Kaempferol

1 Aesculus sp. 2 Ailanthus sp. 3 Akebia sp. 4 Allium sp. 5 Althaea sp. 6 Anagallis sp. 7 Anchusa sp. 8 Anthemis sp. 9 Baptisia sp. 10 Bupleurum sp. 11 Callitris sp. 12 Calluna sp. 13 Cassia sp. 14 Casuarina sp. 15 Centaurea sp. 16 Centella sp. 17 Cerbera sp. 18 Chaerophyllum sp. 19 Chamaemelum sp. 20 Chenopodium sp. 21 Cicuta sp. 22 Cimicifuga sp. 23 Cinnamomum sp. 24 Cochlospermum sp. 25 Coriandrum sp. 26 Cornus sp. 27 Crataegus sp. 28 Drimys sp. 29 Drosera sp. 30 Echinacea sp. 31 Epilobium sp. 32 Eucalyptus sp. 33 Euphorbia sp. 34 Foeniculum sp. 35 Galium sp. 36 Genista sp. 37 Geranium sp. 38 Ginkgo sp. 39 Glycyrrhiza sp. 40 Gossypium sp. 41 Haematoxylum sp. 42 Hamamelis sp. 43 Hippophae sp. 44 Hydrophyllum sp. 45 Hypericum sp. 46 Ilex sp. 47 Inula sp. 48 Juniperus sp. 49 Kadsura sp. 50 Kaempferia sp. 51 Larix sp. 52 Larrea sp. 53 Lycium sp. 54 Melaleuca sp. 55 Menyanthes sp. 56 Meum sp. 57 Moringa sp. 58 Myristica sp. 59 Olea sp. 60 Ononis sp. 61 Orchis sp. 62 Paeonia sp. 63 Persicaria sp. 64 Phyllanthus sp. 65 Picea sp. 66 Pimpinella sp. 67 Pinus sp. 68 Pistacia sp. 69 Platanus sp. 70 Potentilla sp. 71 Primula sp. 72 Pulsatilla sp. 73 Rhamnus sp. 74 Rhus sp. 75 Ribes sp. 76 Rosa sp. 77 Sambucus sp. 78 Schinus sp. 79 Smilax sp. 80 Solidago sp. 81 Syzygium sp. 82 Terminalia sp. 83 Thuja sp. 84 Tilia sp. 85 Trifolium sp. 86 Tussilago sp. 87 Verbascum sp. 88 Vincetoxicum sp. 89 Zanthoxylum sp.

IC50: N/A

Kaempferol, a phytoestrogen and one of the most common dietary flavonoids, is widely distributed in tea, broccoli, gingko biloba, onions, grapes, apples, medicinal herbs and other plant sources. Growing evidences have indicated that Kae has antioxidative and anti-inflammatory properties.

In vitro: Previous studies demonstrated that kaempferol was able to reduce LPS-challenged TNF-α and IL-1β expression in activated macrophages and also inhibited the TNF-α-induced translocation of NF-κB subunit p65 to the nucleus and the secretion of IL-6 and monocyte chemoattractant protein-1 (MCP-1) [1].

In vivo: BALB/c mice with ALI, induced by intranasal instillation of LPS, were treated with kaempferol 1 h prior to LPS exposure. Kaempferol treatment attenuated pulmonary edema of mice with ALI after LPS challenge, as shown bu the fact that it markedly decreased the lung W/D ratio, protein concentration and the amounts of inflammatory cells in BALF. Similarly, LPS mediated overproduction of proinflammatory cytokines in BALF was reduced by kaempferol strongly. Histological studies demonstrated kaempferol inhibited LPS-induced alveolar hemorrhage, alveolar wall thickness and leukocytes infiltration in lung with evidence of reduced myeloperoxidase activity substantially. Kaempferol also efficiently increased superoxide dismutase activity in lung when compared with LPS group,which was obviously reduced by LPS administration [1].

Clinical trial: N/A

Reference:
[1] Chen X,Yang X,Liu T,Guan M,Feng X,Dong W,Chu X,Liu J,Tian X,Ci X,Li H,Wei J,Deng Y,Deng X,Chi G,Sun Z.  Kaempferol regulates MAPKs and NF-κB signaling pathways to attenuate LPS-induced acute lung injury in mice. Int Immunopharmacol.2012 Oct;14(2):209-16.

Kaempferol ameliorates symptoms of metabolic syndrome by regulating activities of liver X receptor-beta.[Pubmed:25959373]

J Nutr Biochem. 2015 Aug;26(8):868-75.

