Automatic Deep Learning Detection of Overhanging Restorations in Bitewing Radiographs.

OBJECTIVE: This study aimed to assess the effectiveness of deep convolutional neural network (CNN) algorithms in detecting and segmentation of overhanging dental restorations in bitewing radiographs. METHOD AND MATERIALS: A total of 1160 anonymized bitewing radiographs were used to progress the Artificial Intelligence (AI) system) for the detection and segmentation of overhanging restorations. The data was then divided into three groups: 80% for training (930 images, 2399 labels), 10% for validation (115 images, 273 labels), and 10% for testing (115 images, 306 labels). A CNN model known as you only look once (YOLOv5) was trained to detect overhanging restorations in bitewing radiographs. After utilizing the remaining 115 radiographs to evaluate the efficacy of the proposed CNN model, the accuracy, sensitivity, precision, F1 score, and area under the receiver operating characteristic curve (AUC) were computed. RESULTS: The model demonstrated a precision of 90.9%, a sensitivity of 85.3%, and an F1 score of 88.0%. Furthermore, the model achieved an AUC of 0.859 on the Receiver Operating Characteristic (ROC) curve. The mean average precision (mAP) at an intersection over a union (IoU) threshold of 0.5 was notably high at 0.87. CONCLUSION: The findings suggest that deep CNN algorithms are highly effective in the detection and diagnosis of overhanging dental restorations in bitewing radiographs. The high levels of precision, sensitivity, and F1 score, along with the significant AUC and mAP values, underscore the potential of these advanced deep learning techniques in revolutionizing dental diagnostic procedures.

Repair versus replacement of defective direct dental restorations: A multinational cross-sectional study with meta-analysis.

OBJECTIVES: When dental practitioners encounter a defective restoration, they are faced with a crucial decision whether to repair or replace it. This study aims to explore international preferences for repair procedures and the clinical steps taken during the repair process. METHOD: An 11-question survey was distributed to dentists across 21 countries via different platforms. The survey comprised two sections: the first included five questions aimed at gathering demographic information, while the second consisted of six questions focusing on participants' practices related to the repair of composite or amalgam restorations A meta-analysis was employed to ascertain the pooled odds ratio of repairing versus replacement. The statistical analysis was carried out using the RevMan 5.3 program and forest plots were generated using the same program to visualize the results. RESULTS: The survey was completed by 3680 dental practitioners. The results indicated a strong tendency to repair defective composite restorations (OR: 14.23; 95 % CI: 7.40, 27.35, p < 0.001). In terms of amalgam, there was a significant tendency to replace the restorations (OR: 0.19; 95 % CI: 0.12, 0.30, p < 0.001). When repairing restorations, the most common protocols were etching with orthophosphoric acid and creating an enamel bevel, regardless of the restorative material used. CONCLUSION: The findings of this study indicate that there exists a knowledge gap among dental practitioners regarding restoration repair. It is imperative that dental practitioners receive proper education and training on restoration repair, to ensure the usage of adequate protocols and restoration survival. CLINICAL SIGNIFICANCE: A significant portion of dental practitioners lack the necessary knowledge and education required for the repair of restorations. Therefore, it is imperative to establish guidelines aimed at enhancing the management of defective restorations, along with protocols for clinical interventions. This includes the incorporation of proper courses in undergraduate, graduate, and continuing education programs.

Comparison of mandibular morphometric parameters in digital panoramic radiography in gender determination using machine learning.

