Flavonoids

 

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Recent Publications (PDF)

Tolerability and Benefit of a Tetramethoxyluteolin-containing Skin Lotion

As many as 40% of people have sensitive skin and at least half of them suffer from pruritus associated with allergies, atopic dermatitis (AD), chronic urticaria (CU), cutaneous mastocytosis (CM), and psoriasis. Unfortunately, the available topical formulations contain antihistamines that are often not as effective as those containing corticosteroids. Certain natural flavonoids have anti-inflammatory actions. We recently reported that the natural flavonoid tetramethoxyluteolin has potent antiallergic and anti-inflammatory actions in vitro and in vivo. This flavonoid was formulated in a skin lotion along with olive fruit extract and was first tested for tolerability in 25 patients with mastocytosis or mast cell activation syndrome and very sensitive skin who reported back through a questionnaire. The skin lotion was then used by eight patients, four with AD and four with psoriasis, who had not received any topical treatment for at least 2 months, twice daily for 2 weeks. The use of this tetramethoxyluteolin formulation resulted in significant improvement of the skin lesions and could be useful adjuvant treatment for allergic and inflammatory skin conditions.

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The Novel Flavone Tetramethoxyluteolin is a Potent Inhibitor of Human Mast Cells

Background: Mast cells (MCs) are hematopoietic cells that mature in tissues and are involved in allergy, immunity, and inflammation by secreting multiple mediators. The natural flavone luteolin has anti-inflammatory actions and inhibits human mast cells (MCs).

 

Objective: We sought to investigate the ability of luteolin and its novel structural analog 39,49,5,7-tetramethoxyluteolin (methlut) to inhibit human MC mediator expression and release in vitro and in vivo.

 

Conclusion: Methlut is a promising MC inhibitor for the treatment of allergic and inflammatory conditions. (J Allergy Clin Immunol 2015;135:1044-52.)

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Methoxyluteolin Inhibits Neuropeptide-stimulated Proinflammatory Mediator Release via mTOR Activation from Human Mast Cells

Mast cells (MCs) are critical for allergic reactions but are also important in inflammatory processes. Stimulation by neuropeptides, such as substance P (SP) and neurotensin (NT), leads to release of preformed molecules stored in numerous MC secretory granules and newly synthesized proinflammatory mediators, including tumor necrosis factor, C-X-C motif chemokine ligand 8, and vascular endothelial growth factor. Here, we investigate the role of mammalian target of rapamycin (mTOR) signaling in the stimulation of cultured human LAD2 MCs by NT or SP, as well as the inhibitory effect of the natural flavonoids 39,49,5,7-tetrahydroxyflavone (luteolin) and its novel structural analog 39,49,5,7-tetramethoxyflavone (methoxyluteolin). Stimulation by NT (10 mM) or SP (1 mM) increases (P , 0.0001) gene expression (after 6 hours) and release (after 24 hours) of tumor necrosis factor, C-X-C motif chemokine ligand 8, and vascular endothelial growth factor. This occurs via activation of both mTOR complexes, as denoted by the increased phosphorylated (p) protein levels (P , 0.0001) of the downstream mTORC1 substrate pp70S6KThr389 and mTORC2 component pmTORSer2448. Pretreatment of human MCs using the mTORC1 inhibitor rapamycin, the mTORC1/mTORC2 inhibitor Torin1, or the two flavonoids decreases both gene expression and release (P , 0.0001) of all three mediators. Methoxyluteolin is a more potent human MC inhibitor than luteolin or Torin1, implicating other MC protein targets in addition to the mTOR complex. These findings indicate thatmTORis partially involved in the neuropeptide stimulation of MCs, but the novel flavonoid methoxyluteolin inhibits the response entirely, suggesting that it may be developed for treatment of allergic and inflammatory diseases.

