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A method of ultra-fast liquid chromatography in series with tandem mass spectrometry for the rapid and sensitive detection of 57 compounds in Spatholobi Caulis (the vine stem of Spatholobus suberectus Dunn) within 35 min was established. This assay can simultaneously determine a variety of compounds without matrix interference in multiple reaction monitoring mode including evaluating the quality of different batches of Spatholobi Caulis from several areas and further identifying the characteristic compounds efficiently. After comprehensive validation, this method can be used to determinate samples rapidly, precisely, accurately, repeatably, and sensitivity. There were significant content differences in 12 batches of Spatholobi Caulis, which were further classified and systematically differentiated applying multivariate statistical analysis. Furthermore, orthogonal partial least squares discrimination analysis results indicated that (-)-gallocatechin (10), (-)-epiafzelechin (20), 4,7,2'-trihydroxy-4'-methoxyisoflavanol (51), and biochanin A (53) characterize compounds to discernment internal quality of Spatholobi Caulis, and recommended as quality control indicators. Hence, presented work provides a method for further study on pharmaceutic preparation, metabolism, as well as for the design, production optimization process, and clinical application., (© 2020 Wiley-VCH GmbH.)

The stems of Mahonia fortunei (MF) are commonly used in Chinese Traditional Medicine and contain multiple bioactive compounds, including 3,4,5-trimethoxyphenol-1-O-β-d-glucopyranoside (1), 5-hydroxypicolinic acid methyl ester (2), acortatarin A (3), syringic acid (4), 9-epi-acortatarin A (5), vomifoliol (6), corydaldine (7), noroxyhydrastinine (8), columbamine (9), jatrorrhizine (10), palmatine (11), berberine (12) and schisandrin (13). The pharmacokinetics of these 13 compounds in the rat plasma were assessed using a novel sensitive, rapid, and specific UPLC-ESI-MS/MS method after oral administration of an aqueous extract of MF stems. Carbamazepine was employed as the internal standard (IS) and all samples were precipitated with acetonitrile. Chromatographic separation was performed on a C 18 column using a gradient elution at 0.3 mL/min, with the mobile phase consisting of acetonitrile and 0.06 % formic acid and 5 mM ammonium acetate aqueous solution. The calibration curves showed satisfactory linearity in the examination area (r 2  ≥ 0.99). The accuracy, precision, extraction recovery, matrix effect, and stability were within acceptable ranges. The method successfully assessed the pharmacokinetics of these 13 compounds. In vitro, compound 12 exhibited potent inhibitory activity against production of nitric oxide (NO) in the RAW264.7 cell line when stimulated by lipopolysaccharide (LPS), while compounds 7, 12, and 13 were the most potent inhibitors of NO production in the BV2 cell line when stimulated by LPS. The IC 50 values of compounds 7, 12 and 13 were 42.81, 20.55 and 22.74 μM. We conclude that these compounds have promise for clinical application, although their synergistic action may be more effective than that by any single compound alone., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is an age-related neurodegenerative disease that is mediated by multiple signaling pathways. In recent years, the components of Psoralea Fructus (PF) have demonstrated some anti-Alzheimer effects both in vitro and in vivo. To further reveal the active compounds of PF and their mechanisms regulating key targets of AD, in this study, we identified four prenylated compounds from the 70% ethanolic aqueous extract of PF, namely bavachin, bavachinin, bavachalcone, and isobavachalcone. Multi-target bioactivity analysis showed that these compounds could differentially inhibit neuroinflammation, oxidative damage, and key AD-related protein targets, such as amyloid β-peptide 42, β-secretase, glycogen synthase kinase 3β, and acetylcholinesterase. These compounds may generate beneficial effects in AD prevention and treatment., Competing Interests: The authors declare no conflict of interest.

