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luteolin |
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CHEBI:15864 |
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A tetrahydroxyflavone in which the four hydroxy groups are located at positions 3', 4', 5 and 7. It is thought to play an important role in the human body as an antioxidant, a free radical scavenger, an anti-inflammatory agent and an immune system modulator as well as being active against several cancers. |
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This entity has been manually annotated by the ChEBI Team.
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CHEBI:12082, CHEBI:14536, CHEBI:6578, CHEBI:25086
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ChemicalBook:CB72747669, ChemicalBook:CB7282616, ChemicalBook:CB71453798, eMolecules:524934, Selleckchem:Luteolin(Luteolol), ZINC000018185774 |
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Luteolin is a flavone, a type of flavonoid, with a yellow crystalline appearance.
Luteolin is the main yellow dye from the Reseda luteola plant, used for dyeing since at least the first millennium B.C. Luteolin was first isolated in pure form, and named, in 1829 by the French chemist Michel Eugène Chevreul. The luteolin empirical formula was determined by the Austrian chemists Heinrich Hlasiwetz and Leopold Pfaundler in 1864. In 1896, the English chemist Arthur George Perkin proposed the correct structure for luteolin. Perkin's proposed structure for luteolin was confirmed in 1900 when the Polish-Swiss chemist Stanislaw Kostanecki (1860–1910) and his students A. Różycki and J. Tambor synthesized luteolin. |
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InChI=1S/C15H10O6/c16-8-4-11(19)15-12(20)6-13(21-14(15)5-8)7-1-2-9(17)10(18)3-7/h1-6,16-19H |
IQPNAANSBPBGFQ-UHFFFAOYSA-N |
OC1=CC(O)=C2C(=O)C=C(OC2=C1)C1=CC=C(O)C(O)=C1 |
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Arabidopsis thaliana
(NCBI:txid3702)
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Found in
cell suspension culture
(BTO:0000221).
From MetaboLights
See:
MetaboLights Study
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Arabidopsis thaliana
(NCBI:txid3702)
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From MetaboLights
See:
MetaboLights Study
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Brassica napus
(NCBI:txid3708)
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Found in
leaf lamina
(BTO:0000719).
From MetaboLights
See:
MetaboLights Study
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Brassica napus
(NCBI:txid3708)
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From MetaboLights
See:
MetaboLights Study
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Brassica napus
(NCBI:txid3708)
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From MetaboLights
See:
MetaboLights Study
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Olea europaea
(NCBI:txid4146)
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Found in
leaf
(BTO:0000713).
Methanolic extract of dried olive leaves
See:
PubMed
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Sorghum bicolor
(NCBI:txid4558)
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From MetaboLights
See:
MetaboLights Study
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Mimosa diplotricha
(NCBI:txid512270)
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Found in
aerial part
(BTO:0001658).
Ethanolic extract of aerial part
See:
PubMed
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Cirsium japonicum
(NCBI:txid516546)
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Found in
whole plant
(BTO:0001461).
Hot methanolic extract of dried whole plant
See:
PubMed
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Lepisorus ussuriensis
(NCBI:txid699700)
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Found in
whole plant
(BTO:0001461).
See:
PubMed
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radical scavenger
A role played by a substance that can react readily with, and thereby eliminate, radicals.
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vascular endothelial growth factor receptor antagonist
An antagonist at the vascular endothelial growth factor receptor.
plant metabolite
Any eukaryotic metabolite produced during a metabolic reaction in plants, the kingdom that include flowering plants, conifers and other gymnosperms.
c-Jun N-terminal kinase inhibitor
apoptosis inducer
Any substance that induces the process of apoptosis (programmed cell death) in multi-celled organisms.
EC 2.3.1.85 (fatty acid synthase) inhibitor
An EC 2.3.1.* (acyltransferase transferring other than amino-acyl group) inhibitor that interferes with the action of fatty acid synthase (EC 2.3.1.85), a multi-enzyme protein involved in fatty acid synthesis.
immunomodulator
Biologically active substance whose activity affects or plays a role in the functioning of the immune system.
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nephroprotective agent
Any protective agent that is able to prevent damage to the kidney.
angiogenesis inhibitor
An agent and endogenous substances that antagonize or inhibit the development of new blood vessels.
anti-inflammatory agent
Any compound that has anti-inflammatory effects.
antineoplastic agent
A substance that inhibits or prevents the proliferation of neoplasms.
immunomodulator
Biologically active substance whose activity affects or plays a role in the functioning of the immune system.
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View more via ChEBI Ontology
2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4H-chromen-4-one
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2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4-benzopyrone
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ChemIDplus
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2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4H-1-benzopyran-4-one
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ChemIDplus
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3',4',5,7-Tetrahydroxyflavone
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KEGG COMPOUND
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5,7,3',4'-Tetrahydroxyflavone
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KEGG COMPOUND
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digitoflavone
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ChEBI
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flacitran
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ChEBI
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Luteolin
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KEGG COMPOUND
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Luteolol
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ChemIDplus
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Salifazide
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ChemIDplus
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292084
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Reaxys Registry Number
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Reaxys
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491-70-3
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CAS Registry Number
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ChemIDplus
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491-70-3
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CAS Registry Number
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NIST Chemistry WebBook
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Zima V, Radilová K, Kožíšek M, Albiñana CB, Karlukova E, Brynda J, Fanfrlík J, Flieger M, Hodek J, Weber J, Majer P, Konvalinka J, Machara A (2020) Unraveling the anti-influenza effect of flavonoids: Experimental validation of luteolin and its congeners as potent influenza endonuclease inhibitors. European journal of medicinal chemistry 208, 112754 [PubMed:32883638] [show Abstract] The biological effects of flavonoids on mammal cells are diverse, ranging from scavenging free radicals and anti-cancer activity to anti-influenza activity. Despite appreciable effort to understand the anti-influenza activity of flavonoids, there is no clear consensus about their precise mode-of-action at a cellular level. Here, we report the development and validation of a screening assay based on AlphaScreen technology and illustrate its application for determination of the inhibitory potency of a large set of polyols against PA N-terminal domain (PA-Nter) of influenza RNA-dependent RNA polymerase featuring endonuclease activity. The most potent inhibitors we identified were luteolin with an IC50 of 72 ± 2 nM and its 8-C-glucoside orientin with an IC50 of 43 ± 2 nM. Submicromolar inhibitors were also evaluated by an in vitro endonuclease activity assay using single-stranded DNA, and the results were in full agreement with data from the competitive AlphaScreen assay. Using X-ray crystallography, we analyzed structures of the PA-Nter in complex with luteolin at 2.0 Å resolution and quambalarine B at 2.5 Å resolution, which clearly revealed the binding pose of these polyols coordinated to two manganese ions in the endonuclease active site. Using two distinct assays along with the structural work, we have presumably identified and characterized the molecular mode-of-action of flavonoids in influenza-infected cells. | Gu C, Stashko MA, Puhl-Rubio AC, Chakraborty M, Chakraborty A, Frye SV, Pearce KH, Wang X, Shears SB, Wang H (2019) Inhibition of Inositol Polyphosphate Kinases by Quercetin and Related Flavonoids: A Structure-Activity Analysis. Journal of medicinal chemistry 62, 1443-1454 [PubMed:30624931] [show Abstract] Dietary flavonoids inhibit certain protein kinases and phospholipid kinases by competing for their ATP-binding sites. These nucleotide pockets have structural elements that are well-conserved in two human small-molecule kinases, inositol hexakisphosphate kinase (IP6K) and inositol polyphosphate multikinase (IPMK), which synthesize multifunctional inositol phosphate cell signals. Herein, we demonstrate that both kinases are inhibited by quercetin and 16 related flavonoids; IP6K is the preferred target. Relative inhibitory activities were rationalized by X-ray analysis of kinase/flavonoid crystal structures; this detailed