Kaempferol is a dietary flavonol previously shown to regulate cellular lipid and glucose metabolism. However, its molecular mechanisms of action and target proteins have remained elusive, probably due to the involvement of multiple proteins. This study investigated the molecular targets of Kaempferol. Ligand binding of Kaempferol to liver X receptors (LXRs) was quantified by time-resolved fluorescence resonance energy transfer and surface plasmon resonance analyses. Kaempferol directly binds to and induces the transactivation of LXRs, with stronger specificity for the beta-subtype (EC50 = 0.33 muM). The oral administration of Kaempferol in apolipoprotein-E-deficient mice (150 mg/day/kg body weight) significantly reduced plasma glucose and increased high-density lipoprotein cholesterol levels and insulin sensitivity compared with the vehicle-fed control. Kaempferol also reduced plasma triglyceride concentrations and did not cause liver steatosis, a common side effect of potent LXR activation. In immunoblotting analysis, Kaempferol reduced the nuclear accumulation of sterol regulatory element-binding protein-1 (SREBP-1). Our results show that the suppression of SREBP-1 activity and the selectivity for LXR-beta over LXR-alpha by Kaempferol contribute to the reductions of plasma and hepatic triglyceride concentrations in mice fed Kaempferol. They also suggest that Kaempferol activates LXR-beta and suppresses SREBP-1 to enhance symptoms in metabolic syndrome.

Inhibitory effects of kaempferol on the invasion of human breast carcinoma cells by downregulating the expression and activity of matrix metalloproteinase-9.[Pubmed:25453494]

Biochem Cell Biol. 2015 Feb;93(1):16-27.

Matrix metalloproteinases (MMPs) have been regarded as major critical molecules assisting tumor cells during metastasis, for excessive ECM (ECM) degradation, and cancer cell invasion. In the present study, in vitro and in vivo assays were employed to examine the inhibitory effects of Kaempferol, a natural polyphenol of flavonoid family, on tumor metastasis. Data showed that Kaempferol could inhibit adhesion, migration, and invasion of MDA-MB-231 human breast carcinoma cells. Moreover, Kaempferol led to the reduced activity and expression of MMP-2 and MMP-9, which were detected by gelatin zymography, real-time PCR, and western blot analysis, respectively. Further elucidation of the mechanism revealed that Kaempferol treatment inhibited the activation of transcription factor activator protein-1 (AP-1) and MAPK signaling pathway. Moreover, Kaempferol repressed phorbol-12-myristate-13-acetate (PMA)-induced MMP-9 expression and activity through suppressing the translocation of protein kinase Cdelta (PKCdelta) and MAPK signaling pathway. Our results also indicated that Kaempferol could block the lung metastasis of B16F10 murine melanoma cells as well as the expression of MMP-9 in vivo. Taken together, these results demonstrated that Kaempferol could inhibit cancer cell invasion through blocking the PKCdelta/MAPK/AP-1 cascade and subsequent MMP-9 expression and its activity. Therefore, Kaempferol might act as a therapeutic potential candidate for cancer metastasis.

Kaempferol suppresses collagen-induced platelet activation by inhibiting NADPH oxidase and protecting SHP-2 from oxidative inactivation.[Pubmed:25645952]

Free Radic Biol Med. 2015 Jun;83:41-53.

Reactive oxygen species (ROS) generated upon collagen stimulation act as second messengers to propagate various platelet-activating events. Among the ROS-generating enzymes, NADPH oxidase (NOX) plays a prominent role in platelet activation. Thus, NOX has been suggested as a novel target for anti-platelet drug development. Although Kaempferol has been identified as a NOX inhibitor, the influence of Kaempferol on the activation of platelets and the underlying mechanism have never been investigated. Here, we studied the effects of Kaempferol on NOX activation, ROS-dependent signaling pathways, and functional responses in collagen-stimulated platelets. Superoxide anion generation stimulated by collagen was significantly inhibited by Kaempferol in a concentration-dependent manner. More importantly, Kaempferol directly bound p47(phox), a major regulatory subunit of NOX, and significantly inhibited collagen-induced phosphorylation of p47(phox) and NOX activation. In accordance with the inhibition of NOX, ROS-dependent inactivation of SH2 domain-containing protein tyrosine phosphatase-2 (SHP-2) was potently protected by Kaempferol. Subsequently, the specific tyrosine phosphorylation of key components (Syk, Vav1, Btk, and PLCgamma2) of collagen receptor signaling pathways was suppressed by Kaempferol. Kaempferol also attenuated downstream responses, including cytosolic calcium elevation, P-selectin surface exposure, and integrin-alphaIIbbeta3 activation. Ultimately, Kaempferol inhibited platelet aggregation and adhesion in response to collagen in vitro and prolonged in vivo thrombotic response in carotid arteries of mice. This study shows that Kaempferol impairs collagen-induced platelet activation through inhibition of NOX-derived ROS production and subsequent oxidative inactivation of SHP-2. This effect suggests that Kaempferol has therapeutic potential for the prevention and treatment of thrombovascular diseases.

