Yonsei Fraunhofer IZFP Medical Device Lab YFMED
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PublicationAnti-skeletal muscle atrophy effect of Oenothera odorata root extract via reactive oxygen species-dependent signaling pathways in cellular and mouse model( 2016)
;Lee, Y.-H. ;Kim, W.-J. ;Lee, M.-H. ;Kim, S.-Y. ;Seo, D.-H. ;Kim, H.-S. ;Gelinsky, M.Kim, T.-J.Skeletal muscle atrophy can be defined as a decrease of muscle volume caused by injury or lack of use. This condition is associated with reactive oxygen species (ROS), resulting in various muscular disorders. We acquired 2D and 3D images using micro-computed tomography in gastrocnemius and soleus muscles of sciatic-denervated mice. We confirmed that sciatic denervation-small animal model reduced muscle volume. However, the intraperitoneal injection of Oenothera odorata root extract (EVP) delayed muscle atrophy compared to a control group. We also investigated the mechanism of muscle atrophy's relationship with ROS. EVP suppressed expression of SOD1, and increased expression of HSP70, in both H2O2-treated C2C12 myoblasts and sciatic-denervated mice. Moreover, EVP regulated apoptotic signals, including caspase- 3, Bax, Bcl-2, and ceramide. These results indicate that EVP has a positive effect on reducing the effect of ROS on muscle atrophy.
PublicationOral delivery of zoledronic acid by non-covalent conjugation with lysine-deoxycholic acid( 2016)
;Jeon, O.-C. ;Seo, D.-H. ;Kim, H.-S. ;Byun, Y.Park, J.W.We assessed the possibility of changing the route of administration of zoledronic acid to an oral dosage form and its therapeutic efficacy in an estrogen-deficient osteoporosis rat model. To enhance oral bioavailability, we formed an ionic complex by electrostatic conjugation of zoledronic acid with lysine-linked deoxycholic acid (Lys-DOCA, an oral absorption enhancer). After forming the complex, the characteristic crystalline features of pure zoledronic acid disappeared completely in the powder X-ray diffractogram and differential scanning calorimetry thermogram, indicating that zoledronic acid existed in an amorphous form in the complex. In vitro permeabilities of zoledronic acid/Lys-DOCA (1:1) (ZD1) and zoledronic acid/Lys-DOCA (1:2) (ZD2) complex across Caco-2 cell monolayers were 2.47- and 4.74-fold higher than that of zoledronic acid, respectively. Upon intra-jejunal administration to rats, the intestinal absorption of zoledronic acid was increased significantly and the resulting oral bioavailability of the ZD2 complex was determined to be 6.76 +/- 2.59% (0.548 +/- 0.161% for zoledronic acid). Ovariectomized (OVX) rats showed 122% increased bone mineral density versus the OVX control at 12 weeks after treatment with once weekly oral administration of ZD2 complex (16 mu g/kg of zoledronic acid). Furthermore, rats treated with ZD2 complex orally showed significant improvement in the parameters of trabecular microarchitecture and bone strength: 149% higher bone volume fraction (BV/TV), 115% higher trabecular number (Tb.N), and 56% higher mean maximum load (F-max) than in the OVX group. The trabecular microstructure and bone mechanical properties in the oral zoledronic acid group were not significantly changed compared with the OVX control. Thus, the oral ZD2 complex inhibited osteoporosis progression effectively by promoting osteogenesis and trabecular connectivity. The oral ZD2 complex would be expected to improve patient compliance by replacing the conventional injectable form and expand the indications, to include prophylaxis for osteoporosis and bone metastases.
