Lactobacillus-fermented milk products attenuate bone loss in an experimental rat model of ovariectomy-induced post-menopausal primary osteoporosis.

AIM: In this study, we investigated the anti-osteoporotic effect of two fermented milk products (FMPs) fermented by Lactobacillus plantarum A41 and Lactobacillus fermentum SRK414 on a rat model of ovariectomy-induced post-menopausal primary osteoporosis. METHODS AND RESULTS: The two Lactobacillus FMPs increased the bone volume and bone mineral density (BMD) in ovariectomized (OVX) rats, and normalized the bone biomarkers in the serum. Additionally, they altered the gene expression levels of bone-metabolism-related markers. Furthermore, the two Lactobacillus FMPs downregulated bone-apoptosis-related genes stimulated by ovariectomy. Interestingly, the Lactobacillus FMPs decreased the levels of inflammation markers in the serum, bone, ileum and colon of the rats. Gut bacterial populations were also affected upon FMP treatment due to increase in the abundance of the genus Lactobacillus and Faecalibacterium prausnitzii. CONCLUSIONS: Milk products fermented by L. plantarum A41 and L. fermentum SRK414 can exhibit anti-osteoporotic effects on post-menopausal osteoporosis via regulating the expression of bone-metabolism-related markers. SIGNIFICANCE AND IMPACT OF THE STUDY: The two Lactobacillus FMPs used in the study can be an ideal method that has its potential of treating post-menopausal osteoporosis instead of drug treatments.

Epigenetic gene regulation by histone demethylases: emerging role in oncogenesis and inflammation.

Histone N-terminal tails of nucleosomes are the sites of complex regulation of gene expression through post-translational modifications. Among these modifications, histone methylation had long been associated with permanent gene inactivation until the discovery of Lys-specific demethylase (LSD1), which is responsible for dynamic gene regulation. There are more than 30 members of the Lys demethylase (KDM) family, and with exception of LSD1 and LSD2, all other KDMs possess the Jumonji C (JmjC) domain exhibiting demethylase activity and require unique cofactors, for example, Fe(II) and α-ketoglutarate. These cofactors have been targeted when devising KDM inhibitors, which may yield therapeutic benefit. KDMs and their counterpart Lys methyltransferases (KMTs) regulate multiple biological processes, including oncogenesis and inflammation. KDMs' functional interactions with retinoblastoma (Rb) and E2 factor (E2F) target promoters illustrate their regulatory role in cell cycle progression and oncogenesis. Recent findings also demonstrate the control of inflammation and immune functions by KDMs, such as KDM6B that regulates the pro-inflammatory gene expression and CD4+ T helper (Th) cell lineage determination. This review will highlight the mechanisms by which KDMs and KMTs regulate the target gene expression and how epigenetic mechanisms may be applied to our understanding of oral inflammation.

Three-dimensional isotropic T2-weighted fast spin-echo (VISTA) ankle MRI versus two-dimensional fast spin-echo T2-weighted sequences for the evaluation of anterior talofibular ligament injury.

AIM: To compare the performance of axial images of the ankle joint on three-dimensional (3D) volume isotropic turbo spin echo acquisition (VISTA) with that of two-dimensional (2D) fast spin echo (FSE) T2-weighted images for the diagnosis of anterior talofibular ligament (ATFL) injury. MATERIALS AND METHODS: This retrospective study included 101 patients who underwent both 2D FSE T2-weighted and 3D VISTA magnetic resonance imaging (MRI) of the ankle. The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of both sequences were measured. The anatomical identification score and diagnostic performances of both sequences were evaluated by two radiologists. The diagnostic performances of 3D VISTA and 2D FSE images were analysed in terms of sensitivity, specificity, and accuracy for diagnosing ATFL injury. Surgically or clinically confirmed diagnoses were used as reference standards. RESULTS: The margin sharpness scores on 3D VISTA were significantly inferior to those of 2D FSE (p<0.001). Other scores (entire length, entire width) were not significantly different between the two imaging methods. The SNRs and CNRs of 3D VISTA were significantly higher than those of 2D FSE (p<0.001). When diagnoses were classified as normal and abnormal, the specificity of the 3D VISTA images for the diagnosis of ATFL injury was 95.7%, significantly superior to 2D FSE (84.3-85.7%). There were no significant differences between 3D VISTA and 2D FSE images in sensitivity or accuracy for diagnosis (p=0.227-1.000), with the exception of accuracy by reader 1 (p=0.039). CONCLUSION: 3D VISTA imaging has a diagnostic performance comparable to that of 2D FSE for the diagnosis of ATFL injury, although 3D VISTA is inferior to 2D FSE for the evaluation of margin sharpness. Replacing axial and coronal images with 3D VISTA can save imaging time without negatively impacting the diagnostic ability for ATFL injury.

