Fukinolic acid

In vitro and in vivo evaluation of antioxidant activity of Petasites japonicus Maxim. flower buds extracts.[Pubmed:31762379]

Biosci Biotechnol Biochem. 2020 Mar;84(3):621-632.

The antioxidant activity of Petasites japonicus flower buds cultivated in Tokushima, Japan, was examined in vitro and in vivo. The flower bud extracts were assayed using either oxygen radical absorbance capacity or 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity. Antioxidants in the 80% ethanol extract were investigated using online high-performance liquid chromatography-DPPH and were identified as caffeic acid, 3-O-caffeoylquinic acid, Fukinolic acid, 3,4-di-O-caffeoylquinic acid, 3,5-di-O-caffeoylquinic acid, and 4,5-di-O-caffeoylquinic acid using liquid chromatography-mass spectrometry. Fukinolic acid was the most active compound based on its activity and abundance. Administering the extracts orally to ICR mice prior to iron injection significantly suppressed plasma thiobarbituric acid reactive substance (TBARS) production. Moreover, TBARS and triglyceride concentrations in the plasma of C57BL/6 mice fed with a high fat diet were also significantly decreased by the extract. The results suggest that antioxidative compounds in P. japonicus can be used in the management of oxidative stress.

Identification of fukinolic acid from Cimicifuga heracleifolia and its derivatives as novel antiviral compounds against enterovirus A71 infection.[Pubmed:30063999]

Int J Antimicrob Agents. 2019 Feb;53(2):128-136.

Human enterovirus 71 (EV-A71) infections cause a wide array of diseases ranging from diarrhoea and rashes to hand-foot-and-mouth disease and, in rare cases, severe neurological disorders. No specific antiviral drug therapy is currently available. Extracts from 75 Chinese medicinal plants selected for antiviral activity based on the Chinese pharmacopeia and advice from traditional Chinese medicine clinicians were tested for activity against EV-A71. The aqueous extract of the rhizome of Cimicifuga heracleifolia (Sheng Ma) and Arnebia euchroma (Zi Cao) showed potent antiviral activity. The active fractions were isolated by bioassay-guided purification, and identified by a combination of high-resolution mass spectrometry and nuclear magnetic resonance. Fukinolic acid and cimicifugic acid A and J, were identified as active anti-EV-A71 compounds for C. heracleifolia, whereas for A. euchroma, two caffeic acid derivatives were tentatively deduced. Commercially available Fukinolic acid analogues such as L-chicoric acid and D-chicoric also showed in vitro micromolar activity against EV-A71 lab-strain and clinical isolates.

NIR Spectroscopy of Actaea racemosa L. rhizome - En Route to Fast and Low-Cost Quality Assessment.[Pubmed:28403500]

Planta Med. 2017 Aug;83(12-13):1085-1096.

Rhizomes of Actaea racemosa L. (formerly Cimicifuga racemosa) gained increasing interest as a plant-derived drug due to its hormone-like activity and the absence of estrogenic activity. According to the Current Good Manufacturing Practices guidelines and pharmacopeial standards, quality assessment of herbal starting materials includes tests on identity and substitution, as well as quantification of secondary metabolites, usually by HPTLC and LC methods. To reduce the laboratory effort, we investigated near-infrared spectroscopy for rapid species authentication and quantification of metabolites of interest.Near-infrared spectroscopy analysis is carried out directly on the milled raw plant material. Spectra were correlated with reference data of polyphenols and triterpene glycosides determined by LC/diode array detection and LC/evaporative light scattering detection, respectively. Quantification models were built and validated by cross-validation procedures. Clone plants, derived by vegetative propagation, and plants of a collection from different geographical origins cultivated in Berlin were analysed together with mixed batches from wild harvests purchased at wholesalers.Generally, good to excellent correlations were found for the overall content of polyphenols with coefficients of determination of R(2) > 0.93. For individual polyphenols such as Fukinolic acid, only models containing clone plants succeeded (R(2) > 0.92). For the total content of triterpene glycosides, results were generally worse in comparison to polyphenols and were observed only for the mixed batches (R(2) = 0.93).Next to quantitative analysis, near-infrared spectroscopy was proven as a rapid alternative to other, more laborious methods for species authentication. Near-infrared spectroscopy was able to distinguish different Actaea spp. such as the North American Actaea cordifolia and the Asian Actaea cimicifuga, Actaea dahurica, Actaea heracleifolia, and Actaea simplex.

