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Reactive Oxygen Species-Dependent Activation of Bax and Poly(ADP-ribose) Polymerase-1 Is Required for Mitochondrial Cell Death Induced by Triterpenoid Pristimerin in Human Cervical Cancer Cells

Naturally occurring triterpenoid compounds have long been used as anti-inflammatory, antimalarial, and insecticidal agents. It has become evident that some of the natural or synthetic triterpenoids have promising clinical potential as both a therapeutic and chemopreventive agent for cancer. However, the molecular basis for the antitumor activity of triterpenoid has yet to be defined. In this study, we show that pristimerin, a natural triterpenoid, induces mitochondrial cell death in human cervical cancer cells and that reactive oxygen species (ROS)-dependent activation of both Bax and poly(ADP-ribose) polymerase-1 (PARP-1) is critically required for the mitochondrial dysfunction. We also showed that c-Jun N-terminal kinase (JNK) is involved in ROS-dependent Bax activation. Treatment of pristimerin induced an increase in intracellular ROS, JNK activation, conformational change, and mitochondrial redistribution of Bax, mitochondrial membrane potential loss, and cell death. The PARP-1 was also found to be activated by pristimerin treatment. An antioxidant, N-acetyl-l-cysteine (NAC), inhibited pristimerin-induced JNK activation, Bax relocalization, and PARP-1 activation, as well as mitochondrial cell death. Moreover, inhibition of JNK clearly suppressed conformational change and mitochondrial translocation of Bax and subsequent mitochondrial cell death but did not affect PARP-1 activation. Inhibition of PARP-1 with 1,5-dihydroxyisoquinoline (DIQ) or with small interfering RNA of PARP-1 significantly attenuated pristimerin-induced mitochondrial membrane potential loss and cell death but did not affect JNK activation and Bax relocalization. These results indicate that the natural triterpenoid pristimerin induces mitochondrial cell death through ROS-dependent activation of both Bax and PARP-1 in human cervical cancer cells and that JNK is involved in ROS-dependent Bax activation.

A New flavonolignan from the aerial Parts of Oryza sativa L. inhibits nitric oxide production in RAW 264.7 macrophage cells

Fresh and chopped aerial parts of Oryza sativa were extracted in 80% aqueous mehthanol, and the concentrated extract was successively partitioned using n-hexane, ethyl acetate (EtOAc), nbutanol, and H2O. From the EtOAc fraction, a new flavonolignan (2) and a known flavonolignan, salcolin B (1), were isolated through repeated SiO2 and octadecyl silica gel column chromatography. Based on NMR, mass spectrometer, and IR spectroscopic data, the chemical structure of compound (2) was determined to be tricin-4’-O-[erythro-β-guaiacyl-(7’’-O-methyl)-glyceryl] ether, which has thus far never been reported and was named salcolin C (2). Salcolin B (1) and salcolin C (2) dose-dependently inhibited nitric oxide production in RAW 264.7 cells with IC50 values of 29.8±0.6 and 10.8±1.0 μM, respectively, without visible toxic effect.

Triterpenoid pristimerin synergizes with taxol to induce cervical cancer cell death through reactive oxygen species-mediated mitochondrial dysfunction.

A combined treatment with conventional chemotherapies can enhance the effectiveness of chemotherapeutic agents against cancers. Here, we have shown that the naturally occurring triterpenoids synergistically enhance the response of cervical cancer cells to taxol. Of the triterpenoid compounds, pristimerin enhanced the anticancer effect of taxol with the highest efficiency by combination. Pristimerin synergizes with taxol to inhibit clonogenic survival and tumor growth in nude mice, and to enhance cell death in cervical cancer cells. A combined treatment with taxol and pristimerin induced cervical cancer cell death by increasing intracellular reactive oxygen species levels, upregulation of death receptor death receptor 5 (DR5), activation of Bax, and dissipation of mitochondrial membrane potential. Treatment with N-acetyl-L-cysteine, a thiol-containing antioxidant completely blocked combined treatment-induced Bax translocation as well as DR5 upregulation. Moreover, inhibition of Jun N-terminal kinase/c-Jun pathway attenuated cell death by blocking DR5 upregulation and Bax activation. These results indicate that the triterpenoid, pristimerin, synergistically enhances taxol response of cervical cancer cells through DR5 expression and Bax activation. Furthermore, the reactive oxygen species-dependent activation of the Jun N-terminal kinase/c-Jun pathway is required for the DR5 upregulation and Bax activation. The molecular mechanism revealed by this study may aid in the design of future combination cancer therapies against cells with intrinsically reduced sensitivity to taxol.

