Publications by authors named "Sung Hee Cho"

51 Publications

Intrasubject Radiographic Progression of Hallux Valgus Deformity in Patients With and Without Metatarsus Adductus: Bilateral Asymmetric Hallux Valgus Deformity.

J Foot Ankle Surg 2021 Jun 11. Epub 2021 Jun 11.

Department of Mechanical Engineering, Korea Advanced Institute of Science and Technology, Daejon, Korea. Electronic address:

This study was to analyze intrasubject radiographic progression of the hallux valgus deformity by comparing the mildly and severely affected sides in patients with bilateral asymmetric hallux valgus in the whole group as well as the metatarsus adductus and the nonmetatarsus adductus subgroups. A total of 186 patients with bilateral asymmetrical hallux valgus deformity with a difference of 5° or greater in the hallux valgus angle were included, and 11 radiographic measurements were analyzed. The radiographic differences between the mildly and severely affected sides were compared. Correlation between the changes in the hallux valgus angle and those in other measurements was analyzed, and multiple regression analyses were performed. The anteroposterior talo-second metatarsal angle showed no significant difference between the mildly and severely affected sides. Changes in the intermetatarsal angle and sesamoid rotation angle were significantly associated with the progression of hallux valgus angle in the whole group as well as the nonmetatarsus adductus subgroup. Change in the intermetatarsal angle (p = .006) was the significant factor associated with the progression of hallux valgus angle in the metatarsus adductus subgroup. The anteroposterior talo-second metatarsal angle might be useful in evaluating the overall foot shape in the hallux valgus deformity. Progression of the hallux valgus deformity might be pathophysiologically different between those with and without metatarsus adductus.
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http://dx.doi.org/10.1053/j.jfas.2020.05.025DOI Listing
June 2021

Comparison of Bone Mineral Density and Markers of Bone Turnover in Osteoporotic Women after 6-Month Treatment with Alendronate or Bazedoxifene: A Randomized Controlled Trial.

J Bone Metab 2021 May 31;28(2):131-137. Epub 2021 May 31.

Department of Orthopedic Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.

Background: In a randomized controlled trial, we compared the bone mineral densities (BMDs) and blood markers of bone turnover during short-term treatment of osteoporotic women with bisphosphonate alendronate or bazedoxifene, a selective estrogen receptor modulator.

Methods: Ten and eleven patients were randomized to the alendronate and bazedoxifene groups, respectively. BMDs were measured before and after 6 months of treatment. Blood tests were used to measure the levels of osteocalcin (OC), C-terminal telopeptide of type I collagen (CTX), vitamin D3, and parathyroid hormone pretreatment and after 3 and 6 months of treatment. The variables were compared statistically.

Results: The alendronate group showed decreases in blood levels of both OC and CTX during the study period (P<0.001 and P=0.002, respectively), while the bazedoxifene group had a decrease only in OC levels (P=0.012). After 6 months of treatment, BMDs significantly increased in the alendronate group at multiple bone sites, including the L1-4 lumbar vertebrae, femur trochanter, and total femur. However, there was no significant increase in BMD in the bazedoxifene group. BMDs were not significantly different between the 2 groups.

Conclusions: Patients treated with alendronate showed more rapid suppression of markers of bone turnover and higher BMD than those treated with bazedoxifene during a short-term regime. Considering the effects and complications of each medication, the relationship between bone turnover rate and bone quality will need to be investigated in future studies.
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http://dx.doi.org/10.11005/jbm.2021.28.2.131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206607PMC
May 2021

Sex-specific Changes in Brain Estrogen Metabolism Induced by Acute Trimethyltin Exposure.

In Vivo 2021 Mar-Apr;35(2):793-797

Department of Pharmacology, School of Medicine, Eulji University, Daejeon, Republic of Korea;

Background/aim: In this study, we investigated sex-specific effects of acute exposure to trimethyltin, a known neurotoxicant on metabolic steroids.

Materials And Methods: We administered intraperitoneally 2.3 mg/kg trimethyltin to 4-week-old male mice and measured the levels of metabolic steroids 24 h after treatment. We also measured mRNA and protein levels of cytochrome P450 1B1 using real-time polymerase chain reaction and western blotting.

Results: Cortisol levels in the cortex increased in both sexes following acute trimethyltin exposure. The estradiol levels decreased, and the 4-hydroxyestradiol levels increased only in females. We also observed increased cytochrome P450 1B1 mRNA and protein levels only in the female cortex.

Conclusion: Acute trimethyltin exposure induces distinct sex-specific metabolic changes in the brain before significant sexual maturation.
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http://dx.doi.org/10.21873/invivo.12319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045079PMC
June 2021

Neurochemical Effects of 4-(2Chloro-4-Fluorobenzyl)-3-(2-Thienyl)-1,2,4-Oxadiazol-5(4H)-One in the Pentylenetetrazole (PTZ)-Induced Epileptic Seizure Zebrafish Model.

Int J Mol Sci 2021 Jan 28;22(3). Epub 2021 Jan 28.

Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea.

Epilepsy is one of the most common neurological disorders, and it is characterized by spontaneous seizures. In a previous study, we identified 4-(2-chloro-4-fluorobenzyl)-3-(2-thienyl)-1,2,4-oxadiazol-5(4H)-one (GM-90432) as a novel anti-epileptic agent in chemically- or genetically-induced epileptic zebrafish and mouse models. In this study, we investigated the anti-epileptic effects of GM-90432 through neurochemical profiling-based approach to understand the neuroprotective mechanism in a pentylenetetrazole (PTZ)-induced epileptic seizure zebrafish model. GM-90432 effectively improved PTZ-induced epileptic behaviors via upregulation of 5-hydroxytryptamine, 17-β-estradiol, dihydrotestosterone, progesterone, 5α -dihydroprogesterone, and allopregnanolone levels, and downregulation of normetanephrine, gamma-aminobutyric acid, and cortisol levels in brain tissue. GM-90432 also had a protective effect against PTZ-induced oxidative stress and zebrafish death, suggesting that it exhibits biphasic neuroprotective effects via scavenging of reactive oxygen species and anti-epileptic activities in a zebrafish model. In conclusion, our results suggest that neurochemical profiling study could be used to better understand of anti-epileptic mechanism of GM-90432, potentially leading to new drug discovery and development of anti-seizure agents.
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http://dx.doi.org/10.3390/ijms22031285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865321PMC
January 2021

Reproductive dysfunction linked to alteration of endocrine activities in zebrafish exposed to mono-(2-ethylhexyl) phthalate (MEHP).

Environ Pollut 2020 Oct 11;265(Pt B):114362. Epub 2020 Mar 11.

