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Tumor-associated macrophage (TAM)-derived IL-6 is involved in small-cell lung cancer (SCLC) progression and chemoresistance via the activation of signal transducer and activator of transcription 3 (STAT3) in the tumor microenvironment. This study aimed to identify natural compounds that suppress cell–cell interactions between TAMs and SCLC cells by inhibiting STAT3 activation. We used a library of natural compounds to identify candidate agents possessing anti-SCLC effects by inhibiting macrophage-induced tumor proliferation. SBC-3 and SBC-5, human SCLC cell lines, were used for in vitro experiments. Furthermore, we assessed the efficacy of these candidate agents in a murine xenograft model of human SCLC. Among the natural compounds examined, onionin A (ONA) inhibited IL-6-induced STAT3 activation and SCLC cell proliferation. ONA also reduced the secretion of IL-6 from macrophages and interfered with the direct effect of cell–cell interactions between macrophages and SCLC cells. Furthermore, ONA administration suppressed tumor progression in a tumor-bearing mouse model. ONA was identified as the most useful candidate for targeting cell–cell interactions between cancer cells and TAMs for anti-SCLC therapy.

Resin glycosides are well known as the purgative ingredients, which are characteristic of convolvulaceous plants. Calystegia hederacea Wall. is a perennial herbaceous vine that is widespread throughout India and East Asia. All parts of this plant are used for the treatment of menoxenia, gonorrhea, etc. Alkaline hydrolysis of the crude resin glycoside fraction of the whole plants of C. hederacea yielded four new glycosidic acids, calyhedic acids A, B, C, and D, along with two known glycosidic acids, calysolic acids A and C, and three known organic acids, 2S-methylbutyric, tiglic, and 2R,3R-nilic acids. Their structures were characterized on the basis of spectroscopic data and chemical evidence. Calyhedic acids A, B, and D were penta-, hexa-, and hepta-glycosides of 12S-hydroxyhexadecanoic acid, respectively, and cayhedic acid C was an isomer of calyhedic acid D, in which the 12S-hydroxyhexadecanoyl residue of calyhedic acid D was replaced by a 11S-hydroxyhexadecanoyl residue. Additionally, cytotoxic activity toward HL-60 human promyelocytic leukemia cells of the crude resin glycoside fraction, the glycosidic acid fraction, calyhedic acid A, and calysolic acid A from C. hederacea was evaluated. Furthermore, to clarify the structure-activity relationship of resin glycosides, the activities of six genuine resin glycosides with calysolic acid A or calysolic acid C as the glycosidic acid, which were isolated from C. soldanella, were examined. Among them, the crude resin glycoside fraction and five genuine resin glycosides with macrolactone structures demonstrated clear cytotoxic activities, while the glycosidic acid fraction, calyhedric acid A, calysolic acid A, and a genuine non-macrolactone-type resin glycoside were either inactive or exhibited weaker activity than the tested macrolactone-type resin glycosides.

Two atypical cyclic-type sulfides, garlicnin P (1) and garlicnin J2 (2), and one thiabicyclic-type sulfide, garlicnin Q (3), were isolated from the acetone extracts of garlic, Allium sativum, bulbs cultivated in the Kumamoto city area, and their structures characterized. Their production pathways are also discussed.

Newly identified bicyclic sulfoxides, welsonins A1 (1) and A2 (2), were isolated from acetone extracts of the bulbs of the Welsh onion (Allium fistulosum). In this study, the structures of 1 and 2, which are tetrahydrothiophene-S-oxide derivatives, were characterized by spectroscopic analysis. These compounds appeared to be derived from the coupling of 1-propenyl sulfenic acid and uronic acid. Welsonin A1 (1) showed the potential to suppress tumor-cell proliferation by inhibiting the polarization of alternatively activated M2 macrophages.

