Cupressuflavone

Strong and Selective Inhibitory Effects of the Biflavonoid Selamariscina A against CYP2C8 and CYP2C9 Enzyme Activities in Human Liver Microsomes.[Pubmed:32290339]

Pharmaceutics. 2020 Apr 10;12(4). pii: pharmaceutics12040343.

Like flavonoids, biflavonoids, dimeric flavonoids, and polyphenolic plant secondary metabolites have antioxidant, antibacterial, antiviral, anti-inflammatory, and anti-cancer properties. However, there is limited data on their effects on cytochrome P450 (P450) and uridine 5'-diphosphoglucuronosyl transferase (UGT) enzyme activities. In this study we evaluate the inhibitory potential of five biflavonoids against nine P450 activities (P450s1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A) in human liver microsomes (HLMs) using cocktail incubation and liquid chromatography-tandem mass spectrometry (LC-MS/MS). The most strongly inhibited P450 activity was CYP2C8-mediated amodiaquine N-dealkylation with IC50 ranges of 0.019~0.123 muM. In addition, the biflavonoids-selamariscina A, amentoflavone, robustaflavone, Cupressuflavone, and taiwaniaflavone-noncompetitively inhibited CYP2C8 activity with respective Ki values of 0.018, 0.083, 0.084, 0.103, and 0.142 muM. As selamariscina A showed the strongest effects, we then evaluated it against six UGT isoforms, where it showed weaker inhibition (UGTs1A1, 1A3, 1A4, 1A6, 1A9, and 2B7, IC50 1.7 muM). Returning to the P450 activities, selamariscina A inhibited CYP2C9-mediated diclofenac hydroxylation and tolbutamide hydroxylation with respective Ki values of 0.032 and 0.065 muM in a competitive and noncompetitive manner. However, it only weakly inhibited CYP1A2, CYP2B6, and CYP3A with respective Ki values of 3.1, 7.9, and 4.5 muM. We conclude that selamariscina A has selective and strong inhibitory effects on the CYP2C8 and CYP2C9 isoforms. This information might be useful in predicting herb-drug interaction potential between biflavonoids and co-administered drugs mainly metabolized by CYP2C8 and CYP2C9. In addition, selamariscina A might be used as a strong CYP2C8 and CYP2C9 inhibitor in P450 reaction-phenotyping studies to identify drug-metabolizing enzymes responsible for the metabolism of new chemicals.

Growth inhibitory activity of biflavonoids and diterpenoids from the leaves of the Libyan Juniperus phoenicea against human cancer cells.[Pubmed:31157484]

Phytother Res. 2019 Aug;33(8):2075-2082.

Three biflavonoids [Cupressuflavone (1), amentoflavone (2), and sumaflavone (3)], four diterpenoids [13-epi-cupressic acid (4), imbricatholic acid (5), 3-hydroxy-sandaracopimaric acid (6), and dehydroabietic acid (7)], and one lignan [beta-peltatin methyl ether (8)] were isolated from the cytotoxic fractions of the extracts of the leaves of the Libyan Juniperus phoenicea L. The structures of these compounds were elucidated by spectroscopic means. Cytotoxicity of compounds 1-6 were assessed against the human lung cancer cell line A549 using the MTT assay. Compounds 1 and 3 showed cytotoxicity against the A549 cells (IC50 = 65 and 77 muM, respectively), whereas compound 2 did not show any activity. Diterpenes 4-6 exhibited weak cytotoxicity against the A549 cells with the IC50 values of 159, 263, and 223 muM, respectively. The cytotoxicity of each compound was compared with the anticancer drug, etoposide (IC50 = 61 muM). Cupressuflavone (1) was evaluated also for cytotoxicity against both the human PC3 cancer cell line and the normal prostate cell line (PNT2), and this compound revealed a high degree of cytotoxic selectivity towards the prostate cancer cells (PC3), with IC50 value of 19.9 muM, without any evidence of cytotoxicity towards the normal prostate cell line (PNT2).

Bioactive Constituents of Juniperus turbinata Guss. from La Maddalena Archipelago.[Pubmed:29790302]

Chem Biodivers. 2018 Aug;15(8):e1800148.

