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1.  Anti-tuberculosis Cycloartane Triterpenoids from Radermachera boniana 
Journal of natural products  2011;74(5):1318-1322.
Three new triterpenoids, bonianic acids A (1), and B (2) and 3-O-acetyluncaric acid (3) were isolated from the leaves and twigs of Radermachera boniana (Bignoniaceae), together with six known compounds ursolic acid (4), oleanolic acid (5), 3-epi-oleanolic acid (6), 3α-O-acetyl-α-boswellic acid (7), ergosterol peroxide (8), and β-sitostenone (9). Ergosterol peroxide (8), bonianic acids A (1) and B (2) exhibited significant activity against Mycobacterium tuberculosis H37Rv strain.
PMCID: PMC3703769  PMID: 21469696
2.  Compounds from the Fruits of the Popular European Medicinal Plant Vitex agnus-castus in Chemoprevention via NADP(H):Quinone Oxidoreductase Type 1 Induction 
As part of our continuing efforts in the search for potential biologically active compounds from medicinal plants, we have isolated 18 compounds including two novel nitrogen containing diterpenes from extracts of the fruits of Vitex agnus-castus. These isolates, along with our previously obtained novel compound vitexlactam A (1), were evaluated for potential biological effects, including cancer chemoprevention. Chemically, the nitrogenous isolates were found to be two labdane diterpene alkaloids, each containing an α, β-unsaturated γ-lactam moiety. Structurally, they were elucidated to be 9α-hydroxy-13(14)-labden-16,15-amide (2) and 6β-acetoxy-9α-hydroxy-13(14)-labden-15,16-amide (3), which were named vitexlactams B and C, respectively. The 15 known isolates were identified as vitexilactone (4), rotundifuran (5), 8-epi-manoyl oxide (6), vitetrifolin D (7), spathulenol (8), cis-dihydro-dehydro-diconiferylalcohol-9-O-β-D-glucoside (9), luteolin-7-O-glucoside (10), 5-hydroxy-3,6,7,4′-tetramethoxyflavone (11), casticin (12), artemetin (13), aucubin (14), agnuside (15), β-sitosterol (16), p-hydroxybenzoic acid (17), and p-hydroxybenzoic acid glucose ester (18). All compound structures were determined/identified on the basis of 1D and/or 2D NMR and mass spectrometry techniques. Compounds 6, 8, 9, and 18 were reported from a Vitex spieces for the first time. The cancer chemopreventive potentials of these isolates were evaluated for NADP(H):quinone oxidoreductase type 1 (QR1) induction activity. Compound 7 demonstrated promising QR1 induction effect, while the new compound vitexlactam (3) was only slightly active.
PMCID: PMC3638617  PMID: 23662135
3.  Phytoconstituents from Vitex agnus-castus fruits 
Fitoterapia  2010;82(4):528-533.
A new labdane-diterpene, viteagnusin I (1), together with 23 known phytoconstituents were isolated from the fruits of Vitex agnus-castus L, and their structures characterized by spectroscopic method (NMR and MS). The known compounds include ten flavonoids, five terpenoids, three neolignans, and four phenolic compounds, as well as one glyceride. Biological evaluation identified apigenin, 3-methylkaempferol, luteolin, and casticin as weak ligands of delta and mu opioid receptors, exhibiting dose-dependent receptor binding.
PMCID: PMC3081944  PMID: 21163339
Vitex agnus-castus; labdane diterpene; viteagnusin I; flavonoids; opioid activity
4.  Analgesic Effect of Coptis chinensis rhizomes (Coptidis Rhizoma) Extract on Rat Model of Irritable Bowel Syndrome 
Journal of ethnopharmacology  2011;135(3):754-761.
Aim of study
Coptis chinensis rhizomes (Coptidis Rhizoma, CR), also known as “Huang Lian”, is a common component of traditional Chinese herbal formulae used for the relief of abdominal pain and diarrhea. Yet, the action mechanism of CR extract in the treatment of irritable bowel syndrome is unknown. Thus, the aim of our present study is to investigate the effect of CR extract on neonatal maternal separation (NMS)-induced visceral hyperalgesia in rats and its underlying action mechanisms.