OBJECTIVE: This study aimed to evaluate the usability of morphometric features obtained from mandibular panoramic radiographs in gender determination using machine learning algorithms. MATERIALS AND METHODS: High-resolution radiographs of 200 patients aged 20-77 (41.0 ± 12.7) were included in the study. Twelve different morphometric measurements were extracted from each digital panoramic radiography included in the study. These measurements were used as features in the machine learning phase in which six different machine learning algorithms were used (k-nearest neighbor, decision trees, support vector machines, naive Bayes, linear discrimination analysis, and neural networks). To evaluate the reliability, we have performed tenfold cross-validation and we repeated this 10 times for every classification process. This process enhances the reliability of the results for other datasets. RESULTS: When all 12 features are used together, the accuracy rate is found to be 82.6 ± 0.5%. The classification accuracies are also compared using each feature alone. Three features that give the highest accuracy are coronoid height (80.9 ± 0.9%), condyle height (78.2 ± 0.5%), and ramus height (77.2 ± 0.4%), respectively. When compared to the classification algorithms, the highest accuracy was obtained with the naive Bayes algorithm with a rate of 84.0 ± 0.4%. CONCLUSION: Machine learning techniques can accurately determine gender by analyzing mandibular morphometric structures from digital panoramic radiographs. The most precise results are achieved by evaluating the structures in combination, using attributes obtained from applying the MRMR algorithm to all features.

Awareness of possible complications associated with direct composite restorations: A multinational survey among dentists from 13 countries with meta-analysis.

OBJECTIVES: Resin-based composites (RBCs) evolved into favoured materials for teeth restorations, marking a significant change in dental practice. Despite many advantages, RBCs exhibit various limitations in their physical and chemical properties. Therefore, we assessed the dentists' awareness of possible complications after direct composite restorations and their opinions about this material. METHODS: The online questionnaire was created in English in May 2023. A 16-item survey was dedicated to general dentists and specialists. The first section included four questions related to demographic characteristics. The second section comprised twelve questions and focused on awareness of potential side effects of composite restorations, the most crucial advantages and disadvantages of composite resins, and the frequency of experienced clinical complications after the application of composite materials. RESULTS: A total of 1830 dentists from 13 countries took part in the survey. Dentists most often declared awareness of low adhesion to the dentine (77.5 %) and, most rarely, solubility in oral fluids (42.6 %). Aesthetics was identified as the main advantage of composite fillings (79 %), followed by the possibility of repair (59 %) and adhesion to enamel (57 %). Polymerisation shrinkage was a major disadvantage for most countries (70 % overall). Analysing the declared potential clinical complications for all countries, statistically significant findings were obtained for marginal discolouration (OR=2.982, 95 % CI: 1.321-6.730, p-value=0.009) and borderline significance for secondary caries (OR=1.814, 95 % CI: 0.964-3.415, p-value=0.065). CONCLUSIONS: Dentists value aesthetics and repairability but are aware of shrinkage and experience discolouration. The issue of toxicity and solubility seems to be the least known to dentists. CLINICAL SIGNIFICANCE: Dentists should use RBCs with critical caution due to possible side effects. Despite the undoubted aesthetics of direct composite restorations, it is necessary to remember potential clinical complications such as marginal discolouration or secondary caries.

Cationic ribosomal proteins can inhibit pro-inflammatory action stimulated by LPS+HMGB1 and are hindered by advanced glycation end products.

We previously found that ribosomal protein L9 (RPL9) is a novel advanced glycation end product (AGE)-binding protein that can decrease pro-inflammatory TNF-α expression stimulated by lipopolysaccharide (LPS) plus high-mobility group box 1 (HMGB1), suggesting that RPL9 has a role in regulating LPS+HMGB1-stimulated inflammatory reactions. Among the various ribosomal proteins, it was found that RPS5 reproduced the regulatory activity of RPL9 on LPS+HMGB1-stimulated TNF-α expression in macrophage-like RAW264.7 cells. RPL9 and RPS5 share a common feature as cationic proteins. Polylysine, a cationic polypeptide, and a synthetic peptide of the cationic region from RPL9 also exhibited reducing activity on LPS+HMGB1-induced TNF-α expression. By pull-down assay, RPL9 and RPS5 were confirmed to interact with AGEs. When AGEs coexisted with LPS, HMGB1, plus RPL9 or RPS5, the reducing effect of TNF-α expression by these cationic ribosomal proteins was shown to be abrogated. The results suggest that cationic ribosomal proteins have a regulatory role in the pro-inflammatory response induced by LPS+HMGB1, and in the pathophysiological condition of accumulating AGEs, this regulatory effect is abolished, which exacerbates inflammation.