Chemical Analysis Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon, 34114, Republic of Korea. Electronic address:

This study aimed to investigate the effect of mono-(2-ethylhexyl) phthalate (MEHP), one of the major phthalate metabolites that are widespread in aquatic environments, on reproductive dysfunction, particularly on endocrine activity in adult male and female zebrafish. For 21 days, the zebrafish were exposed to test concentrations of MEHP (0, 2, 10, and 50 μg/mL) that were determined based on the effective concentrations (ECx) for zebrafish embryos. Exposure to 50 μg/mL MEHP in female zebrafish significantly decreased the number of ovulated eggs as well as the hepatic VTG mRNA abundance when those of the control group. Meanwhile, in female zebrafish, the biosynthetic concentrations of 17β-estradiol (E2) and the metabolic ratio of androgen to estrogen were remarkably increased in all MEHP exposed group compared with those in the control group, along with the elevated levels of cortisol. However, no significant difference was observed between these parameters in male zebrafishes. Therefore, exposure to MEHP causes reproductive dysfunction in female zebrafishes and this phenomenon can be attributed to the alteration in endocrine activities. Moreover, the reproductive dysfunction in MEHP-exposed female zebrafishes may be closely associated with stress responses, such as elevated cortisol levels. To further understand the effect of MEHP on the reproductive activities of fish, follow-up studies are required to determine the interactions between endocrine activities and stress responses. Overall, this study provides a response biomarker for assessing reproductive toxicity of endocrine disruptors that can serve as a methodological approach for an alternative to chronic toxicity testing.
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http://dx.doi.org/10.1016/j.envpol.2020.114362DOI Listing
October 2020

Biomechanical comparison of single-bundle versus double-bundle anterior cruciate ligament reconstruction: a meta-analysis.

Knee Surg Relat Res 2020 Mar 12;32(1):14. Epub 2020 Mar 12.

Department of Orthopaedic Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, 15, Jinju-daero 816 beon-gil, Jinju-si, Gyeongsangnam-do, Republic of Korea, 660-751.

Background: Of the many issues regarding surgical techniques related to anterior cruciate ligament reconstruction (ACLR), single-bundle (SB) or double-bundle (DB) ACLR is one of the most debated topics. However, it is unclear which of the techniques yields better outcomes after ACLR for ACL injury. The purpose of this meta-analysis was to compare the benefits of SB versus DB ACLR in terms of biomechanical outcomes.

Methods: The electronic databases MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and Scopus were searched for relevant articles comparing the outcomes of SB-ACLR versus DB-ACLR that were published until November 2019.

Results: Seventeen biomechanical studies were included. The anterior laxity measured using the anterior drawer test showed significantly better results in DB-ACLR when compared with SB-ACLR. In addition, outcomes of the anterior tibial translation test under a simulated pivot shift presented with better results at low flexion and 30° in DB-ACLR, compared with SB-ACLR. However, there were no significant biomechanical differences between the groups in internal rotation.

Conclusions: The present study demonstrated that both techniques for ACLR are associated with restoration of normal knee kinematics. DB-ACLR is superior to SB-ACLR in terms of restoration of anteroposterior stability. However, which technique yields better improvement in internal rotation laxity, and internal rotation laxity under a simulated pivot shift at a specific angle, remains unclear.

Level Of Evidence: This is a level II meta-analysis.
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http://dx.doi.org/10.1186/s43019-020-00033-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219200PMC
March 2020

Acute Valproate Exposure Induces Sex-Specific Changes in Steroid Hormone Metabolism in the Cerebral Cortex of Juvenile Mice.

Neurochem Res 2020 Sep 29;45(9):2044-2051. Epub 2020 Jun 29.

Department of Pharmacology, School of Medicine, Eulji University, 77, Gyeryong- ro 771 beon-gil, Jung-gu, Daejeon, 34824, Republic of Korea.

Valproic acid (VPA), an antiepileptic and mood stabilizer, modulates neurotransmission and gene expression by inhibiting histone deacetylase activity. It is reported that VPA may affects the steroid hormone level. In this study, VPA-induced acute metabolic alterations were investigated using liquid chromatography-tandem mass spectrometry in prepubertal mice brain. In VPA-treated (400 mg/kg in saline solution, intraperitoneal) mice, cortisol levels were increased (female: P < 0.004, male: P < 0.003) and 17β-estradiol levels were decreased (Both P < 0.03). Furthermore, in the VPA-treated male mice, dihydrotestosterone levels were increased (P < 0.02) and testosterone were decreased (P < 0.002). The 4-hydroxylase activity was upregulated in the female VPA-treated mice (P < 0.01) and the 5α-reductase activity was increased in the male VPA-treated mice (P < 0.003). These results indicate sex specific differences in VPA-induced steroid metabolism in the brain cortex.
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http://dx.doi.org/10.1007/s11064-020-03065-4DOI Listing
September 2020

Development and validation of an LC-MS/MS method for profiling 39 urinary steroids (estrogens, androgens, corticoids, and progestins).

Biomed Chromatogr 2020 Feb 10;34(2):e4723. Epub 2019 Dec 10.

Center for Chemical Analysis, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Republic of Korea.

Abnormal production or metabolism of steroid hormones is responsible for the development of endocrine diseases. Thus, accurate quantification of steroid hormones is needed for both research into clinical conditions and diagnostic and monitoring purposes. An improved analytical method for profiling 39 steroids in urine using LC-MS/MS was developed. As a pre-treatment procedure prior to LC-tandem mass spectrometry (LC-MS/MS) analysis, hydrolysis using β-glucuronidase and solid-phase extraction for purifying the samples were performed. Steroids were separated using Waters ACQUITY BEH C column (2.1 × 100 mm, 1.7 μm) and a mobile phase consisting of eluent A (0.01% formic acid and 1 mm ammonium formate in water) and eluent B (0.01% formic acid and 1 mm ammonium formate in methanol) with a gradient program at a flow rate of 0.4 mL/min. Under the optimized method, the linearity of calibration curves was higher than 0.992. The limits of detection at signal-to-noise ratio of 3 were 0.03-90 ng/mL. The developed novel LC-MS/MS method can quantitatively profile 39 steroids in a single analytical run. Steroid profiling based on quantitative results could improve the diagnosis and monitoring of hormone-dependent diseases.
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http://dx.doi.org/10.1002/bmc.4723DOI Listing
February 2020

Development of a liquid chromatography/tandem mass spectrometry method for monitoring of long-term exposure to parabens.

Rapid Commun Mass Spectrom 2019 Jan;33(1):67-73

Chemical Analysis Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon, 305-600, South Korea.

Rationale: Parabens, the alkyl esters of 4-hydroxybenzoic acid, are a family of compounds widely used as preservatives in cosmetic products, including for children, and some are permitted in foods. Parabens are known to be weak endocrine disruptors because they interfere with the function of endogenous hormones through binding to estrogen receptors. Therefore, the levels of parabens in biological samples indicate endocrine-disruptive exposure. In particular, hair samples can provide information on accumulated exposure to parabens.

Methods: For monitoring of long-term exposure to parabens, an improved analytical method for rapid and direct determination in hair sample was developed involving ultra-performance liquid chromatography-tandem mass spectrometry using on-line extraction. Five parabens (methyl-, ethyl-, propyl-, butyl- and benzylparaben) were separated within 10 min after incubation with 1 N HCl. Parabens were separated using a Waters BEH C column (2.1 mm × 100 mm, 1.7 μm) and a mobile phase consisting of 10 mM ammonium acetate in water and acetonitrile with a gradient program at a flow rate of 300 μL/min. The analysis of the separated parabens was monitored with electrospray negative ionization tandem mass spectrometry.

