Resokaempferol

Predictive QSAR model confirms flavonoids in Chinese medicine can activate voltage-gated calcium (CaV) channel in osteogenesis.[Pubmed:32256687]

Chin Med. 2020 Mar 31;15:31.

Background: Flavonoids in Chinese Medicine have been proven in animal studies that could aid in osteogenesis and bone formation. However, there is no consented mechanism for how these phytochemicals action on the bone-forming osteoblasts, and henceforth the prediction model of chemical screening for this specific biochemical function has not been established. The purpose of this study was to develop a novel selection and effective approach of flavonoids on the prediction of bone-forming ability via osteoblastic voltage-gated calcium (CaV) activation and inhibition using molecular modelling technique. Method: Quantitative structure-activity relationship (QSAR) in supervised maching-learning approach is applied in this study to predict the behavioral manifestations of flavonoids in the CaV channels, and developing statistical correlation between the biochemical features and the behavioral manifestations of 24 compounds (Training set: Kaempferol, Taxifolin, Daidzein, Morin, Scutellarein, Quercetin, Apigenin, Myricetin, Tamarixetin, Rutin, Genistein, 5,7,2'-Trihydroxyflavone, Baicalein, Luteolin, Galangin, Chrysin, Isorhamnetin, Naringin, 3-Methyl galangin, Resokaempferol; test set: 5-Hydroxyflavone, 3,6,4'-Trihydroxyflavone, 3,4'-Dihydroxyflavone and Naringenin). Based on statistical algorithm, QSAR provides a reasonable basis for establishing a predictive correlation model by a variety of molecular descriptors that are able to identify as well as analyse the biochemical features of flavonoids that engaged in activating or inhibiting the CaV channels for osteoblasts. Results: The model has shown these flavonoids have high activating effects on CaV channel for osteogenesis. In addition, scutellarein was ranked the highest among the screened flavonoids, and other lower ranked compounds, such as daidzein, quercetin, genistein and naringin, have shown the same descending order as previous animal studies. Conclusion: This predictive modelling study has confirmed and validated the biochemical activity of the flavonoids in the osteoblastic CaV activation.

Metabolic engineering of yeast for fermentative production of flavonoids.[Pubmed:28634125]

Bioresour Technol. 2017 Dec;245(Pt B):1645-1654.

Yeast Saccharomyces cerevisiae was engineered for de novo production of six different flavonoids (naringenin, liquiritigenin, kaempferol, Resokaempferol, quercetin, and fisetin) directly from glucose, without supplementation of expensive intermediates. This required reconstruction of long biosynthetic pathways, comprising up to eight heterologous genes from plants. The obtained titers of kaempferol 26.57+/-2.66mgL(-1) and quercetin 20.38+/-2.57mgL(-1) exceed the previously reported titers in yeast. This is also the first report of de novo biosynthesis of Resokaempferol and fisetin in yeast. The work demonstrates the potential of flavonoid-producing yeast cell factories.

Antibacterial and Cytotoxic Phenolic Metabolites from the Fruits of Amorpha fruticosa.[Pubmed:28075580]

J Nat Prod. 2017 Jan 27;80(1):169-180.

Fourteen new natural products, namely, 2-[(Z)-styryl]-5-geranylresorcin-1-carboxylic acid (1), amorfrutin D (2), 4-O-demethylamorfrutin D (3), 8-geranyl-3,5,7-trihydroxyflavanone (4), 8-geranyl-5,7,3'-trihydroxy-4'-methoxyisoflavone (5), 6-geranyl-5,7,3'-trihydroxy-4'-methoxyisoflavone (6), 8-geranyl-7,3'-dihydroxy-4'-methoxyisoflavone (7), 3-O-demethyldalbinol (8), 6a,12a-dehydro-3-O-demethylamorphigenin (9), (6aR,12aR,5'R)-amorphigenin (10), amorphispironones B and C (11 and 12), Resokaempferol 3-O-beta-d-glucopyranosyl-(1-->2)-beta-d-glucopyranoside-7-O-alpha-l-rhamnopyrano side (13), and daidzein 7-O-beta-d-glucopyranosyl-(1-->2)-beta-d-glucopyranoside (14), together with 40 known compounds, were isolated from the fruits of Amorpha fruticosa. The structures of the new compounds were elucidated by 1D and 2D NMR spectroscopic analysis as well as from the mass spectrometry data. ECD calculations were performed to determine the absolute configurations of 11 and 15. Compounds 1, 4-6, and 16-23 showed potent to moderate antibacterial activities against several Gram-positive bacteria with MIC values ranging from 3.1 to 100 muM. In addition, compounds 11 and 24-33 were significantly cytotoxic against the L5178Y mouse lymphoma cell line and exhibited IC50 values from 0.2 to 10.2 muM.

