JP2020125281A - Floating particulate matter-induced inflammation suppressant, and food for suppressing floating particulate matter-induced inflammation - Google Patents
Floating particulate matter-induced inflammation suppressant, and food for suppressing floating particulate matter-induced inflammation Download PDFInfo
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Abstract
Description
本発明は、浮遊粒子状物質誘発性炎症抑制剤及び浮遊粒子状物質誘発性炎症抑制用食品に関し、詳しくは、ＰＭ２．５や黄砂などの浮遊粒子状物質によって誘発される炎症を抑制するための浮遊粒子状物質誘発性炎症抑制剤及び浮遊粒子状物質誘発性炎症抑制用食品に関する。 The present invention relates to a suspended particulate matter-induced inflammation inhibitor and a suspended particulate matter-induced inflammation-suppressed food, and more specifically, for inhibiting inflammation induced by suspended particulate matter such as PM2.5 and yellow sand. The present invention relates to a suspended particulate matter-induced inflammation suppressant and a foodstuff for suppressing suspended particulate matter-induced inflammation.
アレルギー症状の緩和には、アレルゲンだけでなくアレルギー増悪因子にも注意する必要がある。ヒトは１日当たり１５〜２０ｍ3の空気を吸っており、汚染された空気の吸入は健康に大きな影響を与えることが示唆される。
大気中には、花粉やカビ胞子のようなアレルゲンの他、主にダニやカビなどの微生物の残骸を主成分とするハウスダスト、ＰＭ２．５、黄砂、タバコの煙、建材や香料由来の化学物質などの物質が含まれており、これらがアレルギー症状の悪化や呼吸器疾患の増悪に関与することが危惧されている。
To alleviate allergic symptoms, it is necessary to pay attention to allergen exacerbation factors as well as allergens. Humans inhale 15 to 20 m 3 of air per day, suggesting that inhalation of polluted air has a great impact on health.
In the air, in addition to allergens such as pollen and mold spores, house dust, which mainly contains the residue of microorganisms such as mites and molds, PM2.5, yellow sand, tobacco smoke, chemistry derived from building materials and fragrances Substances such as substances are contained, and it is feared that these substances may contribute to worsening allergic symptoms and exacerbation of respiratory diseases.
近年、近隣諸国の急速な工業化に伴い、当地での大気汚染が深刻化している。偏西風により、その大気汚染物質が運ばれてくるため、わが国でもＰＭ２．５に代表される大気汚染物質問題が顕在化している。
また、気候変動や乾燥地域での家畜の過放牧により砂漠化が進んでいる。そのため、東アジア地域の砂漠地域西側では、偏西風に乗って黄砂が飛来する。中国や韓国の大陸では、視界が非常に悪くなるなど、日常生活に支障を来たすレベルの黄砂の飛来が、毎年観測されている。わが国においても、黄砂の飛散は、花粉やＰＭ２．５同様に問題となっており、天気予報での飛散予想や注意喚起がされている。これらは、アレルギー患者の増悪分子と考えられており、黄砂誘導型炎症への対応も重要である。
In recent years, with the rapid industrialization of neighboring countries, air pollution in the area has become serious. Since the air pollutants are carried by the westerly wind, the air pollutant problem represented by PM2.5 has become apparent in Japan.
In addition, desertification is progressing due to climate change and overgrazing of livestock in arid regions. Therefore, in the western part of the desert area in East Asia, yellow sand flies along with a westerly wind. On the continents of China and South Korea, the arrival of yellow sand at a level that hinders daily life such as poor visibility is observed every year. In Japan as well, the scattering of yellow sand is a problem, as is the case with pollen and PM2.5, and weather forecasts call for forecasts and warnings. These are considered to be exacerbating molecules in allergic patients, and it is also important to deal with Kosa-induced inflammation.
一方、屋外由来の大気汚染物質とは別に、空気の汚染物質を考える上で忘れてならないのが、室内環境の微生物汚染由来の浮遊物質である。ダニやカビに代表される微生物汚染は、総称してハウスダストと呼ばれることが多いが、これには、居住者個人が対応しなければならないという特徴がある。花粉や、ＰＭ２．５、黄砂などの屋外由来の大気汚染物質は屋内で増殖することはないが、ダニやカビは生物であるため、放置すると住居内で増加の一途をたどる可能性がある。特にダニは、昨今の高断熱・高気密住宅の登場により、一年中生息することが可能となっただけでなく、人の生活と深く関係している。ダニの餌はフケ、垢、カビなどであり、生息場所は、布団などの寝具、カーペットなどである。つまり、「人の生活空間」は「ダニの生息場所」と同じといえる。ダニの餌の最大の供給源はヒトであるため、放置しておくとヒトの日常生活の場でダニは爆発的に増加するといわれている。ダニの虫体や糞は、乾燥と物理的な破砕により微粒子化され、ヒトの日常行動の中で大気中に浮遊する。 On the other hand, in addition to air pollutants derived from the outdoors, what is important to consider when considering air pollutants are suspended substances derived from microbial pollution in the indoor environment. Microbial contamination represented by mites and molds is often generically called house dust, which has the characteristic that each resident must deal with it. Outdoor pollutants such as pollen and PM2.5 and yellow sand do not multiply indoors, but mites and molds are living organisms, so if left unattended, there is a possibility that they will continue to increase in the home. In particular, mites are not only able to live all year round due to the advent of highly insulated and airtight houses these days, but they are also closely related to human life. The baits of mites are dandruff, dirt, mold, etc., and their habitat is bedding such as futons and carpets. In other words, it can be said that the "human living space" is the same as the "mite habitat". Since humans are the largest source of tick food, it is said that if left unattended, ticks will explosively increase in human daily life. The mite bodies and feces are mimicked by drying and physical crushing, and are suspended in the air during human daily activities.
