Effects of flavonoids on cytochrome P450-dependent acetaminophen metabolism in rats and human liver microsomes.
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Flavonoids are widely occurring in our diet. In this study, the effects of nine flavonoids on acetaminophen (APAP) oxidation and related cytochrome P450 (P450) enzyme activities were investigated. With rat liver microsomes, APAP oxidation was stimulated 2- to 4-fold by 50 microM flavone or tangeretin and inhibited 65% by myricetin or quercetin. Only a slight inhibition of APAP oxidation was caused by naringenin. All the effects cited herein were from experiments with 50 microM flavonoids. With human liver microsomal samples that had high P450 3A4 activity, APAP oxidation was stimulated 1.6- to 3.0-fold by tangeretin, nobiletin, and flavone, but inhibited 40-60% by myricetin and quercetin. With human P450 1A2 expressed in Hep G2 cells, APAP oxidation was inhibited completely by flavone or quercetin. With expressed P450 3A4, this reaction was stimulated 4-fold by flavone, but inhibited 60% by quercetin. The expressed human P450 2E1-dependent APAP oxidation was only slightly affected by flavone and quercetin. The mechanisms of the inhibition and stimulation were complex and varied with the different P450 forms and flavonoids used in the system. The O-deethylation of ethoxyresorufin in rat liver microsomes was effectively inhibited by myricetin (IC50, 15 microM) and moderately inhibited by flavone, tangeretin, and quercetin (IC50, 50-80 microM); with P450 1A2 in Hep G2 cell microsomes, the activity was markedly inhibited by flavone (IC50, 2.5 microM). The microsomal P450s 2E1 and 3A activities were inhibited by myricetin (IC50, 85-90 microM), but not effectively inhibited by other flavonoids.(ABSTRACT TRUNCATED AT 250 WORDS)Keywords:
Myricetin
Microsoma
Fisetin
IC50
Acetaminophen
Nobiletin
Despite the fast development of vaccines, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still circulating and generating variants of concern (VoC) that escape the humoral immune response. In this context, the search for anti-SARS-CoV-2 compounds is still essential. A class of natural polyphenols known as flavonoids, frequently available in fruits and vegetables, is widely explored in the treatment of different diseases and used as a scaffold for the design of novel drugs. Therefore, herein we evaluate seven flavonoids divided into three subclasses, isoflavone (genistein), flavone (apigenin and luteolin) and flavonol (fisetin, kaempferol, myricetin, and quercetin), for COVID-19 treatment using cell-based assays and in silico calculations validated with experimental enzymatic data. The flavonols were better SARS-CoV-2 inhibitors than isoflavone and flavones. The increasing number of hydroxyl groups in ring B of the flavonols kaempferol, quercetin, and myricetin decreased the 50% effective concentration (EC50) value due to their impact on the orientation of the compounds inside the target. Myricetin and fisetin appear to be preferred candidates; they are both anti-inflammatory (decreasing TNF-α levels) and inhibit SARS-CoV-2 mainly by targeting the processability of the main protease (Mpro) in a non-competitive manner, with a potency comparable to the repurposed drug atazanavir. However, fisetin and myricetin might also be considered hits that are amenable to synthetic modification to improve their anti-SARS-CoV-2 profile by inhibiting not only Mpro, but also the 3′–5′ exonuclease (ExoN).
Myricetin
Fisetin
Flavonols
Flavones
Isorhamnetin
Hesperetin
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Fisetin
Myricetin
Chrysin
Thioflavin
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For naturally occurring flavones, quercetin, fisetin, nobiletin, and tangeritin, protect cultured rat liver epithelial-like cells against aflatoxin B1-induced cytotoxicity and inhibit the binding of [3H] aflatoxin B1 to cellular DNA. The methoxy-substituted flavones, nobiletin and tangeritin, show greater protection against cytotoxicity than do the hydroxy-substituted compounds, quercetin and fisetin.
