Nickel Nanoparticles Induced Hepatotoxicity in Mice via Lipid-Metabolism-Dysfunction-Regulated Inflammatory Injury.

Nickel nanoparticles (NiNPs) have wide applications in industry and biomedicine due to their unique characteristics. The liver is the major organ responsible for nutrient metabolism, exogenous substance detoxification and biotransformation of medicines containing nanoparticles. Hence, it is urgent to further understand the principles and potential mechanisms of hepatic effects on NiNPs administration. In this study, we explored the liver impacts in male C57/BL6 mice through intraperitoneal injection with NiNPs at doses of 10, 20 and 40 mg/kg/day for 7 and 28 days. The results showed that NiNPs treatment increased serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and induced pathological changes in liver tissues. Moreover, hepatic triglyceride (TG) content and lipid droplet deposition identified via de novo lipogenesis (DNL) progression were enhanced after NiNPs injection. Additionally, sustained NiNPs exposure induced a remarkable hepatic inflammatory response, significantly promoted endoplasmic reticulum stress (ER stress) sensors Ire1α, Perk and Atf6, and activated the occurrence of liver cell apoptosis. Overall, the research indicated that NiNPs exposure induced liver injury and disturbance of lipid metabolism. These findings revealed the public hazard from extreme exposure to NiNPs and provided new information on biological toxicity and biosafety evaluation.

[Study of salivary metabonomics in patients with oral squamous cell carcinoma and leukoplakia].

PURPOSE: The objective of this study was to detect and analyze the existence of differential metabolites from saliva of patients with oral squamous cell carcinoma(OSCC) by metabonomics method, and to evaluate its application value on clinical diagnosis or screening of OSCC. METHODS: The collected saliva samples for OSCC patients, oral leukoplakiac(OLK) patients who were pathologically diagnosed and met the inclusion criteria were analyzed using metabonomics methods (GC-TOF-MS). The results were analyzed by principal component analysis and orthogonal partial least squares discriminant analysis using SIMCA software. RESULTS: The metabolic profiles of OSCC, OLK and healthy control group showed significant differences (P<0.05). In total, 15 typical differential metabolites among the three groups were detected. Further study focusing on metabolic pathway revealed imbalance of protein, energy and lipid metabolism between OSCC and OLK patients. Abnormal tricarboxylic acid cycle was detected as well. CONCLUSIONS: Metabonomics methods is feasible for differential metabolites analysis,15 differential metabolites were detected in OSCC,OLK patients and healthy people. These findings will contribute to the early screening of oral squamous cell carcinoma.

[Related factors of atrophic glossitis in 124 consecutive cases].

PURPOSE: To study the relationship between atrophic glossitis and anemia, anemia types and other related factors(oral candida infection, xerostomia) in 124 consecutive cases. METHODS: One hundred and twenty-four cases with atrophic glossitis and 53 healthy controls were collected from Qingdao local population. The main indexes including general status, oral examination findings, hemoglobin (Hb), mean red blood cell volume (MCV), vitamin B12, ferritin, folic acid, anemia and anemia type, xerostomia and candida infection were statistically analyzed using SPSS 20.0 software package for Student's t test. RESULTS: Among 124 cases of glossitis group, 48.39% were found with anemia, 41.94% with xerostomia, 79.03% with Candida infection, 29.03% with Vitamin B12 deficiency, 22.58% with ferritin deficiency, 11.29% with folic acid deficiency. The contents of hemoglobin, ferritin and vitamin B12 in glossitis group were significantly lower than those in the control group(P<0.05), and the number of glossitis patients with anemia, xerostomia and candida infection were significantly higher than those in the control group (P<0.05). There was no significant difference in folic acid content between the two groups(P<0.05). CONCLUSIONS: Occurrence of atrophic glossitis is closely related to anemia, vitamin B12 deficiency, ferritin deficiency, xerostomia, oral candida infection. There is no correlation with folic acid deficiency. Patients with atrophic glossitis accompanied by anemia have a higher proportion of macrocytic anemia.

A personalized computational model predicts cancer risk level of oral potentially malignant disorders and its web application for promotion of non-invasive screening.