Results: The linearity of the method was demonstrated by r  ≥ 0.994. The limits of detection as defined by a signal-to-noise ratio of 3 were 1-5 ng/g. The mean concentration of the five parabens in hair of human subjects was measured to be 55.6 ± 24.3 to 136.9 ± 48.5 ng/g.

Conclusions: The levels of parabens in hair samples may play an important role in understanding probable endocrine-disruptive exposure, and the described method could be used to evaluate and monitor long-term exposure to parabens as endocrine disruptors.
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http://dx.doi.org/10.1002/rcm.8302DOI Listing
January 2019

A Comparison of Results after Anterior Cruciate Ligament Reconstruction in over 40 and under 40 Years of Age: A Meta-Analysis.

Knee Surg Relat Res 2018 Jun;30(2):95-106

Department of Orthopaedic Surgery, Institute of Health Sciences, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju, Korea.

Purpose: Anterior cruciate ligament (ACL) injury is one of the most common injuries that occur in the knee, and ACL reconstruction (ACLR) is commonly performed for preventing aggravation of degenerative changes and restoring of knee stability in young, athletic patients. This meta-analysis has a purpose of evaluating the clinical and arthrometrical outcomes of ACLR in a group of middle age patients (40 years and older) and comparing with patients under 40 years of age.

Methods: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Web of Science, and SCOPUS electronic databases were searched for relevant articles comparing the outcomes of ACLR between younger and older than 40 years of age until December 2016. Data searching, extraction, analysis, and quality assessment were performed based on the Cochrane Collaboration guidelines. Clinical outcomes were evaluated and compared between groups. The results were presented as mean difference for continuous outcomes with 95% confidence intervals whereas risk ratio for binary outcomes.

Results: Seven studies were included in the meta-analysis. Based on International Knee Documentation Committee classification, side-to-side difference, Tegner activity score, Lysholm knee score, there were no significant clinical and mechanical differences between the groups.

Conclusions: This meta-analysis confirmed that after ACLR, middle age (>40 years) and young age (<40 years) patients did not present with significant difference in clinical and arthrometric results.
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http://dx.doi.org/10.5792/ksrr.17.065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5990226PMC
June 2018

Effective professional intraoral tooth brushing instruction using the modified plaque score: a randomized clinical trial.

J Periodontal Implant Sci 2018 Feb 27;48(1):22-33. Epub 2018 Feb 27.

Department of Dentistry and Periodontology, Hanyang University College of Medicine, Seoul, Korea.

Purpose: The purpose of this study was to evaluate the efficacy of the modified plaque score (MPS) for assessing the oral hygiene status of periodontitis patients.

Methods: A total of 116 patients were included in this study. After evaluation of the Löe and Silness gingival index (GI), Silness and Löe plaque index (PlI), O'Leary plaque control record (PCR), and MPS, patients were randomly assigned to either a conventional tooth brushing instruction (C-TBI) group (n=56) or a professional intraoral tooth brushing instruction (P-TBI) group (n=60). The MPS and clinical parameters were re-evaluated after scaling and a series of root planing. The convergent validity of MPS with the PlI and PCR was assessed. The measurement time for MPS and PCR was compared according to the proficiency of the examiner.

Results: After root planing, the GI, PlI, PCR, and MPS improved from their respective baseline values in both groups. Three different plaque indices including the MPS, showed significant differences between the C-TBI group and the P-TBI group after root planing. The MPS showed significant concurrence with the PCR and PlI. The mean time for PCR measurement was 2.76±0.71 times longer than that for MPS measurement after 2 weeks of training.

Conclusions: MPS seems to be a practical plaque scoring system compared with the PlI and PCR. These findings suggest that repetitive plaque control combined with an easily applicable plaque index (MPS) may facilitate more effective oral hygiene education and improved periodontal health.
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http://dx.doi.org/10.5051/jpis.2018.48.1.22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841264PMC
February 2018

The determination of polycyclic aromatic hydrocarbons in human urine by high-resolution gas chromatography-mass spectrometry.

Biomed Chromatogr 2018 May 16;32(5):e4166. Epub 2018 Jan 16.

Center for Chemical Analysis, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon, Korea.

Polycyclic aromatic hydrocarbons (PAHs), organic compounds formed by at least two condensed aromatic rings, are ubiquitous environmental pollutants that are produced by incomplete combustion of organic materials. PAHs have been classified as carcinogenIC to humans by the International Agency for Research on Cancer, because they can bind to DNA, causing mutations. Therefore, the levels of PAHs in human urine can be used as an indicator for potential carcinogenesis and cell mutation. An analytical method was developed for the accurate measurement of PAHs in urine using high-resolution gas chromatography-mass spectrometry. Urine samples were extracted by an Oasis HLB extraction cartridge after enzymatic hydrolysis with a β-glucuronidase/arylsulfatase cocktail. The 18 PAHs were separated using an Agilent DB-5 MS capillary column (30 m × 0.25 mm, 0.25 μm) and monitored by time-of-flight mass spectrometry. Under the optimized method, the linearity of calibration curves was >0.994. The limits of detection at a signal-to-noise ratio of 3 were 10-100 ng/L. The coefficients of variation were in the range of 0.4-9.0%. The present method was highly accurate for simultaneous determination of 18 PAHs in human urine and could be applied to monitoring and biomedical investigations to check exposure of PAHs.
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http://dx.doi.org/10.1002/bmc.4166DOI Listing
May 2018

Simultaneous determination of bisphenol A and estrogens in hair samples by liquid chromatography-electrospray tandem mass spectrometry.

J Chromatogr B Analyt Technol Biomed Life Sci 2017 Jul 11;1058:8-13. Epub 2017 May 11.

Center for Chemical Analysis, Korea Research Institute of Chemical Technology (KRICT), Daejeon, 305-600, Republic of Korea. Electronic address:

Bisphenol A (BPA), an endocrine disrupter, is widely used to make chemicals for polycarbonate, plastics, beverage containers, epoxy resins, and cash register receipts. BPA is one of the known xenoestrogens, which have weak estrogenic activity and cause obesity, diabetes, breast cancer, and reproductive disorders. Even though the concentration level of metabolomes in hair is usually lower than that in urine and blood, there are several reasons why we chose to use hair samples. First, the sampling procedure of hairs is simple. Second, it is also easy to preserve the sample for long term and track the drug-exposure record of a given sample. Third, deformation and contamination of samples rarely occur. In this study, an improved analytical method to determine the levels of BPA and estrogens in hair samples was developed by liquid chromatography-electrospray tandem mass spectrometry (LC-ESI/MS/MS). Hair samples were extracted by an Oasis HLB extraction cartridge after incubation with 1N HCl and derivatized with dansyl chloride to increase sensitivity. BPA and estrogens (estrone, 17β-estradiol, and estriol) were separated using Shiseido CAPCELL PAK C column (2.0×100mm, 3μm) and a mobile phase consisting of 10mM ammonium acetate in water and acetonitrile with a gradient program at a flow rate of 0.3mL/min and were monitored with electrospray tandem mass spectrometry (ESI-MS/MS). The linearity of this method was over 0.995. The limits of detection (LOD) at a signal-to-noise (S/N) ratio of 3 were 0.25-6.0ng/g. The alteration of estrogens levels induced by BPA may play important role to understanding probable endocrine disruptive exposure, and the described methods could be used to evaluate and monitor exposure of endocrine disruptor.
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http://dx.doi.org/10.1016/j.jchromb.2017.05.007DOI Listing
July 2017

Simultaneous determination of volatile organic compounds with a wide range of polarities in urine by headspace solid-phase microextraction coupled to gas chromatography/mass spectrometry.

