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1.
J Periodontal Implant Sci ; 53(4): 269-282, 2023 Aug.
Article in English | MEDLINE | ID: mdl-36468488

ABSTRACT

PURPOSE: Dental fear hinders patients from receiving appropriate dental treatment. In particular, the noise generated by high-speed air turbines and ultrasonic scalers can adversely affect patients. Many efforts have been made to reduce the discomfort caused by noise, but no methods are definitively recommended. The purpose of this study was to determine the efficacy of active noise-canceling (ANC) headphones in reducing the pain and discomfort associated with dental scaling. METHODS: Fifty-five patients requiring scaling and root planing, aged ≥19 years and showing no auditory problems, were included. Scaling was performed for the bilateral maxillary molars and premolars while patients wore headphones, with ANC turned either on or off. The degree of noise and pain reduction in the on and off conditions were surveyed using a visual analog scale (VAS). The Wilcoxon signed-rank test was performed to compare noise- and pain-related discomfort with ANC turned on and off. RESULTS: The sample included 28 men and 27 women with a mean age of 45.45±13.12 years. The average noise-related discomfort score was 3.84±2.12 and 2.95±1.99 when noise-canceling was turned off and on, respectively, with a statistically significant difference (P<0.05). Similarly, the average pain-related discomfort score was 3.78±2.00 and 3.09±1.96 when noise-canceling was turned off and on, respectively, which was a statistically significant difference (P<0.05). CONCLUSIONS: The use of ANC headphones seems to reduce the discomfort caused by noise and pain in patients undergoing scaling. TRIAL REGISTRATION: Clinical Research Information Service Identifier: KCT0007093.

2.
J Periodontal Implant Sci ; 52(3): 194-205, 2022 Jun.
Article in English | MEDLINE | ID: mdl-35775695

ABSTRACT

PURPOSE: This study aimed to determine the long-term outcomes after peri-implantitis treatment and the factors affecting these outcomes. METHODS: This study included 92 implants in 45 patients who had been treated for peri-implantitis. Clinical data on the characteristics of patients and their implants were collected retrospectively. The change in the marginal bone level was calculated by comparing the baseline and the most recently obtained (≥3 years after treatment) radiographs. The primary outcome variable was progression of the disease after the treatment at the implant level, which was defined as further bone loss of >1.0 mm or implant removal. A 2-level binary logistic regression analysis was used to identify the effects of possible factors on the primary outcome. RESULTS: The mean age of the patients was 58.7 years (range, 22-79 years). Progression of peri-implantitis was observed in 64.4% of patients and 63.0% of implants during an observation period of 6.4±2.7 years (mean±standard deviation). Multivariable regression analysis revealed that full compliance to recall visits (P=0.019), smoking (P=0.023), placement of 4 or more implants (P=0.022), and marginal bone loss ≥4 mm at baseline (P=0.027) significantly influenced the treatment outcome. CONCLUSIONS: The long-term results of peri-implantitis treatment can be improved by full compliance on the part of patients, whereas it is impaired by smoking, placement of multiple implants, and severe bone loss at baseline. Encouraging patients to stop smoking and to receive supportive care is recommended before treatment.

3.
J Periodontal Implant Sci ; 52(3): 230-241, 2022 Jun.
Article in English | MEDLINE | ID: mdl-35775698

ABSTRACT

PURPOSE: The purpose of this study was to evaluate failed implants and reimplantation survival and to identify the relative risk factors for implant re-failure. METHODS: Ninety-one dental implants were extracted between 2006 and 2020 at the National Health Insurance Service Ilsan Hospital, including 56 implants in the maxilla and 35 implants in the mandible that were removed from 77 patients. Patient information (e.g., age, sex, and systemic diseases) and surgical information (e.g., the date of surgery and location of the implants and bone grafts) were recorded. If an implant prosthesis was used, prosthesis information was also recorded. RESULTS: In total, 91 first-time failed dental implants in 77 patients were analyzed. Of them, 69 implants in 61 patients received reimplantation after failure. Sixteen patients (22 implants) refused reimplantation or received reimplantation at a different site. Eight of the 69 reimplants failed again. The 1-year survival rate of the 69 reimplants was 89.4%. Age at reimplantation and smoking significantly increased the risk of reimplantation failure. However, a history of taking anti-thrombotic agents showed a statistically significant negative association with reimplantation failure. Of the failed implants, 66% showed early failure and 34% showed late failure of the initial implantation. All 8 re-failed implants showed early failure. Only 3 of these 8 failed reimplants were re-tried and the second reimplants all survived. CONCLUSIONS: The total survival rate of implants, which included reimplants and second reimplants was 99.2%, although the survival rate of the initial implantations was 96.3%. Previous failure did not affect the success of the next trial. Reimplantation failure was more strongly affected by patient factors than by implant factors. Therefore, each patient's specific factors need to be meticulously controlled to achieve successful reimplantation.