大気汚染物質の有害性から、それらの生体への曝露を防止することが試みられている。具体的には、空気清浄機の使用やマスクの着用である。 Due to the harmfulness of air pollutants, attempts have been made to prevent their exposure to living organisms. Specifically, use of an air purifier and wearing of a mask.
室内のような閉鎖系空間では、空気清浄機の稼働が考えられるが、家庭内で空気清浄機を稼働させても、床掃除をしないと微細な埃で床が白くなる、あるいは、空気清浄機の上部に埃が積もることからも、不十分であることが示唆される。実際に、閉鎖空間内の空気清浄度を維持するには、クリーンルームのような大掛かりな装置が必要不可欠である。 It is possible to operate the air purifier in a closed space such as indoors, but even if the air purifier is operated at home, the floor will become white with fine dust if the floor is not cleaned, or the air purifier Insufficient dust is also suggested from the upper part of the area. In fact, a large-scale device such as a clean room is indispensable for maintaining the air cleanliness in the enclosed space.
屋外のような開放空間では、マスク着用者を街でよく見かける。マスク素材の微粒子通過阻止性がフィルターとしての効果を発揮すると期待されるようであるが、実際は、マスク素材の阻止性能が十分発揮されるためには、医療用のＮ９５マスクのように、マスクが顔表面に完全に密着し、隙間があってはならない。吸気時にはマスクの体内側が陰圧になるため、マスクと顔の間に隙間があると、空気は抵抗の高いマスク面よりも、抵抗のない隙間から入り込むため、マスクの阻止機能は十分機能しない。また、Ｎ９５マスク装着時の呼吸は呼吸器官への負荷が高く息苦しいため、長時間の装着は不向きである。 In open spaces such as outdoors, mask wearers are often seen in town. It seems that the particulate material blocking property of the mask material is expected to exert an effect as a filter, but in actuality, in order to sufficiently exhibit the blocking performance of the mask material, a mask like a medical N95 mask is required. Fully adhere to the surface of the face with no gaps. Since there is a negative pressure inside the mask at the time of inhalation, if there is a gap between the mask and the face, the air enters through the gap without resistance rather than the mask surface with high resistance, and the blocking function of the mask does not function sufficiently. In addition, when wearing the N95 mask, breathing has a heavy load on the respiratory organs and makes it difficult to breathe, so it is not suitable for wearing for a long time.
以上のことから、大気汚染物質をフィルター除去するだけで生体への曝露を予防するには限界があることが示唆される。
このように、生体への大気汚染物質の曝露が不可避であることを前提とした大気汚染物質の有害性から生体を守る方法として、生体に抗炎症作用を導入することが有効な手段と考えられる。
From the above, it is suggested that there is a limit in preventing exposure to living organisms by only removing air pollutants by filtering.
Thus, as a method of protecting the body from the harmful effects of air pollutants on the premise that exposure of air pollutants to the body is unavoidable, introducing an anti-inflammatory action into the body is considered to be an effective means. ..
屋外由来の大気汚染物質による健康被害を受ける対象者は、現在、ＰＭ２．５等の飛散時に体調を悪化させるわが国の国民は当然のこと、工業化の急速な進展に環境対策が追いつかない中国、インド、ベトナム等の国々、およびその近隣諸国の国民も考えられる。わが国のみならず上記の多くの国々で健康被害を訴える人々にとっても、健康回復に貢献することが期待される。
屋内の大気汚染物質であるハウスダストによる健康被害を受ける対象者は、高気密高断熱住宅が増加している先進国および急速に都市化が発展している新興国の人々である。
The target people who suffer from health hazards from air pollutants originating from the outside are now sick when PM2.5 etc. are scattered. It is natural for Japanese citizens that environmental measures cannot keep up with the rapid progress of industrialization in China and India. People of countries such as Vietnam, Vietnam, and neighboring countries are also conceivable. It is expected that it will contribute to the recovery of health not only in Japan but also in many of the above-mentioned countries, who complain of health damage.
Targets of health hazards from house dust, an indoor air pollutant, are people in developed countries with increasing numbers of highly airtight and well-insulated houses and emerging countries with rapid urbanization.
なお、ジャバラの果汁や果皮には、抗花粉症作用があることが知られているが（例えば、特許文献１など参照）、浮遊粒子状物質誘発性炎症抑制については報告されていない。また、これまでの抗炎症研究では、リポ多糖（ＬＰＳ）を炎症誘発剤として使用していたが（例えば、非特許文献１など参照）、本発明者らの検討によれば、後述するように、ＬＰＳと浮遊粒子状物質とでは、組成が大きく異なる上、炎症誘発機序も異なることが示唆された。
従って、従来の研究結果からは、ナリンゲニンが浮遊粒子状物質誘発性炎症抑制作用を奏することは全く示唆されず、かつ、自明と認識され得るような事実でもなかった。
It is known that the fruit juice and skin of bellows have an anti-hay fever effect (see, for example, Patent Document 1), but airborne particulate matter-induced inflammation suppression has not been reported. Further, in the previous anti-inflammatory research, lipopolysaccharide (LPS) was used as an inflammation-inducing agent (see, for example, Non-Patent Document 1). However, according to the study by the present inventors, as described below. It was suggested that LPS and suspended particulate matter differ greatly in composition and also differ in proinflammatory mechanism.
Therefore, from the results of the conventional studies, it was not suggested at all that naringenin has an action of suppressing airborne particulate matter-induced inflammation, nor was it a fact that could be recognized as obvious.