Rapid Commun Mass Spectrom 2017 Apr;31(7):613-622

Center for Chemical Analysis, Korea Research Institute of Chemical Technology (KRICT), Daejeon, 305-600, Korea.

Rationale: Volatile organic compounds (VOCs) are ubiquitous environmental pollutants that have a high vapor pressure at room temperature. Some VOCs have been classified as carcinogenic to humans by the International Agency for Research on Cancer (IARC), because they can bind to DNA and cause cell mutations. Therefore, monitoring of VOCs in human urine is very important to evaluate the correlation between exposure to VOCs and human disease.

Methods: We have developed an improved analytical method for the simultaneous determination of VOCs with a wide range of polarities in human urine samples by headspace solid-phase microextraction (HS-SPME) coupled to gas chromatography/mass spectrometry (GC/MS). In the improved method, a bi-polar carboxen-polydimethylsiloxane (CAR/PDMS) fiber was used for the optimized extraction of 15 VOCs with a wide range of polarities, including benzene, toluene, ethylbenzene, xylenes (BTEX), alkylbenzenes, cresols, and naphthalene, in human urine samples. Extracted VOCs from the human urine were effectively separated by GC using a mid-polarity column (DB-35, 35% phenylmethylpolysiloxane) and monitored by MS using extracted ion monitoring (EIM) mode.

Results: Under the optimized method, the linearity of the calibration curves was greater than 0.993. The limits of detection (LODs) at a signal-to-noise (S/N) ratio of 3 were 0.3-0.6 ng/mL. The coefficients of variation were in the range of 0.1-9.7% for within-day variation and 0.2-14.2% for day-to-day variation.

Conclusions: The method was shown to be rapid and simple for the simultaneous determination of VOCs with a wide range of polarities in human urine and it could be applied to monitoring and to biomedical investigations to check exposure to VOCs. Copyright © 2017 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/rcm.7827DOI Listing
April 2017

Targeting CD36-mediated inflammation reduces acute brain injury in transient, but not permanent, ischemic stroke.

CNS Neurosci Ther 2015 Apr 12;21(4):385-91. Epub 2014 Sep 12.

Burke-Cornell Medical Research Institute, White Plains, NY, USA; Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, USA.

Aims: The pathology of stroke consists of multiple pro-death processes, and CD36 has been suggested as a multimodal target to reduce oxidative stress and inflammation in ischemic stroke. Using CD36-deficient mice and SS-31, a cell permeable tetrapeptide known to down-regulate CD36 pathways, the current study investigated whether targeting CD36 is effective in transient and permanent ischemic stroke.

Methods: Wild-type or CD36-deficient mice were subjected to either 30-min transient or permanent focal ischemic stroke. In parallel, a cohort of mice subjected to either transient or permanent stroke received either vehicle or 5 mg/kg of SS-31. Monocyte chemoattractant protein-1 (MCP-1) and its receptor CCR2, mRNA levels, and infarct volume and percent hemispheric swelling were measured in the postischemic brain.

Results: CD36 deficiency or SS-31 treatment significantly attenuated MCP-1 or CCR2 mRNA up-regulation and injury size in the transient ischemic stroke. However, the approaches failed to show the protective effect in permanent ischemic stroke.

Conclusion: The study revealed that targeting CD36 has a beneficial effect on transient but not permanent focal ischemic stroke. The study thus precludes a generalized strategy targeting CD36 in ischemic stroke and suggests careful consideration of types of stroke and associated pathology in developing stroke therapies.
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http://dx.doi.org/10.1111/cns.12326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4362808PMC
April 2015

Effects of computerized physician order entry on medication turnaround time and orders requiring pharmacist intervention.

Res Social Adm Pharm 2014 Sep-Oct;10(5):756-67. Epub 2013 Dec 3.

College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul, South Korea. Electronic address:

Background: Previous studies have demonstrated that computerized physician order entry (CPOE) of prescriptions reduces both turnaround time (TAT) and medication errors. However, these studies have been performed primarily in large academic centers with a relatively small number of medication orders. As such, many studies investigating the impact of CPOE on the level of pharmacist intervention have yielded conflicting results.

Objective: The objective of this study was to examine the effects of CPOE on medication order TAT and the frequency of medication orders requiring pharmacist intervention in a community-based medical center.

Methods: A prospective cohort study was conducted at a community-based medical center. A total of 24,767 prescriptions written for 940 patients over a six-month period were stratified into CPOE or non-CPOE (handwritten) cohorts. TAT between cohorts were tested using analysis of variance and Tukey's Honestly Significant Difference test. The number of orders requiring pharmacist intervention was compared between cohorts and tested using chi-square test or Fisher's exact test. Medication orders requiring pharmacist intervention were stratified by patient characteristics, therapeutic class, and types of medication error.

Results: Medication orders not using CPOE were approximately 8 times more likely to require pharmacist intervention (2.26% versus 0.29%; P < 0.001), with the majority of pharmacist interventions performed to prevent medication errors. The overall mean TAT for medication orders was significantly shorter in the CPOE group in comparison with the non-CPOE group (22.2 ± 86.5 min versus 81 ± 256.7 min; P < 0.001). CPOE orders nearly eliminated medication errors with wrong dosage forms and formulary issues.

Conclusions: Medication orders entered via CPOE are associated with a significant reduction in medication TAT and less likely to require pharmacist intervention. Use of CPOE may improve quality of patient care and efficiency of health care delivery.
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http://dx.doi.org/10.1016/j.sapharm.2013.11.004DOI Listing
June 2015

In vivo roles of conjugation with glutathione and O6-alkylguanine DNA-alkyltransferase in the mutagenicity of the bis-electrophiles 1,2-dibromoethane and 1,2,3,4-diepoxybutane in mice.

Chem Res Toxicol 2013 Nov 6;26(11):1765-74. Epub 2013 Nov 6.

Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-0146, United States.