Background: The fruit of Psoralea corylifolia L., Psoraleae fructus (PF), is widely used in traditional Chinese medicine as a well-known herbal tonic. Previous studies have shown that PF and its major constituents may have potential values in the treatment of Parkinson and Alzheimer diseases, though their pharmacokinetics and brain distribution were largely unknown., Purpose: To develop a liquid chromatographic-tandem mass spectrometry (LC-MS/MS) method for simultaneous studies of the plasma pharmacokinetics and cerebral nuclei (including cerebellum, thalamus, brainstem, hippocampus, corpus striatum and cortex) distribution in rats of eleven known PF compounds following as psoralen, isopsoralen, psoralidin, bavachin, bavachinin, isobavachin, isobavachalcone, bavachalcone, neobavaisoflavone, corylifol A, and corylin., Methods: Rats were orally administered via gavage at a single dose of PF extract at 1.2 g/kg. The eleven known PF compounds were extracted from rat plasma and cerebral nuclei at different time points, and then determined by the established LC-MS/MS method. Non-compartmental pharmacokinetic profiles were calculated, and the distribution in rat plasma and cerebral nuclei were compared., Results: The results showed that all the tested compounds were quickly absorbed into rat plasma and distributed almost evenly to the cerebral nuclei. The distribution concentrations at different nuclei varied at one determined time point, but the overall trends were basically similar to the plasma concentration-time results. Psoralen and isopsoralen, the two highest coumarins contained in PF, displayed far higher plasma concentrations (AUC 0→∞, plasma ≈53,884∼65,578 ng·h/ml) and central nervous system penetration (AUC 0→∞, brain nuclei ≈44,659∼65,823 ng·h/g) than the prenylflavonoids (other compounds except psoralidin, AUC 0→∞, plasma ≈69∼324 ng·h/ml; AUC 0→∞, brain nuclei ≈119∼3662 ng·h/g). However, the total brain-to-plasma ratios of the prenylflavonoids were higher than the coumarins, suggesting the prenylflavonoids can more readily enter the brain than the coumarins., Conclusion: The established LC-MS/MS method is sensitive and specific for the simultaneous quantitation of the eleven PF compounds in rat plasma and cerebral nuclei. The results of plasma pharmacokinetics and cerebral nuclei distribution may reveal the possible substance basis for the CNS activities of PF, and highlight the application possibility of PF and its major constituents in the treatment of Parkinson and Alzheimer diseases., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Glycyrrhizae radix et rhizoma has been used as a traditional Chinese medicine for the treatment of various diseases. Triterpenoids and flavonoids from the plant have many beneficial effects and their chemical structures are modified in the gastrointestinal tract after oral administration. However, absorption of these triterpenoids and flavonoids still needs to be defined. Here, the uptake and transepithelial transport of the selected major triterpenoids, glycyrrhizin ( 1 ), glycyrrhetic acid-3- O -mono-β-d-glucuronide ( 2 ), and glycyrrhetinic acid ( 3 ); and the selected major flavonoids, licochalcone A ( 4 ), licochalcone B ( 5 ), licochalcone C ( 6 ), echinatin ( 7 ), isoliquiritin apioside ( 8 ), liquiritigenin ( 9 ), liquiritin apioside ( 10 ) isolated from Glycyrrhizae radix et rhizoma , were investigated in the human intestinal epithelium-like Caco-2 cell monolayer model. Compounds 3 , 5 - 7 , and 9 were designated as well-absorbed compounds, 2 and 4 were designated as moderately absorbed ones, and 1 , 8 , and 10 were assigned for the poorly absorbed ones. The absorption mechanism of well and moderately absorbed compound was mainly passive diffusion to pass through the human intestinal Caco-2 cell monolayer. These findings provided useful information for predicting their oral bioavailability and the clinical application., Competing Interests: The authors declare no conflict of interest.

Angelicae Pubescentis Radix (APR), a well-known traditional Chinese medicine, is widely used for the treatments of rheumatism and headache for centuries. To assess the absorption characteristics of coumarins from APR, a sensitive and reliable UPLC-MS/MS method was established for the simultaneous determination of sixteen coumarins from APR, including psoralen, xanthotoxin, bergapten, bergaptol, isoimperatorin, imperatorin, columbianetin, columbianetin acetate, columbianadin, oxypeucedanin hydrate, angelol B, umbelliferone, scopoletin, osthole, meranzin hydrate and nodakenetin. The specificity, linearity, sensitivity, precision, accuracy, recovery, matrix effect and stability of the method were all validated to be satisfactory. The method was then applied to the in vitro transport of APR extract (APRE) across human intestinal epithelial Caco-2 cell and in vivo pharmacokinetics in rats after oral administration of APRE. All of the tested coumarins were well or moderately absorbed across Caco-2 monolayers, and could be quickly absorbed into rat blood circulation after oral administration. Columbianetin was the most easily absorbed compound across Caco-2 cell, and also had extremely highest plasma concentration in vivo. Excellent correlation between in vitro absorption across Caco-2 cell monolayers and in vivo pharmacokinetics of coumarins from APRE was well verified. The results provided valuable information for the overall absorption characteristics of the coumarins from APR, as well as for its further studies of in vivo active substances in the further., (Copyright © 2017 Elsevier B.V. All rights reserved.)

A new ferulic acid ester named 4-methyl-3- trans -hexenylferulate ( 1 ), together with eight known phenolic acid esters ( 2 - 9 ), was isolated from the methanolic extract of the roots and rhizomes of Notopterygium incisium . Their structures were elucidated by extensive spectroscopic techniques, including 2D NMR spectroscopy and mass spectrometry. 4-Methoxyphenethyl ferulate ( 8 ) NMR data is reported here for the first time. The uptake and transepithelial transport of the isolated compounds 1 - 9 were investigated in the human intestinal Caco-2 cell monolayer model. Compounds 2 and 6 were assigned for the well-absorbed compounds, compound 8 was assigned for the moderately absorbed compound, and compounds 1 , 3 , 4 , 5 , 7 , and 9 were assigned for the poorly absorbed compounds. Moreover, all of the isolated compounds were assayed for the inhibitory effects against nitric oxide (NO) production in the lipopolysaccharide-activated RAW264.7 macrophages model and L-N ⁶-(1-iminoethyl)-lysine (L-NIL) was used as a positive control. Compounds 1 , 5 , 8 , and 9 exhibited potent inhibitory activity on NO production with the half maximal inhibitory concentration (IC 50 ) values of 1.01, 4.63, 2.47, and 2.73 μM, respectively, which were more effective than L-NIL with IC 50 values of 9.37 μM. These findings not only enriched the types of anti-inflammatory compounds in N. incisum but also provided some useful information for predicting their oral bioavailability and their suitability as drug leads or promising anti-inflammatory agents., Competing Interests: The authors declare no conflict of interest.