上述の現状に鑑み、本発明は、ＰＭ２．５や黄砂などの浮遊粒子状物質によって誘発される炎症を抑制するのに有効な浮遊粒子状物質誘発性炎症抑制剤及び浮遊粒子状物質誘発性炎症抑制用食品を提供することを目的としている。 In view of the above-mentioned present situation, the present invention provides a suspended particulate matter-induced inflammation inhibitor effective for suppressing inflammation induced by suspended particulate matter such as PM2.5 and yellow sand, and suspended particulate matter-induced inflammation. The purpose is to provide food for suppression.
上記課題を解決するため、本発明は下記構成を備える。
すなわち、本発明にかかる浮遊粒子状物質誘発性炎症抑制剤は、ナリンゲニン及び／又はナリルチンを有効成分とする。
本発明にかかる浮遊粒子状物質誘発性炎症抑制剤は、また、ジャバラ果皮成分を有効成分とする。
本発明にかかる浮遊粒子状物質誘発性炎症抑制用食品は、ナリンゲニン及び／又はナリルチンを有効成分とする。
本発明にかかる浮遊粒子状物質誘発性炎症抑制用食品は、また、ジャバラ果皮成分を有効成分とする。
In order to solve the above problems, the present invention has the following configurations.
That is, the suspended particulate matter-induced inflammation suppressant according to the present invention contains naringenin and/or nariltin as active ingredients.
The suspended particulate matter-induced inflammation suppressant of the present invention also comprises a bellows skin component as an active ingredient.
The foodstuff for suppressing airborne particulate matter-induced inflammation according to the present invention contains naringenin and/or nariltin as active ingredients.
The food for suppressing airborne particulate matter-induced inflammation according to the present invention also comprises a bellows skin component as an active ingredient.
本発明にかかる浮遊粒子状物質誘発性炎症抑制剤及び浮遊粒子状物質誘発性炎症抑制用食品によれば、ＰＭ２．５に代表される大気汚染物質によって誘発される炎症を抑制することができる。 According to the suspended particulate matter-induced inflammation inhibitor and the suspended particulate matter-induced inflammation inhibitory food of the present invention, inflammation induced by air pollutants represented by PM2.5 can be suppressed.
以下、本発明にかかる浮遊粒子状物質誘発性炎症抑制剤及び浮遊粒子状物質誘発性炎症抑制用食品の好ましい実施形態について、詳しく説明するが、本発明の範囲はこれらの説明に拘束されることはなく、以下の例示以外についても、本発明の趣旨を損なわない範囲で適宜変更実施し得る。 Hereinafter, preferred embodiments of the suspended particulate matter-induced inflammation inhibitor and the suspended particulate matter-induced inflammation-suppressing food according to the present invention will be described in detail, but the scope of the present invention is restricted to these explanations. However, other than the following examples, appropriate modifications may be made without departing from the spirit of the present invention.
「浮遊粒子状物質」とは、一般に、大気中に浮遊する粒子状物質のうち、粒径が１０μｍ以下のものと定義されている。このうち、直径２．５μｍ以下のものは、「ＰＭ２．５」と呼ばれている。
浮遊粒子状物質には、工場などから排出される煤塵や粉塵、ディーゼル車の排出ガス中に含まれる黒煙（ディーゼル排気微粒子：ＤＰＥ）など人為的発生源によるものや、黄砂などに代表される土壌の飛散や、ダニやカビなどの微生物あるいはその死骸など自然発生源によるものなど、実に様々である。また、生成機構の違いから分類すると、発生源から直接粒子として大気中に排出される一次粒子と、ガス状物質として排出されたものが大気中で光化学反応などにより粒子に変化した二次粒子に分類される。具体的事例としては、ＰＭ２．５、黄砂、大気粉塵、化石燃料の燃焼物、ＤＰＥ、ハウスダスト、ダニ虫体および糞の分解物、カビの分解物などがこれに当たる。
本発明にかかる浮遊粒子状物質誘発性炎症抑制剤及び浮遊粒子状物質誘発性炎症抑制用食品は、上記の如き浮遊粒子状物質によって誘発される炎症を抑制するものである。
The term “suspended particulate matter” is generally defined as a particulate matter suspended in the atmosphere and having a particle size of 10 μm or less. Among them, those having a diameter of 2.5 μm or less are called “PM2.5”.
The suspended particulate matter is represented by soot and dust emitted from factories and the like, artificial sources such as black smoke (diesel exhaust particulate: DPE) contained in the exhaust gas of diesel vehicles, and yellow sand. There are various things such as scattering of soil and natural sources such as microorganisms such as mites and molds or dead bodies of them. In addition, when classifying according to the difference in the generation mechanism, primary particles emitted into the atmosphere as particles directly from the generation source and secondary particles that have been emitted as gaseous substances into particles due to photochemical reactions in the atmosphere. being classified. Specific examples thereof include PM2.5, yellow sand, atmospheric dust, combustion products of fossil fuels, DPE, house dust, decomposed products of mite bodies and feces, decomposed products of mold, and the like.
The suspended particulate matter-induced inflammation inhibitor and the suspended particulate matter-induced inflammation inhibitory food according to the present invention suppress the inflammation induced by the suspended particulate matter as described above.
ナリルチンは、フラボノイドの一種であり、アグリコンがナリンゲニンであり、糖部分がβ−ルチノースであるフラバノン配糖体である。
本発明者の検討によれば、ナリンゲニンは浮遊粒子状物質誘発性炎症抑制作用を発揮する。そして、ナリルチンは、ナリンゲニンに脱グリコシル化された後、結腸細胞に吸収されるので、ナリンゲニンを生体内での活性体とするプロドラッグのように機能するものと考えられる。
従って、本発明の浮遊粒子状物質誘発性炎症抑制剤及び浮遊粒子状物質誘発性炎症抑制用食品は、活性本体であるナリンゲニン、及び／又は、生体内でナリンゲニンに変換されるナリルチンを有効成分とするものである。
Nariltin is a type of flavonoid, and is a flavanone glycoside whose aglycone is naringenin and whose sugar moiety is β-rutinose.