Usefulness of the oblique coronal plane in ankle MRI of the calcaneofibular ligament.

AIM: To evaluate the usefulness and diagnostic accuracy of oblique coronal MRI of the calcaneofibular ligament (CFL) view for diagnosis of CFL injury. MATERIAL AND METHODS: This retrospective study included 91 patients who were suspected to have CFL injury who underwent CFL view imaging. Anatomical identification of the CFL on orthogonal MRI sequences and CFL views was evaluated. Two radiologists evaluated the CFL based on an entire length view, an entire width view, and margin sharpness using a four-point scale. Diagnostic accuracy using orthogonal and CFL views was evaluated by calculating sensitivity, specificity, and accuracy. Arthroscopic or clinical findings were used as the reference standard. RESULTS: Both readers found identification of lesions using the entire length, entire width, and sharp margin from CFL view images to be superior to that based on orthogonal images. The sensitivity and accuracy of diagnosing CFL injury were significantly higher when using the CFL view compared to the orthogonal view, although specificity was not significantly different between the CFL view and orthogonal view images. CONCLUSIONS: CFL view imaging enables better anatomical evaluation and improved sensitivity and accuracy of diagnosis of CFL injury. CFL view images should therefore be used to evaluate potential CFL injuries.

Relationship between polymorphisms near the IL28B gene and spontaneous HBsAg seroclearance: a systematic review and meta-analysis.

Polymorphisms near the interleukin (IL) 28B gene have been proposed to be associated with spontaneous clearance of the hepatitis C virus. The purpose of this study was to assess the relationship between IL28B polymorphisms and the rate of spontaneous hepatitis B surface antigen (HBsAg) seroclearance by means of meta-analysis. MEDLINE/PubMed and EMBASE were utilized to identify relevant studies. Odds ratio (OR) and 95% confidence interval (CI) were analysed together to assess the strength of the association. Subgroup analyses were mainly performed according to ethnicity. A total of 4028 cases with persistent chronic hepatitis B and 2327 spontaneously recovered controls were included from 11 studies. The single nucleotide polymorphism (SNP), rs12979860, had no significant association with HBsAg seroclearance (OR = 0.98, 95% CI: 0.84-1.14 in the dominant model; OR = 1.00, 95% CI: 0.68-1.46 in the recessive model; and OR = 0.95, 95% CI: 0.82-1.09 in the allelic model). The SNP, rs12980275, had no significant association either (OR = 1.03, 95% CI: 0.84-1.26 in the dominant model; OR = 1.17, 95% CI: 0.46-2.96 in the recessive model; and OR = 1.04, 95% CI: 0.86-1.26 in the allelic model), nor did the SNP, rs8099917 (OR = 0.94, 95% CI: 0.77-1.15 in the dominant model; OR = 0.74, 95% CI: 0.34-1.62 in the recessive model; and OR = 0.93, 95% CI: 0.77-1.13 in the allelic model). Similarly, the results of subgroup analyses by ethnicity also showed no association in either the Asian group or non-Asian group. We concluded that there was no significant association between common IL28B polymorphisms and the rate of spontaneous HBsAg seroclearance.

Usefulness of meniscal width to transverse diameter ratio on coronal MRI in the diagnosis of incomplete discoid lateral meniscus.