Different modulation of STING/TBK1/IRF3 signaling by advanced glycation end products.

Advanced glycation end products (AGEs) are a heterogeneous group of compounds that are non-enzymatically produced by reactions between carbonyl compounds and proteins. Many types of AGEs are produced according to the type or concentration of the reacting carbonyl compound. We have previously demonstrated that a glycolaldehyde-derived AGE suppresses stimulator of interferon gene (STING)/TANK-binding kinase 1 (TBK1)/interferon regulatory transcription factor 3 (IRF3), which is a component of the innate immune system. In this report, we investigated the effects of AGEs prepared by several carbonyl compounds on STING/TBK1/IRF3 signaling. AGEs used in the present study were numbered based on the carbonyl compound type: AGE1, derived from glucose; AGE2, derived from glyceraldehyde; AGE3, derived from glycolaldehyde; AGE4, derived from methylglyoxal; and AGE5, derived from glyoxal. AGEs derived from aldehyde (AGE2 and AGE3) and dicarbonyl compounds (AGE4 and AGE5) suppressed cyclic GMP-AMP (cGAMP)-induced activation of STING/TBK1/IRF3 signaling, with different suppression efficiencies observed. Lysine modification by carbonyl compounds was related to the efficiency of the suppressive effect on STING/TBK1/IRF3 signaling. Among the AGEs used, only AGE1 enhanced cGAMP-induced activation of STING/TBK1/IRF3 signaling. Enhancing the modulation of STING/TBK1/IRF3 signaling by AGE1 was mediated by toll-like receptor 4. These results indicated that modulation of STING/TBK1/IRF3 signaling by prepared AGEs is dependent on the type and concentration of the carbonyl compound present. Modulating STING/TBK1/IRF3 signaling by AGEs may involve modification of lysine residues in proteins.

Assessment of the Prevalence of Radix Entomolaris and Distolingual Canal in Mandibular First Molars in 15 Countries: A Multinational Cross-sectional Study with Meta-analysis.

AIM: The aim of this study was two-folded: i) to assess the prevalence of Distolingual Canal (DLC) and Radix Entomolaris (RE) in Mandibular First Molars (M1Ms), using Cone Beam Computed Tomography (CBCT) images and ii) to assess the impact of sociodemographic factors on the prevalence of these conditions worldwide. METHODS: CBCT images were scanned retrospectively and the ones including bilateral M1Ms were included in the study. The evaluation was performed by 1 researcher in each country, trained with CBCT technology. A written and video instruction program explaining the protocol to be followed step-by-step was provided to all observers to calibrate them. The CBCT imaging screening procedure consisted of evaluating axial sections from coronal to apical. The presence of DLC and RE in M1Ms (yes/no) was identified and recorded. RESULTS: Six thousand three hundred four CBCTs, representing 12,608 M1Ms, were evaluated. A significant difference was found between countries regarding the prevalence of both RE and DLC (P < .05). The prevalence of DLC ranged from 3% to 50%, and the overall prevalence was 22% (95% CI: 15%-29%). RE prevalence ranged from 0% to 12%, and the overall prevalence was 3% (95% CI: 2%-5%). There were no significant differences between left and right M1Ms or between genders for either DLC or RE (P > .05). CONCLUSION: The overall prevalence of RE and DLC in M1Ms was 3% and 22%. Additionally, both RE and DLC showed substantial bilaterally. These variations should be considered by endodontic clinicians during endodontic procedures in order to avoid potential complications.

Attitude and practice of regenerative endodontic procedures among endodontists and paediatric dentists: A multinational survey from 13 countries.

