ABSTRACT
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.
Subject(s)
Cholestenone 5 alpha-Reductase/metabolism , Cornus/chemistry , Hydrolyzable Tannins/pharmacology , Interleukins/metabolism , Prostatic Hyperplasia/metabolism , Tumor Necrosis Factor-alpha/metabolism , Animals , Cell Line , Cell Proliferation/drug effects , Cell Survival/drug effects , Gene Expression Regulation/drug effects , Humans , Hydrolyzable Tannins/chemistry , Hydrolyzable Tannins/isolation & purification , Male , Molecular Structure , Prostatic Hyperplasia/drug therapy , Rats , Th1 CellsABSTRACT
BACKGROUND/AIM: Despite the Warburg effect, mitochondria play an essential role in the survival and maintenance of cancer cells. Thus, mitochondria have been considered a target for anticancer agents. Here, we identified a mitochondria-targeting anticancer agent from natural products. MATERIALS AND METHODS: Morphological and functional changes in mitochondria were determined by a fluorescence-based High Content Imaging System. Using human non-small cell lung cancer (NSCLC) cell lines (H1299, H226B, and A549), cell viability and colony formation assays, cell cycle analysis, and immunoblotting were performed to determine cytotoxic and proapoptotic effects of papuamine. RESULTS: Using a natural product chemical library, we identified papuamine as an active compound to inhibit viability and ATP production of NSCLC cells. Papuamine depleted intracellular ATP by causing mitochondrial dysfunction, as indicated by the loss of the mitochondrial membrane potential and increased mitochondrial superoxide generation. Papuamine significantly inhibited viability and colony formation of NSCLC cells by inducing apoptosis. CONCLUSION: Papuamine has a potential as a novel mitochondria-targeting anticancer agent.
Subject(s)
Alkaloids/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Mitochondria/pathology , A549 Cells , Adenosine Triphosphate/metabolism , Adenylate Kinase/metabolism , Alkaloids/chemistry , Alkaloids/pharmacology , Carcinoma, Non-Small-Cell Lung/pathology , Cell Survival/drug effects , Humans , Lung Neoplasms/pathology , Mitochondria/drug effects , Tumor Stem Cell Assay , Up-Regulation/drug effectsABSTRACT
Mitochondria play a pivotal role in cancer bioenergetics and are considered a potential target for anticancer therapy. Considering the limited efficacy and toxicity of currently available mitochondria-targeting agents, it is necessary to develop effective mitochondria-targeting anticancer drugs. By screening a large chemical library consisting of natural products with diverse chemical entities, we identified gracillin, a steroidal saponin, as a mitochondria-targeting antitumor drug. Gracillin displayed broad-spectrum inhibitory effects on the viability of a large panel of human cancer cell lines, including those carrying acquired resistance to chemotherapy or EGFR-targeting drugs, by inducing apoptosis. We show that gracillin attenuates mitochondria-mediated cellular bioenergetics by suppressing ATP synthesis and by producing reactive oxygen species (ROS). Mechanistically, gracillin disrupts complex II (CII) function by abrogating succinate dehydrogenase (SDH) activity without affecting the succinate:ubiquinone reductase. The gracillin-induced cell death was potentiated by 3-nitropropionic acid (3-NPA) or thenoyltrifluoroacetone (TTFA), which inhibit CII by binding to the active site of SDHA or to the ubiquinone-binding site, respectively. Finally, we show that gracillin effectively suppressed the mutant-Kras-driven lung tumorigenesis and the growth of xenograft tumors derived from cell lines or patient tissues. Gracillin displayed no obvious pathophysiological features in mice. Collectively, gracillin has potential as a CII-targeting antitumor drug.
