The Presence of Urinary Ketones according to Metabolic Status and Obesity.

BACKGROUND: Recently, new concepts about obesity and normal weight subtypes with metabolic conditions are rising and ketone bodies are emerging as a significant indicator of metabolic health. This study aimed to find a relationship between ketonuria and those subtypes. METHODS: The data of 19,036 subjects were analyzed in this cross-sectional study (2013-2017 Korea National Health and Nutrition Examination Survey, KNHANES). Based on body mass index and adult treatment panel III with modification of waist circumference, individuals were categorized into 4 groups: metabolically healthy normal weight (MHNW), metabolically healthy obese (MHO), metabolically unhealthy normal weight (MUNW), and metabolically unhealthy obese (MUO). Individuals were divided into 2 groups, positive and negative ketonuria groups, and the metabolic parameters were compared. RESULTS: The metabolic indicators of the positive ketonuria group showed better results than those of the negative ketonuria group and the MHNW group showed the highest proportion of positive ketonuria. The MHNW group showed higher urinary ketones than the MUO group (odds ratio [OR], 0.391; 95% confidence interval [CI], 0.254-0.601) in men. In women, OR of having ketonuria was 0.698 (95% CI, 0.486-1.002) in the MHO group and 0.467 (95% CI, 0.226-0.966) in the MUNW group compared to the MHNW group, respectively. CONCLUSION: Compared to the MHNW group, the MUO group showed lower presence of ketonuria in men, and tendency to have less ketonuria in women.

A novel topoisomerase 2a inhibitor, cryptotanshinone, suppresses the growth of PC3 cells without apparent cytotoxicity.

DNA topoisomerase 2, which is ubiquitously expressed in eukaryotic cells, is an essential nuclear enzyme that promotes cell survival by regulating DNA topology and chromatid separation. This enzyme has been validated as a target for anticancer agent screening. It can be poisoned by common chemotherapeutics, such as etoposide and doxorubicin, which leads to the accumulation of cytotoxic enzyme-linked DNA double-stranded breaks. However, recent studies have suggested that the topoisomerase 2a isozyme is predominantly responsible for the carcinogenic side effects associated with etoposide and doxorubicin chemotherapy. Thus, we need to find a promising topoisomerase 2-targeting anticancer agent that avoids these carcinogenic side effects. Recent studies have found that cryptotanshinone has obvious anticancer activities against diverse cancer cells. Here, we demonstrate that cryptotanshinone markedly decreases the steady-state mRNA level of topoisomerase 2a, thereby decreasing the protein and activity levels of this enzyme. Moreover, cryptotanshinone exhibited dramatic in vitro and in vivo antitumor activity with low toxicity to normal tissues. Collectively, our findings support the development of cryptotanshinone as a promising candidate for treating cancer by targeting topoisomerase 2a.

Aberrant DNA methylation-induced gene inactivation is associated with the diagnosis and/or therapy of T-cell leukemias.

Aberrant hypermethylation of tumor suppressor genes is known to play an important role in the development of many tumors, and aberrant DNA hypermethylation was recently identified in hematologic malignancies, where it is thought to hold relevance in leukemogenesis. Here, we report that there are differences in the DNA methylation patterns seen in normal peripheral blood and two T-cell leukemia cell lines. We identify nine genes (CLEC4E, CR1, DBC1, EPO, HAL-DOA, IGF2, IL12B, ITGA1, and LMX1B) that are significantly hypermethylated in T-cell leukemias cell lines, and suggest that aberrant hypermethylation of these normally unmethylated genes may induce their transcriptional and expressional silencing. Furthermore, we observed that the expression levels of DNMT1 and DNMT3a were significantly decreased by 5-aza-2'-deoxycytidine (5-Aza-dC), which is a demethylation agent known to deplete DNA methyltransferases (DNMTs) in leukemia cancer cells and restore the expression levels of their target genes in Jurkat cells. This result suggests that the overexpression of DNMTs could contribute to the development of T-cell leukemias by inducing hypermethylation of the target genes. Together, our results show that aberrant hypermethylation is an important molecular mechanism in the progression of T-cell leukemias, and thus could prove useful as a prognostic and/or diagnostic marker. Moreover, 5-Aza-dC might be a promising candidate for the treatment of T-cell leukemia.