structure-activity analysis revealed hydrophobic and polar ligand/protein interactions, the degree of flexibility of key amino acid side chains, and the importance of water molecules. The seven most potent IP6K inhibitors were incubated with intact HCT116 cells at concentrations of 2.5 μM; diosmetin was the most selective and effective IP6K inhibitor (>70% reduction in activity). Our data can instruct on pharmacophore properties to assist the future development of inositol phosphate kinase inhibitors. Finally, we propose that dietary flavonoids may inhibit IP6K activity in cells that line the gastrointestinal tract. | Fan S, Habib A, Liu J, Tan J (2018) LED enhances anti-inflammatory effect of luteolin (3',4',5,7-tetrahydroxyflavone) in vitro. American journal of translational research 10, 283-291 [PubMed:29423013] [show Abstract] Neuroinflammation is a complex pathological process usually results from abnormal microglial activation, thus, intervention in a microglial stimulation pathway could be a promising approach for the treatment of neurodegenerative diseases. Luteolin is an important bioflavonoid possesses anti-inflammatory properties, which is widely studied over these years. Light emitting diode (LED) therapy is reported to be a potential therapeutic strategy for many diseases including neurodegenerative diseases. However, little is known about the anti-inflammatory effect of LED therapy on activated microglial cells, even less is known whether there is a synergistic anti-inflammatory effect exist in LED and luteolin therapy. In this study, we aimed to confirm the anti-inflammatory effect of luteolin and LED combination therapy in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. We showed that luteolin inhibited LPS-induced cytotoxicity, tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) production through modulation of p38 and extracellular signal-regulated kinase (ERK) signaling in BV2 cells. In addition, LED therapy enhanced the anti-inflammatory effect of luteolin. These results suggest that a synergistic effect between luteolin and LED could be a new effective therapy in relieving neuroinflammation. | Qing W, Wang Y, Li H, Ma F, Zhu J, Liu X (2017) Preparation and Characterization of Copolymer Micelles for the Solubilization and In Vitro Release of Luteolin and Luteoloside. AAPS PharmSciTech 18, 2095-2101 [PubMed:28004344] [show Abstract] Luteolin (LUT) and luteoloside (LUS) belong to flavonoids with high anticancer potential and were loaded into biodegradable diblock copolymer micelles of methoxy polyethylene glycol-polycaprolactone (mPEG5K-PCL10K), methoxy polyethylene glycol-polylactide-co-glycolide (mPEG5K-PLGA10K), and methoxy polyethylene glycol-polylactide (mPEG5K-PDLLA10K) by a self-assembly method, creating water-soluble LUT and LUS copolymer micelles, respectively. The solubilization formulations of the copolymer micelles were optimized with response surface methodology (RSM). The obtained drug micelles are torispherical under transmission electron microscope (TEM) with an average diameter of about 70 nm. The mPEG5K-PLGA10K exhibited higher loading capacity for LUS which was 4.33%, and LUT- (or LUS)-loaded mPEG5K-PCL10K exhibited a better stability and encapsulation efficiency which was 65.1 and 55.8%, respectively. The in vitro drug release study showed above 47% of LUT was released from micelles at pH 7.4 PBS; however, no more than 35% of LUT was released at pH 6.4 PBS within 24 h. Meanwhile, no more than 30% of LUS was released from micelles whether at pH 6.4 or 7.4 PBS solution within 24 h. | Palko-Labuz A, Sroda-Pomianek K, Uryga A, Kostrzewa-Suslow E, Michalak K (2017) Anticancer activity of baicalein and luteolin studied in colorectal adenocarcinoma LoVo cells and in drug-resistant LoVo/Dx cells. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 88, 232-241 [PubMed:28110189] [show Abstract] Due to the type-specific diversity of cancer cells, an analysis and elucidation of molecular mechanisms responsible for anticancer properties of biologically active compounds are essential. Plant-derived polyphenolic compounds such as flavonoids may be useful in cancer chemoprevention or treatment because they influence diverse molecular pathways in cancer cells. In these studies anticancer activity of natural occurring flavones, baicalein and luteolin was investigated in colon cancer cells LoVo and in their drug resistant subline LoVo/Dx. Inhibitory activity of these flavones on cells growth and their ability to induce apoptosis were observed. A less pronounced influence of studied flavones on proliferation and apoptosis of LoVo/Dx as compared with LoVo cells well correlated with significantly lower cytotoxicity of these compounds in drug-resistant cells. These effects may be related to overexpression of multidrug transporter P-glycoprotein in drug-resistant LoVo/Dx cells. Our studies indicated that baicalein could be a substrate of this drug transporter. | Cook MT, Liang Y, Besch-Williford C, Hyder SM (2017) Luteolin inhibits lung metastasis, cell migration, and viability of triple-negative breast cancer cells. Breast cancer (Dove Medical Press) 9, 9-19 [PubMed:28096694] [show Abstract] Most breast cancer-related deaths from triple-negative breast cancer (TNBC) occur following metastasis of cancer cells and development of tumors at secondary sites. Because TNBCs lack the three receptors targeted by current chemotherapeutic regimens, they are typically treated with extremely aggressive and highly toxic non-targeted treatment strategies. Women with TNBC frequently develop metastatic lesions originating from drug-resistant residual cells and have poor prognosis. For this reason, novel therapeutic strategies that are safer and more effective are sought. Luteolin (LU) is a naturally occurring, non-toxic plant compound that has proven effective against several types of cancer. With this in mind, we conducted in vivo and in vitro studies to determine whether LU might suppress metastasis of TNBC. In an in vivo mouse metastasis model, LU suppressed metastasis of human MDA-MB-435 and MDA-MB-231 (4175) LM2 TNBC cells to the lungs. In in vitro assays, LU inhibited cell migration and viability of MDA-MB-435 and MDA-MB-231 (4175) LM2 cells. Further, LU induced apoptosis in MDA-MB-231 (4175) LM2 cells. Relatively low levels (10 µM) of LU significantly inhibited vascular endothelial growth factor (VEGF) secretion in MDA-MB-231 (4175) LM2 cells, suggesting that it has the ability to suppress a potent angiogenic and cell survival factor. In addition, migration of MDA-MB-231 (4175) LM2 cells was inhibited upon exposure to an antibody against the VEGF receptor, KDR, but not by exposure to a VEGF165 antibody. Collectively, these data suggest that the anti-metastatic properties of LU may, in part, be due to its ability to block VEGF production and KDR-mediated activity, thereby inhibiting tumor cell migration. These studies suggest that LU deserves further investigation as a potential treatment option for women with TNBC. | Wang L, Chen Q, Zhu L, Li Q, Zeng X, Lu L, Hu M, Wang X, Liu Z (2017) Metabolic Disposition of Luteolin Is Mediated by the Interplay of UDP-Glucuronosyltransferases and Catechol-O-Methyltransferases in Rats. Drug metabolism and disposition: the biological fate of chemicals 45, 306-315 [PubMed:28031430] [show Abstract] Luteolin partially exerts its biologic effects via its metabolites catalyzed by UDP-glucuronosyltransferases (UGTs) and catechol-O-methyltransferases (COMTs). However, the interplay of UGTs and COMTs in mediating luteolin disposition has not been well clarified. In this study, we investigated the glucuronidation and methylation pathways of luteolin mediated by the interplay of UGTs and COMTs in vivo and in vitro. A total of nine luteolin metabolites was detected in rat plasma and bile by liquid chromatography-tandem mass spectrometry, namely, three glucuronides, two methylated metabolites, and four methylated glucuronides. Luteolin-3'-glucuronide (Lut-3'-G) exhibited the highest systemic exposure among these metabolites. Kinetics studies in rat liver S9 fractions suggested two pathways, as follows: 1) Luteolin was glucuronidated to luteolin-7-glucuronide, luteolin-4'-glucuronide, and Lut-3'-G by UGTs, and then Lut-7-G was methylated to chrysoeriol-7-glucuronide and diosmetin-7-glucuronide by COMTs. 2) Alternatively, luteolin was methylated to chrysoeriol and diosmetin by COMTs, and then chrysoeriol and diosmetin were glucuronidated by UGTs to their respective glucuronides. The methylation rate of luteolin was significantly increased by the absence of glucuronidation, whereas the glucuronidation rate was increased by the absence of methylation, but to a lesser extent. In conclusion, two pathways mediated by the interplay of UGTs and COMTs are probably involved in the metabolic disposition of luteolin. The glucuronidation and methylation of luteolin compensate for each other, although glucuronidation is the predominant pathway. | Nunes C, Almeida L, Barbosa RM, Laranjinha J (2017) Luteolin suppresses the JAK/STAT pathway in a cellular model of intestinal inflammation. Food & function 8, 387-396 [PubMed:28067377] [show Abstract] Current treatment strategies for inflammatory bowel diseases (IBDs) are associated with a lower efficacy and with several side effects that strongly affect the quality of life of IBD patients. Consequently, the development of new therapies, combining efficacy and safety is an important goal in the field of intestinal inflammation. In this context, evidence supports that polyphenols can be promising candidates due to their ability to modulate intracellular inflammatory signalling cascades. Luteolin, a naturally occurring flavonoid, exhibits anti-inflammatory properties in several models of inflammation. However, its action against intestinal inflammation has been poorly explored. Therefore, there is a lack of scientific knowledge about the potential impact of luteolin in the intestinal inflammation, particularly regarding the underlying molecular mechanisms by which luteolin can exert its anti-inflammatory action. We assessed the potential anti-inflammatory effect of luteolin in a cellular model of intestinal inflammation using cytokine-stimulated HT-29 colon epithelial cells, and the underlying key molecular mechanisms were identified. Luteolin