Subject(s)
Carcinogenesis/genetics , Cell Death/drug effects , Lung Neoplasms/drug therapy , Spirostans/pharmacology , Animals , Apoptosis/drug effects , Carcinogenesis/drug effects , Cell Death/genetics , Electron Transport Complex II/genetics , Heterografts , Humans , Lung Neoplasms/genetics , Mice , Mitochondria/drug effects , Mitochondria/genetics , Nitro Compounds/metabolism , Oxidation-Reduction , Propionates/metabolism , Reactive Oxygen Species , Thenoyltrifluoroacetone/metabolismABSTRACT
The adhesion of cancer cells to the extracellular matrix (ECM) is crucial for cell proliferation, survival, and metastasis. Thus, it is necessary to inhibit cell-ECM adhesion by blocking the activation of the associated signaling to control cancer. Here, we identify erybraedin A (EBA) as a potential Src inhibitor that blocks cell adhesion and viability in non-small-cell lung cancer (NSCLC). EBA significantly inhibited the adhesion of NSCLC cells to fibronectin. EBA also markedly inhibited the activation of Src and its downstream targets, including FAK and Akt. The interaction between integrin ß1 or integrin ß3 and Src was inhibited by EBA treatment. A docking study revealed the bindings of EBA to the ATP-binding pocket and the allosteric regulatory site of the Src kinase. Additionally, EBA markedly inhibited the viability and the colony formation of NSCLC cells and induced apoptotic cell death. These results describe novel biological properties of EBA, which can block the Src-mediated adhesion and survival of NSCLC cells, suggesting the potential of EBA as an anticancer Src inhibitor that warrants further development in advanced preclinical and clinical settings.
Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Cell Adhesion/drug effects , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Pterocarpans/pharmacology , src-Family Kinases/antagonists & inhibitors , Apoptosis/drug effects , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Cell Survival/drug effects , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , src-Family Kinases/metabolismABSTRACT
Chromatographic isolation of the 80% MeOH extract of Acer ginnala (AG) yielded seven galloyl derivatives: gallic acid (1), ginnalin B (2), acertannin (3), maplexin D (4), maplexin E (5), quercetin-3-O-(2''-galloyl)-α-L-rhamnopyranoside (6), and kaempferol-3-O-(2''-galloyl)-α-L-rhamnopyranoside (7). This is the first study to report the isolation of compounds 4 and 5 from AG. Galloyl derivatives 3-7 exhibited potent radical scavenging activities, with 5 and 7 showing particularly strong inhibitory activities against nitric oxide production in lipopolysaccharides- (LPS-) stimulated RAW264.7 cells. In addition, oral administration of AG extract (500 mg/kg b.w.) improved symptoms of hyperglycemia and blunted the increases in serum GOT/GPT levels in a rat model of streptozotocin-induced diabetes. These results suggest that galloyl derivatives (1-7) are antioxidant and anti-inflammatory agents and that AG extract has potential as a functional material or novel herbal medicine for treating diabetes mellitus.
ABSTRACT
Purpose: Histone deacetylase inhibitors (HDI) are promising anticancer therapies; however, drug resistance limits their efficacy. Here, we investigated the molecular mechanisms underlying HDI resistance, focusing on the mechanism of HDI-mediated induction of insulin-like growth factor 2 (IGF2) based on our previous study.Experimental Design: The methylation status of CCCTC-binding factor (CTCF)-binding sites in the IGF2/H19 imprinting control region (ICR) were determined by methylation-specific PCR and bisulfite sequencing. The effectiveness of single or combinatorial blockade of DNA methyltransferase 1 (DNMT1) and histone deacetylase (HDAC) was evaluated using cell viability assay and patient-derived tumor xenograft (PDX) model.Results: HDAC inhibition by vorinostat increased acetylated STAT3 (K685), resulting in transcriptional upregulation of DNMT1 DNMT1-mediated hypermethylation of CTCF-binding sites in the IGF2/H19 ICR decreased CTCF insulator activity, leading to a transcriptional upregulation of IGF2 and activation of the insulin-like growth factor 1 receptor (IGF-1R) pathway in cells with acquired or de novo vorinostat resistance. Strategies targeting DNMT1 diminished the IGF2 expression and potentiated vorinostat sensitivity in preclinical models of lung cancer with hypermethylation in the H19/IGF2 ICR. The degree of ICR hypermethylation correlated with vorinostat resistance in patient-derived lung tumors and in patients with hematologic malignancies.Conclusions: DNMT1-mediated transcriptional upregulation of IGF2 is a novel mechanism of resistance to HDIs, highlighting the role of epigenetic deregulation of IGF2 in HDI resistance and the potential value of the H19/IGF2 ICR hypermethylation and DNMT1 expression as predictive biomarkers in HDI-based anticancer therapies. Clin Cancer Res; 23(5); 1299-311. ©2016 AACR.