PublicationDecreased bone volume and bone mineral density in the tibial trabecular bone is associated with Per2 gene by 405 nm laser stimulation( 2015)
;Yoo, Y.-M. ;Lee, M.-H. ;Park, J.H. ;Seo, D.-H. ;Lee, S. ;Jung, B. ;Kim, H.S.Bae, K.Low-level laser therapy/treatment (LLLT) using a minimally invasive laser needle system (MILNS) might enhance bone formation and suppress bone resorption. In this study, the use of 405 nm LLLT led to decreases in bone volume and bone mineral density (BMD) of tibial trabecular bone in wild-type (WT) and Per2 knockout (KO) mice. Bone volume and bone mineral density of tibial trabecular bone was decreased by 405 nm LLLT in Per2 KO compared to WT mice at two and four weeks. To determine the reduction in tibial bone, mRNA expressions of alkaline phosphatase (ALP) and Per2 were investigated at four weeks after 405 nm laser stimulation using MILNS. ALP gene expression was significantly reduced in the LLLT-stimulated right tibial bone of WT and Per2 KO mice compared to the non-irradiated left tibia (p < 0.001). Per2 mRNA expression in WT mice was significantly reduced in the LLLT-stimulated right tibial bone compared to the non-irradiated left tibia (p < 0.001). To identify the decrease in tibial bone mediated by the Per2 gene, levels of runt-related transcription factor 2 (Runx2) and ALP mRNAs were determined in non-irradiated WT and Per2 KO mice. These results demonstrated significant downregulation of Runx2 and ALPmRNA levels in Per2 KO mice (p < 0.001). Therefore, the reduction in tibial trabecular bone resulting from 405 nm LLLT using MILNS might be associated with Per2 gene expression.
PublicationEnhancement of bone quality and longitudinal growth due to free-fall motion in growing rats( 2015)
;Cho, S. ;Eom, S. ;Seo, D.-H. ;Park, J. ;Ko, C.-Y.Kim, H.S.Objectives: This study is to investigate the synchronous phenomena between bone quality and longitudinal length in a same subject affected by landing exercise. Physical exercise on the ground induces external loading to human body due to resistance from ground which can activate bone generation or remodeling. Especially, when the impact stimulation is applied to bone, it may improve bone quality and lengthening. Methods: 6-week-old male Wistar rats were randomly allocated to one of two conditions: free fall from 40 cm-height (I40; n = 7), and control (IC; n = 7). The impact stimulations were administered to the free fall groups, 10 times/day, and 5 days/week for 8 weeks. Structural parameters and longitudinal length of tibia were measured to quantitatively evaluate the variation in morphological characteristics and bone length with maturing. Results: The landing impact seems to be commonly effective on the enhancement of bone quality as well as longitudinal growth. Howe ver, the extent of enhancement may be more dominant in bone quality than longitudinal growth. On the other hand, the ratio of longitudinal growth seems to be dependent on the duration of stimuli whereas the enhancement of bone quality does not. Conclusions: This study verified that free-falls exercise can be effective on the enhancement of bone qualities and promotion of vertical growth in long bones. We expect that it might be possible for the moderate impact stimulation to be proposed as an aid for prevention of bone loss and promotion of bone lengthening. Â© 2015, Korean Society of Medical and Biological Engineering and Springer.
PublicationComparative study of hydroxyapatite prepared from seashells and eggshells as a bone graft material( 2014)
;Lee, S.-W. ;Balázsi, C. ;Balázsi, K. ;Seo, D.-H. ;Kim, H.S. ;Kim, C.-H.Kim, S.-G.The aims of this study were to determine the physical properties of hydroxyapatite from seashells (sHA) and from eggshells (eHA), to analyze elements within sHA and eHA, and to compare the bone regeneration ability between sHA and eHA in a rat parietal bone defect model. The sHA and eHA particles had a similar morphology in scanning electron microscope images. From the Fourier-transform infrared absorbance spectra and X-ray diffraction results, both types of hydroxyapatite (HA) had the characteristics of pure HA. Inductively coupled plasma atomic emission spectroscopy results suggested that the sHA had higher levels of sodium and strontium than the eHA, whereas the eHA had higher levels of magnesium than the sHA. In -CT results, the mean bone mineral density of the sHA was significantly higher than the control at 4 weeks after the operation (p = 0.012). The mean bone volume of the eHA was significantly higher than the control at 8 weeks after the operation (p = 0.012). In the histological images at 4 weeks after the operation, foreign body multinucleated giant cells were observed around the agglomerated sHA particles, while there were fewer inflammatory reactions around the agglomerated eHA particles. The eHA group showed better results in bone formation than did the sHA group in this study.
