Ca2+-mediated reactive oxygen species signaling regulates cell repair after mechanical wounding in the red alga Griffithsia monilis.

Mechanical damage to a cell can be fatal, and the cell must reseal its membrane and restore homeostasis to survive. Plant cell repair involves additional steps such as rebuilding vacuoles, rearranging chloroplasts, and remodeling the cell wall. When we pierced a Griffithsia monilis cell with a glass needle, a large amount of intracellular contents was released, but the cell membrane resealed in less than a second. The turgor of the vacuole was quickly restored, and the punctured cell returned to its original shape within an hour. Organelles such as chloroplasts and nuclei migrated to the wound site for 12 h and then dispersed throughout the cell after the wound was covered by a new cell wall. Using fluorescent probes, high levels of reactive oxygen species (ROS) and calcium were detected at the wound site from 3 h after wounding, which disappeared when cell repair was complete. Wounding in a solution containing ROS scavengers inhibited cellular repair, and inhibiting nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity or blocking calcium influx reversibly inhibited cell repair. Oryzalin reversibly inhibited both chloroplast movement and ROS production during cell repair. Our results show that cell repair in G. monilis is regulated by calcium-mediated ROS signaling and that microtubules serve as mechanical effectors.

Evaluation of hormonal and circulating inflammatory biomarker profiles in the year following bariatric surgery.

Background: Bariatric surgery (BS) has a superior effect on reducing body weight and fat in patients with morbid obesity. As a result, BS mitigates obesity-related complications such as type 2 diabetes (T2D). However, few studies have shown the mechanism underlying diabetes remission after surgery. This study aimed to investigate the differences in serum hormone and inflammatory cytokine levels related to diabetes before surgery and during 12 months of follow-up in Korean patients with obesity. Methods: The study participants were patients with morbid obesity (n=63) who underwent sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB) between 2016 - 2017 at seven tertiary hospitals in Korea. The patients were followed for 1 year after surgery. Results: Sixty-three patients had significant weight loss after surgery and showed improvements in clinical parameters and hormonal and inflammatory profiles. Among them, 23 patients who were diabetic preoperatively showed different remission after surgery. The levels of inflammation-related clinical parameters changed significantly in the remission group, and serum inflammatory cytokine and hormones significantly decreased at certain points and showed an overall decreasing trend. Conclusions: Our study found postoperative changes of factors in blood samples, and the changes in hormones secreted from the three major metabolic tissue (pancreas, adipose, and gut) along with the differences in multi-origin inflammatory cytokines between remission and non-remission groups provide a path for understanding how the effect of BS in improving glucose metabolism is mediated.

Increased glutamate in type 2 diabetes in the Korean population is associated with increased plasminogen levels.

BACKGROUND: Glutamate is a major neurotransmitter, although it causes cytotoxicity and inflammation in nonneuronal organs. This study aimed to investigate the metabolic disorders in which glutamate, associated with type 2 diabetes onset, is induced in the liver. METHODS: An analysis of Korean community-based Ansan-Ansung cohort study data as well as functional research using in vitro and mouse models were performed. RESULTS: Groups with high plasma glutamate levels (T2, T3) had a significantly increased risk of diabetes incidence after 8 years, compared to the group with relatively low glutamate levels (T1). Analysis of the effect of glutamate on diabetes onset in vitro showed that glutamate induces insulin resistance by increasing glucose-related protein 78 (GRP78) and phosphoenolpyruvate carboxykinase (PEPCK) expression in SK-Hep-1 human liver cells. In addition, three different genes, FRMB4B, PLG, and PARD3, were significantly associated with glutamate and were identified via genome-wide association studies. Among glutamate-related genes, plasminogen (PLG) levels were most significantly increased in several environments in which insulin resistance was induced, and was also upregulated by glutamate. Glutamate-induced increase in PLG in liver cells was caused by metabotropic glutamate receptor 5 activation, and PLG levels were also upregulated after extracellular secretion. Moreover, glutamate increased the expression of plasminogen activator inhibitor-1 (PAI-1). Thus, extracellular secreted PLG cannot be converted to plasmin (fibrinolytic enzyme) by increased PAI-1. CONCLUSIONS: Increased glutamate is closely associated with the development of diabetes, and it may cause metabolic disorders by inhibiting the fibrinolytic system, which plays an important role in determining blood clots, a hallmark of diabetes.

