TAK-778
(Synonyms: 二乙基4-((6R,8S)-8-甲基-9-氧亚基-5,6,8,9-四氢噻庚英并[4,5:4,5]苯并[1,2-D][1,3]二噁戊环-6-碳杂草酰氨基)苯甲基膦酸基酯) 目录号 : GC34175
TAK-778是依普黄酮的衍生物，已显示在体外和体内模型中能诱导骨生长。
Cas No.:180185-61-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Cell experiment: | Human bone marrow cells are used and cultured in α-MEM supplemented with 10% fetal bovine serum, 50 mg/mL gentamicin, 0.3 mg/mL fungizone, 100 nM Mdexamethasone, 5 mg/L ascorbic acid, and 7 mM bglycerophosphate. Subconfluent cells in primary culture are harvested after treatment with 1 mM EDTA and 0.25% trypsin and the first passage is subcultured in 24-well culture plates at a cell density of 2×104 cells/well in culture medium containing the same volume of TAK-778 (10 μM), Tamoxifen (10 μM), and TAK-778 (10 μM)+Tamoxifen (10 μM). Cells subcultured in medium supplemented with vehicle are used as a control. During the culture period, cells are incubated at 37°C in a humidified atmosphere of 5% CO2 and 95% air, and the medium is changed every 3 or 4 days[1]. |
Animal experiment: | Eight-week-old female Wistar-Imamichi rats are used in this study. Forty Wistar-Imamichi rats are divided into sham-operated, vehicle, TAK-778, tamoxifen, and combination (TAK-778 and tamoxifen) treatment groups. Two weeks after ovariectomy, animals are orally administered TAK-778 [100 mg/kg body weight (BW), three times per week] and/or tamoxifen (200 mg/kg BW, three times per week) for 3 months. Rats orally administered vehicle and sham operated rats serve as controls. On 13 and 3 days before killing, tetracycline (30 mg/kg BW) or calcein (5 mg/kg BW) is injected subcutaneously, and lumbar vertebrae (L2-L5) are removed for bone analysis[3]. |
References: [1]. Rosa AL, et al. TAK-778 enhances osteoblast differentiation of human bone marrow cells via an estrogen-receptor-dependent pathway. J Cell Biochem. 2004 Mar 1;91(4):749-55. | |
TAK-778 is a derivative of ipriflavone and has been shown to induce bone growth in in vitro and in vivo models.
TAK-778 is a derivative of ipriflavone and has been shown to induce bone growth in in vitro and in vivo models.Continuous treatment with TAK-778 (10 μM) for 1 to 21 days results in an increase in the area of mineralized nodules. TAK-778 at concentrations of 1 μM and higher significantly stimulates the activity of cellular Alkaline phosphatase (ALP). TAK-778 increases slightly but significantly the DNA content of the cells at the confluence stage. Treatment with TAK-778 also results in dose-dependent increases in the amount of soluble collagen and osteocalcin secreted into culture medium from days 5 to 7. TAK-778 enhances the secretion of both TGF-β and IGF-I at every time point during the 21 days of culture. Treatment of the cells with TAK-778 does not induce ALP activity, but does result in a dose-dependent increase in the saturated cell density. TAK-778 at a concentration of 10 μM significantly reduces the saturated cell density[2].
Treatment with a single local application of TAK-778/PLGA-MC (0.2 to 5 mg/site) results in a dose-dependent increase in the radio-opaque area formed in the defect. Histological studies show the defect area is occupied by a bony bridge and the newly-formed radio-opaque area corresponds to a calcified bone containing bone marrow cavities surrounded by thick osteoid seams with cuboidal osteoblasts. There is no significant difference in either of the indices between placebo- or TAK-778/PLGA-MC-treated skulls. Two months after the operation, the TAK-778/PLGA-MC pellets induce radiological osseous union across the defects[2]. Oral treatment of OVX rats with TAK-778 causes a more pronounced increase in bone mineral density (BMD) of the lumbar vertebrae compare to vehicle controls[3].
[1]. Rosa AL, et al. TAK-778 enhances osteoblast differentiation of human bone marrow cells via an estrogen-receptor-dependent pathway. J Cell Biochem. 2004 Mar 1;91(4):749-55. [2]. Notoya K, et al. Enhancement of osteogenesis in vitro and in vivo by a novel osteoblast differentiation promoting compound, TAK-778. J Pharmacol Exp Ther. 1999 Sep;290(3):1054-64. [3]. Cai M, et al. TAK-778 induces osteogenesis in ovariectomized rats via an estrogen receptor-dependent pathway. J Bone Miner Metab. 2011 Mar;29(2):168-73.