significantly inhibited interleukine-8 (IL-8) production, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression and nitric oxide (˙NO) overproduction induced by cytokines, indicating that luteolin negatively modulates key inflammatory signalling cascades underlying intestinal inflammation. Mechanistically, the inhibition of the JAK/STAT pathway was identified as a critical mechanism by which luteolin exerts its intestinal anti-inflammatory action. This study uncovers novel molecular mechanisms by which luteolin may act against intestinal inflammation, which might support the use of luteolin as a future therapeutic strategy in IBD. | Zhang L, Zhao X, Tao GJ, Chen J, Zheng ZP (2017) Investigating the inhibitory activity and mechanism differences between norartocarpetin and luteolin for tyrosinase: A combinatory kinetic study and computational simulation analysis. Food chemistry 223, 40-48 [PubMed:28069121] [show Abstract] Flavonoids are an important type of natural tyrosinase inhibitor, but their inhibitory activity and mechanism against tyrosinase are very different because of their different structures. In this study, the inhibitory activity and mechanism differences between norartocarpetin and luteolin for tyrosinase were investigated by a combination of kinetic studies and computational simulations. The kinetic analysis showed that norartocarpetin reversibly inhibited tyrosinase in a competitive manner, whereas luteolin caused reversible noncompetitive inhibition. Both norartocarpetin and luteolin showed a single type of quenching and a static-type quenching mechanism. A computational simulation indicated that the hydroxyl groups of the B ring of norartocarpetin interacted with tyrosinase residues Asn81 and His85 in the active pocket, while the hydroxyl groups of the B ring of luteolin bound residues Asn81 and Cys83. HPLC and UPLC-MS/MS further confirmed that luteolin acted as a substrate or a suicide inhibitor, yet norartocarpetin acted as an inhibitor. | Xiong J, Wang K, Yuan C, Xing R, Ni J, Hu G, Chen F, Wang X (2017) Luteolin protects mice from severe acute pancreatitis by exerting HO-1-mediated anti-inflammatory and antioxidant effects. International journal of molecular medicine 39, 113-125 [PubMed:27878246] [show Abstract] Reseda odorata L. has long been used in traditional Asian medicine for the treatment of diseases associated with oxidative injury and acute inflammation, such as endotoxemia, acute lung injury, acute myocardial infarction and hepatitis. Luteolin, the main component of Reseda odorata L., which is also widely found in many natural herbs and vege-tables, has been shown to induce heme oxygenase-1 (HO-1) expression to exert anti-inflammatory and antioxidant effects. In this study, we aimed to examine the effects of luteolin on mice with severe acute pancreatitis (SAP), and to explore the underlying mechanisms. Cerulein and lipopolysaccharide were used to induce SAP in male Institute of Cancer Research (ICR) mice in the SAP group. The SAP group was divided into 4 subgroups, as follows: the vehicle, luteolin, zinc protoporphyrin (ZnPP) only, and luteolin (Lut) + ZnPP (luteolin plus zinc protoporphyrin treatment) groups. The wet/dry weight ratios, hematoxylin and eosin staining and pathological scores of pancreatic tissues were assessed and compared to those of the control mice. Amylase, lipase, nuclear factor-κB (NF-κB) and myeloperoxidase activities, and malondialdehyde, tumor necrosis factor α (TNFα), interleukin (IL)-6, IL-10 and HO-1 levels, as well as the expression of HO-1 were determined in serum and/or pancreatic tissue samples. SAP was successfully induced in male mice compared to normal control mice. The wet/dry weight ratios, pathological scores, and amylase and lipase activity, as well as the levels of TNFα and IL-6 were significantly reduced in the pancreatic tissues of the mice in the Lut group compared with those of the mice in the vehicle group. The Lut group exhibited a significant increase in HO-1 expression in the pancreas and enhanced serum HO-1 and IL-10 levels compared with the vehicle group. The suppression of HO-1 activity in the ZnPP group significantly abolished the protective effects of luteolin. NF-κB expression in the pancreatic tissues from the mice in the Lut + ZnPP group was significantly increased following the suppression of HO-1 activity. On the whole, our findings demonstrate that luteolin protects mice from SAP by inducing HO-1-mediated anti-inflammatory and antioxidant activities, in association with the suppression of the activation of the NF-κB pathway. | Gao D, Wang DD, Zhang Q, Yang FQ, Xia ZN, Zhang QH, Yuan CS (2017) In Vivo Selective Capture and Rapid Identification of Luteolin and Its Metabolites in Rat Livers by Molecularly Imprinted Solid-Phase Microextraction. Journal of agricultural and food chemistry 65, 1158-1166 [PubMed:28111945] [show Abstract] A method based on molecularly imprinted solid-phase microextraction (MIP-SPME) coupled with liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (QTOF-MS/MS) was developed for the detection of luteolin and its metabolites in vivo. The MIP-SPME fibers were first fabricated by dopamine and silane, and then luteolin MIPs-coated fibers were successfully prepared using luteolin, acrylamide (AM), and ethylene glycol dimethacrylate (EGDMA) as the template, functional monomer and cross-linker, respectively. The characterizations of polymers were analyzed by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), and the Brunauer-Emmett-Teller method (BET). The properties involving adsorption and selective experiments were evaluated, and these results revealed that MIP fibers presented high adsorption capacity and selectivity to luteolin. Furthermore, the developed MIP-SPME coupled with the LC-QTOF-MS/MS method was adopted to capture and identify luteolin and its metabolites in rat livers in vivo, and eventually, apigenin, chrysoeriol, and diosmetin were rapidly identified as metabolites. | Ha SK, Lee JA, Cho EJ, Choi I (2017) Effects of Catechol O-Methyl Transferase Inhibition on Anti-Inflammatory Activity of Luteolin Metabolites. Journal of food science 82, 545-552 [PubMed:28071803] [show Abstract] Although luteolin is known to have potent anti-inflammatory activities, much less information has been provided on such activities of its hepatic metabolites. Luteolin was subjected to hepatic metabolism in HepG2 cells either without or with catechol O-methyl transferase (COMT) inhibitor. To identify hepatic metabolites of luteolin without (luteolin metabolites, LMs) or with COMT inhibitor (LMs+CI), metabolites were treated by β-glucuronidase and sulfatase, and found that they were composed of glucuronide and sulfate conjugates of diosmetin in LMs or these conjugates of luteolin in LMs+CI. LMs and LMs+CI were examined for their anti-inflammatory activities on LPS stimulated Raw 264.7 cells. Expression of iNOS and production of nitric oxide and pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 were suppressed more effectively by the treatment with LMs+CI than LMs. Our data provide a new insight on possible improvement in functional properties of luteolin on target cells by modifying their metabolic pathway in hepatocytes. | Keller AN, Eckle SB, Xu W, Liu L, Hughes VA, Mak JY, Meehan BS, Pediongco T, Birkinshaw RW, Chen Z, Wang H, D'Souza C, Kjer-Nielsen L, Gherardin NA, Godfrey DI, Kostenko L, Corbett AJ, Purcell AW, Fairlie DP, McCluskey J, Rossjohn J (2017) Drugs and drug-like molecules can modulate the function of mucosal-associated invariant T cells. Nature immunology 18, 402-411 [PubMed:28166217] [show Abstract] The major-histocompatibility-complex-(MHC)-class-I-related molecule MR1 can present activating and non-activating vitamin-B-based ligands to mucosal-associated invariant T cells (MAIT cells). Whether MR1 binds other ligands is unknown. Here we identified a range of small organic molecules, drugs, drug metabolites and drug-like molecules, including salicylates and diclofenac, as MR1-binding ligands. Some of these ligands inhibited MAIT cells ex vivo and in vivo, while others, including diclofenac metabolites, were agonists. Crystal structures of a T cell antigen receptor (TCR) from a MAIT cell in complex with MR1 bound to the non-stimulatory and stimulatory compounds showed distinct ligand orientations and contacts within MR1, which highlighted the versatility of the MR1 binding pocket. The findings demonstrated that MR1 was able to capture chemically diverse structures, spanning mono- and bicyclic compounds, that either inhibited or activated MAIT cells. This indicated that drugs and drug-like molecules can modulate MAIT cell function in mammals. | Lin D, Kuang G, Wan J, Zhang X, Li H, Gong X, Li H (2017) Luteolin suppresses the metastasis of triple-negative breast cancer by reversing epithelial-to-mesenchymal transition via downregulation of β-catenin expression. Oncology reports 37, 895-902 [PubMed:27959422] [show Abstract] The metastasis of breast cancer is associated with dismal prognosis and high mortality due to the lack of effective treatment. Luteolin, a natural flavonoid compound, has been shown to exert antitumor activity in various types of cancers. However, the effects and mechanisms of luteolin on the metastasis of triple-negative breast cancer (TNBC) remain elusive. In the present study, we found that pretreatment of highly metastatic TNBC cell lines with luteolin dose‑dependently inhibited cell migration and invasion, and reversed epithelial-mesenchymal transition (EMT) as determined by altered morphological characteristics, downregulated epithelial markers and upregulated mesenchymal markers, and inhibited EMT-related transcription factors. In an in vivo metastasis experiment using a xenograft model, luteolin markedly inhibited lung metastases of breast cancer and the expression of EMT molecules vimentin and Slug in primary tumor tissues. Notably, luteolin also suppressed the expression of β-catenin mRNA and protein in vitro and in vivo. Furthermore, overexpression of β-catenin by adenoviruses blocked these benefits of luteolin on invasion and metastases of breast cancer. In conclusion, all these results indicated that luteolin effectively suppressed metastases of breast cancer by reversing EMT, which may be mediated by downregulation of β-catenin. | Lee YJ, Lim T, Han MS, Lee