According to the study of the present inventor, naringenin exerts an airborne particulate matter-induced inflammation suppressing action. Then, since naliltin is deglycosylated to naringenin and then absorbed into colon cells, it is considered that it functions like a prodrug having naringenin as an active substance in vivo.
Therefore, the suspended particulate matter-induced inflammation inhibitor and the suspended particulate matter-induced inflammation-suppressed food of the present invention contain naringenin, which is an active substance, and/or nariltin, which is converted into naringenin in vivo, as an active ingredient. To do.
また、ナリルチンは、ユズ、カボス、グレープフルーツ、ミカンなど柑橘類全般に含有され、特に果皮に多く含有されている。そして、柑橘類の中では、とりわけジャバラに多く含まれる。
従って、本発明の浮遊粒子状物質誘発性炎症抑制剤及び浮遊粒子状物質誘発性炎症抑制用食品は、また、ジャバラ果皮成分を有効成分とするものである。
Further, nariltin is contained in all citrus fruits such as yuzu, kabos, grapefruit, and mandarin orange, and is particularly contained in the pericarp. And among citrus fruits, it is especially contained in bellows.
Therefore, the suspended particulate matter-induced inflammation inhibitor and the suspended particulate matter-induced inflammation inhibitory food of the present invention also contain the bellows peel component as an active ingredient.
ジャバラ果皮は、ジャバラ果実から手で剥いたもの、公知の自動皮むき機により剥いたもの、果汁圧搾機により果汁を搾った後に残る残渣などが使用できるが、手間を考えると果汁圧搾機の残渣が好ましい。
上記において、ジャバラ果実は、特に限定することなく使用できるが、なかでも、単位重量当たりのナリルチンの含有量が多いことから、摘果された果実や果皮が黄変する以前の未成熟段階の果実が好ましい。未成熟段階の果実は、具体的には、着果から３月〜４月後に摘果した果実が好ましい。なお、ジャバラは、一般的に６月ごろに着果することから、９月〜１０月ごろに収穫された果実が好ましい。
As for the bellows peel, those peeled by hand from the bellows fruit, peeled by a known automatic peeling machine, residues left after squeezing the juice with a juice pressing machine, etc. can be used, but considering the trouble, the residue of the juice pressing machine can be used. Is preferred.
In the above, the bellows fruit can be used without particular limitation, but above all, since the content of nariltin per unit weight is high, the fruit of the immature stage before yellowing of the picked fruit or the peel is yellow. preferable. Specifically, the fruit in the immature stage is preferably a fruit that has been picked 3 to 4 months after the fruit has set. Since the bellows generally reach fruit around June, fruits harvested around September to October are preferable.
ジャバラ果皮は、例えば、生の状態で砂糖などととともにジャムやジュースなどに加工してもよいが、保存性をより高めるため、乾燥させた乾燥果皮が好ましい。乾燥果皮としては、一般的な方法、すなわち、果皮果実をそのまま又は細切したのち、日陰、陽干し、若しくは乾燥機によって乾燥する熱乾燥法、フリーズドライ法、スプレードライ法又はこれらの方法を組み合わせて製造したものが、例示できる。 The bellows peel may be processed into jam, juice, etc. together with sugar and the like in a raw state, but a dried and dried peel is preferable in order to further improve the preservability. As a dried pericarp, a general method, that is, a pericarp fruit as it is or after being shredded, dried in a shade, sun-dried, or dried by a dryer, a heat drying method, a freeze drying method, a spray drying method or a combination thereof Those manufactured by
なお、フリーズドライ法で乾燥したのち、熱乾燥法によって乾燥することによって製造したものが好ましく、８０℃で熱乾燥したものがより好ましい。このようにして製造したじゃばら乾燥果皮は、高いナリルチン濃度を維持したまま、乾燥果皮に含まれるリモネンを蒸発させ、その苦味を抑えることができる。 In addition, it is preferable that the product is produced by drying by a freeze-drying method and then by a heat-drying method, and more preferably by heat-drying at 80° C. In the dried bellows peel thus produced, the limonene contained in the dried peel can be evaporated and the bitterness thereof can be suppressed while maintaining a high concentration of nariltin.
なお、この乾燥果皮はそのままでも使用できるが、食べやすさなどを考慮して、一般的な方法、すなわちボールミル等により粉末状に加工してから使用するほうがより好ましい。 The dried peel can be used as it is, but in consideration of ease of eating and the like, it is more preferable to use the dried peel after processing it into a powder form by a ball mill or the like before use.
粉末状に加工した乾燥果皮は、それ単独でも使用できるが、フリカケ、お茶漬けのもと等と混ぜて使用することにより、又は還元麦芽糖等の糖類と混ぜて顆粒状にすることにより、食味を向上させることができる。また、顆粒状に加工した乾燥果皮は、腸溶カプセル等のカプセルに収容してカプセル剤としてもよく、ステアリン酸マグネシウム等の公知の添加剤、賦形等と混合して、公知の製剤技術により錠剤としてもよい。 The dried pericarp processed into powder can be used alone, but it can be used by mixing it with furikake, the source of ochazuke, etc., or by mixing it with sugars such as reduced maltose to form granules to improve the taste. Can be made. Further, the dried pericarp processed into a granular form may be contained in a capsule such as an enteric-coated capsule to form a capsule, which may be mixed with a known additive such as magnesium stearate, a shaping agent, or the like by a known formulation technique. It may be a tablet.