AIM: To evaluate the clinical utility of the meniscal width to transverse diameter ratio (L/M ratio) of the lateral meniscus in the diagnosis of incomplete discoid lateral meniscus (IDLM) as compared with the arthroscopic diagnosis, meniscal width to tibial diameter ratio (L/T ratio) and conventional lateral meniscus width criteria. MATERIALS AND METHODS: This retrospective study sample included 41 patients with IDLM who underwent knee magnetic resonance imaging (MRI) and arthroscopy, as well as 50 controls with normal lateral menisci. MRI examinations were interpreted independently by two radiologists, both of whom were blinded to clinical information and radiological reports. Assessment of meniscal width (L), maximal transverse diameter of the lateral meniscus (M), and transverse diameter of the tibia (T) was carried out on central coronal sections that were observed to pass through the medial collateral ligament. L/M and L/T ratios were calculated. These results were correlated with arthroscopic findings and analysed statistically using categorical regression analysis and non-parametric correlation analysis. Using arthroscopic findings as the standard of reference, sensitivity and specificity were calculated for: (1) 12, 13, 14, and 15 mm meniscal width thresholds; (2) 40%, 50%, 60%, and 70% L/M ratio thresholds; and (3) 15%, 18%, 20%, and 25% L/T ratio thresholds. RESULTS: The mean L/M ratio of the IDLM was approximately 67% and was statistically significantly higher than the control (44%). The best diagnostic discrimination was achieved using a threshold of 50%. The mean L/T ratio of the IDLM was approximately 23% and was statistically significant. The best diagnostic discrimination was achieved using a threshold of 18%. The threshold of 13 mm of meniscal width also showed high sensitivity and high specificity. CONCLUSION: The use of the L/M ratio or L/T ratio in combination with meniscal width criteria may be a useful method for evaluating IDLM.

Eckols reduce dental pulp inflammation through the ERK1/2 pathway independent of COX-2 inhibition.

OBJECTIVES: The aim of this study was to elucidate the role of 6-6 bieckol (EB1) and pholorofucofuroeckol-A (EB5) from brown seaweed marine algae (Eisenia bicyclis) on lipopolysaccharide (LPS)-induced inflammation in human dental pulp cells (HDPCs). METHODS: The cytotoxicity of EB1 and EB5 was examined by MTT assay on LPS-induced human dental pulp cells. Their role on expression of inflammatory, odontogenic, and osteogenic molecules was determined by Western blot analysis. The dentin mineralization was checked by alkaline phosphatase activity. RESULTS: The five compounds from E. bicyclis have different structure with non-cytotoxic in HDPCs. EB1 and EB5 showed anti-inflammatory properties and inhibited phosphorylated-extracellular signal-regulated kinase (p-ERK1/2) and phosphorylated-c-jun N-terminal kinases (p-JNK) without any cytotoxicity. In particular, EB1 inhibited cyclooxygenase-2 (COX-2) and p-ERK1/2 signaling, and EB5 inhibited only p-ERK1/2 signaling but not COX-2. Both compounds inhibited nuclear factor kappa-B (NF-κB) translocation. Furthermore, EB1 and EB5 increased dentinogenic and osteogenic molecules, and dentin mineralized via alkaline phosphatase activity (ALP) in LPS-induced HDPCs. CONCLUSIONS: This study elucidates that EB1 and EB5 have different types of anti-inflammatory property and help in dentin formation. Therefore, these compounds derived from marine algae of E. bicyclis may be used as selective therapeutic strategies for pulpitis and oral diseases.

Soybean extract showed modulation of retinoic acid-related gene expression of skin and photo-protective effects in keratinocytes.

