Chemopreventive Activity of Ellagitannins from Acer pseudosieboldianum (Pax) Komarov Leaves on Prostate Cancer Cells.

Several studies have shown that compounds from Acer pseudosieboldianum (Pax) Komarov leaves (APL) display potent anti-oxidative, anti-inflammatory, and anti-proliferative activities. Prostate cancer (PCa) is the most common cancer among older men, and DNA methylation is associated with PCa progression. This study aimed to investigate the chemopreventive activities of the compounds which were isolated from APL on prostate cancer cells and elucidate the mechanisms of these compounds in relation to DNA methylation. One novel ellagitannin [komaniin (14)] and thirteen other known compounds, including glucose derivatives [ethyl-ß-D-glucopyranose (3) and (4R)-p-menth-1-ene-7,8-diol 7-O-ß-D-glucopyranoside (4)], one phenylpropanoid [junipetrioloside A (5)], three phenolic acid derivatives [ellagic acid-4-ß-D-xylopyranoside (1), 4-O-galloyl-quinic acid (2), and gallic acid (8)], two flavonoids [quercetin (11) and kaempferol (12)], and five hydrolysable tannins [geraniin (6), punicafolin (7), granatin B (9), 1,2,3,4,6-penta-galloyl-ß-D-glucopyranoside (10), and mallotusinic acid (13)] were isolated from APL. The hydrolyzable tannins (6, 7, 9, 10, 13, and 14) showed potent anti-PCa proliferative and apoptosis-promoting activities. Among the compounds, the ellagitannins in the dehydrohexahydroxydiphenoyl (DHHDP) group (6, 9, 13, and 14), the novel compound 14 showed the most potent inhibitory activity on DNA methyltransferase (DNMT1, 3a and 3b) and glutathione S-transferase P1 methyl removing and re-expression activities. Thus, our results suggested that the ellagitannins (6, 9, 13, and 14) isolated from APL could be a promising treatment option for PCa.

Inhibition of the NLRP3 Inflammasome by a Quercus Serrata Extract and Isolation of the Component Compounds for the Treatment of Arthritis.

Quercus serrata belongs to the Fagaceae family. There are 600 known species of Quercus worldwide. Q. serrata is distributed nationally in Korea, Japan, and China and grows to a height of 10-15 m. It exhibits a light grey bark with longitudinal furrows; the leaves are 6-12 cm long and 2.5-5 cm wide. The Quercus genus reportedly exhibits several types of bioactivity, including antioxidant, anti-inflammatory, antifungal, antimicrobial, and anticancer activity. Additionally, it has been reported that Quercus produces diverse phytochemicals, including tannins, flavonoids, and triterpenoids. Herein, we describe the column chromatographic isolation of five compounds from a Q. serrata extract. The compounds included caffeic acid (1), myricetin-3-O-cellobioside (2), phloroglucinol (3), (S)-2,3-HHDP-D-glucopyranoside (4), and pedunculagin (5). We assessed the 2,2-diphenyl-1-picryl-hydrazyl (DPPH) radical scavenging activity, antioxidant activity, NLR family pyrin domain-containing 3 (NLRP3) inflammasome (including NLRP3, ASC, and caspase-1) inhibitory effects, and collagenase inhibition activity of the Q. serrata extract and its constituent compounds. Our results indicated that the Q. serrata extract and the isolated constituent compounds showed inhibitory activity with reference to nitric oxide production, inflammasome component expression, and collagenase activity. Our findings imply that the Q. serrata extract and the isolated constituent compounds are potential candidates for the treatment of inflammatory diseases such as arthritis.

Inhibitory Activities of Dimeric Ellagitannins Isolated from Cornus alba on Benign Prostatic Hypertrophy.

