Metabolomics Approach to Explore the Effects of Rebamipide on Inflammatory Arthritis Using Ultra Performance Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry

OBJECTIVE: Rebampide is a gastroprotective agent used to treat gastritis. It possesses anti-inflammatory and anti-arthritis effects, but the mechanisms of these effects are not well understood. The objective of this study was to explore mechanisms underlying the therapeutic effects of rebamipide in inflammatory arthritis. METHODS: Collagen-induced arthritis (CIA) was induced in DBA/1J mice. DBA/1J mice were immunized with chicken type II collagen, then treated intraperitoneally with rebamipide (10 mg/kg or 30 mg/kg) or vehicle (10% carboxymethylcellulose solution) alone. Seven weeks later, plasma samples were collected. Plasma metabolic profiles were analyzed using ultra performance liquid chromatography/quadrupole time-of-flight mass spectrometry-based metabolomics study and metabolite biomarkers were identified through multivariate data analysis. RESULTS: Low dose rebamipide treatment reduced the clinical arthritis score compared with vehicle treatment, whereas high dose rebamipide in CIA aggravated arthritis severity. Based on multivariate analysis, 17 metabolites were identified. The plasma levels of metabolites associated with fatty acids and phospholipid metabolism were significantly lower with rebamipide treatment than with vehicle. The levels of 15-deoxy-Δ¹²,¹⁴ prostaglandin J2 and thromboxane B3 decreased only in high dose-treated groups. Certain peptide molecules, including enterostatin (VPDPR) enterostatin and bradykinin dramatically increased in rebamipide-treated groups at both doses. Additionally, corticosterone increased in the low dose-treated group and decreased in the high dose-treated group. CONCLUSION: Metabolomics analysis revealed the anti-inflammatory effects of rebamipide and suggested the potential of the drug repositioning in metabolism- and lipid-associated diseases.

Hormone-Dependent Aging Problems in Women

One of the major social issues nowadays is the aging society. Korea is already an aging society, and 63 cities and districts are ultra-aged societies where the rate of people older than 65 yr exceeds 20%. Among them, more than 67% are women. These statistics reveal the importance of healthcare for older women. Disease and disability of older women are very closely related to the loss of female sex hormones after menopause. Major hormone-dependent aging problems in women such as osteoporosis, Alzheimer's disease (AD), urinary incontinence, and coronary atherosclerosis were surveyed in this review, and the key role of hormones in those diseases and hormone replacement therapy (HRT) were summarized. We expect that this review would provide some understanding of factors that must be considered to give optimal care to older women for healthy lives.

Steroid Hormone Metabolism in Patients with Pelvic Organ Prolapse / 대한산부인과학회잡지

OBJECTIVE: To identify 1) whether the endogenous steroid hormone metabolism in patients with pelvic organ prolapse was different from that of normal women, 2) the relationship between endogenous steroid hormone metabolites and the stage of the pelvic organ prolapse. METHODS: Twenty postmenopausal women who were clinically diagnosed as having pelvic organ prolapse and 20 volunteer postmenopausal women not having pelvic organ prolapse were included in the study. We compared the urinary profiles of endogenous steroids between the two groups and investigated the relationship between urinary profiles of the endogenous steroids and the degree of pelvic organ prolapse. Urinary profiles of the endogenous steroids were assayed by gas chromatography-mass spectrometry. RESULTS: The ages of the patients and control group were 64.6 +/- 6.5 and 63.5 +/- 3.9 years, and the Body Mass Index (BMI) was 23.96 +/- 3.14 and 24.11 +/- 2.73 kg/m2 in patients and in normal subjects, respectively. The number of patients in each stage were 4 in stage I, 4 in stage II, 6 in stage III and 6 in stage IV. 5-androstene-3beta, 16beta, 17beta-triol (5-AT), 11beta-hydroxy androstenedione (An) and 17beta-estradiol were significantly increased in patients with pelvic organ prolapse over that of the control group (0.76 +/- 0.67 vs 0.06 +/- 0.03 micro mole/g creatinine; p=0.002, 1.16 +/- 0.83 vs 0.65 +/- 0.23 micro mole/g creatinine; p=0.04, 15.08 +/- 9.81 vs 8.53 +/- 6.19 micro mole/g creatinine; p=0.04). However, tetrahydrocortisone (THE) was significantly increased in the control group over that in patients having pelvic organ prolapse (9.80 +/- 6.21 vs 5.22 +/- 4.89 micro mole/g creatinine; p=0.04). The androgen metabolites, 5-AT and THE significantly correlated with the POP-Q stage (R=0.418; p=0.027, R=0.46; p=0.016). Among the estrogen metabolites, 17beta-estradiol was correlated to the POP-Q stage but not mathematically significantly (R=0.38; p=0.05) and the 17beta-estradiol/estrone ratio weakly correlated to pelvic organ prolapse stage (R=0.14; p=0.49), by showing a low correlation coefficiency. CONCLUSION: The urinary concentrations of 17beta-estradiol, 5-AT and 11beta-hydroxy An increased in patients with pelvic organ prolapse over that of the control group and 5-AT, THE and 17beta-estradiol showed a relationship to the progression of pelvic organ prolapse in Korean women. The metabolites of endogenous steroid hormones could be contributing factors in the pathogenesis of pelvic organ prolapse.