SH, Baek SH, Nan HY, Lee C (2017) Anticancer effect of luteolin is mediated by downregulation of TAM receptor tyrosine kinases, but not interleukin-8, in non-small cell lung cancer cells. Oncology reports 37, 1219-1226 [PubMed:28035396] [show Abstract] TAM receptor tyrosine kinases (RTKs), Tyro3, Axl and MerTK, transduce diverse signals responsible for cell survival, growth, proliferation and anti-apoptosis. In the present study, we demonstrated the effect of luteolin, a flavonoid with antioxidant, anti-inflammatory and anticancer activities, on the expression and activation of TAM RTKs and the association with its cytotoxicity in non-small cell lung cancer (NSCLC) cells. We observed the cytotoxic effect of luteolin in parental A549 and H460 cells as well as in cisplatin-resistant A549/CisR and H460/CisR cells. Exposure of these cells to luteolin also resulted in a dose‑dependent decrease in clonogenic ability. Next, luteolin was found to decrease the protein levels of all three TAM RTKs in the A549 and A549/CisR cells in a dose‑dependent manner. In a similar manner, in H460 and H460/CisR cells, the protein levels of Axl and Tyro3 were decreased following luteolin treatment. In addition, Axl promoter activity was decreased by luteolin, indicating that luteolin suppresses Axl expression at the transcriptional level. We next found that luteolin abrogated Axl phosphorylation in response to growth arrest-specific 6 (Gas6), its ligand, implying the inhibitory effect of luteolin on Gas6-induced Axl activation. Ectopic expression of Axl was observed to attenuate the antiproliferative effect of luteolin, while knockdown of the Axl protein level using a gold nanoparticle-assisted gene delivery system increased its cytotoxicity. In contrast to the inhibitory effect of luteolin on the expression of TAM RTKs, interleukin-8 (IL-8) production was not decreased by luteolin in H460 and H460/CisR cells, while IL-8 production/cell was increased. Collectively, our data suggest that TAM RTKs, but not IL-8, are promising therapeutic targets of luteolin to abrogate cell proliferation and to overcome chemoresistance in NSCLC cells. | Tambe R, Patil A, Jain P, Sancheti J, Somani G, Sathaye S (2017) Assessment of luteolin isolated from Eclipta alba leaves in animal models of epilepsy. Pharmaceutical biology 55, 264-268 [PubMed:27927066] [show Abstract]
ContextEclipta alba (Linn) Hassk. (Asteraceae) has been reported to be a nerve tonic and has been used to treat epilepsy in folk medicine.ObjectiveThe present study isolates and characterizes luteolin from E. alba and evaluates its antiepileptic potential in chemically induced acute and chronic models in mice.Materials and methodsThe methanol extract (16.85% w/w) of E. alba leaves was subjected to fractionation for isolation of luteolin. In acute pentylenetetrazole (PTZ) model, luteolin (5, 10, 20 mg/kg, i.p.) was administered 30 min prior to PTZ injection (100 mg/kg) in Swiss albino mice. Kindling was induced by chronic administration of PTZ (35 mg/kg) on every alternate day (48 days). Luteolin was investigated on the course of kindling development and oxidative stress markers [reduced glutathione (GSH) and malondialdehyde (MDA)] in kindled mice.ResultsSingle-dose pretreatment with luteolin (10 and 20 mg/kg, i.p.) was found to be effective in an acute PTZ model (100% protection from mortality) and it did not exhibit any effect on motor coordination at the same doses. PTZ-induced kindling was significantly (p < 0.001) prevented by luteolin (5, 10, 20 mg/kg, i.p.) in a dose-dependent manner. Luteolin restored levels of reduced GSH (p < 0.001) and decreased the level of MDA (p < 0.001), a marker of lipid peroxidation.Discussion and conclusionThe results of the present study demonstrated that luteolin had an anticonvulsant effect in an acute PTZ model. Luteolin exhibited and inhibitory effect on the course of kindling and associated oxidative stress and hence could be a potential molecule in the treatment of epilepsy. | Hu W, Xu T, Wu P, Pan D, Chen J, Chen J, Zhang B, Zhu H, Li D (2017) Luteolin improves cardiac dysfunction in heart failure rats by regulating sarcoplasmic reticulum Ca2+-ATPase 2a. Scientific reports 7, 41017 [PubMed:28112209] [show Abstract] We previously found that luteolin (Lut) appeared to improve the contractility of cardiomyocytes during ischemia/reperfusion in rats. The enhancement was associated with the alteration in sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA2a). This finding prompted us to consider if the mechanism worked in heart failure (HF). We studied the regulation of SERCA2a by Lut in failing cardiomyocytes and intact heart of rats. Improvement of contractility and the mechanisms centered on SERCA2a were studied in isolated cardiomyocytes and intact heart. We found that Lut significantly improved contractility and Ca2+ transients, ameliorated expression, activity and stability of SERCA2a and upregulated expression of small ubiquitin-related modifier (SUMO) 1, which is a newfound SERCA2a regulator. Lut also increased phosphorylation of protein kinase B (Akt), phospholaban (PLB) and sumoylation of SERCA2a, specificity protein 1 (Sp1). Transcriptions of SUMO1 and SERCA2a were concurrently increased. Inhibition of posphatidylinositol 3 kinase/Akt (PI3K/Akt) pathway and SERCA2a activity both markedly abolished Lut-induced benefits in vitro and in vivo. Lut upregulated the expression ratio of Bcl-2/Bax, caspase-3/cleaved-Caspase3. Meanwhile, Lut ameliorated the myocardium fibrosis of HF. These discoveries provide an important potential therapeutic strategy that Lut targeted SERCA2a SUMOylation related to PI3K/Akt-mediated regulations on rescuing the dysfunction of HF. | Hytti M, Szabó D, Piippo N, Korhonen E, Honkakoski P, Kaarniranta K, Petrovski G, Kauppinen A (2017) Two dietary polyphenols, fisetin and luteolin, reduce inflammation but augment DNA damage-induced toxicity in human RPE cells. The Journal of nutritional biochemistry 42, 37-42 [PubMed:28113103] [show Abstract] Plant-derived polyphenols are known to possess anti-inflammatory and antioxidant effects. In recent years, several studies have investigated their potential benefits for treating chronic diseases associated with prolonged inflammation and excessive oxidative stress, such as age-related macular degeneration (AMD). Previously, two polyphenols, fisetin and luteolin, have been reported to increase the survival of retinal pigment epithelial (RPE) cells suffering from oxidative stress as well as decreasing inflammation but the benefits of polyphenol therapy seem to depend on the model system used. Our aim was to analyze the effects of fisetin and luteolin on inflammation and cellular viability in a model of nonoxidative DNA damage-induced cell death in human RPE (hRPE) cells. Pretreatment of ARPE-19 or primary hRPE cells with the polyphenols augmented etoposide-induced cell death as measured by the lactate dehydrogenase and 3-(4,5-dimethyldiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. However, the treatment was able to reduce the release of two proinflammatory cytokines, IL-6 and IL-8, which were determined by enzyme-linked Immunosorbent assay. Analyses of caspase 3 activity, p53 acetylation and SIRT1 protein levels revealed the apoptotic nature of etoposide-evoked cell death and that fisetin and luteolin augmented the etoposide-induced acetylation of p53 and decreased SIRT1 levels. Taken together, our findings suggest that the cytoprotective effects of fisetin and luteolin depend on the stressor they need to combat, whereas their anti-inflammatory potential is sustained over a variety of model systems. Careful consideration of disease pathways will be necessary before fisetin or luteolin can be recommended as therapeutic agents for inflammatory diseases in general and specifically AMD. | Pan D, Li D (2016) At the crossroads from bench to bedside: luteolin is a promising pharmacological agent against myocardial ischemia reperfusion injury. Annals of translational medicine 4, 475 [PubMed:28090531] | Tsai PH, Cheng CH, Lin CY, Huang YT, Lee LT, Kandaswami CC, Lin YC, Lee KP, Hung CC, Hwang JJ, Ke FC, Chang GD, Lee MT (2016) Dietary Flavonoids Luteolin and Quercetin Suppressed Cancer Stem Cell Properties and Metastatic Potential of Isolated Prostate Cancer Cells. Anticancer research 36, 6367-6380 [PubMed:27919958] [show Abstract] A highly invasive Du145-III subline was isolated by three successive passages of the parental Du145 prostate tumor cell line (Du145-P) through a Boyden chamber with matrigel-coated membrane support. Du145-III cells showed great invasion potential based on their increased ability to spread/migrate and enhanced expression/secretion of the matrix metalloproteinase 9 (MMP9). Du145-III cells exerted vasculogenic mimicry (VM) properties, reminiscent of endothelial cell characteristics and expressed elevated levels of cancer stem cell (CSC) markers, including Nanog, Sox2, CD44 and ABCG2 and ability to self-renew. Of prominence, MMP9 was required for the induction of VM and for increased stemness in Du145-III cells. Using Du145-III as a model, the effects of dietary flavonoids, luteolin and quercetin, were evaluated on stemness and invasion capacity of Du145-III cells in relation to JNK signaling pathway activation. These flavonoids depressed the malignancy of highly invasive Du145-III cells, VM, anchorage-independent spheroid formation and expression of certain CSC markers. Since luteolin and quercetin were able to target CSC cells and prevent cancer cell invasiveness, may serve as potential anti-angiogenesis and anti-metastasis agents. | Xia N, Chen G, Liu M, Ye X, Pan Y, Ge J, Mao Y, Wang H, Wang J, Xie S (2016) Anti-inflammatory effects of luteolin on experimental autoimmune thyroiditis in mice. Experimental and therapeutic medicine 12, 4049-4054 [PubMed:28101184] [show Abstract] Hashimoto's thyroiditis (HT) is the most common organ-specific autoimmune disease and is believed to be a predominately T cell-mediated autoimmunity. Signal transducer and activator of transcription (STAT)3 is a crucial transcription factor of T cell-mediated immunity, with key roles in the proliferation and migration of T helper (Th) cells, differentiation of Th cells into Th17 cells, and the balance between Treg cells and Th17 cells. Flavonoid luteolin has been shown to markedly inhibit