Materials and methods
Male Sprague-Dawley rats were subjected to 3-hr daily maternal separation from postnatal day 2 to day 21 to form the NMS group. The control group consists of unseparated normal (N) rats. From day 60, rats were administrated CR (0.3, 0.8 and 1.3 g/Kg) or Vehicle (Veh; 0.5% carboxymethylcellulose solution) orally for 7 days for the test and control groups, respectively.
Electromyogram (EMG) signals in response to colonic distension were measured with the NMS rats showing lower pain threshold and increased EMG activity than those of the unseparated (N) rats. CR dose-dependently increased pain threshold response and attenuated EMG activity in the NMS rats. An enzymatic immunoassay study showed that CR treatment significantly reduced the serotonin (5HT) concentration from the distal colon of NMS rats compared to the Veh (control) group. Real-time quantitative PCR and Western-blotting studies showed that CR treatment substantially reduced NMS induced cholecystokinin (CCK) expression compared with the Veh group.
These results suggest that CR extract robustly reduces visceral pain that may be mediated via the mechanism of decreasing 5HT release and CCK expression in the distal colon of rats.
PMCID: PMC3100428  PMID: 21511022
cholecystokinin; Coptis chinensis rhizomes; irritable bowel syndrome; neonatal maternal separation; Ranunculaceae; serotonin
5.  Rubesanolides A and B: Diterpenoids from Isodon rubescens 
Organic letters  2011;13(6):1406-1409.
From the medicinal plant Isodon rubescens, we isolated two novel diterpenes, rubesanolides A (1) and B (2). The compounds contain a unique β-lactone subgroup. This is the first discovery for a natural diterpene having rings A, B and C in chair, boat, and twist-chair conformations, respectively. The structures were elucidated by analysis of spectroscopic data, and the absolute configuration of 1 was determined by X-ray diffraction.
PMCID: PMC3057937  PMID: 21332131
6.  Modified Huo-Luo-Xiao-Ling Dan Suppresses Adjuvant Arthritis by Inhibiting Chemokines and Matrix-Degrading Enzymes 
Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting the joints that can lead to deformities and disability. The prolonged use of conventionally used drugs is associated with severe adverse reactions. Therefore, safer and less expensive therapeutic products are continually being sought. Huo-Luo-Xiao-Ling dan (HLXL), a traditional Chinese herbal mixture, and its modified versions possess anti-arthritic activity. In this paper, we examined the influence of modified HLXL on two of the key mediators of arthritic inflammation and tissue damage, namely, chemokines and matrix-metalloproteinases (MMPs) in the rat adjuvant-induced arthritis (AA) model of RA. We treated arthritic Lewis rats with HLXL (2.3 g/kg) by daily gavage beginning at the onset of AA. The control rats received the vehicle. At the peak phase of AA, rats were sacrificed and their draining lymph node cells (LNC) and spleen adherent cells (SAC) were tested. The HLXL-treated rats showed a significant reduction in the levels of chemokines (RANTES, MCP-1, MIP-1α, and GRO/KC), MMPs (MMP 2 and 9), as well as cytokines (IL-6 and IL-17) that induce them, compared to the control vehicle-treated rats. Thus, HLXL controls arthritis in part by suppressing the mediators of immune pathology, and it might offer a promising alternative/adjunct treatment for RA.
PMCID: PMC3310235  PMID: 22474510
7.  Bioactive Compounds from the Fern Lepisorus contortus 
Journal of natural products  2011;74(2):129-136.
