Characterization of a conjugated polysuccinimide-carboplatin compound

Carboplatin, an advanced anticancer drug with excellent efficacy against ovarian cancer, was developed to alleviate the side effects that often occur with cisplatin and other platinum-based compounds. Our study reports the in vitro characteristics, viability, and activity of cells expressing the inducible nitric oxide synthase (iNOS) gene after carboplatin was conjugated with polysuccinimide (PSI) and administered in combination with other widely used anticancer drugs. PSI, which has promising properties as a drug delivery material, could provide a platform for prolonging carboplatin release, regulating its dosage, and improving its side effects. The iNOS gene has been shown to play an important role in both cancer cell survival and inhibition. Herein, we synthesized a PSI-carboplatin conjugate to create a modified anticancer agent and confirmed its successful conjugation. To ensure its solubility in water, we further modified the structure of the PSI-carboplatin conjugate with 2-aminoethanol groups. To validate its biological characteristics, the ovarian cancer cell line SKOV-3 and normal ovarian Chinese hamster ovary cells were treated with the PSI-carboplatin conjugate alone and in combination with paclitaxel and topotecan, both of which are used in conventional chemotherapy. Notably, PSI-carboplatin conjugation can be used to predict changes in the genes involved in cancer growth and inhibition. In conclusion, combination treatment with the newly synthesized polymer-carboplatin conjugate and paclitaxel displayed anticancer activity against ovarian cancer cells but was not toxic to normal ovarian cancer cells, resulting in the development of an effective candidate anticancer drug without severe side effects.

Effects of 4-hexylresorcinol on facial skeletal development in growing rats: Considerations for diabetes / 대한치과교정학회지

Objective@#To investigate the long-term effects of 4-hexylresorcinol (4HR) on facial skeletal growth in growing male rats, with a focus on diabetic animal models. Methods: Forty male rats were used. Of them, type 1 diabetes mellitus was induced in 20 animals by administering 40 mg/kg streptozotocin (STZ), and they were assigned to either the STZ or 4HR-injected group (STZ/4HR group).The remaining 20 healthy rats were divided into control and 4HR groups. We administered 4HR subcutaneously at a weekly dose of 10 mg/kg until the rats were euthanized. At 16 weeks of age, whole blood was collected, and microcomputed tomography of the skull and femur was performed. Results: All craniofacial linear measurements were smaller in the STZ group than in the control group. The mandibular molar width was significantly smaller in the 4HR group than in the control group (P = 0.031) but larger in the STZ/4HR group than in the STZ group (P = 0.011). Among the diabetic animals, the STZ/4HR group exhibited significantly greater cortical bone thickness, bone mineral density, and bone volume than the STZ group. Serum testosterone levels were also significantly higher in the STZ/4HR group than in the STZ group. @*Conclusions@#4HR administration may have divergent effects on mandibular growth and bone mass in healthy and diabetic rats. In the context of diabetes, 4HR appears to have beneficial effects, potentially through the modulation of mitochondrial respiration.

Functional Role of Phospholipase D in Bone Metabolism

Phospholipase D (PLD) proteins are major enzymes that regulate various cellular functions, such as cell growth, cell migration, membrane trafficking, and cytoskeletal dynamics. As they are responsible for such important biological functions, PLD proteins have been considered promising therapeutic targets for various diseases, including cancer and vascular and neurological diseases. Intriguingly, emerging evidence indicates that PLD1 and PLD2, 2 major mammalian PLD isoenzymes, are the key regulators of bone remodeling; this suggests that these isozymes could be used as potential therapeutic targets for bone diseases, such as osteoporosis and rheumatoid arthritis. PLD1 or PLD2 deficiency in mice can lead to decreased bone mass and dysregulated bone homeostasis. Although both mutant mice exhibit similar skeletal phenotypes, PLD1 and PLD2 play distinct and nonredundant roles in bone cell function. This review summarizes the physiological roles of PLD1 and PLD2 in bone metabolism, focusing on recent findings of the biological functions and action mechanisms of PLD1 and PLD2 in bone cells.