It is well known that tumour-associated macrophages (TAMs) play an important role in tumour development by modulating the tumour microenvironment, and targeting of protumour activation or the M2 polarization of TAMs is expected to be an effective therapy for cancer patients. We previously demonstrated that onionin A (ONA), a natural low molecular weight compound isolated from onions, has an inhibitory effect on M2 macrophage polarization. In the present study, we investigated whether ONA had a therapeutic anti-ovarian cancer effect using in vitro and in vivo studies. We found that ONA reduced the extent of ovarian cancer cell proliferation induced by co-culture with human macrophages. In addition, we also found that ONA directly suppressed cancer cell proliferation. A combinatorial effect with ONA and anti-cancer drugs was also observed. The activation of signal transducer and activator of transcription 3 (STAT3), which is involved in cell proliferation and chemo-resistance, was significantly abrogated by ONA in ovarian cancer cells. Furthermore, the administration of ONA suppressed cancer progression and prolonged the survival time in a murine ovarian cancer model under single and combined treatment conditions. Thus, ONA is considered useful for the additional treatment of patients with ovarian cancer owing to its suppression of the protumour activation of TAMs and direct cytotoxicity against cancer cells.

Adult T-cell leukemia/lymphoma (ATL) is an incurable peripheral T-cell malignancy caused by human T-cell lymphotropic virus type I. In our preceding paper, 214 extracts from 162 plants were screened to elucidate the antiproliferative principles against ATL cell lines. Several withanolides were isolated and the structure-activity relationships (SAR) examined. To extend the search for SAR, 31 further withanolides, previously isolated from solanaceous plants, were tested against ATL cell lines. The presence of a 4β-hydroxy group as well as a 5β,6β-epoxy group appeared to be essential for the activity. In contrast, the presence of a sugar moiety at either the 3- or the 27-position led to a reduction in the activity. Furthermore, 24,25-dihydrowithanolide D (13) was identified as the most potent inhibitor, showing selective toxicity against ATL cell lines by inducing apoptotic cell death.

A new diterpenoid was isolated from the leaves of Clerodendron trichotomumThunb. (Verbenaceae) along with one each of a known diterpenoid, phenylethanoid glycoside, and sterol and two known flavonoids. Their chemical structures were characterized on the basis of spectroscopic data and X-ray analysis. In addition, their antioxidant activities were evaluated using four different analyses.

A novel, efficient, and accurate fingerprinting method using high performance liquid chromatography-photodiode array detection has been developed and optimized for the investigation and demonstration of the variance in chemical properties among Siraitia grosvenorii fruits from different origins. The effects of growth stages, cultivated varieties, collection locations, and fruit portions of the herb on chromatographic fingerprints were examined. Eleven compounds were identified on chromatograms by comparing the retention time and UV spectrum of each peak separately with those of external references. The results revealed that chromatographic fingerprints, combining similarity or hierarchical clustering analysis along with reference compounds, could efficiently identify and distinguish S. grosvenorii fruits from different sources, which provided helpful clues for studying the plants' secondary metabolites and benefitted quality control.

A tomato saponin, esculeoside A, may be metabolized into various steroidal hormones such as pregnane derivatives that are expected to exhibit various bioactivities in the body, such as anti-osteoporosis, anti-menopausal disorder and anti-tumor actions. Therefore, we attempted to examine the esculeoside A contents of fresh tomatoes, tomatoes boiled in water, tomatoes heated using a microwave oven, freeze-dried tomatoes, and commercially available processed tomato products contained in plastic bottles and cans, in order to develop a health food.

We investigated the constituents of Veronicastrum villosulum (Miquel) Yamazaki (Scrophulariaceae), an endangered species belonging to the IA group. From the aerial parts of this plant cultivated at the botanical garden of Sojo University, we isolated two new cucurbitacine-type glycosides, 3-O-alpha-L-rhamnopyranosyl-(1 --2)-[beta-D-glucopyranosyl-(1 --3)]-beta-D-glucopyranosides of 3beta,25-dihydroxycucurbit-5,23(E)-diene-7-one-25-methyl ether and 3beta,23-dihydroxycucurbit-5,24-diene-7-one-23-methyl ether.