Phytochemical investigation of the whole plant of Lepisorus contortus (Christ) Ching led to the isolation of five new phenylethanoid glycosides (1–5), each containing a caffeoyl group, a new flavonoid glycoside (10), as well as 14 known compounds (6–9 and 11–15, syringic acid, vanillic acid, phloretic acid, diplopterol, and β-sitosterol). This is the first report of phenylethanoid glycosides from the family Polypodiaceae. Compounds 1–15 were evaluated for their cancer chemopreventive potential based on their ability to inhibit tumor necrosis factor alpha (TNF-α)-induced NF-κB activity, nitric oxide (NO) production, aromatase, quinone reductase 2 (QR-2), and COX-1/-2 activities. Quercetin-3-O-β-D-glucoside (15) demonstrated inhibition against QR2 with an IC50 value of 6.7 µM, which confirmed kaempferol/quercetin glycosides as the active compounds to inhibit QR2. The compound also demonstrated NF-κB activity with an IC50 value of 33.6 µM. In addition, compounds 1, 2, 4 and 6 showed aromatase activity with IC50 values of 30.7, 32.3, 26.8, and 35.3 µM, respectively.
PMCID: PMC3069126  PMID: 21261296
8.  Anti-Inflammatory Activities of a Chinese Herbal Formula IBS-20 In Vitro and In Vivo 
Irritable bowel syndrome (IBS) is a functional bowel disorder and the etiology is not well understood. Currently there is no cure for IBS and no existing medication induces symptom relief in all patients. IBS-20 is a 20-herb Chinese medicinal formula that offers beneficial effects in patients with IBS; however, the underlying mechanisms are largely unknown. This study showed that IBS-20 potently inhibited LPS- or IFNΓ-stimulated expression of pro-inflammatory cytokines, as well as classically activated macrophage marker nitric oxide synthase 2. Similarly, IBS-20 or the component herb Coptis chinensis decreased LPS-stimulated pro-inflammatory cytokine secretion from JAWS II dendritic cells. IBS-20 or the component herbs also blocked or attenuated the IFNΓ-induced drop in transepithelial electric resistance, an index of permeability, in fully differentiated Caco-2 monolayer. Finally, the up-regulation of key inflammatory cytokines in inflamed colon from TNBS-treated mice was suppressed significantly by orally administrated IBS-20, including IFNΓ and IL-12p40. These data indicate that the anti-inflammatory activities of IBS-20 may contribute to the beneficial effects of the herbal extract in patients with IBS, providing a potential mechanism of action for IBS-20. In addition, IBS-20 may be a potential therapeutic agent against other Th1-dominant gut pathologies such as inflammatory bowel disease.
PMCID: PMC3296463  PMID: 22461841
9.  Development of an Antiviral Screening Protocol: One-Stone-Two-Birds 
As prophylactic therapies and vaccines against viral infections continue to improve, drug resistant strains are continuing to arise; therefore it is imperative to develop new therapeutics against these diseases. For highly pathogenic viruses, such as Ebola and H5N1 influenza virus, the need for antivirals is even more urgent due to limited therapeutics against these viruses. Furthermore, the high pathogenicity of such viruses often makes it difficult to work with such agents. In this report, we describe a protocol called “One-stone-two-birds” which provides a safe and efficient screening system to identify anti-flu (entry) and anti-HIV (replication) activities. Using plant extracts as an example, we demonstrate the utility of this protocol in antiviral screening.
PMCID: PMC3227027  PMID: 22140608
Antiviral; Influenza; HIV; Ebola; Plant extract; Screening
10.  Discovery of cyclooxygenase inhibitors from medicinal plants used to treat inflammation 
Eleven authenticated botanicals used in the traditional Chinese medicine Huo-Luo-Xiao-Ling Dan were screened for ligands to cyclooxygenase (COX) using pulsed ultrafiltration liquid chromatography-mass spectrometry, and a mass spectrometry-based enzyme assay was used to determine the concentration of each of 17 ligands that inhibited COX-1 or COX-2 by 50% (IC50). Acetyl-11-keto-β-boswellic -boswellic acid, acid, acetyl-α-boswellic acid, acetyl-β-boswellic acid, and betulinic acid were COX-1 selective inhibitors with IC50 values of approximately 10 μM. Senkyunolide O and cryptotanshinone were COX-2 selective inhibitors with IC50 values of 5 and 22 μM, respectively. Roburic acid and phenethyl-trans-ferulate inhibited COX-1 and COX-2 equally. COX inhibition and the IC50 values of most of these natural product ligands have not been reported previously.
