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1.
Immunology ; 162(3): 306-313, 2021 03.
Article in English | MEDLINE | ID: mdl-33131052

ABSTRACT

Bisphosphonates distributed to bone exert toxic effects specifically towards osteoclasts. On the other hand, intravenous administration of a nitrogen-containing bisphosphonate (N-BP) such as zoledronate induces acute-phase reactions (APRs), including influenza-like fever 1 day later, indicating an interaction with immunocompetent cells circulating blood. Although it has been reported that activation of γδ T cells is pivotal to induce an APR following treatment with zoledronate, downstream events, including the production of inflammatory cytokines after activation of γδ T cells, remain obscure. We investigated the effects of zoledronate on inflammatory cytokine expression in human peripheral blood mononuclear cells (PBMCs) in vitro. While zoledronate induced mRNA expressions of tumour necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6 and interferon-γ (IFN-γ) in PBMC, depletion of γδ T cells abolished that zoledronate-induced expression of those cytokines, indicating the necessity of γδ T cells for expression induction by zoledronate. However, which types of cells were responsible for the production of those cytokines in blood remained unclear. As it is generally accepted that monocytes and macrophages are primary sources of inflammatory cytokines, CD14+ cells from PBMC were exposed to zoledronate in the presence of PBMC, which resulted in induced expression of mRNAs for IL-1ß, IL-6 and IFN-γ, but not for TNF-α. These results indicate that CD14+ cells are responsible, at least in part, for the production of IL-1ß, IL-6 and IFN-γ in blood exposed to zoledronate. This suggests that CD14+ cells play an essential role in the occurrence of APRs following N-BP administration.


Subject(s)
Acute-Phase Reaction/chemically induced , Bone Density Conservation Agents/toxicity , Cytokines/metabolism , Inflammation Mediators/metabolism , Intraepithelial Lymphocytes/drug effects , Lipopolysaccharide Receptors/metabolism , Lymphocyte Activation/drug effects , Monocytes/drug effects , Zoledronic Acid/toxicity , Acute-Phase Reaction/immunology , Acute-Phase Reaction/metabolism , Cells, Cultured , Coculture Techniques , Cytokines/genetics , Humans , Intraepithelial Lymphocytes/immunology , Intraepithelial Lymphocytes/metabolism , Monocytes/immunology , Monocytes/metabolism
2.
Bioorg Med Chem Lett ; 28(2): 152-154, 2018 01 15.
Article in English | MEDLINE | ID: mdl-29198863

ABSTRACT

Trisubstituted 5-organostibano-1H-1,2,3-triazoles (3a-f) were synthesized by the Cu-catalyzed azide-alkyne cycloaddition of various ethynylstibanes (1) with benzylazide (2) in the presence of CuBr (5 mol%) under aerobic conditions. The reaction of 5-stibanotriazoles with HCl afforded C5-unsubstituted 1,2,3-triazoles (4a-f). The antitumor activity of trisubstituted 5-organostibano-1H-1,2,3-triazoles (3a-f) and their 5-unsubstituted 1,2,3-triazoles (4a-f) were evaluated in several tumor cell lines. All 5-stibanotriazoles (3a-f) exerted an excellent antitumor activity. On the contrary, 5-unsubstituted 1,2,3-triazoles (4a-f) without a diphenylantimony group in the molecule exhibited very low antitumor activity compared with 5-stibanotriazoles (3a-f). In compounds of both the series, the substituted 4-butyl group appeared to decrease antitumor activity. However, results suggested that organometal (antimony) in the molecule was required for greater antitumor activity. In addition, all 5-stibanotriazoles (3a-f), but not all 5-unsubstituted 1,2,3-triazoles (4a-f), exhibited cytotoxicity in normal vascular endothelial cells derived from bovine aorta. Among the compounds (3b-e) that exhibited excellent antitumor activity, those with 4-methylphenyl (3b) and 1-cyclohexenyl (3e) showed relatively low cytotoxicity to vascular endothelial cells. Together, these results suggest that trisubstituted 5-organostibano-1H-1,2,3-triazoles, including compounds 3b and 3e, may serve as potential anticancer therapeutic drugs in the future.