4.
Cell Death Dis ; 13(7): 603, 2022 07 12.
Article in English | MEDLINE | ID: mdl-35831271

ABSTRACT

Autophagy is a biological process that maintains cellular homeostasis and regulates the internal cellular environment. Hyperactivating autophagy to trigger cell death has been a suggested therapeutic strategy for cancer treatment. Mechanistic target of rapamycin (mTOR) is a crucial protein kinase that regulates autophagy; therefore, using a structure-based virtual screen analysis, we identified lomitapide, a cholesterol-lowering drug, as a potential mTOR complex 1 (mTORC1) inhibitor. Our results showed that lomitapide directly inhibits mTORC1 in vitro and induces autophagy-dependent cancer cell death by decreasing mTOR signaling, thereby inhibiting the downstream events associated with increased LC3 conversion in various cancer cells (e.g., HCT116 colorectal cancer cells) and tumor xenografts. Lomitapide also significantly suppresses the growth and viability along with elevated autophagy in patient-derived colorectal cancer organoids. Furthermore, a combination of lomitapide and immune checkpoint blocking antibodies synergistically inhibits tumor growth in murine MC38 or B16-F10 preclinical syngeneic tumor models. These results elucidate the direct, tumor-relevant immune-potentiating benefits of mTORC1 inhibition by lomitapide, which complement the current immune checkpoint blockade. This study highlights the potential repurposing of lomitapide as a new therapeutic option for cancer treatment.


Subject(s)
Antineoplastic Agents , Autophagic Cell Death , Colorectal Neoplasms , Animals , Antineoplastic Agents/pharmacology , Autophagy , Benzimidazoles , Cholesterol/pharmacology , Colorectal Neoplasms/drug therapy , Humans , Mechanistic Target of Rapamycin Complex 1/metabolism , Mice , TOR Serine-Threonine Kinases/metabolism
5.
Mol Cells ; 44(4): 187-194, 2021 Apr 30.
Article in English | MEDLINE | ID: mdl-33935040

ABSTRACT

Inositol phosphates are water-soluble intracellular signaling molecules found in eukaryotes from yeasts to mammals, which are synthesized by a complex network of enzymes including inositol phosphate kinases. Among these, inositol polyphosphate multikinase (IPMK) is a promiscuous enzyme with broad substrate specificity, which phosphorylates multiple inositol phosphates, as well as phosphatidylinositol 4,5-bisphosphate. In addition to its catalytic actions, IPMK is known to non-catalytically control major signaling events via direct protein-protein interactions. In this review, we describe the general characteristics of IPMK, highlight its pleiotropic roles in various physiological and pathological conditions, and discuss future challenges in the field of IPMK signaling pathways.


Subject(s)
Phosphotransferases (Alcohol Group Acceptor)/metabolism , Humans , Signal Transduction
6.
Anal Chem ; 93(5): 2811-2819, 2021 02 09.
Article in English | MEDLINE | ID: mdl-33475355

ABSTRACT

Bacterial riboswitch RNAs are attractive targets for novel antibiotics against antibiotic-resistant superbacteria. Their binding to cognate metabolites is essential for the regulation of bacterial gene expression. Despite the importance of RNAs as therapeutic targets, the development of RNA-targeted, small-molecule drugs is limited by current biophysical methods. Here, we monitored the specific interaction between the adenine-sensing riboswitch aptamer domain (ARS) and adenine at the single-molecule level using α-hemolysin (αHL) nanopores. During adenine-induced tertiary folding, adenine-bound ARS intermediates exhibited characteristic nanopore events, including a two-level ionic current blockade and a ∼ 5.6-fold longer dwell time than that of free RNA. In a proof-of-concept experiment, tertiary RNA folding-targeted drug screening was performed using a protein nanopore, which resulted in the discovery of three new ARS-targeting hit compounds from a natural compound library. Taken together, these results reveal that αHL nanopores are a valuable platform for ultrasensitive, label-free, and single-molecule-based drug screening against therapeutic RNA targets.