Several studies with bacteria and in vitro mammalian systems have provided evidence of the roles of two thiol-based conjugation systems, glutathione (GSH) transferase and O(6)-alkylguanine DNA-alkyltransferase (AGT), in the bioactivation of the bis-electrophiles 1,2-dibromoethane and 1,2,3,4-diepoxybutane (DEB), the latter an oxidation product of 1,3-butadiene. The in vivo relevance of these conjugation reactions to biological activity in mammals has not been addressed, particularly with DEB. In this work, we used transgenic Big Blue mice, utilizing the cII gene, to examine the effects of manipulation of conjugation pathways on liver mutations arising from dibromoethane and DEB in vivo. Treatment of the mice with butathionine sulfoxime (BSO) prior to dibromoethane lowered hepatic GSH levels, dibromoethane-GSH DNA adduct levels (N(7)-guanyl), and the cII mutation frequency. Administration of O(6)-benzylguanine (O(6)-BzGua), an inhibitor of AGT, did not change the mutation frequency. Depletion of GSH (BSO) and AGT (O(6)-BzGua) lowered the mutation frequency induced by DEB, and BSO lowered the levels of GSH-DEB N(7)-guanyl and N(6)-adenyl DNA adducts. Our results provide evidence that the GSH conjugation pathway is a major in vivo factor in dibromoethane genotoxicity; both GSH conjugation and AGT conjugation are major factors in the genotoxicity of DEB. The latter findings are considered to be relevant to the carcinogenicity of 1,3-butadiene.
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http://dx.doi.org/10.1021/tx4003534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3889014PMC
November 2013

Detection and characterization of 1,2-dibromoethane-derived DNA crosslinks formed with O(6) -alkylguanine-DNA alkyltransferase.

Angew Chem Int Ed Engl 2013 Dec 15;52(49):12879-82. Epub 2013 Oct 15.

Department of Biochemistry, Vanderbilt University School of Medicine, 638 RRB, 2220 Pierce Ave., Nashville, TN 37232 (USA).

A combination of chemical modifications and LC-tandem MS was used for the structure elucidation of various ethylene crosslinks of DNA with O(6) -alkylguanine-DNA alkyltransferase (AGT, see picture). The elucidation of the chemical structures of such DNA-protein crosslinks is necessary to understand mechanisms of mutagenesis.
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http://dx.doi.org/10.1002/anie.201307580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4048925PMC
December 2013

Replication past the butadiene diepoxide-derived DNA adduct S-[4-(N(6)-deoxyadenosinyl)-2,3-dihydroxybutyl]glutathione by DNA polymerases.

Chem Res Toxicol 2013 Jun 4;26(6):1005-13. Epub 2013 Jun 4.

Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.

1,2,3,4-Diepoxybutane (DEB), a metabolite of the carcinogen butadiene, has been shown to cause glutathione (GSH)-dependent base substitution mutations, especially A:T to G:C mutations in Salmonella typhimurium TA1535 [Cho, S. H., et al. (2010) Chem. Res. Toxicol. 23, 1544] and Escherichia coli TRG8 cells [Cho, S. H., and Guengerich, F. P. (2012) Chem. Res. Toxicol. 25, 1522]. We previously identified S-[4-(N(6)-deoxyadenosinyl)-2,3-dihydroxybutyl]GSH [N(6)dA-(OH)2butyl-GSH] as a major adduct in the reaction of S-(2-hydroxy-3,4-epoxybutyl)glutathione (DEB-GSH conjugate) with nucleosides and calf thymus DNA and in vivo in livers of mice and rats treated with DEB [Cho, S. H., and Guengerich, F. P. (2012) Chem. Res. Toxicol. 25, 706]. For investigation of the miscoding potential of the major DEB-GSH conjugate-derived DNA adduct [N(6)dA-(OH)2butyl-GSH] and the effect of GSH conjugation on replication of DEB, extension studies were performed in duplex DNA substrates containing the site-specifically incorporated N(6)dA-(OH)2butyl-GSH adduct, N(6)-(2,3,4-trihydroxybutyl)deoxyadenosine adduct (N(6)dA-butanetriol), or unmodified deoxyadenosine (dA) by human DNA polymerases (Pol) η, ι, and κ, bacteriophage polymerase T7, and Sulfolobus solfataricus polymerase Dpo4. Although dTTP incorporation was the most preferred addition opposite the N(6)dA-(OH)2butyl-GSH adduct, N(6)dA-butanetriol adduct, or unmodified dA for all polymerases, the dCTP misincorporation frequency opposite N(6)dA-(OH)2butyl-GSH was significantly higher than that opposite the N(6)dA-butanetriol adduct or unmodified dA with Pol κ or Pol T7. LC-MS/MS analysis of full-length primer extension products confirmed that Pol κ or Pol T7 incorporated the incorrect base C opposite the N(6)dA-(OH)2butyl-GSH lesion. These results indicate the relevance of GSH-containing adducts for the A:T to G:C mutations produced by DEB.
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http://dx.doi.org/10.1021/tx400145eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4049171PMC
June 2013

Ginsenoside Rh2 induces cell cycle arrest and differentiation in human leukemia cells by upregulating TGF-β expression.

Carcinogenesis 2013 Feb 3;34(2):331-40. Epub 2012 Nov 3.

Department of Pharmaceutical Biochemistry, School of Medicine, Kyung Hee University, Seoul 130–701, Republic of Korea.

The triterpene saponin ginsenoside Rh2 has been shown to have antiproliferative effects on various cancer cells. However, the effect of Rh2 on the cell cycle and its underlying molecular mechanism in human leukemia cells are not fully understood. In this study, we found that Rh2 inhibited the proliferation of human leukemia cells concentration- and time-dependently with an IC(50) of ~38 µM. DNA flow cytometric analysis indicated that Rh2 blocked cell cycle progression at the G(1) phase in HL-60 and U937 cells, and this was found to be accompanied by the downregulations of cyclin-dependent kinase (CDK) 4, CDK6, cyclin D1, cyclin D2, cyclin D3 and cyclin E at the protein level. However, CDK inhibitors (CDKIs), such as p21(CIP1/WAF1) and p27(KIP1), were gradually upregulated after Rh2 treatment at the protein and messenger RNA (mRNA) levels. In addition, Rh2 markedly enhanced the bindings of p21(CIP1/WAF1) and p27(KIP1) to CDK2, CDK4 and CDK6, and these bindings reduced CDK2, CDK4 and CDK6 activities. Furthermore, Rh2 induced the differentiation of HL-60 cells as demonstrated by biochemical assays and the expression levels of cell surface antigens. In addition, treatment of HL-60 cells with Rh2 significantly increased transforming growth factor-β (TGF-β) production, and cotreatment with TGF-β neutralizing antibody prevented the Rh2-induced downregulations of CDK4 and CDK6, upregulations of p21(CIP1/WAF1) and p27(KIP1) levels and the induction of differentiation. These results demonstrate that the Rh2-mediated G(1) arrest and the differentiation are closely linked to the regulation of TGF-β production in human leukemia cells.
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http://dx.doi.org/10.1093/carcin/bgs341DOI Listing
February 2013

Mutation spectra of S-(2-hydroxy-3,4-epoxybutyl)glutathione: comparison with 1,3-butadiene and its metabolites in the Escherichia coli rpoB gene.