PMCID: PMC2860736  PMID: 20188172
Cyclooxygenase; COX-2; drug discovery; botanical dietary supplements; senkyunolide O; cryptotanshinone
11.  Isolation and evaluation of kaempferol glycosides from the fern Neocheiropteris palmatopedata 
Phytochemistry  2010;71(5-6):641-647.
Three new kaempferol glycosides, named palmatosides A (1), B (2) and C (3), together with three known kaempferol glycosides, multiflorins A (4) and B (5), and afzelin (6), were isolated from the roots of the fern Neocheiropteris palmatopedata. Palmatosides A (1) and B (2) were determined to be novel kaempferol glycosides, each possessing an unusual sugar moiety containing a 4, 4-dimethyl-3-oxo-butoxy substituent group. The isolated compounds were evaluated for their cancer chemopreventive potential based on their ability to inhibit tumor necrosis factor alpha (TNF-α)-induced NF-κB activity, nitric oxide (NO) production, aromatase, quinone reductase 2 (QR-2) and COX-1/-2 activities. Palmatosides B (2) and C (3) inhibited TNF-α-induced NF-κB activity with IC50 values of 15.7 and 24.1 μM, respectively; multiflorin A (4) inhibited aromatase enzyme with an IC50 value of 15.5 μM; afzelin (6) showed 68.3% inhibition against QR2 at a concentration of 11.5 μg/ml; palmatoside A (1) showed 52 % inhibition against COX-1 enzyme at a concentration of 10 μg/ml; and multiflorin B (5) showed 52 % inhibition against nitric oxide production at a concentration of 20 μg/ml. In addition, compounds 3-6 were shown to bind QR2 enzyme using LC-MS ultrafiltration binding assay.
PMCID: PMC2866494  PMID: 20100622
Neocheiropteris palmatopedata; Polypodiaceae; flavone; kaempferol glycosides; palmatosides; cancer chemoprevention; NF-κB; NO; QR-2; aromatase; COX-1; COX-2
12.  Suppression of Ongoing Experimental Arthritis by a Chinese Herbal Formula (Huo-Luo-Xiao-Ling Dan) Involves Changes in Antigen-Induced Immunological and Biochemical Mediators of Inflammation 
Rheumatoid arthritis (RA) is one of the major autoimmune diseases of global prevalence. The use of the anti-inflammatory drugs for the treatment of RA is associated with severe adverse reactions and toxicity. This limitation has necessitated the search for novel therapeutic products. We report here a traditional Chinese medicine-based herbal formula, Huo luo xiao ling dan (HLXL), which has potent antiarthritic activity as validated in the rat adjuvant-induced arthritis (AA) model. HLXL (2.3 g/Kg) was fed to Lewis (RT.11) rats daily by gavage beginning at the onset of arthritis and then continued through the observation period. HLXL inhibited the severity of ongoing AA. This suppression of arthritis was associated with significant alterations in the T cell proliferative and cytokine responses as well as the antibody response against the disease-related antigen, mycobacterial heat-shock protein 65 (Bhsp65). There was a reduction in the level of the proinflammatory cytokines IL-17 and IL-1β but enhancement of the anti-inflammatory cytokine IL-10 level. In addition, there was inhibition of both the anti-Bhsp65 antibody response and the serum level of nitric oxide. Thus, HLXL is a promising CAM modality for further testing in RA patients.
PMCID: PMC2958519  PMID: 20981317
13.  Anti-Tuberculosis Constituents from the Stem Bark of Micromelum hirsutum 
Planta medica  2005;71(3):261-267.
