Characterization of Effectiveness in Concerted Ih Inhibition and IK(Ca) Stimulation by Pterostilbene (Trans-3,5-dimethoxy-4'-hydroxystilbene), a Stilbenoid.

Pterostilbene (PTER), a natural dimethylated analog of resveratrol, has been demonstrated to produce anti-neoplastic or neuroprotective actions. However, how and whether this compound can entail any perturbations on ionic currents in electrically excitable cells remains unknown. In whole-cell current recordings, addition of PTER decreased the amplitude of macroscopic Ih during long-lasting hyperpolarization in GH3 cells in a concentration-dependent manner, with an effective IC50 value of 0.84 µM. Its presence also shifted the activation curve of Ih along the voltage axis to a more hyperpolarized potential, by 11 mV. PTER at a concentration greater than 10 µM could also suppress l-type Ca2+ and transient outward K+ currents in GH3 cells. With the addition of PTER, IK(Ca) amplitude was increased, with an EC50 value of 2.23 µM. This increase in IK(Ca) amplitude was attenuated by further addition of verruculogen, but not by tolbutamide or TRAM-39. Neither atropine nor nicotine, in the continued presence of PTER, modified the PTER-stimulated IK(Ca). PTER (10 µM) slightly suppressed the amplitude of l-type Ca2+ current and transient outward K+ current. The presence of PTER (3 µM) was also effective at increasing the open-state probability of large-conductance Ca2+-activated K+ (BKCa) channels identified in hippocampal mHippoE-14 neurons; however, its inability to alter single-channel conductance was detected. Our study highlights evidence to show that PTER has the propensity to perturb ionic currents (e.g., Ih and IK(Ca)), thereby influencing the functional activities of neurons, and neuroendocrine or endocrine cells.

Bisoprolol, Known to Be a Selective ß1-Receptor Antagonist, Differentially but Directly Suppresses IK(M) and IK(erg) in Pituitary Cells and Hippocampal Neurons.

Bisoprolol (BIS) is a selective antagonist of ß1 adrenergic receptors. We examined the effects of BIS on M-type K⁺ currents (IK(M)) or erg-mediated K⁺ currents (IK(erg)) in pituitary GH3, R1220 cells, and hippocampal mHippoE-14 cells. As GH3 cells were exposed to BIS, amplitude of IK(M) was suppressed with an IC50 value of 1.21 µM. The BIS-induced suppression of IK(M) amplitude was not affected by addition of isoproterenol or ractopamine, but attenuated by flupirtine or ivabradine. In cell-attached current, BIS decreased the open probability of M-type K⁺ (KM) channels, along with decreased mean opening time of the channel. BIS decreased IK(erg) amplitude with an IC50 value of 6.42 µM. Further addition of PD-118057 attenuated BIS-mediated inhibition of IK(erg). Under current-clamp conditions, BIS depolarization increased the firing of spontaneous action potentials in GH3 cells; addition of flupirtine, but not ractopamine, reversed BIS-induced firing rate. In R1220 cells, BIS suppressed IK(M); subsequent application of ML-213(Kv7.2 channel activator) reversed BIS-induced suppression of the current. In hippocampal mHippoE-14 neurons, BIS inhibited IK(M) to a greater extent compared to its depressant effect on IK(erg). This demonstrated that in pituitary cells and hippocampal neurons the presence of BIS is capable of directly and differentially suppressing IK(M) and IK(erg), despite its antagonism of ß1-adrenergic receptors.

Effect of arthrocentesis plus platelet-rich plasma and platelet-rich plasma alone in the treatment of temporomandibular joint osteoarthritis: A retrospective matched cohort study (A STROBE-compliant article).

