• Molecular & Cellular Toxicology
• /
• v.1 no.2
• /
• pp.73-77
• /
• 2005

Nickel is the one of potent environmental, the occupational pollutants and the classified human carcinogens. It is a serious hazard to human health, when the metal exposure. To prevent human diseases from the heavy metals, it is seemingly important that understanding of how nickel exerts their toxicity and carcinogenic effect at a molecular and a genomic level. The process of nickel absorption has been demonstrated as phagocytosis, iron channel and diffusion. Uptaked nickel has been suggested to induce carcinogenesis via two pathways, a direct DNA damaging pathway and an indirect DNA damaging pathway. The former was originated from the ability of metal to generate Reactive Oxygen Species (ROS) and the reactive intermediates to interact with DNA directly. Ni-generated ROS or Nickel itself, interacts with DNAs and histones to cause DNA damage and chromosomal abnormality. The latter was originated from an indirect DNA damage via inhibition of DNA repair, or condensation and methylation of DNA. Cells have ability to protect from the genotoxic stresses by changing gene expression. Microarray analysis of the cells treated with nickel or nickel compounds, show the specific altered gene expression profile. For example, HIF-I (Hypoxia-Inducible Factor I) and p53 were well known as transcription factors, which are upregulated in response to stress and activated by both soluble and insoluble nickel compounds. The induction of these important transcription factors exert potent selective pressure and leading to cell transformation. Genes of metallothionein and family of heat shock proteins which have been known to play role in protection and damage control, were also induced by nickel treatment. These gene expressions may give us a clue to understand of the carcinogenesis mechanism of nickel. Further discussions on molecular and genomic, are need in order to understand the specific mechanism of nickel toxicity and carcinogenicity.

• Asian Pacific Journal of Cancer Prevention
• /
• v.17 no.sup3
• /
• pp.257-261
• /
• 2016

Cancer causes cells to avoid death while being the second cause of death in the world itself. Damaged cells in the absence of apoptosis will increasingly amplify their inefficient genome. Of the two main apoptosis inducing pathways in cells, the first has p53 protein as the main initiating factor in the cascade. According to research results this protein s mutated in 50% of cancers and sointerest has cooncentrated on the second pathway that features death receptors. Among these receptors TRAIL1/DR5 is especially expressed in cancer cells. So targeting such receptors can initiate the apoptotic cascade in cells. Interestingly by substitution of activating ligands with antibodies as agonists, we could efficiently turn on the apoptosis pathway. First of all, three small peptides from the DR5 protein extracellular domain were synthesized and injected with two different kind of adjuvants (Fround and liposomal encapsulation) separately into mice at 15 day intervals. As a result, liposomal peptides induced the immune system more efficient than Frounds adjuvant and at the end point the antibodies which were obtained from liposomal peptide injection induced much more effective death. Liposomal formol could be used as an adjuvant in immunization utilizing small peptides. They carry, protect and deliver peptides very efficiently. In addition, small peptides of a certain size from the extracellular domain of DR5 proteins not only can induce immune system but also produce antibodies playing a remarkable anti-cancer roles against breast cancer cells (MCF-7).

• Preventive Nutrition and Food Science
• /
• v.12 no.4
• /
• pp.197-201
• /
• 2007

Genistein is an active component of legumes and other related food shown to be associated with prevention of degenerative diseases such as cancer through inducing signaling pathways. Treatment of genistein resulted in the induction of apoptosis in the cultured cancer cells. This induction of apoptosis was demonstrated by the Tunel assay in these cells. Unveiling the potential of genistein in cytotoxicity via apoptosis when it is treated with estrogen can predict the therapeutic capability of genistein in breast cancers in the presence of endogenous estrogen. We have found that apoptosis induced by genistein treatment in the presence of estrogen is agonistic or antagonistic depending on the concentrations and treatment periods applied in MCF-7 breast cancer cells. For the suppression of cell survival, 24 hr of treatment was required to induce a synergistic agonistic response between estrogen and genistein at low concentrations of genistein. After this period, the agonistic pattern of genistein to estrogen disappeared. The decrement of COX-2 expression in MCF-7 cells treated with genistein was accompanied with the activation of AMPK only at a high concentration of genistein. This association between AMPK activation and down-regulation of COX-2 by genistein was dampened in the presence of estrogen. It was also demonstrated that genistein and estrogen regulate cell survival and apoptosis by modulating p53 and caspase-3 in the opposite direction. These results suggest that genistein has the potential to control breast cancer development, and co-treatment with estrogen can cause agonistic or antagonistic action on breast cancer cell control.

