Absorption and Metabolism of Luteolin in Rats and Humans in Relation to in Vitro Anti-inflammatory Effects
Natsumi HayasakaNaoki ShimizuToshikazu KomodaSatoshi MohriTojiro TsushidaTakahiro EitsukaTeruo MiyazawaKiyotaka Nakagawa
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Luteolin is a flavonoid present in plants in the form of aglycone or glucosides. In this study, luteolin glucosides (i.e., luteolin-7- O-β-d-glucoside, luteolin-7- O-[2-(β-d-apiosyl)-β-d-glucoside], and luteolin-7- O-[2-(β-d-apiosyl)-6-malonyl-β-d-glucoside]) prepared from green pepper leaves as well as luteolin aglycone were orally administered to rats. Regardless of the administered luteolin form, luteolin glucuronides were mainly detected from plasma and organs. Subsequently, luteolin aglycone, the most absorbed form of luteolin in rats, was orally administered to humans. As a result, luteolin-3'- O-sulfate was mainly identified from plasma, suggesting that not only luteolin form but also animal species affect the absorption and metabolism of luteolin. When LPS-treated RAW264.7 cells were treated with luteolin glucuronides and luteolin sulfate (the characteristic metabolites identified from rats and humans, respectively), the different luteolin conjugates were metabolized in different ways, suggesting that such difference in metabolism results in their difference in anti-inflammatory effects.Objective: To synthesize luteolin Cr(Ⅲ) complex and study the inhibitory action of luteolin and luteolin Cr(Ⅲ) on glucosi dase, determine the type of inhibitory action. Methods: The luteolin Cr(Ⅲ) complex was synthesized in dehydrated alcohol solution by mixing the luteolin and chromic acetate. After determining the structure of Luteolin Cr(Ⅲ) by IR、UV、TG DTA combined with element analysis method, the activity ofα glucosidase was investigated in the different pH and temperature. Inhibitory action of luteolin and luteolin Cr(Ⅲ) were tested onα glucosidase, and studied the kinetic characteristics by using Lineweaver Burk method. Results: The molecular composition of luteolin Cr(Ⅲ) was C15H9O6 Cr( COOCH3)2(H2O)2 ·2H2O. The optimum pH value ofα glucosidase was 510 temperature 55e. The IC50 value of inhibitory action of luteolin and luteolin Cr(Ⅲ) onα glucosidase were 1.496 mmol/ L and 0.2320 mmol/ L respectively. The type of inhibitory action was competitiveα glucosidase inhibitor. Conclusion: The luteolin Cr(Ⅲ) complex which was combined with luteolin and Cr3+was enhanced the inhibitory action onα glucosidase. It was a good foundation for further study of luteolin Cr(Ⅲ) complex.
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Luteolin is a flavonoid present in plants in the form of aglycone or glucosides. In this study, luteolin glucosides (i.e., luteolin-7- O-β-d-glucoside, luteolin-7- O-[2-(β-d-apiosyl)-β-d-glucoside], and luteolin-7- O-[2-(β-d-apiosyl)-6-malonyl-β-d-glucoside]) prepared from green pepper leaves as well as luteolin aglycone were orally administered to rats. Regardless of the administered luteolin form, luteolin glucuronides were mainly detected from plasma and organs. Subsequently, luteolin aglycone, the most absorbed form of luteolin in rats, was orally administered to humans. As a result, luteolin-3'- O-sulfate was mainly identified from plasma, suggesting that not only luteolin form but also animal species affect the absorption and metabolism of luteolin. When LPS-treated RAW264.7 cells were treated with luteolin glucuronides and luteolin sulfate (the characteristic metabolites identified from rats and humans, respectively), the different luteolin conjugates were metabolized in different ways, suggesting that such difference in metabolism results in their difference in anti-inflammatory effects.
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Luteolin is a flavonoid which is part of our daily nutrition in relatively low amounts (less than 1 mg/day). Nevertheless, some epidemiological studies suggest an inverse correlation between luteolin intake and the risk of some cancer types. Luteolin displays specific anti-inflammatory and anti-carcinogenic effects, which can only partly be explained by its anti-oxidant and free radical scavenging capacities. Luteolin can delay or block the development of cancer cells in vitro and in vivo by protection from carcinogenic stimuli, by inhibition of tumor cell proliferation, by induction of cell cycle arrest and by induction of apoptosis via intrinsic and extrinsic signaling pathways. When compared to other flavonoids, luteolin was usually among the most effective ones, inhibiting tumor cell proliferation with IC(50) values between 3 and 50 microM in vitro and in vivo by 5 to 10 mg/kg i.p., intragastric application of 0.1-0.3 mg/kg/d, or as food additive in concentrations of 50 to 200 ppm. Luteolin has been shown to penetrate into human skin, making it also a candidate for the prevention and treatment of skin cancer.