Although the research on using platelet-rich plasma (PRP) for temporomandibular joint osteoarthritis (TMJ-OA) has advanced, no unified standards exist for determining the joint use of arthrocentesis and the injection dose and frequency of PRP. This study aimed to compare the efficacy of 2 TMJ-OA treatment approaches, arthrocentesis plus platelet-rich plasma (A+PRP) and PRP alone, and attempted to provide another potential treatment option with a single injection of 2 mL of high-concentration and high-purity PRP.This retrospective matched cohort study enrolled 208 patients who were treated for temporomandibular disorders (TMDs) in the Department of Oral and Maxillofacial Surgery of Tainan Sin-Lau Hospital between August of 2013 and January of 2016, from which 90 patients were selected for the final analysis. The predictor variables were treatment outcome indicators, including joint crepitus sounds, TMD-associated headache, jaw range of motion <6 mm, myofascial pain with referral, temporomandibular joint (TMJ) arthralgia, pain when chewing most foods, and maximum assisted opening (MAO). The data were analyzed using χ tests, t tests, and multiple regression analyses.Among the 90 patients, 30 were assigned into the A+PRP group, and 60 were included in the PRP group. A matching method was used to ensure no statistically significant differences in the categorical and continuous variables between the 2 groups. After treatment, both the A+PRP and PRP groups showed improvements in TMJ-OA. The 2 treatment groups did not show statistically significant differences in the symptom improvement rates of joint crepitus sounds, reparative remodeling, and TMJ arthralgia. However, compared with PRP alone, the A+PRP treatment demonstrated superior performance in improving TMD-associated headache, jaw range of motion <6 mm, myofascial pain with referral, and pain when chewing most foods.Both A+PRP and PRP treatments can effectively improve multiple symptoms of TMJ-OA. Based on the results from this study, we recommend a single injection with 2 mL of high-concentration and high-purity PRP for TMJ-OA treatment. For patients with TMJ-OA accompanied by other clinical symptoms, including TMD-associated headache, jaw range of motion <6 mm, myofascial pain with referral, and pain when chewing most foods, a treatment approach using arthrocentesis prior to a PRP injection can achieve a higher efficacy.

Risk of serous retinal detachment in patients with end-stage renal disease on dialysis.

The aim of this retrospective, nationwide, matched cohort study was to investigate the association of serous retinal detachment with having end-stage renal disease (ESRD) while on dialysis. The cohort study included 94,024 patients with ESRD on dialysis registered between January 2000 to December 2009 in the Taiwan National Health Insurance Research Database. An age- and sex-matched control group comprised 94,024 patients selected from the Taiwan Longitudinal Health Insurance Database 2000. Information for each patient was collected from the index date until December 2011. Twenty-seven ESRD patients and 11 controls developed serous retinal detachment (P < 0.001) during follow-up, demonstrating a significantly increased risk of serous retinal detachment in patients with ESRD on dialysis compared with controls (incidence rate ratio = 3.39, 95% confidence interval [CI] = 1.68-6.83). After adjustment for potential confounders, patients were 3.86 times more likely to develop serous retinal detachment than the full cohort (adjusted HR = 3.86, 95% CI = 1.15-12.96). In conclusion, patients with ESRD on dialysis demonstrate an increased risk of serous retinal detachment. Interdisciplinary collaboration between nephrologists and ophthalmologists is important to deal with serous retinal detachment in patients with ESRD on dialysis and prevent impairments of visual acuity.

Advanced glycation end products influence oral cancer cell survival via Bcl-xl and Nrf-2 regulation in vitro.

An irreversible non-enzymatic reaction between carbohydrates and proteins results in the formation of advanced glycation end products (AGEs). AGEs have been demonstrated to be a risk factor of complications in patients with diabetes mellitus (DM). Previous studies have suggested that patients with DM exhibit a higher rate of metastasis of oral cancer and a lower cancer-associated survival rate. The receptor for AGEs (RAGE) has been associated with angiogenesis and an increase in cancer malignancy. Previous studies have suggested that AGE-RAGE regulates cell migration via extracellular signal-regulated kinase (ERK) phosphorylation. Nuclear factor-erythroid 2-related factor 2 (Nrf-2) is associated with the regulation of tumor protein p53 (p53) and the apoptotic response of oral cancer cells. AGEs are associated with oral cancer; however, the mechanism underlying this association remains to be elucidated. The present study hypothesized that AGEs regulate Nrf-2 and downstream pathways through ERK phosphorylation. The results of the current study demonstrated that AGEs inhibit the expression of Nrf-2, p53 and Bcl-2 associated × apoptosis regulator, and increase the expression of apoptosis regulator Bcl-x protein. The effect of AGEs was inhibited through the use of the PD98059. The present study demonstrated that AGEs regulate the downstream pathways Nrf-2 and Bcl-xl via ERK phosphorylation. It is suggested that AGEs regulate the survival of oral cancer cells via Nrf-2 and Bcl-xl through p53 regulation, which explains the poor prognosis of patients with DM who have oral cancer.

