• Asian Pacific Journal of Cancer Prevention
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• v.16 no.15
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• pp.6317-6325
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• 2015

Ginkgo biloba extract (GBE) is a popular phytomedicine and has been used for disorders of the central nervous system, cardiovascular, renal, respiratory, and circulatory diseases. Although GBE is a complex mixture of over 300 compounds, its major components are 24% flavonoids and 6% terpene lactones. In this study, we tested the inhibitory effects of the three major flavonoids (kaempferol, quercetin, and isorhamnetin) from GBE, independently and as mixtures, on aromatase activity using JEG-3 cells (human placental cells) and recombinant proteins (human placental microsome). In both systems, kaempferol showed the strongest inhibitory effects among the three flavonoids; the flavanoid mixtures exerted increased inhibitory effects. The results of exon I.1-driven luciferase reporter gene assays supported the increased inhibitory effects of flavonoid mixtures, accompanied by suppression of estrogen biosynthesis. In the RT-PCR analysis, decreased patterns of aromatase promoter I.1 mRNA expressions were observed, which were similar to the aromatase inhibition patterns of flavonoids and their mixtures. The present study demonstrated that three flavonoids synergistically inhibit estrogen biosynthesis through aromatase inhibition, decrease CYP19 mRNA, and induce transcriptional suppression. Our results support the usefulness of flavonoids in adjuvant therapy for breast cancer by reducing estrogen levels with reduced adverse effects due to estrogen depletion.

• Journal of Sasang Constitutional Medicine
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• v.17 no.2
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• pp.64-73
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• 2005

1. Objectives The purpose of this study was to investigate the effects of the enzyme activity of Palmulgunja-tang with administered orally solution on cytochrome P450 isozyme 2. Methods This study was carried on through following methods. We treated the rat with the {3-naphthoflavone (${\beta}NF$) of 80mg/kg for 3 days i.p injection. Firstable, microsomal protein was separated and total intracellular protein test was done. Then GOT and GPT were measured and assay of cytochrome P450 IAI/2 enzyme activity was performed according to the method of EROD and MROD. (Ethoxyresorufin-O-deethylase(EROD) activity was used to measure cytochrome P450 lAI activity and methoxyresorufin O-demethylase(MROD) activity was used to measure cytochrome P450 lA2 activity. ) 3. Results and Conclusions 1) PGT recovered the liver damage on ${\beta}NF$ inducible CYP IAI/2 by pre-post and high-low condition. 2) At concentration of post-treated 50mg!kg of PGT, the inhibiting of $\betaNF$ metabolites to liver of rat cytochrome P450 lAl was inhibited by 53.0% respectively. 3) PGT showed 36.0% inhibition of ${\beta}NF$-induced lA2 activity at the concentration post-treated 50mg/kg.

• Mass Spectrometry Letters
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• v.9 no.1
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• pp.24-29
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• 2018

DC23, a triazolothione resorcinol analogue, is known to inhibit heat shock protein 90 and pyruvate dehydrogenase kinase which are up-regulated in cancer and diabetes, respectively. This study was performed to elucidate the metabolism of DC23 in human liver microsomes (HLMs). HLMs incubated with DC23 in the presence of uridine 5'-diphosphoglucuronic acid (UDPGA) and/or ${\beta}$-nicotinamide adenine dinucleotide phosphate (NADPH) resulted in the formation of four metabolites, M1-M4. M1 was identified as DC23-N-Oxide, on the basis of LC-MS/MS analysis. DC23 was further metabolized to its glucuronide conjugates (M2, M3, and M4). In vitro metabolic stability studies conducted with DC23 in HLMs revealed significant glucuronide conjugation with a $t_{1/2}$ value of 1.3 min. The inhibitory potency of DC23 on five human cytochrome P450s was also investigated in HLMs. In these experiments, DC23 inhibited CYP2C9-mediated tolbutamide hydroxylase activity with an $IC_{50}$ value of $8.7{\mu}M$, which could have implications for drug interactions.