Benign prostatic hypertrophy (BPH) is an intractable chronic inflammatory disease. We studied the efficacy of two ellagitannins, namely camptothin B (1) and cornusiin A (2) that were isolated from Cornus alba (CA) for the treatment of BPH, which is a common health issue in older men. The ellagitannins (1 and 2) were evaluated on its inhibitory activities of the enzyme 5α-reductase and tumor necrosis factor (TNF)-α, its interleukin (IL)-1ß, IL-6, and IL-8 production, and its anti-proliferation and apoptosis induction in prostate cells that show hypertrophy (RWPE-1 cell). In inhibition of 5α-reductase, the ellagitannins (1 and 2) showed potential effects, compared to the positive control, finasteride. In the case of IL-1ß, IL-6, IL-8, and TNF-α, 1 and 2 showed good inhibitory effects as compared to the control group treated with LPS. The ellagitannins (1 and 2) were also shown to inhibit proliferation of, and induce apoptosis in, the RWPE-1 cell. These results suggest that the ellagitannins (1 and 2) may be good candidates for the treatment of BPH.

Alnus sibirica Compounds Exhibiting Anti-Proliferative, Apoptosis-Inducing, and GSTP1 Demethylating Effects on Prostate Cancer Cells.

Alnus sibirica (AS) is distributed in Korea, Japan, China, and Russia and has reported anti-oxidant, anti-inflammatory, and reducing activities on atopic dermatitis-like skin lesions, along with other beneficial health properties. In the present study, we tried to prove the cancer-preventive activity against prostate cancer. The extracted and isolated compounds, oregonin (1), hirsutenone (2), and hirsutanonol (3), which were isolated from AS, were tested for anti-proliferative activity. To do this, we used the MTT assay; NF-κB inhibitory activity, using Western blotting; apoptosis-inducing activity using flow cytometry; DNA methylation activity, using methylation-specific polymerase chain reaction in androgen-dependent (LNCaP) and androgen-independent (PC-3) prostate cancer cell lines. The compounds (1-3) showed potent anti-proliferative activity against both prostate cancer cell lines. Hirsutenone (2) exhibited the strongest NF-κB inhibitory and apoptosis-inducing activities compared with oregonin (1) and hirsutanonol (3). DNA methylation activity, which was assessed for hirsutenone (2), revealed a concentration-dependent enhancement of the unmethylated DNA content and a reduction in the methylated DNA content in both PC-3 and LNCaP cells. Overall, these findings suggest that hirsutenone (2), when isolated from AS, may be a potential agent for preventing the development or progression of prostate cancer.

Anti-Inflammatory Effects of Fermented Bark of Acanthopanax sessiliflorus and Its Isolated Compounds on Lipopolysaccharide-Treated RAW 264.7 Macrophage Cells.

The fermentation was carried out on the bark of Acanthopanax sessiliflorus (AS). Acanthopanax species have been used in traditional medicine as tonics, sedatives, and antispasmodics. An activity-guided isolation of the fermented bark of A. sessiliflorus (FAS) yielded several phytochemicals: acanthoside D (1), acanthoside B (2), daucosterol (3), protocatechuic acid (4), chlorogenic acid methyl ester (5), ciwujiatone (6), syringaresinol (7), farnesol (8), 3,4-dicaffeoylquinic acid (9), and falcarindiol (10). HPLC analysis showed that content of lignan glycoside (1) was decreased and 4 and 7 were increased after fermentation. Anti-inflammatory activities on FAS showed the decrease of nitric oxide (NO) production, and inhibitory activities of iNOS and COX-2, proinflammatory cytokines (IL-6 and tumor necrosis factor-α), and collagenase. The aglycone, syringaresinol (7), which was increased through fermentation showed enhanced activity than 1. Thus, FAS may have the potential to treat inflammatory disorders, such as arthritis.

Anti-Acne Vulgaris Effects of Pedunculagin from the Leaves of Quercus mongolica by Anti-Inflammatory Activity and 5α-Reductase Inhibition.

Quercus mongolica (QM)-a member of the Fagaceae family-has been used as traditional medicine in Korea, China and Mongolia as a treatment for inflammation of oral, genital or anal mucosa and for external inflammation of skin. To treat acne vulgaris (AV), we evaluated the inhibition of inflammatory cytokines (IL-6 and IL-8) of QM leaf extract (QML) and its main compound, pedunculagin (PD) in vitro and 5α-reductase inhibitory activity by western blotting. As results, QML and PD showed potent NO production inhibitory activity compared with the positive control (PC), NG-monomethyl-L-arginine (L-NMMA). QML and PD was also showed the decreases of IL-6 and IL-8 compared with the PC, EGCG and exhibited potent 5α-reductase type 1 inhibitory activities compared with the PC, dutasteride.