Subject(s)
DNA (Cytosine-5-)-Methyltransferase 1/genetics , Hematologic Neoplasms/drug therapy , Insulin-Like Growth Factor II/genetics , Lung Neoplasms/genetics , RNA, Long Noncoding/genetics , Animals , CCCTC-Binding Factor/genetics , DNA Methylation/genetics , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic/drug effects , Hematologic Neoplasms/genetics , Hematologic Neoplasms/pathology , Histone Deacetylase Inhibitors/adverse effects , Histone Deacetylases/genetics , Humans , Hydroxamic Acids/administration & dosage , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Lung Neoplasms/secondary , Mice , STAT3 Transcription Factor/genetics , Vorinostat , Xenograft Model Antitumor AssaysABSTRACT
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.
Subject(s)
Antioxidants/pharmacology , Cornus/chemistry , Cytostatic Agents/pharmacology , Hydrolyzable Tannins/pharmacology , Prostatic Neoplasms/metabolism , Animals , Antioxidants/chemistry , Apoptosis , Cell Line, Tumor , Cytostatic Agents/chemistry , Cytostatic Agents/isolation & purification , Humans , Hydrolyzable Tannins/chemistry , Hydrolyzable Tannins/isolation & purification , Macrophages/cytology , Macrophages/drug effects , Male , Mice , Molecular Structure , Nitric Oxide/metabolism , Prostatic Neoplasms/drug therapy , RAW 264.7 Cells , S Phase Cell Cycle Checkpoints/drug effectsABSTRACT
Two new phenolic compounds, 4-O-glucopyranosyl-5-O-caffeoylshikimic acid (1) and 2,3-digalloyl oregonin (2), were isolated along with eight known phenolic compounds (3-10) from an 80% acetone extract of Alnus sibirica leaves. The chemical structures of these compounds were elucidated using 1D/2D nuclear magnetic resonance and high resolution-MS. The anti-oxidative activities of these compounds were determined by assaying their 1,1-diphenyl-2-picrylhydrazyl radical and nitroblue tetrazolium superoxide anion scavenging activity. All of the isolated phenolic compounds (1-10) exhibited potent anti-oxidative activities. In particular, 2 and 4, which are diarylheptanoids, and 10 which is ellagitannin exhibited excellent anti-oxidative activities with almost the same potency as that of the positive controls L-ascorbic acid and allopurinol.
Subject(s)
Alnus/chemistry , Antioxidants/chemistry , Antioxidants/pharmacology , Diarylheptanoids/chemistry , Gallic Acid/analogs & derivatives , Glucosides/chemistry , Plant Leaves/chemistry , Shikimic Acid/analogs & derivatives , Ascorbic Acid/pharmacology , Biphenyl Compounds/chemistry , Diarylheptanoids/pharmacology , Drug Evaluation, Preclinical/methods , Free Radical Scavengers/chemistry , Free Radical Scavengers/pharmacology , Gallic Acid/chemistry , Gallic Acid/pharmacology , Glucosides/pharmacology , Hydrolyzable Tannins/pharmacology , Magnetic Resonance Spectroscopy , Phenols/chemistry , Picrates/chemistry , Plant Extracts/chemistry , Shikimic Acid/chemistry , Shikimic Acid/pharmacology , Superoxides/chemistryABSTRACT
The Hsp90 facilitates proper folding of signaling proteins associated with cancer progression, gaining attention as a target for therapeutic intervention. The natural rotenoid deguelin was identified as an Hsp90 inhibitor, but concerns about neurotoxicity have limited prospects for clinical development. In this study, we report progress on deguelin analogues that address this limitation, focusing on the novel analogue SH-1242 as a candidate to broadly target human lung cancer cells, including those that are chemoresistant or harboring KRAS mutations. In a KRAS-driven mouse model of lung cancer, SH-1242 administration reduced tumor multiplicity, volume, and load. Similarly, in human cell line-based or patient-derived tumor xenograft models, SH-1242 induced apoptosis and reduced tumor vasculature in the absence of detectable toxicity. In contrast to deguelin, SH-1242 toxicity was greatly reduced in normal cells and when administered to rats did not produce obvious histopathologic features in the brain. Mechanistic studies revealed that SH-1242 bound to the C-terminal ATP-binding pocket of Hsp90, disrupting the ability to interact with its co-chaperones and clients and triggering a degradation of client proteins without affecting Hsp70 expression. Taken together, our findings illustrate the superior properties of SH-1242 as an Hsp90 inhibitor and as an effective antitumor and minimally toxic agent, providing a foundation for advancing further preclinical and clinical studies.