| Cas No. | 180185-61-9 | SDF | |
| 别名 | 二乙基4-((6R,8S)-8-甲基-9-氧亚基-5,6,8,9-四氢噻庚英并[4,5:4,5]苯并[1,2-D][1,3]二噁戊环-6-碳杂草酰氨基)苯甲基膦酸基酯 | ||
| Canonical SMILES | O=C(NC1=CC=C(CP(OCC)(OCC)=O)C=C1)[C@@H](C2)S[C@@H](C)C(C3=C2C=C4OCOC4=C3)=O | ||
| 分子式 | C24H28NO7PS | 分子量 | 505.52 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.9782 mL | 9.8908 mL | 19.7816 mL |
| 5 mM | 0.3956 mL | 1.9782 mL | 3.9563 mL |
| 10 mM | 0.1978 mL | 0.9891 mL | 1.9782 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
TAK-778 induces osteogenesis in ovariectomized rats via an estrogen receptor-dependent pathway
J Bone Miner Metab 2011 Mar;29(2):168-73.PMID:20700613DOI:10.1007/s00774-010-0208-x.
TAK-778, a derivative of ipriflavone, has been shown to induce bone growth both in vitro and in vivo. Recently, it has been shown that TAK-778 can enhance osteoblast differentiation of human bone marrow cells via an estrogen receptor (ER)-dependent pathway. However, the mechanism by which TAK-778 exerts its effect in vivo has not been determined. Considering the evidence that TAK-778 acts via ER-mediated signaling in vitro, in the present study we tested if TAK-778 induced osteogenesis via an ER-dependent pathway using an ovariectomized (OVX) rat model. Two weeks after test animals underwent ovariectomy, TAK-778 and/or tamoxifen was administered orally over 3 months. Vehicle-treated and sham-operated rats served as controls. The bone mineral density (BMD) of the lumbar vertebrae and sagittal two-dimensional images of the L3 vertebral body were measured. In addition, bone formation rates (BFR) and serum calcium and osteocalcin levels were measured. The results indicated that TAK-778 significantly increased BMD, serum calcium and osteocalcin levels, and BFR when compared to that of the vehicle-treated group. However, tamoxifen, a well-known ER antagonist, clearly inhibited the increase in these parameters induced by TAK-778. In addition, micro-computed tomography scans showed that treatment with TAK-778 increased the structure model index, bone volume/tissue volume, and trabecular thickness parameters and decreased the trabecular separation/spacing in OVX rats. Tamoxifen suppressed these effects when administered in combination with TAK-778. Taken together, the present study showed that TAK-778 enhanced bone formation in OVX rats and that this effect was dependent on an ER-mediated pathway.
TAK-778 enhances osteoblast differentiation of human bone marrow cells cultured on titanium
Biomaterials 2003 Aug;24(17):2927-32.PMID:12742732DOI:10.1016/s0142-9612(03)00129-7.
TAK-778 induces bone growth in in vitro and in vivo models. The aim of this study was to evaluate the osteogenic potential of TAK-778 on human bone marrow cells cultured on commercially pure titanium (cpTi). Cells were cultured either in absence or in presence of TAK-778 (10(-5)M) on cpTi in supplemented alpha-MEM. For attachment evaluation, cells were cultured for 4 and 24h. After 7, 14, and 21 days, cell proliferation, cell viability, total protein content, alkaline phosphatase (ALP) activity, and bone-like formation were evaluated. TAK-778 did not affect cell attachment and viability. Cell number was reduced by TAK-778. ALP activity, total protein content, and bone-like formation were increased by TAK-778. These results suggest that initial cell events such as cell attachment are not affected by TAK-778 while events that indicate osteoblast differentiation including reduced cell proliferation, and increased both ALP activity and bone-like formation are enhanced by TAK-778 in presence of cpTi. It means that TAK-778 could be a useful drug to improve the osseointegration of implants by both enhancing and accelerating bone formation on Ti surface.
TAK-778 enhances osteoblast differentiation of human bone marrow cells via an estrogen-receptor-dependent pathway
J Cell Biochem 2004 Mar 1;91(4):749-55.PMID:14991766DOI:10.1002/jcb.10773.
