WO2001007008A1 - Compositions contenant des composes phenoliques de mimosa - Google Patents
Compositions contenant des composes phenoliques de mimosa Download PDFInfo
- Publication number
- WO2001007008A1 WO2001007008A1 PCT/US2000/012518 US0012518W WO0107008A1 WO 2001007008 A1 WO2001007008 A1 WO 2001007008A1 US 0012518 W US0012518 W US 0012518W WO 0107008 A1 WO0107008 A1 WO 0107008A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- skin
- applying
- composition according
- composition
- treating
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/08—Anti-ageing preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
- A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/60—Sugars; Derivatives thereof
- A61K8/602—Glycosides, e.g. rutin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
- A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
- A61K8/9739—Bryophyta [mosses]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/74—Biological properties of particular ingredients
- A61K2800/78—Enzyme modulators, e.g. Enzyme agonists
- A61K2800/782—Enzyme inhibitors; Enzyme antagonists
Definitions
- the present invention relates to topical cosmetic or pharmaceutical compositions. More specifically, the invention relates to cosmetic compositions containing compounds obtainable from Mimosa pudica , the compositions being useful in maintaining and/or increasing collagen levels in the skin.
- Plants of the genus Mimosa are well-known and widespread throughout the tropical and subtropical regions of the world. Extracts of certain members of this genus, as well as the related genus Acacia , are known to have certain biological activities, for example, as an antispasmodic, astringent, antidiarrheal, and antirheumatic. Particularly well known in the species Mimosa tenuiflora , a shrub the bark of which has been used in the treatment of burns and the prevention of inflammation (Anton et al . , J. Ethnophar acol . 38: 153-157, 1993; FR 2710533).
- M. pudica A less well-known species of Mimosa is M. pudica .
- any proposed biological activity has been based on rooted primarily in ethnic medicine; suggested activities include a remedy for sleeplessness, spasms and convulsions of children.
- M. pudica extracts exhibit useful anti-collagenase activity, which activity is based on a different class of compounds than those identified as actives in M. tenuiflora .
- the present invention relates to topical cosmetic and pharmaceutical compositions comprising an effective amount of a biologically active phenolic compound-containing extract, or active fraction thereof, obtainable from Mimosa pudica .
- Such compositions are useful in the maintenance and enhancement of collagen levels in the skin, and as such are useful in methods of preventing or treating fine lines and wrinkles, as well as preventing or treating the loss of skin firmness or elasticity, which are associated with chrono- and photoaging.
- the composition contains at least one Mimosa pudica flavonoid, more preferably, at least C- glycosyl flavonoids, or a derivative thereof.
- a phenol- containing extract of Mimosa pudica possesses strong biological activity, with the ability to maintain or enhance the levels of collagen in skin cells. More specifically, when provided to human fibroblasts, a phenolic-containing fraction of M. pudica can increase the collagen levels in these cells by as much as 100% or more, when provided at relatively low concentration. When the active extracts are treated to remove phenolics, the extract loses its activity
- the biologically active extracts of M. pudica useful in this invention can be prepared by any means capable of extracting phenolic compounds from the plant material, using standard extraction techniques. Such extractions include, but are not limited to, ethanol, methanol, ethyl acetate, acetone, chloroform and water, or any other solvent and water. (Englert et al . , supra )
- the active phenolic fraction can be obtained from any portion of the plant, but preferably the extract is taken from the aerial portions of the plant, including leaves, twigs, stem, or bark, as well as seeds.
- pudica phenolics useful in the present invention are preferably flavonoids, such as dihydrorobinetin, fustin, fisetinedol, robinetinedol, catechin, gallocatechin, or epigallocatechin, and derivatives thereof (see, e.g., Cronje et al . , J. Chem. Soc. Perkin Trans. I: 2467-2477, or flavone aglycones, such as chysin, apigenin, luteolin, kaempferol, galangin, quercetin, rhamnetin, myricetin, gossypetin and the like.
- flavonoids such as dihydrorobinetin, fustin, fisetinedol, robinetinedol, catechin, gallocatechin, or epigallocatechin, and derivatives thereof (see, e.g., Cronje et al . , J. Chem. Soc. Perkin Trans
- the compounds are C- glycosyl flavones and aglycones thereof.
