JP2006117550A - Osteoprotegerin production promoter - Google Patents

Osteoprotegerin production promoter Download PDF

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JP2006117550A
JP2006117550A JP2004304561A JP2004304561A JP2006117550A JP 2006117550 A JP2006117550 A JP 2006117550A JP 2004304561 A JP2004304561 A JP 2004304561A JP 2004304561 A JP2004304561 A JP 2004304561A JP 2006117550 A JP2006117550 A JP 2006117550A
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osteoclast differentiation
production
quercetin
production promoter
osteoclast
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Takahiro Inaguma
Kayako Shoji
Eiji Takeda
Hironori Yamamoto
浩範 山本
佳文子 庄子
英二 武田
隆博 稲熊
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Kagome Co Ltd
Univ Of Tokushima
カゴメ株式会社
国立大学法人徳島大学
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<P>PROBLEM TO BE SOLVED: To obtain an osteoprotegerin production promoter that comprises a component as an active ingredient promoting osteoprotegerin production, being readily available and not restricting the use form of preparation. <P>SOLUTION: The osteoprotegerin production promoter comprises quercetin as an active ingredient. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

本発明は、ケルセチンを有効成分として含有する破骨細胞分化抑制因子(Osteoclastogenesis inhibitory factor:OCIF。別名Osteoprotegrin: OPGともいう。)の産生促進剤に関する。 The present invention, quercetin effective osteoclast differentiation inhibiting agent containing as a component (Osteoclastogenesis inhibitory factor: OCIF Alias ​​Osteoprotegrin:.. OPG also referred) relates to the production accelerators.

骨は常に形成と吸収を繰り返している組織であり、骨芽細胞による骨形成と破骨細胞による骨吸収との代謝バランスが保たれることにより良好な状態が維持される。 Bone is a tissue that constantly repeated absorption and formation, good condition can be maintained by the metabolic balance of bone resorption by bone formation and osteoclasts by osteoblasts is maintained. しかしながら、代謝バランスが崩れ、破骨細胞が過剰に生成されると、骨粗鬆症、骨パジェット病、慢性関節リウマチなどの骨吸収性疾患の発症につながる。 However, it collapsed metabolic balance, the osteoclasts are excessively formed, osteoporosis, Paget's disease, leading to the development of bone resorption diseases, such as rheumatoid arthritis. これらの疾病を治療又は予防するためには、破骨細胞の分化・活性化を抑制することが有効である。 For treating or preventing these diseases, it is effective to suppress the differentiation and activation of osteoclasts.

破骨細胞の分化・活性化を抑制する方法としては、ビスフォスフォネートを使用し波状縁を消失あるいはアポトーシスを促進することにより抑制する方法や、カルシトニンを使用し受容体を介して抑制する方法などがよく知られているが、現在においても破骨細胞の分化・活性化を抑制することについて、様々な角度からさかんに研究が進められている。 As a method of suppressing the differentiation and activation of osteoclasts, a method of suppressing by promoting the disappearance or apoptosis wavy edges using bisphosphonates, method of suppressing via the use calcitonin and receptor While such is well known, for suppressing the differentiation and activation of osteoclasts even in currently underway is actively studied from various angles.

そのような中、破骨細胞分化抑制因子の産生を促進することにより破骨細胞の分化を抑制するとの報告がなされた(例えば、特許文献1参照)。 Among such, it reported to inhibit osteoclast differentiation by promoting the production of osteoclast differentiation inhibiting factor has been made (for example, see Patent Document 1). 破骨細胞分化抑制因子の産生による破骨細胞の分化抑制は、広い活性スペクトルを持つことから、破骨細胞の分化・活性化を抑制する方法としては好ましいものと思われる。 Differentiation inhibiting osteoclast by production of osteoclast differentiation inhibiting factor, because of its broad spectrum of activity, appear to be preferred as a method of suppressing the differentiation and activation of osteoclasts. しかし、この文献に記載の破骨細胞分化抑制因子の産生促進剤は、乳由来塩基性タンパク質を有効成分として用いており、このタンパク質は熱や酸に弱いことから使用形態に制限がある。 However, production promoter of osteoclast differentiation inhibiting agent according to this document is using a milk-derived basic protein as an active ingredient, the protein is limited to use form from weak to heat and acid.

