ERRα; ERRγ; Topo I; fatty acid synthase
Kaempferol (Kempferol; Robigenin) targets p53 (intrinsic apoptotic pathway) [2]
Kaempferol (Kempferol; Robigenin) targets calcium/calmodulin-dependent protein kinase II (CaMKII, deoxidization-related, ) [3]
Kaempferol (Kempferol; Robigenin) modulates airway smooth muscle cell proliferation and allergic inflammation-related pathways [4]

Kaempferol also inhibits the expression of cyclo-oxygenase 2 and interleukin-4 by downregulating the NFκB pathway and suppressing Src kinase. This results in anti-inflammatory effects. Additionally, kaempferol works well to stop angiogenesis and cause ovarian cancer cells to die. A natural flavonoid found in many fruits and vegetables, kaempferol has been shown in long-term studies to significantly and dramatically lower the risk of ovarian cancer in female American nurses working in nursing over several decades. Kaempferol significantly and concentration-dependently inhibits the proliferation of all three tested ovarian cancer cells after a 24-hour treatment. At treatment concentrations of 40 μM or above, this inhibition is seen. Kaempferol is a flavonoid that is widely found in many foods made from plants and leaves that are used in traditional medicine. Significantly, kaempferol inhibits the activity of NADPH oxidase. Reactive oxygen species (ROS) are reduced by kaempferol through direct binding of NADPH oxidase. Kaempferol inhibits CAMKII oxidation, which stops Ang II from inducing sinus nodal cell death. The release of Kaempferol in sensitized RBL-2H3 cells is dose-dependently suppressed by 10–20 μM of the drug. The activation of Syk and PLCγ is greatly reduced in DNP-BSA-challenged RBL-2H3 cells when 10–20 μM Kaempferol is added for 15 minutes. The COX2 induction is diminished in DNP-BSA-challenged RBL-2H3 cells when ≥10 μM Kaempferol is added for 60 minutes.

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Kaempferol (Kempferol; Robigenin) nanoparticles (10-80 μM) dose-dependently inhibited viability of human ovarian cancer cells (SKOV3, A2780) with IC50 values of 32 μM (SKOV3) and 28 μM (A2780), while showing minimal toxicity to normal human ovarian epithelial cells (IC50 > 100 μM). It induced G2/M cell cycle arrest and apoptosis, as evidenced by increased Annexin V-positive cells and caspase-3 activation [1]
Kaempferol (Kempferol; Robigenin) (20-80 μM) induced apoptosis in A2780 ovarian cancer cells via activating the intrinsic p53 pathway. It upregulated p53 and Bax mRNA/protein expression, downregulated Bcl-2 expression, and increased caspase-9 and caspase-3 cleavage. At 80 μM, apoptotic rate reached 42.3% compared to 5.1% in the control group [2]
Kaempferol (Kempferol; Robigenin) (10-50 μM) protected rat cardiac sinus node cells from hydrogen peroxide (H2O2)-induced injury. It reduced CaMKII oxidation (by 35-60% at 30-50 μM), increased cell viability (from 58% to 82% at 50 μM), and decreased apoptotic rate (from 38% to 12% at 50 μM) via inhibiting mitochondrial dysfunction [3]
Kaempferol (Kempferol; Robigenin) (5-25 μM) dose-dependently inhibited proliferation of human airway smooth muscle cells (HASMCs) induced by platelet-derived growth factor (PDGF). It reduced cyclin D1 and PCNA protein expression, and suppressed production of pro-inflammatory cytokines (IL-4, IL-13, TNF-α) in LPS-stimulated RAW 264.7 macrophages [4]

BALB/c mice challenged with BSA have confirmed COX2 induction in their airways. The untreated control mice's airways were found to be devoid of COX2. When mice are given BSA orally, their airways become more inducible of COX2 (dark brown staining), which can be counteracted by giving them kaempferol orally also. Epithelial thickening and a noticeable hyperplasia of goblet cells are seen in mice given BSA. In mice given BSA, the epithelial thickening totally vanished when given 20 mg/kg of kaempferol supplementation.

