva secretion and local blood supply up to 20 weeks, preserved saliva-producing acinar cells, parasympathetic innervation and microvessels as found in mouse models, and also activated autophagy and inhibited fibrogenesis in irradiated glands. : These data indicate the translational potential of transient activation of Hedgehog pathway to preserve salivary function following irradiation.
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http://dx.doi.org/10.7150/thno.26509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134926PMC
September 2019

Relationship between body mass index and outcomes for patients with oral squamous cell carcinoma.

Oral Dis 2019 Jan 17;25(1):87-96. Epub 2018 Sep 17.

Department of Oral and Maxillofacial-Head and Neck Oncology, Beijing Stomatological Hospital, Capital Medical University, Beijing, China.

Objective: The purpose of our study was to investigate body mass index (BMI) as a prognostic factor and to examine the relationship between pretreatment BMI and oral squamous cell carcinoma (OSCC) outcomes in northern Chinese patients.

Methods: This retrospective study enrolled 633 patients with OSCC who underwent surgery between 2004 and 2014.

Results: Most baseline characteristics (gender, sites, smoking history, comorbidity, hypertension, T stage, clinical features, perineural invasion, flap reconstruction) were differentiated by BMI groups. Overall, the Kaplan-Meier curves indicated no significant relationship between BMI and disease-free survival (DFS) or disease-specific survival (DSS). Interestingly, obese patients exhibited higher risks of recurrence and death than normal-weight patients (DFS: HR: 1.86, 95% CI: 1.16-2.96; DSS: HR: 2.04, 95% CI: 1.08-3.86). However, postoperative complications occurred more frequently in underweight patients than in normal-weight patients.

Conclusions: Obesity may contribute to a higher recurrence rate and a worse prognosis in OSCC patients than in normal-weight patients in northern China. However, underweight patients have a higher risk of postoperative complications.
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http://dx.doi.org/10.1111/odi.12963DOI Listing
January 2019

Nodal Stage: Is It a Prognostic Factor for Submandibular Gland Cancer?

J Oral Maxillofac Surg 2018 Aug 21;76(8):1794-1799. Epub 2017 Nov 21.

Professor, Department of Oral and Maxillofacial-Head and Neck Oncology, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China. Electronic address:

Purpose: Submandibular gland cancer is relatively rare. The purpose of this study was to estimate 5-year overall survival (OS) and disease-free survival (DFS) and to identify prognostic factors associated with OS and DFS for submandibular cancer.

Materials And Methods: The authors implemented a retrospective cohort study and enrolled a sample of patients with submandibular gland cancer. The predictor variables were age, gender, tumor stage, nodal stage, margin status, and extracapsular spread. The outcome variables were 5-year OS and 5-year DFS. Kaplan-Meier methods were used to estimate survival and Cox hazards models were used to identify prognostic variables.

Results: The sample was composed of 52 patients with submandibular gland cancer (mean age, 47.4 yr; 51.9% men). The median follow-up was 81 months (range, 11 to 159 months). The 5-year OS and DFS rates were 76.9 and 67.3%, respectively. Fixed mass, positive neck node, and positive margin status were relevant predictors of OS and DFS. Nodal stage was the relevant independent predictor affecting the disease outcome of submandibular gland cancer.

Conclusion: These results identified several important prognostic factors associated with survival rate in patients with submandibular gland cancer. These prognostic variables include symptoms at presentation, pathologic nodal status, and margin status. These outcomes suggest that heightening vigilance of clinical characteristics for this disease might provide the impetus for improving the survival rate.
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http://dx.doi.org/10.1016/j.joms.2017.11.012DOI Listing
August 2018

Prognostic Factors in Malignant Sublingual Salivary Gland Tumors.

J Oral Maxillofac Surg 2017 Jul 18;75(7):1542-1548. Epub 2016 Dec 18.

Professor, Department of Oral and Maxillofacial-Head and Neck Oncology, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China. Electronic address:

Purpose: The present study identified the prognostic factors and outcomes for malignant sublingual salivary gland tumors, which are rare.