Chem Res Toxicol 2012 Jul 15;25(7):1522-30. Epub 2012 Jun 15.

Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, 638 Robinson Research Building, 2200 Pierce Avenue, Nashville, TN 37232-0146, USA.

S-(2-Hydroxy-3,4-epoxybutyl)glutathione (DEB-GSH conjugate) is formed from the reaction of 1,2:3,4-diepoxybutane (DEB) with glutathione (GSH), and the conjugate is considerably more mutagenic than several other butadiene-derived epoxides-including DEB-in Salmonella typhimurium TA1535 [Cho, S.-H., (2010) Chem. Res. Toxicol. 23, 1544-1546]. We previously identified six DNA adducts in the reaction of the DEB-GSH conjugate with nucleosides and calf thymus DNA and two DNA adducts in livers of mice and rats treated with DEB [Cho, S.-H. and Guengerich, F. P. (2012) Chem. Res. Toxicol. 25, 706-712]. To define the role of GSH conjugation in 1,3-butadiene (BD) metabolism and characterize the mechanism of GSH transferase (GST)-enhanced mutagenicity of DEB, mutation spectra of BD and its metabolites in the absence and presence of GST/GSH and mouse liver microsomes were compared in the rpoB gene of Escherichia coli TRG8. The presence of GST considerably enhanced mutations. The mutation spectra derived from the DEB-GSH conjugate, the DEB/GST/GSH system, and the BD/mouse liver microsomes/GST/GSH system matched each other and were different from those derived from the other systems devoid of GSH. The major adducts in E. coli TRG8 cells treated with the DEB/GST/GSH system, the BD/mouse liver microsomes/GST/GSH system, or the DEB-GSH conjugate were S-[4-(N(7)-guanyl)-2,3-dihydroxybutyl]GSH, S-[4-(N(3)-adenyl)-2,3-dihydroxybutyl]GSH, and S-[4-(N(6)-deoxyadenosinyl)-2,3-dihydroxybutyl]GSH, indicating the presence of the GSH-containing DNA adducts in the systems. These results, along with the strong enhancement of mutagenicity by GST in this system, indicate the relevance of these GSH-containing DNA adducts.
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http://dx.doi.org/10.1021/tx3002109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3848527PMC
July 2012

Conjugation of butadiene diepoxide with glutathione yields DNA adducts in vitro and in vivo.

Chem Res Toxicol 2012 Mar 9;25(3):706-12. Epub 2012 Jan 9.

Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, 638 Robinson Research Building, 2200 Pierce Avenue, Nashville, Tennessee 37232-0146, USA.

1,2,3,4-Diepoxybutane (DEB) is reported to be the most potent mutagenic metabolite of 1,3-butadiene, an important industrial chemical and environmental pollutant. DEB is capable of inducing the formation of monoalkylated DNA adducts and DNA-DNA and DNA-protein cross-links. We previously reported that DEB forms a conjugate with glutathione (GSH) and that the conjugate is considerably more mutagenic than several other butadiene-derived epoxides, including DEB, in the base pair tester strain Salmonella typhimurium TA1535 [Cho et al. (2010) Chem. Res. Toxicol. 23, 1544-1546]. In the present study, we determined steady-state kinetic parameters of the conjugation of the three DEB stereoisomers-R,R, S,S, and meso (all formed by butadiene oxidation)-with GSH by six GSH transferases. Only small differences (<3-fold) were found in the catalytic efficiency of conjugate formation (k(cat)/K(m)) with all three DEB stereoisomers and the six GSH transferases. The three stereochemical DEB-GSH conjugates had similar mutagenicity. Six DNA adducts (N(3)-adenyl, N(6)-adenyl, N(7)-guanyl, N(1)-guanyl, N(4)-cytidyl, and N(3)-thymidyl) were identified in the reactions of DEB-GSH conjugate with nucleosides and calf thymus DNA using LC-MS and UV and NMR spectroscopy. N(6)-Adenyl and N(7)-guanyl GSH adducts were identified and quantitated in vivo in the livers of mice and rats treated with DEB ip. These results indicate that such DNA adducts are formed from the DEB-GSH conjugate, are mutagenic regardless of sterochemistry, and are therefore expected to contribute to the carcinogenicity of DEB.
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http://dx.doi.org/10.1021/tx200471xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3850785PMC
March 2012

Microsurgical repair of the inferior alveolar nerve: success rate and factors that adversely affect outcome.

J Oral Maxillofac Surg 2012 Aug 16;70(8):1978-90. Epub 2011 Dec 16.

Department of Oral and Maxillofacial Surgery, Northside Hospital, Atlanta, GA, USA.

Purpose: The objectives of this study were to determine the likelihood of regaining functional sensory recovery (FSR) after microsurgical repair of the inferior alveolar nerve (IAN), and which variables significantly affected the outcome of that surgery in a large series of patients.

Materials And Methods: This was a retrospective cohort study that evaluated all patients who had undergone microsurgical repair of the IAN by 1 of the senior surgeons (R.A.M.) from March 1986 through December 2005. The requirements for inclusion of a patient in the study included the availability of a complete chart record and a final follow-up visit at least 12 months after surgery. All other patients were excluded. The predictor variables were categorized as demographic, etiologic, and operative. The final outcome variable was the level of recovery of sensory function as determined by standardized neurosensory testing at the last postoperative visit of each patient and based on guidelines established by the Medical Research Council Scale. Risk factors for surgical failure to achieve useful sensory function were determined from analysis of descriptive statistics, including patient age, patient gender, etiology of nerve injury, chief sensory complaint (numbness, pain, or both), time from injury to surgical intervention (in months), intraoperative findings, and surgical procedure. Logistic regression methods and associated odds ratios were used to quantify the association between the risk factors and improvement. Receiver operator characteristic curve analysis was used to find the threshold of those variables that significantly affected patient outcome.

Results: In total, 167 patients (41 male and 126 female patients; mean age, 38.7 years [range, 15-75 years]) underwent 186 IAN repairs (19 patients sustained bilateral IAN injuries). The mean time from injury until surgery was 10.7 months (range, 0-72 months). Successful recovery from neurosensory dysfunction (FSR, defined by the Medical Research Council Scale as ranging from useful sensory function to complete sensory recovery) was observed in 152 repaired IANs (81.7%). With increasing duration from date of injury to IAN repair, the likelihood of FSR decreased (odds ratio, 0.898; P < .001). The odds of achieving FSR exhibited a linear decline between the date of nerve injury and its repair, with a significant drop in rate of successful outcome (FSR) occurring beginning at 12 months after injury. There was also a significant negative relationship between increasing patient age and improvement (odds ratio, 0.97; P = .015), with a threshold drop of achieving FSR at 51 years of age. The cause of the injury, the operative findings, and the type of operation performed to repair the nerve had no significant effect on the likelihood of the patient regaining FSR. The presence of pain after nerve injury did not affect the likelihood of achieving FSR after repair in a statistically significant manner (P = .08). In those patients who did not have pain as a major complaint before nerve repair, pain did not develop after microneurosurgery.