A comprehensive phytochemical study of Juniperus turbinata (Cupressaceae) collected from La Maddalena Archipelago (Sardinia, Italy) is reported. Both the essential oil and the ethanolic extract obtained from the aerial parts were analyzed. The essential oil appears to belong to a new chemotype compared to other Mediterranean juniper accessions, as it was favored by geographic isolation of the isles. It showed a low content of monoterpene hydrocarbons and alpha-terpineol, ent-manoyl oxide, 1,10-di-epi-cubenol as the major constituents. The ethanolic fraction contained mainly diterpenoids. Among these, 15-formyloxyimbricatolic acid (7) is a new natural product since it has hitherto been obtained only by synthetic route. The phenolic fraction contained biflavonoids: Cupressuflavone (9), followed by minor amounts of amentoflavone (10) and hinokiflavone (11). The essential oil and six purified compounds (1 - 4, 8 and 9) were assessed for biological activities, namely antioxidant (assessed by DPPH(.) , ABTS(.+) and FRAP methods) and cytotoxic effects towards selected human tumor cell lines (MDA-MB 231, A375 and HCT116 cells). Compound 3 exhibited higher radical scavenging activity against ABTS(.+) radical than the reference Trolox. Noteworthy, compound 8 showed powerful effects towards tumor cell lines, with IC50 values in the range of 0.060 - 0.201 mum, which make it a promising anticancer drug candidate.

Juniperus chinensis Fruits Attenuate Oxazolone- and 2,4-Dinitrochlorobenzene-Induced Atopic Dermatitis Symptoms in Mice.[Pubmed:29386485]

Biol Pharm Bull. 2018;41(2):259-265.

Juniperus chinensis, commonly Chinese juniper, has been used for treating inflammatory diseases. This study aimed to investigate anti-atopic dermatitis (AD) effects of standardized J. chinensis fruits extract on murine oxazolone- and 2,4-dinitrochlorobenzene (DNCB)-induced models of AD. Ear swelling, epidermis thickening, and eosinophils infiltration in the oxazolone-mediated dermatitis of BALB/c mice were significantly reduced upon topical application of J. chinensis fruits 95% EtOH extract (JCE). Besides, transdermal administration of JCE to SKH-1 hairless mice inhibited the development of DNCB-induced AD-like skin lesions by suppressing transepidermal water loss and improving skin hydration. Decreased total serum immunoglobulin E (IgE) and interleukin (IL)-4 levels could be observed in atopic dorsal skin samples of JCE-treated group. According to the phytochemical analysis, JCE was found to contain isoscutellarein-7-O-beta-D-xyloside, Cupressuflavone, and amentoflavone as main compounds. Therapeutic attempts with the J. chinensis fruits might be useful in the treatment of AD and related skin inflammatory diseases.

Ameliorative effects of Juniperus rigida fruit on oxazolone- and 2,4-dinitrochlorobenzene-induced atopic dermatitis in mice.[Pubmed:29258854]

J Ethnopharmacol. 2018 Mar 25;214:160-167.

ETHNOPHARMACOLOGICAL RELEVANCE: The fruits of Juniperus rigida have been used in Korean traditional medicine for the treatment of inflammatory diseases in humans such as rheumatoid arthritis. AIM OF THE STUDY: This study aimed to investigate the anti-atopic properties of J. rigida fruit in in vivo murine atopic dermatitis (AD) models. METHODS AND RESULTS: BALB/c mouse ears ad SKH-1 hairless mice stimulated with oxazolone (4 weeks) and DNCB (3 weeks), respectively, were treated with the 1% Juniperus rigida fruit EtOH extract (JFE). The JFE improved AD symptoms in both oxazolone- and DNCB-induced AD mice by accelerating skin barrier recovery function and suppressing the overproduction of serum immunoglobulin E (IgE) and interleukin 4 (IL-4). The JFE was found to contain isoscutellarein-7-O-beta-xylopyranoside, Cupressuflavone, podocarpusflavone A, and hinokiflavone as major components based on phytochemical analysis. Eight flavonoids were isolated from JFE, and of those, Cupressuflavone and isoscutellarein-7-O-beta-xylopyranoside strongly down-regulated IL-4 expression and beta-hexosaminidase release in RBL-2H3 cells. CONCLUSION: Therapeutic attempts with J. rigida fruit and its active components might be useful in treating AD and related skin inflammatory diseases.

Anti-inflammatory and analgesic activities of cupressuflavone from Cupressus macrocarpa: Impact on pro-inflammatory mediators.[Pubmed:29130540]

Drug Dev Res. 2018 Feb;79(1):22-28.