- the preferred compounds are maysin, ax-4' ' -OH-maysin, 2"-0- rhamnosylorientin, and 2" -O-rhamnosyl isoorientin and the aglycone luteolin.
- the phenolic compounds per se from whatever source they are obtainable.
- C-glycosyl flavonoids are also obtainable and have been isolated from Zea mays (Snook et al . , Photochemistry 31: 1639-1647, 1992; Snook et al., J. Agric.
- an effective amount of an extract, or an active portion thereof will depend on the purity of the source. For example, if a crude phenolic-containing extract of about 20% purity is employed, the extract will normally be used at a level of about 0.01-10% by weight of the composition. On the other hand, the higher the level of purity, the smaller the percentage required to achieve the same effect. Assuming a substantially pure phenolic extract (i.e., an extract containing at least about 90% active phenolics or flavonoids) , the concentration range will be about .001 to about 5% by weight of the composition, preferably about 0.01 to about 3%, most preferably about 0.1 to about 1%.
- the extract or substantially pure flavonoids or flavonoid aglycones can be delivered in any form appropriate for topical application.
- Such forms include solutions, colloidal dispersions, emulsions (oil-in-water or water-in-oil) , suspensions, powders, creams, lotions, gels, foams, mousses, sprays and the like.
- Methodology for formulation of different vehicle types is well known in the art, and can be found for example in Remington's The Science and Practice of Pharmacy, 19th Edition, Volume II.
- compositions of the invention are useful in the prevention or treatment of any condition in which the activity of collagenase and/or the reduction of collagen levels in the skin are a factor.
- the compositions can be used to reduce the appearance of fine lines and wrinkles on the skin, due to either chrono- or photoaging.
- the compositions are also useful in improving the firmness and elasticity of aging skin.
- the compositions also have a number of therapeutic uses. One example is in the promotion of the process of wound healing.
- the compositions can also be used in the treatment of conditions such as scleroderma, and keloids . Another use is the treatment of collagen-related conditions induced by topical and systemic drugs, e.g. corticosteroids and retinoids .
- Topical corticosteroids are widely used for the treatment of inflammatory skin disorders, but the most common adverse effect is skin atrophy due to decreased collagen synthesis, and the present compositions can be used to treat or prevent the occurrence of atrophy.
- the compositions can be applied directly to the skin in need of treatment in an amount of from about 0.1 ⁇ g/cm 2 to 2 mg/cm 2 of skin.
- For cosmetic purposes e.g., for treatment or prevention of the symptoms of chrono- or photoaging, it is preferable that application be performed from about once per week to about 4 or 5 times daily, preferably from about 3 times a week to about 3 times daily, most preferably about once or twice per day.
- the period of topical application may be over the lifetime of the user, preferably for a period of at least about one month, more preferably from about three months to about twenty years, more preferably from about six months to about ten years, more preferably still from about one year to about five years, thereby resulting in the treatment or prevention of the external signs of aging.
- therapeutic uses such as wound-healing, drug- induced skin-atrophy, keloids and other collagen-related skin conditions, it will ordinarily be necessary to apply the compositions, on an as-needed basis, for example, once or twice daily, until relief of the symptoms is achieved.
- the Mimosa pudica extract employed is a crude extract with 70% ethanol, obtained from Serdex.
- Normal human dermal fibroblasts are seeded and grown to confluence in a 96-well plate prior to being treated with M. pudica extract or fractions thereof, prepared by solvent/solvent extractions (heptane/70% ethanol, ethyl acetate/water) at various concentrations in complete medium. Media alone serves as negative control and TGF- ⁇ serves as positive control. The plates are incubated for 4 days at 37°C/5% C0 2 before the supernatants are harvested and stored at -70°C until an ELISA is performed.
- Antibodies to collagen type 1 or procollagen type 1 are used for ELISA analysis to determine collagen levels.