Soy extracts are well known as medicinal and nutritional ingredients, and exhibit benefits towards human skin including depigmenting or anti-ageing effects. Despite the wrinkle decreasing effects of retinoids on skin as an anti-ageing ingredient, retinoid application can causes photo-sensitive responses such as skin irritation. Thus, their daytime usage is not recommended. The aim of this study is the investigation into the activities of soybean extract as an anti-ageing ingredient and their comparison to retinoids in this respect. Soybean extract decreased the relative ratio of MMP-1/TIMP-1 mRNA to the same degree as retinoic acid in normal human fibroblasts. It also affected mRNA levels of HAS2 and CRABP2 in normal human keratinocytes. Furthermore, we investigated its effect on mRNA expression of histidase, an enzyme that converts histidine into urocanic acid, the main UV light absorption factor of the stratum corneum. Unlike the complete inhibition of histidase exhibited by the mRNA expression of retinoic acid, the effect of soybean extract on histidase gene expression was weaker in normal human keratinocytes. Also, soybean extract pretreatment inhibited UVB-induced cyclobutane pyrimidine dimer formation dose-dependently in normal human keratinocytes. In this study, we found that soybean extract modulated retinoic acid-related genes and showed photo-protective effects. Our findings suggest that soybean extract could be an anti-ageing ingredient that can be safely used under the sunlight.

Metabolic syndrome is associated with increased risk of recurrent colorectal adenomas in Korean men.

OBJECTIVE: Because of the high incidence of recurrent colorectal adenomas, regular surveillance by colonoscopy is recommended. However, there is still a shortage of information on the factors that influence the incidence of recurrent colorectal adenomas in patients with a history of these lesions. The aim of this study was to determine the association between the development of recurrent colorectal adenomas, metabolic syndrome and obesity. SUBJECTS AND METHODS: The hospital-based cohort was composed of 193 patients who had recurrent colorectal adenomas removed between January 2002 and December 2003. The Cox proportional hazard model was used to determine hazard ratio (HR) and 95% confidence interval (CI) between obesity, metabolic syndrome and other factors, and the incidence of recurrent adenomatous polyps. RESULTS: The mean follow-up period was 4.8 person-years. In all, 78 of the patients (40.4%) had recurrent colorectal adenomas. In the overall recurrent adenoma group, significant associations between metabolic syndrome (HR, 1.33; 95% CI, 1.02-1.73), waist circumference (WC) ≥ 90 cm (HR, 1.42; 95% CI, 1.06-1.90) and waist-hip ratio (WHR) ≥ 0.9 (HR, 2.03; 95% CI, 1.55-2.68) were found. Moreover, advanced adenomas were significantly associated with metabolic syndrome (HR, 2.81; 95% CI, 1.86-4.25), body mass index ≥ 25 kg m(-2) (HR, 2.69; 95% CI, 1.64-4.42), WC (HR, 2.16; 95% CI, 1.31-3.54) and WHR (HR, 1.99; 95% CI, 1.28-3.11). In addition, current smoking (HR, 2.60; 95% CI, 1.09-6.25) and alcohol consumption (HR, 2.20; 95% CI, 1.10-4.39) were also significantly associated with recurrent advanced adenoma. CONCLUSION: Metabolic syndrome and obesity were significantly associated with the development of recurrent colorectal adenomas in Korean adult males. Furthermore, these associations were more strongly associated with advanced adenomas.

Prediction of response to entecavir therapy in patients with HBeAg-positive chronic hepatitis B based on on-treatment HBsAg, HBeAg and HBV DNA levels.

Quantitative hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) assays are emerging as effective tools of on-treatment predictors of response to antiviral agents, in addition to monitoring serum HBV DNA levels. However, the dynamic relationship between quantitative HBsAg, as well as HBeAg and HBV DNA, and the predictability of subsequent clinical outcomes during entecavir (ETV) therapy remain unclear. Eighty-two patients with HBeAg-positive chronic hepatitis B (CHB) received ETV therapy for ≥3 years. Virologic response (VR) after 3 years of ETV therapy was achieved in 73 (89.0%) patients. Among baseline and on-treatment factors, on-treatment HBV DNA levels performed better with respect to the prediction of response than HBsAg and HBeAg levels. Especially, the performance of absolute values of HBV DNA with respect to response was superior to HBV DNA decline from the baseline. The best predictive value was an absolute HBV DNA level of 2.3 log(10) IU/mL at month 6 (areas under the curve [AUROC], 0.977; 95% CI, 0.940-1.000; P < 0.001). HBeAg seroconversion after 3 years of therapy was achieved in 26 (31.7%) patients. On-treatment HBeAg levels performed better with respect to the prediction of seroconversion than HBsAg and HBV DNA levels. The best cut-off value for the HBeAg level at month 12 for the prediction of seroconversion was 0.62 log(10) PEIU/mL. Although the HBsAg level at baseline is often used to predict the antiviral potency of entecavir, on-treatment HBV DNA and HBeAg levels are more helpful for prediction of subsequent clinical outcomes in HBeAg-positive CHB patients with entecavir treatment.