Subject(s)
Nanopores , Riboswitch , Drug Evaluation, Preclinical , Hemolysin Proteins , RNA Folding
7.
J Prosthet Dent ; 125(2): 273-278, 2021 Feb.
Article in English | MEDLINE | ID: mdl-32336540

ABSTRACT

STATEMENT OF PROBLEM: Implant-supported prostheses have typically been retained by cement or screws, each of which has advantages and disadvantages. Two new types of prosthesis with complementary advantages and disadvantages have been proposed: the screw- and cement-retained prosthesis, which combines cement and screw retention, and the antiloosening inner-post screw (ALIPS) type, which uses lateral screws. Both esthetic and functional factors should be considered for anterior prostheses; however, clinical studies of the complication rates of these designs are lacking. PURPOSE: The purpose of this retrospective clinical study was to evaluate the complications of dental implant-supported restorations with various prosthetic types in the anterior region and to analyze other factors that affect complications. MATERIAL AND METHODS: This study included 51 patients who had 83 implants placed in the anterior region by a single clinician between August 2009 and December 2016. Surgical and prosthetic features were recorded, and implant complications were analyzed. RESULTS: There were 45 (55.4%) cement-retained implants, 5 (6.0%) screw- and cement-retained prosthesis implants, and 32 (38.6%) ALIPS-retained implants. Peri-implant mucositis was observed most frequently in the ALIPS type (21.9%), but the biological complications did not differ significantly with the prosthetic type. The most common mechanical complication was loss of retention in the cement type of prosthesis (30.4%) and screw loosening in the ALIPS type (43.8%). Implant complications varied with position (maxilla or mandible) and implantation timing (period from tooth extraction to implant placement). CONCLUSIONS: The complications of implants placed in the anterior region were affected by different factors but did not differ significantly with the type of the retention.


Subject(s)
Dental Implants , Dental Restoration Failure , Dental Implants/adverse effects , Dental Prosthesis Retention , Dental Prosthesis, Implant-Supported/adverse effects , Esthetics, Dental , Humans , Retrospective Studies
8.
Biochem Biophys Res Commun ; 533(3): 319-324, 2020 12 10.
Article in English | MEDLINE | ID: mdl-32958249

ABSTRACT

We previously demonstrated that CPNE1 induces neuronal differentiation and identified two binding proteins of CPNE1 (14-3-3γ and Jab1) as potential regulators of CPNE1-mediated neuronal differentiation in hippocampal progenitor cells. To better understand the cellular processes in which CPNE1 participates in neuronal differentiation, we here carried out a yeast two-hybrid screening to find another CPNE1 binding protein. Among the identified proteins, HCLS1-related protein X-1 (HAX1) directly interacts with CPNE1. Immunostaining experiments showed that a fraction of CPNE1 and HAX1 co-localized in the cytosol, particularly in the plasma membrane. In addition, the physical interaction as well as the specific binding regions between CPNE1 and HAX1 were confirmed in vitro and in vivo. Moreover, AKT phosphorylation, Tuj1 (neuronal marker protein) expression, and neurite outgrowth are all reduced in CPNE1/HAX1 overexpressing cells compared to CPNE1 only overexpressing HiB5 cells. Conversely, the HAX1 mutant that does not bind to CPNE1 was unable to inhibit the CPNE1-mediated neuronal differentiation. Together these results indicate that HAX1 is a binding partner of CPNE1 and CPNE1-mediated neuronal differentiation is negatively affected through the binding of HAX1, especially its N-terminal region, with CPNE1.


Subject(s)
Calcium-Binding Proteins/genetics , Cell Differentiation/genetics , Intracellular Signaling Peptides and Proteins/genetics , Neurons/metabolism , Proto-Oncogene Proteins c-akt/genetics , Tubulin/genetics , 14-3-3 Proteins/genetics , 14-3-3 Proteins/metabolism , Animals , COP9 Signalosome Complex/genetics , COP9 Signalosome Complex/metabolism , COS Cells , Calcium-Binding Proteins/metabolism , Cell Line , Cell Membrane/metabolism , Chlorocebus aethiops , Gene Expression Regulation , HEK293 Cells , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Mutation , Neurons/cytology , Phosphorylation , Protein Binding , Proto-Oncogene Proteins c-akt/metabolism , Rats , Signal Transduction , Tubulin/metabolism , Two-Hybrid System Techniques
9.
Mol Cells ; 43(3): 222-227, 2020 Mar 31.
Article in English | MEDLINE | ID: mdl-32209735