Clinical efficacy of a centric relation occlusal splint and intra-articular liquid phase concentrated growth factor injection for the treatment of temporomandibular disorders.

The agony that accompanies the incidence and symptoms of temporomandibular disorders (TMDs) is an important concern in the oral and maxillofacial region. The objective of this study was to explore the clinical findings after centric relation occlusal splint (CROS) treatment and intra-articular injection treatment with liquid phase concentrated growth factors (LPCGFs) in patients with disc displacement without reduction (DDWOR).The group under investigation of this retrospective cohort study included patients with DDWOR who received treatment from April 2014 until March 2016. The predictor variable was the therapeutic method. The outcome variables included joint crepitus sound, visual analog scale (VAS) of temporomandibular joint (TMJ) arthralgia, TMD-associated headache, myofascial pain with referral, deviation of the mandible during opening (DoM), and maximal interincisal opening (MIO). At the stage of CROS treatment, evaluation of all variables adopted the individual as the unit; at the stage after LPCGF injection, the evaluation of joint sound adopted the joint as the unit, whereas the other variables adopted the individual as the unit.Among the 29 patients, 6 (20.68%) were males and 23 (79.31%) were females. Distribution by age ranged from 15 to 84 years (mean age 39.55 ±â€Š15.49 years). After CROS treatment, except for the joint crepitus sound, which failed to achieve significant improvement (P > 0.05), other symptoms, such as DOM, TMD-associated headache, myofascial pain with referral, TMJ arthralgia, and MIO, all achieved statistically significant improvements (P < 0.05). After 2 mL of LPCGF was injected once after CROS treatment, 26 joint crepitus sound symptoms were relieved (P < 0.001) after an average of 48.5 ±â€Š64.1 days.CROS alone can alleviate TMD clinical symptoms, except for the joint crepitus sound. Approximately 72.2% of joint crepitus sounds could be improved within 48 days, on average, once 2 mL of LPCGF was injected. Comparisons were still required in the future, with the effects of other therapeutic methods.

Temporal relationship between dysthymia and temporomandibular disorder: a population-based matched case-control study in Taiwan.

BACKGROUND: Numerous studies have reported a relationship between depression and temporomandibular disorders (TMD), but the conclusions remain undefined. The aim of this article was to examine the temporal relationship between depression and TMD. METHODS: In this retrospective matched case-control study, we recruited all samples from a randomsample sub-dataset of one million insured individuals for the year 2005 (Longitudinal Health Insurance Database (LHID2005)). All beneficiaries were enrolled in the National Health Insurance (NHI) programme in Taiwan. We used propensity scoring and matched the case and control groups (1:1) by ten confounding factors to detect the effect of different types of depression on TMD. RESULTS: The positive correlative factors of TMD included the total number of times medical advice was sought for an unspecified anomaly of jaw size plus malocclusion (TTSMA-JS, p = 0.045), the total number of times medical advice was sought for an anxiety state (TTSMA-AS, p = 0.000), and the total number of times medical advice was sought for a panic disorder (TTSMA-P, p = 0.009). Dysthymia (synonymous with chronic depression) had an effect on TMD. The odds ratio (OR) of dysthymia for TMD measured by multiple logistic regression was 1.91 (p = 0.008) after adjusting for demographic factors, psychiatric comorbidities, and maxillofacial confounders. CONCLUSIONS: This study demonstrated the established temporal relationship between dysthymia and TMD. The inclusion of a psychiatrist on the TMD management team is appropriate.