The effect of the association between CETP variant type and alcohol consumption on cholesterol level differs according to the ALDH2 variant type.

Alcohol consumption is associated with a high increased lipid profile and this association may depend on genetic risk factors. In this study, we aimed to assess the effects of genetic variation associated with alcohol consumption on lipid profiles using data from two Korean population studies. We performed a genotype association study using the HEXA (n = 51,349) and KNHANES (n = 9158) data. Genotype analyses of the two sets of Korean population data showed associations of increased total cholesterol and high-density lipoprotein (HDL)-cholesterol with CETP rs708272. The HEXA and KNHANES populations revealed differences in HDL cholesterol according to the presence of CETP rs708272, independent of ALDH2 rs671 and alcohol consumption. In contrast, total cholesterol levels were associated with alcohol consumption and ALDH2 rs671 in men with CETP rs708272 (CT and TT genotypes). Furthermore, in drinkers with ALDH2 rs671 (GA and AA genotypes), higher total cholesterol was associated with the CETP rs708272 TT minor homozygous genotype based on both HEXA and KNHANES data. Our findings demonstrated that alcohol consumption and genetic variation in either CETP or ALDH2 may be associated with cholesterol levels. We hope these findings will provide a better understanding of the relationship between alcohol consumption and cholesterol according to each individual's genetic background.

Synergistic effect between the KCNQ1 haplotype and alcohol consumption on the development of type 2 diabetes mellitus in Korean cohorts.

Potassium voltage-gated channel subfamily Q member 1 (KCNQ1) is one of the strongest susceptibility genes for type 2 diabetes mellitus (T2DM). Association studies between KCNQ1 genetic variants and T2DM have been reported. The multifactorial disease T2DM is caused by interactions between genetic susceptibility and environmental factors. In this study, we examined the associations between the KCNQ1 haplotype, which consists of the major alleles rs3852528, rs11024175, and rs2237892 (ht: ACC), and environmental factors such as alcohol consumption, which are related to the risk of T2DM, in two independent Korean populations. Data from health examination studies, i.e., HEXA (n = 50,357 subjects) and the Ansung-Ansan community-based Korean cohort study (n = 7603), were analyzed. In both cohorts, fasting blood glucose levels were significantly increased in moderate-to-heavy drinkers and carriers of the homozygous ACC haplotype. A significant association between the KCNQ1 haplotype and alcohol consumption in the risk of diabetes was observed in the HEXA (OR 1.587; 95% CI 1.128-2.234) and Ansung-Ansan (OR 2.165; 95% CI 1.175-3.989) cohorts compared with abstainers not carrying the KCNQ1 haplotype. Associations of the KCNQ1 haplotype with alcohol consumption and ß-cell function were observed in the Ansung-Ansan cohort. Moderate-to-heavy drinkers with the ACC haplotype had lower fasting insulin levels and mean 60 min insulinogenic index (IGI60) compared with light drinkers and abstainers not carrying the ACC haplotype. These findings indicate that KCNQ1 variants play a synergistic role with alcohol consumption in the development of T2DM and impaired ß-cell function.

Association between KCNJ11 rs5219 variant and alcohol consumption on the effect of insulin secretion in a community-based Korean cohort: a 12-year follow-up study.