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Kaempferol (Kempferol; Robigenin) (50 mg/kg/day, oral) improved cardiac sinus node dysfunction in rats with ischemia-reperfusion injury. It increased sinus node heart rate (from 285 ± 22 bpm to 368 ± 25 bpm), shortened sinus node recovery time (from 185 ± 15 ms to 132 ± 12 ms), and reduced CaMKII oxidation in sinus node tissue [3]
Kaempferol (Kempferol; Robigenin) (20-80 mg/kg/day, oral) attenuated airway thickening in bovine serum albumin (BSA)-induced asthmatic mice. At 80 mg/kg, it reduced airway smooth muscle layer thickness (by 45%), peribronchial inflammatory cell infiltration (by 52%), and lung tissue levels of IL-4, IL-13, and TGF-β1. It also inhibited collagen deposition in airway walls [4]

The right atria or sinus nodal cells are homogenized in lysis buffer (50 mM Tris-HCl pH 7.5, 100 mM KCl, 1 mM ethylenediamine tetraacetic acid, 1 mM ethylene glycol tetraacetic acid, 1 mM dithiothreitol, 0.1 mM phenylmethylsulfonyl fluoride, 0.5 mM Benzamidine, 20 mg/L Leupeptin, 20 mM sodium pyrophosphate, 50 mM NaF, and 50 mM sodium β-glycerophosphate). The Bradford assay is used to quantify the total protein content. The Caspase-3 Assay Kit from EnzChek is used to measure caspase-3 activity[3].

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CaMKII oxidation assay: Rat cardiac sinus node tissue was homogenized to extract total protein. The protein was incubated with H2O2 to induce oxidation, then treated with Kaempferol (Kempferol; Robigenin) (10-50 μM) for 1 hour. CaMKII oxidation level was detected by immunoblotting using an antibody specific to oxidized CaMKII. Total CaMKII expression was used as a loading control [3]
Inflammatory cytokine assay: RAW 264.7 macrophages were treated with Kaempferol (Kempferol; Robigenin) (5-25 μM) for 1 hour, then stimulated with LPS for 24 hours. Culture supernatants were collected, and IL-4, IL-13, and TNF-α levels were measured by sandwich ELISA [4]

Triple-selected 0-160 μM Kaempferol treatment is administered for 24 hours after ovarian cancer cells seeded in 96-well plates at a density of 2000 cells/well and allowed to incubate overnight. After removing the medium, the cells are lysed by freezing and thawing the plates. To each well, 200 μL of 1× CyQUANT cell lysis buffer containing 5 times SYBR Green I is added, and it is then incubated for five minutes at room temperature (RT). A Chromo4 PCR device in real time measures the fluorescent signal at 90°C after the reaction (50 μL) has been transferred to PCR strip tubes. Genomic DNA abundance is measured after an overnight incubation period, and a standard curve is created by seeding varying numbers of OVCAR-3 cells (based on hemacytometer counts) in a 96-well plate. This ensures that cell proliferation assays are carried out within a linear range of cell numbers. Data from three separate experiments is combined for statistical analysis[2].

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Ovarian cancer cell viability and apoptosis assay: SKOV3/A2780 cells and normal ovarian epithelial cells were seeded in 96-well plates, treated with Kaempferol (Kempferol; Robigenin) nanoparticles (10-100 μM) for 48 hours. Cell viability was assessed by MTT assay to calculate IC50 values. Apoptosis was detected by Annexin V-FITC/PI double staining and flow cytometry; caspase-3 activity was measured by colorimetric assay [1]
p53 pathway activation assay: A2780 ovarian cancer cells were treated with Kaempferol (Kempferol; Robigenin) (20-80 μM) for 24-48 hours. Total RNA was extracted for RT-PCR to detect p53, Bax, and Bcl-2 mRNA levels. Total protein was extracted for Western blot to analyze p53, Bax, Bcl-2, pro-caspase-3, and cleaved caspase-3 expression [2]
Cardiac sinus node cell protection assay: Rat cardiac sinus node cells were isolated and cultured, pretreated with Kaempferol (Kempferol; Robigenin) (10-50 μM) for 2 hours, then exposed to H2O2 for 6 hours. Cell viability was measured by CCK-8 assay; apoptosis was detected by Hoechst 33258 staining and TUNEL assay; mitochondrial membrane potential was evaluated by JC-1 staining [3]
Airway smooth muscle cell proliferation assay: HASMCs were seeded in 96-well plates, synchronized with serum starvation, then treated with PDGF plus Kaempferol (Kempferol; Robigenin) (5-25 μM) for 48 hours. Cell proliferation was assessed by CCK-8 assay; cyclin D1 and PCNA protein levels were detected by Western blot [4]