Subject(s)
Antineoplastic Agents/pharmacology , Benzopyrans/pharmacology , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , HSP90 Heat-Shock Proteins/metabolism , Humans , Mice , Mice, Transgenic , Rats , Rats, Sprague-Dawley , Xenograft Model Antitumor AssaysABSTRACT
Histone deacetylases (HDACs) are considered promising targets in the treatment of hematologic malignancies and several types of solid tumors, including non-small cell lung cancer (NSCLC). However, the efficacy of HDAC inhibitors in solid tumors is marginal, and the mechanisms underlying resistance to HDAC inhibitors are largely unknown. Here, we demonstrate the involvement of type 1 insulin-like growth factor receptor (IGF-1R) signaling in resistance to HDAC inhibitors in NSCLC. Using MTT and soft-agar colony formation assays, we selected NSCLC cell lines that exhibited intrinsic resistance to vorinostat. Treatment with vorinostat activated IGF-1R signaling in vorinostat-resistant but not vorinostat-sensitive NSCLC cells. Other HDAC inhibitors, including trichostatin A, sodium butyrate, and depsipeptide, also activated IGF-1R signaling in vorinostat-resistant NSCLC cells. Blockade of IGF-1R signaling via IGF-1R monoclonal antibodies (mAbs) or through knockdown of IGF-1R via RNA interference sensitized vorinostat-resistant cells to HDAC inhibition. Finally, IGF-1R mAbs sensitized xenograft tumors of vorinostat-resistant cells to vorinostat treatment in vivo. These findings suggest that IGF-1R activation is generally involved in resistance to HDAC inhibitors and that targeting IGF-1R is an effective strategy for overcoming resistance to HDAC inhibitors in NSCLC.
Subject(s)
Histone Deacetylase Inhibitors/pharmacology , Receptor, IGF Type 1/metabolism , Animals , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Resistance, Neoplasm , Epigenomics , Female , Gene Expression , Humans , Hydroxamic Acids/pharmacology , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mice , Mice, Nude , Receptor, IGF Type 1/antagonists & inhibitors , Vorinostat , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: Quercetin-3-O-(2â³-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.
Subject(s)
Cyclooxygenase 2/metabolism , Dermatitis, Atopic/drug therapy , Eosinophils , Nitric Oxide Synthase Type II/metabolism , Quercetin/analogs & derivatives , Administration, Cutaneous , Animals , Cells, Cultured , Cyclooxygenase 2/drug effects , Cyclooxygenase 2/genetics , Dermatitis, Atopic/blood , Dermatitis, Atopic/enzymology , Female , Immunoglobulin E/blood , Interleukin-13/blood , Interleukin-4/blood , Interleukin-5/blood , Leukocyte Count , Macrophages/drug effects , Macrophages/enzymology , Mice , Nitric Oxide Synthase Type II/drug effects , Nitric Oxide Synthase Type II/genetics , Peptidoglycan/pharmacology , Quercetin/administration & dosage , Quercetin/therapeutic use , RNA, Messenger/metabolismABSTRACT
The roots of Rosa multiflora THUNB. (RM) has been used in oriental traditional medicines as remedies for scabies, rheumatic arthralgia and stomatitis which were practicably related with today's inflammatory and allergic diseases. In the present study, we evaluated whether RM root extract (RME) and its major constituent, 2-(3,4-dihydroxyphenyl)-6-(4-hydroxyphenyl)-8-(2,4-dihydroxyphenyl)-2,3-trans-6,7-cis-7,8-trans-3,4,7,8-tetrahydro-2H,6H-pyrano[2,3-f] chromene-3,7,9-triol (RM-3) belongs to condensed tannins, improve atopic dermatitis (AD)-like skin lesions in NC/Nga mice induced by mite antigen. Topical application of RME as well as RM-3 improved skin severity and suppressed mRNA levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) on skin tissues, in addition, significantly reduced T helper 2 (Th2) immune responses via interleukin 10 (IL-10) up-regulation. Thus, RME, contains lots of condensed tannins such as RM-3 which possesses potent anti-inflammtory and immune-modulatory effects, may be useful for treatment of skin allergies and can be developed as new alternative herbal therapy against AD.