Materials And Methods: A retrospective cohort study of patients treated for malignant sublingual salivary gland tumors from 1997 to 2011 was performed. The predictor variables, including age, gender, tumor stage, nodal stage, perineural invasion, margin status, and lymphovascular invasion, were analyzed. The Cox regression model was used to determine the prognostic factors for locoregional recurrence, distant metastasis, and survival.

Results: Of the 38 patients, 16 (42.1%) were men. Their mean age was 53 years (range 36 to 75). A total of 11 patients (28.9%) had T3-T4 tumors, and 6 (15.8%) had positive neck lymph nodes. The recurrence rate at 5 years was 18.4%. The distant metastasis rate at 5 years was 23.7%. Multivariable analysis confirmed the independent prognostic importance of patient age, N stage, and limited tongue mobility in locoregional recurrence and mortality at 5 years.

Conclusions: Our results suggest that patient age, N stage, and limited tongue mobility are useful as independent predictors of locoregional recurrence and mortality in patients with malignant sublingual salivary gland tumors.
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http://dx.doi.org/10.1016/j.joms.2016.12.010DOI Listing
July 2017

Prognostic Factors Associated With Decreased Survival in Patients With Acinic Cell Carcinoma of the Parotid Gland.

J Oral Maxillofac Surg 2017 Feb 1;75(2):416-422. Epub 2016 Jul 1.

Professor, Department of Oral and Maxillofacial-Head and Neck Oncology, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China. Electronic address:

Purpose: Acinic cell carcinoma (ACC) of the parotid gland is relatively rare. This study aimed to estimate 5-year survival and to identify prognostic factors associated with survival of ACC of the parotid gland.

Materials And Methods: Thirty-seven patients with ACC of the parotid gland were included in this retrospective cohort study. They were treated in Beijing Stomatological Hospital from January 2000 to December 2011. Predictor variables, including age, gender, tumor stage, nodal stage, perineural invasion, and margin status, were analyzed. The Cox regression model was used to determine prognostic factors for overall survival (OS) and disease-free survival (DFS).

Results: Of the 37 patients, 20 were men (54.1%). Mean age was 42 years (range, 13 to 73 yr). Six patients (16.2%) had T3 or T4 tumors and 5 (13.5%) had positive neck nodes. The 5-year OS and DFS were 86.5 and 78.3%, respectively. Positive margin status was associated with worse OS. Patients older than 60 years with a fixed mass, high-grade tumor and nodal stage, perineural invasion, and angiolymphatic invasion had adverse OS and DFS (P < .05).

Conclusions: The present study identified several important prognostic factors associated with OS and DFS in patients with ACC. These prognostic variables include symptoms at presentation, clinical tumor stage and pathologic nodal status, and histopathology-related factors. All these factors were important in patient therapy and could prolong survival rate.
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http://dx.doi.org/10.1016/j.joms.2016.06.185DOI Listing
February 2017

Rescue Effects and Underlying Mechanisms of Intragland Shh Gene Delivery on Irradiation-Induced Hyposalivation.