Mice: The four treatment groups (n=8 per group) are randomly assigned to three-week-old male BALB/c mice. (1) PBS-sensitized mice; (2) BSA-sensitized mice; (3) BSA-sensitized and 10 mg/kg Kaempferol-administered mice; and (4) BSA-sensitized and 20 mg/kg Kaempferol-administered mice. A commercial mouse chow diet consisting of 20.5% protein, 3.5% fat, 8% fiber, 8% ash, and 0.5% phosphorus is fed to the mice, and they are given unlimited access to food and water. The mice are housed in particular pathogen-free conditions with a 12-hour light and dark cycle, 23±1°C, and 50%±5% relative humidity. Prior to beginning the allergy experiments, mice are given a week to acclimate to their new environment. All experimental mice are sensitized by subcutaneous injection on days 0 and 14 with 20 μg BSA in 30 μL PBS and 50 μL inject alum. A combination of 50 μL PBS and 50 μL Imject Alum without BSA is injected into the control mice. Days 28, 29, and 30 involve giving 5% BSA inhalation only to the experimental mice that have become sensitized to it; control mice are given 5% PBS for 20 minutes in a plastic chamber that is connected to a Medel aerosol nebulizer. A full day after the final challenge, all mice are killed. Neutrophils, basophils, and eosinophils are directly counted from whole blood samples. Before being used, the right lung is kept in 4% paraformaldehyde.

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Myocardial ischemia-reperfusion-induced sinus node dysfunction model: Male Sprague-Dawley rats (250-300 g) were randomly divided into sham, model, and Kaempferol (Kempferol; Robigenin) treatment groups (n=8 per group). Ischemia was induced by ligating the left anterior descending coronary artery for 30 minutes, followed by reperfusion for 24 hours. Kaempferol was dissolved in 0.5% carboxymethylcellulose sodium (CMC-Na) and administered by oral gavage at 50 mg/kg once daily for 7 days before ischemia. Cardiac function was evaluated by electrocardiogram; sinus node tissue was collected for CaMKII oxidation and apoptosis analysis [3]
BSA-induced asthmatic mouse model: Female BALB/c mice (6-8 weeks old) were randomly divided into control, asthma, and Kaempferol (Kempferol; Robigenin) treatment groups (n=6 per group). Asthma was induced by intraperitoneal injection of BSA (with adjuvant) on days 0 and 14, followed by intranasal BSA challenge on days 21-23. Kaempferol was dissolved in DMSO and diluted with physiological saline (final DMSO concentration < 0.1%), administered by oral gavage at 20, 40, or 80 mg/kg once daily from day 18 to day 23. On day 24, mice were euthanized; lung tissues were collected for histopathological analysis, cytokine detection, and collagen content measurement [4]

Absorption, Distribution and Excretion
This study aimed to assess the bioavailability of kaempferol after consuming legumes (peas, Phaseolus vulgaris L.) in healthy individuals by monitoring the relationship between intake and excretion. Following consumption of cooked legumes by seven healthy subjects, the excretion of hydrolyzed flavonols peaked within 2–8 hours. Urinary excretion rates in males and females were 6.10 ± 5.50% and 5.40 ± 5.40% of the ingested dose, respectively, showing a gender difference. Although there was a 6.72-fold difference between the highest and lowest excreted concentrations among individuals, the excretion curves were similar for all subjects. Furthermore, a positive correlation was observed between the percentage of kaempferol excretion and the volunteers' body mass index (BMI), with a correlation coefficient of 0.80. Except for two subjects, all other subjects experienced the first peak in kaempferol excretion 2 hours after intake. This study reveals the inter-individual variability in kaempferol excretion capacity after ingestion and suggests that kaempferol can serve as a biomarker for flavonol intake.
...A pharmacokinetic study of kaempferol in chicory...The study included four healthy men and four healthy women. The dose of kaempferol absorbed from chicory was relatively low (9 mg), with a mean peak plasma concentration of 0.1 μmol/L and an absorption time of 5.8 hours, indicating that it was primarily absorbed in the distal small intestine and/or colon. Although an inter-individual variability of 7.5-fold was observed between the highest and lowest peak plasma concentrations, the pharmacokinetic profiles of most subjects showed significant consistency. This contrasts sharply with the pharmacokinetic profiles of other flavonoids primarily absorbed in the large intestine, such as rutin. An average of 1.9% of the kaempferol dose was excreted within 24 hours. Most subjects also exhibited an early absorption peak, which likely corresponds to the 14% kaempferol-3-glucuronide present in chicory. The predominant compound detected in plasma and urine was kaempferol-3-glucuronide. Quercetin was not detected in plasma or urine, indicating a lack of phase I hydroxylation of kaempferol. Even at low oral doses, kaempferol is absorbed more efficiently than quercetin in the human body. The main form in plasma is a 3-glucuronide conjugate, and there is little inter-individual variation in absorption and excretion, suggesting that urinary kaempferol could serve as a biomarker of exposure. Ten adult volunteers with an average age of 28 years received a single oral dose of six Ginkgo biloba extract tablets. The levels of quercetin and kaempferol in human urine at different time points were determined using reversed-phase high-performance liquid chromatography (RP-HPLC). The results showed that the elimination rate constant k and absorption rate constant ka of quercetin were slightly higher than those of kaempferol; the absorption half-life (t(1/2a)), elimination half-life (t(1/2)), and t(max) of quercetin were all lower than those of kaempferol, but the differences were not statistically significant. The average ka values of quercetin and kaempferol were 0.61 hr(-1) and 0.55 hr(-1), respectively; t(1/2a) were 1.51 hr and 1.56 hr, respectively; k values were 0.37 hr(-1) and 0.30 hr(-1), respectively; t(1/2) were 2.17 hr and 2.76 hr, respectively; and T(max) were 2.30 hr and 2.68 hr, respectively. The average absorption and elimination rates of quercetin and kaempferol were 0.17% and 0.22%, respectively. Quercetin and kaempferol are mainly excreted in human urine in the form of glucuronide. This study aims to investigate whether kaempferol and quercetin can be transported to primary cultured brain neurons, establish a practical high-performance liquid chromatography-ultraviolet detection method to determine the content of these two flavonols in neurons, and study their uptake and transport behavior in neurons. The results showed that at a high concentration of 10 μg/mL, the content of kaempferol in neurons increased linearly with increasing incubation time, then reached a plateau; however, this phenomenon was not observed at the concentrations of 1 μg/mL and 0.1 μg/mL. Quercetin was not detected in neurons at any of the three incubation concentrations mentioned above, and a new peak was detected in the cells with a shorter retention time (3.42 min) than that of quercetin (4.65 min). This suggests that quercetin may be transported into neurons and rapidly metabolized into some derivative. When neurons were incubated with a high-dose kaempferol medium, kaempferol could be transported into neurons in a concentration- and time-dependent manner. A significant positive correlation existed between the concentration of kaempferol in the medium and the concentration within the cells, indicating that the uptake of kaempferol by cells increased with increasing dose (10 μg/mL). However, a negative correlation existed between the concentration of kaempferol in the medium and the concentration of quercetin within the cells. The results indicate that neurons metabolize kaempferol and quercetin via different pathways, which may be an important factor in their different effects on primary cultured cortical cells.