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In this study, we investigated the intestinal absorption of luteolin and luteolin 7‐ O ‐β‐glucoside in rats by HPLC. The absorption analysis using rat everted small intestine demonstrated that luteolin was converted to glucuronides during passing through the intestinal mucosa and that luteolin 7‐ O ‐β‐glucoside was absorbed after hydrolysis to luteolin. Free luteolin, its conjugates and methylated conjugates were present in rat plasma after dosing. This suggests that some luteolin can escape the intestinal conjugation and the hepatic sulfation/methylation. LC/MS analysis showed that the main conjugate which circulates in the blood was a monoglucuronide of the unchanged aglycone. Luteolin in propyleneglycol was absorbed more rapidly than that in 0.5% carboxymethyl cellulose. The plasma concentration of luteolin and its conjugates reached the highest level 15 min and 30 min after dosing with luteolin in propyleneglycol, respectively. HPLC analysis also allowed us to demonstrate the presence of free luteolin and its monoglucuronide in human serum after ingestion of luteolin.
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Abstract Background Luteolin has been demonstrated to possess numerous biological effects. However, the effect of luteolin on LPS (Lipopolysaccharides) stimulation in CPEK cells has not been investigated. Hypothesis/Objectives An in vitro model of atopic canine dermatitis was used to identify the antioxidant effect of luteolin as a new treatment that is capable of improving the conditions of veterinary patients. Methods CPEK cells were treated with or without luteolin in the presence or absence of LPS. A cell viability assay was performed to test luteolin toxicity and the protective effect of luteolin after LPS stimulation. Additionally, enzyme‐linked immunosorbent assay (ELISA) kits were used to detect the levels of IL‐33, IL‐1β, IL‐6, and IL‐8. Results Luteolin was capable to significantly decrease levels expression of IL‐33, IL 1β, IL‐6, and IL‐8. Conclusions and clinical importance Luteolin could be a new pharmacological treatment for canine atopic dermatitis.
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To elucidate the bioavailability of luteolin and its glycosides in Chrysanthemum morifolium flowers, the absorption and metabolism of luteolin from them was investigated in rats and Caco-2 cells using HPLC and LC-MS. After oral administration of C. morifolium extract (1.7 g/kg body weight (bw), equivalent to 22.8 and 58.3 μmol/kg bw of luteolin and luteolin-7-O-glucoside, respectively) to rats, luteolin and its glycosides were quickly absorbed and luteolin, luteolin monoglucoside, and luteolin monoglucuronide were detected in the plasma. Their levels were highest at 1 h after administration (0.76 ± 0.27 μM). These compounds were also detected in media on the basolateral side from Caco-2 cells treated with the C. morifolium extract. These results suggest that luteolin and luteolin monoglucoside are rapidly absorbed after administration of C. morifolium flower extract and that luteolin, luteolin monoglucoside, and luteolin monoglucuronide may circulate in humans.
Chrysanthemum morifolium
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혈관 증식 질환에서 세포주기 활성화와 진행은 중요한 치료 목적으로 사용된다. Luteolin는 glycosylated 형태로 샐러리, 후추, 들깨 잎 그리고 카밀레 차에 존재하며 항돌연변이, 항종양, 항산화 그리고 항염증을 나타낸다. 본 연구에서는 흰쥐 동맥으로부터 분리한 혈관평활근세포를 배양하여 소태아혈청으로 유도된 증식에서 luteolin 효과에 대해 조사했다. Luteolin이 5% 소태아혈청으로 유도된 흰쥐의 혈관평활근세포 증식과 DNA 합성을 5, 20 그리고 $50{\mu}M$ 에서 억제했다. 혈관평활근세포 증식을 각각 29.6, 50.8 그리고 83.1% 억제했고 DNA 합성은 각각 25.8, 57.6 그리고 81.0% 억제했다. 게다가, 유세포분석 결과 소태아혈청으로 유도된 혈관평활근세포의 세포주기는 luteolin에 의해 차단되었다. 이러한 결과는 세포독성에 의해서도 나타날 수 있기 때문에 WST-1 분석으로 세포독성을 확인한 결과 세포독성 없이 세포주기를 차단하는 효과임을 확인했다. 이상의 결과들은 luteolin이 혈관스텐트와 동맥경화의 치료를 위한 의미있는 항증식 물질임을 보여준다. Cell cycle activation and progression in vascular proliferative disease represent potent therapeutic targets. Luteolin, which occurs as glycosylated forms in celery, green pepper, perilla leaf, and camomile tea, has demonstrated antimutagenic, antitumorigenic, antioxidant, and antiinflammatory properties. In this study, we investigated the effect of luteolin on the proliferation of primary cultured rat aortic vascular smooth muscle cells induced by 5% fetal bovine serum. Luteolin at concentrations of 5, 20, and $50{\mu}M$ significantly inhibited this proliferation by 29.6, 50.8, and 83.1%, respectively. The incorporation of $[^3H]$ -thymidine into DNA was also inhibited by 25.8, 57.6, and 81.0%, respectively. Flow cytometry analysis of DNA content revealed that FBS-inducible cell cycle progression was blocked by luteolin. Luteolin showed no cytotoxicity in VSMCs in this experimental condition according to WST-1 assays. Luteolin may represent a potential anti-proliferative agent for treatment of angioplasty restenosis and atherosclerosis.