Tyr705 activation/phosphorylation of STAT3 and exert anti-inflammatory effects in multiple sclerosis. In the present study, the effect of luteolin on experimental autoimmune thyroiditis (EAT) was analyzed in C57BL/6 mice. Hematoxylin and eosin examination showed that luteolin attenuated lymphocytic infiltration and follicle destruction in thyroid glands. Immunohistochemistry results demonstrated that luteolin significantly reduced the phosphorylation of STAT3 within the thyroid. An in vitro study was carried out in a RAW264.7 macrophage cell line. Western blot findings demonstrated that luteolin significantly inhibited interferon-γ-induced increases in cyclooxygenase 2, phosphorylated STAT1 and phosphorylated STAT3 expression levels and the secretion of the proinflammatory cytokine tumor necrosis factor-α in supernatants. The present findings indicated that luteolin may exert potent anti-inflammatory effects on murine EAT, which may provide a novel therapeutic medication strategy for the early intervention of HT. | Usman Amin M, Khurram M, Khan TA, Faidah HS, Ullah Shah Z, Ur Rahman S, Haseeb A, Ilyas M, Ullah N, Umar Khayam SM, Iriti M (2016) Effects of Luteolin and Quercetin in Combination with Some Conventional Antibiotics against Methicillin-Resistant Staphylococcus aureus. International journal of molecular sciences 17, E1947 [PubMed:27879665] [show Abstract] The present study was designed to evaluate the effects of flavonoids luteolin (L) and quercetin + luteolin (Q + L) in combination with commonly used antibacterial agents against methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates and S. aureus (ATCC 43300). Minimum inhibitory concentrations (MICs) of L and Q + L, as well as the MICs of flavonoids in combination with antibiotics were determined and results showed an increased activity of flavonoids with antibiotics. The synergistic, additive, or antagonistic relationships between flavonoids (L and Q + L) and antibiotics were also evaluated, and additive and synergistic effects were observed for some antibiotic + flavonoid combinations. In addition, some combinations were also found to damage the bacterial cytoplasmic membrane, as assessed through potassium leakage assay. The effects of flavonoids and flavonoids + antibiotics on mecA gene mutations were also tested, and no functional variation was detected in the coding region. | Xin SB, Yan H, Ma J, Sun Q, Shen L (2016) Protective Effects of Luteolin on Lipopolysaccharide-Induced Acute Renal Injury in Mice. Medical science monitor : international medical journal of experimental and clinical research 22, 5173-5180 [PubMed:28029146] [show Abstract] BACKGROUND Sepsis can cause serious acute kidney injury in bacterium-infected patients, especially in intensive care patients. Luteolin, a bioactive flavonoid, has renal protection and anti-inflammatory effects. This study aimed to investigate the effect and underlying mechanism of luteolin in attenuating lipopolysaccharide (LPS)-induced renal injury. MATERIAL AND METHODS ICR mice were treated with LPS (25 mg/kg) with or without luteolin pre-treatment (40 mg/kg for three days). The renal function, histological changes, degree of oxidative stress, and tubular apoptosis in these mice were examined. The effects of luteolin on LPS-induced expression of renal tumor necrosis factor-α (TNF-α), NF-κB, MCP-1, ICAM-1, and cleaved caspase-3 were evaluated. RESULTS LPS resulted in rapid renal damage of mice, increased level of blood urea nitrogen (BUN), and serum creatinine (Scr), tubular necrosis, and increased oxidative stress, whereas luteolin pre-treatment could attenuate this renal damage and improve the renal functions significantly. Treatment with LPS increased TNF-α, NF-κB, IL-1β, cleaved caspase-3, MCP-1, and ICAM-1 expression, while these disturbed expressions were reversed by luteolin pre-treatment. CONCLUSIONS These results indicate that luteolin ameliorates LPS-mediated nephrotoxicity via improving renal oxidant status, decreasing NF-κB activation and inflammatory and apoptosis factors, and then disturbing the expression of apoptosis-related proteins. | Hwang SH, Paek JH, Lim SS (2016) Simultaneous Ultra Performance Liquid Chromatography Determination and Antioxidant Activity of Linarin, Luteolin, Chlorogenic Acid and Apigenin in Different Parts of Compositae Species. Molecules (Basel, Switzerland) 21, E1609 [PubMed:27886116] [show Abstract] Linarin (LA), luteolin (LE), chlorogenic acid (CA) and apigenin (AP) are four major flavonoids with various promising bioactivities found in Compositae (COP) species. A reliable, reproducible and accurate method for the simultaneous and quantitative determination of these four major flavonoids by Ultra Performance Liquid Chromatography (UPLC) analysis was developed. This method should be appropriate for the quality assurance of COP. The UPLC separation was carried out using an octadecylsilane (ODS) Hypersil (2.1 mm × 250 mm, 1.9 μm) and a mobile phase composed of acetonitrile and 0.1% formic acid in water at a flow rate 0.44 mL/min and ultraviolet (UV) detection 254 nm. Gradient elution was employed. The method was precise, with relative standard deviation below 3.0% and showed excellent linearity (R² > 0.999). The recoveries for the four flavonoids in COP were between 95.49%-106.23%. The average contents of LA, LE, CA and AP in different parts (flower, leave and stem) of COP were between 0.64-1.47 g/100 g, 0.66-0.89 g/100 g, 0.32-0.52 g/100 g and 0.16-0.18 g/100 g, respectively. The method was accurate and reproducible and it can provide a quantitative basis for quality control of COP. | Zhang Q, Yang J, Wang J (2016) Modulatory effect of luteolin on redox homeostasis and inflammatory cytokines in a mouse model of liver cancer. Oncology letters 12, 4767-4772 [PubMed:28101223] [show Abstract] Liver cancer is one of the leading causes of cancer-associated mortality worldwide. Due to changes in lifestyle and daily exposure to various chemicals, which may lead to chemical intoxication, liver cancer has become a prominent disease in humans. Chemical-induced carcinogenesis in experimental animals has become a reliable model for the investigation of liver cancer-associated biological alterations that may mimic human hepatic cancer. Liver cancer in BALB/c mice was induced by administering diethylnitrosamine (DN) in drinking water for 6 weeks. Luteolin (LUT) is a flavone that is found in the leaves of the majority of spice-associated plants. In the present study, 20 µg/kg of body weight LUT was administered intraperitoneally every alternate day to treat the DN-induced liver cancer in mice. LUT improved the host system by modifying the levels of α-fetoprotein, enzymatic antioxidants, such as superoxide dismutase and catalase, marker enzymes, such as AST and ALT, and lipid peroxides in the plasma or liver tissue. LUT also reduced the levels of glutathione and the inflammatory cytokines interleukin-2 and interferon-γ in the plasma or liver tissue. These findings augmented the treatment against liver cancer and supported the effective anticancer activity of LUT against DN-induced liver carcinogenesis in mice. | Arslan BY, Arslan F, Erkalp K, Alagöl A, Sevdi MS, Yıldız G, Küçük SH, Altınay S (2016) Luteolin ameliorates colistin-induced nephrotoxicity in the rat models. Renal failure 38, 1735-1740 [PubMed:27764981] [show Abstract]
Introduction and aimTo study the protective, preventive effect of luteolin from colistin-induced nephrotoxicity.Material and methodFour different treatment options were tested on rats: colistin, luteolin, and a combination of colistin and luteolin, intraperitoneally as two doses a day, for seven days. Another group of rats were used as the control and treated with sterile saline. Serum creatinine levels were measured before and after treatment. Histological changes and colistin-induced apoptosis (Insitu BrdU-red DNA Fragmentation Assay Kit) of the renal tissues were examined after the scarification procedure.ResultsIn the Colistin Group, post-treatment creatinine levels were statistically higher than the pretreatment levels (p = .001). In the remaining groups, no significant changes were observed. Cells that undergo apoptosis were counted and it was shown that all groups except the colistin-treated group had a similar number of apoptotic cells, whereas the colistin-treated group had statistically higher number of apoptotic cells compared to other groups (p = .0001). Renal histological damage was also measured and the score of the colistin treated group was higher as compared to other groups.ConclusionThe results obtained from this study demonstrated us that luteolin was capable of preventing colistin-induced nephrotoxicity and that this effect was significant at histopathological level. | Shen ML, Wang CH, Lin CH, Zhou N, Kao ST, Wu DC (2016) Luteolin Attenuates Airway Mucus Overproduction via Inhibition of the GABAergic System. Scientific reports 6, 32756 [PubMed:27595800] [show Abstract] Airway mucus overproduction is one of the most common symptoms of asthma that causes severe clinical outcomes in patients. Despite the effectiveness of general asthma therapies, specific treatments that prevent mucus overproduction in asthma patients remain lacking. Recent studies have found that activation of GABAA receptors (GABAAR) is important for promoting mucus oversecretion in lung airway epithelia. Here, we report that luteolin, a natural flavonoid compound, suppresses mucus overproduction by functionally inhibiting the GABAergic system. This hypothesis was investigated by testing the effects of luteolin on goblet cell hyperplasia, excessive mucus secretion, and GABAergic transmission using histological and electrophysiological approaches. Our results showed that 10 mg/kg luteolin significantly decreased the number of goblet cells in the lung tissue and inhibited mucus overproduction in an in vivo asthma model induced by ovalbumin (OVA) in mice. Patch-clamp recordings showed that luteolin inhibited GABAAR-mediated currents in A549 cells. Furthermore, the inhibitory effects of luteolin on OVA-induced goblet cell hyperplasia and mucus overproduction were occluded by the GABAAR antagonist picrotoxin. In conclusion, our observations indicate that luteolin effectively attenuates mucus overproduction at least partially by inhibiting GABAARs, suggesting the potential