Rapid identification and evaluation of antioxidant compounds from extracts of Petasites japonicus by hyphenated-HPLC techniques.[Pubmed:21656532]

Biomed Chromatogr. 2012 Feb;26(2):199-207.

Gradient HPLC coupled to Diode Array Detector (DAD), MS/MS and NMR was applied to the rapid structure determination of major compounds of methanol extracts from leaves and roots of Petasites japonicus. The relative antioxidant capacities of the compounds were evaluated by an HPLC system with post-column on-line antioxidant detection based on 2,2'-azinobis-3-ethylbenzothiazoline-6-sulfonic acid radical scavenging. Six compounds were successfully separated on a reverse-phase C(18) column and were identified as 5-caffeoylquinic acid (5-CQA), Fukinolic acid (FA), 3,5-di-O-caffeoylquinic acid (3,5-DCQA), quercetin-3-O-(6''-acetyl)-beta-glucopyranoside (QAG), 4,5-di-O-caffeoylquinic acid (4,5-DCQA) and kaempferol-3-O-(6''-acetyl)-beta-glucopyranoside (KAG) by MS/MS and (1)H NMR data. Among these compounds, those containing a caffeoyl moiety (5-CQA, FA, 3,5- and 4,5-DCQA) showed relatively strong radical scavenging capacity, with 3,5-DCQA having the greatest radical scavenging capacity in leaf (23.09% of total antioxidant capacity) and root (26.47%) extracts. The relative radical scavenging portion of QAG was only 3.41% in the leaves and KAG did not show any radical scavenging activity. These results demonstrate that the hyphenated HPLC techniques can be successfully applied to rapidly identify structures and evaluate antioxidant activities without prior purification of compounds from plant tissues of P. japonicus.

Fukinolic acid derivatives and triterpene glycosides from black cohosh inhibit CYP isozymes, but are not cytotoxic to Hep-G2 cells in vitro.[Pubmed:20406160]

Curr Drug Saf. 2010 Apr;5(2):118-24.

Black cohosh (Actaea racemosa L. [syn. Cimifuga racemosa L.]) extracts (BCE) are marketed worldwide for the management of menopausal symptoms. However, recently more than 75 cases of hepatotoxicity associated with black cohosh ingestion have been reported. While these cases have not been fully substantiated for causality, the data suggest that herb-drug interactions may be involved rather than a direct hepatotoxic event. This work describes the in vitro inhibition of four CYP450 enzymes (1A2, 2D6, 2C9, 3A4) by black cohosh extracts and identifies the active inhibitory constituents. Ethanol extracts (75 and 80% ethanol) and a 40% isopropanol extract induced a concentration-dependent inhibition of all CYP450 isozyme activities, with median inhibitory concentrations (IC(50)) ranging from 21.9 microg/ml to 65.0 microg/ml. Isolation of the active chemical constituents, showed that the triterpene glycosides were weakly active (IC(50) 25-100 microM), while Fukinolic acid and cimicifugic acids A and B strongly inhibited all CYP isozymes (IC(50) 1.8-12.6 microM). None of the extracts inhibited the growth of Hep-G2 cells in concentrations up to 50 microg/ml. These data suggest that BCEs are not directly hepatotoxic, but may have the potential to induce herb-drug interactions, which may in turn explain the rare cases of hepatotoxicity observed in women using multiple medications and dietary supplements, including black cohosh.

Hyaluronidase inhibitors from "Cimicifugae Rhizoma" (a mixture of the rhizomes of Cimicifuga dahurica and C. heracleifolia).[Pubmed:20192237]

J Nat Prod. 2010 Apr 23;73(4):573-8.

From the 80% acetone extract of "Cimicifugae Rhizoma" (a mixture of Cimicifuga dahurica and C. heracleifolia used medicinally), seven new fukiic acid derivatives (1-7) and a new phenylethanoid derivative (8) were isolated along with eight known compounds (9-16). Fukinolic acid (9) and cimicifugic acids A-J (10-16, 5-7) showed stronger hyaluronidase inhibitory activities than the positive control, rosmarinic acid.

Phenolic constituents of the aerial parts of Cimicifuga simplex and Cimicifuga japonica.[Pubmed:20184336]

J Nat Prod. 2010 Apr 23;73(4):609-12.