Kaempferol enhances the suppressive function of Treg cells by inhibiting FOXP3 phosphorylation.[Pubmed:25870037]

Int Immunopharmacol. 2015 Oct;28(2):859-65.

Kaempferol is a natural flavonoid found in many vegetables and fruits. Epidemiologic studies have described that Kaempferol intake could reduce risk of cancer, especially lung, gastric, pancreatic and ovarian cancers. Recent studies have shown that Kaempferol could also be beneficial to the body to defend against inflammation, and infection by bacteria and viruses; however, the molecular mechanism of its immunoregulatory function remains largely unknown. Through screening a small molecule library of traditional Chinese medicine (TCM), we identified that Kaempferol could enhance the suppressive function of regulatory T cells (Tregs). Kaempferol was found to increase FOXP3 expression level in Treg cells and prevent pathological symptoms of collagen-induced arthritis in a rat animal model. Kaempferol could also reduce PIM1-mediated FOXP3 phosphorylation at S422. Our study reveals a molecular mechanism that underlies the anti-inflammatory action of Kaempferol for the prevention and treatment of inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus, and ankylosing spondylitis.

Neuroprotection of kaempferol by autophagy in models of rotenone-mediated acute toxicity: possible implications for Parkinson's disease.[Pubmed:20594614]

Neurobiol Aging. 2012 Apr;33(4):767-85.

This study aims to elucidate the processes underlying neuroprotection of Kaempferol in models of rotenone-induced acute toxicity. We demonstrate that Kaempferol, but not quercetin, myricetin or resveratrol, protects SH-SY5Y cells and primary neurons from rotenone toxicity, as a reduction of caspases cleavage and apoptotic nuclei are observed. Reactive oxygen species (ROS) levels and mitochondrial carbonyls decrease significantly. Mitochondrial network, transmembrane potential and oxygen consumption are also deeply preserved. We demonstrate that the main event responsible for the Kaempferol-mediated antiapoptotic and antioxidant effects is the enhancement of mitochondrial turnover by autophagy. Indeed, fluorescence and electron microscopy analyses show an increase of the mitochondrial fission rate and mitochondria-containing autophagosomes. Moreover, the autophagosome-bound microtubule-associated protein light chain-3 (LC3-II) increases during Kaempferol treatment and chemical/genetic inhibitors of autophagy abolish Kaempferol protective effects. Autophagy affords protection also toward other mitochondrial toxins (1-methyl-4-phenyilpiridinium, paraquat) used to reproduce the typical features of Parkinson's disease (PD), but is inefficient against apoptotic stimuli not directly affecting mitochondria (H(2)O(2), 6-hydroxydopamine, staurosporine). Striatal glutamatergic response of rat brain slices is also preserved by Kaempferol, suggesting a more general protection of Kaempferol in Parkinson's disease. Overall, the data provide further evidence for Kaempferol to be identified as an autophagic enhancer with potential therapeutic capacity.

Kaempferol enhances endothelium-dependent relaxation in the porcine coronary artery through activation of large-conductance Ca(2+) -activated K(+) channels.[Pubmed:25652142]

Br J Pharmacol. 2015 Jun;172(12):3003-14.