Accuracy of MRI findings in chronic lateral ankle ligament injury: comparison with surgical findings.

AIM: To evaluate the accuracy of magnetic resonance imaging (MRI) findings in chronic lateral ankle ligament injury in comparison with that of surgical findings. MATERIALS AND METHODS: Forty-eight cases (25 men, 23 women, mean age 36 years) of clinically suspected chronic ankle ligament injury underwent MRI studies and surgery. Sagittal, coronal, and axial, T1-weighted, spin-echo, proton density and T2-weighted, fast spin-echo images with fat saturation were obtained in all patients. MRI examinations were read in consensus by two fellowship-trained academic musculoskeletal radiologists who evaluated the lateral ankle ligaments, including the anterior talofibular ligament (ATFL) and calcaneofibular ligament (CFL) without clinical information. The results of the MRI studies were then compared with the surgical findings. RESULTS: The MRI findings of ATFL injury showed a sensitivity of detection of complete tears of 75% and specificity of 86%. The sensitivity of detection of partial tears was 75% and the specificity was 78%. The sensitivity of detection of sprains was 44% and the specificity was 88%. Regarding the MRI findings of CFL injury, the sensitivity of detection of complete tears was 50% and the specificity was 98%. The sensitivity of detection of partial tear was 83% and the specificity was 93%. The sensitivity of detection of sprains was 100% and the specificity was 90%. Regarding the ATFL, the accuracies of detection were 88, 58, 77, and 85% for no injury, sprain, partial tear, and complete tear, respectively, and for the CFL the accuracies of detection were 90, 90, 92, and 96% for no injury, sprain, partial tear, and complete tear, respectively. CONCLUSIONS: The diagnosis of a complete tear of the ATFL on MRI is more sensitive than the diagnosis of a complete tear of the CFL. MRI findings of CFL injury are diagnostically specific but are not sensitive. However, only normal findings and complete tears were statistically significant between ATFL and CFL (p < 0.001).

BubR1 as a prognostic marker for recurrence-free survival rates in epithelial ovarian cancers.

BACKGROUND: Epithelial ovarian cancer is one of the most lethal malignancies, and has a high recurrence rate. Thus, prognostic markers for recurrence are crucial for the care of ovarian cancer. As ovarian cancers frequently exhibit chromosome instability, we aimed at assessing the prognostic significance of two key mitotic kinases, BubR1 and Aurora A. METHODS: We analysed paraffin-embedded tissue sections from 160 ovarian cancer patients whose clinical outcomes had been tracked after first-line treatment. RESULTS: The median recurrence-free survival in patients with a positive and negative expression of BubR1 was 27 and 83 months, respectively (P<0.001). A positive BubR1 expression was also associated with advanced stage, serous histology and high grade. In contrast, Aurora A immunostaining did not correlate with any of the clinical parameters analysed. CONCLUSION: BubR1, but not Aurora A, is a prognostic marker for recurrence-free survival rates in epithelial ovarian cancers.

Porphyromonas gingivalis Impairs Oral Epithelial Barrier through Targeting GRHL2.