一方、ケルセチンは、たまねぎ等が有する黄色い色素であり、フラボノイドの一種である。 Meanwhile, quercetin is a yellow dye onion like has is a type of flavonoid. このケルセチンに、破骨細胞の分化を抑制する作用があることは知られている(例えば、非特許文献1参照)。 This quercetin, that function to suppress differentiation of osteoclasts is known (e.g., see Non-Patent Document 1). しかし、ここでは破骨細胞のマーカーであるTRAP活性の破骨細胞分化因子(Osteoclast differentiation factor:ODF。別名RANKLともいう。)による上昇が阻害されることが示されているだけであり、破骨細胞分化抑制因子については何ら記載されていない。 However, where osteoclast differentiation factor TRAP activity, a marker of osteoclast (Osteoclast differentiation factor:.. ODF also called alias RANKL) is only increased by is shown to be inhibited, osteoclast no description is for cell differentiation inhibitory factor.

また、ケルセチンに、多剤耐性抑制作用、アミラーゼ阻害作用、紫外線防護作用等があることは知られているが(例えば、特許文献2〜4参照)、破骨細胞分化抑制因子の産生促進活性があることは知られていなかった。 Also, quercetin, multidrug resistance suppressing effect, amylase inhibitory activity, it is known that there is a UV protection action and the like (e.g., see Patent Documents 2 to 4), the production promoting activity of osteoclast differentiation inhibiting factor It has not been known that there is.

特開2004−115509号公報 JP 2004-115509 JP 特開平5−70348号公報 JP 5-70348 discloses 特開平5−236910号公報 JP-5-236910 discloses 特開平6−88063号公報 JP 6-88063 discloses

本発明は上記観点からなされたものであり、破骨細胞の分化を抑制するため、破骨細胞分化抑制因子の産生を促進することができる破骨細胞分化抑制因子の産生促進剤を提供することを課題とする。 The present invention has been made from the viewpoint, for suppressing the osteoclast differentiation, to provide a production promoter of osteoclast differentiation inhibiting agent which can promote the production of osteoclast differentiation inhibiting factor a an object of the present invention.

より詳しくは、破骨細胞分化抑制因子の産生を促進することができる成分であって、入手容易でかつ製剤の使用形態に制限を与えない成分を有効成分として含有する破骨細胞分化抑制因子の産生促進剤を提供することを課題とする。 More specifically, a component which can promote the production of osteoclast differentiation inhibiting factor, the osteoclast differentiation inhibiting agent containing the component which does not give limit to the use form of easy and formulation available as an active ingredient it is an object of the present invention to provide a production promoter.

本発明者らは、上記課題を解決するために破骨細胞分化抑制因子の産生を促進させることができる成分を探索した結果、ケルセチンに破骨細胞分化抑制因子の産生促進活性があることを見出し、発明を完成させるに至った。 The present inventors have found, as a result of searching for a component which can promote the production of osteoclast differentiation inhibiting factors in order to solve the above problems, it found that there is a production promoting activity of osteoclast differentiation inhibiting factors quercetin This has led to the completion of the invention.

すなわち、本発明は、ケルセチンを有効成分として含有する破骨細胞分化抑制因子産生促進剤を提供するものである。 That is, the present invention is to provide a osteoclast differentiation inhibitory factor production promoter containing quercetin as an active ingredient.

また、本発明は、破骨細胞分化抑制因子の産生を促進する活性を有するケルセチンの、破骨細胞分化抑制因子が産生されることにより治療可能な各種疾患に対する治療剤の製造における使用、及び、破骨細胞分化抑制因子の産生を促進する活性を有するケルセチンの治療的に有効な量を、破骨細胞分化抑制因子の産生が促進されることが必要な患者に投与することを含む、破骨細胞分化抑制因子が産生されることにより治療可能な各種疾患に対する治療方法を提供するものである。 The present invention also quercetin have the activity of promoting the production of osteoclast differentiation inhibiting factor, in the manufacture of therapeutic agents for treatable various diseases by the osteoclast differentiation inhibiting factors produced, and, comprising administering a therapeutically effective amount of quercetin have the activity of promoting the production of osteoclast differentiation inhibitory factor, the patient is required that the production of osteoclast differentiation inhibiting agent is promoted, osteoclast cell differentiation inhibitory factor is to provide a treatment for treatable various diseases by being produced.

本発明の破骨細胞分化抑制因子産生促進剤を適用することにより、破骨細胞分化抑制因子の産生が促進され、破骨細胞の分化が抑制されるため、骨粗鬆症、骨パジェット病、慢性関節リウマチなどの骨吸収性疾患に対し、有効に治療及び予防をすることができる。 By applying the osteoclast differentiation inhibitory factor production promoter of the present invention, it promotes the production of osteoclast differentiation inhibiting factor, since the differentiation of osteoclasts is inhibited, osteoporosis, Paget's disease, rheumatoid arthritis to bone resorption diseases, such as, it can be effectively treated and prevented.