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Fisetin
Flavones
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Flavonoid류와 진정제의 시험관 내 암세포증식억제효과를 관찰하기 위하여, 암세포의 말초형 benzodiazepine 수용체(이하 PBR로 약함) 활성도와 포도당 활용도에 대한 효과를 유방암 세포를 대상으로 검색하였다. 동시에 이미 항암활성이 잘 알려진 flavonoid류와의 상호작용도 관찰하였다. Fisetin (3,7,3',4'-tetrahydroxyflavone)과 diazepam의 암세포 증식 억제 효과는 악성도가 높은 MDA-MB-231 유방암 세포에서 MCF-7 유방암세포보다 저명하게 관찰되었다. MDA-MB-231 유방암세포에서, Apigenin (4',5,7-Trihydroxyflavone)과 fisetin 같은 flavonoid류처럼, $10^{-6}$ M 농도의 dazepam을 3일간 처치하였을 때 암세포 증식 억제효과를 나타내었으며, 이는 PBR 배위자들의 암세포 증식 증진효과와는 차이를 나타낸 것이다. Flavonoid 류처럼, MDA-MB-231 유방암세포에서, $10^{-6}$ M dazepam의 3일간 처치는 암세포의 PBR mRNA 발현에 큰 영향을 미치지 않았다. $10^{-6}$ M diazepam의 6 일간 처치는 암세포의 증식억제 효과가 증가되어 나타났으며, 암세포의 PBR mRNA 발현도 억제되었다. MDA-MB-231 유방암 세포에서, apigenin, fisetin과 diazepam은 포도당 유용도를 억제하였으며, 인슐린에 의한 포도당 유용도 증강효과도 억압하였다. Apigenin은 diazepam의 암세포 증식 억제 효과를 부가적으로 증강시켰다. 요약하면, 본 연구결과는 flavonoid류와 진정제의 시험관내 암세포 증식 억제효과와 부가적인 상호작용을 보여주고 있다. 결론적으로, 본 연구는 향후 좀더 진척된 시험을 위한 실험적인 기반 정보이다. The beneficial use of sedatives is often required for medically ill patients. This study examined the effect of plant flavonoids and diazepam peripheral-type benzodiazepine receptor (PBR) activation and glucose utilization in breast cancer cells, along with their interactions. In estrogen receptor negative MDA-MB-231 cells, the anti-proliferative activity of fisetin (3,7,3',4'-tetrahydroxyflavone) and diazepam was more prominent than in estrogen receptor positive MCF-7 cells. Unlike PBR ligands, treatment with $10^{-6}$ M concentration of diazepam for 3 days exhibited anti-proliferative effects, while similar to apigenin (4',5,7-Trihydroxyflavone) and fisetin, diazepam hardly affected the PBR mRNA expression by MDA-MB-231 cells. Treatment with $10^{-6}$ M concentration of flavonoids and diazepam for 3 days inhibited the glucose utilization of MDA-MB-231 cells. Treatment with $10^{-6}$ M concentration of flavonoids and diazepam for 6 days showed increased cytotoxicity and reduced the PBR mRNA expression of the MDA-MB-231 cells. Apigenin enhanced diazepam-induced anti-proliferative effects on the MDA-MB-231 cells as well. All together, this study showed the in vitro anti-proliferative activity of flavonoids and diazepam on MDA-MB-231 breast cancer cells, plus additive enhancements. In conclusion, this study provides experimental basis for advanced trials in the future.
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Hyperuricemia (HUA) is the fourth most common basic metabolic disease that can cause damage to multiple organs throughout the body. In this study, a hybrid compound consisting of myricetin and nobiletin was synthesized and its biological activity was evaluated. We named the hybrid compound MNH, and its structure was confirmed by spectroscopy. This study used serum metabolomics profiling with LC/MS and 16S rRNA gene sequencing analysis to explore the anti-HUA efficacy of MNH on a yeast paste-induced mouse model. The results showed that serum uric acid (UA), creatinine (CRE) and urea nitrogen (BUN) levels were significantly decreased after the intervention of MNH. The efficacy of MNH in lowering UA was somewhat greater than that of myricetin and nobiletin. In addition, MNH could repair the renal histopathological damage. Moreover, serum metabolomics demonstrated that MNH regulated the metabolic pathways involved in glycerophospholipid metabolism, arachidonic acid metabolism and alanine
Myricetin
Nobiletin
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Fisetin
Myricetin
Morin
Flavonols
Secondary metabolite
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Plants have long been providing mankind with remedies of different ailments. Flavonoids, a family of naturally occurring polyphenolic compounds are ubiquitous in plants. Development of polyphenol-based drugs has not attracted much attention by researchers and drug companies. Therefore, despite extensive studies on polyphenols, this vast group of compounds is underrepresented in clinical medicine. Fisetin (3,7,3',4'-tetrahydroxyflavone) belongs to the flavonol subgroup of flavonoids together with quercetin, myricetin and kaempferol and is found in several fruits and vegetables including strawberries, apples, persimmons and onions. Fisetin is showing promise as a useful natural agent against cancer and has been evaluated for its potential inhibitory role against cancer in several in vitro and in vivo studies. The Akt/mTOR pathway is known to play a central role in various cellular processes that contribute to the malignant phenotype. Accordingly, inhibition of this signaling cascade has been a focus of recent therapeutic studies. Novel inhibitors of PI3-K, Akt, and mTOR are now passing through early phase clinical trials. Herein, we review the effect of fisetin on the PI3- K/Akt/mTOR pathway as studied in different cancer cell models.
Fisetin
Myricetin
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Fisetin
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Purpose: To investigate the anti-inflammatory effects of kaempferol, myricetin, fisetin and ibuprofen in rat pups.Methods: The expression levels of cyclooxygenase (COX)-1, COX-2 and tumour necrosis factor-α (TNF-α) were determined by western blotting; the inhibition of these proteins by plant compounds was evaluated. In addition, a computational simulation of the molecular interactions of the compounds at the active sites of the proteins was performed using a molecular docking approach. Absorption, distribution, metabolism and excretion (ADME) and toxicity analysis of the plant compounds was also performed.Results: Kaempferol, myricetin and fisetin inhibited the activities of COX-1, COX-2 and TNF-α by 70–88%. The computational simulation revealed the molecular interactions of these compounds at the active sites of COX-1, COX-2 and TNF-α. ADME and toxicity analysis demonstrated that the three plant compounds were safe.Conclusion: The data obtained indicate that myricetin, kaempferol and fisetin exert anti-inflammatory effects in neonatal rats, with fewer side effects than those of ibuprofen.Keywords: Non-steroidal anti-inflammatory drugs, Cyclooxygenase-1, Cyclooxygenase-2, Tumour necrosis factor-α
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Myricetin
ADME
Ibuprofen
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We synthesized a series of analogs of fisetin, myricetin and nobiletin, as well as related fluorescein-and biotin-based flavone-probe molecules, on a suitable scale for biological and structure-activity relationship studies.
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Myricetin
Nobiletin
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