for therapeutic administration of luteolin in the treatment of mucus overproduction in asthma patients. | Yang D, Tan X, Lv Z, Liu B, Baiyun R, Lu J, Zhang Z (2016) Regulation of Sirt1/Nrf2/TNF-α signaling pathway by luteolin is critical to attenuate acute mercuric chloride exposure induced hepatotoxicity. Scientific reports 6, 37157 [PubMed:27853236] [show Abstract] Inorganic mercury, though a key component of pediatric vaccines, is an environmental toxicant threatening human health via accumulating oxidative stress in part. Luteolin has been of great interest because of its antiinflammatory, anticarcinogenic and antioxidative effects. Here we hypothesized that luteolin would attenuate hepatotoxicity induced by acute inorganic mercury exposure. Kunming mice were treated with luteolin (100 mg/kg) 24 h after administration of 4 mg/kg mercuric chloride (HgCl2). The results showed that luteolin ameliorated HgCl2 induced anemia and hepatotoxicity, regulating radical oxygen species (ROS) production and hepatocyte viability in vitro and oxidative stress and apoptosis in vivo. Furthermore, luteolin reversed the changes in levels of inflammation- and apoptosis-related proteins involving NF-κB, TNF-α, Sirt1, mTOR, Bax, p53, and Bcl-2, and inhibited p38 MAPK activation. Luteolin enhanced antioxidant defense system based on Keap1, Nrf2, HO-1, NQO1, and KLF9. Moreover, luteolin did not affect miRNA-146a expression. Collectively, our findings, for the first time, elucidate a precise mechanism for attenuation of HgCl2-induced liver dysfunction by dietary luteolin via regulating Sirt1/Nrf2/TNF-α signaling pathway, and provide a foundation for further study of luteolin as a novel therapeutic agent against inorganic mercury poisoning. | Yokoyama T, Kosaka Y, Mizuguchi M (2015) Structural Insight into the Interactions between Death-Associated Protein Kinase 1 and Natural Flavonoids. Journal of medicinal chemistry 58, 7400-7408 [PubMed:26322379] [show Abstract] Death-associated protein kinase 1 (DAPK1) is a 160 kDa serine/threonine protein kinase that belongs to the Ca(2+)/calmodulin-dependent protein kinase subfamily. DAPK1 is a possible target for the treatment of acute ischemic stroke and endometrial adenocarcinomas. In the present study, we investigated the binding characteristics of 17 natural flavonoids to DAPK1 using a 1-anilinonaphthalene-8-sulfonic acid competitive binding assay and revealed that morin was the strongest binder among the selected compounds. The crystallographic analysis of DAPK1 and 7 selected flavonoid complexes revealed the structure-binding affinity relationship in atomic-level detail. It was suggested that the high affinity of morin could be accounted for by the ionic interaction between 2'-OH and K42 and that such an interaction would not take place with either cyclin-dependent protein kinases or PIM kinases because of their broader entrance regions. Thus, morin would be a more selective inhibitor of DAPK1 than either of these other types of kinases. In addition, we found that the binding of kaempferol to DAPK1 was associated with a chloride ion. The present study provides a better understanding of the molecular properties of the ATP site of DAPK1 and may be useful for the design of specific DAPK1 inhibitors. | Iakovleva I, Begum A, Pokrzywa M, Walfridsson M, Sauer-Eriksson AE, Olofsson A (2015) The flavonoid luteolin, but not luteolin-7-O-glucoside, prevents a transthyretin mediated toxic response. PloS one 10, e0128222 [PubMed:26020516] [show Abstract] Transthyretin (TTR) is a homotetrameric plasma protein with amyloidogenic properties that has been linked to the development of familial amyloidotic polyneuropathy (FAP), familial amyloidotic cardiomyopathy, and senile systemic amyloidosis. The in vivo role of TTR is associated with transport of thyroxine hormone T4 and retinol-binding protein. Loss of the tetrameric integrity of TTR is a rate-limiting step in the process of TTR amyloid formation, and ligands with the ability to bind within the thyroxin binding site (TBS) can stabilize the tetramer, a feature that is currently used as a therapeutic approach for FAP. Several different flavonoids have recently been identified that impair amyloid formation. The flavonoid luteolin shows therapeutic potential with low incidence of unwanted side effects. In this work, we show that luteolin effectively attenuates the cytotoxic response to TTR in cultured neuronal cells and rescues the phenotype of a Drosophila melanogaster model of FAP. The plant-derived luteolin analogue cynaroside has a glucoside group in position 7 of the flavone A-ring and as opposed to luteolin is unable to stabilize TTR tetramers and thus prevents a cytotoxic effect. We generated high-resolution crystal-structures of both TTR wild type and the amyloidogenic mutant V30M in complex with luteolin. The results show that the A-ring of luteolin, in contrast to what was previously suggested, is buried within the TBS, consequently explaining the lack of activity from cynaroside. The flavonoids represent an interesting group of drug candidates for TTR amyloidosis. The present investigation shows the potential of luteolin as a stabilizer of TTR in vivo. We also show an alternative orientation of luteolin within the TBS which could represent a general mode of binding of flavonoids to TTR and is of importance concerning the future design of tetramer stabilizing drugs. | Narwal M, Haikarainen T, Fallarero A, Vuorela PM, Lehtiö L (2013) Screening and structural analysis of flavones inhibiting tankyrases. Journal of medicinal chemistry 56, 3507-3517 [PubMed:23574272] [show Abstract] Flavonoids are known for their beneficial effects on human health, and therefore the therapeutic potential of these compounds have been extensively studied. Flavone has been previously identified as a tankyrase inhibitor, and to further elucidate whether tankyrases would be inhibited by other flavonoids, we performed a systematic screening of tankyrase 2 inhibitory activity using 500 natural and naturally derived flavonoids covering nine different flavonoid classes. All identified tankyrase inhibitors were flavones. We report crystal structures of all the hit compounds in complex with the catalytic domain of human tankyrase 2. Flavone derivatives in all 10 crystal structures bind to the nicotinamide binding site of tankyrase 2. Potencies of the active flavones toward tankyrases vary between 50 nM and 1.1 μM, and flavones show up to 200-fold selectivity for tankyrases over ARTD1. The molecular details of the interactions revealed by cocrystal structures efficiently describe the properties of potent flavone derivatives inhibiting tankyrases. | Jeon YW, Suh YJ (2013) Synergistic apoptotic effect of celecoxib and luteolin on breast cancer cells. Oncology reports 29, 819-825 [PubMed:23229294] [show Abstract] Breast cancer is heterogeneous and often hormone-dependent. There are many breast cancer treatment options, including endocrine therapy, chemotherapy, radiotherapy and targeted therapy. Unfortunately, not all patients respond to first-line treatments, and others will eventually relapse despite an initial response. Therapeutic options for these patients are limited. In the past decade, several studies have demonstrated the antitumor effect of celecoxib and luteolin in breast cancer as single treatment. The effect of combination treatment of celecoxib and luteolin in human breast cancer cells has not been well characterized. The present study examined the synergistic effect of celecoxib and luteolin on the human breast cancer cell lines MCF-7 and MDA-MB-231. We analyzed cell proliferation, cell death, apoptosis and changes in protein expression by performing cell survival assays, apoptosis assays and western blotting. The combination treatment significantly decreased cancer cell viability, and it had a greater efficiency in killing tumor cells after 72 h of treatment, compared to treatment with either agent alone or the control in a concentration- and time-dependent manner (P=0.01). The combination treatment demonstrated a greater than additive increase in breast cancer cell apoptosis (P=0.01). Decreased levels of Akt phosphorylation (pAkt) were noted after celecoxib and luteolin combination treatment. The combination of celecoxib and luteolin provided superior inhibition of breast cancer cell growth than either celecoxib or luteolin treatment alone. These results suggest that celecoxib and luteolin combination may be a new possible treatment option for breast cancer. | Guo DJ, Li F, Yu PH, Chan SW (2013) Neuroprotective effects of luteolin against apoptosis induced by 6-hydroxydopamine on rat pheochromocytoma PC12 cells. Pharmaceutical biology 51, 190-196 [PubMed:23035972] [show Abstract]
ContextApoptotic neuronal cell death plays an important role in Parkinson's disease (PD), a progressive neurodegenerative disorder. Luteolin, a flavonoid, has been shown to possess various pharmacological properties including strong antioxidant capacity.ObjectiveThis study investigated the neuroprotective effect of luteolin against cytotoxicity induced by 6-hydroxy-dopamine (6-OHDA) (250 µM) in rat pheochromocytoma (PC12) cell line.Materials and methodsThe neuroprotective effect of luteolin against 6-OHDA-induced cytotoxicity in PC12 was evaluated by using cell viability test, nuclear staining and flow cytometry. In addition, the apoptotic role of luteolin was unveiled by monitoring mRNA expression of proapoptotic and anti-apoptotic genes.ResultsPretreatment with luteolin (3.13, 6.25, 12.5, 25 or 50 µM) could markedly attenuate 6-OHDA-induced PC12 cell viability loss in a concentration-dependent manner. Cell morphologic analysis and nuclear staining assays showed that luteolin (3.13, 12.5 or 50 µM) protected the cells from 6-OHDA-induced damage. As shown in the flow cytometry assay, the increased apoptotic rate induced by 6-OHDA could be significantly (p < 0.001) suppressed by luteolin (12.5 or 50 µM) pretreatment. The protection of luteolin (50 µM) against 6-OHDA-induced cell damage was shown to be through suppressing the over-expression of Bax gene (p < 0.01), inhibiting the reduction of Bcl-2 gene expression (p < 0.05) and markedly depressing the enhanced Bax/Bcl-2 ratio. Luteolin also downregulated the gene expression level of p53.Discussion and conclusionLuteolin has protective effects against 6-OHDA-induced cell apoptosis and might be a potential nutritional supplement which could be used to prevent neurodegenerative diseases such as PD. | Androutsopoulos VP, Spandidos DA (2013) The flavonoids diosmetin and luteolin exert synergistic cytostatic effects in human hepatoma HepG2 cells via CYP1A-catalyzed metabolism, activation of JNK and ERK and P53/P21 up-regulation. The Journal of nutritional biochemistry 24, 496-504 [PubMed:22749133] [show Abstract] Various types of tumors are known to overexpress enzymes belonging to the CYP1 family of cytochromes P450. The present study aimed to characterize the metabolism and further antiproliferative activity of the natural flavonoid diosmetin in the CYP1-expressing human hepatoma cell line HepG2. Diosmetin was converted to luteolin in HepG2 cells after 12 and 30 h of incubation. In the presence of the CYP1A inhibitor α-naphthoflavone, the conversion of diosmetin to luteolin was attenuated. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays revealed luteolin to be more cytotoxic than diosmetin. The antiproliferative effect of diosmetin in HepG2 cells was attributed to blockage at the G2/M phase as determined by flow cytometry. Induction of G2/M arrest was accompanied by up-regulation of phospho-extracellular-signal-regulated kinase (p-ERK), phospho-c-jun N-terminal kinase, p53 and p21 proteins. More importantly, induction of G2/M arrest and p53 and p-ERK up-regulation were reversed by the application of the CYP1 inhibitor α-naphthoflavone. Taken together, the data provide new evidence on the tumor-suppressing role of cytochrome P450 CYP1A enzymes and extend the hypothesis that the anticancer activity of dietary flavonoids is enhanced by P450-activation. | Lolli G, Cozza G, Mazzorana M, Tibaldi E, Cesaro L, Donella-Deana A, Meggio F, Venerando A, Franchin C, Sarno S, Battistutta R, Pinna LA (2012) Inhibition of protein kinase CK2 by flavonoids and tyrphostins. A structural insight. Biochemistry 51, 6097-6107 [PubMed:22794353] [show Abstract] Sixteen flavonoids and related compounds have been tested for their ability to inhibit three acidophilic Ser/Thr protein kinases: the Golgi apparatus casein kinase (G-CK) recently identified with protein FAM20C, protein kinase CK1, and protein kinase CK2. While G-CK is entirely insensitive to all compounds up to 40 μM concentration, consistent with the view that it is not a member of the kinome, and CK1 is variably inhibited in an isoform-dependent manner by fisetin and luteolin, and to a lesser extent by myricetin and quercetin, CK2 is susceptible to drastic inhibition by many flavonoids, displaying with six of them IC(50) values < 1 μM. A common denominator of these compounds (myricetin, quercetin, fisetin, kaempferol, luteolin, and apigenin) is a flavone scaffold with at least two hydroxyl groups at positions 7 and 4'. Inhibition is competitive with respect to the phospho-donor substrate ATP. The crystal structure of apigenin and luteolin in complex with the catalytic subunit of Zea mays CK2 has been solved, revealing their ability to interact with both the hinge region (Val116) and the positive area near Lys68 and the conserved water W1, the two main polar ligand anchoring points in the CK2 active site. Modeling experiments account for the observation that luteolin but not apigenin inhibits also CK1. The observation that luteolin shares its pyrocatechol moiety with tyrphostin AG99 prompted us to solve also the structure of this compound in complex with CK2. AG99 was found inside the ATP pocket, consistent with its mode of inhibition competitive with respect to ATP. As in the case of luteolin, the pyrocatechol group of AG99 is critical for binding, interacting with the positive area in the deepest part of the CK2 active site. | Trivella DB, dos Reis CV, Lima LM, Foguel D, Polikarpov I (2012) Flavonoid interactions with human transthyretin: combined structural and thermodynamic analysis. Journal of structural biology 180, 143-153 [PubMed:22842046] [show Abstract] Transthyretin (TTR) is a carrier protein involved in human amyloidosis. The development of small molecules that may act as TTR amyloid inhibitors is a promising strategy to treat these pathologies. Here we selected and characterized the interaction of flavonoids with the wild type and the V30M amyloidogenic mutant TTR. TTR acid aggregation was evaluated in vitro in the presence of the different flavonoids. The best TTR aggregation inhibitors were studied by Isothermal Titration Calorimetry (ITC) in order to reveal their thermodynamic signature of binding to TTRwt. Crystal structures of TTRwt in complex with the top binders were also obtained, enabling us to in depth inspect TTR interactions with these flavonoids. The results indicate that changing the number and position of hydroxyl groups attached to the flavonoid core strongly influence flavonoid recognition by TTR, either by changing ligand affinity or its mechanism of interaction with the two sites of TTR. We also compared the results obtained for TTRwt with the V30M mutant structure in the apo form, allowing us to pinpoint structural features that may facilitate or hamper ligand binding to the V30M mutant. Our data show that the TTRwt binding site is labile and, in particular, the central region of the cavity is sensible for the small differences in the ligands tested and can be influenced by the Met30 amyloidogenic mutation, therefore playing important roles in flavonoid binding affinity, mechanism and mutant protein ligand binding specificities. | Puhl AC, Bernardes A, Silveira RL, Yuan J, Campos JL, Saidemberg DM, Palma MS, Cvoro A, Ayers SD, Webb P, Reinach PS, Skaf MS, Polikarpov I (2012) Mode of peroxisome proliferator-activated receptor γ activation by luteolin. Molecular pharmacology 81, 788-799 [PubMed:22391103] [show Abstract] The peroxisome proliferator-activated receptor γ (PPARγ) is a target for treatment of type II diabetes and other conditions. PPARγ full agonists, such as thiazolidinediones (TZDs), are effective insulin sensitizers and anti-inflammatory agents, but their use is limited by adverse side effects. Luteolin is a flavonoid with anti-inflammatory actions that binds PPARγ but, unlike TZDs, does not promote adipocyte differentiation. However, previous reports suggested variously that luteolin is a PPARγ agonist or an antagonist. We show that luteolin exhibits weak partial agonist/antagonist activity in transfections, inhibits several PPARγ target genes in 3T3-L1 cells (LPL, ORL1, and CEBPα) and PPARγ-dependent adipogenesis, but activates GLUT4 to a similar degree as rosiglitazone, implying gene-specific partial agonism. The crystal structure of the PPARγ ligand-binding domain (LBD) reveals that luteolin occupies a buried ligand-binding pocket (LBP) but binds an inactive PPARγ LBD conformer and occupies a space near the β-sheet region far from the activation helix (H12), consistent with partial agonist/antagonist actions. A single myristic acid molecule simultaneously binds the LBP, suggesting that luteolin may cooperate with other ligands to bind PPARγ, and molecular dynamics simulations show that luteolin and myristic acid cooperate to stabilize the Ω-loop among H2', H3, and the β-sheet region. It is noteworthy that luteolin strongly suppresses hypertonicity-induced release of the pro-inflammatory interleukin-8 from human corneal epithelial cells and reverses reductions in transepithelial electrical resistance. This effect is PPARγ-dependent. We propose that activities of luteolin are related to its singular binding mode, that anti-inflammatory activity does not require H12 stabilization, and that our structure can be useful in developing safe selective PPARγ modulators. | Lee WC, Jung HA, Choi JS, Kim YS, Lee SM (2011) Protective effects of luteolin against apoptotic liver damage induced by D-galactosamine/lipopolysaccharide in mice. Journal of natural products 74, 1916-1921 [PubMed:21899269] [show Abstract] In this study, the protective effects of luteolin (1, a major component of Cirsium japonicum) were examined against d-galactosamine (GalN)/lipopolysaccharide (LPS)-induced fulminant hepatic failure. Mice received an intraperitoneal injection of 1 (25, 50, 100, and 200 mg·kg(-1)) 1 h before treatment with GalN (700 mg·kg(-1))/LPS (10 μg·kg(-1)). Treatment with GalN/LPS resulted in increased mortality and serum aminotransferase activity. These increases were attenuated by pretreatment with 1. Treatment with GalN/LPS induced an increase in the serum level of tumor necrosis factor-α (TNF-α) and protein expression of TNF-α receptor-associated death domain, and these increases were prevented by 1. In addition, 1 attenuated apoptosis induced by GalN/LPS treatment, which was analyzed using a caspase-3 and -8 activity assay, as well as by proapoptotic BH3-only protein and cytochrome c protein expression, and by a terminal deoxynuleotidyl transferase-mediated dUTP nick end-labeling method. After GalN/LPS injection, nuclear phosphorylated c-Jun levels showed a significant increase, which were attenuated by 1. The present findings suggest that luteolin ameliorates D-GalN/LPS-induced liver injury and that this protection is likely due to inhibition of the extrinsic and intrinsic apoptotic pathways. | Raines T, Jones P, Moe N, Duncan R, McCall S, Ceremuga TE (2009) Investigation of the anxiolytic effects of luteolin, a lemon balm flavonoid in the male Sprague-Dawley rat. AANA journal 77, 33-36 [PubMed:19263826] [show Abstract] The purpose of this study was to investigate the anxiolytic effects of luteolin and its potential interaction with the gamma-aminobutyric acid (GABAA) receptor in male Sprague-Dawley rats. Lemon balm has traditionally been used as an herbal remedy in the treatment of many medical conditions, including anxiety. Luteolin is a major component of the essential oil lemon balm. We divided 55 rats into 5 groups: (1) control (negative control), (2) luteolin, (3) midazolam (positive control), (4) flumazenil and luteolin, and (5) midazolam and luteolin. The behavioral component of anxiety was examined by using the elevated plus-maze (open arm time/total time) and motor movements. Data analyses were performed using a 2-tailed multivariate analysis of variance and Sheffé post hoc test. Our data suggest that luteolin does not produce anxiolysis by modulation of the GABAA