また、本発明の破骨細胞分化抑制因子産生促進剤は、上記のような一般の骨吸収性疾患に対してだけでなく、一般の骨吸収性疾患を除く、癌性高カルシウム血症、悪性腫瘍骨転移の抑制、癌に伴う骨痛などの癌に伴う骨病変に対しても有効な治療剤として使用することができる。 Moreover, osteoclast differentiation inhibiting factor production promoter of the present invention, not only for general bone resorption diseases, such as described above, except for general bone resorption diseases, cancerous hypercalcemia, malignancy inhibition of tumor bone metastases, can be used as an effective therapeutic agent against bone lesions associated with cancer, such as bone pain associated with cancer.

また、上記以外の疾患に対しても、破骨細胞分化抑制因子の産生を促進することにより治療可能な疾患に対し、本発明の破骨細胞分化抑制因子産生促進剤は効果的かつ患者に安心して適用できる治療剤として使用することができる。 Moreover, even for diseases other than the above, Ahn against disease treatable by promoting the production of osteoclast differentiation inhibiting factor, osteoclast differentiation inhibiting factor production promoter of the present invention is effective and the patient it can be used as a therapeutic agent capable Kokoroshite applicable.

以下、本発明を詳細に説明する。 The present invention will be described in detail.

本発明の破骨細胞分化抑制因子産生促進剤は、ケルセチンを有効成分として含有する。 Osteoclast differentiation inhibiting factor production promoter of the present invention contains quercetin as an active ingredient.

ケルセチンは、フラボノイドのうち、フラボノールに分類されるポリフェノール化合物で、タマネギ、ホウレン草、ケール、パセリなどに多く含まれている。 Quercetin, among flavonoids, polyphenols compounds classified into flavonols, onions, spinach, kale, are included in many such parsley.

ケルセチンを得る技術は確立されているので、通常行われている方法をもとにケルセチンを得ることができる。 Since techniques for obtaining quercetin has been established, a process which is usually performed can be obtained quercetin based. また、市販のものを用いてもよい。 It may also be used commercially.

本発明の破骨細胞分化抑制因子産生促進剤においては、ケルセチンを単独で用いてもよいし、医薬用として通常用いられている他の任意成分を含有させてもよい。 In osteoclast differentiation inhibitory factor production promoter of the present invention, to quercetin may be used alone, it may contain other optional ingredients which are generally used as pharmaceutical.

本発明の破骨細胞分化抑制因子産生促進剤(破骨細胞分化抑制因子産生促進剤含有医薬組成物の形態も含む)の剤型は、特に限定されないが、一般に製剤上許容される1または2種類以上の担体、賦形剤、統合剤、防腐剤、安定剤、香味剤等と共に混合して、錠剤、顆粒剤、カプセル剤、水薬、ドリンク剤等の内服剤型とすることが好ましい。 Dosage form of osteoclast differentiation inhibitory factor production promoter of the present invention (including the form of osteoclast differentiation inhibiting factor production promoter containing pharmaceutical composition), 1 or 2 is not particularly limited, is generally on the formulation acceptable or more carriers, excipients, integration agents, preservatives, stabilizers, are mixed with flavoring agents such as, tablets, granules, capsules, drenches, it is preferable that the oral dosage form, such as drinks. このような製剤化は、通常、医薬の製造に用いられる方法に従って製剤化することができる。 Such formulation usually can be formulated according to methods used in the manufacture of a medicament.

本発明の破骨細胞分化抑制因子産生促進剤(破骨細胞分化抑制因子産生促進剤含有医薬組成物の形態も含む)の投与量としては、疾患の種類、症状、患者の年齢、体重等により異なるが、成人1日当たり、ケルセチンが0.5〜500mg摂取できるような量の破骨細胞分化抑制因子産生促進剤を投与するのが好ましい。 The dosage of osteoclast differentiation inhibitory factor production promoter of the present invention (including the form of osteoclast differentiation inhibiting factor production promoter containing pharmaceutical composition), type of disease, symptoms, patient's age and weight, etc. different, per day per adult, quercetin preferred to administer amounts of osteoclast differentiation inhibitory factor production promoter such as can be ingested 0.5 to 500 mg.

