Urinary Biopyrrin Levels and Their Relationship with the Menstrual Cycle and Concomitant Symptoms Among Healthy Nonpregnant Women of Reproductive Age: A Cohort Study.

Background: Urinary biopyrrin (UBP) is an oxidative metabolite formed from the reaction of bilirubin with reactive oxygen species. Previous studies have explored the relationship between UBP levels and certain diseases or pregnancy. However, UBP levels in healthy nonpregnant women have not been well examined. We aimed to clarify the representative value of UBP in healthy nonpregnant women and explore its relationship with menstrual cycles and concomitant symptoms. Methods: We included healthy, nonpregnant Japanese women aged 20-39 years with normal body mass index and menstrual cycle. In total, 1260 urine samples collected during 43 menstrual cycles of 36 women were analyzed to determine the representative values and reference intervals of UBP levels. The correlation between daily UBP levels and the order of the day was explored, and median UBP levels of 5-day clusters were compared using Friedman and Mann-Whitney U tests. These analyses were also conducted in women with concomitant symptoms during the menstrual cycle. Results: The median UBP level in all samples was 0.2291 (reference: 0.0102-2.9335) µmol/gCr. There was no significant relationship between the median UBP level and menstrual cycle, regardless of the presence of self-manageable symptoms during or before menstruation. Conclusions: The representative UBP value and its reference interval can serve as standards for comparison with other populations. Our findings suggest that the UBP level may be an objective oxidative stress indicator that is less sensitive to menstrual cycle and concomitant symptoms. UBP levels in healthy nonpregnant women could be assessed regardless of the menstrual cycle and concomitant symptoms.

Discrimination of malignant transformation from benign endometriosis using a near-infrared approach.

The aim of the present single-center retrospective study was to investigate the discrimination of malignant transformation from ovarian endometrioma (OE) using a near-infrared approach ex vivo. Cystic fluid samples were collected from patients with OE (n=34) and endometriosis-associated ovarian cancer (EAOC) (n=12). The light reflected from each sample of cystic fluid [change in luminance, Δl (cd/m2) = background luminance-cystic fluid luminance at 800 nm] was spectrally measured by a near-infrared CCD camera with band-path filter (800 nm). The Δl in EAOC was significantly lower compared with that in OE. On regression analysis, a positive correlation was observed between the Δl and Hb level in the cystic fluid, and this association was exponential. The diagnostic sensitivity and specificity of Δl was 83.3 and 94.1% at the cutoff value of 21.5 cd/m2, with an area under the ROC curve of 0.897. The present ex vivo study potentially provides a powerful near-infrared approach for quantitative discrimination between EAOC and benign OE, with high sensitivity and specificity, which may have clinical applications.

Determination of Cadmium in Brown Rice Samples by Fluorescence Spectroscopy Using a Fluoroionophore after Purification of Cadmium by Anion Exchange Resin.

Simple analytical methods are needed for determining the cadmium (Cd) content of brown rice samples. In the present study, we developed a new analytical procedure consisting of the digestion of rice using HCl, Cd purification using anion exchange resin, and then determining the Cd content using fluorescence spectroscopy. Digestion with 0.1 M HCl for 10 min at room temperature was sufficient to extract Cd from the ground rice samples. The Cd in the extract was successfully purified in preference to other metals using Dowex 1X8 chloride form resin. Low concentrations of Cd in the eluate could be determined using fluorescence spectroscopy with a fluoroionophore. Overall, the actual limit of quantification value for the Cd content in rice was about 0.1 mg-Cd/kg-rice, which was sufficiently low compared with the regulatory value (0.4 mg-Cd/kg-rice) given by the Codex Alimentarius Commission. We analyzed authentic brown rice samples using our new analytical procedure and the results agreed well with those determined using inductively coupled plasma optical emission spectrometry (ICP-OES). Since the fluoroionophore recognized Zn2+ and Hg2+ as well as Cd2+, a sample containing high concentration of Zn2+ or Hg2+ might cause a false positive result.

Transverse Relaxation Rate of Cyst Fluid Can Predict Malignant Transformation of Ovarian Endometriosis.

PURPOSE: Heme and iron accumulation due to repeated hemorrhage in endometriosis may contribute to a pivotal role in carcinogenesis. We evaluate the clinical application of MR relaxometry in a series of ovarian endometriosis (OE) and endometriosis-associated ovarian cancer (EAOC). MATERIALS AND METHODS: A prospective study of diagnostic accuracy was conducted among 82 patients (67 OE and 15 EAOC) to compare MR relaxometry and biochemical measurement of cyst fluid total iron concentration. Transverse relaxation rate R2 value was determined using a single-voxel, multi-echo MR sequence (HISTO) by a 3T-MR system. Phantom experiments were also performed to assess the correlation between the ex vivo R2 values and total iron concentrations. RESULTS: Both the results of phantom experiments and in vivo human data confirmed that in vivo R2 values were highly correlated with total iron concentrations. Compared to OE, EAOC exhibit decreased in vivo R2 values and total iron levels, regardless of their age, menopausal status and cyst size. The use of in vivo R2 values retained excellent accuracy in distinguishing EAOC versus OE (sensitivity and specificity: 86% and 94%). CONCLUSIONS: We have demonstrated that MR relaxometry provides a noninvasive predictive tool to discriminate between EAOC and OE.

Cyst fluid hemoglobin species in endometriosis and its malignant transformation: The role of metallobiology.