Cytotoxic and Neuroprotective Biflavonoids from the Fruit of Rhus parviflora

Six biflavonoids, succedaneaflavanone (1), mesuaferrone B (2), rhusflavanone (3), rhusflavone (4), agathisflavone (5), and cupressuflavone (6), were isolated from the fruits of Rhus parviflora. The chemical structures of the compounds were determined based on NMR, fast atom bombardment mass spectrometry, and IR. Biflavonoid compounds were evaluated for cytotoxicity against human cancer cell lines, including human colon carcinoma (HCT-116), human breast carcinoma (MCF-7), and human cervical carcinoma (HeLa). Biflavonoids 2, 3, and 5 showed significant cytotoxicity with IC50 values of 17.25 μM (mesuaferrone B against HCT-116), 17.50 μM (rhusflavone against MCF-7), and 15.20 μM (agathisflavone against HeLa). Compound 5 showed inhibition of β-secretase activity at a 10 μM concentration. Compound 6 showed inhibition of cyclin-dependent kinases (CDK2 and CDK5) with IC50 values of 18.58 and 9.29 μM, respectively.

Flavonoid glycosides from the fruit of Rhus parviflora and inhibition of cyclin dependent kinases by hyperin

Chrysoeriol-7-O-β-d-glucopyranoside (1), luteolin-7-O-β-d-glucopyranoside (2), quercetin-3-O-β-d-glucopyranoside (3), quercetin-3-O-β-d-galactopyranoside (4), and quercetin-3-O-α-l-rhamnopyranoside (5) were isolated for the first time from the fruits of Rhus parviflora. The chemical structures of the compounds were determined using nuclear magnetic resonance, fast atom bombardment mass spectrometry, and infrared spectroscopy. Compound 4 (hyperin) inhibited cyclin dependent kinases (CDK2 and CDK5) in vitro with IC50 values of 21.02 and 10.28 μM, respectively.

New flavonolignan glucoside from the aerial parts of Oryza sativa

A new flavonolignan glucoside, tricin-4′-O-(erythro-β-guaiacylglyceryl)ether 9′′-O-β-D-glucopyranoside (9′′-O-glucopyranosyl salcolin B), was isolated from the aerial parts of Oryza sativa L. The structure of the compound was established on the basis of NMR, FAB-MS, and IR spectroscopic data.

Triterpenoids from Fragaria ananassa calyx and their inhibitory effects on melanogenesis in B16-F10 mouse melanoma cells.

Column chromatographic technology was applied to isolate six purified ursane triterpenoids from the calyx of Fragaria ananassa and they were identified on the basis of spectroscopic methods to be ursolic acid (1), pomolic acid (2), 2-oxo-pomolic acid (3), 3-O-acetyl pomolic acid (4), fupenzic acid (5) and euscaphic acid (6). This is the first study in which these compounds have been isolated from the calyx of F. ananassa. Compared to a well-known inhibitor, α-arbutin, compounds 2–6 showed a significant decrease in intracellular melanin content in B16-F10 cells, and in culture media melanin.

Fucosterols from Hizikia fusiformis and their proliferation activities on osteosarcoma-derived cell MG63

Four fucosterol derivatives were isolated from the ethyl acetate fraction of Hizikia fusiformis. The chemical structures of the sterols were elucidated as fucosterol (1), a mixture of 24R,28R- and 24S,28R-epoxy-24-ethylcholesterol at the ratio of 3 to 2 (2), and 24R-saringosterol (3), all of which exhibited proliferation activity on MG63 cells.

Feruloyl Sucrose Esters from Oryza sativa Roots and Their Tyrosinase Inhibition Activity

One new feruloyl sucrose ester, 3-feruloyl-4′,6′-diacetyl sucrose (1), along with five known feruloyl sucrose esters, 3,6-diferuloyl-3′,6′-diacetyl sucrose (2), smilaside A (3), 3,6-diferuloyl-6′-acetyl sucrose (4), 3-feruloyl-6′-acetyl sucrose (5), and 3,6-diferuloyl sucrose (6), was isolated from Oryza sativa roots. The chemical structures of the compounds were determined by spectroscopic data analysis. The six isolated feruloyl sucrose esters were evaluated for their inhibitory effect on mushroom tyrosinase in vitro.

Germinated soy germ with increased soyasaponin Ab improves BMP-2-induced bone formation and protects against in vivo bone loss in osteoporosis

Osteoporosis is frequently induced following menopause, and bone fractures result in serious problems including skeletal deformity, pain, and increased mortality. Therefore, safe and effective therapeutic agents are needed for osteoporosis. This study aimed to clarify the bone protecting effects of germinated soy germ extracts (GSGE) and their mode of action. GSGE increased expression of alkaline phosphatase (ALP) and osteocalcin (OCL) by stimulating the expression of runt-related transcription factor 2 (Runx2) and osterix (Osx) through activation of Smad signaling molecules. Furthermore, germination of soy germ increased levels of nutritional components, especially soyasaponin Ab. The anabolic activity of soyasaponin Ab in GSGE was also evaluated. GSGE and soyasaponin Ab significantly protected against ovariectomy (OVX)-induced bone loss and improved bone-specific alkaline phosphatase (BALP) level in mouse serum. These in vitro and in vivo study results demonstrated that GSGE and soyasaponin Ab have potential as therapeutic candidate agents for bone protection in postmenopausal osteoporosis.