上記のようにして得られた本発明の破骨細胞分化抑制因子産生促進剤は、骨粗鬆症、骨パジェット病、慢性関節リウマチなどの骨吸収性疾患に対し、有効な治療剤及び予防剤となる。 Osteoclast differentiation inhibiting factor production promoter of the present invention obtained as described above, osteoporosis, Paget's disease, with respect to bone resorption diseases, such as rheumatoid arthritis, an effective therapeutic and prophylactic agents. また、本発明の破骨細胞分化抑制因子産生促進剤は、一般の骨吸収性疾患を除く、癌性高カルシウム血症、悪性腫瘍骨転移の抑制、癌に伴う骨痛などの癌に伴う骨病変に対しても、有効な治療剤となる。 Moreover, osteoclast differentiation inhibiting factor production promoter of the present invention, except for general bone resorption diseases, cancerous hypercalcemia, suppression of malignant tumor bone metastases, bone associated with cancer, such as bone pain associated with cancer even for lesions, it becomes an effective therapeutic agent. さらにまた、上記以外の疾患に対しても、破骨細胞分化抑制因子の産生を促進することにより治療可能な疾患に対し、有効な治療剤となる。 Furthermore, even for diseases other than the above, with respect to a disease treatable by promoting the production of osteoclast differentiation inhibiting factor, it becomes an effective therapeutic agent.

また、本発明の破骨細胞分化抑制因子産生促進剤を飲食品用として通常用いられている他の任意成分に添加して破骨細胞分化抑制因子産生促進剤含有飲食品を得てもよい。 Furthermore, other commonly the optional components may be obtained osteoclast differentiation inhibitory factor production promoter containing food or beverage is added which is used as food and drink for osteoclast differentiation inhibitory factor production promoter of the present invention.

本発明の破骨細胞分化抑制因子産生促進剤含有飲食品の種類や形態としては、上記の破骨細胞分化抑制因子産生促進活性作用が期待できるものであれば特に限定されるものではない。 As the type and form of the osteoclast differentiation inhibiting factor production promoter containing food or beverage of the present invention is not limited in particular as long as it osteoclast differentiation inhibiting factor production promoting activity effect described above can be expected. 例えば、日本茶、ジュース、ゼリー、ビスケット、タブレットなどに適用することができる。 For example, Japanese green tea, can be applied juice, jelly, biscuits, such as a tablet. 種々の飲食品原料に、ケルセチンを所要量配合させることができる。 In various food and beverage raw material, it can be required amount of quercetin. また、ケルセチンをそのままカプセルに充填してサプリメント剤とすることもできる。 It is also possible to quercetin as it is filled into capsules and supplements agent. ケルセチンを配合する際に特に留意することはなく、通常の製造方法により加工製造することができる。 Quercetin never particularly note in formulating, it can be processed prepared by conventional manufacturing methods. 配合量は、飲食品の種類により異なるが、味を損なわず、且つ十分な破骨細胞分化抑制因子産生促進活性効果を得るためには、飲食品全量に対して、ケルセチンを0.5mg〜100g/100gの割合で配合させるのが好ましい。 The amount varies depending on the type of food or beverage without impairing the taste, in order to obtain and sufficient osteoclast differentiation inhibitory factor production promoting activity effects against food products the total amount, 0.5Mg~100g quercetin It is preferable to blend at a rate of / 100 g.

本発明の破骨細胞分化抑制因子産生促進剤を含有する飲食品は、健康食品等を含む各種機能性食品に適用されることができ、特に飲食品の最終商品形態に対し、破骨細胞分化抑制因子の産生を促進するために用いられる旨の表示を付してもよい。 Food or drink containing osteoclast differentiation inhibitory factor production promoter of the present invention can be applied to various functional foods including health foods, to particular final product form of food or drink, osteoclast differentiation it may be subjected an indication used to promote the production of suppressor.

以下、実施例を挙げて本発明を具体的に説明する。 Hereinafter, the present invention will be specifically described by examples.
<方法> <Method>