Oral mucosa provides the first line of defense against a diverse array of environmental and microbial irritants by forming the barrier of epithelial cells interconnected by multiprotein tight junctions (TJ), adherens junctions, desmosomes, and gap junction complexes. Grainyhead-like 2 (GRHL2), an epithelial-specific transcription factor, may play a role in the formation of the mucosal epithelial barrier, as it regulates the expression of the junction proteins. The current study investigated the role of GRHL2 in the Porphyromonas gingivalis (Pg)-induced impairment of epithelial barrier functions. Exposure of human oral keratinocytes (HOK-16B and OKF6 cells) to Pg or Pg-derived lipopolysaccharides (Pg LPSs) led to rapid loss of endogenous GRHL2 and the junction proteins (e.g., zonula occludens, E-cadherin, claudins, and occludin). GRHL2 directly regulated the expression levels of the junction proteins and the epithelial permeability for small molecules (e.g., dextrans and Pg bacteria). To explore the functional role of GRHL2 in oral mucosal barrier, we used a Grhl2 conditional knockout (KO) mouse model, which allows for epithelial tissue-specific Grhl2 KO in an inducible manner. Grhl2 KO impaired the expression of the junction proteins at the junctional epithelium and increased the alveolar bone loss in the ligature-induced periodontitis model. Fluorescence in situ hybridization revealed increased epithelial penetration of oral bacteria in Grhl2 KO mice compared with the wild-type mice. Also, blood loadings of oral bacteria (e.g., Bacteroides, Bacillus, Firmicutes, ß-proteobacteria, and Spirochetes) were significantly elevated in Grhl2 KO mice compared to the wild-type littermates. These data indicate that Pg bacteria may enhance paracellular penetration through oral mucosa in part by targeting the expression of GRHL2 in the oral epithelial cells, which then impairs the epithelial barrier by inhibition of junction protein expression, resulting in increased alveolar tissue destruction and systemic bacteremia.

Association of cyclin D1 G870A polymorphism with uterine leiomyoma in women whose body mass index values are above 25 kg/m2.

BACKGROUND: Many studies have shown that a polymorphism (G870A) in cyclin D1 (CCND1) is associated with carcinogenesis in a variety of cancers. Our aim was to determine if an association exists between the CCND1 G870A polymorphism and uterine leiomyoma in Korean women. METHODS: Blood samples of 331 cases and 204 controls aged 47.4 +/- 7.6 and 46.8 +/- 10.4 years (mean +/- SD), respectively, were collected. CCND1 genotyping was determined by PCR and restriction fragment length polymorphism. RESULTS: Allelic frequencies of cases (A, 0.53; G, 0.47) were not significantly different from those of controls (A, 0.49; G, 0.51) (P = 0.22). After adjustment for menarche age and BMI, multivariate logistic regression analysis showed that the AA genotype was not associated with increased risk for uterine leiomyoma [odds ratio (OR) = 1.38, 95% confidence interval (CI); 0.85-2.26, P = 0.19]. However, in stratification analysis of cases and controls with BMI >25 kg/m(2), allelic frequencies of cases (A, 0.56; G, 0.44) were significantly different from controls (A, 0.36; G, 0.64) (P = 0.005), and the AA genotype was associated with increased risk for uterine leiomyoma (OR = 3.61, 95% CI; 1.02-12.73, P = 0.046). Furthermore, the OR for AA compared with combined GG and AG genotypes was 3.16 (95% CI 1.01-9.92, P = 0.048). CONCLUSIONS: The A allele and AA genotype of CCND1 G870A polymorphism have a significant association with an increased risk of the uterine leiomyoma in obese Korean women.

Characteristics of recurrence in adult-type granulosa cell tumor.

Granulosa cell tumor (GCT) of the ovary is a very rare neoplasm, which is characterized by an indolent clinical course. Thus, the clinical characteristics, optimal treatment, and follow-up protocols are not well established. The goal of this study is to evaluate clinical findings, prognostic factors, and recurrent features of GCT in Korean patients. Between 1987 and 2005, 42 cases of GCT were diagnosed in our institution. There were 35 cases showing adult-type GCT, which were available for evaluation. All charts were reviewed, and the clinical data along with treatment results were retrospectively studied. Statistical analyses were performed for risk factors of recurrence and disease-free survival. GCT accounted for 3% of all ovarian malignancies in our institution during the study period. The median age was 45 years (range, 24-68 years). Abdominal and hormone-related symptoms were the main causes of first presentation. There were eight cases of recurrence including two cases of disease-related deaths during the median follow-up period of 177 months (range, 8-212 months). Factors affecting the recurrence involved residual tumor and stage, but residual tumor was the only significant factor of recurrence in multivariate analysis. The median time to relapse was 75 months (range, 55-137 months), and the liver was the most common extra-pelvic metastatic site followed by the intestine. Continuous long-term follow-up with pelvic and whole-abdominal surveillance is absolutely required. Active management including complete tumorectomy is the most important treatment modality in both primary surgeries and recurrent cases.