Subject(s)
Antineoplastic Agents/pharmacology , Triazoles/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cattle , Cell Line , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Endothelial Cells/drug effects , Humans , Molecular Structure , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistry
3.
Biol Pharm Bull ; 37(5): 802-7, 2014.
Article in English | MEDLINE | ID: mdl-24790002

ABSTRACT

Sapacitabine (CS-682 or CYC682; 1-[2-C-cyano-2-deoxy-ß-D-arabino-pentfuranosyl]N4-palmitoyl cytosine), a novel antitumor 2'-deoxycytidine analogue, shows a marked reduction in the water solubility because of the fatty acid side chain on the N4 group of the cytosine moiety. Poor water solubility is one of the important reasons why sapacitabine does not exert maximum antitumor activity. Therefore, we attempted to improve the water solubility of sapacitabine using a novel surfactant, Soluplus®, which consisted of a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. In this study, we examined whether Soluplus® increased the water solubility and an antitumor activity of sapacitabine. The cytotoxicity of Soluplus® alone was lower than that of Tween 80 and Kolliphor® D-α-tocopherylpolyethylene glycol 1000 succinate (TPGS). The water solubility and the chemosensitivity of sapacitabine against several tumor cell lines to sapacitabine markedly increased upon using Soluplus®. In addition, the potential of Soluplus® including sapacitabine in increasing the antitumor activity was compared with sapacitabine alone in vivo. Although the total dose in the experimental period was considerably lower than the effective dose of sapacitabine alone, the life span of mice treated with sapacitabine containing 40 mg/mL Soluplus® increased by 150%. If Soluplus® was used as the solubilizing agent in clinical trials of sapacitabine, a low administration dose was appeared to require, and thus side effects might be prevented.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Arabinonucleosides/chemistry , Arabinonucleosides/pharmacology , Cytosine/analogs & derivatives , Polyethylene Glycols/pharmacology , Polyvinyls/pharmacology , Surface-Active Agents/pharmacology , Animals , Cell Line, Tumor , Cytosine/chemistry , Cytosine/pharmacology , Dose-Response Relationship, Drug , Mice , Polyethylene Glycols/chemistry , Polysorbates/chemistry , Polysorbates/pharmacology , Polyvinyls/chemistry , Solubility/drug effects , Surface-Active Agents/chemistry , Survival Analysis , Vitamin E/analogs & derivatives , Vitamin E/chemistry , Vitamin E/pharmacology
4.
Am J Orthod Dentofacial Orthop ; 146(2): 166-74, 2014 Aug.
Article in English | MEDLINE | ID: mdl-25085299

ABSTRACT

INTRODUCTION: It has been found that controlled movement of the anterior teeth can be obtained by attaching a certain length of power arm onto an archwire in sliding mechanics. However, the impact of the archwire/bracket play on anterior tooth movement has not been clarified. The purpose of this study was to compare the effect of the power arm on anterior tooth movements with different dimensions of bracket slots and archwires. METHODS: A 3-dimensional finite element method was used to simulate en-masse anterior tooth retraction in sliding mechanics. Displacements of the maxillary central incisor and the archwire deformation were calculated when applying retraction forces from different lengths of power arms. RESULTS: When a 0.017 × 0.022-in archwire was engaged into the 0.018-in slot bracket, bodily movement of the incisor was obtained with 9.1-mm length of the power arm. When a 0.022-in slot system was coupled with a 0.019 × 0.025-in archwire, bodily movement was observed with a power arm length of 11.6 mm. CONCLUSIONS: Archwire/bracket play has a remarkable impact on anterior tooth movement. An effective torque application to the anterior teeth becomes clinically difficult in sliding mechanics combined with power arms when the archwire/bracket play is large.


Subject(s)
Finite Element Analysis , Imaging, Three-Dimensional/methods , Orthodontic Appliance Design , Orthodontic Brackets , Orthodontic Space Closure/methods , Orthodontic Wires , Tooth Movement Techniques/methods , Alveolar Process/physiology , Biomechanical Phenomena , Computer Simulation , Cone-Beam Computed Tomography/methods , Elastic Modulus , Humans , Image Processing, Computer-Assisted/methods , Incisor/physiopathology , Models, Biological , Orthodontic Space Closure/instrumentation , Periodontal Ligament/physiology , Tooth Movement Techniques/instrumentation , Torque
5.
In Vitro Cell Dev Biol Anim ; 58(7): 521-528, 2022 Aug.
Article in English | MEDLINE | ID: mdl-35925448