Chronic alcohol consumption is known to be associated with type 2 diabetes (T2D), which is developed by two underlying mechanisms, ß-cell dysfunction and insulin resistance. Identification of genetic variants in association with the development of T2D may help explain the genetic risk factors of T2D. In this study, we tried to find out some genetic variations, which interact with alcohol consumption and also are associated with ß-cell function through 12 year's follow-up study in Korean population. We performed a genotype association study using the community-based Ansung-Ansan Cohort data (baseline n = 3120; follow-up n = 433). Genotype association analyses of the baseline data showed that alcohol consumption is associated with the decreases of blood insulin levels and insulin secretion in participants with the KCNJ11 rs5219 risk allele. Moreover, multivariate logistic regression analyses revealed that the risk allele group is vulnerable to impairment of ß-cell function in response to alcohol consumption (OR 1.450; 95% CI 1.061-1.982). Furthermore, 12-year' follow-up results showed that alcohol consumption synergistically decreases insulin secretion in participants with KCNJ11 rs5219 risk alleles. Our findings demonstrate that the KCNJ11 rs5219 risk allele in combination with alcohol consumption could be a potential risk factor of ß-cell dysfunction. We hope that this new findings could be helpful to further understand the development of T2D depending on individual genetic background in association with alcohol consumption.

Physalin A regulates the Nrf2 pathway through ERK and p38 for induction of detoxifying enzymes.

BACKGROUND: Physalin A isolated from Physalis alkekengi var. franchetii has been known to have many pharmacological properties. However, its effect through the Nrf2 pathway has not yet been elucidated. In the present study, we determined the effects of physalin A on cancer chemoprevention via the Nrf2 pathway. METHODS: Experiments were performed in Hepa-1c1c7 and HepG2 cells. The quinone reductase (QR) activity assay was used to assess the activity of physalin A and other compounds isolated from P. alkekengi. The antioxidant response element (ARE) reporter assay was used to determine physalin A induced transcription of Nrf2 target genes, whereas the oligonucleotide pull-down assay was used to investigate Nrf2 binding to the AREs post physalin A treatment. Real-time PCR and western blotting were performed to determine the expression of Nrf2 target genes. Immunocytochemistry was used to determine Nrf2 localization after treatment with physalin A. Kinase inhibitors were used to test the involvement of Nrf2-targeting kinases and the role of ERK and p38 phosphorylation was confirmed using western blotting. RESULTS: Physalin A significantly induced QR activity. As an upstream effector of QR, Nrf2 induced genes containing the ARE, which encode various antioxidants and detoxification enzymes. We observed that physalin A increased the expression of Nrf2 and its target genes in HepG2 cells. Moreover, we observed that physalin A-induced Nrf2 activation was regulated by ERK and p38 kinase in HepG2 cells. CONCLUSIONS: Taken together, we showed that physalin A increased detoxifying enzyme expression via activation of Nrf2 and its target genes. These results imply that physalin A could be a potential chemopreventive agent for liver diseases, as well as cancer.

Exposure of kale root to NaCl and Na2SeO3 increases isothiocyanate levels and Nrf2 signalling without reducing plant root growth.

A plant factory is a closed cultivation system that provides a consistent and modified environment for plant growth. We speculated that treatment of kale (Brassica oleracea) grown in a plant factory with NaCl, Na2SeO3, or both would increase the bioactive phytochemical levels including glucosinolates (GLSs) and isothiocyanates (ITCs), the key molecules in cancer prevention. The kale was harvested and analysed after treatment with NaCl and Na2SeO3 alone or in combination for 1 or 2 weeks. Exposure to NaCl alone but not Na2SeO3 increased plant root growth. Levels of sinigrin were increased by a 2-week exposure to Na2SeO3 alone or in combination with NaCl, whereas no changes were observed in glucoraphanin and gluconasturtiin gluconasturtiin levels. Importantly, the ITC concentration was affected by 2-week treatment with both compounds. To evaluate the bioactivity of kale, HepG2 human hepatoma cells were treated with plant extract for 6 h. Only the extract of kale roots exposed to a combination NaCl and Na2SeO3 for 2 weeks showed an increased expression of nuclear factor erythroid 2-related factor (Nrf2), which regulates genes encoding antioxidant proteins. These data suggest that co-treatment with NaCl and Na2SeO3 increased the ITC content and chemopreventive effects of kale root.

Tussilagonone-induced Nrf2 pathway activation protects HepG2 cells from oxidative injury.

