Young-Won Chin

Herb-drug interactions: focus on metabolic enzymes and transporters.

As the uses of herbal medicines from traditional natural products are increased, the need for pharmacokinetic studies and relevant data are also increased for safe pharmacotherapy. The market entry for the traditional herbal medicine is easier compared with that for synthetic drugs because of a lower regulatory barrier. Thus, the exact mechanisms for the absorption, distribution, metabolism and excretion of active components in herbal medicines and the potential herb-drug interactions are not always fully understood. Recently, there has been an increasing interest in pharmacokinetic studies of herbal remedies and relevant data of commonly used herbal remedies are accumulating in this field. In this review, the effects of nine botanicals (ginkgo, green tea, grapes, licorice, saw palmetto, garlic milk thistle, ginseng and St. John’s wort) on metabolic enzymes and transporters affecting absorption and disposition of herbal products are summarized. The source of samples (extracts and individual components), the species (human and animal) and in vivo and in vitro systems were separately reviewed for a better understanding of herb-drug interactions.

Selective induction of apoptosis of human oral cancer cell lines by avocado extracts via a ROS-mediated mechanism.

Avocados have a high content of phytochemicals with potential chemopreventive activity. Previously we reported that phytochemicals extracted from avocado meat into a chloroform partition (D003) selectively induced apoptosis in cancer but not normal, human oral epithelial cell lines. In the present study, we observed that treatment of human oral cancer cell lines containing high levels of reactive oxygen (ROS) with D003 increased ROS levels twofold to threefold and induced apoptosis. In contrast, ROS levels increased only 1.3-fold, and apoptosis was not induced in the normal cell lines containing much lower levels of basal ROS. When cellular ROS levels in the malignant cell lines were reduced by N-acetyl-l-cysteine (NAC), cells were resistant to D003 induced apoptosis. NAC also delayed the induction of apoptosis in dominant negative FADD-expressing malignant cell lines. D003 increased ROS levels via mitochondrial complex I in the electron transport chain to induce apoptosis. Normal human oral epithelial cell lines transformed with HPV16 E6 or E7 expressed higher basal levels of ROS and became sensitive to D003. These data suggest that perturbing the ROS levels in human oral cancer cell lines may be a key factor in selective apoptosis and molecular targeting for chemoprevention by phytochemicals.

Antioxidant and cytoprotective compounds from Berberis vulgaris (barberry).

Activity‐guided fractionation of an EtOAc‐soluble partition of the MeOH extract from the root bark of Berberis vulgaris L. (barberry), using a hydroxyl radical‐scavenging assay, led to the isolation and identification of three phenolic compounds of a previously known structure, N‐(p‐trans‐coumaroyl)tyramine, cannabisin G and (±)‐lyoniresinol. Of these, cannabisin G and (±)‐lyoniresinol exhibited antioxidant activity in this bioassay. Furthermore, it was found that cannabisin G showed cytoprotective activity in cultured MCF‐7 cells modulated by hydrogen peroxide. Copyright

Anti-inflammatory effects of methanol extracts of the root of Lilium lancifolium on LPS-stimulated Raw264.7 cells.

AIM OF THE STUDY Lilium lancifolium is commonly used to treat bronchitis, pneumonia, etc. In this study, we investigated the anti-inflammatory effects of methanol extracts of the root of Lilium lancifolium (LL extracts) in LPS-stimulated Raw264.7 cells. MATERIAL AND METHODS Levels of NO, PGE(2) and pro-inflammatory cytokines (IL-6 and TNF-alpha) in the supernatant fraction were determined using sandwich ELISA. Expression of COX-2 and iNOS, phosphorylation of MAPK subgroups (ERK and JNK), and NF-kappaB activation in extracts were detected via Western blot and immunocytochemistry assays. RESULTS The LL extract significantly inhibited NO, PGE(2), IL-6 and TNF-alpha production in LPS-stimulated cells, and suppressed iNOS and COX-2 expression. A mechanism-based study showed that phosphorylation of ERK1/2 and JNK and translocation of the NF-kappaB p65 subunit into nuclei were inhibited by the LL extract. Furthermore, interleukin-4 and interleukin-13 production in Con A-induced splenocytes was suppressed. CONCLUSION These results indicate that anti-inflammatory effects of methanol extracts from Lilium lancifolium are due to downregulation of iNOS and COX-2 via suppression of NF-kappaB activation and nuclear translocation as well as blocking of ERK and JNK signaling in LPS-stimulated Raw264.7 cells.

Bioactivity-guided isolation of cytotoxic constituents of Brucea javanica collected in Vietnam

Five new triterpenoids (1-5), together with two known quassinoids, bruceantin (6) and bruceine A (7), and a known flavonolignan, (-)-hydnocarpin (8), were isolated from the chloroform-soluble subfraction of a methanol extract of the combined twigs, leaves, and inflorescence of Brucea javanica collected in Vietnam. The structures of the new compounds 1-5 were established on the basis of spectroscopic methods. All isolates were evaluated for cytotoxicity against a small panel of human cancer cell lines. Quassinoids 6 and 7 were found to be highly active against these cell lines. (-)-Hydnocarpin (8) showed a potentiating effect when combined with both 6 and 7, during cytotoxicity testing using the MCF-7 human breast cancer cell line.