Subject(s)
Dermatitis, Atopic/drug therapy , Mites/immunology , Phytotherapy , Plant Extracts/therapeutic use , Proanthocyanidins/therapeutic use , Rosa/chemistry , Skin/drug effects , Administration, Topical , Animals , Antigens , Cyclooxygenase 2/metabolism , Cyclooxygenase 2 Inhibitors/isolation & purification , Cyclooxygenase 2 Inhibitors/pharmacology , Cyclooxygenase 2 Inhibitors/therapeutic use , Dermatitis, Atopic/immunology , Dermatitis, Atopic/metabolism , Dermatitis, Atopic/pathology , Female , Immunologic Factors/isolation & purification , Immunologic Factors/pharmacology , Immunologic Factors/therapeutic use , Interleukin-10/metabolism , Mice , Mice, Inbred Strains , Nitric Oxide Synthase Type II/metabolism , Plant Extracts/chemistry , Plant Extracts/pharmacology , Plant Roots/chemistry , Proanthocyanidins/isolation & purification , Proanthocyanidins/pharmacology , RNA, Messenger/metabolism , Severity of Illness Index , Skin/metabolism , Skin/pathology , Th2 Cells/metabolism , Up-RegulationABSTRACT
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.
Subject(s)
Anti-Inflammatory Agents/isolation & purification , Anti-Inflammatory Agents/pharmacology , Antioxidants/isolation & purification , Antioxidants/pharmacology , Caffeic Acids/isolation & purification , Caffeic Acids/pharmacology , Glycosides/isolation & purification , Glycosides/pharmacology , Hemiterpenes/isolation & purification , Hemiterpenes/pharmacology , Spiraea/chemistry , Animals , Anti-Inflammatory Agents/chemistry , Antioxidants/chemistry , Biphenyl Compounds/pharmacology , Caffeic Acids/chemistry , Free Radical Scavengers/chemistry , Free Radical Scavengers/pharmacology , Glycosides/chemistry , Hemiterpenes/chemistry , Lipopolysaccharides/pharmacology , Macrophages/drug effects , Mice , Molecular Structure , Nitric Oxide/biosynthesis , Nuclear Magnetic Resonance, Biomolecular , Picrates/pharmacology , StereoisomerismABSTRACT
Quercetin and its derivatives have anti-inflammatory and anti-oxidant effects. However, the effect of quercetin-3-O-(2â³-galloyl)-α-l-rhamnopyranoside (QGR), a new quercetin derivative, on the tumor necrosis factor (TNF)-α-stimulated production of inflammatory mediators in keratinocytes is unclear. In addition, the effect of QGR on the ERK and NF-κB-mediated inflammatory process has not been studied. In human keratinocyte HaCat cells, we investigated the effect of QGR on the TNF-α-stimulated production of inflammatory mediators in relation to the nuclear factor (NF)-κB, which regulates the transcription genes involved in immune and inflammatory responses. QGR inhibited the TNF-α-stimulated production of cytokines and chemokines in HaCaT cells. QGR, dexamethasone, cyclosporine A, Bay 11-7085 (an inhibitor of NF-κB activation) and cell signaling ERK inhibitor attenuated the TNF-α-induced formation of inflammatory mediators and activation of the NF-κB and ERK. Unlike other compounds, dexamethasone and cyclosporine A did not reduce formation of reactive oxygen species. The results show that QGR may attenuate TNF-α-stimulated inflammatory mediator production in HaCaT cells by suppressing the activation of the ERK-mediated NF-κB pathway that is mediated by reactive oxygen species. Additionally, QGR may exhibit a preventive effect against the proinflammatory mediator-induced skin diseases by inhibiting the activation of the ERK and NF-κB pathways.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cytokines/immunology , MAP Kinase Signaling System/drug effects , NF-kappa B/immunology , Quercetin/analogs & derivatives , Tumor Necrosis Factor-alpha/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/isolation & purification , Cell Culture Techniques , Cell Line , Cytokines/biosynthesis , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/immunology , Dose-Response Relationship, Drug , Enzyme-Linked Immunosorbent Assay , Humans , Keratinocytes/drug effects , Keratinocytes/enzymology , Keratinocytes/immunology , MAP Kinase Signaling System/immunology , Molecular Structure , NF-kappa B/antagonists & inhibitors , Quercetin/chemistry , Quercetin/isolation & purification , Quercetin/pharmacology , Reactive Oxygen Species/immunology , Reactive Oxygen Species/metabolism , Tumor Necrosis Factor-alpha/immunologyABSTRACT