Hit, Lead & Candidate Discovery Inflammation is a complex biological process that is generally occurs in response to pathological triggers. Both neurodegenerative diseases and cancer have been linked to inflammation. The analgesic and anti-inflammatory effects of Cupressuflavone (CUF) isolated from Cupressus macrocarpa were examined. The analgesic effects of CUF (40, 80 and 160 mg/kg po) were assessed in the acetic acid-induced writhing and hot plate models in mice with diclofenac sodium as the reference standard (100 mg/kg). CUF dose-dependently inhibited the writhing response in mice by 25, 48, and 62%, at the three CUF doses with 160 mg/kg being equivalent to the diclofenac control. CUF dose-dependently increased the hot plate model reaction time with a maximal effect after 120 min. In the carrageenan-induced paw edema model of inflammation, CUF demonstrated anti-inflammatory activity by inhibiting paw edema by 55, 60, and 64% at doses of 40, 80, and 160 mg/kg po, respectively. CUF also reduced the plasma pro-inflammatory mediators PGE2 (44, 54, and 58%), TNF-alpha (26, 37, and 53%), IL-1beta (19, 33, and 41%), and IL-6 (32, 44, and 55%) at the three doses tested with the highest dose having similar effects to diclofenac sodium (100 mg/kg). This finding from this study indicates that CUF has both analgesic and anti-inflammatory effects.

Chemical Fingerprint and Quantitative Analysis for the Quality Evaluation of Platycladi cacumen by Ultra-performance Liquid Chromatography Coupled with Hierarchical Cluster Analysis.[Pubmed:28977346]

J Chromatogr Sci. 2018 Jan 1;56(1):41-48.

Platycladi cacumen (dried twigs and leaves of Platycladus orientalis (L.) Franco) is a frequently utilized Chinese medicinal herb. To evaluate the quality of the phytomedcine, an ultra-performance liquid chromatographic method with diode array detection was established for chemical fingerprinting and quantitative analysis. In this study, 27 batches of P. cacumen from different regions were collected for analysis. A chemical fingerprint with 20 common peaks was obtained using Similarity Evaluation System for Chromatographic Fingerprint of Traditional Chinese Medicine (Version 2004A). Among these 20 components, seven flavonoids (myricitrin, isoquercitrin, quercitrin, afzelin, Cupressuflavone, amentoflavone and hinokiflavone) were identified and determined simultaneously. In the method validation, the seven analytes showed good regressions (R >/= 0.9995) within linear ranges and good recoveries from 96.4% to 103.3%. Furthermore, with the contents of these seven flavonoids, hierarchical clustering analysis was applied to distinguish the 27 batches into five groups. The chemometric results showed that these groups were almost consistent with geographical positions and climatic conditions of the production regions. Integrating fingerprint analysis, simultaneous determination and hierarchical clustering analysis, the established method is rapid, sensitive, accurate and readily applicable, and also provides a significant foundation for quality control of P. cacumen efficiently.

Phytochemical analysis of the ethanolic extract of Agathis robusta (C. Moore ex F. Muell.) F.M. Bailey.[Pubmed:28278682]

Nat Prod Res. 2017 Jul;31(14):1604-1611.

This work reports the phytochemical analysis of the ethanolic extract obtained from the leaves of Agathis robusta (C. Moore ex F. Muell.) F.M. Bailey. The methodology utilised during this study comprised classical chromatographic and spectroscopic techniques. Six compounds were identified: agathisflavone (1), 7''-O-methyl-agathisflavone (2), Cupressuflavone (3), rutin (4), shikimic acid (5) and (2S)-1,2-Di-O-[(9Z,12Z,15Z)-octadeca-9,12,15-trienoyl]-3-O-beta-d-galactopyranosy l glycerol (6). These belong to four major classes of natural compounds: bi-flavonoids (1-3); diglycosidic flavonoids (4); cycloexen-carboxylic acids (5); glycerol-glycolipids (6). To the best of our knowledge, compounds (3-6) were identified for the first time in this study as constituents of A. robusta. Anyway, the majority of these compounds has chemotaxonomic relevance and is mostly in accordance with the current botanical classification of this species. Moreover, they also present several pharmacological properties among which, the antibacterial, anti-inflammatory and protective ones are the most important and may explain why this species is used in the ethno-medicinal field.

Modulatory effect of standardised amentoflavone isolated from Juniperus communis L. agianst Freund's adjuvant induced arthritis in rats (histopathological and X Ray anaysis).[Pubmed:28012393]

Biomed Pharmacother. 2017 Feb;86:381-392.