The Effect of Xanthigen on the Expression of Brown Adipose Tissue Assessed by ¹8F-FDG PET.

Brown adipose tissue (BAT) is related with energy expenditure, in contrary to fat-storing white adipose tissue. Recent studies have shown that cold exposure could be related with the expression of BAT in adult subjects assessed by ¹8F-fluorodeoxyglucose (FDG) positron emission tomography (PET). In addition, the application in previous clinical trials showed positive effect of xanthigen containing fucoxanthin and punicic acid on body weight and liver fat content. In this short-term intervention study, we evaluated the effect of xanthigen on the expression of BAT by ¹8F-FDG PET. Two healthy obese premenopausal women were enrolled and xanthigen 600 mg (2 capsules including fucoxanthin 3 mg, punicic acid 174 mg) was given for 3 months without dietary and exercise intervention. Body composition and dietary intake were assessed monthly. Laboratory test and ¹8F-FDG PET were performed before and after intervention. After intervention, there was neither weight reduction nor remarkable laboratory change. However, BAT, assessed by ¹8F-FDG PET, was detected in both cervical, supraclavicular and paravertebral space in one subject, even though her body weight showed mild increase. This result suggested that xanthigen can induce BAT in a healthy adult. However, a further large well-controlled study is needed.

Radioresistance in a human laryngeal squamous cell carcinoma cell line is associated with DNA methylation changes and topoisomerase II α.

Accumulating evidence suggests that changes in methylation patterns may help mediate the sensitivity or resistance of cancer cells to ionizing radiation. The present study provides evidence for the involvement of radioresistance-induced DNA methylation changes in tumor radioresistance. We established radioresistant laryngeal cancer cells via long-term fractionated irradiation, and examined differences in DNA methylation between control and radioresistant laryngeal cancer cells. Interestingly, we found that the promoter-CpG islands of 5 previously identified radioresistance-related genes (TOPO2A, PLXDC2, ETNK2, GFI1, and IL12B) were significantly altered in the radioresistant laryngeal cancer cells. Furthermore, the demethylation of these gene promoters with a DNA methyltransferase inhibitor (5-aza-2'-deoxycytidine) increased their transcription levels. Treatment with 5-aza-2'-deoxycytidine also sensitized the radioresistant laryngeal cancer cells to irradiation, indicating that changes in DNA methylation contributed to their radioresistance. Of the tested genes, the expression and activity levels of TOPO2A were tightly associated with the radioresistant phenotype in our system, suggesting that the hypermethylation of TOPO2A might be involved in this radioresistance. Collectively, our data suggest that radiation-induced epigenetic changes can modulate the radioresistance of laryngeal cancer cells, and thus may prove useful as prognostic indicators for radiotherapy.

Mitogen-activated protein kinase phosphatase-1 inhibition and sustained extracellular signal-regulated kinase 1/2 activation in camptothecin-induced human colon cancer cell death.

Camptothecins are commonly used chemotherapeutics; in some models, they enhance signaling via the mitogen-activated protein kinase (MAPK) pathway through effects on upstream kinases. To evaluate the impact of camptothecin (CPT) on MAPKs in human colon cancer, we studied HCT116 and CaCo2 colon cancer cells. We found that HCT116 cells highly express mitogen-activated protein kinase phosphatase-1 (MKP1), which selectively inactivates extracellular signal-regulated kinase (ERK), whereas MKP1 levels were undetectable in CaCo2 cells. CPT did not affect ERK activity in CaCo2 cells, but did induce a striking increase in ERK activity in HCT116 cells in association with a corresponding decrease in MKP1. The reduction in MKP1 expression occurred at a posttranscriptional level and was blocked by the proteasome inhibitor MG132, whereas that CPT-induced downregulation of MKP1 was not due to proteasome-mediated degradation. Treatment of HCT116 cells with CPT induced a sustained activation of nuclear ERK, which was required for CPT-induced apoptosis. P38 and JNK activity were unaffected by CPT, suggesting that the effects of CPT are mediated specifically by ERK. These results suggest that targeting dual-specificity MAPK phosphatases in colon cancer cells may be a viable strategy for optimizing camptothecin-based therapeutic protocols.