Quercetin and its derivatives have antioxidant and anti-inflammatory effects. Nevertheless, in human keratinocytes, compared to the reports on other toxic insults, researches on the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis that may be involved in skin diseases are rare. Furthermore, the effect of quercetin-3-O-(2"-galloyl)-α-l-rhamnopyranoside (QGR), a new quercetin derivative, on TRAIL-induced apoptosis in keratinocytes has not been studied. In this respect, we investigated the effect of QGR on TRAIL-induced apoptosis in human keratinocytes. TRAIL triggers apoptosis by inducing a decrease in Bid, Bcl-2, Bcl-xL and survivin protein levels, increase in Bax and VDAC1 levels, 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 QGR prevented TRAIL-induced apoptosis-related protein activation, formation of reactive oxygen species, nuclear damage, and cell death. In contrast, quercetin induces cytotoxicity and had an additive effect on TRAIL-induced apoptosis-related protein activation and cell death. These results suggest that the QGR, unlike quercetin, 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. These data suggest that QGR could be effective in the prevention of TRAIL-induced apoptosis-mediated skin diseases.
Subject(s)
Apoptosis/drug effects , BH3 Interacting Domain Death Agonist Protein/antagonists & inhibitors , Caspase 8/metabolism , Caspase Inhibitors/pharmacology , Keratinocytes/drug effects , Mitochondria/drug effects , Quercetin/analogs & derivatives , TNF-Related Apoptosis-Inducing Ligand/metabolism , BH3 Interacting Domain Death Agonist Protein/metabolism , Blotting, Western , Cell Survival/drug effects , Cells, Cultured , Humans , Keratinocytes/enzymology , Molecular Structure , Quercetin/chemistry , Quercetin/pharmacology , Reactive Oxygen Species/antagonists & inhibitors , Reactive Oxygen Species/metabolism , Signal Transduction/drug effectsABSTRACT
Three new orcinol (3-hydroxy-5-methylphenol)-conjugated hydrolysable tannins, together with two known compounds were isolated from the leaves of Cleyera japonica (CJ), and have been tentatively named cleyeratannin A (1), cleyeratannin B (2) and cleyeratannin C (3). The chemical structures of these compounds were elucidated using 1 dimensional (1D)/2D NMR and high resolution FAB-MS, and the absolute configuration was confirmed by circular dichroism (CD). To evaluate their anti-oxidative activities, 1,1-diphenyl-2-picrylhydrazyl (DPPH)/free radical scavenging activity and nitroblue tetrazolium (NBT)/superoxide anion scavenging activity were determined.
Subject(s)
Antioxidants/chemistry , Free Radical Scavengers/chemistry , Hydrolyzable Tannins/chemistry , Plant Extracts/chemistry , Resorcinols/chemistry , Theaceae/chemistry , Nitroblue Tetrazolium/chemistry , Superoxides/chemistryABSTRACT
Chromatographic separation of the 80% MeOH extract of the leaves of Ilex rotunda (IR) led to isolation of two new hemiterpene glycosides, tentatively named as rotundarpenoside A (1) and rotundarpenoside B (2), along with five known caffeoyl derivatives (3-7). The chemical structures of these compounds were elucidated using 1D/2D NMR, HR-MS, and the absolute configuration was confirmed by Mosher's method. In order to evaluate their anti-oxidative activities, 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity and xanthine oxidase superoxide scavenging activities (NBT) were determined.