BACKGROUND: Regenerative endodontics (RET) refers to biologically based procedures that aim to restore damaged tooth structures and reinstate the pulp-dentine complex to its normal physiological state. AIM: The purpose of this study was to examine the attitudes and practices of endodontists and paediatric dentists regarding RET. DESIGN: A survey was conducted among endodontists and paediatric dentists from 13 countries. A number of factors were evaluated, including frequency of RET application, followed guidelines, disinfection techniques, intracanal medication type, scaffold type, preferred coronal seal material, and follow-up period. RESULTS: Among the 1394 respondents, 853 (61.2%) and 541 (38.8%) were endodontists and paediatric dentists, respectively. Almost half (43%) of participants have not performed RET yet. The American Association of Endodontics guideline (47.3%) was selected as the primary source for the clinical protocol. The most frequently selected irrigant solution was 1.5%-3% NaOCl at the first (26.1%) and second (13.6%) sessions. A blood clot (68.7%) and MTA (61.9%) were the most frequently selected scaffold type and coronal barrier. Most participants preferred a 6-month follow-up period. CONCLUSION: According to this survey, deviations exist from current RET guidelines regarding all aspects evaluated. Standardizing clinical protocols and adhering to available guidelines would help to ensure more predictable outcomes.

Potential Renal Acid Load, Salivary Buffer Capacity and Healthy Eating Index as Predictors of Children's Dental Caries: A Cross-Sectional Study.

INTRODUCTION: Dental caries is one of the most common childhood diseases. This study purposed to investigate the prediction capability of potential renal acid load (PRAL), salivary buffer capacity (SBC), and Healthy Eating Index (HEI) on children's dental caries. METHODS: The decay, missing, filing, and teeth for primary teeth (dmft)/Decay, Missing, Filling, and Teeth for permanent teeth (DMFT) indexes of the children aged 7-12 years who applied to our faculty were recorded. Approximately 1 mL of unstimulated saliva samples were collected, and SBC was evaluated. PRAL and HEI scores were calculated by entering the data in the form of a daily nutrition record of the children into the BeBiS software (Ebispro for Windows, Stuttgart, Germany). The association of dental caries indices with PRAL, SBC, and HEI was analyzed using an independent sample t-test. A binomial logistic regression analysis was performed to predict the dental caries burden. The statistical significance level was adjusted to a=0.05. RESULTS: A total of 150 children, 88 (58.6%) females and 62 (41.4%) males, were included in the study. Significant differences were found between the low and high dental caries groups for dmft regarding PRAL and SBC (p<0.001). A significant difference was found between the low and high dental caries groups for DMFT in terms of SBC (p<0.05). CONCLUSION: In our study, established regression models significantly predicted dental caries in primary teeth. SBC was the most influential factor in predicting dental caries compared to PRAL and HEI. There was a significant relationship between SBC, PRAL, and caries in primary teeth. In the model we created, the strongest predictor was SBC.

Glycolaldehyde-derived advanced glycation end products promote macrophage proliferation via the JAK-STAT signaling pathway.

BACKGROUND: Advanced glycation end products (AGEs) are heterogeneous proinflammatory molecules produced by a non-enzymatic glycation reaction between reducing sugars (and their metabolites) and biomolecules with amino groups, such as proteins. Although increases in and the accumulation of AGEs have been implicated in the onset and exacerbation of lifestyle- or age-related diseases, including diabetes, their physiological functions have not yet been elucidated in detail. METHODS AND RESULTS: The present study investigated the cellular responses of the macrophage cell line RAW264.7 stimulated by glycolaldehyde-derived AGEs (Glycol-AGEs) known as representative toxic AGEs. The results obtained showed that Glycol-AGEs significantly promoted the proliferation of RAW264.7 cells at a low concentration range (1-10 µg/mL) in a concentration-dependent manner. On the other hand, neither TNF-α production nor cytotoxicity were induced by the same concentrations of Glycol-AGEs. The increases observed in cell proliferation by low concentrations of Glycol-AGEs were also detected in receptor triple knockout (RAGE-TLR4-TLR2 KO) cells as well as in wild-type cells. Increases in cell proliferation were not affected by various kinase inhibitors, including MAP kinase inhibitors, but were significantly suppressed by JAK2 and STAT5 inhibitors. In addition, the expression of some cell cycle-related genes was up-regulated by the stimulation with Glycol-AGEs. CONCLUSIONS: These results suggest a novel physiological role for AGEs in the promotion of cell proliferation via the JAK-STAT pathway.