Hum Gene Ther 2016 May;27(5):390-9

1 Institute for Regenerative Medicine, College of Medicine, Texas A&M Health Science Center , Temple, Texas.

Irreversible hypofunction of salivary glands is common in head and neck cancer survivors treated with radiotherapy and can only be temporarily relieved with current treatments. We found in an inducible sonic hedgehog (Shh) transgenic mouse model that transient activation of the Hedgehog pathway after irradiation rescued salivary gland function in males by preserving salivary stem/progenitor cells and parasympathetic innervation. To translate these findings into feasible clinical application, we evaluated the effects of Shh gene transfer to salivary glands of wild-type mice on irradiation-induced hyposalivation. Shh or control GFP gene was delivered by noninvasive retrograde ductal instillation of corresponding adenoviral vectors. In both male and female mice, Shh gene delivery efficiently activated Hedgehog/Gli signaling, and significantly improved stimulated saliva secretion and preserved saliva-producing acinar cells after irradiation. In addition to preserving parasympathetic innervation through induction of neurotrophic factors, Shh gene delivery also alleviated the irradiation damage of the microvasculature, likely via inducing angiogenic factors, but did not expand the progeny of cells responsive to Hedgehog/Gli signaling. These data indicate that transient activation of the Hedgehog pathway by gene delivery is promising to rescue salivary function after irradiation in both sexes, and the Hedgehog/Gli pathway may function mainly in cell nonautonomous manners to achieve the rescue effect.
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http://dx.doi.org/10.1089/hum.2016.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4841000PMC
May 2016

Histological characteristics following a long-term nitrate-rich diet in miniature pigs with parotid atrophy.

Int J Clin Exp Pathol 2015 1;8(6):6225-34. Epub 2015 Jun 1.

Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology Beijing, China.

The aim of this study was to investigate the histological characteristics following a 2-year nitrate-rich diet in miniature pigs with parotid atrophy. Using averages collected data from three time points at 6, 12, and 24 months following the induction of parotid gland atrophy, salivary nitrate levels of the nitrate-diet parotid-atrophied group (17.3 ± 3.9 ng/µl) were close to those of the control group (19.6 ± 5.1 ng/µl). Compared to the control group, the nitrate-diet group had significantly higher nitrate levels in blood (P < 0.05) and urine (P < 0.001). Histological and electron microscopy analyses showed no abnormalities in the organs of experimental or control animals. No significant differences on apoptosis rate were found in liver and kidney tissues between the standard- and nitrate-diet groups. Therefore, dietary nitrate supplementation could restore salivary nitrate levels. High-dose nitrate loading for 2 years had no observed systemic toxicity in miniature pigs with parotid atrophy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4525833PMC
June 2016

MSCs derived from iPSCs with a modified protocol are tumor-tropic but have much less potential to promote tumors than bone marrow MSCs.

Proc Natl Acad Sci U S A 2015 Jan 29;112(2):530-5. Epub 2014 Dec 29.

Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine at Scott & White, Temple, TX 76502

Mesenchymal stem or stromal cells (MSCs) have many potential therapeutic applications including therapies for cancers and tissue damages caused by cancers or radical cancer treatments. However, tissue-derived MSCs such as bone marrow MSCs (BM-MSCs) may promote cancer progression and have considerable donor variations and limited expandability. These issues hinder the potential applications of MSCs, especially those in cancer patients. To circumvent these issues, we derived MSCs from transgene-free human induced pluripotent stem cells (iPSCs) efficiently with a modified protocol that eliminated the need of flow cytometric sorting. Our iPSC-derived MSCs were readily expandable, but still underwent senescence after prolonged culture and did not form teratomas. These iPSC-derived MSCs homed to cancers with efficiencies similar to BM-MSCs but were much less prone than BM-MSCs to promote the epithelial-mesenchymal transition, invasion, stemness, and growth of cancer cells. The observations were probably explained by the much lower expression of receptors for interleukin-1 and TGFβ, downstream protumor factors, and hyaluronan and its cofactor TSG6, which all contribute to the protumor effects of BM-MSCs. The data suggest that iPSC-derived MSCs prepared with the modified protocol are a safer and better alternative to BM-MSCs for therapeutic applications in cancer patients. The protocol is scalable and can be used to prepare the large number of cells required for "off-the-shelf" therapies and bioengineering applications.
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http://dx.doi.org/10.1073/pnas.1423008112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4299223PMC
January 2015

Spatial and temporal expression of c-Kit in the development of the murine submandibular gland.

J Mol Histol 2014 Aug 20;45(4):381-9. Epub 2014 Feb 20.

Molecular Laboratory for Gene Therapy and Tooth Regeneration, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, 100050, China.