Effect of Flat-Plane Splint Vertical Thickness on Disc Displacement Without Reduction: A Retrospective Matched-Cohort Study.

PURPOSE: The efficacy of occlusal splints for treating temporomandibular disorders (TMDs) remains controversial. This study aimed to evaluate and compare the effectiveness of flat-plane splints (FPSs) with a vertical thickness of 3 mm (VT3) and 5 mm (VT5) in treating disc displacement without reduction (DDWOR). MATERIALS AND METHODS: This retrospective matched-cohort study selected the study participants from 400 TMD patients treated in the Department of Oral and Maxillofacial Surgery of Tainan Sin-Lau Hospital, Tainan, Taiwan, between August 2013 and July 2015. The thickness of occlusal splints was the predictor variable. The outcome variables included joint crepitus sound, deviation of the mandible during opening, TMD-associated headache, myofascial pain with referral, temporomandibular joint (TMJ) arthralgia, and maximum assisted opening. The case and control groups were matched 1:1 by propensity scoring to ensure that there were no statistical differences in the categorical variables and continuous variables. The analysis used χ2 tests, t tests, and multiple regression analyses. RESULTS: We allocated 162 patients into 2 groups, with 81 patients each: VT3 group and VT5 group. Both VT3 FPSs and VT5 FPSs effectively improved the DDWOR. At 12 months after treatment, the VT5 group showed remarkable improvement in joint crepitus sound and TMJ arthralgia compared with the VT3 group. No statistical differences in other TMJ-associated symptoms such as deviation of the mandible during opening, TMD-associated headache, and myofascial pain with referral were observed between the 2 groups. CONCLUSIONS: Both VT3 and VT5 FPSs can effectively improve various clinical symptoms of DDWOR. We suggest that VT5 FPS treatment for at least 1 year is a suitable option for DDWOR patients with joint crepitus sound and TMJ arthralgia. For DDWOR patients without joint crepitus sound and TMJ arthralgia, there are no differences between the VT3 and VT5 FPSs.

Evaluation of the Antibacterial Potential of Liquid and Vapor Phase Phenolic Essential Oil Compounds against Oral Microorganisms.

The aim of the present study was to determine the antibacterial activities of the phenolic essential oil (EO) compounds hinokitiol, carvacrol, thymol, and menthol against oral pathogens. Aggregatibacter actinomycetemcomitans, Streptococcus mutans, Methicillin-resistant Staphylococcus aureus (MRSA), and Escherichia. coli were used in this study. The minimum inhibitory concentrations (MICs), minimum bactericidal concentrations (MBCs), bacterial growth curves, temperature and pH stabilities, and synergistic effects of the liquid and vapor EO compounds were tested. The MIC/MBC of the EO compounds, ranging from the strongest to weakest, were hinokitiol (40-60 µg/mL/40-100 µg/mL), thymol (100-200 µg/mL/200-400 µg/mL), carvacrol (200-400 µg/mL/200-600 µg/mL), and menthol (500-more than 2500 µg/mL/1000-more than 2500 µg/mL). The antibacterial activities of the four EO phenolic compound based on the agar diffusion test and bacterial growth curves showed that the four EO phenolic compounds were stable under different temperatures for 24 h, but the thymol activity decreased when the temperature was higher than 80°C. The combination of liquid carvacrol with thymol did not show any synergistic effects. The activities of the vaporous carvacrol and thymol were inhibited by the presence of water. Continual violent shaking during culture enhanced the activity of menthol. Both liquid and vaporous hinokitiol were stable at different temperatures and pH conditions. The combination of vaporous hinokitiol with zinc oxide did not show synergistic effects. These results showed that the liquid and vapor phases of hinokitiol have strong anti-oral bacteria abilities. Hinokitiol has the potential to be applied in oral health care products, dental materials, and infection controls to exert antimicrobial activity.