マウス骨芽細胞様細胞株 ST−2細胞(理研細胞バンク)およびマウス頭蓋冠より抽出し培養した初代培養系骨芽細胞 Primary osteoblast 細胞(POB)を、破骨細胞分化促進ホルモンであるデキサメタゾン(Sigma)および活性型ビタミンD3(Sigma)をそれぞれ10nM、ならびにケルセチン(Sigma)5μMまたは10μMを含むα−MEM 培地で(Sigma)培養した(37℃)。 Mouse osteoblast-like cell line ST-2 cells (Riken Cell Bank) and mouse calvaria than extracted and cultured the primary culture osteoblasts Primary osteoblast cells (POB), a osteoclast differentiation promoting hormone dexamethasone (Sigma ) and active vitamin D3 (Sigma), respectively 10 nM, as well as quercetin (Sigma) in alpha-MEM medium containing 5μM or 10 [mu] M (Sigma) incubated (37 ° C.). 培養24時間後、細胞よりTRI-Reagent (Invitrogen)を用いて全RNAを抽出し、全RNA(2.5μg)は、DNase I(Invitrogen)処理後、oligo dT プライマー(Invitrogen)、1st Strand Buffer(Invitrogen)、2.5mM dNTP、(Invitrogen)0.1M DTT(Invitrogen)、逆転写酵素(M-MLV-RT)(Invitrogen)を含む反応溶液で42℃1時間、さらに95℃で2分間反応させてcDNAを合成した。 24 hours of culture, using the TRI-Reagent (Invitrogen) from cells to extract total RNA, total RNA (2.5 [mu] g) after DNase I (Invitrogen) treatment, oligo dT primer (Invitrogen), 1st Strand Buffer ( Invitrogen), 2.5mM dNTP, (Invitrogen) 0.1M DTT (Invitrogen), reverse transcriptase (M-MLV-RT) (Invitrogen) reaction solution containing at 42 ° C. 1 hour, allowed to react for 2 minutes at further 95 ° C. with cDNA It was synthesized.

合成したcDNAを用いて破骨細胞分化抑制因子遺伝子の発現についてPCR法により検討を行った。 It was examined by PCR for the expression of osteoclast differentiation inhibiting factor gene using the synthesized cDNA. コントロールとして、ほぼ全ての細胞中に存在し、発現量が一定であるβ As a control, present in almost all cells, the expression amount is constant β
-アクチンを用いた。 - Actin was used. 以下に、使用したプライマーの配列を示す。 Hereinafter, a sequence of the primer used. PCRは、i)95℃ PCR is, i) 95 ℃
1分、ii)95℃ 1分、58℃ 1分、72℃ 2分、を30サイクル、iii)72℃ 5分で行った。 1 minute, ii) 95 ° C. 1 min, 58 ° C. 1 min, 72 ° C. 2 minutes, was carried out in 30 cycles, iii) 72 ° C. 5 minutes.

PCR産物を1.5%アガロースゲル((株)ニッポンジーン)で電気泳動し、エチジウムブロマイド(片山化学工業(株))染色により検出した。 The PCR product was electrophoresed on a 1.5% agarose gel (Co. Nippon Gene), ethidium bromide (Katayama Chemical Industries Co.) were detected by staining.
得られたバンドを画像解析ソフト(NIH image:米国National Institute of Health 製)を用いて解析し、色の濃度を定量化してβ−アクチンの測定値を基準に相対値化した。 The resulting band image analysis software: and analyzed using (NIH image US National Ltd. Institute of Health), and the concentration of color relative valued based on the measured value of quantified by β- actin.

1)OCIF:センスプライマー(配列番号1) 1) OCIF: sense primer (SEQ ID NO: 1)
aggaccacaatgaacaagtggctg aggaccacaatgaacaagtggctg
2)OCIF:アンチセンスプライマー(配列番号2) 2) OCIF: antisense primer (SEQ ID NO: 2)
gtctcacctgagaagaacccatc gtctcacctgagaagaacccatc
3)β-アクチン:センスプライマー(配列番号3) 3) β- actin: sense primer (SEQ ID NO: 3)
catcgtgggccgctctaggcacca catcgtgggccgctctaggcacca
4)β-アクチン:アンチセンスプライマー(配列番号4) 4) β- actin: antisense primer (SEQ ID NO: 4)
cggttggccttagggttcaggggg cggttggccttagggttcaggggg

尚、前記培養に用いた培地が、デキサメタゾンおよび活性型ビタミンD3を含まない場合、及びデキサメタゾンおよび活性型ビタミンD3を含みケルセチンを含まない場合についても、破骨細胞分化抑制因子遺伝子の発現について調べた。 Incidentally, the medium used for the culture, if without dexamethasone and activated vitamin D3, and the case without the quercetin include dexamethasone and active vitamin D3 was also examined for the expression of osteoclast differentiation inhibiting factor gene .

各実施例、比較例、及び参考例の添加条件は、下記の表1に示すとおりである。 Each Example and Comparative Example, and the addition conditions of Reference Examples are as shown in Table 1 below.