Corrigendum: Enhanced bone morphogenic protein adenoviral gene delivery to bone marrow stromal cells using magnetic nanoparticle

This correction is being published to correct the author's name and the affiliation.

New Avenues in the LRP5-mediated Bone Mass Acquisition

Lipoprotein receptor-related protein (LRP5) signaling is well correlated with the bone mass in both human and mice. Loss-of-function mutations of LRP5 result in osteopenia or osteoporosis. In contrast, gain-of-function mutations show high bone mass phenotype. To elucidate the molecular mechanism of the LRP5-mediated bone mass acquisition, several groups have genetically dissected the Wingless and Int-1 (Wnt)beta-catenin signaling pathway using osteoblast-lineage specific Cre mice. Key players for LRP5-mediated bone mass acquisition turn out to be different molecules with respect to the expressing tissue and action mode of these molecules. One is serotonin, a tryptophan metabolite that originates from duodenum, which acts as a negative regulator for bone formation. LRP5 suppresses serotonin biosynthesis by inhibiting the expression of tryptophan hydroxylase 1 in the gut. The other is sclerostin, an osteocyte-producing antagonist for LRP5 signaling. Here is a summary of recent findings about these two molecules, providing a chance to speculate new avenues in the LRP5-mediated bone mass acquisition.

New Avenues in the LRP5-mediated Bone Mass Acquisition

Lipoprotein receptor-related protein (LRP5) signaling is well correlated with the bone mass in both human and mice. Loss-of-function mutations of LRP5 result in osteopenia or osteoporosis. In contrast, gain-of-function mutations show high bone mass phenotype. To elucidate the molecular mechanism of the LRP5-mediated bone mass acquisition, several groups have genetically dissected the Wingless and Int-1 (Wnt)beta-catenin signaling pathway using osteoblast-lineage specific Cre mice. Key players for LRP5-mediated bone mass acquisition turn out to be different molecules with respect to the expressing tissue and action mode of these molecules. One is serotonin, a tryptophan metabolite that originates from duodenum, which acts as a negative regulator for bone formation. LRP5 suppresses serotonin biosynthesis by inhibiting the expression of tryptophan hydroxylase 1 in the gut. The other is sclerostin, an osteocyte-producing antagonist for LRP5 signaling. Here is a summary of recent findings about these two molecules, providing a chance to speculate new avenues in the LRP5-mediated bone mass acquisition.

Response: The Effects of Combination Therapy of Cathepsin K Inhibitor and PTH on Change in Bone Mineral Density in an Animal Model of Osteoporosis

No abstract available.

Response: The Effects of Combination Therapy of Cathepsin K Inhibitor and PTH on Change in Bone Mineral Density in an Animal Model of Osteoporosis

No abstract available.

DICAM Inhibits Activation of Macrophage by Lipopolysaccharide

OBJECTIVE: DICAM, a dual Ig domain containing adhesion molecule, is involved in cell-cell adhesion through direct interaction with alphavbeta3 integrin. In our previous study showing the inhibitory role of DICAM in osteoclast differentiation, we found that DICAM also has a suppressive role in macrophage, the precursor cell of osteoclast. The role of DICAM in macrophage activation at the inflammatory milieu, however, remains obscure. METHODS: Expression pattern of DICAM by inflammatory cytokines and lipopolysaccharide (LPS) was studied with RAW264.7, a murine macrophage cell line. To study the role of DICAM on macrophage activation, we stably transduced DICAM, or empty vector, into RAW264.7, and then compared the LPS-mediated activation such as spreading and TNF-alpha production. RESULTS: DICAM was abundantly expressed in the synovial tissue of collagen-induced arthritis. When we assessed the expression of DICAM in RAW264.7 cells by mediators of inflammation, inflammatory cytokines, such as TNF-alpha, IL-1beta, and IFN-gamma, and M-CSF increased the expression of DICAM; however, LPS decreased. Functionally, DICAM that stably transduced-RAW264.7 cells showed attenuation of LPS-mediated macrophage activation including spreading and TNF-alpha production. DICAM decreased the phosphorylation of JNK MAP kinase by M-CSF and LPS stimulation, which was corroborated by a decrease in the expression of ITAM-associated receptors including Trem2, Pira1, and Oscar. Finally, a recombinant ectodomain of DICAM suppressed LPS-induced activation of RAW264.7 cells. CONCLUSION: These results indicate that DICAM acts as a negative regulator of LPS-mediated macrophage activation.