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Flavonols inhibit proinflammatory mediator release, intracellular calcium ion levels and protein kinase C theta phosphorylation in human mast cells

Mast cells are important effector cells in IgE-mediated reactions by secreting histamine, chymase, tryptase, leukotrienes (LTs), prostaglandin D2 (PGD2) and several multifunctional cytokines; they include interleukin-6 (IL-6), IL-8, IL-13, tumor necrosis factor-alpha (TNF-a), stem cell factor (SCF) and many chemotactic factors (Galli, 2000; Mekori & Metcalfe, 2000). These cytokines contribute to the late-phase allergic reactions and to allergic inflammation through the recruitment of immune cells into the site of inflammation (Wedemeyer et al., 2000; Theoharides & Cochrane, 2004). Tryptase, expressed by all subsets of human mast cells and comprising up to 25% of the total intracellular proteins, has emerged as an important mediator in allergic diseases (Shaoheng et al., 1998). Tryptase and other serine proteases are signaling molecules that cleave protease-activated surface receptor-2 (PAR-2) leading to widespread inflammation (Steinhoff et al., 2000; Cottrell et al., 2003). Calcium influx is necessary for mast cell mediator secretion (Kimata et al., 2000b) and PAR-2 activation has also been associated with a brisk increase in intracellular calcium concentration (Dery et al., 1998).

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Flavones inhibit proliferation and increase mediator content in human leukemic mast cells (HMC-1)

Objective: Mast cells are involved in allergic and inflammatory reactions. These cells are also increased in the bone marrow,skin, and other organs in systemic mastocytosis. Flavonoids are naturally occurring molecules with antioxidant,cytoprot ective,and anti-inflammatory activities. Some flavonoids,like quercetin,inhibit the growth of certain malignant cells in culture. Quercetin also inhibits histamine release and induces accumulation of secretory granules in rat basophilic leukemia cells. Method: We investigated the effect of five flavonoids: flavone,ka empferol,morin, myricetin,and quercetin at 1,10,an d 100 lm on proliferation and secretory mediator content (b-hexosaminidase, histami ne, and tryptase) in human leukemic mast cells (HMC- 1),the doubling time of which was about 2 d. Results: Flavone and kaempferol at 100 lm inhibited cell proliferation over 80% on either day 3,4,or 5 of culture. Quercetin showed this level of inhibition only on day 5,myriceti n inhibited by 50% at days 3–5,wher eas morin's inhibition was <20%. All flavonoids (except morin) at 100 lm increased histamine and tryptase content,but not b-hexosaminidase,equ ally at days 3 and 4 of culture quercetin also increased the development of secretory granules. Conclusion: These results indicate that certain flavonoids can inhibit HMC-1 proliferation,ind uce secretory granule development and the accumulation of mediators.

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The Effects of Plant Flavonoids on Mammalian Cells: Implications for Inflammation, Heart Disease, and Cancer

Flavonoids are nearly ubiquitous in plants and are recognized as the pigments responsible for the colors of leaves, especially in autumn. They are rich in seeds, citrus fruits, olive oil, tea, and red wine. They are low molecular weight compounds composed of a three-ring structure with various substitutions. This basic structure is shared by tocopherols (vitamin E). Flavonoids can be subdivided according to the presence of an oxy group at position 4, a double bond between carbon atoms 2 and 3, or a hydroxyl group in position 3 of the C (middle) ring. These characteristics appear to also be required for best activity, especially antioxidant and antiproliferative, in the systems studied. The particular hydroxylation pattern of theBring of the flavonoles increases their activities, especially in inhibition of mast cell secretion. Certain plants and spices containing flavonoids have been used for thousands of years in traditional Eastern medicine. In spite of the voluminous literature available, however, Western medicine has not yet used flavonoids therapeutically, even though their safety record is exceptional. Suggestions are made where such possibilities may be worth pursuing.

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The Isoflavone Genistein Inhibits Proliferation and Increases Histamine Content in Human Leukemic Mast Cells

Mast cells are involved in allergic inflammation and some rare disorders such as systemic mastocytosis and mast cell leukemia. Certain naturally occurring flavonoids have been shown to inhibit mast cell activation and promote maturation of secretory granules. Here, we report that the isoflavone genistein inhibited the growth of human leukemic mast cells (HMC-1) by 68.8, 51.6, and 30.2% at 1024 , 1025 , and 1026 M, respectively, at day 3 (p , 0.001). Genistein at 1024 M increased the histamine content per 2 3 105 cells at day 3 from 5.9 6 1.2 mg/mL to 11.1 6 1.3 mg/mL (n 5 6; p , 0.0001). These results indicate that genistein can inhibit proliferation and induce maturation of HMC-1 cells. (Allergy and Asthma Proc 24:373–377, 2003)

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The flavonoid luteolin inhibits niacin-induced flush

Background and purpose: Sustained release niacin effectively lowers serum cholesterol, LDL and triglycerides, while raising HDL. However, 75% of patients experience cutaneous warmth and itching known as flush, leading to discontinuation. Acetylsalicylic acid (aspirin) reduces this flush only by about 30%, presumably through decreasing prostaglandin D2 (PGD2). We investigated whether niacin-induced flush in a rat model involves PGD2 and 5-HT, and the effect of certain flavonoids. Experimental approach: Three skin temperature measurements from each ear were recorded with an infrared pyrometer for each time point immediately before i.p. injection with either niacin or a flavonoid. The temperature was then measured every 10 min for 60 min.