Antipyretic, analgesic, and anti-inflammatory activities of the seaweed Sargassum fulvellum and Sargassum thunbergii in mice.

Dichloromethane, ethanol, and boiling water extracts of the brown seaweeds Sargassum fulvellum and Sargassum thunbergii were examined for antipyretic, analgesic, and anti-inflammatory activities in mice. The activities were evaluated against yeast-induced pyrexia, tail-flick test, and phorbol myristate acetate-induced inflammation (edema, erythema, and blood flow). The dichloromethane extract (0.4 mg/ear) of Sargassum fulvellum inhibited an inflammatory symptom of mouse ear edema by 79.1%. The ethanol extract (0.4 mg/ear) of Sargassum thunbergii also inhibited edema by 72.1%. No acute toxicity was observed after p.o. administration of each extract (5 g/kg bw). These findings are consistent with various claims that these seaweeds can be used as remedies for inflammation-related symptoms.

Human Papillomavirus 16 E6 Induces FoxM1B in Oral Keratinocytes through GRHL2.

High-risk human papillomavirus (HPV) is a major risk factor for oral and pharyngeal cancers (OPCs), yet the detailed mechanisms by which HPV promotes OPCs are not understood. Forkhead box M1B (FoxM1B) is an oncogene essential for cell cycle progression and tumorigenesis, and it is aberrantly overexpressed in many tumors. We previously showed that FoxM1B was the putative target of an epithelial-specific transcription factor, Grainyhead-like 2 (GRHL2). In the current study, we demonstrate that HPV type 16 (HPV-16) E6 induces FoxM1B in human oral keratinocytes (HOKs) and tonsillar epithelial cells (TECs) in part through GRHL2. FoxM1B was barely detectable in cultured normal human oral keratinocytes (NHOKs) and progressively increased in immortalized HOKs harboring HPV-16 genome (HOK-16B) and tumorigenic HOK-16B/BaP-T cells. Retroviral expression of HPV-16 E6 and/or E7 in NHOKs, TECs, and hypopharyngeal carcinoma cells (FaDu) revealed induction of FoxM1B and GRHL2 by the E6 protein but not E7. Both GRHL2 and FoxM1B were strongly induced in the epidermis of HPV-16 E6 transgenic mice and HPV+ oral squamous cell carcinomas. Ectopic expression of FoxM1B led to acquisition of transformed phenotype in HOK-16B cells. Loss of FoxM1B by lentiviral short hairpin RNA vector or chemical inhibitor led to elimination of tumorigenic characteristics of HOK-16B/BaP-T cells. Luciferase reporter assay revealed that GRHL2 directly bound and regulated the FoxM1B gene promoter activity. Using epithelial-specific Grhl2 conditional knockout mice, we exposed wild-type (WT) and Grhl2 KO mice to 4-nitroquinolin 1-oxide (4-NQO), which led to induction of FoxM1B in the tongue tissues and rampant oral tumor development in the WT mice. However, 4-NQO exposure failed to induce tongue tumors or induction of FoxM1B expression in Grhl2 KO mice. Collectively, these results indicate that HPV-16 induces FoxM1B in part through GRHL2 transcriptional activity and that elevated FoxM1B level is required for oropharyngeal cancer development.

Relevance of common carotid intima-media thickness and carotid plaque as risk factors for ischemic stroke in patients with type 2 diabetes mellitus.