• Molecular Medicine Reports
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• v.19 no.5
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• pp.3903-3911
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• 2019

Female sex steroid hormones, including estradiol (E2) and progesterone (P4), serve significant physiological roles in pregnancy. In particular, E2 and P4 influence placenta formation, maintain pregnancy and stimulate milk production. These hormones are produced by ovaries, adrenal glands and the placenta, of which the latter is a major endocrine organ during pregnancy. However, the mechanism of hormone production during pregnancy remains unclear. In the present study, the regulation of steroid hormones and steroidogenic enzymes was examined in human placenta according to gestational age. In human placental tissues, expression levels of steroidogenic enzymes were determined with reverse transcription-quantitative polymerase chain reaction and western blotting. The mRNA and protein expression of CYP17A1, HSD17B3 and CYP19A1, which are associated with the synthesis of dehydroepiandrosterone (DHEA) and E2, was elevated at different gestational ages in human placenta. In addition, to evaluate the correlation between serum and placental-produced hormones, steroid hormone levels, including pregnenolone (PG), DHEA, P4, testosterone (T) and E2, were examined in serum and placenta. Serum and placenta expression of DHEA and E2 increased with gestational age, whereas T and P4 were differently regulated in placenta and serum. To confirm the mechanism of steroidogenesis in vitro, placental BeWo cells were treated with E2 and P4, which are the most important hormones during pregnancy. The mRNA and protein expression of steroidogenic enzymes was significantly altered by E2 in vitro. These results demonstrated that concentration of steroid hormones was differently regulated by steroidogenic enzymes in the placenta depending on the type of the hormones, which may be critical to maintain pregnancy.

• Molecules and Cells
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• v.46 no.4
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• pp.245-255
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• 2023

This study aimed to exploring the pathophysiological mechanism of 7α,25-dihydroxycholesterol (7α,25-DHC) in osteoarthritis (OA) pathogenesis. 7α,25-DHC accelerated the proteoglycan loss in ex vivo organ-cultured articular cartilage explant. It was mediated by the decreasing extracellular matrix major components, including aggrecan and type II collagen, and the increasing expression and activation of degenerative enzymes, including matrix metalloproteinase (MMP)-3 and -13, in chondrocytes cultured with 7α,25-DHC. Furthermore, 7α,25-DHC promoted caspase-dependent chondrocyte death via extrinsic and intrinsic pathways of apoptosis. Moreover, 7α,25-DHC upregulated the expression of inflammatory factors, including inducible nitric oxide synthase, cyclooxygenase-2, nitric oxide, and prostaglandin E₂, via the production of reactive oxygen species via increase of oxidative stress in chondrocytes. In addition, 7α,25-DHC upregulated the expression of autophagy biomarkers, including beclin-1 and microtubule-associated protein 1A/1B-light chain 3 via the modulation of p53-Akt-mTOR axis in chondrocytes. The expression of CYP7B1, caspase-3, and beclin-1 was elevated in the degenerative articular cartilage of mouse knee joint with OA. Taken together, our findings suggest that 7α,25-DHC is a pathophysiological risk factor of OA pathogenesis that is mediated a chondrocyte death via oxiapoptophagy, which is a mixed mode of apoptosis, oxidative stress, and autophagy.

• Journal of Preventive Medicine and Public Health
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• v.39 no.2
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• pp.177-183
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• 2006