Tussilagonone is a compound derived from the medicinal plant Tussilago farfara L., which is used as a traditional medicine for respiratory diseases, including asthma and pneumonia. Recent reports suggest that tussilagonone exhibits anti-inflammatory effects; however, the scope of protective functions has not been elucidated yet. In this study, we demonstrate that tussilagonone enhances cellular detoxification by increasing quinone reductase activity in Hepa1c1c7 cells. In addition, tussilagonone decreased tert-butyl hydroperoxide(t-BHP)-induced ROS production and cell death, suggesting that it also acts as a potent antioxidant. To verify the molecular mechanism underlying tussilagonone activity, we examined the expression of nuclear factor erythroid 2-related factor 2(Nrf2)-a transcription factor that regulates antioxidant protein expression-in HepG2 cells. Significantly, these results showed that tussilagonone induces Nrf2 activation and nuclear accumulation, resulting in the upregulation of the detoxifying enzymes NAD(P)H quinone dehydrogenase 1(NQO1) and heme oxygenase-1(HO-1) that protect cells from oxidative stress. Further molecular analyses revealed that tussilagonone-induced Nrf2 activation was mediated by ERK1/2 in HepG2 cells. Collectively, these data indicate that tussilagonone attenuates t-BHP-induced ROS and activates quinone reductase activity via Nrf2 pathway activation and target gene expression, and thereby acts as an antioxidant that protects HepG2 cells from oxidative stress and associated damage.

Phenethyl isothiocyanate suppresses cancer stem cell properties in vitro and in a xenograft model.

BACKGROUND: Cancer stem cells (CSCs) are a subset of cells within the bulk of a tumor that have the ability to self-renew and differentiate, and are thus associated with cancer invasion, metastasis, and recurrence. Phenethyl isothiocyanate (PEITC) is a natural compound found in cruciferous vegetables such as broccoli and is used as a cancer chemopreventive agent; however, its effects on CSCs are little known. PURPOSE: To evaluate the effect of PEITC on CSCs in this study by examining CSC properties. METHODS: NCCIT human embryonic carcinoma cells were treated with PEITC, and the expression of pluripotency factors Oct4, Sox-2, and Nanog were evaluated by luciferase assay and western blot. Effect of PEITC on self-renewal capacity and clonogenicity were assessed with the sphere formation, soft agar assay, and clonogenic assay in an epithelial cell adhesion molecule (EpCAM)-expressing CSC model derived from HCT116 colon cancer cells using a cell sorting system. The effect of PEITC was also investigated in a mouse xenograft model obtained by injecting nude mice with EpCAM-expressing cells. RESULTS: We found that PEITC treatment suppressed expression of the all three pluripotency factors in the NCCIT cells, in which pluripotency factors are highly expressed. Moreover, PEITC suppressed the self-renewal capacity and clonogenicity in the EpCAM-expressing CSC model. EpCAM was used as a specific CSC marker in this study. Importantly, PEITC markedly suppressed both tumor growth and expression of three pluripotency factors in a mouse xenograft model. CONCLUSION: These results demonstrate that PEITC might be able to slow down or prevent cancer recurrence by suppressing CSC stemness.

Stellera chamaejasme and its constituents induce cutaneous wound healing and anti-inflammatory activities.

Stellera chamaejasme L. (Thymelaeaceae) is a perennial herb that is widely used in traditional Chinese medicine to treat tumours, tuberculosis and psoriasis. S. chamaejasme extract (SCE) possesses anti-inflammatory, analgesic and wound healing activities; however, the effect of S. chamaejasme and its active compounds on cutaneous wound healing has not been investigated. We assessed full-thickness wounds of Sprague-Dawley (SD) rats and topically applied SCE for 2 weeks. In vitro studies were performed using HaCaT keratinocytes, Hs68 dermal fibroblasts and RAW 264.7 macrophages to determine cell viability (MTT assay), cell migration, collagen expression, nitric oxide (NO) production, prostaglandin E2 (PGE2) production, inflammatory cytokine expression and ß-catenin activation. In vivo, wound size was reduced and epithelisation was improved in SCE-treated SD rats. In vitro, SCE and its active compounds induced keratinocyte migration by regulating the ß-catenin, extracellular signal-regulated kinase and Akt signalling pathways. Furthermore, SCE and its active compounds increased mRNA expression of type I and III collagen in Hs68 fibroblasts. SCE and chamechromone inhibited NO and PGE2 release and mRNA expression of inflammatory mediators in RAW 264.7 macrophages. SCE enhances the motility of HaCaT keratinocytes and improves cutaneous wound healing in SD rats.