- the results show an increase of 100% in collagen levels using the crude extract at 50 ppm; 118%, 142%, and 166%, for more refined fractions of the extract at 50 ppm, compared with 46% increase with 5ng/ml of TGF- ⁇ . This demonstrates the potent activity of M. pudica extracts in enhancing collagen levels.
- a crude extract from the aerial parts of M. pudica is obtained by partitioning a heptane degreased 70% ethanol extract between ethyl acetate and water.
- the nature of the anti-collagenase activity is already shown to be phenolic, as shown above.
- the ethyl acetate extract is subsequently partitioned between butanol and acidified (pH5) water, the butanol residue is taken up in methanol and precipitated with ether and then undergoes a two-step fractionation procedure using preparative HPLC.
- the anti-collagenase activity is evaluated and the most active fraction selected for further refinement. Compounds found in the most active fraction are identified as maysin and ax-4"-OH maysin.
- the panelists are allowed to equilibrate for 30 minutes before commencement.
- the following measurements are obtained: Fine lines and wrinkles, using silicone replicas obtained from the outer canthus area of both sides of the face at each visit; ultrasound imaging of the outer canthus area; skin firmness using a ballistometer .
- the results indicate a 24% and 25% reduction, relative to baseline, in fine lines and skin wrinkles after 4 and 8 weeks respectively, with the extract.
- the clarified samples show a 26% and 30% reduction at 4 and 8 weeks, respectively.
- the vehicle is only 13% effective, a result possibly due to skin hydration.
- Ultrasound indicates the most dense and least areas of the skin, presumed to be associated with higher concentrations of collagen and elastin.
- An improvement in skin density is reflected as an increase in the denser areas and decrease in the thinner areas.
- the vehicle is only effective at 19% and 16%.
- thinner areas decrease by 15% and 14% with the extract, 21% and 18% with the clarified extract, and 15% and 7% with the vehicle.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Birds (AREA)
- Dermatology (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Botany (AREA)
- Biotechnology (AREA)
- Engineering & Computer Science (AREA)
- Gerontology & Geriatric Medicine (AREA)
- Medicines Containing Plant Substances (AREA)
- Cosmetics (AREA)
Abstract
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP00928906A EP1115374A1 (fr) | 1999-07-23 | 2000-05-08 | Compositions contenant des composes phenoliques de mimosa |
CA002344481A CA2344481C (fr) | 1999-07-23 | 2000-05-08 | Compositions contenant des composes phenoliques biologiquement actifs |
AU47070/00A AU757715B2 (en) | 1999-07-23 | 2000-05-08 | Compositions containing mimosa phenolic compounds |
JP2001511895A JP3626727B2 (ja) | 1999-07-23 | 2000-05-08 | ミモザ由来のフェノール化合物を含有する組成物 |
HK02100304.9A HK1038700A1 (zh) | 1999-07-23 | 2002-01-15 | 含有含羞草屬酚類化合物的組合物 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US36084499A | 1999-07-23 | 1999-07-23 | |
US09/360,844 | 1999-07-23 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2001007008A1 true WO2001007008A1 (fr) | 2001-02-01 |
Family
ID=23419627
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2000/012518 WO2001007008A1 (fr) | 1999-07-23 | 2000-05-08 | Compositions contenant des composes phenoliques de mimosa |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP1115374A1 (fr) |
HK (1) | HK1038700A1 (fr) |