ABSTRACT

Inositol polyphosphate multikinase (IPMK) is required for the biosynthesis of inositol phosphates (IPs) through the phosphorylation of multiple IP metabolites such as IP3 and IP4. The biological significance of IPMK's catalytic actions to regulate cellular signaling events such as growth and metabolism has been studied extensively. However, pharmacological reagents that inhibit IPMK have not yet been identified. We employed a structure-based virtual screening of publicly available U.S. Food and Drug Administration-approved drugs and chemicals that identified the antidepressant, vilazodone, as an IPMK inhibitor. Docking simulations and pharmacophore analyses showed that vilazodone has a higher affinity for the ATP-binding catalytic region of IPMK than ATP and we validated that vilazodone inhibits IPMK's IP kinase activities in vitro . The incubation of vilazodone with NIH3T3-L1 fibroblasts reduced cellular levels of IP5 and other highly phosphorylated IPs without influencing IP4 levels. We further found decreased Akt phosphorylation in vilazodone-treated HCT116 cancer cells. These data clearly indicate selective cellular actions of vilazodone against IPMK-dependent catalytic steps in IP metabolism and Akt activation. Collectively, our data demonstrate vilazodone as a method to inhibit cellular IPMK, providing a valuable pharmacological agent to study and target the biological and pathological processes governed by IPMK.


Subject(s)
Antidepressive Agents/therapeutic use , Drug Repositioning/methods , Phosphotransferases (Alcohol Group Acceptor)/drug effects , Vilazodone Hydrochloride/therapeutic use , Antidepressive Agents/pharmacology , Humans , Vilazodone Hydrochloride/pharmacology
10.
J Periodontal Implant Sci ; 49(4): 248-257, 2019 Aug.
Article in English | MEDLINE | ID: mdl-31485375

ABSTRACT

PURPOSE: The purpose of this retrospective study was to investigate the relationships of types of dental insurance coverage in Korea with sociodemographic characteristics and the prevalence of systemic and oral diseases, as well as to evaluate the socioeconomic impact of Korean dental insurance policies. METHODS: Sample cohort data from 2006 to 2015 were obtained from the National Health Insurance Service. Patients were divided into 2 groups. The exposed group comprised patients who received insurance benefits for complete dentures, removable partial dentures, and implant care, while the control group comprised patients who did not receive these benefits. The type of insurance coverage and the prevalence of systemic and oral diseases were compared between the 2 groups. RESULTS: Patients who received benefits in the form of complete dentures, removable partial dentures, and implants had similar sociodemographic characteristics in terms of sex, age, income quintile, and type of insurance coverage to the control group. The prevalence of hypertension, anemia, renal disease, rheumatoid arthritis, osteoporosis, asthma, and cerebral infarction was higher in the exposed group than in the control group (P<0.05). The prevalence of periodontal diseases and dental caries was also higher in the exposed group. CONCLUSIONS: Korean dental health insurance policy has been beneficial for the medical expenses of low-income and elderly people suffering from a cost burden due to systemic diseases. However, since there is a tendency to avoid invasive interventions in older patients due to the high risk of systemic diseases, insurance coverage of dentures may be more helpful from a socioeconomic perspective than coverage of dental implant treatments.

11.
Biochem Biophys Res Commun ; 514(2): 518-523, 2019 06 25.
Article in English | MEDLINE | ID: mdl-31056264

ABSTRACT

Irinotecan is a strong anticancer drug whose mechanism of action has been reported only for the inhibition of DNA topoisomerase I (Topo I) through its active metabolite SN-38. In this study, we present a new mechanism of Irinotecan which inhibits the activities of MDM2, an E3 ligase of tumour suppressor p53, and Bcl-xL, an anti-apoptotic protein, through direct binding. In our structure modelling study, Irinotecan could fit to the binding sites of MDM2 and Bcl-xL for their known drugs, Nutlin-3 and ABT-737, with a better binding affinity than to Topo I. The direct binding of Irinotecan to both proteins was confirmed through a NMR study. We further showed that Irinotecan increased the amount of p53 only in the presence of MDM2 and inhibited the physical interaction of Bcl-xL with Bim, a core pro-apoptotic protein. In addition, we demonstrated that Irinotecan induced the down regulation of proliferation and strong G2/M arrest in HCT116 colon cancer cells shortly after treatment. Collectively, we suggest a new mechanism of action for Irinotecan as a dual target inhibitor of MDM2 and Bcl-xL facilitating the anticancer activities mediated by p53 and Bcl-xL interaction partners.