Factors Affecting the Decision-making of Direct Pulp Capping Procedures among Dental Practitioners: A Multinational Survey from 16 Countries with Meta-analysis.

INTRODUCTION: Direct pulp capping (DPC) procedures require the placement of a bioactive material over an exposure site without selective pulp tissue removal. This web-based multicentered survey had 3 purposes: (1) to investigate the factors that affect clinicians' decisions in DPC cases, (2) to determine which method of caries removal is preferred, and (3) to evaluate the preferred capping material for DPC. METHODS: The questionnaire comprised 3 sections. The first part comprised questions regarding demographic features. The second part comprised questions on how treatment plans change according to factors such as nature, location, number and size of the pulp exposure, and patients' age. The third part composed of questions on the common materials and techniques used in DPC. To estimate the effect size, the risk ratio (RR) and 95% confidence interval (CI) were calculated using a meta-analysis software. RESULTS: A tendency toward more invasive treatment was observed for the clinical scenario with carious-exposed pulp (RR = 2.86, 95% CI: 2.46, 2.32; P < .001) as opposed to the clinical scenario with 2 pulp exposures (RR = 1.38, 95% CI: 1.24, 1.53; P < .001). Complete caries removal was significantly preferred to selective caries removal (RR = 4.59, 95% CI: 3.70, 5.69; P < .001). Among the capping materials, calcium silicate-based materials were preferred over calcium hydroxide-based materials (RR = 0.58, 95% CI: 0.44, 0.76; P < .05). CONCLUSIONS: While carious-exposed pulp is the most important factor in clinical decisions regarding DPC, the number of exposures has the least impact. Overall, complete caries removal was preferred over selective caries removal. In addition, the use of calcium silicate-based materials appears to have replaced calcium hydroxide-based materials.

Prediction of root canal lengths and pulp volume of the maxillary permanent first molar based on stature, crown diameters, and facial morphometry.

This study purposed to develop statistical models to predict palatal (PRL), mesial (MRL), and distal (DRL) root canal length and pulp volume (PV) of the maxillary first permanent molar using stature, gender, mesiodistal (MD), and buccopalatal (BP) crown diameters and some facial morphometries. 57 individuals were included in the study. Cone beam computed tomography was used to measure root canal lengths and PV. The PV calculation was carried out using the software ITK-SNAP 3.4.0. PRL was positively correlated with BP, stature, middle facial height, interalar distance, and bicommissural distance (BCD) (p < 0.05). DRL was positively correlated with BP, MD, and stature (p < 0.05). MRL was positively correlated with BP, MD, stature, lower face height, bizygomatic distance, and BCD (p < 0.05). PV was negatively correlated with age and BCD (p < 0.05). Although all models have significant predictive power for the root lengths and PV, no model could explain variances greater than 30%. The highest and lowest predictive ability was obtained for PRL and DRL, respectively. While the most significant predictor was BP for PRL and DRL, it was the age for PV.

Histamine promotes angiogenesis through a histamine H1 receptor-PKC-VEGF-mediated pathway in human endothelial cells.

Histamine is a well-known inflammatory mediator, but how histamine induces angiogenesis remains poorly understood. In the present study, we demonstrated a dose-dependent dynamic tube formation in the human endothelial cell line EA.hy926 in the presence of histamine that was completely blocked by histamine H1 receptor (H1R) and protein kinase C (PKC) inhibitors. However, histamine H2, H3, and H4 receptor inhibitors did not inhibit tube formation, suggesting that H1R-PKC signaling is involved in histamine-induced tube formation. Moreover, we found an H1-specific induction of vascular endothelial growth factor (VEGF) expression. Inhibition of VEGF receptor 2 (VEGFR2) suppressed the histamine-induced tube formation, indicating that VEGF is downstream of histamine signaling. Additionally, we demonstrated that histamine stimulation induces the expression of critical regulators of angiogenesis such as matrix metalloproteinase (MMP)-9 and MMP-14 metalloproteases, as histamine-induced tube formation is blocked by MMP inhibitors. In summary, our study indicates that histamine can activate the H1R in human endothelial cells and thereby promote tube formation through the PKC, MMP, and VEGF signaling pathways.