Chemical investigation of the aerial parts of Cimicifuga simplex afforded four new Fukinolic acid analogues, cimicifugic acids K-N (1-4), and 10 known compounds, and C. japonica afforded three new Fukinolic acid analogues, cimicifugic acids K-M (1-3), a new phenolic glycoside, shomaside F (5), and 10 known compounds. Cimicifugic acids K-N showed more potent hyaluronidase inhibitory activities than rosmarinic acid.

Anti type I allergic property of Japanese butterbur extract and its mast cell degranulation inhibitory ingredients.[Pubmed:16608208]

J Agric Food Chem. 2006 Apr 19;54(8):2915-20.

Pollenosis is a disease that affects 1 in 10 of the Japanese population. During the season of cedar pollen dispersal, many patients suffer from symptoms such as sniffling, sternutation, and itching of the eyes. Japanese butterbur is a popular vegetable and is one of the few domestic vegetables in Japan. The anti type I allergic effects of an aqueous ethanol extract from aerial parts of Japanese butterbur (JBE) were evaluated in rats and RBL-2H3 mast cells. In the passive cutaneous anaphylaxis reaction in rats, a single oral treatment of JBE (1000 mg/kg) was found to suppress the reaction. In IgE-sensitized RBL-2H3 cells, JBE (10-100 microg/mL) inhibited beta-hexosaminidase release, leukotriene C(4)/D(4)/E(4) synthesis, and TNF-alpha production. Moreover, a high concentration of JBE (1000 microg/mL) suppressed smooth muscle constriction induced by histamine (10 microM) and leukotriene D(4) (10 nM) in a guinea pig trachea strip. The search for components in JBE with an inhibitory activity on mast cell degranulation was guided by inhibition of beta-hexsosaminidase release. Two eremophilane-type sesquiterpenes, six polyphenolic compounds, and two triterpene glycosides were isolated. Of these compounds, Fukinolic acid, a principal polyphenol constituent, showed potent inhibitory activity (IC(50) value = 2.1 microg/mL). Consequently, On the basis of its inhibition of mast cell activation and direct smooth muscle reaction induced by released mediators, JBE was found to suppress the type I allergic reaction.

Polyphenolic constituents of Actaea racemosa.[Pubmed:16562825]

J Nat Prod. 2006 Mar;69(3):314-8.

A new lignan, actaealactone (1), and a new phenylpropanoid ester derivative, cimicifugic acid G (2), together with 15 known polyphenols, protocatechuic acid, protocatechualdehyde, p-coumaric acid, caffeic acid, methyl caffeate, ferulic acid, ferulate-1-methyl ester, isoferulic acid, 1-isoferuloyl-beta-d-glucopyranoside, Fukinolic acid, and cimicifugic acids A, B, and D-F, were isolated from an extract of the rhizomes and roots of black cohosh (Actaea racemosa). The structures of the new compounds were determined on the basis of NMR spectroscopic analysis. Compounds 1 and 2 displayed antioxidant activity in the 1,1-diphenyl-2-picrylhydrazyl (DPPH) free-radical assay with IC(50) values of 26 and 37 microM, respectively. Other antioxidants identified from A. racemosa include cimicifugic acid A (3), cimicifugic acid B (4), and Fukinolic acid (5). Compounds 1 and 2 also exhibited a small stimulating effect on the growth of MCF-7 breast cancer cell proliferation 1.24-fold (14 microM) and 1.14-fold (10 microM), respectively, compared to untreated cells.

Cimipronidine, a cyclic guanidine alkaloid from Cimicifuga racemosa.[Pubmed:16124775]

J Nat Prod. 2005 Aug;68(8):1266-70.

A new cyclic guanidine alkaloid, cimipronidine (1), together with the known compound Fukinolic acid (2), was isolated from the n-BuOH-soluble fraction of Cimicifuga racemosa roots that showed 5-HT7 receptor binding activity. Structure elucidation of 1, a minor constituent, presented unique challenges based on its polarity, but was accomplished with the use of a combination of one- and two-dimensional NMR as well as MS analyses. The relative configuration was established by analyzing the H,H-coupling constants and the results of the 2-D gradient NOESY spectrum. The previously reported serotonergic (5-HT7), highly polar, n-BuOH-soluble fraction was characterized by HPLC-ELSD and was shown to be a mixture containing the following compounds: cimicifugic acids A, B, and F, Fukinolic acid, ferulic acid, isoferulic acid, and compound 1, potentially significant as a marker compound of C. racemosa.