The aim of this study was to evaluate the safety and potential of PCS as the anti-fatigue functional food. PCS was prepared by water extracting-alcohol precipitating method, and its chemical compositions of monosaccharide were analyzed. Then, acute toxicity and anti-fatigue activity of PCS were evaluated. PCS is composed of Rha, Arab, Xyl, Man, Glu, and Gal, its molar ratio is 0.17: 0.30: 0.26: 0.35: 1.00: 0.57. No mortality and general symptoms of toxicity were observed in the PCS treated mice (7.5, 15, and 20g/kg body weight), the body weight and food consumption were not significantly changed compared with the normal control group. The relative weights of main organ, and biochemical indicators also did not markedly change. PCS can significantly prolong the duration of the swimming time to exhaustion in mice, decrease BUN, LA levels, increase LDH activities, and the contents of HG in the PCS treated mice. The dose of 400mg/kg body weight is the optimal dose for anti-fatigue activity both in male and female mice. In conclusion, PCS is a promising traditional natural-based therapeutic remedy for relieving fatigue with high safety., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: The roots of Angelica dahurica cv. Qibaizhi is frequently used in clinical practice as a traditional Chinese medicine. However, a comprehensive study of the pharmacokinetics of this medicine has not been carried out., Method: A sensitive and specific liquid chromatographic-tandem mass (LC-MS/MS) spectrometric method was established to investigate pharmacokinetics of sixteen coumarins of Angelicae dahuricae Radix (ADR) in rat plasma, including xanthotoxol (1), oxypeucedanin hydrate (2), 5-hydroxy-8-methoxypsoralen (3), (-)-marmesin (4), byakangelicin (5), columbianetin (6), psoralen (7), xanthotoxin (8), neobyakangelicol (9), isoimpinellin (10), bergapten (11), heraclenin (12), oxypeucedanin ethanolate (13), imperatorin (14), phellopterin (15), isoimperatorin (16). Detection was performed on a triple quadrupole mass spectrometer in multiple-reaction-mode (MRM)., Results: The method established in this assay was successfully applied to the pharmacokinetic study of the selected coumarins in rat plasma after oral administration of the extract of ADR, and the pharmacokinetic characteristics of sixteen coumarins were clearly elucidated., Conclusion: This pharmacokinetic identification of multiple coumarins of ADR in rats provides a significant basis for better understanding the metabolic mechanism of the herb medicine., (Copyright © 2016 Elsevier GmbH. All rights reserved.)

Colon cancer is the most common cancer and the third leading cause of cancer mortality in humans. Using mass spectrometry-based metabolomics, the current study revealed the accumulation of four uremic toxins (cresol sulfate, cresol glucuronide, indoxyl sulfate, and phenyl sulfate) in the serum of mice harboring adenomatous polyposis coli (APC) gene mutation-induced colon cancer. These uremic toxins, likely generated from the gut microbiota, were associated with an increase in the expression of the proinflammatory cytokine IL-6 and a disorder of lipid metabolism. Nutmeg, which exhibits antimicrobial activity, attenuated the levels of uremic toxins and decreased intestinal tumorigenesis in Apc(min/+) mice. Nutmeg-treated Apc(min/+) mice had decreased IL-6 levels and normalized dysregulated lipid metabolism, suggesting that uremic toxins are responsible, in part, for the metabolic disorders that occur during tumorigenesis. These studies demonstrate a potential biochemical link among gut microbial metabolism, inflammation, and metabolic disorders and suggest that modulation of gut microbiota and lipid metabolism using dietary intervention or drugs may be effective in colon cancer chemoprevention strategies.

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease worldwide, leading to progressive muscle atrophy and paralysis. The limited success of conventional treatment for ALS has prompted investigations into complementary and alternative therapies. Herbal remedies provide good prospects of ALS prevention and treatment, with advantages such as multiple targets, multiple links, and few side effects. Studies in vitro and in vivo have shown that herbs have a great potential for treatment of ALS, with therapeutic effects against oxidative stress, excitatory amino acid toxicity, neuroinflammation, and calcium cytotoxicity. Active monomers or ingredients extracted from herbs are considered promising candidates for ALS. Therefore, we review recent experimental research on monomers and compounds isolated from herbal remedies for preventing and treating ALS., (Copyright © 2013 John Wiley & Sons, Ltd.)

In this study, the technique of high-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (HPLC-ESI-Q-TOFMS) was used to analyze and identify the absorptive constituents and their metabolites in drug-containing urine of Wuzhishan (WZS)-miniature pigs administered with Puerariae Lobatae Radix (PLR) decoction. With the accurate mass measurements (<5 ppm) and effective MS(2) fragment ions, 96 compounds, including eight original constituents and 88 metabolites, were identified from the drug-containing urine. Among these, 64 metabolites were new ones and their structures can be categorized into five types: isoflavones, puerols, O-desmethylangolensins, equols and isoflavanones. In particular, puerol-type constituents in PLR were first proved to be absorptive in vivo. Meanwhile, the metabolic pathways of PLR in vivo were investigated. On the basis of relative content of the identified compounds, 13 major metabolites accounting for approximately 50% of the contents, as well as their corresponding 12 prototype compounds, were determined as the major original absorptive constituents and metabolites of PLR in vivo. The HPLC-ESI-Q-TOFMS technique proved to be powerful for characterizing the chemical constituents from the complicated traditional Chinese medicine matrices in this research., (Copyright © 2013 John Wiley & Sons, Ltd.)