Subject(s)
Irinotecan/pharmacology , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Proto-Oncogene Proteins c-mdm2/metabolism , bcl-X Protein/antagonists & inhibitors , bcl-X Protein/metabolism , Apoptosis/drug effects , Bcl-2-Like Protein 11/metabolism , Binding Sites , Biphenyl Compounds/pharmacology , Cell Cycle Checkpoints/drug effects , Cell Proliferation/drug effects , DNA Topoisomerases, Type I/chemistry , DNA Topoisomerases, Type I/metabolism , HCT116 Cells , Humans , Imidazoles/pharmacology , Irinotecan/chemistry , Models, Molecular , Nitrophenols/pharmacology , Nuclear Magnetic Resonance, Biomolecular , Piperazines/pharmacology , Protein Binding/drug effects , Proto-Oncogene Proteins c-mdm2/chemistry , Signal Transduction/drug effects , Sulfonamides/pharmacology , Tumor Suppressor Protein p53/metabolism , bcl-X Protein/chemistry
12.
J Periodontal Implant Sci ; 48(5): 317-325, 2018 Oct.
Article in English | MEDLINE | ID: mdl-30405939

ABSTRACT

PURPOSE: We investigated correlations between the findings of oral examinations and panoramic radiography in order to determine the efficacy of using panoramic radiographs in screening examinations. METHODS: This study included patients who visited dental clinics at National Health Insurance Service (NHIS) Ilsan Hospital for checkups during 2009-2015 and underwent panoramic radiographic examinations within 1 year prior to the oral examinations. Among the 48,006 patients who received checkups, 1,091 were included in this study. The data were evaluated using the Cohen kappa and interrater agreement coefficients. Accuracy, sensitivity, and specificity were calculated using data from the panoramic radiographs as true positive diagnoses. RESULTS: The interrater agreement coefficient for occlusal caries was 28.8%, and the Cohen kappa coefficient was 0.043 between the oral and panoramic radiographic examinations. Root caries and subgingival calculus were only found on the radiographs, while gingival inflammation was found only by the oral examinations. The oral examinations had a specificity for detecting occlusal dental caries of 100%, while their sensitivity for proximal dental caries and supragingival calculus was extremely low (14.0% and 18.3%, respectively) compared to the panoramic radiographic examinations. The oral examinations showed a relatively low sensitivity of 66.2% and a specificity of 43.7% in detecting tooth loss compared with panoramic radiography. CONCLUSIONS: Panoramic radiography can provide information that is difficult to obtain in oral examinations, such as root caries, furcation involvement, and subgingival calculus, which are factors that can directly affect the survival rate of teeth. It therefore seems reasonable and necessary to add panoramic radiography to large-scale health checkup programs such as that provided by the NHIS.

13.
Clin Implant Dent Relat Res ; 20(5): 799-805, 2018 Oct.
Article in English | MEDLINE | ID: mdl-30048041

ABSTRACT

BACKGROUND: Marginal bone loss (MBL) is considered an important determinant of implant success, and establishing the peri-implant biological width has been regarded to influence MBL around implants. However, few studies have attempted to show the relationship between the crown/abutment gap and MBL. PURPOSE: To evaluate the effect of the prosthetic abutment height on MBL of dental implants. MATERIALS AND METHODS: This study evaluated data which were retrospectively collected through chart and panoramic radiographs of 145 patients (78 males and 67 females; aged 19 to 79 years, mean age 54.1 years) in whom 273 implants were placed by a single clinician between June 2009 and December 2014. The abutment height and the bone level were measured in digital panorama radiographs. All correlations between abutment height and MBL were analyzed using Spearman's test (P < .05). RESULTS: The 273 implants comprised 126 in 67 female patients and 147 in 78 male patients. The mean age of the patients was 54.1 years (range 19-79 years). The prevalence of MBL and the mean MBL decreased as the abutment height increased. Spearman's test showed a significant negative correlation between abutment height and MBL (P < .05). CONCLUSION: The present study suggests that implants with a higher prosthetic abutment show less MBL, with the abutment height recommended to not exceed 4 mm.