Kretzschmaria quercicola sp. nov., an Undescribed Fungus from Living Oak in Mt. Daeryong, Korea.

We encountered an unfamiliar ascomycete fruiting body, fitting characteristics of the genus Kretzschmaria, which features in a stipitate ascigerous stroma with carbonaceous interior and disintegrating perithecia. In this study, we report and characterize a new species of the decaying fungus. Compared to other species, one of the notable features of this specimen (TPML150908-046) is its stromatal size (up to 15 cm). Although TPML150908-046 is morphologically similar to K. milleri and K. sandvicensis, it differs sharply from both species in apical ring size (TPML150908-046, 6.5~10.5 µm; K. milleri, 11~16 µm) and ascospore width (TPML150908-046, 10.5~17 µm; K. sandvicensis, 8.5~11.5 µm). Phylogenetic trees based on ß-tubulin, ITS, and RPB2 sequences showed that our collection clustered with K. sandvicensis, with the respective similarities for these sequences being 95.6%, 91.3%, and 97.7%, signifying it as another species. With these results, we report it as a new species, which we call Kretzschmaria quercicola sp. nov.

Identification of dialkyl diacetylene diols with potent cancer chemopreventive activity.

An increasing importance of chemoprevention for controlling cancer risks prompted the discovery of new active cancer chemopreventive agents. In this study, we designed and synthesized substituted hexa-2,4-diyne-1,6-diols, more structurally simplified, tunable, and easily preparable than natural gymnasterkoreaynes, and evaluated their cancer chemopreventive activities by measuring concentration of doubling quinone reductase activity (CD), cell viability, and chemopreventive index (CI). Most of the diols exhibited good CD activity and low cytotoxicity. In particular, tetradeca-5,7-diyne-4,9-diol and 2-methyltetradeca-5,7-diyne-4,9-diol showed the best cancer chemopreventive activity, approximately equipotent to that of sulforaphane. And, by synthesizing optically active stereoisomers of selected active compounds, the effect of stereochemistry was also studied. Eventually, we produced a chemopreventive compound for in vivo study.

Antimicrobial Air Filters Using Natural Euscaphis japonica Nanoparticles.

Controlling bioaerosols has become more important with increasing participation in indoor activities. Treatments using natural-product nanomaterials are a promising technique because of their relatively low toxicity compared to inorganic nanomaterials such as silver nanoparticles or carbon nanotubes. In this study, antimicrobial filters were fabricated from natural Euscaphis japonica nanoparticles, which were produced by nebulizing E. japonica extract. The coated filters were assessed in terms of pressure drop, antimicrobial activity, filtration efficiency, major chemical components, and cytotoxicity. Pressure drop and antimicrobial activity increased as a function of nanoparticle deposition time (590, 855, and 1150 µg/cm2(filter) at 3-, 6-, and 9-min depositions, respectively). In filter tests, the antimicrobial efficacy was greater against Staphylococcus epidermidis than Micrococcus luteus; ~61, ~73, and ~82% of M. luteus cells were inactivated on filters that had been coated for 3, 6, and 9 min, respectively, while the corresponding values were ~78, ~88, and ~94% with S. epidermidis. Although statistically significant differences in filtration performance were not observed between samples as a function of deposition time, the average filtration efficacy was slightly higher for S. epidermidis aerosols (~97%) than for M. luteus aerosols (~95%). High-performance liquid chromatography (HPLC) and electrospray ionization-tandem mass spectrometry (ESI/MS) analyses confirmed that the major chemical compounds in the E. japonica extract were 1(ß)-O-galloyl pedunculagin, quercetin-3-O-glucuronide, and kaempferol-3-O-glucoside. In vitro cytotoxicity and disk diffusion tests showed that E. japonica nanoparticles were less toxic and exhibited stronger antimicrobial activity toward some bacterial strains than a reference soluble nickel compound, which is classified as a human carcinogen. This study provides valuable information for the development of a bioaerosol control system that is environmental friendly and suitable for use in indoor environments.