The c-Kit pathway is important in the development of many mammalian cells and organs and is indispensable for the development of hematopoiesis, melanocytes, and primordial germ cells. Loss-of-function mutations in c-Kit lead to perinatal death in mouse embryos. Previously, c-Kit has been used as one of salivary epithelial stem or progenitor cell markers in mouse, its specific temporo-spatial expression pattern and function in developing murine submandibular gland (SMG) is still unclear. Here we used quantitative real-time PCR, in situ hybridization, and immunohistochemistry analysis to detect c-Kit expression during the development of the murine SMG. We found that c-Kit was expressed in the epithelia of developing SMGs from embryonic day 11.5 (E11.5; initial bud stage) to postnatal day 90 (P90; when the SMG is completely mature). c-Kit expression in the end bud epithelium increased during prenatal development and then gradually decreased after birth until its expression was undetectable in mature acini at P30. Moreover, c-Kit was expressed in the SMG primordial cord at the initial bud, pseudoglandular, canacular, and terminal end bud stages. c-Kit was also expressed in the presumptive ductal cells adjacent to the developing acini. By the late terminal end bud stage on P14, c-Kit expression could not be detected in ductal cells. However, c-Kit expression was detected in ductal cells at P30, and its expression had increased dramatically at P90. Taken together, these findings describe the spatial and temporal expression pattern of c-Kit in the developing murine SMG and suggest that c-Kit may play roles in epithelial histo-morphogenesis and in ductal progenitor cell homeostasis in the SMG.
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http://dx.doi.org/10.1007/s10735-014-9570-7DOI Listing
August 2014

Transient activation of hedgehog pathway rescued irradiation-induced hyposalivation by preserving salivary stem/progenitor cells and parasympathetic innervation.

Clin Cancer Res 2014 Jan 22;20(1):140-150. Epub 2013 Oct 22.

Institute for Regenerative Medicine at Scott & White, Molecular and Cellular Medicine Department, Texas A&M Health Science Center, Temple, Texas 76502, USA.

Purpose: To examine the effects and mechanisms of transient activation of the Hedgehog pathway on rescuing radiotherapy-induced hyposalivation in survivors of head and neck cancer.

Experimental Design: Mouse salivary glands and cultured human salivary epithelial cells were irradiated by a single 15-Gy dose. The Hedgehog pathway was transiently activated in mouse salivary glands, by briefly overexpressing the Sonic hedgehog (Shh) transgene or administrating smoothened agonist, and in human salivary epithelial cells, by infecting with adenovirus encoding Gli1. The activity of Hedgehog signaling was examined by the expression of the Ptch1-lacZ reporter and endogenous Hedgehog target genes. The salivary flow rate was measured following pilocarpine stimulation. Salivary stem/progenitor cells (SSPC), parasympathetic innervation, and expression of related genes were examined by flow cytometry, salisphere assay, immunohistochemistry, quantitative reverse transcription PCR, Western blotting, and ELISA.

Results: Irradiation does not activate Hedgehog signaling in mouse salivary glands. Transient Shh overexpression activated the Hedgehog pathway in ductal epithelia and, after irradiation, rescued salivary function in male mice, which is related with preservation of functional SSPCs and parasympathetic innervation. The preservation of SSPCs was likely mediated by the rescue of signaling activities of the Bmi1 and Chrm1-HB-EGF pathways. The preservation of parasympathetic innervation was associated with the rescue of the expression of neurotrophic factors such as Bdnf and Nrtn. The expression of genes related with maintenance of SSPCs and parasympathetic innervation in female salivary glands and cultured human salivary epithelial cells was similarly affected by irradiation and transient Hedgehog activation.

Conclusions: These findings suggest that transient activation of the Hedgehog pathway has the potential to restore salivary gland function after irradiation-induced dysfunction.
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http://dx.doi.org/10.1158/1078-0432.CCR-13-1434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951215PMC
January 2014

Cessation of epithelial Bmp signaling switches the differentiation of crown epithelia to the root lineage in a β-catenin-dependent manner.