Assessment of the Prevalence of Middle Mesial Canal in Mandibular First Molar: A Multinational Cross-sectional Study with Meta-analysis.

BACKGROUND: An additional canal found in the mandibular first molar (M1M) is the middle mesial canal (MMC), which is often missed during root canal treatment. In this study, the prevalence of MMC in M1M on cone-beam computed tomography (CBCT) images was evaluated in 15 countries, along with the effect of some demographic factors on its prevalence. METHODS: Deidentified CBCT images were scanned retrospectively, and the ones including bilateral M1Ms were included in the study. A written and video instruction program explaining the protocol to be followed step-by-step was provided to all observers to calibrate them. The CBCT imaging screening procedure consisted of evaluating three planes (coronal, sagittal, and axial) after a 3-dimensional alignment of the long axis of the root(s). The presence of an MMC in M1Ms (yes/no) was identified and recorded. RESULTS: In total, 6304 CBCTs, representing 12,608 M1Ms, were evaluated. A significant difference was found between countries (P < .05). MMC prevalence ranged from 1% to 23%, and the overall prevalence was 7% (95% confidence interval [CI]: 5%-9%). No significant differences were found between the left and right M1M (odds ratio = 1.09, 95% CI: 0.93, 1.27; P > .05) or between genders (odds ratio= 1.07, 95% CI: 0.91, 1.27; P > .05). As for the age groups, no significant differences were found (P > .05). CONCLUSIONS: The prevalence of MMC varies by ethnicity, but it is generally estimated at 7% worldwide. Physicians must pay close attention to the presence of MMC in M1M, especially for opposite M1Ms, due to the prevalence of MMC being significantly bilateral.

Comparison between a glass ionomer cement and a compomer concerning bonded acrylic expander retention and white spot formation : A randomized clinical trial.

BACKGROUND: The goal of the present study was to compare a compomer and a glass ionomer cement (GIC) used for full the cementation of acrylic splint-type maxillary expanders with respect to failure rate and white spot lesions (WSLs) in vivo. METHODS: A total of 120 patients with posterior crossbite and transverse maxillary deficiency were included to the study. The patients were randomly allocated to two groups: GIC group (n = 60) and compomer group (n = 60). The hyrax screw in both groups was activated two times a day for the first week then once a day until the desired amount of expansion was achieved. The rapid maxillary expansion (RME) appliance was left in the mouth for an extra month after the active expansion phase as a retention appliance. Then cementation failures were recorded. In addition, the patients were evaluated for white spot lesions (WSLs) before cementation and after removal of the appliance. RESULTS: A total of 12 (20%) and 2 (3.3%) RME devices failed in the GIC and the compomer group, respectively. This difference between groups was statistically significant (p = 0.044). There were also statistically significant differences between the GIC and compomer groups in terms of WSLs on the central (p = 0.06) and lateral (p = 0.011) incisors, and on the first molar (0.028). However, no differences were observed for the canines (p = 0.185), first (p = 0.457) and second premolars (p = 0.116). In total, there was a statistically significant difference between the GIC and compomer groups (p = 0.048), with more WSLs in the GIC group. CONCLUSIONS: Among the products used in the study, the compomer should be preferred over the GIC for cementation of acrylic splint-type rapid maxillary expanders in terms of failure rate and WSLs.

Glycolaldehyde-derived advanced glycation end products suppress STING/TBK1/IRF3 signaling via CD36.