Three new dammarane-type triterpene saponins ginsenosides Rh(18) (1), Rh(19) (3) and Rh(20) (4), along with two new triterpene sapogenins 12β,23(R)-epoxydammara-24-ene-3β,6α,20(S)-triol (2) and dammara-(20E)22,25-diene-3β,6α,12β,24S-tetrol (5) were isolated from the stems and leaves of Panax ginseng C. A. Mey. Their structures were elucidated on the basis of spectral evidence and comparisons with literature data., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Three new quinolone alkaloids, 1-methyl-2-[7-hydroxy-(E)-9-tridecenyl]-4(1H)-quinolone (1), 1-methyl-2-[(Z)-4-nonenyl]-4(1H)-quinolone (2), 1-methyl-2-[(1E,5Z)-1,5-undecadienyl]-4(1H)-quinolone (3) and one new natural product, 1-methyl-2-[(E)-1-undecenyl]-4(1H)-quinolone (4), were isolated from the dried and nearly ripe fruits of Evodia rutaecarpa (Juss.) Benth., along with thirteen known compounds (5-17). In addition, one new artificial product, 1-methyl-2-[7-carbonyl-(E)-9-tridecenyl]-4(1H)-quinolone (1A) was also obtained. The structures of these compounds were determined by spectroscopic analyses. The cytotoxic activities of all of the compounds against the human cancer cell lines HL-60, N-87, H-460, and Hep G(2) cells were evaluated by MTT assay. The results showed that these alkaloids inhibited cell proliferation with IC(50) values between 14μM and 22μM., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Three new sesquiterpenoids, 1α-(3″-ethyl-cis-crotonoyloxy)-8-angeloyloxy-3β,4β-epoxy-bisabola-7(14),10-diene (1), 7β-angeloyloxy-14-hydroxy-notonipetranone (2) and 1α-hydroxy-7β-(4-methylsenecioyloxy)-oplopa-3(14)Z,8(10)-dien-2-one (3) were isolated from ethanolic extract of the dried flower buds of Tussilago farfara L., along with nine known sesquiterpenoids (4-12). All of these compounds were evaluated for their effect on the inhibition of nitric oxide (NO) production induced by lipopolysaccharide in macrophage cell line RAW 264.7 and exhibited inhibitory activity on NO production in a dose-dependent manner. 7β-(4-Methylsenecioyloxy)-oplopa-3(14)E,8(10)-dien-2-one (8) was proved to be the best among these tested sesquiterpenoids with an IC(50) value of 10.80 μM., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Extraction of roots of Patrinia rupestris (Pall.) Juss. gave a new iridoid compound, 1β,3α-diethyloxy-7-hydromethyl-4-(3-methyl-butyryloxymethyl)-cyclopenta-4(4a),7(7a)-diene[c]pyran-6-one (1), together with a known compound, (1α,4aα, 6α,7β,7aα)-[4a,5,6,7,7a-hexahydro-6,7-dihydroxy-1-(3-methyl-1-oxobutoxy) cyclopenta[c]pyran-4,7-diyl]bis(methylene) 3-methyl-butanoic acid ester (2). The structure of 1 was characterised by HRESIMS, IR, UV, 1-D NMR and 2-D NMR methods. Compound 2 was isolated from this genus for the first time.

Dehydrodiisoeugenol (DDIE), a major active lignan from the seed and aril of the fruit of Myristica fragrans Houtt., functions as a potential anti-inflammatory agent by inhibiting lipopolysaccharide-stimulated nuclear factor kappa B activation and cyclooxygenase-2 expression in macrophages. However, the metabolism of DDIE remains unknown. This report describes the metabolic fate of DDIE in liver microsomes, urine, and feces of rats treated with DDIE. DDIE metabolites were isolated by sequential column chromatography and high-performance liquid chromatography from liver microsomes incubations, urine, and feces. Nine metabolites ( M-1 to M-9), including 5 new metabolites, were determined spectroscopically using ultra-violet (UV), mass spectrometry (MS), nuclear magnetic resonance (NMR), and circular dichroism (CD). Analysis of the isolated metabolites showed that DDIE undergoes four major pathways of metabolism in the rat: oxidation (including hydroxylation, hydroformylation, and acetylation), demethylation, ring-opening, and dehydrogenation. In contrast to the metabolites from liver microsomes, the major metabolites In vivo were generated from DDIE by multiple metabolic reactions. Given these results, we describe a metabolic pathway for DDIE in the rat that gives insight into the metabolism of DDIE and the mechanism of DDIE bioactivity in humans., (© Georg Thieme Verlag KG Stuttgart · New York.)

The bidirectional intestinal permeability of the active constituents from the roots of Saposhnikovia divaricata, including four coumarins, anomalin (1), 5-methoxy-7-(3,3-dimethylallyloxy)coumarin (2), decursin (3), and decursinol angelate (4), as well as four chromones, cimifugin (5), prim-O-glucosylcimifugin (6), 3'- O-angeloylhamaudol (7), and sec-O-glucosylhamaudol (8), was studied by using the Caco-2 cell monolayer. These compounds were assayed by HPLC, and their transport parameters, including apparent permeability coefficients (P(app)), were then calculated. The bidirectional P(app) values of the compounds were compared with those of the markers, propranolol and atenolol. Compounds 1-5 and 7 were assigned to well-absorbed compounds, while 6 and 8 were assigned to moderately absorbed compounds. The transport of 1-7 increased linearly as a function of time up to 180 min and concentration within the test range of 10-200 µM, thus their passive diffusion mechanism was proposed. The results provided some useful information for predicting the intestinal absorption in vivo of these compounds., (© Georg Thieme Verlag KG Stuttgart · New York.)