BACKGROUND: Despite their high accuracy to recognize oral potentially malignant disorders (OPMDs) with cancer risk, non-invasive oral assays are poor in discerning whether the risk is high or low. However, it is critical to identify the risk levels, since high-risk patients need active intervention, while low-risk ones simply need to be follow-up. This study aimed at developing a personalized computational model to predict cancer risk level of OPMDs and explore its potential web application in OPMDs screening. METHODS: Each enrolled patient was subjected to the following procedure: personal information collection, non-invasive oral examination, oral tissue biopsy and histopathological analysis, treatment, and follow-up. Patients were randomly divided into a training set (N = 159) and a test set (N = 107). Random forest was used to establish classification models. A baseline model (model-B) and a personalized model (model-P) were created. The former used the non-invasive scores only, while the latter was incremented with appropriate personal features. RESULTS: We compared the respective performance of cancer risk level prediction by model-B, model-P, and clinical experts. Our data suggested that all three have a similar level of specificity around 90%. In contrast, the sensitivity of model-P is beyond 80% and superior to the other two. The improvement of sensitivity by model-P reduced the misclassification of high-risk patients as low-risk ones. We deployed model-P in web.opmd-risk.com, which can be freely and conveniently accessed. CONCLUSION: We have proposed a novel machine-learning model for precise and cost-effective OPMDs screening, which integrates clinical examinations, machine learning, and information technology.

Regulation of proliferation and cell cycle by protein regulator of cytokinesis 1 in oral squamous cell carcinoma.

Protein regulator of cytokinesis 1 (PRC1), a microtubule-associated protein, has emerged as a critical regulator of proliferation and apoptosis, acting predominantly in numerous tumors. However, its function in oral squamous cell carcinoma (OSCC) is still unknown. To establish the roles of PRC1 in OSCC, 95 oral clinical samples (54 OSCC, 24 oral leukoplakia [OLK], and 17 normal oral mucosa) and seven oral cell lines (6 OSCC and 1 normal oral cell lines) were analyzed using a series of molecular and genomic assays both in vivo and in vitro were conducted in this study. Herein, we provide evidence demonstrating that expression of PRC1 closely correlates with the degree of epithelial dysplasia in OLK (n = 24) (p < 0.001), and the poor differentiation, large tumor volume, lymph node metastasis, and high-clinical stage in OSCC (n = 54) (p < 0.05), illustrating that PRC1 has a promotive influence on tumor progression in OSCC. Simultaneously, we observed that PRC1 knockdown in OSCC cell lines caused G2/M phase arrest (p < 0.05), inhibited cell proliferation in vitro (p < 0.05) and tumor growth in vivo (p < 0.001). Furthermore, the effects of PRC1 on the regulation of proliferation and cell cycle transition in OSCC samples were mediated by p53. The p53/PRC1/EGFR signaling pathway was found to be implicated in the tumor progression of OSCC. Based on our data, we demonstrate that PRC1 is a key factor in regulating proliferation and the cell cycle, pointing to the potential benefits of PRC1-targeted therapies for OSCC.

Reduced CX3CL1 Secretion Contributes to the Susceptibility of Oral Leukoplakia-Associated Fibroblasts to Candida albicans.

Candida leukoplakia (OLK) is a kind of oral leukoplakia combined with chronic candidal infection, which plays an important role in the malignant transformation of OLK. However, little is known about the etiology, including susceptibility of leukoplakia to candidal adhesion, invasion and infection. Some antimicrobial peptides secreted by oral epithelial cells or fibroblasts potentially have antifungal activities against Candida albicans (C. albicans). In this study, we established three co-culture models to simulate different C. albicans-fibroblasts interactions during progression of candida leukoplakia. The susceptibility of oral leukoplakia-associated fibroblasts (LKAFs) to C. albicans and its underlying mechanism were determined. Samples of 14 LKAFs and 10 normal fibroblasts (NFs) were collected. The co-culture models showed that LKAFs had promoted the adhesion, invasion, and survival of C. albicans compared with NFs. CX3CL1, a chemokine with antifungal activity, was less abundant in LKAFs than NFs. Overexpression of CX3CL1 via transfection in LKAFs could partly restore the resistance to C. albicans. We also showed that inhibition of ERK could suppress CX3CL1 secretion. While phosphor-ERK was inhibited in LKAFs compared with NFs. Besides, the mRNA expression of a shedding enzyme for CX3CL1, disintegrin and metalloproteinase domain (ADAM) 17 was decreased in LKAFs than NFs. In conclusion, LKAFs produced and secreted less CX3CL1 by inhibiting the ERK signaling pathway, thereby contributing to impaired cell resistance to C. albicans.

Single and 14-day repeated dose inhalation toxicity studies of hexabromocyclododecane in rats.