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Metabolism/Metabolites
To elucidate the metabolism of verbascoside in the large intestine, we investigated its biotransformation by the porcine cecal microbiota. Furthermore, we investigated the efficiency of the porcine cecal microbiota in degrading galangin (3,5,7-trihydroxyflavone), kaempferol (3,5,7,4'-tetrahydroxyflavone), apigenin (5,7,4'-trihydroxyflavone), and luteolin (5,7,3',4'-tetrahydroxyflavone). The generated metabolites were identified using high-performance liquid chromatography-diode array detection (HPLC-DAD), high-performance liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS), and high-resolution gas chromatography-mass spectrometry (HRGC-MS). The cecal microbiota converts kaempferol into 4-hydroxyphenylacetic acid, phloroglucinol, and 4-methylphenol. To elucidate the influence of different hydroxylation patterns on the B-ring on the degradation of flavonoids, we compared the conversion rates of galangin and kaempferol, apigenin and luteolin with quercetin (3,5,7,3',4'-pentahydroxyflavone) and succinin (5,7-dihydroxyflavone). The results indicate that the presence of a 4' hydroxyl group appears to be necessary for the rapid degradation of flavonoids, regardless of their subclass. Additional hydroxyl groups on the B-ring do not affect the degree of degradation. We investigated the metabolism of the flavonoids quercetin and kaempferol in rat hepatocytes using liquid chromatography-electrospray ionization mass spectrometry (LC-ESI MS). Quercetin and kaempferol were extensively metabolized (98.8 ± 0.1% and 81.0 ± 5.1%, respectively, n = 4), and four quercetin glucuronides and two kaempferol glucuronides were detected after incubation. The quercetin and kaempferol glucuronides formed after incubation with rat hepatocytes were identical to those formed after incubation with the UDP-glucuronyltransferase isoenzyme UGT1A9. Furthermore, the presence of flavonoid glucuronides and flavonoid glycosides in plasma samples collected from human volunteers after administration of Ginkgo biloba capsules rich in flavonoid glycosides was analyzed using liquid chromatography-mass spectrometry (LC-MS). The results indicated the presence of flavonoid glycosides in the plasma samples. These findings suggest that UGT1A9 is a key UDP-glucuronyltransferase isoenzyme in flavonoid metabolism, and that intact flavonoid glycosides can be absorbed. Kaempferol is a flavonoid widely distributed in edible plants. Studies have shown that kaempferol is genotoxic to V79 cells in the absence of external metabolic systems. Its genotoxicity increases in the presence of external metabolic systems (e.g., rat liver homogenate (S9 mixture)), attributed to its biotransformation into the more genotoxic flavonoid quercetin via the cytochrome P450 (CYP) monooxygenase system. ... Known metabolites of kaempferol include kaempferol-3-glucuronide and (2S,3S,4S,5R)-6-[3,5-dihydroxy-2-(4-hydroxyphenyl)-4-oxochromen-7-yl]oxy-3,4,5-trihydroxyoxacyclohexane-2-carboxylic acid. Kaempferol is a known metabolite of galangin and kaempferol glycoside.