BACKGROUND AND PURPOSE: Kaempferol, a plant flavonoid present in normal human diet, can modulate vasomotor tone. The present study aimed to elucidate the signalling pathway through which this flavonoid enhanced relaxation of vascular smooth muscle. EXPERIMENTAL APPROACH: The effect of Kaempferol on the relaxation of porcine coronary arteries to endothelium-dependent (bradykinin) and -independent (sodium nitroprusside) relaxing agents was studied in an in vitro organ chamber setup. The whole-cell patch-clamp technique was used to determine the effect of Kaempferol on potassium channels in porcine coronary artery smooth muscle cells (PCASMCs). KEY RESULTS: At a concentration without direct effect on vascular tone, Kaempferol (3 x 10(-6) M) enhanced relaxations produced by bradykinin and sodium nitroprusside. The potentiation by Kaempferol of the bradykinin-induced relaxation was not affected by N(omega)-nitro-L-arginine methyl ester, an inhibitor of NO synthase (10(-4) M) or TRAM-34 plus UCL 1684, inhibitors of intermediate- and small-conductance calcium-activated potassium channels, respectively (10(-6) M each), but was abolished by tetraethylammonium chloride, a non-selective inhibitor of calcium-activated potassium channels (10(-3) M), and iberiotoxin, a selective inhibitor of large-conductance calcium-activated potassium channel (KCa 1.1; 10(-7) M). Iberiotoxin also inhibited the potentiation by Kaempferol of sodium nitroprusside-induced relaxations. Kaempferol stimulated an outward-rectifying current in PCASMCs, which was abolished by iberiotoxin. CONCLUSIONS AND IMPLICATIONS: The present results suggest that, in smooth muscle cells of the porcine coronary artery, Kaempferol enhanced relaxations caused by endothelium-derived and exogenous NO as well as those due to endothelium-dependent hyperpolarization. This vascular effect of Kaempferol involved the activation of KCa 1.1 channels.

Potent inhibitory effect of naturally occurring flavonoids quercetin and kaempferol on in vitro osteoclastic bone resorption.[Pubmed:12473376]

Biochem Pharmacol. 2003 Jan 1;65(1):35-42.

Several recent studies have suggested that flavonols, a class of phytochemicals with many biological activities, might exert a protective effect against post-menopausal bone loss. In the present study, we investigated the effects of quercetin and Kaempferol, two of the major naturally occurring flavonols on the in vitro bone resorbing activity of osteoclasts. Our results indicate that both compounds, at concentrations ranging from 0.1 to 100 microM reduce bone resorption in a time and dose-dependent manner. Significant inhibitory effects were observed at concentrations as low as 0.1 microM especially with Kaempferol. The IC(50)s, or concentration inhibitory of 50% of basal resorption, calculated for quercetin and Kaempferol were 1.6 and 5.3 microM, respectively. Using highly purified rabbit osteoclasts, we showed that both flavonols directly induce apoptosis of mature osteoclasts in the same dose-range effective for inhibiting bone resorption. When osteoclasts were treated with 50 microM of quercetin and Kaempferol, intracellular reactive oxygen species levels decreased significantly by 75 and 25%, respectively, indicating these molecules keep their antioxidant properties at this concentration. However, at concentrations below 50 microM, neither quercetin nor Kaempferol exerted antiradical action, suggesting that antioxidant properties cannot fully explain the inhibitory effect on bone resorption. Finally, we report that Kaempferol-, but not the quercetin-induced inhibition of bone resorption was partially abolished by the presence of the pure anti-estrogen ICI 182780 suggesting that Kaempferol's estrogenic effect could be involved in the inhibition of bone resorption. The present study demonstrates that flavonols widely distributed in human diet such as quercetin and Kaempferol, exert a potent inhibitory effect on in vitro bone resorption.

Downregulation of PLK-1 expression in kaempferol-induced apoptosis of MCF-7 cells.[Pubmed:19356725]

Eur J Pharmacol. 2009 Jun 2;611(1-3):17-21.

The molecular mechanisms underlying the Kaempferol-induced cell death have not yet been fully explained. To investigate the role of Kaempferol, widely distributed in foods, in tumor progression, human breast cancer cell line, MCF-7, was treated with Kaempferol. Apoptosis was indicated by the accumulation of a sub-G1 population, as well as the appearance of 4'-6-diamidino-2-phenylindole (DAPI)-stained apoptotic nuclei in the MCF-7 cells after the administration of Kaempferol. Western blot analysis showed cleavage of Poly (ADP-ribose) polymerase (PARP), caspase-7, Bax, and caspase-9 indicating that the intracellular pathway of apoptosis was involved. Kaempferol also downregulated the expression of polo-like kinase 1 (PLK-1), which has been reported to regulate mitotic progression and to be upregulated in several human tumors. Taken together, these findings indicate that Kaempferol-induced apoptosis by initiation of intrinsic caspase cascade and downregulation of PLK-1 expression.

Kaempferol attenuates 2-deoxy-d-ribose-induced oxidative cell damage in MC3T3-E1 osteoblastic cells.[Pubmed:19336918]

Biol Pharm Bull. 2009 Apr;32(4):746-9.