Key results: Niacin (7.5mg per rat, equivalent to a human dose of 1750mg per 80 kg) maximally increased ear temperature to 1.9±0.2 oC at 45 min. Quercetin and luteolin (4.3mg per rat; 1000 mg per human), administered i.p. 45 min prior to niacin, inhibited the niacin effect by 96 and 88%, respectively. Aspirin (1.22mg per rat; 325mg per human) inhibited the niacin effect by only 30%. Niacin almost doubled plasma PGD2 and 5-HT, but aspirin reduced only PGD2 by 86%. In contrast, luteolin inhibited both plasma PGD2 and 5-HT levels by 100 and 67%, respectively.

Conclusions and implications. Niacin-induced skin temperature increase is associated with PGD2 and 5-HT elevations in rats; luteolin may be a better inhibitor of niacin-induced flush because it blocks the rise in both mediators.

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Luteolin as a therapeutic option for multiple sclerosis

Multiple sclerosis (MS) remains without an effective treatment in spite of intense research efforts. Interferon-beta (IFN-) reduces duration and severity of symptoms in many relapsing-remitting MS patients, but its mechanism of action is still not well understood. Moreover, IFN- and other available treatments must be given parenterally and have a variety of adverse effects. Certain naturally occurring flavonoids, such as luteolin, have anti-oxidant and anti-inflammatory effects, including inhibition of activated peripheral blood leukocytes from MS patients. Luteolin also inhibits mast cells, as well as mast cell-dependent T cell activation, recently implicated in MS pathogenesis. Moreover, luteolin and structurally similar flavonoids can inhibit experimental allergic allergic encephalomyelitis (EAE), an animal model of MS in rodents. An appropriate luteolin formulation that permits sufficient absorption and reduces its metabolism could be a useful adjuvant to IFN- for MS therapy.

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Luteolin inhibits myelin basic protein-induced human mast cell activation and mast cell-dependent stimulation of Jurkat T cells

Background and purpose: Allergic inflammation and autoimmune diseases, such as atopic dermatitis, psoriasis and multiple sclerosis (MS), involve both mast cell and T-cell activation. However, possible interactions between the two and the mechanism of such activations are largely unknown.

Experimental approach: Human umbilical cord blood-derived cultured mast cells (hCBMCs) and Jurkat T cells were incubated separately or together, following activation with myelin basic protein (MBP), as well as with or without pretreatment with the flavonoid luteolin for 15 min. The supernatant fluid was assayed for inflammatory mediators released from mast cells and interleukin (IL)-2 release from Jurkat cells.

Key results: MBP (10 mM) stimulates hCBMCs to release IL-6, IL-8, transforming growth factor (TGF)-b1, tumour necrosis factor-a (TNF-a), vascular endothelial growth factor (VEGF), histamine and tryptase (n¼6, Po0.05). Addition of mast cells to Jurkat cells activated by anti-CD3/anti-CD28 increases IL-2 release by 30-fold (n¼3, Po0.05). MBP-stimulated mast cells and their supernatant fluid further increase Jurkat cell IL-2 release (n¼3, Po0.05). Separation of mast cells and activated Jurkat cells by a Transwell permeable membrane inhibits Jurkat cell stimulation by 60%. Pretreatment of Jurkat cells with a TNF-neutralizing antibody reduces IL-2 release by another 40%. Luteolin pretreatment inhibits mast cell activation (n¼3–6, Po0.05), Jurkat cell activation and mast cell-dependent Jurkat cell stimulation (n¼3, Po0.05).

Conclusions and implications: Mast cells can stimulate activated Jurkat cells. This interaction is inhibited by luteolin, suggesting that this flavonoid may be useful in the treatment of autoimmune diseases.

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