Fetal bovine serum
Flavones
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Luteolin has been shown to possess potent antioxidant and anti-inflammatory/anti-allergic activities. In order to evaluate a chemopreventive role of luteolin in inflammatory responses involved in the pathogenesis of atherosclerosis and cancer etc., the metabolic fate of luteolin in rats and humans was investigated by HPLC analysis, and its effect on cell surface expression of adhesion molecules in human umbilical vein endothelial cells(HUVECs) was examined by ELISA. Luteolin monoglucuronide, which was a main metabolite, and free luteolin were detected in rat plasma and human serum. Luteolin monoglucuronide was hydrolyzed to free luteolin by beta-glucuronidase released from neutrophils stimulated with lonomycin and Cytocharasine B. Luteolin suppressed the TNF-alpha induced ICAM-1 expression significantly. Among nine flavonoids (40 microM) examined, chrysin, apigenine, quercetin and galangin also demonstrated suppressive effct on it. These results suggest the posssibility that deconjugation of luteolin monoglucuronide occurs and that free luteolin showed functional acyivities such as suppression of TNF-alpha induced ICAM- 1 expression at inflammation site.
Chrysin
Galangin
Flavones
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Бұл зерттеужұмысындaКaно моделітурaлы жәнеоғaн қaтыстытолықмәліметберілгенжәнеуниверситетстуденттерінебaғыттaлғaн қолдaнбaлы (кейстік)зерттеужүргізілген.АхметЯссaуи университетініңстуденттеріүшін Кaно моделіқолдaнылғaн, олaрдың жоғaры білімберусaпaсынa қоятынмaңыздытaлaптaры, яғнисaпaлық қaжеттіліктері,олaрдың мaңыздылығытурaлы жәнесaпaлық қaжеттіліктерінеқaтыстыөз университетінқaлaй бaғaлaйтындығытурaлы сұрaқтaр қойылғaн. Осы зерттеудіңмaқсaты АхметЯсaуи университетіндетуризмменеджментіжәнеқaржы бaкaлaвриaт бaғдaрлaмaлaрыныңсaпaсынa қaтыстыстуденттердіңқaжеттіліктерінaнықтaу, студенттердіңқaнaғaттaну, қaнaғaттaнбaу дәрежелерінбелгілеу,білімберусaпaсын aнықтaу мен жетілдіружолдaрын тaлдaу болыптaбылaды. Осы мaқсaтқaжетуүшін, ең aлдыменКaно сaуaлнaмaсы түзіліп,116 студенткеқолдaнылдыжәнебілімберугежәнеоның сaпaсынa қaтыстыстуденттердіңтaлaптaры мен қaжеттіліктерітоптықжұмыстaрaрқылыaнықтaлды. Екіншіден,бұл aнықтaлғaн тaлaптaр мен қaжеттіліктерКaно бaғaлaу кестесіменжіктелді.Осылaйшa, сaпa тaлaптaры төрт сaнaтқa бөлінді:болуытиіс, бір өлшемді,тaртымдыжәнебейтaрaп.Соңындa,қaнaғaттaну мен қaнaғaттaнбaудың мәндеріесептелдіжәнестуденттердіңқaнaғaттaну мен қaнaғaттaнбaу деңгейлерінжоғaрылaту мен төмендетудеосытaлaптaр мен қaжеттіліктердіңрөліaйқын aнықтaлды.Түйінсөздер:сaпa, сaпaлық қaжеттіліктер,білімберусaпaсы, Кaно моделі.
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