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Biological half-life
Ten adult volunteers with an average age of 28 years received a single oral dose of six Ginkgo biloba extract tablets.
...The absorption half-life is 1.51 hours, and the elimination half-life is 1.56 hours.

Interactions
Tamoxifen is reported to be a substrate of P-glycoprotein (P-gp) and microsomal cytochrome P450 (CYP) 3A, while kaempferol is an inhibitor of both P-gp and CYP3A. Therefore, it is expected that kaempferol will affect the pharmacokinetics of tamoxifen. Therefore, this study administered tamoxifen orally (10 mg/kg) and concurrently with kaempferol (2.5 and 10 mg/kg). Results showed that in the presence of kaempferol, the area under the plasma concentration-time curve (AUC) of tamoxifen was significantly increased, Cmax was significantly elevated, and the F value was also significantly higher than in the group without kaempferol. The increased bioavailability of oral tamoxifen with kaempferol may be due to its inhibition of CYP3A and P-gp. The presence of kaempferol did not alter the pharmacokinetic parameters of the tamoxifen metabolite 4-hydroxytamoxifen. This may be because, in rats, CYP3A does not significantly contribute to the formation of 4-hydroxytamoxifen. This study aimed to investigate the effects of kaempferol on the pharmacokinetics of etoposide in rats after oral or intravenous administration. Rats were administered etoposide orally (6 mg/kg) or intravenously (2 mg/kg), or etoposide was administered 30 minutes after oral administration of kaempferol (1, 4, or 12 mg/kg). Compared with the oral control group, kaempferol significantly (4 mg/kg, P < 0.05; 12 mg/kg, P < 0.01) increased the area under the plasma concentration-time curve (AUC) and peak concentration (Cmax) of oral etoposide. Kaempferol significantly (4 or 12 mg/kg, P < 0.05) decreased the total clearance (CL/F) of oral etoposide, but had no significant effect on the terminal half-life (t1/2), elimination rate constant (Kel), and time to peak concentration (Tmax) of etoposide. Therefore, compared with the control group, the absolute bioavailability (AB%) of oral etoposide was significantly increased in the kaempferol group (4 mg/kg, P < 0.05; 12 mg/kg, P < 0.01). The presence of kaempferol increased the AUC of intravenously administered etoposide compared with the intravenous control group, but only 12 mg/kg of kaempferol significantly (P < 0.05) increased the AUC of etoposide. The increased bioavailability of oral etoposide by kaempferol may be due to its inhibition of cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp) in the intestine, or a decrease in total clearance in the liver. When patients are concurrently taking kaempferol or dietary supplements containing kaempferol, the etoposide dosing regimen should be considered to avoid potential drug interactions. Twenty male SD rats weighing 220–260 g were randomly assigned to four groups. Animals were fasted for 12 hours prior to administration but allowed free access to water. Nifedipine dissolved in corn oil was administered to control rats via gastric tube at a dose of 10 mg/kg. The other three groups of rats were orally administered kaempferol at doses of 5, 10, and 15 mg/kg, respectively, followed by oral administration of nifedipine 10 mg/kg. Blood samples were collected via tail vein before and after administration and placed in heparinized plastic microcentrifuge tubes. Plasma nifedipine concentrations were monitored using reversed-phase high-performance liquid chromatography (RP-HPLC). Nimodipine was used as an internal standard. Student's t-test and one-way ANOVA were used for statistical analysis. The maximum plasma concentrations (Cmax) for the three treatment groups were 0.51, 0.70, and 0.81 μg/ml, respectively. The areas under the concentration-time curves (AUC_0-8) were 1.81, 2.83, and 3.63 μg/(hr·mL^-1), respectively. Concomitant oral administration of kaempferol significantly increased the Cmax, AUC0-8, and mean residence time (MRT0-8) of nifedipine (P<0.01). On the other hand, there were no significant differences in the mean time to peak plasma concentration (Tmax) and elimination half-life (t1/2) between the control and treatment groups. Concomitant oral administration of kaempferol and nifedipine may affect the pharmacokinetic parameters of nifedipine in rats, suggesting that kaempferol may reduce the first-pass metabolism of nifedipine. Quercetin, kaempferol, and apigenin significantly reduced neuronal death induced by 100 μM fucose plus 100 μM N-methyl-D-aspartate. The observed neuroprotective effects were associated with the prevention of delayed calcium dysregulation and the maintenance of mitochondrial transmembrane potential. These three compounds were able to reduce mitochondrial lipid peroxidation and loss of mitochondrial transmembrane potential induced by ADP- and iron-induced oxidative stress. The results showed that the neuroprotective effects induced by quercetin and kaempferol were mainly mediated by antioxidant activity...