• Bulletin of the Korean Chemical Society
• /
• v.21 no.9
• /
• pp.867-874
• /
• 2000

Two new azobenzene crown ether calix[4]arenes, 10 and 11, were synthesized by two pathways. In the first pathway,two ethoxy nitrobenzene groups were attached to t-butylcalix[4]arenes in a 1,3 position. Subsequent reduction ofthe nitrobenzene group s by metallic zinc in an alkaline solution afforded 10 and 11 in8% and 12%,respectively. In the second pathway,an azobenzene containing two glycolic units was prepared prior connect-ing to t-butylcalix[4]arenes. The yields from the second approach (5%, 8% for 10 and 11, respectively) were lower than those from the former approach. Single crystals of 10 suitable for X-ray crystallography was ob-tained by recrystallization in methanol.Both the X-ray structure and the 1H-NMR spectrum of 10 indicated that the stereoisomer of the azobenzene moiety was trans and the calixarene platform was in cone conformation. 1H NMR spectroscopy suggested that 10 underwent an observable cis-trans isomerization in CDCl3 under room light and upon UV irradiation with cis:trans ratios of 33:67 and 36:64,respectively. Compound 6 which was the precursor of 11showed fluxional behavior and was found to have mixed conformations ofcone and partial cone with a ratio of 47:53 at -30 $^{\circ}C.$ 1H NMR spectrum of 11 suggested that 11 was initially isolated as cis azobenzene with calix[4]arene in cone conformation and underwent conformational interconversion through calix[4]arene annulas in a similar fashion to 6 upon exposing to light. The complexation studies of 10 with picrate salts of Na+ and K+ using 1H NMR spectroscopysuggested that Na+ preferred to bind the cis form of 10 while K+ preferred to bind the trans form. The stereoisomer of the azobenzene unit in 11 changed partially from cis to trans upon complexing with K+.

• Molecules and Cells
• /
• v.42 no.4
• /
• pp.292-300
• /
• 2019

Immunometabolism, defined as the interaction of metabolic pathways with the immune system, influences the pathogenesis of metabolic diseases. Metformin and carbon monoxide (CO) are two pharmacological agents known to ameliorate metabolic disorders. There are notable similarities and differences in the reported effects of metformin and CO on immunometabolism. Metformin, an anti-diabetes drug, has positive effects on metabolism and can exert anti-inflammatory and anti-cancer effects via adenosine monophosphate-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms. CO, an endogenous product of heme oxygenase-1 (HO-1), can exert anti-inflammatory and antioxidant effects at low concentration. CO can confer cytoprotection in metabolic disorders and cancer via selective activation of the protein kinase R-like endoplasmic reticulum (ER) kinase (PERK) pathway. Both metformin and CO can induce mitochondrial stress to produce a mild elevation of mitochondrial ROS (mtROS) by distinct mechanisms. Metformin inhibits complex I of the mitochondrial electron transport chain (ETC), while CO inhibits ETC complex IV. Both metformin and CO can differentially induce several protein factors, including fibroblast growth factor 21 (FGF21) and sestrin2 (SESN2), which maintain metabolic homeostasis; nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of the antioxidant response; and REDD1, which exhibits an anticancer effect. However, metformin and CO regulate these effects via different pathways. Metformin stimulates p53- and AMPK-dependent pathways whereas CO can selectively trigger the PERK-dependent signaling pathway. Although further studies are needed to identify the mechanistic differences between metformin and CO, pharmacological application of these agents may represent useful strategies to ameliorate metabolic diseases associated with altered immunometabolism.