Anti-Inflammatory Effects of Alnus Sibirica Extract on In Vitro and In Vivo Models.

Alnus sibirica extracts (ASex) have long been used in Oriental medicine to treat various conditions. To provide a scientific basis for this application and the underlying mechanism, we investigated the anti-inflammatory effects of ASex in vitro and in vivo. The in vitro model was established using human dermal fibroblasts (HDFs) treated with inflammatory stimulants (lipopolysaccharide, tumor necrosis factor-alpha, interferon-gamma). Lactate dehydrogenase and reverse transcription-polymerase chain reaction showed that ASex inhibited the increased expression of acute-phase inflammatory cytokines. The in vivo model was established by inducing skin inflammation in NC/Nga mice via the repeated application of house dust mite (HDM) ointment to the ears and back of the mice for eight weeks. HDM application increased the severity of skin lesions, eosinophil/mast cell infiltration, and serum immunoglobulin E levels, which were all significantly decreased by ASex treatment, demonstrating the same degree of protection as hydrocortisone. Overall, ASex showed excellent anti-inflammatory effects both in vitro and in vivo, suggesting its potential as an excellent candidate drug to reduce skin inflammation.

Alnus Sibirica Extracts Suppress the Expression of Inflammatory Cytokines Induced by Lipopolysaccharides, Tumor Necrosis Factor-α, and Interferon-γ in Human Dermal Fibroblasts.

The effects of Alnus sibirica (AS) extracts on cytokine expression induced by inflammatory stimulants were examined in human dermal fibroblasts (HDFs) and RAW264.7 cells. The anti-oxidative effect and effect on cell viability of AS extracts were evaluated, and four extracts with the highest anti-oxidative effects were selected. HDFs and RAW264.7 cells were treated with inflammatory stimulants, and the expression of cytokines involved in acute (IL-6 and IL-10) and chronic (IL-18) inflammation, the initiation of the immune response (IL-33), and non-specific immune responses (IL-1ß, IL-8, and TNF-α) were determined using a reverse-transcription polymerase chain reaction. LPS increased the expression of all the cytokines, except for IL-18; however, AS extracts, particularly AS2 and AS4, reduced this increase, and TNF-α treatment markedly increased the expression of cytokines related to non-specific immune responses. IFN-γ treatment induced no significant changes, except for increased IL-33 expression in HDFs. AS extracts inhibited the increase in the expression of IL-33 and other cytokines in HDFs. Thus, the exposure of HDFs and RAW264.7 cells to inflammatory stimulants increased the expression of cytokines related to all the inflammatory processes. HDFs are involved not only in simple tissue regeneration but also in inflammatory reactions in the skin. AS2 and AS4 may offer effective therapy for related conditions.

Inhibitory Effects on NO Production and DPPH Radicals and NBT Superoxide Activities of Diarylheptanoid Isolated from Enzymatically Hydrolyzed Ehthanolic Extract of Alnus sibirica.

Alnus sibirica (AS) is geographically distributed in Korea, Japan, Northeast China, and Russia. Various anti-oxidant, anti-inflammation, anti-atopic dermatitis and anti-cancer biological effects of AS have been reported. Enzymatic hydrolysis decomposes the sugar bond attached to glycoside into aglycone which, generally, has a superior biological activity, compared to glycoside. Enzymatic hydrolysis of the extract (EAS) from AS was processed and the isolated compounds were investigated-hirsutanonol (1), hirsutenone (2), rubranol (3), and muricarpon B (4). The structures of these compounds were elucidated, and the biological activities were assessed. The ability of EAS and the compounds (1-4) to scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals and Nitroblue tetrazolium (NBT) superoxide, and to inhibit NO production was evaluated in vitro. EAS showed more potent antioxidant and anti-inflammatory activity than AS. All investigated compounds showed excellent antioxidant and anti-inflammatory activities.

Anti-Inflammatory and Anti-Urolithiasis Effects of Polyphenolic Compounds from Quercus gilva Blume.