receptor; however, luteolin may modulate motor movements and locomotion. | Ando C, Takahashi N, Takahashi N, Hirai S, Nishimura K, Lin S, Uemura T, Goto T, Yu R, Nakagami J, Murakami S, Kawada T (2009) Luteolin, a food-derived flavonoid, suppresses adipocyte-dependent activation of macrophages by inhibiting JNK activation. FEBS letters 583, 3649-3654 [PubMed:19854181] [show Abstract] Interaction between adipocytes and macrophages contributes to the development of insulin resistance in obese adipose tissues. In this study, we examined whether luteolin, food-derived flavonoid, could suppress the production of inflammatory mediators of the interaction between adipocytes and macrophages. Experiments using a coculture system of adipocytes and macrophages showed that luteolin suppressed the production of inflammatory mediators. In addition, activated macrophages were targets for the suppressive effect of luteolin. Luteolin inhibited the phosphorylation of JNK and suppressed the production of inflammatory mediators in the activated macrophages. The findings indicate that luteolin can inhibit the interaction between adipocytes and macrophages to suppress the production of inflammatory mediators, suggesting that luteolin is a valuable food-derived compound for the treatment of metabolic syndrome. | Zhou Q, Yan B, Hu X, Li XB, Zhang J, Fang J (2009) Luteolin inhibits invasion of prostate cancer PC3 cells through E-cadherin. Molecular cancer therapeutics 8, 1684-1691 [PubMed:19509250] [show Abstract] Luteolin, a common dietary flavonoid, has been found to have antitumor properties and therefore poses special interest for the development of preventive and/or therapeutic agent for cancers. E-cadherin, a marker of epithelial cells, mediates cell-cell adhesion. Decreased expression of E-cadherin results in a loss of cell-cell adhesion and an increased cell invasion. Many studies have shown the antiproliferative activities of luteolin on cancer cells. However, the effects of luteolin on invasion of cancer cells remain unclear. In this article, we show that luteolin inhibits invasion of prostate cancer PC3 cells through E-cadherin. We found that Luteolin induced expression of E-cadherin through mdm2. Overexpression of mdm2 or knockdown of E-cadherin could restore invasion of PC3 cells after luteolin treatment. Luteolin inhibits mdm2 through AKT and overexpression of active AKT attenuated luteolin-induced expression of E-cadherin, suggesting that luteolin regulates E-cadherin through AKT/mdm2 pathway. The in vivo experiments showed that luteolin inhibited spontaneous lung metastasis of PC3 cells implanted onto the nude mice. These findings provide a new sight into the mechanisms that luteolin is against cancer cells, and suggest that molecular targeting of E-cadherin by luteolin may be a useful strategy for treatment of invasive prostate cancers. | Lin Y, Shi R, Wang X, Shen HM (2008) Luteolin, a flavonoid with potential for cancer prevention and therapy. Current cancer drug targets 8, 634-646 [PubMed:18991571] [show Abstract] Luteolin, 3',4',5,7-tetrahydroxyflavone, is a common flavonoid that exists in many types of plants including fruits, vegetables, and medicinal herbs. Plants rich in luteolin have been used in Chinese traditional medicine for treating various diseases such as hypertension, inflammatory disorders, and cancer. Having multiple biological effects such as anti-inflammation, anti-allergy and anticancer, luteolin functions as either an antioxidant or a pro-oxidant biochemically. The biological effects of luteolin could be functionally related to each other. For instance, the anti-inflammatory activity may be linked to its anticancer property. Luteolin's anticancer property is associated with the induction of apoptosis, and inhibition of cell proliferation, metastasis and angiogenesis. Furthermore, luteolin sensitizes cancer cells to therapeutic-induced cytotoxicity through suppressing cell survival pathways such as phosphatidylinositol 3'-kinase (PI3K)/Akt, nuclear factor kappa B (NF-kappaB), and X-linked inhibitor of apoptosis protein (XIAP), and stimulating apoptosis pathways including those that induce the tumor suppressor p53. These observations suggest that luteolin could be an anticancer agent for various cancers. Furthermore, recent epidemiological studies have attributed a cancer prevention property to luteolin. In this review, we summarize the progress of recent research on luteolin, with a particular focus on its anticancer role and molecular mechanisms underlying this property of luteolin. | Kaneko M, Takimoto H, Sugiyama T, Seki Y, Kawaguchi K, Kumazawa Y (2008) Suppressive effects of the flavonoids quercetin and luteolin on the accumulation of lipid rafts after signal transduction via receptors. Immunopharmacology and immunotoxicology 30, 867-882 [PubMed:18720166] [show Abstract] Quercetin (QUER) and luteolin (LUTE) are dietary flavonoids capable of regulating the production of cytokines, such as tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6). However, their mechanisms of action are not fully understood. In lipopolysaccharide-triggered (LPS)-triggered signaling via Toll-like receptor 4 (TLR4), QUER and LUTE suppresses not only the degradation of the inhibitor of kappaB (IkappaB), with resultant activation of nuclear factor-kappaB (NF-kappaB), but also the phosphorylation of p38 and Akt in bone marrow-derived macrophages that have been stimulated with LPS. We report here that, in TNF-alpha-induced signaling, QUER and LUTE significantly suppressed the production of IL-6 and activation of NF-kappaB. Accumulation of lipid rafts, the initial step in the signaling pathway, was significantly inhibited when macrophages were treated with QUER or with LUTE prior to exposure to LPS. Similarly, the accumulation of lipid rafts was inhibited by the flavonoids when B cells were activated via the membrane IgM and when T cells were activated via CD3. In contrast, QUER and LUTE did not inhibit the activation of phorbol myristate acetate-induced NF-kappaB in macrophages. Our observations suggest that QUER and LUTE interact with receptors on the cell surface and suppress the accumulation of lipid rafts that occurs downstream of the activation of the receptors. | Seelinger G, Merfort I, Wölfle U, Schempp CM (2008) Anti-carcinogenic effects of the flavonoid luteolin. Molecules (Basel, Switzerland) 13, 2628-2651 [PubMed:18946424] [show Abstract] 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. | Lee S, Seo DH, Park HL, Choi Y, Jung S (2003) Solubility enhancement of a hydrophobic flavonoid, luteolin by the complexation with cyclosophoraoses isolated from Rhizobium meliloti. Antonie van Leeuwenhoek 84, 201-207 [PubMed:14574115] [show Abstract] A plant flavone, luteolin is a well-known inducer of nod genes in the Rhizobium meliloti. Its poor aqueous solubility was greatly enhanced by the complexation with a family of cyclosophoraoses synthesized in R.meliloti. Nuclear magnetic resonance (NMR) spectroscopic analysis showed that the chemical shifts of the aromatic ring moieties of the luteolin were changed greatly by the complexation with cyclosophoraoses. Fourier transform infrared (FTIR) spectroscopic analysis also showed a restricted vibrational pattern in carbonyl stretching region of the luteolin due to the complexation. This effective complex formation of cyclosophoraoses with a plant flavone, luteolin, suggests that rhizobial cyclosophoraoses play an important role as a solubility enhancer of the hydrophobic legume-derived flavonoids. | Kotanidou A, Xagorari A, Bagli E, Kitsanta P, Fotsis T, Papapetropoulos A, Roussos C (2002) Luteolin reduces lipopolysaccharide-induced lethal toxicity and expression of proinflammatory molecules in mice. American journal of respiratory and critical care medicine 165, 818-823 [PubMed:11897650] [show Abstract] Luteolin is a flavonoid that has been shown to reduce proinflammatory molecule expression in vitro. In the present study, we have tested the ability of luteolin to inhibit lipopolysaccharide (LPS)- induced lethal toxicity and proinflammatory molecule expression in vivo. Mice receiving LPS (Salmonella enteriditis LPS, 32 mg/kg, intraperitoneally) exhibited high mortality with only 4.1% of the animals surviving seven days after the LPS challenge. On the contrary, mice that had received luteolin (0.2 mg/kg, intraperitoneally) before LPS showed an increased survival rate with 48% remaining alive on Day 7. To investigate the mechanism by which luteolin affords protection against LPS toxicity we measured intercellular adhesion molecule-1 (ICAM-1) and tumor necrosis factor-alpha (TNF-alpha) production in response to LPS in the presence or absence of luteolin pretreatment. Treatment of animals with LPS increased serum TNF-alpha levels in a time-dependent manner. The increase in peak serum TNF-alpha levels was sensitive to luteolin pretreatment. Luteolin pretreatment also reduced LPS-stimulated ICAM-1 expression in the liver and abolished leukocyte infiltration in the liver and lung. We conclude that luteolin protects against LPS-induced lethal toxicity, possibly by inhibiting proinflammatory molecule (TNF-alpha, ICAM-1) expression in vivo and reducing leukocyte infiltration in tissues. | Romanová D, Vachálková A, Cipák L, Ovesná Z, Rauko P (2001) Study of antioxidant effect of apigenin, luteolin and quercetin by DNA protective method. Neoplasma 48, 104-107 [PubMed:11478688] [show Abstract] A DNA protective capacity of three flavonoids, apigenin (AP), luteolin (LU) and quercetin (QU) against free radicals generated by H202, resp. Fe2+ is reported. This effect corresponding with scavenging of free radicals or with chelating of iron was assayed at two concentrations of flavonoids studied (1 microM and 10 microM). The quantitative analysis has shown that LU possesses the highest DNA protective effect of flavonoids investigated in the presence of H2O2. On the other hand, in the presence of 10 microM Fe2+, AP exhibited the highest DNA protective effect at the concentration of 1 microM and the following order was reached at the stoichiometric concentrations (10 microM) of Fe2+. It is believed that this discrepancy is caused by the ability of LU and QU iron-complex formation as it was separately investigated using UV-VIS spectrometry. |
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