ABSTRACT

The articular cartilage is an avascular tissue, and oxygen tensions in its superficial and deeper zones are estimated to be 6% and 1%. Degeneration of the articular cartilage begins from the surface zone in osteoarthritis. We previously reported that monocarboxylate transporter-1, a transmembrane transporter for monocarboxylates, played an essential role in the interleukin-1ß-induced expression of NADPH oxidase-2, a reactive oxygen species-producing enzyme, and reactive oxygen species-dependent death of mouse chondrogenic ATDC5 cells cultured in a normal condition (20% oxygen). Here, we investigated the effect of oxygen tension on interleukin-1ß-induced events described above in ATDC5 cells. Interleukin-1ß induced the death of ATDC5 cells under 20% and 6% oxygen but did not under 2% and 1% oxygen. Interleukin-1ß induced Mct1 (monocarboxylate transporter-1 gene) and Nox2 (NADPH oxidase-2 gene) mRNAs' expression under 20% oxygen in 24 h, respectively, but not under 2% oxygen. On the other hand, a 24-h incubation with interleukin-1ß upregulated the expression of Nos2 (inducible nitric oxide synthase gene) mRNA irrespective of oxygen tension. Furthermore, inhibition of I-κB kinase suppressed the interleukin-1ß-induced expression of Mct1 mRNA in the cells cultured under 20% and 2% oxygen, indicating NF-κB plays an essential role in the induction of the Mct1 gene expression. The results suggest that interleukin-1ß induces monocarboxylate transporter-1 in an oxygen tension-dependent manner required for cell death in ATDC5 cells. These results might explain some part of the degenerative process of the articular cartilage, which begins from its superficial zone in the pathogenesis of osteoarthritis.


Subject(s)
Cartilage, Articular , Osteoarthritis , Rodent Diseases , Animals , Cells, Cultured , Chondrocytes , Interleukin-1beta/metabolism , Interleukin-1beta/pharmacology , Mice , NADPH Oxidases/metabolism , NADPH Oxidases/pharmacology , NF-kappa B/metabolism , Nitric Oxide Synthase Type II/metabolism , Osteoarthritis/pathology , Oxygen/metabolism , Oxygen/pharmacology , RNA, Messenger/genetics , Reactive Oxygen Species/metabolism , Rodent Diseases/metabolism , Rodent Diseases/pathology
6.
Anticancer Res ; 41(5): 2287-2296, 2021 May.
Article in English | MEDLINE | ID: mdl-33952454

ABSTRACT

BACKGROUND/AIM: Indoleamine 2,3-dioxygenase (IDO) is regarded as an important molecular target for cancer immune therapy. This study aimed to examine the IDO1 inhibitory activity of newly synthesized indomethacin derivatives to develop an IDO1 inhibitor. MATERIALS AND METHODS: The inhibitory effects of indole-containing compounds against recombinant human IDO1 (rhIDO1) were evaluated. RESULTS: While some drugs including those with an indole scaffold could inhibit rhIDO1, simple indole compounds were inactive. A total of 27 indomethacin derivatives, including 18 newly synthesized derivatives, were evaluated. Numerous derivatives showed enhanced IDO1 inhibitory activity. The functional group at the 3-position had a strong effect on IDO1 inhibitory activity. The IDO1 inhibitory activity was not directly correlated with tumor cell cytotoxicity. CONCLUSION: We report the finding of novel IDO1 inhibitors and the structure-activity relationship based on indomethacin derivatives. Our findings will be beneficial for the development of IDO1 inhibitors for cancer immune therapy.


Subject(s)
Enzyme Inhibitors/pharmacology , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Indomethacin/pharmacology , Structure-Activity Relationship , Biocatalysis/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Enzyme Inhibitors/chemistry , Humans , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Indomethacin/chemistry , Magnetic Resonance Spectroscopy/methods , Molecular Structure
7.
Rapid Commun Mass Spectrom ; 24(10): 1405-10, 2010 May 30.
Article in English | MEDLINE | ID: mdl-20411579

ABSTRACT

A size-selected argon (Ar) gas-cluster ion beam (GCIB) was applied to the secondary ion mass spectrometry (SIMS) of a 1,4-didodecylbenzene (DDB) thin film. The samples were also analyzed by SIMS using an atomic Ar(+) ion projectile and X-ray photoelectron spectroscopy (XPS). Compared with those in the atomic-Ar(+) SIMS spectrum, the fragment species, including siloxane contaminants present on the sample surface, were enhanced several hundred times in the Ar gas-cluster SIMS spectrum. XPS spectra during beam irradiation indicate that the Ar GCIB sputters contaminants on the surface more effectively than the atomic Ar(+) ion beam. These results indicate that a large gas-cluster projectile can sputter a much shallower volume of organic material than small projectiles, resulting in an extremely surface-sensitive analysis of organic thin films.