AIMS: We have previously reported that advanced glycation end products derived from incubation of albumin with glycolaldehyde (glycol-AGE), lead to suppression of the toll-like receptor 4 (TLR4) signaling response to lipopolysaccharide. Glycol-AGE-induced suppression of TLR4 signaling is involved in the downregulation of CD14, which is an adaptor protein necessary for transferring lipopolysaccharide to TLR4. Therefore, glycol-AGEs impair the innate immune response through suppression of the upstream process in TLR4 signaling. However, the effect of glycol-AGEs on intracellular signaling related to the innate immune response remains unclear. This study aimed to examined the effect of glycol-AGEs on stimulator of interferon gene (STING) signaling in macrophages. MAIN METHODS: In differentiated THP-1 cells, which are a human monocytic leukemia cell line, cyclic GMP-AMP (cGAMP) transfection was used to activate STING signaling. The phosphorylation levels of TANK-binding kinase 1 (TBK1)/interferon regulatory transcription factor 3 (IRF3) were evaluated by western blot analysis. Downstream cytokine levels were evaluated by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assays. KEY FINDINGS: Glycol-AGEs suppressed cGAMP-induced phosphorylation of TBK1 and IRF3, as well as the production of cytokines regulated by IRF3. There was no effect of glycol-AGEs on the efficacy of cGAMP transfection. Treatment of a neutralizing antibody against CD36 prevented cGAMP-induced phosphorylation of TBK1 and IRF3, and also upregulation of interferon-ß and C-X-C motif chemokine ligand 10 in glycol-AGE-treated cells. SIGNIFICANCE: Glycol-AGEs negatively regulate cGAMP-induced activation of STING/TBK1/IRF3 signaling via CD36. Our findings suggest that glycol-AGEs lead to impairment of the innate immune response by suppressing intracellular signaling.

Nordihydroguaiaretic acid inhibits glyoxalase I, and causes the accumulation of methylglyoxal followed by cell-growth inhibition.

BACKGROUND: Methylglyoxal (MGO) is a known toxic byproduct of glycolysis, with MGO-induced cytotoxicity believed to contribute to the pathogenesis of several diseases. Glyoxalase I (GLO1) is a key enzyme for eliminating MGO in mammalian cells, therefore, compounds affecting GLO1 activity are potential therapeutic agents for MGO-induced disorders. Previously, we found nordihydroguaiaretic acid (NDGA) as a potent GLO1 inhibitor. METHODS: The inhibitory characteristics of NDGA were determined spectrophotometrically with recombinant GLO1. NDGA-induced growth-inhibition and accumulation of MGO-derived advanced glycation end products (AGEs) were examined in EA.hy926 cells. RESULTS: NDGA showed significant inhibition of GLO1 enzymatic activity in a dose-dependent manner. Its Ki value was estimated to be 146-fold lower than that of myricetin, a known GLO1 inhibitor. The co-addition of MGO with NDGA to the cells resulted in significant growth inhibition, suggesting that MGO accumulation, sufficient to affect cell growth, was caused by NDGA inhibiting GLO1. These findings were supported by the observations that the addition of aminoguanidine, a typical MGO scavenger, significantly reversed cell-growth inhibition by co-addition of MGO with NDGA, and that an increase in intracellular MGO-derived AGEs was observed during incubation with the co-addition of MGO with NDGA. CONCLUSION: NDGA was found to be a novel and potent inhibitor of GLO1. The co-addition of NDGA with MGO to the cells resulted in increased intracellular MGO accumulation followed by enhanced cell-growth inhibition.

Potential of a Novel Chemical Compound Targeting Matrix Metalloprotease-13 for Early Osteoarthritis: An In Vitro Study.