The Use of Solid-Phase Concentrated Growth Factors for Surgical Defects in the Treatment of Dysplastic Lesions of the Oral Mucosa.

PURPOSE: Use of the skin graft and artificial dermis to reconstruct a defect after the excision of dysplastic lesions of the oral mucosa has been practiced for years. The purpose of this case series was to introduce a novel resolution-that is, an operating procedure using solid-phase concentrated growth factors (SPCGFs) to reconstruct oral mucosa defects-and observe the postoperative results and evaluate its clinical effects. MATERIALS AND METHODS: In this consecutive serial case study of patients with oral dysplastic lesions who underwent operations from April 2015 through July 2015, the primary endpoint of the study was to observe the clinical wound-healing profile at 1 week, 3 weeks, 3 months, and 6 months postoperatively. The secondary endpoint was to observe maximal interincisal opening (MIO) and wound pain preoperatively and at 1 and 3 days, 1 and 3 weeks, and 3 and 6 months postoperatively. The minimum follow-up was 8 months, and the longest was 1 year. RESULTS: All sites had healed with complete epithelialization after 3 weeks postoperatively. All patients had a wound-healing score no higher than 3 at 3 weeks postoperatively. The preoperative MIO was 52 ± 4.64 mm and the 6-month postoperative MIO was 49.2 ± 3.03 mm. No patient reported further pain from 3 weeks postoperatively. No recurrence of the lesion was found at or after the 6-month follow-up period. CONCLUSION: The results of this study show that the use of SPCGFs to reconstruct oral mucosa defects is feasible and practical. The efficacy of SPCGFs needs to be verified by additional studies with higher-level evidence bases in the future.

Dysthymia increases the risk of temporomandibular disorder: A population-based cohort study (A STROBE-Compliant Article).

Numerous studies have investigated the relationship between depression and temporomandibular disorders (TMD), but the conclusions remain vague. The aim of this study was to examine the causal effect between depression and TMD.The reporting of this study conforms to the STROBE statement. In this retrospective cohort study, all samples were recruited from a representative subdataset of 1 million insured persons for the year 2005 Longitudinal Health Insurance Database, who were randomly selected from all beneficiaries enrolled in the National Health Insurance program of Taiwan. We used a propensity score and stratified 926,560 patients into 2 groups (propensity1 = 588,429 and propensity2 = 338,131) and 4 cohorts (propensity1 with depression = 18,038, propensity1 without depression = 570,391, propensity2 with depression = 38,656, propensity2 without depression = 299,475) to detect the development of TMD among the depressive and nondepressive patients between 2004 and 2013.The positive correlative factors of TMD included female, total number of times seeking medical advice (TTSMA) for anxiety state, TTSMA for generalized anxiety disorder, TTSMA for mandible fracture, and TTSMA for unspecified anomaly of jaw size. The propensity2 group was represented by elder and female-predominant patients who used more psychiatric health resources. Among 3 types of depression, only dysthymia (so-called chronic depression) had a causal impact on TMD in the propensity 2 group. In the propensity 2 group, the hazard ratio of dysthymia for TMD measured by Cox's regression was 1.64 (95% confidence interval 1.28-2.09), after adjusting for demographic factors, psychiatric comorbidities, and maxillofacial confounders. The first-onset mean time of TMD as the consequence of dysthymia was 3.56 years (sd = 2.74, min = 0.08, median = 2.99, max = 9.73).This study demonstrates that dysthymia increases the risk of TMD in elderly and female-predominant patients who use more psychiatric health resources.

Risk of Retinal Artery Occlusion in Patients With End-Stage Renal Disease: A Retrospective Large-Scale Cohort Study.