ETHOPHARMACOLOGIC RELEVANCE: Juniperus communis. L. is a shrub or small evergreen tree, native to Europe, South Asia, and North America, and belongs to family Cupressaceae. It has been used traditionally in unani system and in Swedish medicine as a decoction in inflammatory diseases. The main chemical constituents, which were reported in J. communis L. was alpha-pinene,, apigenin, sabinene, beta-sitosterol, campesterol, limonene, Amentoflavone (AF), Cupressuflavone, and many others. AIM: The aim of present study was to isolate the amentoflavone from the plant juniperus communis L. extracts and its protective effects against Freund's adjuvant induced arthritis in rats. MATERIAL METHODS: Adjuvant arthritis was induced by an injection of 1mg heat killed Mycobacterium tuberculosis (CFA) into the left hind paw of rat by sub planter route (at day 0). The experiment was designed and modified as per method available in literature. RESULTS: The study showed that at a dose of 40mg/kg of amentoflavone (AF) from methanolic extract of Juniperus Communis L. possessed potentially useful anti-arthritic activity as it gave a positive result in controlling inflammation in the adjuvant induced experimental model. CONCLUSION: From the present experimental findings of both pharmacological and biochemical parameters observed, it had been concluded that at the doses of 20mg/kg and 40mg/kg of AF fraction from methanolic extract of Juniperus communis L. It possesses useful anti-arthritic activity since it gives a positive result in controlling inflammation in the adjuvant induced arthritic model in rats. The drug is a promising anti-arthritic agent of plant origin in the treatment of inflammatory disorders.

Protective effect of Cupressus sempervirens extract against indomethacin-induced gastric ulcer in rats.[Pubmed:27486357]

Interdiscip Toxicol. 2015 Mar;8(1):25-34.

Cupressus sempervirens (C. sempervirens) belongs to the family Cupressaceae. It is widspread in Northern Africa, Greece, Turkey, North America, Cyprus and Syria. Cupressuflavone is the major ingredient of the plant leave extract. The aim of the present study was to evaluate the antiulcerogenic activity of the extract of C. sempervirens leaves in gastric ulcer tissues induced by indomethacin. The results of the present study revealed that indomethacin significantly decreased glutathione S-transferase (GST), glutathione peroxidase (GPx), catalase (CAT), reduced glutathione (GSH), glutathione reductase (GR) and superoxide dismutase (SOD) levels, while it increased significantly lipid peroxidation (MDA), nitric oxide (NO) and protein carbonyl (PC) levels in gastric tissue. Furthermore, indomethacin decreased p53 expression, while it increased bcl-2 expression in gastric tissue. Pretreatment with 5%, 10% & 20% of the LD50 of C. sempervirens and Cupressuflavone of indomethacin-treated rats restored all the above parameters to approach normal values. C. sempervirens at the highest dose was more effective than the two lower doses. C. sempervirens proved more potent than Cupressuflavone. In conclusion, C. sempervirens exerted antiulcerogenic activity and the effect was dose-dependent and related to the Cupressuflavone ingredient of the plant leave extract.

Cytotoxic flavonoids and other constituents from the stem bark of Ochna schweinfurthiana.[Pubmed:25553908]

Nat Prod Res. 2015;29(17):1684-7.

Seven flavonoids, hemerocallone (1), 6,7-dimethoxy-3',4'-dimethoxyisoflavone (2), amentoflavone (4), agathisflavone (6), Cupressuflavone (8), robustaflavone (9) and epicatechin (10), together with three other compounds, lithospermoside (3), beta-D-fructofuranosyl-alpha-D-glucopyranoside (5) and 3beta-O-D-glucopyranosyl-beta-stigmasterol (7), were isolated from the ethyl acetate extract of the stem bark of Ochna schweinfurthiana F. Hoffm. All the compounds were characterised by spectroscopic and mass spectrometric methods, and by comparison with literature data. Cytotoxicity of the extracts and compounds against cervical adenocarcinoma (HeLa) cells was evaluated by MTT assay. Compounds 4 and 6 exhibited good cytotoxic activity, with IC50 values of 20.7 and 10.0 muM, respectively.

Protective role of Cupressuflavone from Cupressus macrocarpa against carbon tetrachloride-induced hepato- and nephrotoxicity in mice.[Pubmed:25338212]

Planta Med. 2014 Dec;80(18):1665-71.