BACKGROUND AND PURPOSE: An increase in the common carotid artery intima-media thickness (CCA-IMT) is generally considered an early marker of atherosclerosis. This cross-sectional study assessed the CCA-IMT and plaque score as vascular risk factors in patients with ischemic stroke and type 2 diabetes. MATERIALS AND METHODS: Brain MR imaging and carotid ultrasonography were performed in 133 subjects with type 2 diabetes. IMT was measured at both CCAs. Differences in the variables between case and control subjects were compared statistically. To determine the independent factors related to CCA-IMT and plaque score, we performed stepwise multiple regression analysis. RESULTS: Sex, current smoking habit, history of hypertension, and high-density lipoprotein (HDL) levels differed significantly between the case and control groups. CCA-IMT and plaque score in patients with diabetes and acute ischemic stroke were significantly greater than in patients with diabetes who were stroke-free. The crude odds ratios suggested that CCA-IMT and plaque score are risk factors of acute ischemic stroke in patients with type 2 diabetes. However, when we adjusted for cerebrovascular risk factors, CCA-IMT and plaque score did not remain significantly associated with acute ischemic stroke. CONCLUSION: Increased CCA-IMT and plaque score are associated with acute ischemic stroke in patients with type 2 diabetes. The higher CCA-IMT and plaque score found in ischemic stroke in patients with type 2 diabetes seem to be induced by cerebrovascular risk factors. Therefore, to prevent ischemic stroke in patients with type 2 diabetes, strict control of hyperglycemia, hypertension, smoking, and low HDL, together with monitoring of CCA-IMT and carotid plaque, may be important.

Effects of Bioactive Compounds on Odontogenic Differentiation and Mineralization.

Direct pulp capping involves the placement of dental materials directly onto vital pulp tissues after deep caries removal to stimulate the regeneration of reparative dentin. This physical barrier will serve as a "biological seal" between these materials and the pulp tissue. Although numerous direct pulp capping materials are available, the use of small bioactive compounds that can potently stimulate and expedite reparative dentin formation is still underexplored. Here, the authors compared and evaluated the pro-osteogenic and pro-odontogenic effects of 4 small bioactive compounds- phenamil (Phen), purmorphamine (Pur), genistein (Gen), and metformin (Met). The authors found that these compounds at noncytotoxic concentrations induced differentiation and mineralization of preosteoblastic MC3T3-E1 cells and preodontoblastic dental pulp stem cells (DPSCs) in a dose-dependent manner. Among them, Phen consistently and potently induced differentiation and mineralization in vitro. A single treatment with Phen was sufficient to enhance the mineralization potential of DPSCs in vitro. More importantly, Phen-treated DPSCs showed enhanced odontogenic differentiation and mineralization in vivo. Our study suggests that these small bioactive compounds merit further study for their potential clinical use as pulp capping materials.

Polyphenol (-)-epigallocatechin gallate protection from ischemia/reperfusion-induced renal injury in normotensive and hypertensive rats.

INTRODUCTION: The effect of epigallocatechin gallate (EGCG) in an in vivo renal model of ischemia with reperfusion (I/R) was compared between normotensive (WKR) and hypertensive (SHR) rats. METHODS: WKR (groups I, II, III) and SHR groups (groups IV, V, VI) were divided into three types. Groups I and IV were sham-operated animals; groups II and V were subjected to 45 minutes of renal I/R; and groups III and VI received 10 mg/kg EGCG intravenously at the time of reperfusion. Three days after renal I/R, we compared renal function markers, malondialdehyde (MDA), and histologic changes. RESULTS: Following renal I/R, levels of blood urea nitrogen (BUN) and serum creatinine (sCr) were increased and serum creatinine clearance (CrCl) decreased in group V compared to group II (P < .001). Those receiving EGCG treatment (groups III and VI) had decreased BUN and sCr compared to non-EGCG I/R groups (P < .001), but not surprisingly, higher than sham groups. CrCl was lowest in the SHR groups. The MDA was significantly decreased after EGCG treatment (P = .028 in group III, P = .002 in group VI). Following renal I/R, tissue necrosis was more severe among SHR (P < .001). However, the ratio of regeneration to damage significantly increased in SHR after EGCG treatment. CONCLUSIONS: The reperfusion injury was greater among SHR compared with WKR in terms of renal function, lipid peroxidation, and tissue damage. EGCG treatment significantly ameliorated renal impairment and promoted tissue regeneration following renal I/R.