本発明にかかる浮遊粒子状物質誘発性炎症抑制剤及び浮遊粒子状物質誘発性炎症抑制用食品の生体への投与形態として、経口摂取による消化管を介した吸収、あるいは、塗布・噴霧による上皮細胞層を介した吸収などが考えられるが、この限りではない。 As a form of administration of the suspended particulate matter-induced inflammation inhibitor and the suspended particulate matter-induced inflammation suppressant according to the present invention to the living body, absorption through the digestive tract by oral ingestion, or epithelial cells by application/spraying Absorption through layers may be considered, but not limited to this.
本発明にかかる浮遊粒子状物質誘発性炎症抑制用食品としては、ヒト用の一般食品、保健機能食品（特定保健用食品、栄養機能食品）、健康食品、栄養補助食品などが含まれる。食品として、具体的には、かまぼこ、ちくわ、はんぺん等の水産加工製品、ソーセージ、ハム、ウインナー等の食肉加工製品、豆腐や油揚げ、コンニャク等の農産加工製品、菓子類、調味料、香辛料や、各種野菜・果実の缶詰・瓶詰等の加工野菜・果実類、チーズ、バター、ヨーグルト等の乳製品、果実ジュース、野菜ジュース、乳清飲料、清涼飲料、健康茶、薬用酒類等の飲料、その他、栄養補強（栄養補助）等を目的とする健康維持のための錠剤、飲料、顆粒等の健康志向の飲食品類などが例示できるが、これらに限定されるものではない。 The food for suppressing airborne particulate matter-induced inflammation according to the present invention includes general foods for humans, foods with health claims (foods for specified health use, foods with nutritional function), health foods, dietary supplements, and the like. As food, specifically, fish-processed products such as kamaboko, chikuwa, and hanpen, meat-processed products such as sausage, ham, and wiener, tofu and fried foods, agricultural-processed products such as konjac, confectionery, seasonings, spices, and Processed vegetables and fruits such as canned and bottled vegetables and fruits, dairy products such as cheese, butter, yogurt, fruit juice, vegetable juice, whey beverages, soft drinks, health tea, drinks such as medicinal liquor, etc., Examples thereof include health-oriented foods and drinks such as tablets, beverages, and granules for the purpose of maintaining health for the purpose of nutritional supplementation (nutrition support), but are not limited thereto.
以下、本発明にかかる浮遊粒子状物質誘発性炎症抑制剤及び浮遊粒子状物質誘発性炎症抑制用食品の効果を実証する実験データを示す。 Hereinafter, experimental data demonstrating the effects of the airborne particulate matter-induced inflammation suppressant and the airborne particulate matter-induced inflammation suppressive food according to the present invention will be shown.
〔実験１〕
＜実験方法＞
ジャバラ果皮中の主要成分であるフラバノン配糖体ナリルチンのアグリコンであるナリンゲニンはＫＬＴ Ｌａｂｏｒａｔｏｒｙより購入し、ジメチルスルホキシドに溶解し試料とした。マウス・マクロファージ様細胞株ＲＡＷ２６４細胞は理化学研究所バイオリソースセンターから入手し、１０％ウシ胎児血清および１００ｕｎｉｔｓ／ｍｌのペニシリンと１００μｇ／ｍｌのストレプトマイシンを含むＤ−ＭＥＭ（以下、培養液と略す）で培養したものを用いた。リポ多糖（ＬＰＳ）は、Ｓｉｇｍａ−Ａｌｄｒｉｃｈより購入した。都市大気粉塵（ＮＩＥＳ ＣＲＭ Ｎｏ．２８）は、国立環境研究所から入手した。
９６ウェルプレートに細胞を１ウェル当たり１．０×１０5個播種し、ナリンゲニンを含む培養液（終濃度：０、５０、１００、２００μＭ）を添加した後、２時間後にＬＰＳ（終濃度１μｇ／ｍｌ）もしくは都市大気粉塵（終濃度：０、１００、２００、３００、４００、５００μｇ／ｍｌ）を含む培養液を添加し、３７℃・５％二酸化炭素雰囲気下の培養装置内で２４時間培養し、培養上清を回収した。回収した培養上清は１５，０００ｒｐｍで１０分間遠心分離し、得られた上清中の一酸化窒素（ＮＯ）はＰｒｏｍｅｇａ社製Ｇｒｉｅｓｓ ｒｅａｇｅｎｔ ｓｙｓｔｅｍを、ＩＬ−６、ＭＣＰ−１、ＴＮＦ−αの濃度はＢｉｏＬｅｇｅｎｄ社製ＥＬＩＳＡキットを用いて、それぞれ定量した。
[Experiment 1]
<Experimental method>
Naringenin, which is an aglycone of the flavanone glycoside nariltin, which is a main component in the bellows skin, was purchased from KLT Laboratory and dissolved in dimethyl sulfoxide to prepare a sample. Mouse macrophage-like cell line RAW264 cells were obtained from RIKEN BioResource Center and cultured in D-MEM (hereinafter abbreviated as culture medium) containing 10% fetal bovine serum, 100 units/ml penicillin and 100 μg/ml streptomycin. What was done was used. Lipopolysaccharide (LPS) was purchased from Sigma-Aldrich. Urban air dust (NIES CRM No. 28) was obtained from the National Institute for Environmental Studies.
1.0×10 5 cells were seeded per well in a 96-well plate, and a culture solution containing naringenin (final concentration: 0, 50, 100, 200 μM) was added, and 2 hours later, LPS (final concentration 1 μg/ ml) or urban air dust (final concentration: 0, 100, 200, 300, 400, 500 μg/ml) was added and cultured for 24 hours in a culture device at 37° C. and 5% carbon dioxide atmosphere. The culture supernatant was collected. The collected culture supernatant was centrifuged at 15,000 rpm for 10 minutes, and the nitric oxide (NO) in the obtained supernatant was measured by using a Griess reagent system manufactured by Promega Co. of IL-6, MCP-1, and TNF-α. The concentration was quantified using an ELISA kit manufactured by BioLegend.