The aim of the present study was to assess the relative concentrations of hemoglobin (Hb) species in endometriosis as a possible indicator of malignancy. Electronic absorption spectroscopy was employed to quantify the Hb species present in the cyst fluid collected from 8 patients with endometriosis-associated ovarian cancer (EAOC), and compared with those present in the cyst fluid of 35 patients with benign endometriotic cysts. The 620/580 nm ratio in the electronic absorption spectrum, which was used as a surrogate indicator of the methemoglobin (metHb)/(oxyhemoglobin+metHb) ratio, was measured in each cyst fluid by ultraviolet/visible grating spectrophotometric microplate reader. The optimal cutoff value was defined according to the analysis of receiver operating characteristic (ROC) curve. The sensitivity and specificity of detection were calculated on the basis of the cutoff value to differentiate EAOC from endometriosis. The 620/580 nm ratio of cyst fluid in EAOC patients was much lower than that measured in women with benign cysts (0.389±0.266 vs. 0.666±0.188, P=0.021). ROC curve analysis performed using 0.35 as the optimal cutoff value indicated that the 620/580 nm ratio had a sensitivity, specificity, positive predictive value (PPV) and negative predictive value of 62.5, 100.0, 100.0 and 92.1%, respectively, in the diagnosis of EAOC. In conclusion, metHb is one of the most abundant Hb species in benign cysts, and the absorption 620/580 nm ratio of cyst fluid exhibits high specificity and PPV as a surveillance test for the early detection of malignant transformation of endometriosis. Thus, metallobiology highlights diverse features involved in Hb homeostasis and the pathogenesis of malignant transformation of endometriosis.

Oxidative Stress and Antioxidant Defense in Endometriosis and Its Malignant Transformation.

The aim of this study was to investigate the role of redox status in endometriosis and its malignant transformation. A search was conducted between 1990 and 2014 through the English language literature (online MEDLINE PubMed database) using the keywords endometriosis combined with malignant transformation, oxidative stress, and antioxidant defense. In benign endometriosis, autoxidation and Fenton reaction of hemoglobin from the ferrous Fe(2+) (oxyhemoglobin) state to the ferric Fe(3+) (methemoglobin) state lead to production of excess reactive oxygen species (ROS) such as O2(-) and (∙)OH. Hemoglobin, heme, and iron derivatives in endometriotic cysts cause distortion in the homeostatic redox balance. Excess oxidative stress could trigger DNA damage and cell death. In contrast, endometriosis-associated ovarian cancer (EAOC) might be associated with an effective antioxidant defense, including heme oxygenases, cytochrome P450 family, and glutathione transferase family. The pattern of redox balance supports that enhanced antioxidants may be involved in the pathogenesis of malignant transformation. In conclusion, oxidant/antioxidant balance function is a double-edged sword, promoting cell death or carcinogenesis. Upregulation of antioxidant functions in endometriotic cyst may result in restoration of cell survival and subsequent malignant transformation.

Cyst fluid iron-related compounds as useful markers to distinguish malignant transformation from benign endometriotic cysts.

OBJECTIVE: The purpose of this study was to investigate cyst fluid levels of total iron, heme iron and free iron in benign endometriotic cysts and endometriosis-associated ovarian cancer (EAOC) and to demonstrate the significance of these biomarkers in differential diagnosis between EAOC and endometriotic cysts. METHODS: Cyst fluid samples were obtained from eleven patients with EAOC and thirty-six women with benign endometriotic cysts at the time of surgery. RESULTS: The median (± SD) total iron levels for endometriotic cysts and EAOC cysts were 244.4 ± 204.9 mg/L and 14.2 ± 36.6 mg/L, respectively. EAOC patients had much lower levels of iron-related compounds compared with endometriotic cyst samples (p< 0.001). When the total iron results were analyzed using the receiver operating characteristics (ROC) curve method, the optimum diagnostic cut-off point was 64.8 mg/L, sensitivity was 90.9%, specificity was 100%, positive predictive value (PPV) was 100%, and negative predictive value (NPV) was 97.3%. Patient demographic characteristics such as tumor size, age at operation, parity and menopause were not correlated with cyst fluid iron levels. CONCLUSIONS: We conclude for the first time that iron-related compounds are important biomarkers that can predict malignant transformation with high sensitivity and specificity for women with endometriosis.

Cystathionine beta-synthase as a carbon monoxide-sensitive regulator of bile excretion.

UNLABELLED: Carbon monoxide (CO) is a stress-inducible gas generated by heme oxygenase (HO) eliciting adaptive responses against toxicants; however, mechanisms for its reception remain unknown. Serendipitous observation in metabolome analysis in CO-overproducing livers suggested roles of cystathionine beta-synthase (CBS) that rate-limits transsulfuration pathway and H(2)S generation, for the gas-responsive receptor. Studies using recombinant CBS indicated that CO binds to the prosthetic heme, stabilizing 6-coordinated CO-Fe(II)-histidine complex to block the activity, whereas nitric oxide (NO) forms 5-coordinated structure without inhibiting it. The CO-overproducing livers down-regulated H(2)S to stimulate HCO(3) (-)-dependent choleresis: these responses were attenuated by blocking HO or by donating H(2)S. Livers of heterozygous CBS knockout mice neither down-regulated H(2)S nor exhibited the choleresis while overproducing CO. In the mouse model of estradiol-induced cholestasis, CO overproduction by inducing HO-1 significantly improved the bile output through stimulating HCO(3) (-) excretion; such a choleretic response did not occur in the knockout mice. CONCLUSION: Results collected from metabolome analyses suggested that CBS serves as a CO-sensitive modulator of H(2)S to support biliary excretion, shedding light on a putative role of the enzyme for stress-elicited adaptive response against bile-dependent detoxification processes.