There is globally increasing prevalence and incidence in end-stage renal disease (ESRD). These patients are frequently reported to have retinal abnormalities and both diseases share some systemic risk factors. Hence, it is clinically relevant to determine whether ESRD is a predictor of retinal artery occlusion (RAO).To investigate the risk of RAO in ESRD patients.A retrospective, nationwide, matched cohort study. The study included 93,766 ESRD patients recruited between 2000 and 2009 from the Taiwan National Health Insurance Research Database. The same number control group included age- and sex-matched patients without ESRD selected from the Taiwan Longitudinal Health Insurance Database, 2000. Data for each patient were collected from the index date until December 2011.The incidence and risk of RAO were compared between the 2 groups. The hazard ratio (HR) for RAO after adjustment for potential confounders was calculated using Cox proportional hazards regression. Kaplan-Meier analysis was used to calculate the cumulative RAO incidence rate.In total, 237 ESRD patients and 73 controls exhibited RAO during follow-up; thus, the RAO incidence rate in ESRD patients was 4.49 times (95% confidence interval (CI), 3.45-5.83) that in the control patients. After adjustment for potential confounders, including diabetes mellitus, hypertension, hyperlipidemia, congestive heart failure, and coronary artery disease, ESRD patients were 2.78 times (95% CI, 2.02-3.84) more likely to develop RAO in cohort for the total sample. Among patients with hypertension, the RAO incidence rate was significantly higher in the ESRD group, and hypertension significantly increased RAO risk even after adjustment for other confounders in the cohort.ESRD increases the risk of RAO, particularly in ESRD patients with hypertension. Therefore, clinicians should educate ESRD patients about RAO and ensure appropriate blood pressure control.

Reducing Trismus After Surgery and Radiotherapy in Oral Cancer Patients: Results of Alternative Operation Versus Traditional Operation.

PURPOSE: In patients with oral cancer, trismus (maximum interincisal opening [MIO] <35 mm) can develop as a result of surgery and radiotherapy. The aim of this study was to provide an alternative operation to both eradicate oral cancer and prevent postsurgical trismus. MATERIALS AND METHODS: In our retrospective cohort study of oral cancer patients who underwent operations during 2010 to 2014, the predictor variable was the type of operation (alternative operation or traditional operation) and the outcome variable was MIO. All of the cases were allocated by 2 periods: the traditional operations were performed from 2010 to 2011, and the alternative operations were performed from 2011 to 2014. All patients received marginal mandibulectomy, anterolateral thigh free flap, and adjuvant radiotherapy or concurrent chemoradiotherapy. In addition to traditional marginal mandibulectomy, the alternative operation included ipsilateral coronoidectomy and myotomy of the temporalis muscle insertion, masseter muscle, and medial pterygoid muscle. MIO was measured at 10 time points. The adjusted variables included demographic data, diagnostic parameters, treatment, and response. RESULTS: Of the 36 male patients with oral cancer, 16 were placed in the alternative operation group (AOG; mean age, 53.5 ± 11.9 years) and 20 were placed in the traditional operation group (TOG; mean age, 50.7 ± 7.1 years). Regarding the outcome indicator of patient MIO, the preoperative MIO in the AOG was on average 7.5 mm shorter than that in the TOG (P < .01), but it was consistently superior to the MIO in the TOG after the operation. Multivariate analysis of variance showed that patients in the AOG were more likely to have postoperative non-trismus. CONCLUSIONS: The alternative operation exhibited superior postoperative MIO values and similar postoperative complication rates. For the prevention of trismus, it is practical to perform the combined operation simultaneously, cutting all ipsilateral jaw closing muscles and the coronoid process and eradicating the tumor.

The Possible Mechanism of Advanced Glycation End Products (AGEs) for Alzheimer's Disease.