Conclusions: Microsurgical repair of an IAN injury resulted in successful restoration of an acceptable level of neurosensory function (FSR) in most patients (152 of 186 repairs [81.7%]) in this study. The likelihood of regaining FSR was inversely related to both time between the injury and its repair and increasing patient age, with significant threshold drops at 12 months after nerve injury and at 51 years of age, respectively.
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http://dx.doi.org/10.1016/j.joms.2011.08.030DOI Listing
August 2012

Study on the hypochlolesterolemic and antioxidative effects of tyramine derivatives from the root bark of Lycium chenese Miller.

Nutr Res Pract 2011 Oct 28;5(5):412-20. Epub 2011 Oct 28.

Department of Food Science and Nutrition, Catholic University of Daegu, 13-13 Hayang-ro, Hayang-eup, Gyeongsan-si, Gyeongbuk 712-702, Korea.

The aim of the present study was to investigate the hypocholesterolemic effect and potential of tyramine derivatives from Lycii Cortex Radicis (LCR), the root bark of lycium (Lycium chenese Miller) in reducing lipid peroxidation. The activities of enzymes, hepatic 3-hydroxy 3-methylglutaryl (HMG) CoA reductase and acyl-CoA:cholesterol acyltransferase (ACAT) and LDL oxidation were measured in vitro and animal experiments were also performed by feeding LCR extracts to rats. The test compounds employed for in vitro study were trans-N-p-coumaroyltyramine (CT) and trans-N-feruloyltyramine (FT), LCR components, N-(p-coumaroyl)serotonin (CS) and N-feruloylserotonin (FS) from safflower seeds, ferulic acid (FA) and 10-gingerol. It was observed that FT and FS at the concentration of 1.2 mg/mL inhibited liver microsomal HMG CoA reductase activity by ~40%, but no inhibition of activity was seen in the cases of CT, CS, FA and 10-gingerol. Whereas, ACAT activity was inhibited ~50% by FT and CT, 34-43% by FS and CS and ~80% by 10-gingerol at the concentration of 1 mg/mL. A significant delay in LDL oxidation was induced by CT, FT, and 10-gingerol. For the animal experiment, five groups of Sprague-Dawley male rats were fed high fat diets containing no test material (HF-control), 1 and 2% of LCR ethanol extract (LCR1 and LCR2), and 1% of extracts from safflower seed (Saf) and ginger (Gin). The results indicated that total cholesterol level was significantly lower in Saf, LCR2 and Gin groups, and HDL cholesterol level was lower only in Gin group when compared with HF-control group; while there was no difference in the serum triglyceride levels among the five experimental groups. The level of liver cholesterol was significantly lower in LCR1 and LCR2 groups than HF-control. Serum levels of TBARS were significantly lower only in LCR2 group when compared with HF-control group. From the observed results, we concluded that LCR can be utilized as a hypocholesterolemic ingredient in combination with ginger, especially for functional foods.
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http://dx.doi.org/10.4162/nrp.2011.5.5.412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3221826PMC
October 2011

Metabolic alteration of urinary steroids in pre- and post-menopausal women, and men with papillary thyroid carcinoma.

BMC Cancer 2011 Aug 8;11:342. Epub 2011 Aug 8.

Future Convergence Research Division, Korea Institute of Science and Technology, Seoul 136-791, Korea.

Background: To evaluate the metabolic changes in urinary steroids in pre- and post-menopausal women and men with papillary thyroid carcinoma (PTC).

Methods: Quantitative steroid profiling combined with gas chromatography-mass spectrometry was used to measure the urinary concentrations of 84 steroids in both pre- (n = 21, age: 36.95 ± 7.19 yr) and post-menopausal female (n = 19, age: 52.79 ± 7.66 yr), and male (n = 16, age: 41.88 ± 8.48 yr) patients with PTC. After comparing the quantitative data of the patients with their corresponding controls (pre-menopause women: n = 24, age: 33.21 ± 10.48 yr, post-menopause women: n = 16, age: 49.67 ± 8.94 yr, male: n = 20, age: 42.75 ± 4.22 yr), the levels of steroids in the patients were normalized to the mean concentration of the controls to exclude gender and menopausal variations.

Results: Many urinary steroids were up-regulated in all PTC patients compared to the controls. Among them, the levels of three active androgens, androstenedione, androstenediol and 16α-hydroxy DHEA, were significantly higher in the pre-menopausal women and men with PTC. The corticoid levels were increased slightly in the PTC men, while progestins were not altered in the post-menopausal PTC women. Estrogens were up-regulated in all PTC patients but 2-hydroxyestrone and 2-hydroxy-17β-estradiol were remarkably changed in both pre-menopausal women and men with PTC. For both menopausal and gender differences, the 2-hydroxylation, 4-hydroxylation, 2-methoxylation, and 4-methoxylation of estrogens and 16α-hydroxylation of DHEA were differentiated between pre- and post-menopausal PTC women (P < 0.001). In particular, the metabolic ratio of 2-hydroxyestrone to 2-hydroxy-17β-estradiol, which could reveal the enzyme activity of 17β-hydroxysteroid dehydrogenase, showed gender differences in PTC patients (P < 1 × 10-7).

Conclusions: These results are expected be helpful for better understanding the pathogenic differences in PTC according to gender and menopausal conditions.
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http://dx.doi.org/10.1186/1471-2407-11-342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3199870PMC
August 2011

Effects of a safflower tea supplement on antioxidative status and bone markers in postmenopausal women.

Nutr Res Pract 2011 Feb 28;5(1):20-7. Epub 2011 Feb 28.

Department of Food Science and Nutrition, Catholic University of Daegu, Geumnak-ro 5, Hayang-eup, Gyeongsan-si, Gyeongbuk 712-702, Korea.

We conducted this study to examine the effects of safflower seed granular tea containing physiologically active polyphenols on antioxidative activities and bone metabolism. Forty postmenopausal women ages 49 to 64-years were recruited from Daegu and Gyeongbuk and were randomly assigned to either a safflower tea supplement (Saf-tea) group (n = 27) or a placebo group (n = 13). The Saf-tea group received 20 g of safflower seed granule tea per day containing a 13% ethanol extract of defatted safflower seeds, whereas the placebo group received a similar type of tea that lacked the ethanol extract. No significant changes in nutrient intake for either the placebo or Saf-tea groups were observed before or after the study period, except vitamin A intake increased after 6 months in the Saf-tea group. Dietary phytoestrogen intakes were similar in the Saf-tea group (60.3 mg) and placebo group (52.5 mg). Significant increases in plasma genistein and enterolactone were observed in the Saf-tea group. After 6 months of supplementation, serum levels of antioxidant vitamins such as α-tocopherol and ascorbic acid increased significantly, and TBARS levels decreased in the Saf-tea group compared to the placebo group. Serum osteocalcin levels were reduced (P < 0.05) in the Saf-tea group after 6 months, whereas serum osteocalcin did not change in the placebo group. Urinary deoxypyridinoline/creatinine excretion was not different between the two groups at baseline, and did not change in either group after 6 months. Bone mineral density decreased significantly in the placebo group (P < 0.01) but not in the supplemented group. It was concluded that polyphenols (72 mg/day), including serotonin derivatives, in the Saf-tea had both antioxidant and potential bone protecting effects in postmenopausal women without liver toxicity.
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http://dx.doi.org/10.4162/nrp.2011.5.1.20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3061265PMC
February 2011

Mutagenicity of a glutathione conjugate of butadiene diepoxide.