Mol Cell Biol 2013 Dec 30;33(23):4732-44. Epub 2013 Sep 30.

Institute for Regenerative Medicine at Scott & White Hospital, Molecular and Cellular Medicine Department, College of Medicine, Texas A&M Health Science Center, Houston, Texas, USA.

The differentiation of dental epithelia into enamel-producing ameloblasts or the root epithelial lineage compartmentalizes teeth into crowns and roots. Bmp signaling has been linked to enamel formation, but its role in root epithelial lineage differentiation is unclear. Here we show that cessation of epithelial Bmp signaling by Bmpr1a depletion during the differentiation stage switched differentiation of crown epithelia into the root lineage and led to formation of ectopic cementum-like structures. This phenotype is related to the upregulation of Wnt/β-catenin signaling and epithelial-mesenchymal transition (EMT). Although epithelial β-catenin depletion during the differentiation stage also led to variable enamel defect and precocious/ectopic formation of fragmented root epithelia in some teeth, it did not cause ectopic cementogenesis and inhibited EMT in cultured dental epithelia. Concomitant epithelial β-catenin depletion rescued EMT and ectopic cementogenesis caused by Bmpr1a depletion. These data suggested that Bmp and Wnt/β-catenin pathways interact antagonistically in dental epithelia to regulate the root lineage differentiation and EMT. These findings will aid in the design of new strategies to promote functional differentiation in the regeneration and tissue engineering of teeth and will provide new insights into the dynamic interactions between the Bmp and Wnt/β-catenin pathways during cell fate decisions.
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http://dx.doi.org/10.1128/MCB.00456-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3838012PMC
December 2013

Single versus dual venous anastomoses of the free fibula osteocutaneous flap in mandibular reconstruction: a retrospective study.

Microsurgery 2013 Nov 3;33(8):652-5. Epub 2013 Sep 3.

Department of Oral and Maxillofacial Surgery, Beijing Stomatological Hospital, Capital Medical University, Beijing, 100050, China.

Objective: The present study was to compare the success rates of single venous anastomosis with dual venous anastomoses of the free fibula osteocutaneous flap in mandibular reconstruction.

Patients And Methods: Retrospective review of all cases of mandibular reconstruction using free fibula osteocutaneous flaps performed by a single surgeon in our department during the period January 2005 to April 2012. All the flaps were harvested and transplanted by the standard protocols. Microvascular anastomosis of either one or two veins was performed. In addition to routine clinical evaluation, the viability of the flap was evaluated by a portable Doppler at the tenth day after surgery.

Results: Two hundred and one free fibula osteocutaneous flaps were performed during this time period. Single venous anastomosis was performed in 112 flaps and dual venous anastomoses were performed in 89 flaps. The overall incidence of vascular thrombosis was 3%, and the success rate of the transplantation was 98.5%. Six cases developed vascular thrombosis postoperatively. One was arterial thrombosis that occurred 12 hours after initial operation in the dual venous anastomoses group. Three venous thrombosis occurred 24 hr after the operation in the single venous anastomosis group. In dual venous anastomoses group, two venous thrombosis occurred 3-4 days after initial operation and attempt to salvage failed in both the cases. Fisher's exact test showed that there was no significant difference of the success rate between single and dual anastomoses groups (P = 0.59).

Conclusions: There is no difference in success rates between single venous anastomosis and dual venous anastomoses for mandibular reconstruction with free fibula osteocutaneous flap.
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http://dx.doi.org/10.1002/micr.22176DOI Listing
November 2013

Active secretion and protective effect of salivary nitrate against stress in human volunteers and rats.

Free Radic Biol Med 2013 Apr 28;57:61-7. Epub 2012 Dec 28.

Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing 100050, People's Republic of China.