Amyloid precursor protein (APP) has been modified by ß and γ-secretase that cause amyloid deposits (plaques) in neuronal cells. Glyceraldhyde-derived AGEs has been identified as a major source of neurotoxicity in Alzheimer's disease (AD). In a previous study, we demonstrated that glyceraldehyde-derived AGEs increase APP and Aß via ROS. Furthermore, the combination of AGEs and Aß has been shown to enhance neurotoxicity. In mice, APP expression is increased by tail vein injection of AGEs. This evidence suggests a correlation between AGEs and the development of AD. However, the role played by AGEs in the pathogenesis of AD remains unclear. In this report, we demonstrate that AGEs up-regulate APP processing protein (BACE and PS1) and Sirt1 expression via ROS, but do not affect the expression of downstream antioxidant genes HO-1 and NQO-1. Moreover, we found that AGEs increase GRP78 expression and enhance the cell death-related pathway p53, bcl-2/bax ratio, caspase 3. These results indicate that AGEs impair the neuroprotective effects of Sirt1 and lead to neuronal cell death via ER stress. Our findings suggest that AGEs increase ROS production, which stimulates downstream pathways related to APP processing, Aß production, Sirt1, and GRP78, resulting in the up-regulation of cell death related pathway. This in-turn enhances neuronal cell death, which leads to the development of AD.

Suppression of antioxidant Nrf-2 and downstream pathway in H9c2 cells by advanced glycation end products (AGEs) via ERK phosphorylation.

Diabetic cardiomyopathy is related to oxidative stress and correlated with the presence of advanced glycation end products (AGEs). In a clinical setting, AGEs can be detected in patients presenting diabetic cardiomyopathy; however, the underlying mechanism has yet to be elucidated. In our previous study, AGEs increase cell hypertrophy via ERK phosphorylation in a process closely related to ROS production. Thus, we propose that AGEs regulate the antioxidant gene nuclear factor-erythroid 2-related factor (Nrf-2). In H9c2 cells treated with AGEs, the expression of Nrf-2 was reduced; however, ERK phosphorylation was shown to increase. Treatment with H2O2 was also shown to increase Nrf-2 and ERK phosphorylation. In cells pretreatment with ROS scavenger NAC, the effects of H2O2 were reduced; however, the effects of the AGEs remained largely unchanged. Conversely, when cells were pretreated with PD98059 (ERK inhibitor), the expression of Nrf-2 was recovered following treatment with AGEs. Our results suggest that AGEs inhibit Nrf-2 via the ERK pathway; however, this influence is partly associated with ROS. Our finding further indicated that AGEs possess both ROS-dependent and ROS-independent pathways, resulting in a reduction in Nrf-2. This report reveals an important mechanism underlying the regulation of diabetic cardiomyopathy progression by AGEs.

Cell migration is regulated by AGE-RAGE interaction in human oral cancer cells in vitro.

Advanced glycation end products (AGEs) are produced in an irreversible non-enzymatic reaction of carbohydrates and proteins. Patients with diabetes mellitus (DM) are known to have elevated AGE levels, which is viewed as a risk factor of diabetes-related complications. In a clinical setting, it has been shown that patients with oral cancer in conjunction with DM have a higher likelihood of cancer metastasis and lower cancer survival rates. AGE-RAGE (a receptor of AGEs) is also correlated with metastasis and angiogenesis. Recent studies have suggested that the malignancy of cancer may be enhanced by glyceraldehyde-derived AGEs; however, the underlying mechanism remains unclear. This study examined the apparently close correlation between AGE-RAGE and the malignancy of SAS oral cancer cell line. In this study, AGEs increased ERK phosphorylation, enhanced cell migration, and promoted the expression of RAGE, MMP2, and MMP9. Using PD98059, RAGE antibody, and RAGE RNAi to block RAGE pathway resulted in the inhibition of ERK phosphorylation. Cell migration, MMP2 and MMP9 expression were also reduced by this treatment. Our findings demonstrate the importance of AGE-RAGE with regard to the malignancy of oral cancer, and help to explain the poor prognosis of DM subjects with oral cancer.

Evaluation physical characteristics and comparison antimicrobial and anti-inflammation potentials of dental root canal sealers containing hinokitiol in vitro.