Quercus gilva Bume (QGB, family Fagaceae) is a tall evergreen oak species tree that grows in warm temperate regions in Korea, Japan, China and Taiwan. Quercus plants have long been the basis of traditional medicines. Their clinical benefits according to traditional medicine include relief of urolithiasis, tremors and inflammation. In the present study, the anti-urolithiasis activity including anti-inflammatory and anti-oxidative activities, of some phenolic compounds isolated from QGB were described. Seven compounds were isolated and identified as picraquassioside D (1), quercussioside (2), (+)-lyoniresinol-9'α-O-ß-d-xylopyranoside (3), (+)-catechin (4), (-)-epicatechin (5), procyanidin B-3 (6), and procyanidin B-4 (7). Compounds 5-7 showed potent anti-oxidative and anti-inflammatory activities. These compounds were further tested for their inhibition of the gene expression of the inflammatory cytokines. The three compounds 5-7 showed dose-dependent inhibitory activities on gene expression of COX-2 and IL-1ß. In vivo, urolithiasis was induced more effectively in an animal model of acute urolithiasis by the administration of QGB extract. These results indicate the potential of compounds from QGB in the treatment of urolithiasis.

Inhibitory Activities of Phenolic Compounds Isolated from Adina rubella Leaves Against 5α-Reductase Associated with Benign Prostatic Hypertrophy.

Adina rubella Hance (AR), a plant native to Korea, has been used as traditional medicine for dysentery, eczema, intoxication, and external hemorrhages. Previous phytochemical studies of AR have reported several components, including terpenoids, phenolics, and alkaloids. The current study evaluated the anti-oxidative and anti-inflammatory activities and 5α-reductase inhibition of isolated compounds of AR leaves to find a potential therapeutic agent for benign prostatic hypertrophy (BPH). Repeated chromatographic isolation of an 80% acetone extract of AR leaves yielded seven phenolic compounds: caffeic acid (1), chlorogenic acid (2), methyl chlorogenate (3), quercetin-3-rutinoside (4), kaempferol-3-O-α-l-rhamnopyranosyl-(1→6)-ß-d-glucopyranoside (5), hyperoside (6), and grandifloroside (7). Compound 7 is a novel compound in AR. Caffeoyl derivatives 1-3 and 7 showed good anti-oxidative activities. In particular, caffeic acid (1) and grandifloroside (7) showed potent anti-inflammatory activities, and 7 also exhibited potent inhibitory activity against TNF-α and 5α-reductase. Our results show that the extract and grandifloroside (7) from leaves of AR might be developed as a source of potent anti-oxidative and anti-inflammatory agents and therapeutic agent for BPH.

Antiproliferative Effects of New Dimeric Ellagitannin from Cornus alba in Prostate Cancer Cells Including Apoptosis-Related S-Phase Arrest.

Activity-guided isolation of 80% acetone extract of Cornus alba, which is traditionally used as an anti-inflammatory, hemostatic and diuretic in Korea, yielded one novel compound, tentatively designated cornusiin H (13), together with 12 known compounds. The known compounds included four flavonoids (catechin (1), quercetin-3-O-ß-D-glucuronide (2), quercetin-3-O-ß-D-glucopyranoside (3), kaempferol-3-O-ß-D-glucopyranoside (4)) and eight hydrolysable tannins (gallic acid (5), 2,6-di-O-galloyl-hamamelofuranoside (6), 2-galloyl-4-caffeoyl-L-threonic acid (7) 2,3-di-O-galloyl-4-caffeoyl-L-threonic acid (8), 1,2,3,4,6-penta-O-galloyl-ß-D-glucopyranoside (9), cornusiin B (10), cornusiin A (11) and camptothin B (12)). All compounds exhibited potent 1,1-diphenyl-2-picrylhydrazyl (DPPH)-free radical scavenging activity. Especially, the radical scavenging activities of 6 and 9-13 were higher than that of vitamin C. Compounds 9, 11, 12 and 13 inhibited the production of nitric oxide (NO) in lipopolysaccharide-stimulated RAW264.7 cells to the same degree as N(G)-Monomethyl-L-arginine (L-NMMA). When the antiproliferative effects of the isolated compounds were assessed in prostate cancer cells, the dimeric ellagitannins (11-13) selectively inhibited LNCaP hormone-dependent prostate cancer cells. Flow cytometry analysis indicated that the dimeric ellagitannins induced apoptosis and S-phase arrest. These results suggest that dimeric ellagitannins from Cornus alba can be developed as functional materials or herbal medicines for prostate tumors such as benign prostate hyperplasia and early-stage prostate cancer.