Subject(s)
Free Radical Scavengers/isolation & purification , Glycosides/isolation & purification , Hemiterpenes/isolation & purification , Ilex/chemistry , Biphenyl Compounds/chemistry , Free Radical Scavengers/pharmacology , Glycosides/pharmacology , Hemiterpenes/pharmacology , Magnetic Resonance Spectroscopy , Molecular Structure , Picrates/chemistry , Plant Leaves/chemistry , Superoxides/chemistry , Xanthine Oxidase/chemistryABSTRACT
Isolation of compounds from the root of Rhodiola sachalinensis (RRS) yielded tyrosol (1), salidroside (2), multiflorin B (3), kaempferol-3,4'-di-O-ß-D-glucopyranoside (4), afzelin (5), kaempferol (6), rhodionin (7), and rhodiosin (8). Quantification of these compounds was performed by high-performance liquid chromatography (HPLC). To investigate the antioxidant and anti-inflammatory effects of the compounds, DPPH radical scavenging, NBT superoxide scavenging and nitric oxide production inhibitory activities were examined in LPS-stimulated Raw 264.7 cells. We suggest that the major active components of RRS are herbacetin glycosides, exhibiting antioxidant activity, and kaempferol, exhibiting anti-inflammatory activity.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Antioxidants/pharmacology , Phenols/pharmacology , Plant Extracts/chemistry , Plant Extracts/pharmacology , Plant Roots/chemistry , Rhodiola/chemistry , Biphenyl Compounds/antagonists & inhibitors , Cell Line , Cell Survival/drug effects , Humans , Nitric Oxide/biosynthesis , Picrates/antagonists & inhibitors , Superoxides/antagonists & inhibitorsABSTRACT
Bambusae Caulis in Liquamen (BCL) is the distilled product of the condensation from the burning of Phyllostachys nigra var. henosis (Gramineae). The activity-guided isolation of BCL yielded four phenolic compounds: 2,6-dimethoxyphenol (1), 1,2-dihydroxybenzene (2), 1,3-dihydroxybenzene (3) and 1,2-dibenzenecarboxylic acid (4). We evaluated the anti-oxidative, anti-inflammatory and whitening effects of these compounds, via assays, of 1,1-diphenyl-2-picrylhydazyl (DPPH) radical scavenging activity and inhibition of nitric oxide (NO) production in lipopolysaccharide-stimulated RAW 264.7 macrophage cells as well as inhibition of tyrosinase activity and melanin production in B16F10 melanoma cells. The results showed that 2 and 3 exhibited significant DPPH radical scavenging activity as well as inhibitory effects on NO production, tyrosinase activity and melanin production. These results suggested that BCL and compounds 2 and 3 can be developed as anti-oxidative, anti-inflammatory and whitening ingredients.
Subject(s)
Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Antioxidants/chemistry , Antioxidants/pharmacology , Phenols/chemistry , Phenols/pharmacology , Plant Extracts/chemistry , Plant Extracts/pharmacology , Animals , Biphenyl Compounds/chemistry , Cell Line , Free Radical Scavengers/chemistry , Free Radical Scavengers/pharmacology , Lipopolysaccharides/pharmacology , Macrophages/drug effects , Macrophages/metabolism , Melanins/metabolism , Monophenol Monooxygenase/metabolism , Nitric Oxide/metabolism , Picrates/chemistry , Poaceae/chemistryABSTRACT
The roots of Ulmus macrocarpa Hance (Ulmaceae) have been used as an oriental traditional medicine for the treatment of inflammation, ulcers, cancers, and parasites. Activity guided isolation from the roots of U. macrocarpa yielded three flavonoids [catechin 7-O-ß-D-apiofuranoside (1), (+)-catechin (2), taxifolin 6-C-glucopyranoside (3)], and one coumarin [fraxin (4)]. To investigate the antioxidative and anti-inflammatory effects of these compounds, DPPH radical scavenging activity and inhibitory activity against nitric oxide (NO) production in LPS-stimulated RAW 264.7 cells were examined and the expression of inducible NO synthase (iNOS) and cyclooxidase-2 (COX-2) were measured by RT-PCR and Western Blotting in HaCaT cells. Compounds 1, 2, and 3 showed moderate antioxidative activities compared with L-ascorbic acid as a positive control. NO production was reduced and the expressions of iNOS and COX-2 and their mRNA were inhibited by the addition of samples (1-4). These results suggest that the phenolic compounds from the roots of U. macrocarpa might be developed as antioxidant and anti-inflammatory agents.