WO (1) | WO2001007008A1 (fr) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003039538A1 (fr) * | 2001-11-07 | 2003-05-15 | Biotech Research Ventures Pte Ltd | Composition contenant un glycone de flavonoide et procede pour utiliser ladite composition comme antiproliferatif |
FR2835427A1 (fr) * | 2002-02-04 | 2003-08-08 | Nuxe Lab | Composition cosmetologique et/ou dermatologique a base d'extrait de barbatimao |
EP1352640A1 (fr) * | 2000-12-15 | 2003-10-15 | Kabushiki Kaisha Yakult Honsha | Compositions pouvant retarder le vieillissement de la peau |
JP2007056035A (ja) * | 2006-10-19 | 2007-03-08 | Fancl Corp | 正常ヒト表皮角化細胞の分化抑制剤 |
FR2902335A1 (fr) * | 2006-06-16 | 2007-12-21 | Nuxe Sa Lab | Utilisation d'un extrait de mimosa dans une composition cosmetique. |
WO2007144518A3 (fr) * | 2006-06-16 | 2008-03-06 | Nuxe Lab | Utilisation d'un extrait de graines de mimosa dans une composition cosmetique |
AU2006223734B2 (en) * | 2005-03-18 | 2012-03-29 | Unigen, Inc. | Composition comprising isoorientin for suppressing histamine |
CN112168815A (zh) * | 2018-08-30 | 2021-01-05 | 中国科学院分子植物科学卓越创新中心 | 黄酮碳苷单体化合物的应用 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2578422A1 (fr) * | 1985-03-05 | 1986-09-12 | Cariel Leon | Composition de traitement a usage topique externe a base de luteoline et procede de preparation |
EP0329834A2 (fr) * | 1988-01-28 | 1989-08-30 | Francisco José Izundegui MacDonnell | Composition pour la régénération et repousse des cheveux, curative et germicide pour la peau et les muqueuses |
EP0349469A1 (fr) * | 1988-06-28 | 1990-01-03 | Julio Tellez Perez | Produit pharmaceutique doté d'activité de régénération de l'épiderme basé sur le principe actif du mimosa tenuiflora et procédé d'obtention correspondant |
WO1998016188A1 (fr) * | 1996-10-13 | 1998-04-23 | Wella Aktiengesellschaft | Utilisation de cire florale dans des agents de soins capillaires liquides |
-
2000
- 2000-05-08 WO PCT/US2000/012518 patent/WO2001007008A1/fr active IP Right Grant
- 2000-05-08 EP EP00928906A patent/EP1115374A1/fr not_active Withdrawn
-
2002
- 2002-01-15 HK HK02100304.9A patent/HK1038700A1/zh unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2578422A1 (fr) * | 1985-03-05 | 1986-09-12 | Cariel Leon | Composition de traitement a usage topique externe a base de luteoline et procede de preparation |
EP0329834A2 (fr) * | 1988-01-28 | 1989-08-30 | Francisco José Izundegui MacDonnell | Composition pour la régénération et repousse des cheveux, curative et germicide pour la peau et les muqueuses |
EP0349469A1 (fr) * | 1988-06-28 | 1990-01-03 | Julio Tellez Perez | Produit pharmaceutique doté d'activité de régénération de l'épiderme basé sur le principe actif du mimosa tenuiflora et procédé d'obtention correspondant |
WO1998016188A1 (fr) * | 1996-10-13 | 1998-04-23 | Wella Aktiengesellschaft | Utilisation de cire florale dans des agents de soins capillaires liquides |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1352640A1 (fr) * | 2000-12-15 | 2003-10-15 | Kabushiki Kaisha Yakult Honsha | Compositions pouvant retarder le vieillissement de la peau |
EP1352640A4 (fr) * | 2000-12-15 | 2008-09-10 | Yakult Honsha Kk | Compositions pouvant retarder le vieillissement de la peau |
WO2003039538A1 (fr) * | 2001-11-07 | 2003-05-15 | Biotech Research Ventures Pte Ltd | Composition contenant un glycone de flavonoide et procede pour utiliser ladite composition comme antiproliferatif |
FR2835427A1 (fr) * | 2002-02-04 | 2003-08-08 | Nuxe Lab | Composition cosmetologique et/ou dermatologique a base d'extrait de barbatimao |