Different response of body weight change according to ketonuria after fasting in the healthy obese.

The relationship between obesity and ketonuria is not well-established. We conducted a retrospective observational study to evaluate whether their body weight reduction response differed by the presence of ketonuria after fasting in the healthy obese. We used the data of 42 subjects, who had medical records of initial urinalysis at routine health check-up and follow-up urinalysis in the out-patient clinic, one week later. All subjects in the initial urinalysis showed no ketonuria. However, according to the follow-up urinalysis after three subsequent meals fasts, the patients were divided into a non-ketonuria group and ketonuria group. We compared the data of conventional low-calorie diet programs for 3 months for both groups. Significantly greater reduction of body weight (-8.6 ± 3.6 kg vs -1.1 ± 2.2 kg, P < 0.001), body mass index (-3.16 ± 1.25 kg/m(2) vs -0.43 ± 0.86 kg/m(2), P < 0.001) and waist circumference (-6.92 ± 1.22 vs -2.32 ± 1.01, P < 0.001) was observed in the ketonuria group compared to the non-ketonuria group. Fat mass and lean body mass were also more reduced in the ketonuria group. In addition, serum free fatty acid concentration after intervention in the ketonuria group showed significant more increment than in the non-ketonuria group. The presence of ketonuria after fasting may be a predicting factor of further body weight reduction.

Changes of body weight and inflammatory markers after 12-week intervention trial: results of a double-blind, placebo-control pilot study.

PURPOSE: Low grade inflammation is a well-known characteristic in obese subjects. We investigated body weight changes and inflammatory markers after 12-week intervention trial. MATERIALS AND METHODS: Twenty-six obese subjects were enrolled and 19 (13 men and 6 women) completed the study. Sibutramine is an FDA-approved drug for body weight control; therefore, we chose this drug as the standard treatment medication in this study. Patients were randomly allocated to receive an anti-inflammatory agent (Diacerein treatment group; n = 12) or placebo (n = 7) for 12 weeks. Anthropometry, body proportion by dual-energy X-ray absorptiometry, and metabolic parameters at the beginning and end of study were measured and compared. RESULTS: The treatment group had a tendency towards more reduction in anthropometry as compared to the placebo group, in body weight reduction (-7.0 kg vs. -4.6 kg), body mass index (-2.51 kg/m² vs. -1.59 kg/m²), and waist circumference (-7.3 cm vs. -4.4 cm). These reductions were not statistically significant. Changes in levels of high-sensitivity C-reactive protein and adiponectin in the treatment group were more favorable than in the placebo group. CONCLUSION: This small pilot study showed no statistical difference for changes in anthropometry, and inflammatory markers between the two groups. Therefore, we could not find any additional effects of Diacerein on weight loss and inflammatory variables in this study.

Ketonuria after fasting may be related to the metabolic superiority.

Obese individuals are less able to oxidize fat than non-obese individuals. Caloric reduction or fasting can detect ketonuria. We investigated the differences of metabolic parameters in the presence of ketonuria after a minimum 8 hr fast in a cross-sectional analysis of 16,523 Koreans (6,512 women and 10,011 men). The relationship between the presence of ketonuria of all subjects and prevalence of obesity, central obesity, metabolic syndrome, and obesity-related metabolic parameters were assessed. The ketonuria group had lower prevalence of obesity, central obesity, and metabolic syndrome than the non-ketonuria group. In addition, all metabolic parameters (including body weight, waist circumference, blood glucose, high-density lipoprotein, triglyceride, blood pressure, and insulin) were favorable in the ketonuria group than in the non-ketonuria group, even after adjustment for age, tobacco use, and alcohol consumption. The odds ratios of having obesity (odds ratio [OR]=1.427 in women, OR=1.582 in men, P<0.05), central obesity (OR=1.675 in women, OR=1.889 in men, P<0.05), and metabolic syndrome (OR=3.505 in women, OR=1.356 in men, P<0.05) were increased in the non-ketonuria group compared to the ketonuria group. The presence of ketonuria after at least an 8 hr fast may be indicative of metabolic superiority.

Correlation of undercarboxylated osteocalcin (ucOC) concentration and bone density with age in healthy Korean women.