＜これまでの抗炎症研究との相違点＞
これまでの研究では、リポ多糖（ＬＰＳ）を炎症誘導剤として使用していた。ＬＰＳはグラム陰性菌細胞の細胞壁外膜の構成成分であり、脂質と多糖から構成された糖脂質である。一方、本実験で用いた大気汚染物質は、国立環境研究所から入手した都市大気粉塵ＮＩＥＳ ＣＲＭ Ｎｏ．２８（１９９６年から２００５年の１０年間に北京市中心部のビルの換気フィルターに捕集された大気粉塵で粒径１０μｍ以下が９９％、２μｍ以下が４０％以上）である。その組成分析は、Ａｎａｌ Ｂｉｏａｎａｌ Ｃｈｅｍ（２００８）３９１：１９９７−２００３に示されているように、明らかにＬＰＳとは異なる。実験に用いた都市大気粉塵の組成をみると、ケイ素（Ｓｉ）が１４．９％、硫黄（Ｓ）が３．９１％と、多く含まれることが特徴的である。ケイ素（Ｓｉ）の存在は黄砂のような土埃成分が多く含まれていること、硫黄（Ｓ）の存在は化石燃料の燃焼由来の化学物質が多く含まれることが推察される。化石燃料の燃焼物が多く含まれるということは、化石燃料由来の芳香性化合物や窒素酸化物も同時に多く含まれることが推察される。
ＬＰＳと都市大気粉塵の炎症誘導作用を、一酸化窒素（ＮＯ）、ＩＬ−６、ＭＣＰ−１、ＴＮＦ−αを指標に比較した。ＬＰＳ濃度は多くの論文で使用される１μｇ／ｍｌとし、マウス・マクロファージ様細胞株ＲＡＷ２６４細胞を刺激した。
図１に示す通り、ＬＰＳ刺激２４時間後のＮＯ濃度は１１．６μＭであったが、都市大気粉塵は添加量１００〜５００μｇ／ｍｌで４．３２〜７．０３μＭであり、ＬＰＳ添加量１μｇ／ｍｌよりも低値を示した。一方、刺激２４時間後のＩＬ−６、ＭＣＰ−１、ＴＮＦ−α濃度では、都市大気粉塵添加１００μｇ／ｍｌのＩＬ−６濃度を除いて、都市大気粉塵添加系は、ＬＰＳ添加量１μｇ／ｍｌでの値を大きく上回り、ＬＰＳ添加時の５倍以上の値を示した。都市大気粉塵は、種々の成分の混合物であることから、炎症誘導物質も種々存在することが予想され、この結果は妥当と考えられる。
以上のことから、ＬＰＳと都市大気粉塵は、ともに炎症誘導作用を示すが、組成は大きく異なるだけでなく、炎症誘導機序は異なることが示唆された。炎症誘導作用機序が異なる以上、ＬＰＳ添加系で観察された抗炎症作用が、都市大気粉塵添加系で同様に発揮される保証はなく、実測して評価する必要があると考えられる。
<Differences from previous anti-inflammatory research>
Previous studies have used lipopolysaccharide (LPS) as an inflammation inducer. LPS is a component of the cell wall outer membrane of Gram-negative bacterial cells, and is a glycolipid composed of a lipid and a polysaccharide. On the other hand, the air pollutants used in this experiment were urban air dust NIES CRM No. obtained from the National Institute for Environmental Studies. 28 (99% of particles with a particle size of 10 μm or less are 99% and particles of air with a particle size of 10 μm or less are 40% or more of atmospheric dust collected in a ventilation filter of a building in the central part of Beijing from 1996 to 2005). Its compositional analysis is clearly different from LPS, as shown in Anal Bioanal Chem (2008) 391: 1997-2003. Looking at the composition of the urban air dust used in the experiment, it is characteristic that silicon (Si) is contained in a large amount of 14.9% and sulfur (S) is contained in a large amount of 3.91%. It is inferred that the presence of silicon (Si) contains a large amount of dust components such as yellow sand, and the presence of sulfur (S) contains a large amount of chemical substances derived from combustion of fossil fuels. The fact that a large amount of fossil fuel combustibles is included suggests that a large amount of fossil fuel-derived aromatic compounds and nitrogen oxides are also contained.
The inflammation-inducing effects of LPS and urban air dust were compared using nitric oxide (NO), IL-6, MCP-1, and TNF-α as indicators. The LPS concentration was 1 μg/ml used in many papers, and the mouse macrophage-like cell line RAW264 cells were stimulated.
As shown in FIG. 1, the NO concentration after 24 hours of LPS stimulation was 11.6 μM, but the amount of urban air dust was 4.32 to 7.03 μM at the addition amount of 100 to 500 μg/ml, and the addition amount of LPS was 1 μg/ml. The value was lower than that of ml. On the other hand, in the IL-6, MCP-1, and TNF-α concentrations 24 hours after stimulation, the LPS addition amount was 1 μg/ml in the urban air dust addition system except for the IL-6 concentration of 100 μg/ml in the addition of city air dust. The value was significantly higher than the value in (1), and was 5 times or more the value when LPS was added. Since urban air dust is a mixture of various components, it is expected that various inflammation inducing substances also exist, and this result is considered to be appropriate.
From the above, it was suggested that LPS and urban air dust both have an inflammation-inducing action, but not only the compositions are significantly different, but the inflammation-inducing mechanism is also different. As long as the mechanism of action of inducing inflammation is different, there is no guarantee that the anti-inflammatory action observed in the LPS-added system will be similarly exerted in the urban air-dust added system, and it is considered necessary to actually measure and evaluate.