Osteoarthritis is a progressive disease characterized by cartilage destruction in the joints. Matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) play key roles in osteoarthritis progression. In this study, we screened a chemical compound library to identify new drug candidates that target MMP and ADAMTS using a cytokine-stimulated OUMS-27 chondrosarcoma cells. By screening PCR-based mRNA expression, we selected 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide as a potential candidate. We found that 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide attenuated IL-1ß-induced MMP13 mRNA expression in a dose-dependent manner, without causing serious cytotoxicity. Signaling pathway analysis revealed that 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide attenuated ERK- and p-38-phosphorylation as well as JNK phosphorylation. We then examined the additive effect of 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide in combination with low-dose betamethasone on IL-1ß-stimulated cells. Combined treatment with 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide and betamethasone significantly attenuated MMP13 and ADAMTS9 mRNA expression. In conclusion, we identified a potential compound of interest that may help attenuate matrix-degrading enzymes in the early osteoarthritis-affected joints.

LCZ696 ameliorates doxorubicin-induced cardiomyocyte toxicity in rats.

Doxorubicin (DOX)-based chemotherapy induces cardiotoxicity, which is considered the main bottleneck for its clinical application. In this study, we investigated the potential benefit of LCZ696, an angiotensin receptor-neprilysin inhibitor against DOX-induced cardiotoxicity in rats and H9c2 cells and determined whether the mechanism underlying any such effects involves its antioxidant activity. Male Sprague-Dawley rats were randomly separated into four groups, each consisting of 15 rats (DOX (1.5 mg/kg/day intraperitoneally for 10 days followed by non-treatment for 8 days); DOX + valsartan (31 mg/kg/day by gavage from day 1 to day 18); DOX + LCZ696 (68 mg/kg/day by gavage from day 1 to day 18); and control (saline intraperitoneally for 10 days). DOX-induced elevation of cardiac troponin T levels on day 18 was significantly reduced by LCZ696, but not valsartan. The DOX-induced increase in myocardial reactive oxygen species (ROS) levels determined using dihydroethidium was significantly ameliorated by LCZ696, but not valsartan, and was accompanied by the suppression of DOX-induced increase in p47phox. LCZ696 recovered the DOX-induced decrease in phosphorylation of adenosine monophosphate-activated protein kinase and increased the ratio of Bax and Bcl-2. In H9c2 cardiomyocytes, LCZ696 reduced DOX-induced mitochondrial ROS generation and improved cell viability more than valsartan. Our findings indicated that LCZ696 ameliorated DOX-induced cardiotoxicity in rat hearts in vivo and in vitro, possibly by mediating a decrease in oxidative stress.

Caries-related salivary parameters and oral microbial flora in patients with type 1 diabetes: A meta-analysis.

OBJECTIVES: This study aimed to conduct a meta-analysis by synthesising the outcomes of studies that investigated the relationship between type 1 diabetes (T1D) and salivary flow rate (SFR), salivary pH (SpH), salivary buffer capacity (SBC), streptococcus Mutans (SM), and lactobacillus (LB) counts. MATERIAL AND METHODS: The PRISMA statement guide was followed for the meta-analysis. Electronic databases were searched, and study selection and data collection processes were performed. The risks of bias in individual studies and across studies were assessed. Mean differences (MD) and Odds Ratio (OR) were used to measure the effect estimates in the comparisons. RESULTS: 29 studies were included in the qualitative and quantitative syntheses. Significantly higher SFR (MD = -0.22, CI: -0.26, -0.18; p < 0.001) and SpH (MD = -0.59, CI: -0.81, -0.36; p < 0.001) were observed in the healthy individuals than T1D individuals. No significant difference was observed among groups in terms of SBC (MD = 0.10, CI: -0.46,0.66; p = 0.73). An increased odds ratio of SM counts were observed regarding the T1D (OR = 3.09, 95% CI: 1.16, 8.20; p = 0.02). No association was found between LB counts and T1D (OR = 2.15, 95% CI: 0.38, 11.98; p = 0.38). CONCLUSIONS: Subjects with T1D have a significantly lesser SFR and SpH than healthy individuals. But no significant difference is available in terms of SBC. Lower SM counts were observed in individuals with T1D, while no association was observed regarding LB counts. The tendency to dental caries is more likely in subjects with T1D due to lower SFR, SpH, and higher SM.