Effect of topical application of quercetin-3-O-(2″-gallate)-α-l-rhamnopyranoside on atopic dermatitis in NC/Nga mice.

BACKGROUND: Quercetin-3-O-(2″-gallate)-α-l-rhamnopyranoside (QGR) is a new quercetin derivative which is isolated from the leaves of Acer ginnala Maxim, a native plant of Korea. Quercetin has several biological effects including antioxidative, anti-inflammatory, and anti-allergic effects. However, the topical effect of QGR on atopic dermatitis (AD) like skin lesion in NC/Nga mice has not been studied. OBJECTIVE: To evaluate the anti-inflammatory and anti-allergic effect of QGR in a murine model of atopic dermatitis. METHODS: We measured inducible nitric oxide synthase (iNOS) and cyclooxygenase -2(COX-2) level in RAW264.7 cell with QGR treatment. And after induction of AD like skin lesions with Dermatophagoides farina (Df) ointment, mice were treated with QGR and control drugs. Clinical scores, interleukin (IL) 4, 5, and 13, serum IgE, eosinophil levels, iNOS and COX-2 level were evaluated. RESULTS: Results show that mRNA level of iNOS and COX-2 in vitro were decreased after QGR treatment. Topical QGR markedly decreased the iNOS and COX-2 mRNA expressions in the skin. QGR also significantly suppressed the increase in the level of total plasma IgE and eosinophils. In addition, topical application of QGR down-regulated the expressions of the cytokines, IL-4,5 and 13, which were induced by Df ointment stimulation. CONCLUSIONS: In the present study, we showed that topical application of QGR ameliorated Df-induced AD-like inflammatory responses in NC/Nga mice. These results demonstrate that QGR might be beneficial in the treatment of AD.

Rotundarpene prevents TRAIL-induced apoptosis in human keratinocytes by suppressing the caspase-8- and Bid-pathways and the mitochondrial pathway.

The extract and hemiterpene glycosides of Ilex rotunda Thunb have demonstrated antioxidant and anti-inflammatory effects. Nevertheless, the effect of rotundarpene on the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in keratinocytes that may be involved in skin diseases has not been studied. In this respect, we investigated the effect of rotundarpene on TRAIL-induced apoptosis in human keratinocytes. TRAIL triggers apoptosis by inducing a decrease in the cytosolic levels of Bid, Bcl-2, Bcl-xL, and survivin proteins, increase in the cytosolic levels of Bax, and increase in the mitochondrial levels of VDAC1, loss of the mitochondrial transmembrane potential, release of cytochrome c, activation of caspases (-8, -9, and -3), cleavage of PARP-1, and an increase in the tumor suppressor p53 levels. Treatment with rotundarpene prevented TRAIL-induced changes in the levels of apoptosis-related proteins, formations of reactive oxygen species and nitric oxide, nuclear damage, and cell death. These results suggest that rotundarpene may reduce TRAIL-induced apoptosis in human keratinocytes by suppressing the activation of the caspase-8- and Bid-pathways and the mitochondria-mediated cell death pathway, which is associated with the formation of reactive oxygen species and reactive nitrogen species. These data suggest that rotundarpene appears to be effective in the prevention of TRAIL-induced apoptosis-mediated skin diseases.

The comparison of DPPH-scavenging capacity and anti-inflammatory effects of phenolic compounds isolated from the stems of Stewartia koreana Nakai.

The Stewartia koreana Nakai (SK) had been used in oriental traditional medicine as a remedy for acute gastroenteritis, liver diseases, quadriplegia and pain. The antioxidant activity guided isolation 80% methyl extract from stems of SK yielded eight phenolic compounds. We evaluated the anti-oxidative and anti-inflammatory effects of these compounds via assays of 1,1-diphenyl-2-picrylhydazyl (DPPH) radicals and inhibition of nitric oxide (NO) production in lipopolysaccharide-stimulated RAW 264.7 macrophage cells. The results demonstrated that syringaresinol (6) exhibited significant DPPH radical-scavenging activity and inhibitory effects on NO production compared with its positive controls, ascorbic acid and L-NMMA, respectively.