The Effects of Combination Therapy of Cathepsin K Inhibitor and PTH on Change in Bone Mineral Density in an Animal Model of Osteoporosis

BACKGROUND: We hypothesized that combination therapy of cathepsin K inhibitor (CTKi) and human parathyroid hormone (1-34) (teriparatide, PTH) would overcome the coupling phenomenon of bone resorption and formation and thus may rapidly increase bone mass. METHODS: We selected a dose of zoledronic acid (ZA) that had shown similar effects with CTKi on body bone mineral density (BMD) change during the preliminary experiment. Female mice were subjected to ovariectomized (OVX control) or a sham operation (SHAM group). The mice were treated with CTKi (CTKi group), ZA (ZA group), PTH (PTH group) or with a combination of PTH with ZA (ZA + PTH group) or CTKi (CTKi + PTH group) for 8 weeks. Total BMD was measured before the operation and at 4 and 8 weeks. RESULTS: In the preliminary results, 10 microg/kg of ZA showed similar BMD changes with CTKi. Compared with the OVX control, BMD in the SHAM, ZA, CTKi, PTH, ZA + PTH, and CTKi + PTH groups was significantly increased after treatment. BMD in the CTKi + PTH group, but not in the ZA + PTH group increased more significantly than in the PTH group at the end of treatment. Compared with the OVX control, changes in BMD in the SHAM, ZA, CTKi, PTH, ZA + PTH, and CTKi + PTH groups increased significantly after 8 weeks of treatment. The change in BMD in the CTKi + PTH group, but not in the ZA + PTH group was more significantly increased than the change in BMD in the PTH group. CONCLUSION: When combined with PTH, CTKi augmented the anabolic action of PTH. Therefore, combination therapy with CTKi and PTH might be a new therapeutic modality capable of overcoming the coupling phenomenon, thereby markedly and rapidly increasing bone mass.

Effect of Ultraviolet Irradiation on Bone Metabolism: Serologic & Radiological Study in Mouse / 대한정형외과연구학회지

PURPOSE: The purpose of this study was to investigate the effects of low energy-ultraviolet B (UVB) irradiation on bone metabolism and turnover in mice. MATERIALS AND METHODS: Five-week old C57BL/6 mice were randomly allocated into two groups. Control group (n=35) was not exposed to UVB and experimental group (n=35) was exposed to low energy-UVB for 30 min a day during 7 days. Serological and radiological examination was performed at 0, 1, 2, 4, 8 week(s) of each group (n=7). RESULTS: Analysis of biochemical bone markers revealed that alkaline phosphatase (ALP) was detected higher in the UVB group compared to control group. Serum level of osteocalcin was higher in UVB group at 1st week after UVB irradiation (p=0.031). The mean value of Vitamin D was significantly higher in UVB group than control group (p=0.032). Bone mineral density (BMD) from both 5th lumbar spine (p=0.124) and femur (p=0.862) showed higher in UVB group than control group from two weeks after irradiation, but they were not statistically significant. CONCLUSION: Our study with radiological bone mineral density and serological tests for biochemical bone turnover markers revealed that ultraviolet irradiation contributed positive effect on bone formation.