Objectives : In this study we examined the association between the genetic markers ACE (A-240T, C-93T, I/D, A2350G), AGT (M235T), AT1R (A1166C), CYP11B2 (T344C, V386A), REN (G2646A), ADRB2 (G46A, C79G, T47C, T1641), GNB3 (C825T) and ADD1 (G460W) and the presence of essential hypertension in adolescents. Methods : The Kangwha Study is an 18-year prospective study that is aimed at elucidating the determinants of the blood pressure level from childhood to early adulthood. For this study, we constructed a case-control dataset of size of 277 and 40 family trios data from the Kangwha Study. For this purpose, we perform a single locus-based case-control association study and a single locus-based TDT (transmission/disequilibrium test) study. Results : In the case-control study, the single locus-based association study indicated that the ADD1 (G460W) (p=0.0403), AGT (M235T) (p=0.0002), and REN (G2646A) (p=0.0101) markers were significantly associated with the risk of hypertension. These results were not confirmed on the TDT study. This study showed that genetic polymorphisms of the ADD1, AGT and REN genes might be related to the hypertension in Korean adolescents. Conclusions : This study provided useful information on genetics markers related to blood pressure. Further study will be needed to confirm the effect of the alpha adducin gene, the angiotensinogen gene and the renin gene on essential hypertension.

• Environmental Mutagens and Carcinogens
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• v.23 no.2
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• pp.56-62
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• 2003

The liver progenitor cells could form a potential target cell population fore both tumor-initiating and -promoting chemicals. Induction of drug-metabolizing and antioxidant enzymes, including AhR-dependent CYP1A1, NQO-1 and AKR1C9, was detected in the rat liver epithelial WB-F344 "stem-like" cells. Additionally, WB-F344 cells express a functional, wild-type form of p53 protein, a biomarker of genotoxic events, and connexin 43, a basic structural unit of gap junctions forming an important type of intercellular communication. In this cellular model, two complementary assays have been established for detection of the modes of action associated with tumor promotion: inhibition of gap junctional intercellular communication (GJIC) and proliferative activity in confluent cells. We found that the PAHs and PCBs, which are AhR agonists, released WB-F344 cells from contact inhibition, increasing both DNA synthesis and cell numbers. Genotoxic effects of some PAHs that lead to apoptosis and cell cycle delay might interfere with the proliferative activity of PAHs. Contrary to that, the nongenotoxic low-molecular-weight PAHs and non-dioxin-like PCB congeners, abundant in the environment, did not significantly affect cell cycle and cell proliferation; however both groups of compounds inhibited GJIC in WB-F344 cells. The release from contact inhibiton by a mechanism that possibly involves the AhR activation, inhibition of GJIC and genotoxic events induced by environmental contaminants are three important modes of action that could play an important role in carcinogenic effects of toxic compounds. The relative potencies to inhibit GJIC, to induce AhR-mediated activity, and to release cells from contact inhibition were determined for a large series of PAHs and PCBs and their metabolites. In vitro bioassays based on detection of events on cellular level (deregulation of GJIC and/or proliferation) or determination of receptor-mediated activities in both ?$stem-like^{\circ}{\times}$ and hepatocyte-like liver cellular models are valuable tools for detection of modes of action of polyaromatic hydrocarbons. They may serve, together with concentration data, as a first step in their risk assessment.

• Journal of Periodontal and Implant Science
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• v.53 no.1
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• pp.20-37
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• 2023