TAK-778, a derivative of ipriflavone, has been shown to induce bone growth in in vitro and in vivo models. However, there are no studies evaluating by which mechanism TAK-778 exerts its effect. Considering the evidences that its precursors act via classical estrogen-receptor (ER)-mediated signaling, in the present study, we tested the hypothesis that TAK-778 induces osteogenesis in human bone marrow cell culture via an ER-dependent pathway. Cells were cultured in 24-well culture plates at a cell density of 2 x 10(4) cells/well in culture medium containing: TAK-778 (10(-5) M), Tamoxifen (10(-5) M), TAK-778 (10(-5) M) + Tamoxifen (10(-5) M), and vehicle. During the culture period, cells were incubated at 37 degrees C in a humidified atmosphere of 5% CO(2) and 95% air. At 7, 14, and 21 days, cell proliferation, cell viability, total protein content, alkaline phosphatase (ALP) activity, and bone-like formation were evaluated. Data were compared by two-way ANOVA and Duncan's multiple range test. TAK-778 did not affect cell viability. Cell number was reduced by TAK-778. Total protein content, ALP activity, and bone-like formation were increased by TAK-778. In general, Tamoxifen did not have any effect on cell behavior. However, when cells were cultured in medium containing both TAK-778 and Tamoxifen, the effect of TAK-778 on osteoblast differentiation was inhibited. The present results show that TAK-778 enhances osteoblast differentiation in human bone marrow cell culture, at least in part, via an ER-dependent pathway, since its effect was inhibited by Tamoxifen, a well-known estrogen receptor antagonist.
The effect of TAK-778 on gene expression of osteoblastic cells is mediated through estrogen receptor
Exp Biol Med (Maywood) 2009 Feb;234(2):190-9.PMID:19064943DOI:10.3181/0808-RM-246.
This study evaluated the effect of TAK-778 [(2R, 4S)-(-)-N-(4-diethoxyphosphorylmethylphenyl)-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxamide)] on in vitro osteogenic events and on gene expression of osteoblastic cells derived from human alveolar bone and the participation of estrogen receptors (ERs) on such effect. Osteoblastic cells were subcultured, with or without TAK-778 (10(-5) M), to evaluate cell growth and viability, total protein content, and alkaline phosphatase (ALP) activity at 7, 14, and 21 days; bone-like formation at 21 days; and gene expression, using cDNA microarray, at 7 days. Also, osteoblastic cells were exposed to TAK-778 (10(-5) M) combined to ICI182,780, a nonspecific ER antagonist (10(-6) M), and gene expression was evaluated by real-time polymerase chain reaction (PCR) at 7 days. TAK-778 induced a reduction in culture growth and an increase in cell synthesis, ALP activity, and bone-like formation. The cDNA microarray showed genes associated with cell adhesion and differentiation, skeletal development, ossification, and transforming growth factor-beta receptor signaling pathway, with a tendency to be higher expressed in cells exposed to TAK-778. The gene expression of ALP, osteocalcin, Msh homeobox 2, receptor activator of NF-kappa B ligand, and intercellular adhesion molecule 1 was increased by TAK-778 as demonstrated by real-time PCR, and this effect was antagonized by ICI182,780. The present results demonstrated that TAK-778 acts at a transcriptional level to enhance the in vitro osteogenic process and that its effect on gene expression of osteoblastic cells is mediated, at least partially, through ERs. Based on these findings, TAK-778 could be considered in the treatment of bone metabolic disorders.
[Effect of beta-TCP containing the bone-growth promoting compound, TAK-778, on the vertex bone of rat--change of volmetric bone formation corresponding to the containing volume of TAK-778]
Nihon Hotetsu Shika Gakkai Zasshi 2006 Jul;50(3):422-31.PMID:17159288DOI:10.2186/jjps.50.422.
Purpose: This study was conducted to histomorphologically determine the quantity of bone formation induced by TAK-778, a 3-benzothiepin derivative, (Takeda Pharmaceutical Co.Ltd.), in various amounts, using b-tricalcium phosphate granules (beta-TCP; OLYMPUS Corp.) as a carrier for the osteogenetic agent. Methods: Ten-week-old female SD rats were used. An incision was made over the parietal region of the head. The cranial periosteum was ablated and a titanium tube was fixed with an adhesive resin cement to the central part of the head, through which a mixture of TAK-778 and beta-TCP was implanted under various conditions. Tissue specimens were prepared at 4, 8, and 16 weeks after the implantation for histomorphological examination, and the proportion of new bone formation was compared at fixed time points using the NIH imaging software. The amount of new bone formation was examined every week after the implantation of TAK-778 at various doses, and the mean values were compared using Fisher's PSLD test (P< 0.05). Results: The histomorphological observations revealed new bone formation in all the groups, irrespective of the amount and the duration of implantation of TAK-778. A comparative study revealed that the amount of new bone formation was the largest at 16 weeks following the implantation of a mixture of beta-TCP and 100 mg of TAK-778. Conclusions: 1. The present study confirmed the acceleration of new bone formation soon after TAK-778 implantation. 2. The results suggested that the action of TAK-778 could be maintained over time if the agent was used in combination with beta-TCP. 3. The time-course of bone formation differed depending on the proportion of TAK-778 and beta-TCP in the mixture used. 4. TAK-778 at the dose of 10 mg or 50 mg was more effective than that at the dose of 100 mg for the early formation of new bone. These results indicate that TAK-778 accelerates the formation of new bone and that beta-TCP is a useful carrier for TAK-778.