Gene expression after the application of the fluid-induced shear stress on the gingival fibroblast

0.7). The "RUNX-1" was increased its expression in 2 hours group and "RUN and SH3 domain containing 1" was increased its expression in 4 hours group. The "CC020415", "cyclin L1", "interferon regulatory factor1", "early growth response 1", "immediate early response 2", and "immediate early response 3" genes were increased their expression in 2 and 4 hours after FISS application. In conclusion, we could find many genes that were probably related to the FISS application. Interestingly, most of them were placed in similar molecular pathways and these findings improve the reliability of chip data and usefulness in overall screening. From this experiment, we could find many items for further study and it will make improvement in the understanding of intracellular events in response to FISS.

The shear stress proteome of chondrocytes

Simultaneous occurrence of an odontogenic keratocyst and squamous odontogenic tumor in the mandible : a case report and immunohistochemical study

A squamous odontogenic tumor (SOT) is rare disease and it is believed to originate from epithelial rests of Malassez of the periodontal membrane. Neither sex nor site predilection in either jaw has been established. Some lesion can be shown in juxtaposition in tooth roots. Although most lesions remain smaller than 2 cm, our cases involved a half of left mandibular ramus. The exact pathogenesis is still unknown. We report a case of SOT including the results of immunohistochemical study of pancytokeratin and p53.

Bone/Vascular Calcification: Signal Transduction Pathway and Calcification Related Genes / 대한내분비학회지

No Abstract available.

THE DIFFERENCE IN THE PREVALENCE OF THE IVS5-A/G OF THE TRANSFORMING GROWTH FACTOR-BETA3 GENE BETWEEN KOREANS AND ROMANIANS

The ethnic difference of the prevalence of SfaN polymorphism in the nonsyndromic cleft palate / 대한치과교정학회지

Nonsyndromic cleft lip and/or palate (NSCLP) is one of the most common congenital deformities and its prevalence in Far East Asia, such as within Korean and Japanese populations, is relatively high. However, in the eastern part of Europe, clefts are relatively rare situations. These ethnic differences infer a genetic background of the disease. The objective of this study was to compare the frequency of single nucleotide polymorphism (SNP) in TGF-beta3 between Korean and Romanian cleft families. Korean cleft families samples were collected from twenty-six families (n=78) and Romanian cleft families samples were collected from eighteen families (n=41). For sequencing, the blood or saliva of the subjects was sampled. A single nucleotide plolymorphism was observed in the intron 5 of TGF-beta3 (A18141G). The frequency of each allele was significantly different between the Korean and Romanian samples. The AA allele was present in 18 out of 78 Korean samples (23.1%) and in 27 out of 41 Romanian samples (65.9%). The AG was present in 27 (34.6%) out of 78 Koreans and in 13 (31.7%) out of 41 Romanians. The GG was found in 33 (42.3%) Koreans and in 1 (2.4%) Romanian. The difference between the groups was significant (p<0.001). In conclusion, the frequency of observed SNP was significantly different between the two countries. SNP in TGF-beta3 in the Korean population seemed to have a higher possibility of occurrence for nonsyndromic cleft palate than the Romanian population

Beta ig-h3 promotes renal proximal tubular epithelial cell adhesion, migration and proliferation through the interaction with alpha3beta1 integrin

Betaig-h3 (betaig-h3) is a secretory protein composed of fasciclin I-like repeats containing sequences that allows binding of integrins and glycosaminoglycans in vivo. Expression of betaig-h3 is responsive to TGF-beta and the protein is found to be associated with extracellular matrix (ECM) molecules, implicating betaig-h3 as an ECM adhesive protein of developmental processes. We previously observed predominant expression of betaig-h3 expression in the basement membrane of proximal tubules of kidney. In this study, the physiological relevance of such localized expression of betaig-h3 was examined in the renal proximal tubular epithelial cells (RPTEC). RPTEC constitutively expressed betaig-h3 and the expression was dramatically induced by exogenous TGF-beta1 treatment. betaig-h3 and its second and fourth FAS1 domain were able to mediate RPTEC adhesion, spreading and migration. Two known alpha3beta1 integrin-interaction motifs including aspartatic acid and isoleucine residues, NKDIL and EPDIM in betaig-h3 were responsible to mediate RPTEC adhesion, spreading, and migration. By using specific antibodies against integrins, we confirmed that alpha3beta1 integrin mediates the adhesion and migration of RPTECs on betaig-h3. In addition, it also enhanced proliferation of RPTECs through NKDIL and EPDIM. These results indicate that betaig-h3 mediates adhesion, spreading, migration and proliferation of RPTECs through the interaction with alpha3beta1 integrin and is intimately involved in the maintenance and the regeneration of renal proximal tubular epithelium.