Reducing sugar, 2-deoxy-D-ribose (dRib), produces reactive oxygen species through autoxidation and protein glycosylation and causes osteoblast dysfunction. Kaempferol, a natural flavonoid, was investigated to determine whether it could influence dRib-induced cellular dysfunction and oxidative cell damage in the MC3T3-E1 mouse osteoblastic cell line. Osteoblastic cells were treated with 30 mM dRib in the presence or absence of Kaempferol (10(-9)-10(-5) M) and markers of osteoblast function and lipid peroxidation were subsequently examined. Kaempferol (10(-9)-10(-5) M) significantly inhibited the dRib-induced decrease in growth of MC3T3-E1 osteoblastic cells. In addition, treatment with Kaempferol resulted in a significant elevation of alkaline phosphatase (ALP) activity, collagen content, and mineralization in the cells. Treatment with Kaempferol increased osteoprotegerin (OPG) secretion and decreased malondialdehyde (MDA) contents of MC3T3-E1 osteoblastic cells in the presence of 30 mM dRib. Taken together, these results suggest that Kaempferol inhibits dRib-induced osteoblastic cell damage and may be useful for the treatment of diabetes-related bone disease.

Ribosomal S6 kinase 2 is a key regulator in tumor promoter induced cell transformation.[Pubmed:17804722]

Cancer Res. 2007 Sep 1;67(17):8104-12.

The ribosomal S6 kinase 2 (RSK2), a member of the p90(RSK) (RSK) family of proteins, is a widely expressed serine/threonine kinase that is activated by extracellular signal-regulated kinase 1/2 and phosphoinositide-dependent kinase 1 in response to many growth factors and peptide hormones. Its activation signaling enhances cell survival. However, the roles of RSK2 in cell transformation have not yet been elucidated. Here, we found that RSK2 is a critical serine/threonine kinase for the regulation of cell transformation. When cells were stimulated with tumor promoters, such as epidermal growth factor (EGF) or 12-O-tetradecanoylphorbol-13-acetate (TPA), phosphorylation of RSK was increased within 5 min. Cell proliferation was suppressed in RSK2(-/-) mouse embryonic fibroblasts (MEFs) compared with RSK2(+/+) MEFs. Moreover, RSK2(-/-) MEFs accumulated at the G(1) phase of the cell cycle under normal cell culture conditions as well as after stimulation with EGF or TPA. In the anchorage-independent cell transformation assay (soft agar), stable expression of RSK2 in JB6 cells significantly enhanced colony formation in either the presence or absence of tumor promoters. Furthermore, knockdown of RSK2 with small interfering RNA-RSK2 suppressed constitutively active Ras (Ras(G12V))-induced foci formation in NIH3T3 cells. In addition, Kaempferol, an inhibitor of RSK2, suppressed EGF-induced colony formation of JB6 Cl41 cells in soft agar, which was associated with inhibition of histone H3 phosphorylation (Ser(10)). These results showed that RSK2 is a key regulator for cell transformation induced by tumor promoters such as EGF and TPA.

Direct activation of the mitochondrial calcium uniporter by natural plant flavonoids.[Pubmed:15324303]

Biochem J. 2004 Nov 15;384(Pt 1):19-24.

During cell activation, mitochondria play an important role in Ca2+ homoeostasis due to the presence of a fast and specific Ca2+ channel in its inner membrane, the mitochondrial Ca2+ uniporter. This channel allows mitochondria to buffer local cytosolic [Ca2+] changes and controls the intramitochondrial Ca2+ levels, thus modulating a variety of phenomena from respiratory rate to apoptosis. We have described recently that SB202190, an inhibitor of p38 MAPK (mitogen-activated protein kinase), strongly activated the uniporter. We show in the present study that a series of natural plant flavonoids, widely distributed in foods, produced also a strong stimulation of the mitochondrial Ca2+ uniporter. This effect was of the same magnitude as that induced by SB202190 (an approx. 20-fold increase in the mitochondrial Ca2+ uptake rate), developed without measurable delay and was rapidly reversible. In intact cells, the mitochondrial Ca2+ peak induced by histamine was also largely increased by the flavonoids. Stimulation of the uniporter by either flavonoids or SB202190 did not require ATP, suggesting a direct effect on the uniporter or an associated protein which is not mediated by protein phosphorylation. The most active compound, Kaempferol, increased the rate of mitochondrial Ca2+ uptake by 85+/-15% (mean+/-S.E.M., n=4) and the histamine-induced mitochondrial Ca2+ peak by 139+/-19% (mean+/-S.E.M., n=5) at a concentration of 1 microM. Given that flavonoids can reach this concentration range in plasma after ingestion of flavonoid-rich food, these compounds could be modulating the uniporter under physiological conditions.

Kaempferol inhibits estrogen receptor α expression in breast cancer cells and induces apoptosis in glioblastoma cells and lung cancer cells by activation of MEK-MAPK.

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