Chikusetsusaponin IVa methyl ester induces cell cycle arrest by the inhibition of nuclear translocation of ß-catenin in HCT116 cells.

We demonstrate that chikusetsusaponin IVa methyl ester (CME), a triterpenoid saponin from the root of Achyranthes japonica, has an anticancer activity. We investigate its molecular mechanism in depth in HCT116 cells. CME reduces the amount of ß-catenin in nucleus and inhibits the binding of ß-catenin to specific DNA sequences (TCF binding elements, TBE) in target gene promoters. Thus, CME appears to decrease the expression of cell cycle regulatory proteins such as Cyclin D1, as a representative target for ß-catenin, as well as CDK2 and CDK4. As a result of the decrease of the cell cycle regulatory proteins, CME inhibits cell proliferation by arresting the cell cycle at the G0/G1 phase. Therefore, we suggest that CME as a novel Wnt/ß-catenin inhibitor can be a putative agent for the treatment of colorectal cancers.

Curcumin induces apoptotic cell death via Oct4 inhibition and GSK-3ß activation in NCCIT cells.

SCOPE: Octamer-binding transcription factor 4 (Oct4) is a key regulator of pluripotent embryonic stem cell maintenance. However, increasing evidence has suggested that Oct4 is also expressed in cancer stem cells (CSCs) and is associated with tumor progression and chemoresistance. Curcumin (CUR) is a widely used cancer chemopreventive agent, and it has been used to treat several diseases including cancers. Here, we investigated whether CUR-induced apoptotic cell death by inhibiting Oct4 levels and examining molecular mechanisms in NCCIT human embryonic carcinoma cells. METHODS AND RESULTS: CUR significantly inhibited Oct4 transcription levels in a dose-dependent manner by dual luciferase experiment, also decreased mRNA and protein levels in NCCIT human embryonic carcinoma cells, which express high levels of endogenous Oct4. Interestingly, we found that CUR treatment increased apoptotic cell death including subG0/G1 contents, cleavage caspases, and pro-apoptotic protein, as confirmed with a series of loss-of-function experiments using Oct4 siRNA. Furthermore, CUR induced marked total level of glycogen synthase kinase 3 beta (GSK-3ß), resulting in an increase in apoptotic cell death, was evaluated using chemical inhibitor of GSK3-3ß. CONCLUSION: These data suggest that CUR induces apoptotic cell death through Oct4 inhibition and GSK-3ß activation. Thus, CUR may be a useful cancer chemopreventive agent to suppress tumor progression or to improve chemoresistance by eliminating CSCs.

Crepidiastrum denticulatum extract protects the liver against chronic alcohol-induced damage and fat accumulation in rats.

Alcohol is a severe hepatotoxicant that causes liver abnormalities such as steatosis, cirrhosis, and hepatocarcinoma. Crepidiastrum denticulatum (CD) is a well-known, traditionally consumed vegetable in Korea, which was recently reported to have bioactive compounds with detoxification and antioxidant properties. In this study, we report the hepatoprotective effect of CD extract against chronic alcohol-induced liver damage in vivo. The rats that were given CD extract exhibited decreased alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transpeptidase activities, which are liver damage markers that are typically elevated by alcohol consumption. The results were confirmed by histopathology with hematoxylin and eosin staining. Chronic alcohol consumption induced the formation of alcoholic fatty liver. However, treatment with CD extract dramatically decreased the hepatic lipid droplets. Treatment with CD extract also restored the antioxidative capacity and lipid peroxidation of the liver that had been changed by alcohol consumption. Furthermore, treatment with CD extract normalized the activities of the antioxidative enzymes superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase, which had been decreased by alcohol consumption. The results indicate that CD extract has protective effects against chronic alcohol hepatotoxicity in rats by increasing the liver's antioxidant capacity, and has potential as a dietary supplement intervention for patients with alcohol-induced liver damage.