Anti-TB bioassay-directed fractionation led to the isolation of six carbazole alkaloids, as well as the γ-lactone derivative of oleic acid, from the CH2Cl2 extract of the stem bark of Micromelum hirsutum. The carbazoles include the new micromeline (2) and five known alkaloids: lansine (3), 3-methylcarbazole (4), methyl carbazole-3-carboxylate (5), 3-formylcarbazole (6), and 3-formyl-6-methoxycarbazole (7). Compound 1 was identified as the lactone derivative of oleic acid, (−)-Z-9-octadecene-4-olide, for which the trivial name micromolide (1) is suggested. It showed potent in vitro anti-TB activity against H37Rv (MIC: 1.5 μg/mL), a selectivity index (SI) of 63, and exhibited activity against the Erdman strain of M. tuberculosis in a J774 mouse macrophage model (EC90: 5.6 μg/mL). Thus, 1 appears worthy of further evaluation as a potential new anti-TB agent. Isolates 2, 3, 6 and 7 had anti-TB MIC values between 14.3 and 42.3 μg/mL, while compounds 4 and 5 were considered inactive (MIC > 128 μg/mL). Structure elucidation and identification were based on spectroscopic analysis, including MS, 1D/2D NMR, and a full 1H spin system analysis of 1.
PMCID: PMC2940840  PMID: 15770548
Micromelum hirsutum; Rutaceae; (−)-Z-9-octadecene-4-olide; micromeline; micromolide; carbazole alkaloids; anti-TB activity
14.  Bioactive 5,6-Dihydro-α-pyrone Derivatives from Hyptis brevipes 
Journal of natural products  2009;72(6):1165-1169.
Six new 5,6-dihydro-α-pyrone derivatives (1–6), namely, brevipolides A–F, together with seven known compounds, including a 5,6-dihydro-α-pyrone derivative (7), three flavonoids, a steroid glycoside, and two triterpenoids, were isolated from the entire plant of Hyptis brevipes. Compounds 1–7 were assigned with the absolute configuration, 5R, 6S, 7S, and 9S, as elucidated by analysis of data obtained from their CD spectra and by Mosher ester reactions. Compounds 2, 6, and 7 exhibited ED50 values of 6.1, 6.7 and 3.6 μM against MCF-7 cells, and compounds 1, 2, 6, and 8 (the known 5,6,3′-trihydroxy-3,7,4′-trimethoxyflavone) gave ED50 values of 5.8, 6.1 7.5, and 3.6 μM against HT-29 cells, respectively. However, no significant cytotoxicity was found against Lu1 cells for any of the compounds isolated. When these compounds were subjected to evaluation in a panel of mechanism-based in vitro assays, compound 7 were found to be active in an enzyme-based ELISA NF-κB assay, with an ED50 value of 15.3 μM. In a mitochondrial transmembrane potential assay, compounds 3, 7, and 8 showed ED50 values of 8.5, 75, and 310 nM, respectively. However, no potent activity was found in a proteasome inhibition assay for any of the isolated compounds.
PMCID: PMC2883770  PMID: 19422206
15.  Isolation and Characterization of Aromatase Inhibitors from Brassaiopsis glomerulata (Araliaceae) 
Phytochemistry letters  2009;2(1):29-33.
The hexane- and ethyl acetate-soluble extracts of the leaves of Brassaiopsis glomerulata (Blume) Regel (Araliaceae), collected in Indonesia, were found to inhibit aromatase, the rate-limiting enzyme in the production of estrogens from androgens, in both enzyme- and cell-based aromatase inhibition (AI) assays. Bioassay-guided fractionation led to the isolation of six known compounds of the steroid and triterpenoid classes (1–6) from the hexane extract, of which 6β-hydroxystimasta-4-en-3-one (5), was moderately active in the cell-based AI assay. Fractionation of the ethyl acetate extract afforded seven pure isolates (7–13) of the modified peptide, fatty acid, monoterpenoid, and benzenoid types, including six known compounds and the new natural product, N-benzoyl-L-phenylalanine methyl ester (9). The absolute stereochemistry of 9 and the other two peptides, 7 and 8, was determined by Marfey’s analysis. Linoleic acid (10) was found to be active in the enzyme-based AI assay, while 9 and (−)-dehydrololiolide (12) showed activity in the cell-based AI assay.