The Pueraria flowers, Puerariae Flos [Puerariae Lobatae Flos (the flowers of P. lobata) and Puerariae Thomsonii Flos (the flowers of P. thomsonii)], have been used as crude drugs to counteract the overconsumption of alcohol in Japan and China. Both types of Puerariae Flos contain a large amount of isoflavones and saponins. Simultaneous analysis of the total saponin and isoflavone fraction within the flowers has proven difficult thus far; however, profile analysis of saponin and isoflavone levels was attempted in this study by using HPLC coupled to an evaporative light scattering detector (ELSD). A characteristic peak of kakkalide was common in the chromatograms of extracts originating from the flowers of P. lobata, though original habitats were different. Tiny peaks of saponins were also observed in chromatograms of all specimens derived from P. lobata. In the chromatograms of six out of eight extracts of Puerariae Thomsonii Flos originating from Guangdong, China, characteristic twin peaks corresponding to tectorigenin 7-O-xylosylglucoside and tectoridin were observed. The distinctive twin peaks were not found in the chromatograms of the extracts produced in Hunan and Sichuan. Although the amounts of total saponins and isoflavones obtained from Puerariae Lobatae Flos were almost the same, those of Puerariae Thomsonii Flos varied remarkably and were not related to habitat. A good yield of a new isoflavone glycoside was obtained from some specimens of Puerariae Thomsonii Flos; the structure was determined to be 6-hydroxygenistein 6,7-di-O-glucoside.

The flowers from Pueraria, which are called Puerariae Flos, have been used since ancient times for recovery from alcohol intoxication. We elucidated the microbial transformation of the main isoflavones (1, 1a and 2) by using 29 commercially available human intestinal bacterial strains together with the bioactivation of the hepatoprotective activity of their metabolites. Tectoridin (1a), which contains only one glucosyl moiety, was metabolized to its aglycone 1b by various bacterial strains. On the other hand, the metabolism of 1 and 2, which both have disaccharide groups, was limited to specific bacterial strains. The metabolites 1c and 2c obtained from the Peptostreptococcus productus strain were completely different from those produced by the other strains. These metabolites were identified as 6-hydroxygenistein and 6-hydroxybiochanin A, respectively. The glycosides 1, 1a and 2 did not show any hepatoprotective activity, whereas aglycones 1b and 2b showed moderate activity. Furthermore, the hepatoprotective activity of the demethylated metabolites 1c and 2c was extremely potent. Although not all people have P. productus in their gastrointestinal tract, the O-demethylated compounds might become one of the bioactivated metabolites when Puerariae Flos is administered orally.

A new lignan glucoside (1) was isolated from the stems of Callicarpa japonica Thunb. var. luxurians Rehd. (Verbenaceae), along with six known lignan glucosides and three known triterpenoids. The chemical structure of 1 was characterized as (+)-lyoniresinol 3 alpha-O-(6''-3,5-dimethoxy-4-hydroxybenzoyl)-beta-D-glucopyranoside on the basis of spectroscopic data. In addition, the radical-scavenging effect of four lignans on the stable free radical 1,1-diphenyl-2-picrylhydrazyl was examined. Among the tested compounds, three compounds, including 1, showed almost the same scavenging activity as that of alpha-tocopherol.

Two new phenyldihydronaphthalene-type lignan glucosides, vitecannasides A (1) and B (2) were isolated from the fruit of Vitex cannabifolia Sieb. et. Zucc. (Verbenaceae) along with the six known lignan derivatives (3-8), four known iridoid glucosides (9-12), three known flavonoids (13-15), and one known phenylbutanone glucoside (16). Their chemical structures were determined on the basis of spectroscopic data as well as chemical evidence. The scavenging effect of 1, 2, and 11-16 on the stable free radical 1,1-diphenyl-2-picrylhydrazyl was examined. Compounds 1, 2, 14, and 15 exhibited stronger activity than that of L: -cysteine. Especially, 14 and 15 showed more potent activity than that of alpha-tocopherol.