• Journal of Ginseng Research
• /
• v.48 no.1
• /
• pp.52-58
• /
• 2024

Background: Skeletal muscle denervation leads to motor neuron degeneration, which in turn reduces muscle fiber volumes. Recent studies have revealed that apoptosis plays a role in regulating denervation-associated pathologic muscle wasting. Korean red ginseng (KRG) has various biological activities and is currently widely consumed as a medicinal product worldwide. Among them, ginseng has protective effects against muscle atrophy in in vivo and in vitro. However, the effects of KRG on denervation-induced muscle damage have not been fully elucidated. Methods: We induced skeletal muscle atrophy in mice by dissecting the sciatic nerves, administered KRG, and then analyzed the muscles. KRG was administered to the mice once daily for 3 weeks at 100 and 400 mg/kg/day doses after operation. Results: KRG treatment significantly increased skeletal muscle weight and tibialis anterior (TA) muscle fiber volume in injured areas and reduced histological alterations in TA muscle. In addition, KRG treatment reduced denervation-induced apoptotic changes in TA muscle. KRG attenuated p53/Bax/cytochrome c/Caspase 3 signaling induced by nerve injury in a dose-dependent manner. Also, KRG decreases protein kinase B/mammalian target of rapamycin pathway, reducing restorative myogenesis. Conclusion: Thus, KRG has potential protective role against denervation-induced muscle atrophy. The effect of KRG treatment was accompanied by reduced levels of mitochondria-associated apoptosis.

• Journal of Microbiology and Biotechnology
• /
• v.25 no.3
• /
• pp.413-417
• /
• 2015

Recently, we isolated HY253, a novel decahydrofluorene analog with a molecular structure of 7,8a-divinyl-2,4a,4b,5,6,7,8,8a,9,9a-decahydro-1H-fluorene-2,4a,4b,9a-tetraol from the roots of Aralia continentalis, which is known as Dokwhal (獨活), a traditional medicinal herb. Moreover, we previously reported its cytotoxic activity on cancer cell proliferation in human lung cancer A549 and cervical cancer HeLa cells. The current study aimed to evaluate its detailed molecular mechanisms in cell cycle arrest and apoptotic induction in human hepatocellular carcinoma HepG2 cells. Flow cytometric analysis of HepG2 cells treated with $60{\mu}M$ HY253 revealed appreciable cell cycle arrest at the G1 phase via inhibition of Rb phosphorylation and down-regulation of cyclin D1. Furthermore, using western blots, we found that up-regulation of cyclin-dependent kinase inhibitors, such as p21^CIP1 and p27^KIP1, was associated with this G₁ phase arrest. Moreover, TUNEL assay and immunoblottings revealed apoptotic induction in HepG2 cells treated with $60{\mu}M$ HY253 for 24 h, which is associated with cytochrome c release from mitochondria, via down-regulation of anti-apoptotic Bcl-2 protein, which in turn resulted in activation of caspase-9 and -3, and proteolytic cleavage of poly(ADP-ribose) polymerase (PARP). Accordingly, we suggest that HY253 may be a potent chemotherapeutic hit compound for treating human liver cancer cells via up-regulation and activation of the p53 gene.

• Journal of the Korean Society of Food Science and Nutrition
• /
• v.44 no.3
• /
• pp.338-346
• /
• 2015

This study was performed to elucidate the anti-proliferative and apoptotic mechanism of flavonoids in HT-29 human colon cancer cells. We investigated the anti-proliferative activity of flavonoids in HT-29 human colon cancer cells via cell viability assay (MTT assay), caspase-3 activity, RT-PCR, and western blotting. We cultured HT-29 cells in the presence of various flavonoids (apigenin, rutin, naringenin, and myricetin) at a concentration of $100{\mu}M$. In the MTT assay, naringenin showed the strongest effect on cell viability in HT-29 colon cancer cells. Caspase-3 activity, a marker of apoptosis, significantly increased upon naringenin treatment. For RT-PCR, myricetin significantly increased Bax protein levels, naringenin increased p53 protein levels, and rutin reduced expression of the anti-apoptotic protein Bcl-2. Western blotting of HT-29 colon cancer cells showed that myricetin increased cleaved caspase-3 protein levels, naringenin significantly increased poly (ADP-ribose) polymerase protein levels, and rutin increased E-cadherin protein levels. These results indicate that flavonoid exerts anticancer effects on human colon HT-29 cells through a caspase-dependent apoptotic pathway.