PMCID: PMC2748821  PMID: 20161072
Brassaiopsis glomerulata; Araliaceae; activity-guided isolation; aromatase inhibitors; breast cancer; modified peptides; monoterpenoids; N-benzoyl-L-phenylalanine methyl ester
16.  Chlorination Diversifies Cimicifuga racemosa Triterpene Glycosides 
Journal of natural products  2007;70(6):1016-1023.
Extracts from roots and rhizomes of black cohosh (Cimicifuga racemosa) are widely used as dietary supplements to alleviate menopausal symptoms. State-of-the-art QC measures involve phytochemical fingerprinting of the triterpene glycosides for species identification and chemical standardization by HPLC. In the course of developing materials and methods for standardization procedures, the major C. racemosa triterpene glycoside (1) was isolated ans initially thought to be cimicifugoside (2). Detailed HR-LC-MS and 1/2D NMR analysis of 1 and 2 unambiguously revealed that 1 is its chlorine-containing derivative of 2, namely 25-chlorodeoxycimigenol-3-O-β-D-xyloside. Accordingly, HPLC profiles of black cohosh preparations require revision of the assignments of the chlorinated (1) and non-chlorinated (2) pair. Besides explaining the substantial shift in polarity (ΔtR[RP-18] ca 20 min), 25-deoxychlorination opens a new pathway of structural diversification in triterpene glycosides chemistry. As chemical conversion of 2 into 1 could be demonstrated, deoxychlorination may be interpreted as artifact formation. Simultaneously, however, it is a potentially significant pathway for the gastric in vivo conversion (“nature's pro drug”) of the relatively polar triterpene glycosides into significantly less polar chlorinated derivatives with altered pharmacological properties.
PMCID: PMC2596075  PMID: 17555351
17.  The Role of Quality Assurance and Standardization in the Safety of Botanical Dietary Supplements 
Chemical research in toxicology  2007;20(4):577-582.
PMCID: PMC2570109  PMID: 17362032
black cohosh; botanical dietary supplements; ginseng; standardization; red clover
18.  Serotonergic Activity-Guided Phytochemical Investigation of the Roots of Angelica sinensis 
Journal of natural products  2006;69(4):536-541.
Serotonin receptor (5-HT7) binding assay-directed fractionation of a methanol extract of the dried roots of Angelica sinensis (Apiaceae) led to the isolation and identification of twenty-one compounds including a new phenolic ester, angeliferulate (1), and three new phthalides, 10-angeloylbutylphthalide (2), sinaspirolide (3) and ansaspirolide (4), along with seventeen known compounds, p-hydroxyphenethyl trans-ferulate (5), Z-ligustilide (6), Z-butylidenephthalide (7), senkyunolide I (8), Z-6-hydroxy-7-methoxy-dihydroligustilide (9), N-butylbenzenesulphonamide (10), 11(S),16(R)-dihydroxy-octadeca-9Z,17-dien-12,14-diyn-1-yl acetate (11), (3R,8S)-falcarindiol (12), heptadeca-1-ene-9,10-epoxy-4,6-diyne-3,8-diol (13), oplopandiol (14), 8-hydroxy-1-methoxy-, Z-9-heptadecene-4,6-diyn-3-one (15), imperatorin, ferulic acid, vanillin, stigmasterol, sucrose, and 1,3-di-linolenin. This is the first report of a sulfonamide (10) identified from a higher plant source, although its presence needs further investigation. Biosynthetic pathways for dimeric phthalides 3 and 4 are proposed. Compound 5, 7, 11, 12, 15, and imperatorin exhibited affinity toward 5-HT7 receptors in a competitive binding assay.
PMCID: PMC1866289  PMID: 16643021

Results 1-18 (18)