Subject(s)
Argon/chemistry , Benzene Derivatives/chemistry , Spectrometry, Mass, Secondary Ion/methods , Photoelectron Spectroscopy , Siloxanes/chemistry , Surface Properties
8.
Bone ; 132: 115216, 2020 03.
Article in English | MEDLINE | ID: mdl-31899346

ABSTRACT

Neutrophils are one of the most abundant leukocytes in the sites of lesion of inflammatory diseases such as periodontitis and rheumatoid arthritis. These diseases are accompanied by bone loss, which worsens the quality of life of the patients. However, the role of neutrophils in the inflammatory bone loss has not been fully investigated. In the present study, we found that human neutrophils enhanced osteoclast differentiation from mouse bone marrow cells co-cultured with mouse osteoblasts in the presence of active vitamin D3. The enhanced osteoclast differentiation was significantly suppressed by elastatinal, a synthetic inhibitor of neutrophil elastase. Also, we found that human neutrophils degraded human recombinant osteoprotegerin (OPG), a decoy receptor for nuclear factor κB (RANK) ligand (RANKL), the essential osteoclast differentiation-inducing factor, expressed by osteoblasts. Degradation of OPG by neutrophils was suppressed by human α1-protease inhibitor, the major endogenous inhibitor of neutrophil elastase. Recombinant human neutrophil elastase degraded human OPG in its death domain-like region. These results indicated that the degradation of OPG by elastase contributed at least in part to the enhanced osteoclast differentiation by neutrophils. There is a possibility that neutrophils play an important role in inflammatory bone loss.


Subject(s)
Osteoclasts , Osteoprotegerin , Animals , Carrier Proteins , Cell Differentiation , Glycoproteins/metabolism , Humans , Membrane Glycoproteins , Mice , Neutrophils/metabolism , Osteoclasts/metabolism , Pancreatic Elastase , Quality of Life , RANK Ligand , Receptor Activator of Nuclear Factor-kappa B , Receptors, Cytoplasmic and Nuclear
9.
Bioorg Med Chem Lett ; 19(14): 3973-6, 2009 Jul 15.
Article in English | MEDLINE | ID: mdl-19297157

ABSTRACT

The first asymmetric synthesis of (S)- and (R)-5-hydroxythalidomides, one of thalidomide's major metabolites, was achieved using HMDS/ZnBr(2)-induced imidation as a key reaction. 5-Hydroxythalidomide was found to be configurationally more stable than thalidomide at physiological pH. Stereochemical biological effects of thalidomide and 5-hydroxythalidomide on anti-angiogenesis and antitumor activities were also investigated using racemic and pure enantiomers.


Subject(s)
Angiogenesis Inhibitors/chemical synthesis , Angiogenesis Inhibitors/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Thalidomide/analogs & derivatives , Thalidomide/chemistry , Angiogenesis Inhibitors/chemistry , Antineoplastic Agents/chemistry , Cell Line , Drug Screening Assays, Antitumor , Humans , Hydrogen-Ion Concentration , Stereoisomerism , Thalidomide/chemical synthesis , Thalidomide/metabolism , Thalidomide/pharmacology
10.
Angle Orthod ; 79(6): 1102-7, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19852600

ABSTRACT

OBJECTIVE: To determine optimal loading conditions such as height of retraction force on the power arm and its position on the archwire in sliding mechanics. MATERIALS AND METHODS: A 3D finite element method (FEM) was used to simulate en masse anterior teeth retraction in sliding mechanics. The degree of labiolingual tipping of the maxillary central incisor was calculated when the retraction force was applied to different heights of a power arm set mesial or distal to the canine. RESULTS: When the power arm was placed mesial to the canine, at the level of 0 mm (bracket slot level), uncontrolled lingual crown tipping of the incisor was observed and the anterior segment of the archwire was deformed downward. At a power arm height of 5.5 mm, bodily movement was produced and the archwire was less deformed. When the power arm height exceeded 5.5 mm, the anterior segment of the archwire was raised upward and lingual root tipping occurred. When the power arm was placed distal to the canine, lingual crown tipping was observed up to a level of 11.2 mm. CONCLUSIONS: Placement of the power arm of an archwire between the lateral incisor and canine enables orthodontists to maintain better control of the anterior teeth in sliding mechanics. Both the biomechanical principles associated with the tooth's center of resistance and the deformation of the archwire should be taken into consideration for predicting and planning orthodontic tooth movement.