Subject(s)
Alveolar Bone Loss/etiology , Dental Abutments/adverse effects , Dental Implant-Abutment Design/adverse effects , Adult , Aged , Alveolar Bone Loss/diagnostic imaging , Dental Implantation, Endosseous/adverse effects , Female , Humans , Male , Middle Aged , Radiography, Panoramic , Retrospective Studies , Young Adult
14.
PLoS One ; 12(8): e0183569, 2017.
Article in English | MEDLINE | ID: mdl-28846705

ABSTRACT

Pancreatic islets can adapt to oscillatory glucose to produce synchronous insulin pulses. Can islets adapt to other oscillatory stimuli, specifically insulin? To answer this question, we stimulated islets with pulses of exogenous insulin and measured their Ca2+ oscillations. We observed that sufficiently high insulin (> 500 nM) with an optimal pulse period (~ 4 min) could make islets to produce synchronous Ca2+ oscillations. Glucose and insulin, which are key stimulatory factors of islets, modulate islet Ca2+ oscillations differently. Glucose increases the active-to-silent ratio of phases, whereas insulin increases the period of the oscillation. To examine the dual modulation, we adopted a phase oscillator model that incorporated the phase and frequency modulations. This mathematical model showed that out-of-phase oscillations of glucose and insulin were more effective at synchronizing islet Ca2+ oscillations than in-phase stimuli. This finding suggests that a phase shift in glucose and insulin oscillations can enhance inter-islet synchronization.


Subject(s)
Calcium Signaling/drug effects , Calcium/metabolism , Hypoglycemic Agents/pharmacology , Insulin/pharmacology , Islets of Langerhans/drug effects , Animals , Glucose/pharmacology , Islets of Langerhans/metabolism , Mice , Models, Biological
15.
BMC Bioinformatics ; 18(Suppl 7): 226, 2017 May 31.
Article in English | MEDLINE | ID: mdl-28617219

ABSTRACT

BACKGROUND: Recently, the metabolite-likeness of the drug space has emerged and has opened a new possibility for exploring human metabolite-like candidates in drug discovery. However, the applicability of metabolite-likeness in drug discovery has been largely unexplored. Moreover, there are no reports on its applications for the repositioning of drugs to possible enzyme modulators, although enzyme-drug relations could be directly inferred from the similarity relationships between enzyme's metabolites and drugs. METHODS: We constructed a drug-metabolite structural similarity matrix, which contains 1,861 FDA-approved drugs and 1,110 human intermediary metabolites scored with the Tanimoto similarity. To verify the metabolite-likeness measure for drug repositioning, we analyzed 17 known antimetabolite drugs that resemble the innate metabolites of their eleven target enzymes as the gold standard positives. Highly scored drugs were selected as possible modulators of enzymes for their corresponding metabolites. Then, we assessed the performance of metabolite-likeness with a receiver operating characteristic analysis and compared it with other drug-target prediction methods. We set the similarity threshold for drug repositioning candidates of new enzyme modulators based on maximization of the Youden's index. We also carried out literature surveys for supporting the drug repositioning results based on the metabolite-likeness. RESULTS: In this paper, we applied metabolite-likeness to repurpose FDA-approved drugs to disease-associated enzyme modulators that resemble human innate metabolites. All antimetabolite drugs were mapped with their known 11 target enzymes with statistically significant similarity values to the corresponding metabolites. The comparison with other drug-target prediction methods showed the higher performance of metabolite-likeness for predicting enzyme modulators. After that, the drugs scored higher than similarity score of 0.654 were selected as possible modulators of enzymes for their corresponding metabolites. In addition, we showed that drug repositioning results of 10 enzymes were concordant with the literature evidence. CONCLUSIONS: This study introduced a method to predict the repositioning of known drugs to possible modulators of disease associated enzymes using human metabolite-likeness. We demonstrated that this approach works correctly with known antimetabolite drugs and showed that the proposed method has better performance compared to other drug target prediction methods in terms of enzyme modulators prediction. This study as a proof-of-concept showed how to apply metabolite-likeness to drug repositioning as well as potential in further expansion as we acquire more disease associated metabolite-target protein relations.