The intestinal transport of four indoloquinazoline alkaloids, rutaecarpine (RCP), evodiamine (EDM), dehydroevodiamine (DEDM) and wuzhuyurutine B (WZYB) isolated from the Evodiae fructus was investigated using the monolayers of the human colon adenocarcinoma cell line Caco-2 as a model system for intestinal absorption. The four alkaloids were measured by high performance liquid chromatography (HPLC) coupled with UV detector. Transport parameters and permeability coefficients were then calculated and compared under identical conditions with those of mannitol, propranolol and paclitaxel. Permeability coefficients were also compared with the reported values for model compounds like propranolol and mannitol. The four alkaloids at a concentration of 5 microM were demonstrated substantial transport across the Caco-2 cell monolayers with moderate to high permeability coefficients and WZYB demonstrated higher-level intestinal transcellular efflux. The transports of DEDM and WZYB were concentration dependent at the concentrations of 5-25 microM. Among four alkaloids, EDM and DEDM are better-transported compounds, and RCP and WZYB are moderate transport compounds. The data support the involvement for multidrug resistance-associated proteins (MRPs) in the intestinal transcellular efflux of WZYB., (Copyright 2008 John Wiley & Sons, Ltd.)

From the roots of Asparagus gobicus, four new nor-lignans, 3'-methoxynyasin, iso-agatharesinol, gobicusins A, B and one new steroidal saponin, 3-O-[beta-D-xylopyranosyl(1-4)-beta-D-glucopyranosyl(1-2)-beta-D-glucopyranosyl]-(25S)-5beta-spirostan-3beta-ol (11) were isolated, together with twelve known compounds. The structures of the new compounds were established by spectroscopic methods including 2D-NMR techniques (1H-1H COSY, HMBC, HMQC) and chemical transformations. Nyasol (5) and 11 exhibited remarkable in vitro cytotoxic activity against cultured HO-8910 (human ovarian carcinoma) and Bel-7402 (human hepatoma) cells with IC50 vales of 30.6 and 29.4 microM, 5.2 and 5.2 microM, respectively.

We assessed the bioavailability of magnesium lithospermate B (MLB), a main polyphenolic component of Salvia miltiorrhiza and a potent antioxidant having various pharmacological activities, to evaluate its action in vivo. The plasma concentrations of lithospermic acid B (LSB) showed a biexponential decrease after intravenous administration of MLB to rats at doses of 4 and 20 mg/kg. The values of area under the concentration-time curve (AUC; 87.8 +/- 10.9 and 1130 +/- 329 microg.min/mL), total body clearance (CL (tot); 55.52 +/- 7.07 and 23.51 +/- 5.98 mL/min/kg), and distribution volume at steady state (V (ss); 7.60 +/- 1.03 and 3.61 +/- 1.16 L/kg) suggested non-linear pharmacokinetics between the two doses. After oral administration of MLB at a high dose of 100 mg/kg, the mean AUC was barely 1.26 +/- 0.36 microg.min/mL. Absolute bioavailability of MLB was calculated to be 0.0002 from the AUC values after both intravenous dosing at 20 mg/kg and oral dosing at 100 mg/kg. The extremely low bioavailability was caused mainly by poor absorption from the rat gastrointestinal tract; about 65 % of the dose was retained in the tract even 4 h after oral administration, and most of the dose was retained even 20 min after infusion in an in situ jejunal loop experiment. Urinary and biliary excretion of LSB were only 0.70 % +/- 0.26 % and 5.10 % +/- 2.36 %, respectively, over a 30 h time period after intravenous injection despite the large CL (tot) and V (ss) values, and were much less (0.010 % +/- 0.001 % and 0.12 % +/- 0.04 %) after oral dosing. These findings suggest that extensive metabolism, including a first-pass effect, and wide distribution of LSB besides the poor absorption contributed significantly to the extremely low systemic bioavailability.

Chemical investigation of the leaves ofPopulus euphraticaOliv. led to the isolation and identification of 13 compounds for the first time, among which 6′-O-cis-cinnamoylsalicin (1) and 6′-O-benzoylsalicortinol (2) were new compounds. The spectral data of 6′-O-trans-cinnamoylsalicin (3) and salicortinol (4) were reported for the first time. Their structures were elucidated on the basis of detailed spectroscopic analysis and comparisons with literature values. [ABSTRACT FROM PUBLISHER]

Abstract: A new indoloquinazoline alkaloid, 10-methoxywuchuyuamide I (1), three new benzylisoquinoline alkaloids, named as coptichic aldehyde (2), coptichine (3) and 13-carboxaldehyde-8-oxocoptisine (4), and a new isoindoline alkaloid, named as coptichinamide (5), together with two known alkaloids, wuchuyuamide I (6) and 8-oxocoptisine (7) were isolated from the Coptidis Rhizoma–Euodiae Fructus couple. Their chemical structures were determined by extensive spectroscopic analyses, including IR, UV, EI–MS, HRESI–MS, 1D and 2D NMR data (1H NMR, 13C NMR, 1H–1H COSY, HSQC and HMBC). Cytotoxicities of the isolated alkaloids against NCI-N87 and Caco-2 cell lines were evaluated. Four benzylisoquinoline alkaloids 2–4 and 7 showed inhibitory activities against NCI-N87 cell with IC50 values range from 8.92 to 35.98μM. The alkaloid 3 was a new antiproliferation compound against NCI-N87 cells. The results provided valuable information for further investigation of alkaloid 3 as a chemopreventive agent. [Copyright &y& Elsevier]