One new chromone and six known flavonol glycosides were isolated from the stems and leaves of Delphinium hybridum cv. “Belladonna Casablanca” (Ranunculaceae). The new chromone glycoside was elucidated as 2-methyl-chromone-5,7-diol 7-O-α-l-rhamnopyranosyl-(1→6)-β-d-glucopyranoside (1). The six known flavonol glycosides were designated as compounds 2–5, being kaempferol-type glycosides, and compounds 6 and 7, being quercetin-type glycosides. The structures of these glycosides were determined by two-dimensional nuclear magnetic resonance (2D NMR) spectroscopic analysis and chemical evidence.

A new phenylethanoid glycoside, named acetyl forsythoside B (1), was isolated from the fruits of Callicarpa japonica Thunb. var. luxurians Rehd. (Verbenaceae) along with forsythoside B (2), brandioside (3), poliumoside (4), actioside (5), and apigenin 7-galacturonide (6). The structures of 1–6 were determined on the basis of spectroscopic data. In addition, the antioxidative activity of 1–4 and 6 was evaluated by the ferric thiocyanate method. All of the tested compounds except 6 exhibited almost the same activity as 3-tert-butyl-4-hydroxyanisole. The radical-scavenging effect of 1–6 on the stable free radical 1,1-diphenyl-2-picrylhydrazyl was also examined. Compounds 1–5 showed almost twice the activity compared to α-tocopherol.

In order to clarify the efficacy of natural-occurring hepatoprotective flavonoids and related miscellaneous compounds, we have investigated the hepatoprotective activity of 41 phenolic compounds on human liver-derived HepG2 cells and evaluated their structure-activity relationships. The hepatoprotective activity of catechin (cyanidanol), which has been used to treat chronic hepatitis, was almost equal to that of glycyrrhizin at 200 μM. The structure-activity relationships of flavanol derivatives as revealed by this investigation suggest that (1) the configuration of the hydroxy group at C-3 does not affect the hepatoprotective activity; (2) the pyrogallol and catechol groups in the B-ring are almost comparable in terms of hepatoprotection; (3) the galloyl group is a key factor for enhancing hepatoprotective activity; (4) the free carboxyl group of gallic acid reduces hepatoprotective activity. The common structural features of the most potent hepatoprotective phenolic compounds are summarized.

Random amplified polymorphic DNA (RAPD) analysis was used to determine the genetic relationships among seventeen species of the Acanthopanax species. The DNA isolated from the leaves of the samples was used as template in polymerase chain reaction (PCR) with twenty random decamer primers in order to distinguish plant subspecies at the level of their genomes. The RAPD patterns were compared by calculating pairwise distances using Dice similarity index, and produced to the genetic similarity dendrogram by unweighted pair-group method arithmetic averaged (UPGMA) analysis, showing three groups; a major cluster(twelve species), minor cluster (4 species) and single-clustering species. The results of RAPD were compatible with the morphological classification, as well as the chemotaxonomic classification of the Acanthopanax species. The Acanthopanax species containing 3,4-seco-lupane type triterpene compounds in their leaves corresponded to the major cluster, another species having oleanane or normal lupane type constituents to minor clusters, and one species not containing triterpenoidal compound to single-cluster.

This report contains the first characterization of acanthodiolglycoside which belongs to pentacyclic lupane triterpene glycoside.

The constituents of the flower buds of Magnolia kobus DC. and M. salicifolia MAXIM. have been investigated. We isolated and identified six bis-tetrahydrofuran-type and three tetrahydrofuran-type lignan derivatives from M. kobus, and one bis-tetrahydrofuran-type lignan and eight phenylpropanoid-type derivatives from M. salicifolia. The structures of these compounds were elucidated on the basis of chemical and spectroscopic evidence.

From the green leaves of Eucommia ulmoides Oliv., 12 compounds were isolated: asperuloside, asperulosidic acid, scandoside 10-O-acetate, deacetyl asperulosidic acid, geniposidic acid, aucubin, isoquercetin, quercetin 3-O-sambubioside, rutin, astragalin, kaempherol 3-O-rutinoside and chlorogenic acid. The structures were determined on the basis of spectral data.