Subject(s)
Cuspid/pathology , Incisor/pathology , Tooth Movement Techniques/methods , Alveolar Process/pathology , Biomechanical Phenomena , Computer Simulation , Elastic Modulus , Finite Element Analysis , Humans , Imaging, Three-Dimensional , Maxilla , Mechanical Phenomena , Models, Biological , Orthodontic Anchorage Procedures/instrumentation , Orthodontic Brackets , Orthodontic Wires , Periodontal Ligament/pathology , Stress, Mechanical , Tooth Crown/pathology , Tooth Movement Techniques/instrumentation , Tooth Root/pathology
11.
Angle Orthod ; 79(4): 703-14, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19537865

ABSTRACT

OBJECTIVE: To investigate the precise longitudinal change in the periodontal ligament (PDL) space width and three-dimensional tooth movement with continuous-force magnitudes in living rats. MATERIALS AND METHODS: Using nickel-titanium closed-coil springs for 28 days, 10-, 25-, 50-, and 100-g mesial force was applied to the maxillary left first molars. Micro-CT was taken in the same rat at 0, 1, 2, 3, 10, 14, and 28 days. The width of the PDL was measured in the pressure and tension sides from 0 to 3 days. Angular and linear measurements were used to evaluate molar position at day 0, 10, 14, and 28. The finite element model (FEM) was constructed to evaluate the initial stress distribution, molar displacement, and center of rotation of the molar. RESULTS: The initial evaluation of PDL width showed no statistical differences among different force magnitudes. Tooth movement was registered 1 hour after force application and gradually increased with time. From day 10, greater tooth movement was observed when 10 g of force was applied. The FEM showed that the center of rotation in the molar is located in the center of five roots at the apical third of the molar roots. CONCLUSION: The rat's molar movement mainly consists of mesial tipping, extrusion of distal roots, intrusion of mesial root, palatal inclination, and mesial rotation. Although the initial tooth movement after the application of different force magnitudes until day 3 was not remarkably different, 10 g of force produced more tooth movement compared with heavier forces at day 28.


Subject(s)
Dental Stress Analysis , Periodontal Ligament/physiology , Tooth Movement Techniques , Tooth Root/physiology , Animals , Dental Stress Analysis/methods , Finite Element Analysis , Imaging, Three-Dimensional , Male , Molar/physiology , Periodontal Ligament/diagnostic imaging , Rats , Rats, Wistar , X-Ray Microtomography/methods
12.
Angle Orthod ; 79(3): 447-53, 2009 May.
Article in English | MEDLINE | ID: mdl-19413387

ABSTRACT

OBJECTIVE: To (1) evaluate the stability of palatal rugae as landmarks for superimposition of dental casts and (2) establish a three-dimensional superimposition method of maxillary dental casts for analyzing orthodontic tooth movement. MATERIALS AND METHODS: The sample consisted of dental casts obtained from 10 patients treated with extraction of bilateral maxillary first premolars and placement of three palatal miniscrews as anchorage for retraction of the anterior teeth. Dental casts were measured by means of laser surface scanning system, and three-dimensional images were reconstructed. Serial dental casts were superimposed on the three miniscrews as registration landmarks (miniscrew-superimposition method), and the displacement of each palatal ruga point during the closure of extraction spaces was measured. Displacement of the central incisors was measured by the miniscrew-superimposition method and the proposed superimposition technique (ruga-palate-superimposition method). Correlation analysis and paired t-tests were performed to determine whether a significant difference existed between the measurements of the two superimposition methods. RESULTS: The medial points of the third palatal rugae and the shape of the palatal vault were stable throughout the treatment. The displacement of the central incisors measured using the ruga-palate-superimposition method showed no significant difference with that measured using the miniscrew-superimposition method. CONCLUSION: The maxillary dental casts can be reliably superimposed on the medial points of the third palatal rugae and the palatal vault as reference landmarks.