Chem Res Toxicol 2010 Oct 29;23(10):1544-6. Epub 2010 Sep 29.

Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.

The mutagenicity and carcinogenicity of the important commodity chemical 1,3-butadiene are attributed to the epoxide products. We confirmed our previous work showing that expression of rat glutathione (GSH) transferase 5-5 enhances the mutagenicity of butadiene diepoxide in Salmonella typhimurium TA1535. A GSH-butadiene diepoxide conjugate was isolated and fully characterized by mass spectrometry and nuclear magnetic resonance as S-(2-hydroxy-3,4-epoxybutyl)GSH. The conjugate had a t(½) of 2.6 h (pH 7.4, 37 °C) and was considerably more mutagenic than butadiene diepoxide or monoepoxide in S. typhimurium. We propose that the GSH conjugate may be a major species involved in butadiene genotoxicity, not a detoxication product.
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http://dx.doi.org/10.1021/tx100304fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3848503PMC
October 2010

Metabolic alterations of DHEA and cholesterol sulphates in the hair of patients with acne measured by liquid chromatography-mass spectrometry.

Exp Dermatol 2010 Jul;19(7):694-6

As the hormonal levels in scalp hair reflects the condition of skin appendage, the level of dehydroepiandrosterone-3-sulphate (DHEAS) and cholesterol sulphate (CS) was evaluated in scalp hair obtained from patients with acne. The hair samples were extracted by alkaline solution and were analysed by liquid chromatography-mass spectrometry coupled to column switching system. The levels of DHEAS in scalp hair of women with acne were higher (P < 0.001) than controls, while the levels of CS in scalp hair of women and men with acne were higher (P < 0.001) than both control subjects. Increased hair levels of both DHEAS and CS could indicate acne development because of its direct action or stimulatory effect on local enzyme activity. It may be also helpful to understand the pathogenesis of acne based on follicular retention hyperkeratosis and increased sebum production of both steroid sulphates.
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http://dx.doi.org/10.1111/j.1600-0625.2010.01094.xDOI Listing
July 2010

Compound K, a metabolite of ginseng saponin, induces apoptosis via caspase-8-dependent pathway in HL-60 human leukemia cells.

BMC Cancer 2009 Dec 18;9:449. Epub 2009 Dec 18.

Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung-Hee University, Seoul 130-701, South Korea.

Background: Compound K [20-O-beta-(D-glucopyranosyl)-20(S)-protopanaxadiol], a metabolite of the protopanaxadiol-type saponins of Panax ginseng C.A. Meyer, has been reported to possess anti-tumor properties to inhibit angiogenesis and to induce tumor apoptosis. In the present study, we investigated the effect of Compound K on apoptosis and explored the underlying mechanisms involved in HL-60 human leukemia cells.

Methods: We examined the effect of Compound K on the viabilities of various cancer cell lines using MTT assays. DAPI assay, Annexin V and PI double staining, Western blot assay and immunoprecipitation were used to determine the effect of Compound K on the induction of apoptosis.

Results: Compound K was found to inhibit the viability of HL-60 cells in a dose- and time-dependent manner with an IC50 of 14 muM. Moreover, this cell death had typical features of apoptosis, that is, DNA fragmentation, DNA ladder formation, and the externalization of Annexin V targeted phosphatidylserine residues in HL-60 cells. In addition, compound-K induced a series of intracellular events associated with both the mitochondrial- and death receptor-dependent apoptotic pathways, namely, (1) the activation of caspases-3, -8, and -9; (2) the loss of mitochondrial membrane potential; (3) the release of cytochrome c and Smac/DIABLO to the cytosol; (4) the translocation of Bid and Bax to mitochondria; and (5) the downregulations of Bcl-2 and Bcl-xL. Furthermore, a caspase-8 inhibitor completely abolished caspase-3 activation, Bid cleavage, and subsequent DNA fragmentation by Compound K. Interestingly, the activation of caspase-3 and -8 and DNA fragmentation were significantly prevented in the presence of cycloheximide, suggesting that Compound K-induced apoptosis is dependent on de novo protein synthesis.

Conclusions: The results indicate that caspase-8 plays a key role in Compound K-stimulated apoptosis via the activation of caspase-3 directly or indirectly through Bid cleavage, cytochrome c release, and caspase-9 activation.
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http://dx.doi.org/10.1186/1471-2407-9-449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806409PMC
December 2009

Metabolomics study with gas chromatography-mass spectrometry for predicting valproic acid-induced hepatotoxicity and discovery of novel biomarkers in rat urine.

Int J Toxicol 2009 Sep-Oct;28(5):392-404. Epub 2009 Jul 15.

Bioanalysis and Biotransformation Research Center, Korea Institute of Science and Technology, Cheongryang, Seoul, South Korea.

Three different doses of valproic acid (20, 100, and 500 mg/kg/d) are administered orally to Sprague-Dawley rats for 5 days, and the feasibility of metabolomics with gas chromatography-mass spectrometry as a predictor of the hepatotoxicity of valproic acid is evaluated. Body weight is found to decrease with the 100-mg/kg/d dose and significantly decrease with the 500-mg/kg/d dose. Mean excreted urine volume is lowest in the 500-mg/kg/d group among all groups. The plasma level of alpha-glutathione-S-transferase, a sensitive and earlier biomarker for hepatotoxicity, increases significantly with administration of 100 and 500 mg/kg/d; however, there is not a significant difference in alpha-glutathione-S-transferase plasma levels between the control and 20-mg/kg/d groups. Clusters in partial least squares discriminant analysis score plots show similar patterns, with changes in physiological conditions and plasma levels of alpha-glutathione-S-transferase; the cluster for the control and 20-mg/kg/d groups does not clearly separate, but the clusters are separate for 100- and 500-mg/kg/d groups. A biomarker of hepatotoxicity, 8-hydroxy-2'-deoxyguanosine and octanoylcarnitine, is identified from nontargeted and targeted metabolic profiling. These results validate that metabolic profiling using gas chromatography-mass spectrometry could be a useful tool for finding novel biomarkers. Thus, a nontargeted metabolic profiling method is established to evaluate the hepatotoxicity of valproic acid and demonstrates proof-of-concept that metabolomic approach with gas chromatography-mass spectrometry has great potential for predicting valproic acid-induced hepatotoxicity and discovering novel biomarkers.
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http://dx.doi.org/10.1177/1091581809340329DOI Listing
March 2010
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