Up to 25% of the circulating nitrate in blood is actively taken up, concentrated, and secreted into saliva by the salivary glands. Salivary nitrate can be reduced to nitrite by the commensal bacteria in the oral cavity or stomach and then further converted to nitric oxide (NO) in vivo, which may play a role in gastric protection. However, whether salivary nitrate is actively secreted in human beings has not yet been determined. This study was designed to determine whether salivary nitrate is actively secreted in human beings as an acute stress response and what role salivary nitrate plays in stress-induced gastric injury. To observe salivary nitrate function under stress conditions, alteration of salivary nitrate and nitrite was analyzed among 22 healthy volunteers before and after a strong stress activity, jumping down from a platform at the height of 68 m. A series of stress indexes was analyzed to monitor the stress situation. We found that both the concentration and the total amount of nitrate in mixed saliva were significantly increased in the human volunteers immediately after the jump, with an additional increase 1h later (p<0.01). Saliva nitrite reached a maximum immediately after the jump and was maintained 1h later. To study the biological functions of salivary nitrate and nitrite in stress protection, we further carried out a water-immersion-restraint stress (WIRS) assay in male adult rats with bilateral parotid and submandibular duct ligature (BPSDL). Intragastric nitrate, nitrite, and NO; gastric mucosal blood flow; and gastric ulcer index (UI) were monitored and nitrate was administrated in drinking water to compensate for nitrate secretion in BPSDL animals. Significantly decreased levels of intragastric nitrate, nitrite, and NO and gastric mucosal blood flow were measured in BPSDL rats during the WIRS assay compared to sham control rats (p<0.05). Recovery was observed in the BPSDL rats upon nitrate administration. The WIRS-induced UI was significantly higher in the BPSDL animals compared to controls, and nitrate administration rescued the WIRS-induced gastric injury in BPSDL rats. In conclusion, this study suggests that stress promotes salivary nitrate secretion and nitrite formation, which may play important roles in gastric protection against stress-induced injury via the nitrate-dependent NO pathway.
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http://dx.doi.org/10.1016/j.freeradbiomed.2012.12.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4059197PMC
April 2013

Sialin (SLC17A5) functions as a nitrate transporter in the plasma membrane.

Proc Natl Acad Sci U S A 2012 Aug 9;109(33):13434-9. Epub 2012 Jul 9.

Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing 100050, China.

In vivo recycling of nitrate (NO(3)(-)) and nitrite (NO(2)(-)) is an important alternative pathway for the generation of nitric oxide (NO) and maintenance of systemic nitrate-nitrite-NO balance. More than 25% of the circulating NO(3)(-) is actively removed and secreted by salivary glands. Oral commensal bacteria convert salivary NO(3)(-) to NO(2)(-), which enters circulation and leads to NO generation. The transporters for NO(3)(-) in salivary glands have not yet been identified. Here we report that sialin (SLC17A5), mutations in which cause Salla disease and infantile sialic acid storage disorder (ISSD), functions as an electrogenic 2NO(3)(-)/H(+) cotransporter in the plasma membrane of salivary gland acinar cells. We have identified an extracellular pH-dependent anion current that is carried by NO(3)(-) or sialic acid (SA), but not by Br(-), and is accompanied by intracellular acidification. Both responses were reduced by knockdown of sialin expression and increased by the plasma membrane-targeted sialin mutant (L22A-L23A). Fibroblasts from patients with ISSD displayed reduced SA- and NO(3)(-)-induced currents compared with healthy controls. Furthermore, expression of disease-associated sialin mutants in fibroblasts and salivary gland cells suppressed the H(+)-dependent NO(3)(-) conductance. Importantly, adenovirus-dependent expression of the sialinH183R mutant in vivo in pig salivary glands decreased NO(3)(-) secretion in saliva after intake of a NO(3)(-)-rich diet. Taken together, these data demonstrate that sialin mediates nitrate influx into salivary gland and other cell types. We suggest that the 2NO(3)(-)/H(+) transport function of sialin in salivary glands can contribute significantly to clearance of serum nitrate, as well as nitrate recycling and physiological nitrite-NO homeostasis.
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http://dx.doi.org/10.1073/pnas.1116633109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3421170PMC
August 2012
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