• Journal of Pharmacopuncture
• /
• v.17 no.2
• /
• pp.7-17
• /
• 2014

Objectives: Condurango is widely used in various systems of complementary and alternative medicines (CAM) against oesophageal and stomach ailments including certain types of cancer. However, until now no systematic study has been conducted to verify its efficacy and dose with proper experimental support. Therefore, we examined if ethanolic extract of Condurango could ameliorate benzo[a]pyrene (BaP)-induced lung cancer in rats, in vivo to validate its use as traditional medicine. Methods: Fifteen male and 15 female Sprague-Dawley (SD) rats were treated with 0.28 mg/kg of Sweet Bee Venom (SBV) (high-dosage group) and the same numbers of male and female SD rats were treated with 0.2 mL/kg of normal saline (control group) for 13 weeks. We selected five male and five female SD rats from the high-dosage group and the same numbers of male and female SD rats from the control group, and we observed these rats for four weeks. We conducted body-weight measurements, ophthalmic examinations, urinalyses and hematology, biochemistry, histology tests. Results: A histological study revealed gradual progress in lung tissue-repair activity in Condurango-fed cancer-bearing rats, showing gradual tissue recovery after three months of drug administration. Condurango has the capacity to generate reactive oxygen species (ROS), which may contribute to a reduction in anti-oxidative activity and to an induction of oxidative stress-mediated cancer cell-death. Condurango-activated pro-apoptotic genes (Bax, caspase-3, caspase-9, p53, cytochrome-c, apaf-1, ICAD and PARP) and down-regulated antiapoptotic-Bcl-2 expression were noted both at mRNA and protein levels. Studies on caspase-3 activation and PARP cleavage by western blot analysis revealed that Condurango induced apoptosis through a caspase-3-dependent pathway. Conclusion: The anticancer efficacy of an ethanolic extract of Condurango for treating BaP-induced lung cancer in rats lends support for its use in various traditional systems of medicine.

• Bulletin of the Korean Chemical Society
• /
• v.35 no.9
• /
• pp.2787-2790
• /
• 2014

Quercetin is a major dietary flavonoid found in onions, apples, tea, and red wine, and potentially has beneficial effects on disease prevention. We carried out this study to investigate the effect of quercetin on UVB-induced matrix metalloproteinase-1 (MMP-1) expression in human keratinocyte HaCaT cells and to further understand the mechanisms of its action. The anti-inflammatory activity of quercetin was investigated and quercetin significantly suppressed the NO production in LPS-stimulated RAW264.7 mouse macrophages. Post treatment of quercetin decreased UV irradiation-induced phosphorylation of JNK, p38 MAPK, and ERK by 91%, 21%, and 17%, respectively. MMP-1 is mainly responsible for the degradation of dermal collagen during the aging process of human skin and quercetin suppressed the UVB-induced MMP-1 by 94%. Binding studies revealed that quercetin binds to p38 with high binding affinity ($1.85{\times}10^6M^{-1}$). The binding model showed that the 4'-hydroxy groups of the B-ring of quercetin participated in hydrogen bonding interactions with the side chains of Lys53, Glu71, and Asp168 and the 5-hydroxy group of the A-ring formed a hydrogen bond with the backbone amide of Met109. The major finding of this study shows that quercetin inhibits phosphorylation of JNK, p38 MAPK, and ERK pathway leading to the prevention of MMP-1 expression in human keratinocyte HaCaT cells. Therefore, our findings suggested the potentials of quercetin as a skin anti-photoaging agent.