Limited toxicological information is available for hexabromocyclododecane (HBCD),a widely used additive brominated flame retardant. Inhalation is a major route of human exposure to HBCD. The aim of this study was to determine the acute inhalation toxicity and potential subchronic inhalation toxicity of HBCD in Sprague-Dawley rats exposed to HBCD only through inhalation. The acute inhalation toxicity of HBCD was determined using the limit test method on five male and five female Sprague-Dawley rats at a HBCD concentration of 5000 mg/m(3). Repeated-dose toxicity tests were also performed, with 20 males and 20 females randomly assigned to four experimental groups (five rats of each sex in each group). There were three treatment groups (exposed to HBCD concentrations of 125,500, and 2000 mg/m(3)) and a blank control group (exposed to fresh air). In the acute inhalation toxicity study, no significant clinical signs were observed either immediately after exposure or during the recovery period. Gross pathology examination revealed no evidence of organ-specific toxicity in any rat. The inhalation LC50(4 h) for HBCD was higher than 5312 ± 278 mg/m3 for both males and females. In the repeated dose inhalation study, daily head/nose-only exposure to HBCD at 132 ± 8.8, 545.8 ± 35.3, and 2166.0 ± 235.9 mg/m(3) for 14 days caused no adverse effects. No treatment-related clinical signs were observed at any of the test doses. The NOAEL for 14-day repeated dose inhalation toxicity study of HBCD is 2000 mg/m(3).

Inhibitory effects of oral Actinomyces on the proliferation, virulence and biofilm formation of Candida albicans.

OBJECTIVE: The pathogenesis of Candida-associated stomatitis involves the dysfunction of flora antagonistic to Candida. Oral Actinomyces species play an important role in regulating the oral microecological balance. The objective of this study was to investigate the antagonism of three oral Actinomyces against Candida albicans. DESIGN: Suspensions, culture supernatants and bacterial lysates of Actinomyces viscosus, Actinomyces naeslundii and Actinomyces odontolyticus were investigated for their actions upon C. albicans. In addition to a commercial strain, six clinical strains of C. albicans were also tested. The proliferation of C. albicans was assessed using a liquid co-cultivation assay. The adhesion, acid protease and extracellular phospholipase activity, hyphae growth, and biofilm formation of C. albicans were measured. RESULTS: The results showed that the suspensions, culture supernatants and cell lysates of 10(8) colony forming units/ml oral Actinomyces significantly inhibited the proliferation of C. albicans (all P<0.001). The culture supernatants exhibited significant antagonistic interactions in terms of adhesion (A. viscosus P<0.001, A. naeslundii P=0.016 and A. odontolyticus P=0.009), acid protease (A. viscosus P=0.035, A. naeslundii P=0.022, A. odontolyticus P<0.001) and phospholipase activities (A. viscosus P=0.011, A. naeslundii P=0.042, A. odontolyticus P=0.021) of Candida, as well as its hyphae growth (A. viscosus P=0.002, A. naeslundii P=0.008, A. odontolyticus P=0.006). Inhibition of C. albicans biofilm formation was also observed. CONCLUSIONS: This study provides preliminary evidence that oral Actinomyces have inhibitory effects on the proliferation, adhesion, metabolic enzyme activity, hyphae formation and biofilm development of C. albicans.

Efficacy and safety of dexamethasone ointment on recurrent aphthous ulceration.

OBJECTIVE: Recurrent aphthous ulceration is the most common oral mucosal lesion and may be associated with many systemic diseases. Topical corticosteroids are used frequently for recurrent aphthous ulceration; however, the number of high-quality clinical experiments available is insufficient, and no reports exist on the blood level of corticosteroids after topical usage in the oral mucosa. The objective was to determine the efficacy and safety of dexamethasone ointment in the treatment of recurrent aphthous ulceration and detect serum dexamethasone concentrations in the patients. METHODS: A randomized, double-blinded, placebo-controlled, parallel, multicenter clinical trial was conducted in 5 centers to compare the efficacy and safety of dexamethasone ointment with placebo. There were 810 patients with minor recurrent aphthous ulcerations screened for study eligibility, and 240 patients were enrolled at 5 centers from March 1, 2009 to April 30, 2010; 120 were assigned randomly to the treatment group and 120 to a control group. Patients were instructed to apply the given agent to the identified ulcer 3 times a day (after meals) for 5 days. The size, pain level, healing ratio, and average duration of ulcers and the safety of the agents were evaluated. The serum concentration of dexamethasone was detected using a high-performance liquid chromatography/mass spectrometry assay. RESULTS: The results showed that baseline characteristics were similar (P>.5). At day 6 ± 2 after treatment, there was significant difference in the variation of ulcer size between the treatment group (7.167 ± 6.3415 mm(2)) and the control group (4.346 ± 7.0666 mm(2); P = .000); and in the variation of pain level between the treatment group (5.623 ± 1.9570) and the control group (4.940 ± 2.2449; P = .001). The healing ratio was 83.33% in the treatment group and 54.70% in the control group (P = .000). No severe adverse reactions were observed. No serum dexamethasone was detected before or after the use of the agents (<0.502 ng/mL). CONCLUSION: Dexamethasone ointment was efficient in the treatment of recurrent aphthous ulceration and was safe as evaluated using clinical assessment and serum level detection.