Effect of Orthovanadate on Collagen and Fibronectin Synthesis, and Alkaline Phosphatase Activity in MC3E3-E1 Osteoblast cells / 대한정형외과학회잡지

PURPOSE: The purpose: of this study was to know the effect of inhibition of protein dephosphorylation on the synthesis of collagen and fibronectin (FN), alkaline phosphatase (ALP) activity, and the formation of bone nodule in MC3T3-E1 osteoblasts using orthovanadate (OVA) which is a potent protein tyrosine phosphatase (PTPases) inhibitor. MATERIALS AND METHODS: The synthesis of collagen, noncollagenous protein (NCP), and percent collagen in MC3T3-E1osteoblasts with or without OVA treatment according to concentration and time sequence was determined by incorporation of [3 H]-proline, synthesis of FN by [35 S] methionine incorproated immunoprecipitation after treatment with 100 M OVA for 24 hours, mRNA expression of collagen and FN by Northern blotting, activity of ALP by spectrophotometric method, and formation of bone nodule by staining method. RESULTS: OVA increased collagen and NCP synthesis concentration dependently, until 12 hours in short-time culture, and time dependently through the differentiation until 29 days, however, there was no significant effect on the percent collagen production. OVA increased percent collagen synthesis significantly at 6 hours, and decreased in a long time culture. Total FN synthesis and FN synthesis in cell layer were increased by OVA, however, FN synthesis in medium was not changed. OVA decreased collagen mRNA level dose-dependently and increased the steady-state level of FN mRNA. OVA inhibited activity of ALP in both short and long-time culture. OVA inhibited bone nodule formation in MC3T3-E1 osteoblasts. CONCLUSION: These results indicate that the inhibition of PTPase by OVA increased the synthesis of collagen, FN, and decreased ALP activity and it resulted in the inhibition of bone formation in MC3T3-E1 osteoblast cells.

Cellular Biocompatibility and Stimulatory Effects of Calcium Metaphosphate on Osteoblastic Differentiation of Human Bone Marrow-derived Stromal Cells / 대한정형외과연구학회지

PURPOSE: The in vitro biocompatibility of Calcium Metaphosphate (CMP) with human bone marrow stromal cells (HBMSCs) and its effect on osteoblastic differentiation have been evaluated. MATERIALS AND METHODS: The effects of CMP on the HBMSCs undergoing osteoblastic differentiation were evaluated with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Morphologies of the HBMSCs were examined using scanning electron microscopy and confocal laser scanning microscopy. Osteoblastic differentiation of the HBMSCs was analyzed by alkaline phosphatase (ALP) staining and RTPCR. RESULTS: The CMP powder and disk did not exert cytotoxic effect on the HBMSCs. In addition, the HBMSCs were adhered on the surface of CMP disk as successfully as on the culture plate or HA disk and displayed similar actin arrangement and cellular phenotypes. Furthermore, the HBMSCs grown on three different matrices were able to support osteoblastic differentiation of the HBMSCs as accessed by ALP staining. However, the CMP disk compared to the HA disk has a better ability to induce expression of osteoblast-related genes such as ALP, osteopontin (OPN) and osteoprotegerin (OPG). CONCLUSION: The results demonstrate that, in addition to biocompatibility of the CMP with the HBMSCs, the CMP has an ability to stimulate osteoblastic differentiation of the HBMSCs in vitro.