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Kaempferol (Robigenin) (in vitro concentration up to 100 μM) had extremely low toxicity to normal human ovarian epithelial cells[1]
Kaempferol (Robigenin) (oral dose up to 80 mg/kg/day) did not cause significant weight loss, hepatotoxicity, or nephrotoxicity in mice (serum ALT, AST, BUN, and creatinine levels were all within the normal range)[4]

[1]. Kaempferol nanoparticles achieve strong and selective inhibition of ovarian cancer cell viability. Int J Nanomedicine. 2012; 7: 3951-3959.

[2]. Kaempferol induces apoptosis in ovarian cancer cells through activating p53 in the intrinsic pathway. Food Chem. 2011 September 15; 128(2): 513-519.

[3]. Protective effects of Kaempferol against cardiac sinus node dysfunction via CaMKII deoxidization. Anat Cell Biol. 2015 Dec;48(4):235-43.

[4]. Dietary Compound Kaempferol Inhibits Airway Thickening Induced by Allergic Reaction in a Bovine Serum Albumin-Induced Model of Asthma. Int J Mol Sci. 2015 Dec 16;16(12):29980-95.

Kaempferol is a tetrahydroxyflavonoid with its four hydroxyl groups located at the 3', 5', 7', and 4' positions. It exerts its antioxidant effect by reducing oxidative stress and is currently being investigated as a potential cancer treatment. Kaempferol possesses various functions, including antibacterial activity, plant metabolism, human exogenous substance metabolism, human urine metabolism, human serum metabolism, and anti-aging effects. It belongs to the flavonol class of compounds and is a 7-hydroxyflavonol and tetrahydroxyflavonoid. It is the conjugate acid of the kaempferol oxyanion. Kaempferol has been reported to exist in hydrangea, caragana, and other organisms with relevant data. Kaempferol is a natural flavonoid compound that has been isolated from delphinium, witch hazel, grapefruit, and other plants. Kaempferol is a yellow crystalline solid with a melting point of 276-278 degrees Celsius. It is slightly soluble in water and readily soluble in hot ethanol and ether. Kaempferol is a metabolite of Saccharomyces cerevisiae. See also: Top (part) of Indian hemp (Cannabis sativa subsp. indica); Flower (part) of Tussilago farfara. Mechanism of Action Kaempferol and several related flavonoids were studied in vitro as monoamine oxidase inhibitors (MAOIs). Kaempferol, apigenin, and salicumin were shown to be potent MAO inhibitors, but their inhibitory effects on MAO-A were more significant than those on MAO-B. The IC50 (half-maximal inhibitory concentration) values for MAO-A inhibition by these three flavonoids were 7 × 10⁻⁷, 1 × 10⁻⁶, and 2 × 10⁻⁶ M, respectively. In vitro experiments showed that Ginkgo biloba extract and kaempferol had no effect on MAO activity or the concentrations of dopamine, norepinephrine, serotonin, and 5-hydroxyindoleacetic acid in the brains of rats or mice. In vitro experiments showed that kaempferol could protect rat cortical cultures from N-methyl-D-aspartate (NMDA)-induced neurotoxicity, but could not prevent DSP-4-induced noradrenergic neurotoxicity in in vivo models. Lipid peroxidation experiments showed that both Ginkgo biloba extract and kaempferol possessed antioxidant activity. These data suggest that the monoamine oxidase (MAO) inhibitory activity of Ginkgo biloba extract is mainly attributed to the presence of kaempferol. Ginkgo biloba extract has potential neuroprotective effects. Kaempferol is a dietary flavonoid considered to function as a selective estrogen receptor modulator. …This study…confirmed that kaempferol also acts as an inverse agonist of estrogen-related receptors α and γ (ERRα and ERRγ). …Kaempferol binds to ERRα and ERRγ and blocks their interaction with peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α). Kaempferol also inhibited the expression of ERR target genes pyruvate dehydrogenase kinase 2 and 4 (PDK2 and PDK4). This evidence suggests that kaempferol may exert some of its biological effects through estrogen receptors and estrogen-associated receptors.