Urinary Profiles of the Endogenous Steroids in Pre-Menopausal Women with Uterine Leiomyoma / 대한불임학회지

Uterine leiomyoma is the most common solid pelvic tumor, occurring in 20~30% of women who are over 30 years of age1 and it accompanies with the symptoms such as uterine bleeding, dysmenorrhea, pain and the pressure on the urinary tract lead to blockage of the urinary tract. it some-times becomes a factor in sterility.2 Leiomyoma is a benign neoplasm that arises from uterine smooth muscle. it is hypothesized that leiomyoma originates from the somatic mutations in myometrial cells, resulting in progressive loss of growthregulation.3,4 Ovarian hormones are believed to stimulate the growth of leiomyoma because there is an increased incidence of leiomyoma after menarche and these tumors enlarge during pregnancy and regress after menopause. The growth of leiomyoma is variable among women with regular menstruation cycles and even among myoma nodules in the same uterus. One possible reason for this variation is thaovarian hormones, especially estrogen, stimulate individual myoma nodules by varying degree. 5 Therefore, therapeutic attempt based on over-come the state of hyperestrogenism have been tried. Treatment with competitive inhibitors of estrogen receptors (ER)6,7 or gonadotropin-releasing hor-mone agonist2,8,9 has been studied for those reasons. it was found that mean ER content was significantly greater in leiomyoma than in myometrium. 10~14 And ER content of the fibroid was reported to signifIcantly correlate wIth the myoma-shrinkage.15 But there were no consistent results as the concentration of estrogen in uterine leiomyoma.16,17 in this study, we determined the concentrations of urinary steroids, including estrogens as well as androgens, which are closely related to the estrogen biosynthesis, in premenopausal women with leiomyoma using Gas Chromatography-Mass Spectrometry (GC-MS). The urinary levels of the same endogenous steroids in age-matched healthy premenopausal women were also estimated by comparing urinary steroid levels between the two groups. From these results, we studied the effect of endogenous steroids and the metabolic changes in the leiomyoma, and we especially observed the difference in the estrogen level between the two groups to predict the role of estrogens in the prevention of and the therapy for leiomyoma

Relationship between Urinary Endogenous Steroid Metabolites and Lower Urinary Tract Function in Postmenopausal Women