Subject(s)
Imaging, Three-Dimensional/methods , Incisor/pathology , Tooth Movement Techniques/methods , Adolescent , Adult , Bicuspid/surgery , Bone Screws , Cephalometry/methods , Female , Humans , Image Processing, Computer-Assisted/methods , Image Processing, Computer-Assisted/statistics & numerical data , Imaging, Three-Dimensional/statistics & numerical data , Lasers , Male , Models, Dental , Orthodontic Anchorage Procedures/instrumentation , Orthodontic Space Closure/methods , Palate/pathology , Serial Extraction , Young Adult
13.
Heliyon ; 5(7): e02123, 2019 Jul.
Article in English | MEDLINE | ID: mdl-31372564

ABSTRACT

PURPOSE: To evaluate the accuracy of the maxillary segment positioning method using a splint fabricated by computer-aided design/computer-aided manufacturing (CAD/CAM) and surgical navigation in patients who required two-jaw surgery. METHODS: Subjects were 35 patients requiring two-jaw surgery. A 3-dimensional (3D) skull model was prepared using cone-beam computed tomography (CBCT) data and dentition model scan data. Two-jaw surgery was simulated using this model, and a splint for maxillary positioning was fabricated by CAD/CAM. Using coordinate transformation software, the coordinate axis of surgical simulation data was merged with the navigation system, and data were imported to the navigation system. The maxillary segment was placed using the CAD/CAM splint, and consistency of the maxillary segment position with that planned by simulation was confirmed using the navigation system. CBCT taken at 4 weeks postoperatively and the prediction image fabricated using surgical simulation were superimposed. Predicted movement distances (PMD) at 6 arbitrary measurement points and actual movement distance (AMD) in surgery were measured. Differences of 3D measurements between the surgical simulation and postoperative results were evaluated. RESULTS: No significant differences were seen between PMD and AMD at most measurement points on the X and Y axes. Although significant differences between PMD and AMD were seen on the Z axis, no difference was evident between linear distance on the estimated image and postoperative CBCT image at most measurement points in 3D space. Mean error at measurement points between the PMD and AMD ranged from 0.57 mm to 0.78 mm on the X axis, 0.64 mm-1.03 mm on the Y axis, and 0.84 mm-0.90 mm in the Z axis. CONCLUSION: Position of the maxillary segment moved by the CAD/CAM splint in Le Fort I osteotomy was almost consistent with the position established by simulation using the navigation system, confirming clinical accuracy.

15.
Dent Mater J ; 35(6): 946-951, 2016.
Article in English | MEDLINE | ID: mdl-27904089

ABSTRACT

To investigate the chemical structure-cytotoxicity relationship of methacrylate-based resin monomers, we studied their effects on anti-oxidant responsive element (ARE)-mediated transcription. HepG2 cells stably expressing an ARE-regulated luciferase reporter gene were cultured for 6 h with various concentrations of several resin monomers and subjected to a luciferase assay. The doseresponse curves observed for hydrophobic monomers with different hydrocarbon chains (MMA, EMA, PMA and BMA) began to rise at concentrations between 0.5 and 1 mM; the curves rose as the monomer concentrations increased up to 5 (BMA), 10 (PMA), or 30 mM (MMA and EMA). In contrast, hydrophilic monomers having a hydroxyl group (HEMA and HPMA) showed bell-shaped curves, and stimulated the reporter expression more strongly than the hydrophobic monomers in a low concentration range (0.5-5 mM). The results suggest that introduction of a hydroxyl group in a methacrylate-based resin monomer increases its intracellular electrophilic reactivity and cytotoxicity.


Subject(s)
Genes, Reporter , Methacrylates/toxicity , Resins, Synthetic , Fibroblasts , Humans , Luciferases , Oxidants
16.
Oncogene ; 22(30): 4617-26, 2003 Jul 24.
Article in English | MEDLINE | ID: mdl-12879005

ABSTRACT

A human placenta cDNA library was screened by the expression cloning method for gene products that interact with matrix metalloproteinases (MMPs), and we isolated a cDNA whose product formed a stable complex with pro-MMP-2 and pro-MMP-9. The cDNA encoded the metastasis suppressor gene KiSS-1. KiSS-1 protein was shown to form a complex with pro-MMP. KiSS-1 protein is known to be processed to peptide ligand of a G-protein-coupled receptor (hOT7T175) named metastin, and suppresses metastasis of tumors expressing the receptor. Active MMP-2, MMP-9, MT1-MMP, MT3-MMP and MT5-MMP cleaved the Gly118-Leu119 peptide bond of not only full-length KiSS-1 protein but also metastin decapeptide. Metastin decapeptide induced formation of focal adhesion and actin stress fibers in cells expressing the receptor, and digestion of metastin decapeptide by MMP abolished its ligand activity. Migration of HT1080 cells expressing hOT7T175 that harbor a high-level MMP activity was only slightly suppressed by either metastin decapeptide or MMP inhibitor BB-94 alone, but the combination of metastin decapeptide and BB-94 showed a synergistic effect in blocking cell migration. We propose that metastin could be used as an antimetastatic agent in combination with MMP inhibitor, or MMP-resistant forms of metastin could be developed and may also be efficacious.