<結果> <Result>

破骨細胞分化抑制因子遺伝子の発現の結果を図1及び図2に示す The results of expression of osteoclast differentiation inhibiting factor gene in Figures 1 and 2

図1及び図2に示すように、用いたST−2及びPOBの両細胞においてデキサメタゾンおよび活性型ビタミンD3添加により破骨細胞分化抑制因子mRNAの発現量は著しく減少する(比較例1の結果参照)。 As shown in FIGS. 1 and 2, ST-2 and expression of osteoclast differentiation inhibiting factor mRNA by dexamethasone and active vitamin D3 added in both cell of POB is greatly reduced (Comparative Example 1 Results reference by using ). しかし、デキサメタゾンおよび活性型ビタミンD3を添加した場合であっても、ケルセチン5μMまたは10μMで処理すると、破骨細胞分化抑制因子mRNAの発現量は参考例1のデキサメタゾンおよび活性型ビタミンD3非添加と同等のレベルを示す(実施例1及び2の結果参照)。 However, even if the addition of dexamethasone and active vitamin D3, equivalent is treated with quercetin 5μM or 10 [mu] M, the expression amount of osteoclast differentiation inhibitory factor mRNA is the added non dexamethasone and active vitamin D3 of Reference Example 1 shows the levels (see results of examples 1 and 2).

これにより、ケルセチンに破骨細胞分化抑制因子の産生促進作用があることが確認できた。 As a result, it was confirmed that the quercetin there are the production promoting action of osteoclast differentiation inhibiting factor. よって、ケルセチンは破骨細胞分化抑制因子の産生促進剤の有効成分として使用することができる。 Therefore, quercetin can be used as an active ingredient of production promoter of osteoclast differentiation inhibiting factors.

ST−2細胞における破骨細胞分化抑制因子mRNAの発現量の相対値を示すグラフである。 It is a graph showing the relative value of the expression level of osteoclast differentiation inhibitory factor mRNA in ST-2 cells. POB細胞における破骨細胞分化抑制因子mRNAの発現量の相対値を示すグラフである。 Is a graph showing the relative value of the expression level of osteoclast differentiation inhibitory factor mRNA in POB cells.

Claims (1)

  1. ケルセチンを有効成分として含有する破骨細胞分化抑制因子産生促進剤。 Osteoclast differentiation inhibiting factor production promoting agent containing as an active ingredient quercetin.
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WO2008155397A2 (en) 2007-06-20 2008-12-24 Galapagos N.V. Molecular targets and compounds, and methods to identify the same, useful in the treatment of bone and joint degenerative diseases
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WO2008051586A3 (en) * 2006-10-24 2008-09-25 Costa Silvia R Da Anti-resorptive and bone building dietary supplements and methods of use
WO2008051594A3 (en) * 2006-10-24 2008-10-09 Costa Silvia R Da Anti-resorptive and bone building dietary supplements and methods of use
US9446087B2 (en) 2006-10-24 2016-09-20 David W. Krempin Anti-resorptive and bone building dietary supplements and methods of use
EP2415469A1 (en) * 2006-10-24 2012-02-08 David W. Krempin Anti-Resorptive and Bone Building Dietary Supplements and Methods of Use
WO2008155397A2 (en) 2007-06-20 2008-12-24 Galapagos N.V. Molecular targets and compounds, and methods to identify the same, useful in the treatment of bone and joint degenerative diseases
WO2008155397A3 (en) * 2007-06-20 2009-04-09 Galapagos Nv Molecular targets and compounds, and methods to identify the same, useful in the treatment of bone and joint degenerative diseases
EP2565649A1 (en) * 2007-06-20 2013-03-06 Galapagos N.V. Molecular targets and compounds, and methods to identify the same, useful in the treatment of bone and joint degenerative diseases
JP2010538244A (en) * 2007-06-20 2010-12-09 ガラパゴス・ナムローゼ・フェンノートシャップGalapagos N.V. Useful molecular targets and compounds in the treatment of degenerative diseases of bone and joint and identification method
US7897184B1 (en) 2009-08-13 2011-03-01 Access Business Group International Llc Topical composition with skin lightening effect
US8202556B2 (en) 2009-08-13 2012-06-19 Access Business Group International Llc Topical composition with skin lightening effect
KR101300846B1 (en) * 2010-12-17 2013-08-29 대한민국(농촌진흥청장) Compositions for treatment and prevention of bone diseases comprising extract of rhamnus davurica pall.

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