Subject(s)
Drug Repositioning , Enzymes/metabolism , Antimetabolites/metabolism , Area Under Curve , Databases, Factual , Enzymes/chemistry , Gaucher Disease/drug therapy , Gaucher Disease/enzymology , Gaucher Disease/pathology , Glucosylceramidase/therapeutic use , Humans , ROC Curve
16.
Exp Cell Res ; 356(1): 85-92, 2017 07 01.
Article in English | MEDLINE | ID: mdl-28412242

ABSTRACT

Copine1 (CPNE1), known as a calcium-dependent membrane-binding protein, has tandem C2 domains and an A domain. We previously demonstrated that CPNE1 directly induces neuronal differentiation via Protein kinase B (AKT) phosphorylation in the hippocampal progenitor cell line, HiB5. To better understand its cellular function, we carried out a yeast two-hybrid screening to find CPNE1 binding partners. Among the identified proteins, 14-3-3γ appears to directly interact with CPNE1. Between CPNE1 and 14-3-3γ, the physical interaction as well as the specific binding regions of CPNE1 was confirmed in vitro and in vivo. Furthermore, among the seven 14-3-3 isotypes, only 14-3-3γ directly interacts with CPNE1. Our results also demonstrate that AKT phosphorylation, neurite outgrowth and expression of the neuronal marker protein are increased when 14-3-3γ is overexpressed in CPNE1 high expressed HiB5 cells. Furthermore, the neighboring Ser54 amino acids residue of C2A domain in CPNE1 has an important role in binding with 14-3-3γ, and in differentiation-related function of CPNE1. Moreover, mutation of Ser54 amino acids residue in CPNE1 effectively decreased association with 14-3-3γ and neuronal differentiation of HiB5 cells. Collectively, our findings indicate that 14-3-3γ regulates the differentiation ability of CPNE1 through the binding with C2A domain of CPNE1 in HiB5 cells.


Subject(s)
14-3-3 Proteins/metabolism , Calcium-Binding Proteins/metabolism , Hippocampus/cytology , Neurogenesis/genetics , Stem Cells/cytology , 14-3-3 Proteins/genetics , Animals , COS Cells , Calcium-Binding Proteins/genetics , Cell Line , Chlorocebus aethiops , HEK293 Cells , Humans , Phosphorylation , Protein Binding/genetics , Protein Domains , Proto-Oncogene Proteins c-akt/metabolism , RNA Interference , RNA, Small Interfering/genetics
17.
PLoS One ; 12(2): e0172901, 2017.
Article in English | MEDLINE | ID: mdl-28235104

ABSTRACT

Insulin is secreted in a pulsatile manner from multiple micro-organs called the islets of Langerhans. The amplitude and phase (shape) of insulin secretion are modulated by numerous factors including glucose. The role of phase modulation in glucose homeostasis is not well understood compared to the obvious contribution of amplitude modulation. In the present study, we measured Ca2+ oscillations in islets as a proxy for insulin pulses, and we observed their frequency and shape changes under constant/alternating glucose stimuli. Here we asked how the phase modulation of insulin pulses contributes to glucose regulation. To directly answer this question, we developed a phenomenological oscillator model that drastically simplifies insulin secretion, but precisely incorporates the observed phase modulation of insulin pulses in response to glucose stimuli. Then, we mathematically modeled how insulin pulses regulate the glucose concentration in the body. The model of insulin oscillation and glucose regulation describes the glucose-insulin feedback loop. The data-based model demonstrates that the existence of phase modulation narrows the range within which the glucose concentration is maintained through the suppression/enhancement of insulin secretion in conjunction with the amplitude modulation of this secretion. The phase modulation is the response of islets to glucose perturbations. When multiple islets are exposed to the same glucose stimuli, they can be entrained to generate synchronous insulin pulses. Thus, we conclude that the phase modulation of insulin pulses is essential for glucose regulation and inter-islet synchronization.


Subject(s)
Glucose/metabolism , Insulin/metabolism , Islets of Langerhans/metabolism , Animals , Calcium Signaling , Cells, Cultured , Homeostasis , Insulin Secretion , Kinetics , Male , Mice, Inbred C57BL
18.
J Adv Prosthodont ; 6(6): 512-20, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25551012