Phenolic esters from the rhizomes of Cimicifuga racemosa do not cause proliferation effects in MCF-7 cells.[Pubmed:15971118]

Planta Med. 2005 Jun;71(6):495-500.

Five phenylpropanoid esters, caffeoylglycolic acid, 2-caffeoylpiscidic acid (cimicifugic acid D), 3,4-dihydroxyphenacyl caffeate (petasiphenone), 3,4-dihydroxyphenyl-2-oxopropyl isoferulate (cimiciphenol) and 3,4-dihydroxyphenacyl isoferulate (cimiciphenone) were isolated from a commercially available extract of the rhizomes of Cimicifuga racemosa (L.) Nutt. (syn. Actaea racemosa L.) for the first time; the known cimicifugic acids A, B, E, F, Fukinolic acid, fukiic acid and caffeic acid were also obtained. Cimiciphenone and caffeoylglycolic acid are new natural products. The structures were elucidated by means of spectroscopic data (ESI-MS, 1H-, 13C-NMR, COSY, HMQC, HMBC and NOE experiments). Ferulic acid and isoferulic acid were detected by HPLC analysis in comparison to standards. The estrogenic activity of the isolated compounds was tested in an estrogen-dependent MCF-7 mamma carcinoma cell line; 17beta-estradiol (10(-11) M) and the phytoestrogen coumestrol (10(-7) - 10(-5) M) were used as references. The results suggest that, in contrast to an earlier report, the phenolic esters do not exert a proliferative (estrogenic) effect in this test system.

Biosynthesis of fukinolic acid isolated from Petasites japonicus.[Pubmed:15502374]

Biosci Biotechnol Biochem. 2004 Oct;68(10):2212-4.

The biosynthesis of Fukinolic acid, which had been isolated from the Japanese fuki vegetable, Petasites japonicus, was investigated by feeding selected (13)C-labeled compounds to axenic cultures of P. japonicus. [1,2-(13)C(2)] sodium acetate and [1-(13)C] L-tyrosine were incorporated into the fukiic acid sub group, while [3-(13)C] L-phenylalanine was incorporated into the caffeic acid moiety.

In vitro formation of quinoid metabolites of the dietary supplement Cimicifuga racemosa (black cohosh).[Pubmed:12870886]

Chem Res Toxicol. 2003 Jul;16(7):838-46.

Botanical dietary supplements containing Cimicifuga racemosa (Actaea racemosa; black cohosh) are used commonly by women to assuage menopausal symptoms including hot flashes and sleep disorders. Despite the popularity of such supplements, little is known about the metabolism or possible toxicity of many compounds that could be concentrated therein. The aim of this study was to selectively identify phase I metabolites resulting from metabolic bioactivation of constituents of black cohosh in vitro and to determine whether evidence of such metabolites could be found in the urine of perimenopausal women taking black cohosh oral supplements. A variation of an ultrafiltration mass spectrometric assay devised previously was used to screen an extract of black cohosh for the formation of electrophilic phase I metabolites that had been trapped as GSH conjugates. Mercapturates (N-acetylcysteine conjugates) corresponding to the GSH conjugates identified during screening were synthesized and characterized using LC-MS/MS with product-ion scanning. During a phase I clinical trial of black cohosh in perimenopausal women, urine was collected from seven subjects, each of whom took a single oral dose of either 32, 64, or 128 mg of the black cohosh extract. These urine samples were analyzed for the presence of mercapturate conjugates using positive-ion electrospray LC-MS and LC-MS/MS. On the basis of their propensity to form GSH adducts following metabolic activation by hepatic microsomes and NADPH in vitro, a total of eight electrophilic metabolites of black cohosh were detected, including quinoid metabolites of Fukinolic acid, fukiic acid, caffeic acid, and cimiracemate B. Additional quinoid metabolites were formed from hydroxytyrosol and dihydroxyphenyl lactic acid, neither of which had been isolated previously from black cohosh. However, mercapturate conjugates of these black cohosh constituents were not detected in urine samples from women who consumed single oral doses of up to 256 mg of a standardized black cohosh extract. Therefore, for moderate doses of a dietary supplement containing black cohosh, this study found no cause for safety concerns over the formation of quinoid metabolites in women.