Resokaempferol-mediated anti-inflammatory effects on activated macrophages via the inhibition of JAK2/STAT3, NF-kappaB and JNK/p38 MAPK signaling pathways.[Pubmed:27261558]

Int Immunopharmacol. 2016 Sep;38:104-14.

The excessive or prolonged production of inflammatory mediators can result in numerous chronic diseases, such as rheumatoid arthritis, atherosclerosis, diabetes, and cancer. Therefore, for many inflammatory-related diseases, pharmaceutical intervention is required to restrain the excessive release of such inflammatory mediators. Novel therapeutics and mechanistic insight are sought for the management of chronic inflammatory diseases. Resokaempferol (RES) is a type of flavonoid recently reported to demonstrate anti-cancer properties. However, the anti-inflammatory capacity of RES has not been studied to date. Therefore, this study investigated whether RES is capable of suppressing the inflammatory response to lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and the mechanism by which this is achieved. We found that RES attenuated the LPS-induced production of nitric oxide (NO), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), interleukin (IL)-1beta, tumor necrosis factor-alpha (TNF-alpha), monocyte chemotactic protein 1 (MCP-1) and IL-6. RES also inhibited the nuclear translocation of signal transducer and activator of transcription (STAT) 3 and reduced the LPS-mediated phosphorylation of Janus kinase (JAK) 2 and STAT3 at the sites of Ser727 and Tyr705. RES also inhibited the activation of NF-kappaB and JNK/p38 MAPK signaling pathways in LPS-induced RAW264.7 cells. Additionally, RES inhibited the activation of the JAK2/STAT3 pathway in exogenous IL-6-activated RAW264.7 macrophages. We conclude that RES inhibits the inflammatory response in activated macrophages by blocking the activation of the JAK2/STAT3 pathway by both LPS and IL-6 signaling.

Assembly of a novel biosynthetic pathway for production of the plant flavonoid fisetin in Escherichia coli.[Pubmed:26192693]

Metab Eng. 2015 Sep;31:84-93.

Plant secondary metabolites are an underutilized pool of bioactive molecules for applications in the food, pharma and nutritional industries. One such molecule is fisetin, which is present in many fruits and vegetables and has several potential health benefits, including anti-cancer, anti-viral and anti-aging activity. Moreover, fisetin has recently been shown to prevent Alzheimer's disease in mice and to prevent complications associated with diabetes type I. Thus far the biosynthetic pathway of fisetin in plants remains elusive. Here, we present the heterologous assembly of a novel fisetin pathway in Escherichia coli. We propose a novel biosynthetic pathway from the amino acid, tyrosine, utilizing nine heterologous enzymes. The pathway proceeds via the synthesis of two flavanones never produced in microorganisms before--garbanzol and Resokaempferol. We show for the first time a functional biosynthetic pathway and establish E. coli as a microbial platform strain for the production of fisetin and related flavonols.

The flavonoid scaffold as a template for the design of modulators of the vascular Ca(v) 1.2 channels.[Pubmed:21557738]

Br J Pharmacol. 2011 Nov;164(6):1684-97.

BACKGROUND AND PURPOSE: Previous studies have pointed to the plant flavonoids myricetin and quercetin as two structurally related stimulators of vascular Ca(v) 1.2 channel current (I(Ca1.2) ). Here we have tested the proposition that the flavonoid structure confers the ability to modulate Ca(v) 1.2 channels. EXPERIMENTAL APPROACH: Twenty-four flavonoids were analysed for their effects on I(Ca1.2) in rat tail artery myocytes, using the whole-cell patch-clamp method. KEY RESULTS: Most of the flavonoids stimulated or inhibited I(Ca1.2) in a concentration- and voltage-dependent manner with EC(50) values ranging between 4.4 microM (kaempferol) and 16.0 microM (myricetin) for the stimulators and IC(50) values between 13.4 microM (galangin) and 100 microM [(+/-)-naringenin] for the inhibitors. Key structural requirements for I(Ca1.2) stimulatory activity were the double bond between C2 and C3 and the hydroxylation pattern on the flavonoid scaffold, the latter also determining the molecular charge, as shown by molecular modelling techniques. Absence of OH groups in the B ring was key in I(Ca1.2) inhibition. The functional interaction between quercetin and either the stimulator myricetin or the antagonists Resokaempferol, crysin, genistein, and 5,7,2'-trihydroxyflavone revealed that quercetin expressed the highest apparent affinity, in the low microM range, for Ca(v) 1.2 channels. Neither protein tyrosine kinase nor protein kinase Calpha were involved in quercetin-induced stimulation of I(Ca1.2). CONCLUSIONS AND IMPLICATIONS: Quercetin-like plant flavonoids were active on vascular Ca(v)1.2 channels. Thus, the flavonoid scaffold may be a template for the design of novel modulators of vascular smooth muscle Ca(v)1.2 channels, valuable for the treatment of hypertension and stroke.