Hinokitiol displays potent antimicrobial activity. It has been used in toothpaste and oral-care gel to improve the oral lichen planus and reduce halitosis. The aim of this study was to evaluate the antimicrobial activity of 3 different dental root canal sealers with hinokitiol (sealers+H) and their physical and biological effects. AH Plus (epoxy amine resin-based, AH), Apexit Plus (calcium-hydroxide-based, AP), and Canals (zinc-oxide-eugenol-based, CA), were used in this study. The original AH and CA exhibited strong anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) activity, but AP did not. The setting time, working time, flowability, film thickness, and solubility of each sealer+0.2%H complied with ISO 6876:2001. CA+0.2%H exhibited high cytotoxicity, but the others sealers+0.2%H did not. Because hinokitiol combined with Zn2+ in CA creates a synergistic effect. The physical tests of AP+0.5%-1%H complied with ISO 6876:2001, improved antimicrobial activity, inhibited inflammation genes cyclooxygenase-2 (COX-2) and hypoxia-inducible factor-1α (HIF-1α) mRNA in MG-63 cells and human gingival fibroblasts (HGF), and down-regulated lysyl oxidase (LOX) mRNA of HGF. In summary, AH and CA demonstrated strong antimicrobial activity, but AP did not. Application of hinokitiol increases AH anti-MRSA activity should less than 0.2% for keep well flowability. AP+0.5%-1% hinokitiol exhibited strong physical, antibacterial, and anti-inflammation potentials, and inhibited S. aureus abscess formation. Applying an appreciable proportion of hinokitiol to epoxy-amine-resin-based and calcium-hydroxide-based root canal sealers is warranted, but the enhanced cytotoxicity and synergistic effect must be considered.

Cucurbitacin E as inducer of cell death and apoptosis in human oral squamous cell carcinoma cell line SAS.

Human oral squamous cell carcinoma (OSCC) is a common form of malignant cancer, for which radiotherapy or chemotherapy are the main treatment methods. Cucurbitacin E (CuE) is a natural compound previously shown to be an antifeedant as well as a potent chemopreventive agent against several types of cancer. The present study investigates anti-proliferation (using MTT assay, CuE demonstrated cytotoxic activity against SAS cell with IC50 values at 3.69 µM) and induced apoptosis of human oral squamous cell carcinoma SAS cells after 24 h treatment with CuE. Mitochondrial membrane potential (MMP) and caspase activity were studied and our results indicate that CuE inhibits cell proliferation as well as the activation of apoptois in SAS cells. Both effects increased in proportion to the dosage of CuE and apoptosis was induced via mitochondria- and caspase-dependent pathways. CuE can induce cell death by a mechanism that is not dependent on apoptosis induction, and thus represents a promising anticancer agent for prevention and treatment of OSCC.

Cell hypertrophy and MEK/ERK phosphorylation are regulated by glyceraldehyde-derived AGEs in cardiomyocyte H9c2 cells.

Diabetic cardiomyopathy has been shown to promote hypertrophy, leading to heart failure. Recent studies have reported a correlation between diabetic cardiomyopathy and oxidative stress, suggesting that the accumulation of advanced glycation end products (AGEs) induces the production of reactive oxygen species (ROS). In a clinical setting, AGEs have been shown to increase the risk of cardiovascular disease; however, the relationship between AGEs and cardiac hypertrophy remains unclear. This study sought to identify the role of AGEs in cardiac hypertrophy by treating H9c2 cells with glyceraldehyde-derived AGEs (200 µg/ml) or H2O2 (50 µM) for 96 h. Our results demonstrate that AGEs significantly increased protein levels and cell size. These effects were effectively blocked with PD98059 (10 µM; MEK/ERK inhibitor) pretreatment, suggesting that AGEs caused cell hypertrophy via the MEK/ERK pathway. We then treated cells with AGEs and H2O2 for 0-120 min and employed the Odyssey infrared imaging system to detect MEK/ERK phosphorylation. Our results show that AGEs up-regulated MEK/ERK phosphorylation. However, this effect was blocked by NAC (5 mM; ROS inhibitor), indicating that AGEs regulate MEK/ERK phosphorylation via ROS. Our findings suggest that glyceraldehyde-derived AGEs are closely related to cardiac hypertrophy and further identify a molecular mechanism underlying the promotion of diabetic cardiomyopathy by AGEs.