Abstract: Ethnopharmacological relevance: The rhizome of Atractylodes macrocephala (Compositae) is one of the most well-known traditional Chinese medicine in China, Japan and Korea, which has a long history of use for the treatment of splenic asthenia, edema, anorexia, and excessive perspiration, etc. As active compounds of anti-inflammatory activity of this medicinal plant have not been fully elucidated, the aim of this study was to isolate and identify the active constituents inhibiting nitric oxide (NO) production from the rhizomes of A. macrocephala. Materials and methods: Inhibitory activity against NO production in lipopolysaccharide-activated RAW264.7 macrophages was evaluated by Griess reaction. Fifteen polyacetylenes were isolated from the active ethyl acetate extract using activity-guided screening. The structures of all compounds were elucidated by spectroscopic methods and comparison with published data. The compounds were further tested for their inhibitory activity against NO production. Results: Seven new polyacetylenes, named atractylodemaynes A–G (1–7), along with eight known ones (8–15) were isolated. Compound 14 was isolated for the first time from the rhizomes of A. macrocephala. The study showed that the tested compounds exhibited inhibitory activity against NO production in a dose-dependent manner. Among them, compounds 10, 11 and 12 had relatively stronger inhibitory effect with IC50 values of 28, 23 and 19μM, respectively. Conclusion: The results demonstrated that the polyacetylenes might greatly contribute to the anti-inflammatory activity of the rhizomes of A. macrocephala. [Copyright &y& Elsevier]

A new limonoid compound, named evorubodinin (1), was isolated from the dried and nearly ripe fruits of Euodia rutaecarpa (Juss.) Benth. var. bodinieri (Dode) Huang (family Rutaceae), together with two known limonoid compounds, limonin (2) and evolimorutanin (3). The chemical structure of 1 was elucidated by spectroscopic method and single-crystal X-ray diffraction. The inhibitory effects of the isolated compounds 1–3 and the structurally related compounds evodol (4), shihulimonin A1 (5), evodirutaenin (6), 12α-hydroxyrutaevin (7), and rutaevin (8) on nitric oxide (NO) production in lipopolysaccharide-activated RAW264.7 macrophages were also assayed. All compounds 1–8 showed the inhibitory activity, in which both 7 and 8 with the uncommon 5β-H configuration more efficiently inhibited NO production. The results provided valuable information for further investigation of compounds 1–8 as anti-inflammatory agents or lead compounds. [ABSTRACT FROM AUTHOR]

The biotransformation of atractylenolide II, a major bioactive principle of the rhizomes of Atractylodes macrocephala Koidz., was investigated in vitro by incubation with rat hepatic microsomes pretreated with sodium phenobarbital. The biotransformation products were extracted and purified by chromatographic methods. Seven biotransformation products (BP1–BP7) were obtained and their structures were elucidated by NMR and MS data analyses and by comparison with the previously reported values, including four new compounds, namely 4(R),15-epoxy-atractylenolide II (BP1), 4(R),15-epoxy-13-hydroxyatractylenolide II (BP5), 4(R),15-epoxy-1β-hydroxyatractylenolide II (BP6), and 4(R),15-dihydroxyatractylenolide II (BP7). The biotransformation pathway of atractylenolide II by hepatic microsomes was deducted based on the structure resolution of the products. [ABSTRACT FROM AUTHOR]

A simple and sensitive high-performance liquid chromatographic method was developed for the simultaneous determination and pharmacokinetic analysis of seven alkaloids dehydroevodiamine (DHED), 10-hydroxyrutaecarpine (HDR), evodiamine (EDM), rutaecarpine (RCP), 1-methyl-2-n-nonyl-4(1H)quinolone (MNQ), evocarpine (ECP), and dihydroevocarpine (DHE), and two flavonoids isorhamnetin-7-O-rutinoside (RIM) and diosmetin-7-O-β-d-glucopyranoside (GRD) in rat plasma after oral administration of Wuzhuyu decoction. The flow rate was kept at 1.0 ml/min and the detection wavelength was set at 300 nm. The calibration curves were linear in the range of 0.5013–30.076 μg/ml for DHED, 0.2161–21.608 μg/ml for RIM, 0.161–12.876 μg/ml for HDR, 0.2146–21.457 μg/ml for GRD, 2.0464–40.928 μg/ml for EDM, 1.0398–31.194 μg/ml for RCP, 0.5970–35.818 μg/ml for MNQ, 0.8371–20.928 μg/ml for ECP, and 0.5167–31.003 μg/ml for DHE. The precision (relative standard deviation (RSD), %) for all was less than 10% and the accuracy (relative error (RE), %) was within ± 10%. The results demonstrated that the assay had remarkable reproducibility with acceptable accuracy and precision. The lower limit of quantifications for the compounds in plasma ranged from 0.12 to 0.23 μg/ml and the lower limit of detections ranged from 0.024 to 0.076 μg/ml. This validated method has been successfully applied in the pharmacokinetics study of seven alkaloids and two flavonoids after orally administrating the Wuzhuyu decoction to rats. [ABSTRACT FROM PUBLISHER]