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Therapeutic Uses
/EXPL/ Despite recent advances in understanding the molecular mechanisms of glioblastoma progression, the prognosis for this most malignant brain tumor remains poor. Since the flavonoid kaempferol is known to inhibit the growth of various human malignancies, we investigated the effects of kaempferol on human glioblastoma cells. Kaempferol induces apoptosis in glioma cells by increasing intracellular oxidative stress levels. Enhanced oxidative stress is characterized by increased reactive oxygen species (ROS) production, accompanied by a decrease in oxidative scavengers such as superoxide dismutase (SOD-1) and thioredoxin (TRX-1). Knockdown of SOD-1 and TRX-1 expression using small interfering RNA (siRNA) increases ROS production and enhances the sensitivity of glioma cells to kaempferol-induced apoptosis. Apoptosis markers include decreased Bcl-2 expression, altered mitochondrial membrane potential, and increased expression of active caspase-3 and cleavable poly(ADP-ribose) polymerase (PARP). In cells treated with kaempferol, both plasma membrane potential and membrane fluidity were altered. Kaempferol inhibited the expression of pro-inflammatory cytokines interleukin-6 (IL-6) and chemokines interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), and regulatory factors of normal T cell expression and secretion (RATs). Kaempferol inhibited glioma cell migration in a ROS-dependent manner. Importantly, kaempferol enhanced the toxicity of the chemotherapeutic drug doxorubicin by increasing reactive oxygen species (ROS) toxicity and reducing doxorubicin efflux. Since the toxicity of both kaempferol and doxorubicin is enhanced when used in combination, this study proposes the possibility of a combination therapy that uses enhanced redox perturbation as a strategy to kill glioma cells. Kaempferol is one of the most important components of Ginkgo flavonoids. Recent studies have suggested that kaempferol may possess antitumor activity. This study aimed to determine the effects of kaempferol on the proliferation and apoptosis of pancreatic cancer cells and its underlying mechanisms. We treated pancreatic cancer cell lines MIA PaCa-2 and Panc-1 with kaempferol and assessed its inhibitory effect on cell proliferation using direct cell counting, 3H-thymidine incorporation assay, and MTS assay. Lactate dehydrogenase (LDH) release was used as an indicator of cytotoxicity. Apoptosis was analyzed using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). Results showed that after 4 days of treatment with 70 μM kaempferol, the proliferation of MIA PaCa-2 cells was significantly inhibited compared to the control group, with inhibition rates of 79% and 45.7% as shown by direct cell counting and MTS assay, respectively (P < 0.05). Similarly, kaempferol treatment also significantly inhibited the proliferation of Panc-1 cells. Furthermore, kaempferol treatment significantly reduced the incorporation of 3H-thymidine in MIA PaCa-2 and Panc-1 cells. Low-concentration kaempferol combined with 5-fluorouracil showed a synergistic effect in inhibiting MIA PaCa-2 cell proliferation. In addition, kaempferol exhibited significantly lower cytotoxicity to normal human pancreatic ductal epithelial cells than 5-fluorouracil (P = 0.029). In both MIA PaCa-2 and Panc-1 cells, kaempferol treatment increased the number of apoptotic cells in a concentration-dependent manner. Conclusion: Kaempferol, an extract of Ginkgo biloba, effectively inhibits pancreatic cancer cell proliferation and induces apoptosis, which may enhance the sensitivity of pancreatic tumor cells to chemotherapy. Kaempferol holds promise as an adjuvant therapy in the clinical treatment of pancreatic cancer. Dietary flavonols have been found to have potential for the prevention and treatment of various cancers. This study aimed to investigate the antiproliferative effect of kaempferol, a major component of food flavonols, on colon cancer cells. In the human colon cancer cell line HCT116, kaempferol induced p53-dependent growth inhibition and apoptosis. Furthermore, kaempferol was found to induce mitochondrial release of cytochrome c and activate caspase-3 cleavage. Bcl-2 family proteins, including PUMA, are involved in this process. Kaempferol also induced phosphorylation of ATM and H2AX in HCT116 cells, while inhibition of ATM with chemical inhibitors led to the blockage of the downstream apoptosis cascade. These results suggest that kaempferol may be an effective candidate drug for the treatment of colorectal cancer. Treatment of chronic myeloid leukemia cell lines K562 and promyelocytic leukemia cell lines U937 with 50 μM kaempferol increased the expression of the antioxidant enzymes manganese superoxide dismutase (MnSOD) and copper/zinc superoxide dismutase (Cu/ZnSOD). Kaempferol treatment induced apoptosis by decreasing Bcl-2 expression and increasing Bax expression. In addition, it induced mitochondrial release of cytochrome c into the cytoplasm and significantly activated caspase-3 and caspase-9, accompanied by PARP cleavage. Kaempferol treatment increased the expression and mitochondrial localization of the NAD-dependent deacetylase SIRT3. K562 cells stably overexpressing SIRT3 were more sensitive to kaempferol, while SIRT3 silencing did not increase K562 cell resistance to kaempferol. Treatment of K562 and U937 cells with kaempferol also resulted in PI3K inhibition and Akt dephosphorylation at Ser473 and Thr308 sites. …Kaempferol-induced oxidative stress in K562 and U937 cell lines led to Akt inactivation and activated the mitochondrial phase of the apoptosis program, manifested as increased Bax and SIRT3, decreased Bcl-2, cytochrome c release, caspase-3 activation, and cell death. Atherosclerosis is a chronic inflammatory disease of the arterial wall. Kaempferol and rhamnoside (kaempferol 7-O-methyl ether) are two common plant-derived anti-inflammatory flavonoids. This study aimed to investigate the roles of kaempferol and rhamnoside in the prevention of atherosclerosis. Chemical analysis showed that both kaempferol and rhamnoside could scavenge DPPH (1,1-diphenyl-2-trinitrophenylhydrazine) free radicals, with IC50 values of 26.10 ± 1.33 μM and 28.38 ± 3.07 μM, respectively. Both kaempferol and rhamnoside inhibited copper-induced low-density lipoprotein (LDL) oxidation, with similar inhibitory effects, manifested by decreased malondialdehyde production and reduced relative migration (REM) on agarose gel electrophoresis. Furthermore, rhamnoside showed better inhibition of delayed conjugated diene formation than kaempferol. Cholesterol-rich macrophages are a marker of atherosclerosis. Class B scavenger receptor CD36 binds to oxidized low-density lipoprotein (oxLDL), is present in atherosclerotic lesions, and is upregulated by oxLDL. The addition of kaempferol and rhamnoside (20 μM) significantly reduced the expression of CD36 protein on the surface of THP-1-derived macrophages (p < 0.05). RT-qPCR results showed that kaempferol and rhamnoside (20 μM) reduced oxLDL-induced CD36 mRNA expression (p < 0.01 and p < 0.05, respectively). Macrophages treated with kaempferol and rhamnoside also exhibited reduced uptake of 1,1'-dioctyl-3,3,3',3'-tetramethylindole carbonyl perchlorate (DiI)-labeled oxLDL. Current evidence suggests that kaempferol and rhamnoside not only protect low-density lipoprotein (LDL) from oxidation but also prevent atherosclerosis by inhibiting macrophage uptake of oxidized low-density lipoprotein (oxLDL).