Rotundarpene inhibits toll-like receptor 2 activation-induced production of inflammatory mediators in keratinocytes by suppressing the Akt and NF-κB pathways.

Microbial components have been shown to be involved in the pathogenesis of inflammatory skin diseases. The extract of from the barks of Ilex rotunda Thunb has demonstrated anti-inflammatory and anti-oxidant effects. However, the effect of hemiterpene rotundarpene (4-caffeoyl-3-methyl-but-2-ene-1,4-diol) on the Toll-like receptor (TLR)-2 activation-induced production of inflammatory mediators in keratinocytes has not been studied. Using human keratinocytes, we investigated the effect of rotundarpene on the inflammatory mediator production in relation to the TLR-2-mediated-Akt and NF-κB pathways, which regulates the transcription genes involved in immune and inflammatory responses. Rotundarpene, Akt inhibitor, Bay 11-7085 and N-acetylcysteine each attenuated the lipoteichoic acid- or peptidoglycan-induced production of cytokines and chemokines, expression of TLR-2, activation of NF-κB and Akt, and formation of reactive oxygen species in keratinocytes. Cyclosporine A attenuated the bacterial component-induced production of inflammatory mediators but did not reduce the formation of reactive oxygen species. The results show that rotundarpene may attenuate the bacterial component-stimulated production of inflammatory mediators in keratinocytes by suppressing the TLR-2-mediated activation of the Akt and NF-κB pathways. The effect of rotundarpene may be attributed to its inhibitory effect on the formation of reactive oxygen species. Rotundarpene may exert a preventive effect against the bacterial component-mediated inflammatory skin diseases.

Anti-inflammatory activity of sulfate-containing phenolic compounds isolated from the leaves of Myrica rubra.

Three sulfated phenolic compounds, juglanin B (11R)-O-sulfate (1), myricetin 3´-O-sulfate (2), and ampelopsin 3´-O-sulfate (3), were isolated from the leaves of Myrica rubra. Compound 1 was a new sulfated lignan, 2 was a new sulfated flavone, and 3 was a known sulfated flavone. The structures of the new compounds (1 and 2) were determined by acid hydrolysis and spectroscopic methods, including IR, FAB-MS, 1D and 2D NMR. The inhibitory activities of compounds 1-3 and their hydrolysates (1a-3a) against LPS-induced cytokine (TNF-α, IL-1ß, and IL-6) production in macrophage RAW 264.7 cells were evaluated. The 2 new compounds (1 and 2) and their aglycones (1a and 2a) significantly reduced LPS-induced expression of iNOS and COX-2 proteins.

Anti-oxidative and anti-inflammatory activities of caffeoyl hemiterpene glycosides from Spiraea prunifolia.

Activity guided isolation of a Spiraea prunifolia extract yielded five caffeoyl hemiterpene glycosides: 4'-(6-O-caffeoyl-ß-D-glucopyranosyl)-2'-methyl butyric acid, 1-O-caffeoyl-6-O-(4'-hydroxy-2'-methylene-butyroyl)-ß-D-glucopyranoside, 1,2-O-dicaffeoyl-6-O-(4'-hydroxy-2'-methylene-butyroyl)-ß-D-glucopyranoside, 1-O-caffeoyl-6-O-(4'-caffeoyl-2'-methylene-butyroyl)-ß-D-glucopyranoside, and 1-O-caffeoyl-6-O-(4'-caffeoyl-3'-hydroxy-2'-methylene-butyroyl)-ß-D-glucopyranoside, and nine known compounds. Structures were elucidated by analysis of 1D and 2D NMR spectra and FAB-MS. To evaluate the anti-oxidative and anti-inflammatory properties of all fourteen compounds, DPPH radical scavenging, NBT superoxide scavenging, and inhibition of nitric oxide production in LPS-stimulated RAW264.7 cells were examined. Three of the caffeoyl hemiterpene glycosides exhibited potent anti-oxidative and anti-inflammatory activities compared with Vitamin C and l-NMMA, which were used as positive controls.