Nine indoloquinazoline alkaloids (1–9) were isolated from the dried and nearly ripe fruits of Euodia rutaecarpa (Juss.) Benth. (Euodiae Fructus), along with limonin and β-sitosterol. Their structures were elucidated on the basis of their spectroscopic data. Among them, compounds 1 and 2 were new compounds and characterized as (7R,8S)-7-hydroxy-8-methoxy-rutaecarpine and (7R,8S)-7-hydroxy-8-ethoxy-rutaecarpine, respectively, and 1-hydroxy-rutaecarpine (3) and (7R,8S)-7,8-dihydroxy-rutaecarpine (4) were isolated from Euodiae Fructus for the first time. The nine indoloquinazoline alkaloids were evaluated for their cytotoxic activities against human promyelocytic leukemia HL-60 cells and human gastric carcinoma N-87 cells. [ABSTRACT FROM PUBLISHER]

Abstract: Ethnopharmacological relevance: Cibotium barometz (L.) J. Sm. (Dicksoniaceae) has been traditionally used as anti-inflammatory and anodyne. Aim of the study: To investigate the constituents in the rhizomes of Cibotium barometz, and evaluate their permeability in the human Caco-2 model. Materials and methods: The rhizomes extracts of Cibotium barometz were isolated by chromatographic techniques. Structures of isolated compounds were identified by spectroscopic methods. The permeability of the main constituents was evaluated using human Caco-2 cell monolayer as a model system. Results: Three unusual sesquiterpenes having 1-indanone nucleus (1, 3 and 4) and an unusual orthoester spiropyranosyl derivative of protocatechuic acid (2) were isolated from the rhizomes of Cibotium barometz. Among these, the bilateral permeation of 1, 3 and 4 in Caco-2 model was examined. The apparent permeability coefficients (P app) of 1 was identical with those of propranolol, which is often used as reference standard of high permeability. The P app values of 3 and 4 were in agreement with those of atenolol, which is often used as reference standard of poor permeability. The permeation rates of 1, 3 and 4 increased linearly as a function of time up to 180min and with the concentration within the test range of 25–200μM. Conclusions: This is the first report on the presence of compounds 2 and 3 in this plant and 4 was a new compound. Compound 1 is assigned for a well-absorbed, and 2 and 3 are assigned for the poorly absorbed compounds in human intestine. A passive diffusion mechanism for transport of 1, 3 and 4 in Caco-2 model was proposed. The results provided some useful information for predicting the oral bioavailability of 1, 3 and 4. [Copyright &y& Elsevier]

Novel sesquiterpene, named crossostephin (1), and coumarin, named biscopoletin (2), together with four known compounds, artesin, tanacetin, scopoletin, and scopolin, were isolated from the 70% ethanolic extract of the whole herbs of Crossostephium chinense (L.) Makino. Their structures were determined by spectroscopic methods, including IR, UV, EIMS, HRFTICRMS, 1D and 2D NMR spectral analyses. Both scopoletin and scopolin were isolated from the title plant for the first time. [ABSTRACT FROM AUTHOR]

A new linear pyranocoumarin named (−)-hydroxydecursinol ( 1 ) and a new biscoumarin named (±)-dahuribiscoumarin ( 2 ), together with six known compounds isoimperatorin ( 3 ), imperatorin ( 4 ), phellopterin ( 5 ), isodemethylfuropinarine ( 6 ), demethylfuropinarine ( 7 ), and (+)-decursinol ( 8 ) were isolated from the 75% ethanolic extract of the roots of Angelica dahurica var. formosana cv. Chuanbaizhi. Their structures were elucidated by extensive spectroscopic techniques, including 2D NMR spectroscopy and mass spectrometry, and the structure of 2 was confirmed by single-crystal X-ray diffraction. All of the isolated compounds were evaluated for the inhibition against nitric oxide (NO) production in the lipopolysaccharide (LPS)-activated RAW264.7 macrophage cell line, and exhibited the inhibitory activity on NO production in a concentration-dependent manner. Furthermore, real-time PCR analysis revealed that compounds 2 , 5 – 8 could significantly suppress the expression levels of inducible nitric oxide synthase mRNA in a concentration-dependent manner. And their primary structure–activity relationships of NO inhibitory effects were also briefly discussed. These compounds are potential candidates for further bioassay studies to determine their suitability as drug leads. [ABSTRACT FROM AUTHOR]

Abstract: A sensitive RP-HPLC–DAD method was established to quantify dehydrodiisoeugenol (DDIE) in rat cerebral nuclei. The assay procedure involved one-step extraction of DDIE and daidzein, as an internal standard, from rat plasma and various cerebral nuclei with ethyl acetate. Chromatographic separation was performed on a Diamonsil™ ODS C18 column with methanol–water (81:19, v/v) as a mobile phase. The UV absorbance of the samples was measured at the wavelength of 270nm. The analysis method was proved to be precise and accurate at linearity ranges in plasma and each cerebral nucleus with correlation coefficients of ≥0.9971. The results indicated that the method established was successfully applied to cerebral nuclei distribution study of DDIE after intravenous administration at a single dose of 40mg/kg to rat. DDIE showed high concentration in all of cerebral nuclei at 8min, which indicated that DDIE could cross the blood–brain barrier rapidly and might be one of the main bioactive substances of nutmeg. The results provide fundamental data for evaluating the effects of DDIE on the central nervous system and to be developed into an effective anxiogenic agent. [Copyright &y& Elsevier]