Purpose: Our pilot study showed that a 3-dimensional dual drug delivery scaffold (DDDS) loaded with Chinese herbs significantly increased the regenerated bone volume fraction. This study aimed to confirm the synergistic anti-inflammatory and osteogenic preclinical effects of this system. Methods: The targets and pathways of parthenolide and naringin were predicted. Three cell models were used to assess the anti-inflammatory effects of parthenolide and the osteogenic effects of naringin. First, the distance between the cementoenamel junction and alveolar bone crest (CEJ-ABC) and the bone mineral density (BMD) of surgical defects were measured in a rat model of periodontitis with periodontal fenestration defects. Additionally, the mRNA expression levels of matrix metallopeptidase 9 (MMP9) and alkaline phosphatase (ALP) were measured. Furthermore, the number of inflammatory cells and osteoclasts, as well as the protein expression levels of tumor necrosis factor-alpha (TNF-α) and levels of ALP were determined. Results: Target prediction suggested prostaglandin peroxidase synthase (PTGS2) as a potential target of parthenolide, while cytochrome P450 family 19 subfamily A1 (CYP19A1) and taste 2 receptor member 31 (TAS2R31) were potential targets of naringin. Parthenolide mainly targeted inflammation-related pathways, while naringin participated in steroid hormone synthesis and taste transduction. In vitro experiments revealed significant antiinflammatory effects of parthenolide on RAW264.7 cells, and significant osteogenic effects of naringin on bone marrow mesenchymal stem cells and MC3T3-E1 cells. DDDS loaded with parthenolide and naringin decreased the CEJ-ABC distance and increased BMD and ALP levels in a time-dependent manner. Inflammation was significantly alleviated after 14 days of DDDS treatment. Additionally, after 56 days, the DDDS group exhibited the highest BMD and ALP levels. Conclusions: DDDS loaded with parthenolide and naringin in a rat model achieved significant synergistic anti-inflammatory and osteogenic effects, providing powerful preclinical evidence.

• Journal of Nutrition and Health
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• v.27 no.4
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• pp.347-355
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• 1994

Indolo[3,2-b]carbazole(ICZ) is a potent Ah receptor agonist with biological activities similar in several respects to those of the potent environmental toxin, TCDD. ICZ is produced during the oilgomerization of indole-3-carbinol(I3C), a breakdown product of the glucobrassicin present in food plants of the Brassica genus. In the present study we examined ICZ levels in tissues and excreta of rats treated with I3C or dietary cabbage of established glucobrasicin content, and in feces of conventional and germfree rats fed on a basal diet, and of humans. We also examined the levels of cytochrome P4501A1 induction, as determined by the ethoxyresorufin ο-deethylase assay, in tissues of animals that received cabbage-supplemented diets, or which were treated with purified I3C or ICZ. Our findings indicated that incorporation of either homogenized or whole freeze-dried cabbage in the feed led to large increases(16-60 fold) in the levels of ICZ in the feces and lower gastrointestinal tract of rats. We observed that whereas ICZ is readily detectable at about the same levels(2.00$\pm$0.50 ppb) in the feces of conventional rats fed on a purified diet and in human feces, levels of ICZ in the feces of germfree animals fed on the basal diet were at the limits of detection(0.40$\pm$0.20 ppb), indication that gut bacteria are important for the production of ICZ from essential dietary constituents in the basal diet. We showed that in contrast to the near 7000-fold difference in CYP1A1 inducing potencies of ICZ and TCDD in cells in culture, their inducing potencies differ by only about an order of magnitude in rats. Nonetheless, the levels of ICZ remaining in livers twenty hours after I3C treatment appear too low to account for the induced activity. This result indicates that ICZ may be rapidly cleared from the liver or that substances other than, or in addition to, ICZ be responsible for the enzyme-inducing activity of orally administered I3C or its precursors.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.27 no.3
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• pp.214-220
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• 2001

The clinical application of the three-dimensional radiographic technique had been limited to standard Broadbent-Bolton cephalometer with biplanar stereoradiography. We developed a new method for compensating the error of head position in ordinary non-biplanar cephalostat. It became to possible to use the three dimensional cephalogram commonly in clinical bases. 1. The method of methemetical compensation of head positioning error in non-biplanar condition was evaluated with dry skull. The error of the method of first and the second trial was $0.46{\pm}1.21$, $0.33{\pm}0.90mm$, which means the error of the head positioning correction in conventional cephalogram was within clinical acceptance. 2. The reproducibility of this system for clinical application was 0.54 mm ($-2.99{\sim}2.26mm$) which defines the absolute mean difference of the first and second trial. Compare to the The landmark identification error $1.2{\pm}1.6mm$, the error of the measurement was within the range of landmark identification error. The result indicates the adequate clinical accuracy of the computation of three-dimensional coordinates by compensation of the error of the head position in ordinary non-biplanar cephalostat.