To investigate the relationship between the endogenous steroid hormones and the lower urinary tract function in postmenopausal women. Thirty postmeopausal volunteer women who did not have lower urinary tract symptoms or hormone replacement therapy were enrolled in this study. Urodynamic studies included uroflowmetry, multi-channel cystometry, and urethral pressure profilometry were conducted. Gas Chromatography- Mass Spectroscopy (GC-MS) was used to measure the urinary endogenous steroid hormone metabolites. The relationship between the urinary profile of the endogenous steroids and the urodynamic parameters of these patients were investigated. The mean ages of the patients were 60.6 +/- 5.5 years, and the Body Mass Index (BMI) averaged 24.56 +/- 2.23 (kg/m2). Of the progesterone metabolites, pregnandiol was significantly related to the residual volume in the uroflowmetry and the functional urethral length parameters (R=0.98, p=0.000; R= -0.65, p=0.04). Pregnantriol was significantly related to the maximum flow rate, the residual volume in uroflowmetry, the maximum urethral closure pressure and the functional urethral length (R=-0.64, p=0.04; R=0.82, p=0.01; R=0.04, p=0.04; R=- 0.79, p=0.01). In the androgen metabolites, androstenedione, 5-AT, 11- keto Et, 11-betahydroxy Et, THS, and THE were significantly related to the residual volume in uroflowmetry (R=0.92, p=0.001; R=0.84, p=0.008; R=0.99, p=0.000; R=0.72, p=0.03; R=0.97, p=0.000; R=0.85, p=0.00). beta-THF/alpha-THF was significantly related to the maximum flow rate, the residual volume in uroflowmetry, the maximum urethral closure pressure and the functional urethral length (R=-0.76, p=0.02; R=0.67, p=0.04; R=0.74, p=0.02; R=-0.92, p=0.000). alpha-cortol was significantly related to the residual volume in uroflowmetry, the maximum urethral closure pressure and the functional urethral length (R=0.81, p=0.01; R=0.71, p=0.03; R=-0.87, p=0.000). Of the estrogen metabolites, estrone (E1) was significantly related to the normal desire to void (R=0.68, p=0.04) and 17 beta-estradiol/estrone was also significantly related to the normal and strong desire to void (R=-0.70, p=0.03 and R=-0.74, p=0.02, respectively). The urinary progesterone and androgen metabolite concentrations were positively related to the residual volume in uroflowmetry and positively or negatively related to MUCP and FUL. However, the urinary estrone concentration was positively related to the normal desire to void and 17 beta-estradiol/estrone was significantly related to the normal and strong desire to void.

Correlation between Steroid Hormone Metabolites and Leiomyomas of Uterus / 대한불임학회지

OBJETIVE: To elucidate 1) whether there are any differences in the urine concentrations of steroid hormone metabolites between patients with leiomyoma and normal controls 2) the correlation between urinary profiles of steroid hormones and leiomyomas of the uterus according to their type, location, volume, and weight. MATERIALS OF METHODS: The study population consisted of 37 premenopausal patients with uterine leiomyoma and the control group consisted of 25 premenopausal normal volunteer women without uterine leiomyoma. Confirmation of the existence of uterine leiomyoma was done by ultrasonography and histopathological examination after surgery. The volume of the leiomyoma was estimated by trans-abdominal and/or trans-vaginal ultrasonography. The Leiomyomas were divided into 3 types (subserosal, intramural and submucosal). Seventeen patients had subserosal type of leiomyoma, 10 with the intramural type and 10 with the submucosal type. The locations of the leiomyoma were also divided into 3 groups (fundus, body and isthmus). Seventeen patients showed a fundus location, 10 in body, and 10 in isthmus. We compared urinary profiles of the endogenous steroids between patients with leiomyomas and normal controls, and also investigated the relationship between urinary profiles of the endogenous steroids and leiomyomas according to their type, location, volume and weight by using highly sensitive Gas Chromatography-Mass Spectrometry (GC-MS) system. RESULTS: The mean ages of the patients with leiomyomas and the control group were 43.1+/-5.6 and 40.6+/-7.2 years, the weights were 63.4+/-7.3 and 59.4+/-8.1 kg, and their heights were 155.4+/-4.8 and 159.3+/-4.8 cm respectively. Seventeen patients had subserosal, 10 had intramural, and 10 had submucosal leiomyomas. There were 17 patients with leiomyoma located in fundus, 10 in body and 10 in isthmus. 17beta-estradiol, 5-AT, 11-keto ET, 11beta-hydroxy An, 11beta-hydroxy Et, THS, THA, THE, alpha-cortolone, alpha-cortol, beta-cortol, 11beta-OH Et/11beta-OH An and E2/E1 were significantly increased in patients with leiomyoma than in the control group. 17beta-estradiol was significantly increased in the intramural and the submucosal types than in the subserosal type. There was no significant difference in the concentrations of urinary steroids according to the locations of leiomyomas. There was no significant relationship between the concentration of urinary steroids and the volume of the leiomyomas. 17beta-estradiol significantly decreased as the weight of uterus increased (r=-0.322, p=0.04). CONCLUSION: The concentrations of steroid hormone metabolites were generally increased in patients with leiomyoma but were not significantly related to the volume and weight of the leiomyomas. Our study suggests that steroid hormones may be involved in the initiation of leiomyomas but may not be involved in their progression. In addition, the concentrations of steroid hormone metabolites are not related to the leiomyoma type and location.