Six new glucosides of benzofuran (1 – 6), together with three known glucosides of benzofuran (8 , 9 , 14), nine flavonoids (12, 13 , 15 , 18 , 19 , 20 , 21 , 22 and 24), three coumarins (16 , 17 , 23) and four other-typic compounds (7 , 10 , 11 and 25) were isolated from the fruits of Psoralia corylifolia L. Their structures were elucidated by extensive spectroscopic methods. The biosynthesis pathway of benzofuran system was discussed. Besides, all isolated compounds and additional ring-opening derivatives of psoralen/isopsoralen (P-1 , P-2 , IP-1 and IP-2) were assayed for inhibition of nitric oxide (NO) production on lipopolysaccharides-induced RAW 264.7 macrophage cells. The results of the assay showed that the glycosides showed weaker or no effects, while most isolated non-glycoside compounds showed moderate or high activities. And the structure-activity relationships of non-glycoside compounds were discussed. [Display omitted] • Six new benzofuranyl glucosides (1 – 6) were described by extensive spectra. • Two glycosides (12 and 14) were found in Psoralea corylifolia for the first time. • The biosynthesis pathways of benzofurans and furocoumarins were discussed. • Non-glycosides mildly or strongly inhibited NO production, rather than glycosides. • Structure-activity relationships of test non-glycosides were discussed [ABSTRACT FROM AUTHOR]

Chuanxiong Rhizoma (CR), a well-known traditional Chinese medicine originated from the rhizome of Ligusticum chuanxiong Hort., was effective for treating various vascular diseases. To identify the metabolites of CR in vivo , the drug-containing urine samples of WZS-miniature pigs after orally administrated CR decoction were collected, after sequential column chromatography 17 metabolites ( M1 – M17 ) were isolated from the methanol extract of the urine samples. Their structures, including nine phthalides ( M1 – M9 ) and eight phenolic acids ( M10 – M17 ), were identified by spectroscopic means. Among them, 8 were new ones ( M1 – M6 , M11 – M12 ). On the basis of the structures of identified metabolites, seven original constituents, including 2 phthalides (senkyunolideI/H) and 5 phenolic acids (ferulic acid, isoferulic acid, caffeic acid, 3-hydroxycinnamoyl acid and 4-hydroxybenzonic acid) were deduced to be the major absorbed original constituents of CR in vivo . This is the first study on the metabolites of CR decoction in non-rodent animal (WZS-miniature pig), the results will give an insight into the metabolism profiles of phthalides and phenolic acids in CR decoction in vivo . [ABSTRACT FROM AUTHOR]

Abstract: The aim of the present research was to establish a comprehensive strategy to identify the metabolites of isoimperatorin after biotransformation with rat liver microsomes in vitro, and further describe metabolic kinetic characteristics of isoimperatorin and its main metabolites. Utilizing liquid chromatography with time of flight mass spectrometry (LC–TOF–MS), 18 metabolites (M 1–18) were characterized according to the typical fragment ions and literature data. Among them, M-2, 3, 5, 9, 10, and 15 were new compounds. To further verify structures of the metabolites, five main metabolites were obtained from the magnifying biotransformation incubation system, and their chemical structures were elucidated as 8-hydroxyoxypeucedanin (M-3), hydroxypeucedanin hydrate (M-4), E-5-(4-hydroxy-3-methyl-2-alkenyloxy)-psoralen (M-11), Z-5-(4-hydroxy-3-methyl-2-alkenyloxy)-psoralen (M-12), and oxypeucedanin (M-16) by various spectroscopy methods including IR, MS and NMR. A simple new liquid chromatography with triple quadrupole tandem mass spectrometry (LC–QqQ–MS) method was developed for the simultaneous determination of isoimperatorin and its main metabolites. The analysis was performed on a Diamonsil™ ODS C18 column with acetonitrile–water containing 0.1% formic acid as mobile phase. Total run time was 20.0min. The results suggested that the method we exhibited was successfully applied for analysis of isoimperatorin and its metabolites. The study provides essential data for proposing metabolite pathway and further pharmacological study of isoimperatorin. [Copyright &y& Elsevier]

Abstract: Algal fucoidan is a marine sulfated polysaccharide that evidences a variety of biological activities. We assessed the potential activity of the sulfated polysaccharide from Ecklonia cava, on anti-inflammatory activity in LPS-stimulated RAW 264.7 cells. In this study, E. cava was hydrolyzed by five carbohydrases and five proteases. Our findings demonstrated that the AMG extract has the highest yield and exerts the most profound inhibitory effects against NO production. To identify the active compounds, we conducted micro-filtration membrane, ethanol-added separation, and anion exchange and gel permeation chromatography; the purified polysaccharide (PPS) was subsequently obtained. PPS significantly inhibited NO production, prostaglandin-E2 (PGE2) production and suppressed inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression in LPS-stimulated RAW 264.7 cells. Thus, PPS inhibited NO and PGE2 production via the inhibition of iNOS and COX-2. These results indicate that the anti-inflammatory activity of PPS may be attributable to the modulation of anti-inflammatory agents. [Copyright &y& Elsevier]