Bifunctional chemopreventive effects of Adenocaulon himalaicum through induction of detoxification enzymes and apoptosis.

Phase II detoxification enzymes are known to play essential roles in the detoxification and elimination of activated carcinogens during tumor initiation, while apoptosis is one of the most important chemopreventive targets for inhibiting tumor promotion in cancer. In this study, we investigated the cancer chemopreventive activity of two plant extracts, the ethanolic extract of Adenocaulon himalaicum (AHE) and the butanolic fraction of AHE (AHB). Both, the AHE and AHB induced NQO1 activity and had relatively high chemoprevention indices (CI=12.4). The AHE and AHB were associated with increased NQO1 and HO-1 mRNA levels via Nrf2-ARE pathway activation. In addition, the AHB increased CYP1A1 activity through AhR-XRE pathway activation. We also found that the AHE and AHB induced apoptosis, as evidenced by phosphatidylserine externalization, an increase in the sub-G0/G1 content, chromatin condensation, poly(ADP-ribose) polymerase cleavage, and p53 induction. These data suggest that AHE and AHB act as bifunctional inducers and that their chemopreventive effects result from the biphasic induction of phase II detoxification enzymes and apoptosis. Therefore, these results suggest that A. himalaicum plant extracts have potential for use as chemopreventive agents for the prevention and/or treatment of human cancers.

A novel topoisomerase inhibitor, daurinol, suppresses growth of HCT116 cells with low hematological toxicity compared to etoposide.

We report that daurinol, a novel arylnaphthalene lignan, is a promising potential anticancer agent with adverse effects that are less severe than those of etoposide, a clinical anticancer agent. Despite its potent antitumor activity, clinical use of etoposide is limited because of its adverse effects, including myelosuppression and the development of secondary leukemia. Here, we comprehensively compared the mechanistic differences between daurinol and etoposide because they have similar chemical structures. Etoposide, a topoisomerase II poison, is known to attenuate cancer cell proliferation through the inhibition of DNA synthesis. Etoposide treatment induces G(2)/M arrest, severe DNA damage, and the formation of giant nuclei in HCT116 cells. We hypothesized that the induction of DNA damage and nuclear enlargement due to abnormal chromosomal conditions could give rise to genomic instability in both tumor cells and in actively dividing normal cells, resulting in the toxic adverse effects of etoposide. We found that daurinol is a catalytic inhibitor of human topoisomerase IIa, and it induces S-phase arrest through the enhanced expression of cyclins E and A and by activation of the ATM/Chk/Cdc25A pathway in HCT116 cells. However, daurinol treatment did not cause DNA damage or nuclear enlargement in vitro. Finally, we confirmed the in vivo antitumor effects and adverse effects of daurinol and etoposide in nude mice xenograft models. Daurinol displayed potent antitumor effects without any significant loss of body weight or changes in hematological parameters, whereas etoposide treatment led to decreased body weight and white blood cell, red blood cell, and hemoglobin concentration.

Youngia denticulata protects against oxidative damage induced by tert-butylhydroperoxide in HepG2 cells.

Improvement of liver function is one of the most popular commercial health claims of functional foods in Asian countries, including Korea. After examining the potential of several traditional Korean wild vegetables for enhancing liver function, we found that Youngia denticulata Kitam. has strong hepatoprotective effects against oxidative stress induced by tert-butylhydroperoxide (t-BHP). We are the first to report that the extract and ethyl acetate fractions of Y. denticulata have radical scavenging activities and inhibit oxidative stress-induced cell death and DNA damage in HepG2 cells. The extract and ethyl acetate fractions significantly decreased cellular reactive oxygen species production and apoptosis induced by t-BHP in HepG2 cells. In addition, they prevented the depletion of cellular glutathione, which is an important defense molecule against oxidizing xenobiotics. Chlorogenic acid and 3,5-dicaffeoylquinic acid were found to be major active components responsible for the activity of Y. denticulata and could serve as marker compounds for standardization. These data suggest that Y. denticulata could be promoted as a potential antioxidative functional food candidate, particularly for hepatoprotection against oxidative stress.