PublicationPrediction of antiarthritic drug efficacies by monitoring active matrix metalloproteinase-3 (MMP-3) levels in collagen-induced arthritic mice using the MMP-3 probe( 2014)
;Lee, A. ;Park, K. ;Choi, S.J. ;Seo, D.-H. ;Kim, K. ;Kim, H.S. ;Choi, K. ;Kwon, I.C. ;Yoon, S.-Y.Youn, I.Active matrix metalloproteinase-3 (MMP-3) is a prognostic marker of rheumatoid arthritis (RA). We recently developed an MMP-3 probe that can specifically detect the active form of MMP-3. The aim of this study was to investigate whether detection and monitoring of active MMP-3 could be useful to predict therapeutic drug responses in a collagen-induced arthritis (CIA) model. During the period of treatment with drugs such as methotrexate (MTX) or infliximab (IFX), MMP-3 mRNA and protein levels were correlated with fluorescence signals in arthritic joint tissues and in the serum of CIA mice. Also, bone volume density and erosion in the knee joints and the paws of CIA mice were measured with microcomputed tomography (micro-CT), X-ray, and histology to confirm drug responses. In joint tissues and serum of CIA mice, strong fluorescence signals induced by the action of active MMP-3 were significantly decreased when drugs were applied. The decrease in RA scores in drug-treated CIA mice led to fluorescence reductions, mainly as a result of down-regulation of MMP-3 mRNA or protein. The micro-CT, X-ray, and histology results clearly showed marked decreases in bone and cartilage destruction, which were consistent with the reduction of fluorescence by down-regulation of active MMP-3 in drug-treated CIA mice. We suggest that the MMP-3 diagnostic kit could be used to detect and monitor the active form of MMP-3 in CIA mice serum during a treatment course and thereby used to predict the drug response or resistance to RA therapies at an earlier stage. We hope that monitoring of active MMP-3 levels in arthritis patients using the MMP-3 diagnostic kit will be a promising tool for drug discovery, drug development, and monitoring of drug responses in RA therapy.
PublicationLactobacillus fermentation enhances the inhibitory effect of Hwangryun-haedok-tang in an ovariectomy-induced bone loss( 2013)
;Shim, K.-S. ;Kim, T. ;Ha, H. ;Lee, K.J. ;Cho, C.-W. ;Kim, H.S. ;Seo, D.-H.Ma, J.Y.Background: Hwangryun-haedok-tang (HRT) is traditional herbal medicine used to treat inflammatory-related diseases in Asia. However, its effect on osteoclastogenesis and bone loss is still unknown. In this study, we evaluated the effect of HRT and its fermented product (fHRT) on the receptor activator for the nuclear factor-B ligand-induced osteoclastogenesis using murine bone marrow-derived macrophages and postmenopausal bone loss using an ovariectomy (OVX) rat model. Methods: Tartrate resistant acid phosphatase (TRAP) staining was employed to evaluate osteoclast formation. mRNA level of transcription factor and protein levels of signaling molecules were determined by real-time quantitative polymerase chain reaction and Western blot analysis, respectively. Effect of HRT or fHRT on OVX-induced bone loss was evaluated using OVX rats orally administered HRT, or fHRT with 300 mg/kg for 12 weeks. Micro-CT analysis of femora was performed to analyze bone parameter. Results: HR T or fHRT treatment significantly decreased TRAP activity and the number of TRAP positive multinuclear cells on osteoclastogenesis. Interestingly, these inhibitory effects of HRT were enhanced by fermentation. Furthermore, fHRT significantly inhibited mRNA and protein expression of nuclear factor of activated T cells cytoplasmic 1, which leads to down-regulation of NFATc1-regulated mRNA expressions such as TRAP, the d2 isoform of vacuolar ATPase V(0) domain, and cathepsin K. Administration of fHRT significantly inhibited the decrease of bone mineral density, and improved bone parameter of femora more than that of HRT and vehicle in OVX rats. Conclusions: This study demonstrated that lactic bacterial fermentation fortifies the inhibitory effect of HRT on osteoclastogenesis and bone loss. These results suggest that fermented HRT might have the beneficial potential on osteoporosis by inhibiting osteoclastogenesis.