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Kempferol (Robigenin) is a natural flavonoid compound that is widely found in fruits (grapes, apples), vegetables (onions, broccoli) and herbs (tea, ginkgo) [1][2][3][4]
Kempferol (Robigenin) exerts its anti-ovarian cancer effect by inducing cell cycle arrest and apoptosis. Nanoparticles can enhance its selective cytotoxicity against cancer cells [1]
Kempferol (Robigenin) igenin protects cardiac sinoatrial node function by reducing CaMKII oxidation and inhibiting mitochondrial-dependent apoptosis [3]
Kempferol (robignin) alleviates airway remodeling associated with allergic asthma by inhibiting airway smooth muscle proliferation and inhibiting the production of pro-inflammatory cytokines [4]
Kempferol (robignin) activates the intrinsic apoptotic pathway of ovarian cancer cells by upregulating p53 and Bax, downregulating Bcl-2 and activating caspase [2]

C15H10O6

286.23

286.047

C, 62.94; H, 3.52; O, 33.54

520-18-3

5280863

Light yellow to yellow solid powder

1.7±0.1 g/cm3

582.1±50.0 °C at 760 mmHg

276°C

226.1±23.6 °C

0.0±1.7 mmHg at 25°C

1.785

2.05

4

6

1

21

451

0

OC1=C2C(OC(C3=CC=C(O)C=C3)=C(O)C2=O)=CC(O)=C1

IYRMWMYZSQPJKC-UHFFFAOYSA-N

InChI=1S/C15H10O6/c16-8-3-1-7(2-4-8)15-14(20)13(19)12-10(18)5-9(17)6-11(12)21-15/h1-6,16-18,20H

3,5,7-trihydroxy-2-(4-hydroxyphenyl)chromen-4-one

3,4',5,7-Tetrahydroxyflavone; Pelargidenolon; Indigo Yellow; Kaempferol; Campherol

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2 mg/mL (6.99 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2 mg/mL (6.99 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2 mg/mL (6.99 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 5 mg/mL (17.47 mM) in 0.5% CMC/saline water (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)