Subject(s)
Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Proteins/metabolism , Binding Sites , Cell Line , Cell Movement , Cloning, Molecular , DNA, Complementary/metabolism , Green Fluorescent Proteins , HeLa Cells , Humans , Kinetics , Kisspeptins , Ligands , Luminescent Proteins , Neoplasm Metastasis , Peptides/chemistry , Peptides/metabolism , Placenta/metabolism , Plasmids/metabolism , Protein Binding , Recombinant Proteins/chemistry , Reverse Transcriptase Polymerase Chain Reaction , Time Factors , Transfection , Tumor Cells, Cultured , Tumor Suppressor Proteins
17.
Anticancer Res ; 25(4): 2729-35, 2005.
Article in English | MEDLINE | ID: mdl-16080518

ABSTRACT

In this study, the involvement of ATP-binding cassette (ABC) transporters in in vitro chemosensitivity of surgically removed human renal cell carcinomas was investigated. The relative expression levels of transporter mRNAs in the renal tumors from 13 patients were similar to those in the surrounding normal kidney tissues. Five renal cell carcinomas cultured successfully in vitro for 14 days showed significantly decreased expression of multi-drug resistance-associated proteins 2 and 6 (MRP2 and MRP6) mRNAs. In vitro chemosensitivity testing of the same specimens using the collagen-gel matrix assay indicated that some anticancer drugs were effective, especially cisplatin, which is an MRP2 substrate. MRP2 mRNA expression in renal carcinoma was significantly increased when cells were cultured in the presence of conjugated bilirubin. In an established renal proximal tubule epithelial cell line (RPTEC), conjugated bilirubin increased MRP2 expression at the mRNA and protein levels, and decreased the cisplatin sensitivity of the cells. These results indicate that MRP2 expression in renal cell carcinoma may be regulated by conjugated bilirubin in the body and decreased during in vitro culture. Thus, the effectiveness of anticancer drugs selected on the basis of in vitro chemosensitivity testing of clinical cancers may be overestimated.


Subject(s)
ATP-Binding Cassette Transporters/metabolism , Bilirubin/pharmacology , Carcinoma, Renal Cell/metabolism , Kidney Neoplasms/metabolism , Membrane Transport Proteins/biosynthesis , Multidrug Resistance-Associated Proteins/biosynthesis , ATP-Binding Cassette Transporters/biosynthesis , ATP-Binding Cassette Transporters/genetics , Antineoplastic Agents/pharmacology , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/genetics , Cisplatin/pharmacology , Drug Screening Assays, Antitumor , Humans , Inhibitory Concentration 50 , Kidney Neoplasms/drug therapy , Kidney Neoplasms/genetics , Membrane Transport Proteins/genetics , Multidrug Resistance-Associated Protein 2 , Multidrug Resistance-Associated Proteins/genetics , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Tumor Cells, Cultured
18.
Gan To Kagaku Ryoho ; 32(11): 1635-9, 2005 Oct.
Article in Japanese | MEDLINE | ID: mdl-16315893

ABSTRACT

In vitro chemosensitivity test using a collagen-gel method was done on 165 primary gastric cancers. All of 5-FU, CBDCA, CDDP and docetaxel showed a high sensitivity. The effects of per oral (po) administration of TS-1, a combination of po TS-1 and intraperitoneal (ip) administration of CDDP, ip 5-FU and ip docetaxel, were evaluated in athymic mice bearing peritoneal dissemination of a gastric cancer cell line (MKN-45-P that shows a high rate of metastasis to the peritoneal cavity of nude mice). Nude mice were inoculated by ip with 10(7) MKN-45-P cells. No survival benefit was obtained after po administration of TS-1 (12 mg/kg) alone or ip CDDP alone. However, a combination of po TS-1 (8 mg/kg x 10 days, from day 3) and ip CDDP (3.5 mg/kg, day 6 and 13) showed a significant survival improvement than that of po TS-1 or ip CDDP treatment alone. ip administration of 30 mg/kg (3 times/week x 3 weeks) or 15 mg/kg (6 times/week x 3 weeks) of 5-FU significantly improved the survival of mice bearing MKN-45-P. 5-FU concentration of ascites after ip administration of 30 mg/kg of 5-FU was 600-fold higher than po administration of 12 mg/kg of TS-1 at peak level. ip injections of docetaxel of 8 mg/kg, and 2 mg/kg improved the survival of 4 and 1 mice, respectively, and they were tumor-free on day 90. Survival of mice treated with ip injection of CBDCA (100 mg/kg, on day 3, or 50 mg/ kg on day 3 and 10) was significantly better than the control group. These results suggest the potential of po TS-1 + ip CDDP, ip 5-FU, ip docetaxel and ip CBDCA administration for the treatment of peritoneal dissemination of gastric cancer.