Phenolic compounds with pancreatic lipase inhibitory activity from Korean yam (Dioscorea opposita)

Abstract Twenty-three phenolic compounds were isolated from Dioscorea opposita by bioactivity-guided method and their inhibitory effect against pancreatic lipase was evaluated. A total of 15 isolates reduced lipase activity at IC50 values of less than 50 µM and 3,3′,5-trihydroxy-2′-methoxybibenzyl showed the highest inhibition with an IC50 value of 8.8 µM. This study is a first to reveal the pancreatic lipase inhibitory activity by both D. opposita and its isolated compounds.

Mangosteen xanthones mitigate ovalbumin-induced airway inflammation in a mouse model of asthma

α- and γ-Mangostin, which are the major xanthones purified from a Mangosteen, Garcinia mangostana Linn., exhibit a wide range of anticancer, antioxidant, and anti-inflammatory activities. Here, we assessed their therapeutic effects in a mouse model of ovalbumin (OVA)-induced allergic asthma. Animals were treated with α- and γ-mangostins orally for 3 days at doses of 10 and 30 mg/kg daily, 1h before the OVA challenge. Administration of α- and γ-mangostins significantly reduced the major pathophysiological features of allergic asthma, including inflammatory cell recruitment into the airway, airway hyperresponsiveness (AHR), and increased levels of Th2 cytokines. In addition, α- and γ-mangostins attenuated the increases in phosphoinositide 3-kinase (PI3K) activity, phosphorylation of Akt, and NF-κB in nuclear protein extracts after OVA challenge. In conclusion, α- and γ-mangostin may have therapeutic potential for the treatment of allergic asthma.

Identification of myricetin and scutellarein as novel chemical inhibitors of the SARS coronavirus helicase, nsP13.

Abstract Severe acute respiratory syndrome (SARS) is an infectious disease with a strong potential for transmission upon close personal contact and is caused by the SARS-coronavirus (CoV). However, there are no natural or synthetic compounds currently available that can inhibit SARS-CoV. We examined the inhibitory effects of 64 purified natural compounds against the activity of SARS helicase, nsP13, and the hepatitis C virus (HCV) helicase, NS3h, by conducting fluorescence resonance energy transfer (FRET)-based double-strand (ds) DNA unwinding assay or by using a colorimetry-based ATP hydrolysis assay. While none of the compounds, examined in our study inhibited the DNA unwinding activity or ATPase activity of human HCV helicase protein, we found that myricetin and scutellarein potently inhibit the SARS-CoV helicase protein in vitro by affecting the ATPase activity, but not the unwinding activity, nsP13. In addition, we observed that myricetin and scutellarein did not exhibit cytotoxicity against normal breast epithelial MCF10A cells. Our study demonstrates for the first time that selected naturally-occurring flavonoids, including myricetin and scultellarein might serve as SARS-CoV chemical inhibitors.

Absorption, tissue distribution, tissue metabolism and safety of α-mangostin in mangosteen extract using mouse models.

The commercially available herbal products as the form of extract were usually mixtures containing various compounds. In spite of the purported efficacy in each active constituent, the coexisting constituents in the herbal extract might interfere with the efficacy and safety and affect the pharmacokinetic properties of active constituents. To compare for the pharmacokinetic properties of α-mangostin, a major bioactive compound, in mangosteen extract and pure α-mangostin, the pharmacokinetics as well as tissue distribution, in vitro metabolism, plasma protein binding and safety evaluation were conducted in mice because a mouse model is required a small amount of compounds and useful to develop disease models. The absorption of α-mangostin was increased and hepatic metabolism of α-mangostin was decreased in mice treated with mangosteen extract. However, the intestinal metabolism α-mangostin is comparable and still extensive in mice treated with α-mangostin and mangosteen extract. Intraperitorial LC50 of α-mangostin and mangosteen extract was 150 and 231 mg/kg, respectively. These findings may be valuable to explain the different pharmacokinetics and safety of α-mangostin and mangosteen extract. Furthermore, these findings are useful to design the efficacy and safety investigation of α-mangostin or mangosteen extract in mice with disease models or combination therapies to extrapolate into the clinical levels.

Anti-allergic effect of lambertianic acid from Thuja orientalis in mouse bone marrow-derived mast cells

Lambertianic acid is a bioactive diterpene found in the leaves of Thuja orientalis. Its effect on the bone marrow-derived mast cell (BMMC) mediated allergy and inflammation mechanism remains unknown. In this study, lambertianic acid was evaluated for its effect on the allergic mediators, including prostaglandin D2 (PGD2), leukotriene C4 (LTC4), β-hexosaminidase (β-Hex) and cyclooxygenase-2 (COX-2) protein, in phorbol 12-myristate 13-acetate (PMA) plus calcimycin-stimulated BMMCs. The results revealed that lambertianic acid inhibited the production of interleukin-6 (IL-6), PGD2 and LTC4, the expression of COX-2 and the degranulation of β-hexosaminidase in the PMA plus calcimycin-induced BMMCs. Taken together, these findings implied that lambertianic acid may possess the potential in the treatment of allergy.