Results of Vitreous Surgery for Proliferative Vitreoretinopathy

A retrospective study of the effect of vitrectomy, scleral bucling and intraocular tamponade (SF6 gas or silicone oil) was carried out in 39 patients with retinal detachment complicated by proliferative vitreoretinopathy. Complete anatomic retinal reattachment posterior to the encircling scleral buckle was obtained in 53% (21/40) of these eyes. Useful vision was restored in 52% of the 21 anatomically successful cases. Anatomic success was not correlated with severity of proliferative vitreoretinopathy and lens status. The most frequent postoperative complication was cataract in phakic eyes and recurrent retinal detachment in aphakic eyes.

Results of Vitreous Surgery for Proliferative Vitreoretinopathy

A retrospective study of the effect of vitrectomy, scleral bucling and intraocular tamponade (SF6 gas or silicone oil) was carried out in 39 patients with retinal detachment complicated by proliferative vitreoretinopathy. Complete anatomic retinal reattachment posterior to the encircling scleral buckle was obtained in 53% (21/40) of these eyes. Useful vision was restored in 52% of the 21 anatomically successful cases. Anatomic success was not correlated with severity of proliferative vitreoretinopathy and lens status. The most frequent postoperative complication was cataract in phakic eyes and recurrent retinal detachment in aphakic eyes.

A Case of Retinal Detachment with Equatorial Scleral Staphyloma

While retinal detachment is not rarely associated with posterior staphyloma and macular hole, very few cases of retinal detachment with equatorial scleral staphyloma are reported until recentily. In the course of retinal detachment surgery, an equatorial staphyloma is found unexpectedly and makes surgical treatment difficult. We experienced a 70 year old woman who had retinal detachment due to a hole at the 1 o'clock equator. During the retinal detachment surgery, a large equatorial staphyloma was noted right over the retinal hole. Scleral surface buckling procedure and graft using the preserved human sclera were performed. After the follow up period of 6 months, retina was still reattached.

Pupillary Dilatation with Mydriatics in Diabetic Retinopathy

As the number of diabetic patient increases, it is important to manage diabetic retinopathy. Clinically sufficient pupillary dilatation should be obtained for fundoscopic examination and laser photocoagulation theraphy of diabetic patient but we experienced insufficient and delayed pupillary dilatation after instillation of mydriatics. In order to examine abnormality of pupillary dilatation and its relationship to the stage of diabetic retiniopathy, the course of pupillary diameter was measured with Haab's pupillometer after instillation of one drop of 1% Mydriacyl(R) and 2.5% Mydfrin(R) in 72 patients with diabetes mellitus (40-69 years old) and 11 normal controls (40-69 years old). The following results were obtained. After instillation of 1% Mydracy(R), the maximum pupillary diameter was smaller in diabetic retinopathy group than in controls. As the severity of diabetic retinopathy was increased, maximum pupillary diameter was decreased. After instillation of 2.5% Mydfrin(R), the delay of the average time to reach maximal mydriasis in diabetic group was larger than that in controls. This delay was proportional to the severity of diabetic retinopathy. Therefore it was considered that the abservation of the course of pupillary diameter after instillation of mydriatics would be useful for diagnosis of the severity of diabetic retinopathy.

A Case of Retinal Detachment with Equatorial Scleral Staphyloma

While retinal detachment is not rarely associated with posterior staphyloma and macular hole, very few cases of retinal detachment with equatorial scleral staphyloma are reported until recentily. In the course of retinal detachment surgery, an equatorial staphyloma is found unexpectedly and makes surgical treatment difficult. We experienced a 70 year old woman who had retinal detachment due to a hole at the 1 o'clock equator. During the retinal detachment surgery, a large equatorial staphyloma was noted right over the retinal hole. Scleral surface buckling procedure and graft using the preserved human sclera were performed. After the follow up period of 6 months, retina was still reattached.