WO2003066013A1 (fr) * | 2002-02-04 | 2003-08-14 | Laboratoire Nuxe | Composition cosmetique et/ou dermatologique a base d'extrait de barbitamao. |
AU2006223734B2 (en) * | 2005-03-18 | 2012-03-29 | Unigen, Inc. | Composition comprising isoorientin for suppressing histamine |
FR2902335A1 (fr) * | 2006-06-16 | 2007-12-21 | Nuxe Sa Lab | Utilisation d'un extrait de mimosa dans une composition cosmetique. |
WO2007144518A3 (fr) * | 2006-06-16 | 2008-03-06 | Nuxe Lab | Utilisation d'un extrait de graines de mimosa dans une composition cosmetique |
JP2007056035A (ja) * | 2006-10-19 | 2007-03-08 | Fancl Corp | 正常ヒト表皮角化細胞の分化抑制剤 |
CN112168815A (zh) * | 2018-08-30 | 2021-01-05 | 中国科学院分子植物科学卓越创新中心 | 黄酮碳苷单体化合物的应用 |
Also Published As
Publication number | Publication date |
---|---|
HK1038700A1 (zh) | 2002-03-28 |
EP1115374A1 (fr) | 2001-07-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6290993B1 (en) | Compositions containing mimosa phenolic compounds | |
KR20090057971A (ko) | 멘얀테스 트리폴리아타 잎 추출물을 포함하는 항-노화 조성물 및 그의 사용 방법 | |
ES2567131T3 (es) | Extracto de Vanilla planifolia, procedimiento para su obtención, y composición cosmética o dermatológica que locontiene | |
JP2004517836A (ja) | 植物アルガニア・スピノーザの葉抽出物を含有する化粧品および/または皮膚薬調製物 | |
US9370541B2 (en) | Extract of the above-ground portions of gynandropsis gynandra or cleome gynandra, and cosmetic, dermatological or pharmaceutical compositions including same | |
KR20100042279A (ko) | Age 형성의 억제 | |
CN111712305B (zh) | 木棉树花提取物,以及含有其的化妆品、药物或皮肤病学组合物 | |
JPH10279491A (ja) | インターロイキン4産生抑制剤 | |
RU2571690C2 (ru) | Композиции, содержащие павловнин и/или экстракты павловнии, и их использование | |
JP2008525462A (ja) | しわの外観を減少させるための方法および組成物 | |
JP2003002819A (ja) | 皮膚組成物 | |
KR101837446B1 (ko) | 알파-망고스틴, 베타-망고스틴, 감마-망고스틴 또는 가르탄닌 화합물을 유효성분으로 함유하는 피부 주름 개선 또는 피부 보습용 조성물 | |
WO2001007008A1 (fr) | Compositions contenant des composes phenoliques de mimosa | |
KR20150003193A (ko) | 화장품 및 제약 조성물에 플라보노이드를 포함하는 엠벨리아 콘신나 추출물 | |
KR100787783B1 (ko) | 스코폴레틴을 유효성분으로 함유하는 피부주름 개선용 화장료 조성물 | |
KR20160146246A (ko) | 항산화, 미백 및 주름개선 효과를 갖는 조성물 | |
AU2014233649A1 (en) | Compositions comprising Paulownia tomentosa wood extracts and uses thereof | |
US20130028849A1 (en) | Agent For Stimulating The Expression of Loxl | |
KR101656928B1 (ko) | 끈끈이여뀌 추출물을 유효성분으로 함유하는 광노화 방지 및 피부주름개선을 위한 조성물 | |
US20110135772A1 (en) | Skin care agent and compositions thereof | |
KR101757674B1 (ko) | 도깨비바늘 추출물을 유효성분으로 함유하는 피부 탄력 증진 및 피부 주름 개선용 화장료 조성물 | |
KR101972073B1 (ko) | 시링가레시놀을 포함하는 노화 억제용 조성물 | |
JPH1045613A (ja) | インターロイキン4産生抑制剤 | |
KR101697236B1 (ko) | 상지의 분배추출물을 유효성분으로 함유하는 화장료 조성물 | |
KR20160112546A (ko) | 시링산을 유효성분으로 포함하는 피부상태 개선용 조성물 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AU CA JP |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE |
|
ENP | Entry into the national phase |
Ref document number: 2344481 Country of ref document: CA Ref country code: CA Ref document number: 2344481 Kind code of ref document: A Format of ref document f/p: F |
|
WWE | Wipo information: entry into national phase |
Ref document number: 47070/00 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2000928906 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref country code: JP Ref document number: 2001 511895 Kind code of ref document: A Format of ref document f/p: F |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWP | Wipo information: published in national office |
Ref document number: 2000928906 Country of ref document: EP |
|
WWG | Wipo information: grant in national office |
Ref document number: 47070/00 Country of ref document: AU |