ABSTRACT

PURPOSE: The purpose of this study was to assess the surface characteristics and the biocompatibility of zirconium (Zr) coating on Ti-6Al-4V alloy surface by radio frequency (RF) magnetron sputtering method. MATERIALS AND METHODS: The zirconium films were developed on Ti-6Al-4V discs using RF magnetron sputtering method. Surface profile, surface composition, surface roughness and surface energy were evaluated. Electrochemical test was performed to evaluate the corrosion behavior. Cell proliferation, alkaline phosphatase (ALP) activity and gene expression of mineralized matrix markers were measured. RESULTS: SEM and EDS analysis showed that zirconium deposition was performed successfully on Ti-6Al-4V alloy substrate. Ti-6Al-4V group and Zr-coating group showed no significant difference in surface roughness (P>.05). Surface energy was significantly higher in Zr-coating group than in Ti-6Al-4V group (P<.05). No difference in cell morphology was observed between Ti-6Al-4V group and Zr-coating group. Cell proliferation was higher in Zr-coating group than Ti-6Al-4V group at 1, 3 and 5 days (P<.05). Zr-coating group showed higher ALP activity level than Ti-6Al-4V group (P<.05). The mRNA expressions of bone sialoprotein (BSP) and osteocalcin (OCN) on Zr-coating group increased approximately 1.2-fold and 2.1-fold respectively, compared to that of Ti-6Al-4V group. CONCLUSION: These results suggest that zirconium coating on Ti-6Al-4V alloy could enhance the early osteoblast responses. This property could make non-toxic metal coatings on Ti-6Al-4V alloy suitable for orthopedic and dental implants.

19.
J Adv Prosthodont ; 5(4): 402-8, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24353877

ABSTRACT

PURPOSE: The aim of this study was to evaluate the surface properties and in vitro bioactivity to osteoblasts of magnesium and magnesium-hydroxyapatite coated titanium. MATERIALS AND METHODS: Themagnesium (Mg) and magnesium-hydroxyapatite (Mg-HA) coatings on titanium (Ti) substrates were prepared by radio frequency (RF) and direct current (DC) magnetron sputtering.The samples were divided into non-coated smooth Ti (Ti-S group), Mg coatinggroup (Ti-Mg group), and Mg-HA coating group (Ti-MgHA group).The surface properties were evaluated using scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS). The surface roughness was evaluated by atomic force microscopy (AFM). Cell adhesion, cell proliferation and alkaline phosphatase (ALP) activity were evaluated using MC3T3-E1 cells. Reverse transcription polymerase chain reaction (RT-PCR) analysis was performed. RESULTS: Cross-sectional SEM images showed that Mg and Mg-HA depositionson titanium substrates were performed successfully. The surface roughness appeared to be similaramong the three groups. Ti-MgHA and Ti-Mg group had improved cellular responses with regard to the proliferation, alkaline phosphatase (ALP) activity, and bone-associated markers, such as bone sialoprotein (BSP) and osteocalcin (OCN) mRNA compared to those of Ti-S group. However, the differences between Ti-Mg group and Ti-MgHA group were not significant, in spite of the tendency of higher proliferation, ALP activity and BSP expression in Ti-MgHA group. CONCLUSION: Mg and Mg-HAcoatings could stimulate the differentiation into osteoblastic MC3T3-E1 cells, potentially contributing to rapid osseointegration.

20.
J Periodontal Implant Sci ; 43(4): 198-205, 2013 Aug.
Article in English | MEDLINE | ID: mdl-24040573

ABSTRACT

PURPOSE: The aim of this study was to evaluate the surface properties and biological response of an anodized titanium surface by cell proliferation and alkaline phosphatase activity analysis. METHODS: Commercial pure titanium (Ti) disks were prepared. The samples were divided into an untreated machined Ti group and anodized Ti group. The anodization of cp-Ti was formed using a constant voltage of 270 V for 60 seconds. The surface properties were evaluated using scanning electron microscopy, X-ray photoelectron spectroscopy, and an image analyzing microscope. The surface roughness was evaluated by atomic force microscopy and a profilometer. The contact angle and surface energy were analyzed. Cell adhesion, cell proliferation, and alkaline phosphatase activity were evaluated using mouse MC3T3-E1 cells. RESULTS: The anodized Ti group had a more porous and thicker layer on its surface. The surface roughness of the two groups measured by the profilometer showed no significant difference (P>0.001). The anodized Ti dioxide (TiO2) surface exhibited better corrosion resistance and showed a significantly lower contact angle than the machined Ti surface (P>0.001). Although there was no significant difference in the cell viability between the two groups (P>0.001), the anodized TiO2 surface showed significantly enhanced alkaline phosphatase activity (P<0.001). CONCLUSIONS: These results suggest that the surface modification of Ti by anodic oxidation improved the osteogenic response of the osteoblast cells.

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