＜ナリンゲニンによる都市大気粉塵誘導性炎症反応の抑制効果＞
図１の通り、ナリンゲニンは、都市大気粉塵添加（添加量１００〜５００μｇ／ｍｌ）によるＮＯ、ＩＬ−６、ＭＣＰ−１の産生誘導を添加量依存的に抑制した。これより、ナリンゲニンには、都市大気粉塵による炎症誘導を抑制する作用があることが示唆された。
但し、ＴＮＦ−αに関しては、抑制効果はほとんど認められず、この点はＬＰＳ刺激時の結果（非特許文献１参照）と異なった。これは、ＬＰＳと都市大気粉塵の炎症誘導機序の違いによることを意味する可能性もある。
<Inhibitory effect of naringenin on urban air dust-induced inflammatory response>
As shown in FIG. 1, naringenin suppressed the production induction of NO, IL-6, and MCP-1 by addition of urban air dust (addition amount of 100 to 500 μg/ml) in an addition amount-dependent manner. From this, it was suggested that naringenin has an action of suppressing inflammation induction by urban air dust.
However, almost no suppressive effect was observed for TNF-α, which was different from the result of LPS stimulation (see Non-Patent Document 1). This may mean that LPS and urban air dust are different in the mechanism of inducing inflammation.
〔実験２〕
国立環境研究所から入手したゴビ黄砂ＮＩＥＳ ＣＲＭ Ｎｏ．３０（ゴビ砂漠南西部の黄砂発生源地域で採取した黄砂を含む表層土をもとに、風工学的手法で分離捕集した砂塵系ダストで、２０１１年５月の黄砂発生シーズンに北緯４４度、東経１０９度付近の４地点で、１２００ｋｇの黄砂を含む表層土を採取し、Ｓａｉｎｓｈａｎｄ気象観測センター内の管理施設に設置したダスト発生チャンバーを用い、その表層土から砂塵を発生させたもので、サイクロン型分粒器（分離限界径１０μｍ）を用いて、微小ダストのみを分離捕集し、約２ｋｇの二次原料を得た。その後国立環境研究所において、精製分離と回転ブレンダーによる均質化を行い１．２ｋｇの最終原料を得、60Ｃｏ照射（２５ｋＧｙ）による滅菌処理をしたもの）を用いた。その組成は、Ａｎａｌｙｔｉｃａｌ Ｍｅｔｈｏｄｓ，２０１３，５，４０８８−４０９５に記載されるように、ケイ素（Ｓｉ）が２４．１％を占めるが硫黄（Ｓ）は検出限界以下と推定される。
黄砂濃度を１００μｇ／ｍｌの条件で、ＬＰＳと都市大気粉塵の実験（実験１）と同様に、マウス・マクロファージ細胞株ＲＡＷ２６４細胞に添加し、ナリンゲニンの効果を評価した。結果を図２に示す。
ナリンゲニンは、都市大気粉塵添加時と同様、ＮＯ産生とＩＬ−６産生には、濃度依存的に効果的な阻害効果を示したが、ＭＣＰ−１およびＴＮＦ−αに対しては、阻害効果は緩慢であった。黄砂の炎症誘導作用とナリンゲニンによる阻害作用は、ＬＰＳとは異なるため、従来のＬＰＳ刺激におけるナリンゲニンの抗炎症作用が黄砂刺激においても同様に発揮される保証はなく、実測して評価する必要があると考えられる。
[Experiment 2]
Gobi Kosa NIES CRM No. obtained from National Institute for Environmental Studies. 30 (Dust-based dust separated and collected by wind engineering method based on the surface soil containing yellow sand collected in the yellow sand source area in the southwestern part of the Gobi Desert. , Collected surface soil containing 1200 kg of yellow sand at 4 points near 109 degrees east longitude, and generated dust from the surface soil using the dust generation chamber installed in the management facility in the Sainshand meteorological observation center. Only a small amount of dust was separated and collected using a cyclone type particle sizer (separation limit diameter: 10 μm) to obtain about 2 kg of secondary raw material, which was then purified and separated at the National Institute for Environmental Studies and homogenized by a rotary blender. Then, 1.2 kg of the final raw material was obtained, and 60 Co irradiation (25 kGy) sterilized) was used. As described in Analytical Methods, 2013, 5, 4088-4095, its composition is estimated that silicon (Si) accounts for 24.1% but sulfur (S) is below the detection limit.
The effect of naringenin was evaluated by adding to the mouse macrophage cell line RAW264 cells in the same manner as in the experiment of LPS and urban air dust (Experiment 1) under the condition of yellow sand concentration of 100 μg/ml. The results are shown in Figure 2.
Naringenin showed an effective inhibitory effect on NO production and IL-6 production in a concentration-dependent manner, as in the case of adding urban air dust, but an inhibitory effect on MCP-1 and TNF-α. It was slow. Since the inflammation-inducing action of yellow sand and the inhibitory action of naringenin are different from those of LPS, there is no guarantee that the anti-inflammatory action of naringenin in the conventional LPS stimulation will be similarly exhibited in the yellow sand stimulation, and it is necessary to actually measure and evaluate it. it is conceivable that.