Subject(s)
Antineoplastic Agents/administration & dosage , Peritoneal Neoplasms/drug therapy , Peritoneal Neoplasms/secondary , Stomach Neoplasms/pathology , Animals , Antimetabolites, Antineoplastic/administration & dosage , Carboplatin/administration & dosage , Cisplatin/administration & dosage , Docetaxel , Drug Combinations , Drug Screening Assays, Antitumor , Fluorouracil/administration & dosage , Infusions, Parenteral , Mice , Mice, Nude , Neoplasm Seeding , Oxonic Acid/administration & dosage , Pyridines/administration & dosage , Taxoids/administration & dosage , Tegafur/administration & dosage
19.
J Dent Biomech ; 6: 1758736014566337, 2015.
Article in English | MEDLINE | ID: mdl-25610497

ABSTRACT

The porpose of this study was to determine the optimal length of power arms for achieving controlled anterior tooth movement in segmented arch mechanics combined with power arm. A three-dimensional finite element method was applied for the simulation of en masse anterior tooth retraction in segmented power arm mechanics. The type of tooth movement, namely, the location of center of rotation of the maxillary central incisor in association with power arm length, was calculated after the retraction force was applied. When a 0.017 × 0.022-in archwire was inserted into the 0.018-in slot bracket, bodily movement was obtained at 9.1 mm length of power arm, namely, at the level of 1.8 mm above the center of resistance. In case a 0.018 × 0.025-in full-size archwire was used, bodily movement of the tooth was produced at the power arm length of 7.0 mm, namely, at the level of 0.3 mm below the center of resistance. Segmented arch mechanics required shorter length of power arms for achieving any type of controlled anterior tooth movement as compared to sliding mechanics. Therefore, this space closing mechanics could be widely applied even for the patients whose gingivobuccal fold is shallow. The segmented arch mechanics combined with power arm could provide higher amount of moment-to-force ratio sufficient for controlled anterior tooth movement without generating friction, and vertical forces when applying retraction force parallel to the occlusal plane. It is, therefore, considered that the segmented power arm mechanics has a simple appliance design and allows more efficient and controllable tooth movement.

20.
Pharmacogenetics ; 13(1): 29-38, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12544510

ABSTRACT

To test the hypothesis that analyses of drug targets for polymorphism will help to establish gene-based information for the treatment of cancer patients, we investigated the functional single-nucleotide polymorphisms in the human cytidine deaminase (HDCA) gene. The cDNAs from 52 leukaemia/lymphoma samples and 169 control blood samples were direct-sequenced and analysed for the polymorphisms. Three different polymorphisms (A79C, G208A and T435C) were identified in the coding region of the HDCA gene and displayed allelic frequencies of 20.1%, 4.3% and 70.1%, respectively. No association with susceptibility to disease was observed. A novel polymorphism, G208A produced an alanine to threonine substitution (A70T) within the conserved catalytic domain. By introduction of the polymorphic HCDA genes into the yeast CDA-null mutants, the HCDA-70T showed 40% and 32% activity of prototype for cytidine and ara-C substrates, respectively (P < 0.01). The ara-C IC50 value of the yeast transformants carrying HCDA-70T was 757 +/- 33 micromol and was significantly lower (P < 0.01) than that of prototype (941 +/- 58 micromol). This study demonstrated a population characterized with 208A genotype for, which potentially leads one more sensitive to ara-C treatment than prototype. Accumulation of polymorphisms in the genes responsible for drug metabolism and determination of polymorphism-induced biological variations could provide the additional therapeutic strategies in risk-stratified protocols for the treatment of childhood malignancies.


Subject(s)
Cytarabine/pharmacology , Cytidine Deaminase/genetics , Polymorphism, Single Nucleotide , Saccharomyces cerevisiae/drug effects , Child, Preschool , Cytidine Deaminase/biosynthesis , Cytidine Deaminase/chemistry , DNA, Complementary/genetics , Deamination/drug effects , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic , Humans , Leukemia/genetics , Microbial Sensitivity Tests , Recombinant Proteins/chemistry , Saccharomyces cerevisiae/genetics , Sequence Alignment
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