The hepatoprotective and nephroprotective activity of Cupressuflavone isolated from Cupressus macrocarpa was investigated against CCl4-induced toxicity in mice. Cupressuflavone was administered (40, 80, and 160 mg/kg/day) for five days. CCl4 was administered (0.5 mL/kg intraperitoneally) at the end of the experiment. A substantial increase (p < 0.001) in the levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase, total bilirubin, cholesterol, creatinine, uric acid, urea, and malondialdehyde was observed in the CCl4-treated group compared to the normal control group. In contrast, a significant reduction (p < 0.001) in glutathione and superoxide dismutase contents as well as the total protein level was evident in the CCl4-intoxicated mice. Cupressuflavone pretreatment markedly inhibited the CCl4-induced increase in alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase, cholesterol, creatinine, uric acid, urea, and malondialdehyde levels in a dose-dependent manner (p < 0.001 at all the tested doses). In addition, a significant (p < 0.001) and dose-dependent decrease in the total bilirubin levels was evident by Cupressuflavone pretreatment (80 and 160 mg/kg/day) when compared to the CCl4-intoxicated group. Furthermore, Cupressuflavone administration significantly increased the activity of antioxidant parameters glutathione and superoxide dismutase as well as the serum protein levels (p < 0.001 at all the tested doses) in a dose-dependent manner. Histological observations confirmed the strong hepato- and nephroprotective activity. These findings suggest that Cupressuflavone could exert a beneficial effect against oxidative stress by enhancing the antioxidant defense status, reducing lipid peroxidation, and protecting against the pathological changes induced by CCl4 in the liver and kidney tissues. The structure of Cupressuflavone was identified by NMR, UV, and HRESI-MS/MS spectral data.

[Chemical constituents from seeds of Sophora alopecuroides].[Pubmed:25090709]

Zhong Yao Cai. 2014 Jan;37(1):72-3.

OBJECTIVE: To study the chemical constituents of Sophora alopecuroides seeds. METHODS: Five compounds were isolated and purified from this plant by various chromatographic methods. Structures were elucidated on the basis of spectral analysis. RESULTS: The structures were identified as 5"-methoxy-6-C-beta-D-glucopyranosyl-6"-C-beta-D-xylopyranosyl Cupressuflavone(1),5,6-dihydroxy-3,7, 3',4'-tetramethoxyflavone(2),butein(3),beta-daucosterol(4) and 3'-methoxyluteolin(5). CONCLUSION: Compounds 2,4 and 5 are isolated from Sophora alopecuroides for the first time.

A Phytopharmacological Review on a Medicinal Plant: Juniperus communis.[Pubmed:27419205]

Int Sch Res Notices. 2014 Nov 11;2014:634723.

Juniperus communis is a shrub or small evergreen tree, native to Europe, South Asia, and North America, and belongs to family Cupressaceae. It has been widely used as herbal medicine from ancient time. Traditionally the plant is being potentially used as antidiarrhoeal, anti-inflammatory, astringent, and antiseptic and in the treatment of various abdominal disorders. The main chemical constituents, which were reported in J. communis L. are alpha-pinene, beta-pinene, apigenin, sabinene, beta-sitosterol, campesterol, limonene, Cupressuflavone, and many others. This review includes the last 20 years journals and various books update on this plant, representing its pharmacological activity and health benefits against various diseases.

Study of the hepatoprotective effect of Juniperus phoenicea constituents.[Pubmed:24035959]

Pak J Pharm Sci. 2013 Sep;26(5):999-1008.

Different fraction obtained from the aerial parts of Juniperus phoenicea showed significant activity as hepatoprotective when investigated against carbon tetrachloride induced liver injury. The hepatoprotective activity was evaluated through the quantification of biochemical parameters and confirmed using histopathology study. Phytochemical investigation of the petroleum ether, chloroform and methanol fractions utilizing different chromatographic techniques resulted in the isolation of five known diterpenoids namely: 13-epicupressic acid (1), imbricatolic acid (2), 7alpha-hydroxysandaracopimaric acid (3), 3beta-hydroxysandaracopimaric acid (4), isopimaric acid (5), four flavonoid derivatives: Cupressuflavone (6), hinokiflavone (7), hypolaetin-7-O-beta-xylopyranoside (9), (-) catechin (10), inaddition to sucrose (8). Both physical and spectral data were used for structure determination and all isolates were evaluated for their hepatoprotective activity. Compounds 2 and 6 were effective, however; 7 was the most active. Hepatoprotective activity of 7 is comparable with the standard drug silymarin in reducing the elevated liver enzymes and restoring normal appearance of hepatocytes. Hepatoprotective effect of combination of 6, 7 and silymarin with the diterpene sugiol was also explored.