〔実験３〕
細胞をヒト気道上皮細胞株ＢＥＡＳ−２Ｂ細胞（ＤＳファーマバイオメディカル株式会社より購入）を用い、ＢＥＧＭ培地（ＬＯＮＺＡより購入）を培養液として、ＲＡＷ２６４細胞での実験と同様に、炎症誘導刺激物質としてＬＰＳ、都市大気粉塵、黄砂を用い、ナリンゲニン（濃度：０、１００、２００μＭ）の抗炎症効果を、ＩＬ−６の産生抑制作用により評価した。結果を図３に示す。
都市大気粉塵は、ＢＥＡＳ−２Ｂ細胞へのＩＬ−６産生誘導作用は認められなかった。ＬＰＳと黄砂によるＩＬ−６の産生誘導は認められ、ナリンゲニンの添加濃度依存的に産生阻害作用が認められた。
[Experiment 3]
Human airway epithelial cell line BEAS-2B cells (purchased from DS Pharma Biomedical Co., Ltd.) were used as cells, and BEGM medium (purchased from LONZA) was used as a culture medium, as an inflammation-inducing stimulant similar to the experiment with RAW264 cells. Using LPS, urban air dust, and yellow sand, the anti-inflammatory effect of naringenin (concentration: 0, 100, 200 μM) was evaluated by the inhibitory effect on IL-6 production. Results are shown in FIG.
IL-6 production-inducing effect on BEAS-2B cells was not recognized by urban air dust. Induction of IL-6 production by LPS and yellow sand was observed, and a production inhibitory effect was observed depending on the concentration of naringenin added.
〔実験４〕
株式会社ビオスタから入手したダニ虫体抽出物を、最終濃度１００、５０、１０、５μｇ／ｍｌの条件で、ＬＰＳと都市大気粉塵の実験（実験１）と同様に、マウス・マクロファージ細胞株ＲＡＷ２６４細胞に添加し、ナリンゲニンの効果を評価した。
＜ナリンゲニンによるダニ虫体抽出物誘導性炎症反応の抑制効果＞
図４の通り、ナリンゲニンは、ダニ虫体抽出物添加（添加量５〜１００μｇ／ｍｌ）によるＮＯ、ＩＬ−６、ＭＣＰ−１の産生誘導を添加量依存的に抑制した。これより、ナリンゲニンには、ダニ虫体抽出物による炎症誘導を抑制する作用があることが示唆された。但し、ＴＮＦ−αに関しては、抑制効果はほとんど認められず、この点はＬＰＳ刺激時の結果（非特許文献１参照）と異なった。これは、ＬＰＳとダニ虫体抽出物の炎症誘導機序の違いによることを意味する可能性もある。
[Experiment 4]
The mite body extract obtained from Biosta Co., Ltd. was used under the conditions of final concentrations of 100, 50, 10, and 5 μg/ml in the same manner as in the experiment of LPS and urban air dust (Experiment 1), the mouse macrophage cell line RAW264 cells. Was added to evaluate the effect of naringenin.
<Inhibitory effect of mite body extract-induced inflammatory reaction by naringenin>
As shown in FIG. 4, naringenin suppressed the production induction of NO, IL-6, and MCP-1 by addition of a mite body extract (addition amount of 5 to 100 μg/ml) in an addition amount-dependent manner. From these results, it was suggested that naringenin has an action of suppressing inflammation induction by a mite body extract. However, almost no suppressive effect was observed for TNF-α, which was different from the result of LPS stimulation (see Non-Patent Document 1). This may mean that it is due to a difference in the mechanism of inflammation induction between LPS and mite body extract.
〔実験５〕
株式会社ビオスタから入手したダニ糞抽出物を、最終濃度１００、５０、１０、５μｇ／ｍｌの条件で、ＬＰＳと都市大気粉塵の実験（実験１）と同様に、マウス・マクロファージ細胞株ＲＡＷ２６４細胞に添加し、ナリンゲニンの効果を評価した。
＜ナリンゲニンによるダニ糞抽出物誘導性炎症反応の抑制効果＞
図５の通り、ナリンゲニンは、ダニ虫体抽出物添加（添加量５〜１００μｇ／ｍｌ）によるＮＯ、ＩＬ−６、ＭＣＰ−１の産生誘導を添加量依存的に抑制した。これより、ナリンゲニンには、ダニ虫体抽出物による炎症誘導を抑制する作用があることが示唆された。但し、ＴＮＦ−αに関しては、抑制効果はほとんど認められず、この点はＬＰＳ刺激時の結果（非特許文献１参照）と異なった。これは、ＬＰＳとダニ虫体抽出物の炎症誘導機序の違いによることを意味する可能性もある。
また、ダニ抽出物でも、虫体抽出物と糞抽出物で、炎症誘導作用とナリンゲニンによる抑制効果の度合いが異なることから、従来のＬＰＳ刺激におけるナリンゲニンの抗炎症作用がダニ刺激においても同様に発揮される保証はなく、実測して評価する必要があると考えられる。
[Experiment 5]
The mite fecal extract obtained from Biosta Co., Ltd. was applied to mouse macrophage cell line RAW264 cells under the conditions of final concentrations of 100, 50, 10 and 5 μg/ml, similarly to the experiment of LPS and urban air dust (Experiment 1). Added to evaluate the effect of naringenin.
<Inhibition effect of mite fecal extract-induced inflammatory reaction by naringenin>
As shown in FIG. 5, naringenin suppressed the production induction of NO, IL-6, and MCP-1 by addition of a mite body extract (addition amount of 5 to 100 μg/ml) in an addition amount-dependent manner. From these results, it was suggested that naringenin has an action of suppressing inflammation induction by a mite body extract. However, almost no suppressive effect was observed for TNF-α, which was different from the result of LPS stimulation (see Non-Patent Document 1). This may mean that it is due to a difference in the mechanism of inflammation induction between LPS and mite body extract.
Moreover, even in the mite extract, since the degree of the inflammation-inducing action and the inhibitory effect by naringenin are different between the insect body extract and the fecal extract, the anti-inflammatory action of naringenin in the conventional LPS stimulation is similarly exerted even in the mite stimulation. There is no guarantee that it will be done, and it is considered necessary to actually measure and evaluate.
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