Uncarboxylated osteocalcin (ucOC) is important in evaluating vitamin K status and it is inversely associated with bone mineral density (BMD). We studied the correlationship between ucOC and BMD in healthy Korean women. This study recruited 337 healthy women between ages 20-70 were recruited. Serum ucOC, calcium, alkaline phosphatase, body mass index (BMI), and BMD were measured and compared. Mean BMI was lowest (20.3+/-1.9 kg/m(2)) in the 20 yr old group and highest (24.8+/-2.6 kg/m(2)) in the 60 yr old group. Women age 20-70 yr old had ucOC inversely related to BMD independent of other factors that may influence BMD. Serum ucOC concentration and BMD of lumbar spine showed a significant inverse relationship. Serum mean alkaline phosphatase was lowest (122+/-30 IU/L) in the age 30 group and highest (190.3+/-55.8 IU/L) in the age 60 group. Serum ucOC was inversely associated with BMI, and positively associated with alkaline phosphatase. Uncarboxylated osteocalcin (ucOC) was inversely associated with spinal BMD in healthy Korean women. Serum mean ucOC was highest in the age 20 group, followed by age 50 group, which may indicate vitamin K insufficiency could be related to high bone turnover in these groups. These results suggest that vitamin K supplement may be considered to help both bone growth and bone loss during these periods.

Hair iron and other minerals' level in breast cancer patients.

Little is known about hair minerals in cancer patients, and serum iron level has been shown to be elevated in breast cancer patients. Therefore, the aim of this study was to evaluate hair iron and hair minerals' level related to hair iron in breast cancer patients compared to controls. We compared hair mineral analysis data of 40 breast cancer subjects with age and body mass index-matched normal control data (n = 144) by cross-sectional analysis. All breast cancer patients were newly diagnosed at one Breast Cancer Center in Ajou University and had their hair cut before anti-cancer chemotherapy, and the normal controls (without breast cancer) also had their hair cut for various reasons in out-patient clinics of the Department of Family Practice and Community Health. Breast cancer patients had low calcium, magnesium, iron, copper, manganese, and zinc, whereas they had high arsenic, sodium, and potassium compared with the normal control. The hair iron level was positively correlated with hair calcium (r = 0.761, P < 0.001), magnesium (r = 0.643, P < 0.001), and manganese (r = 0.550, P < 0.001) and negatively correlated with arsenic (r = -0.537, P < 0.001). The hair iron level was significantly associated with the hair calcium (beta = 0.778, P < 0.001) and manganese (beta = 0.240, P < 0.001) by using multiple linear regression analysis. We observed different hair mineral patterns in breast cancer patients compared to normal controls. Especially, hair iron level was significantly reduced and associated with hair calcium and manganese levels.

Insulin resistance is associated with arterial stiffness independent of obesity in male adolescents.

To determine the relationship between insulin resistance (IR) and arterial stiffness independent of obesity in male adolescents, we evaluated body fat, lipid parameters, indices of IR (fasting insulin, and the homeostasis model assessment of insulin resistance [HOMA-IR]), indices of insulin sensitivity (IS) (fasting glucose/fasting insulin [GF/IF], and the quantitative insulin sensitivity check index [QUICKI]), and lifestyle parameters in 256 male adolescents. We divided the study group into the following four subgroups based on the median value of HOMA-IR and obesity: non-obese with IS, non-obese with IR, obese with IS, and obese with IR. In order to estimate arterial stiffness, we measured brachial ankle pulse wave velocity (baPWV). Despite having a high body mass index (BMI), obese-IS adolescents showed a significantly lower fasting insulin and baPWV, but had higher IS indices than non-obese-IR adolescents. After an adjustment for age, BMI, waist-to-hip ratio, mean blood pressure, heart rate, total cholesterol level, triglyceride, alanine aminotransferase (ALT) level, physical activity, and television and computer usage, multiple regression models showed that baPWV was independently correlated with IR and IS indices. In conclusion, our results demonstrate an association between IR and baPWV independent of weight, suggesting that IR is a risk factor for the development of early atherosclerosis. Interventions that decrease IR in addition to weight reduction may be necessary to alter the early development of cardiovascular risk.