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Aim of the study: The traditional Japanese (kampo) medicine inchinkoto (ICKT) is used in Eastern Asia as a choleretic and hepatoprotective agent. Previously, we reported that ICKT ameliorates murine concanavalin A (con A)-induced hepatitis via suppression of interferon (IFN)-γ and interleukin (IL)-12 production. In the present study, we investigated the active ingredients of ICKT. Materials and methods: ICKT and extracts of its component herbs were fractionated, and their effects on liver injury and cytokine production in vivo (biochemical markers of liver injury and cytokine levels in serum) and in vitro (cytokine and nitrite production in the cultures of splenocytes and peritoneal macrophages). Results: Decoctions of component herbs, Artemisiae Capillari Spica (Artemisia capillaris Thunberg: ‘Inchinko’ in Japanese), Gardeniae Fructus (Gardenia jasminoides Ellis: ‘Sanshishi’) and Rhei Rhizoma (Rheum palmatum Linné: ‘Daio’) were administered orally. Inchinko and Sanshishi decreased serum transaminases and IFN-γ concentrations. Examination of fractions of component herbs suggested that capillarisin, a component of Inchinko, has potent hepatoprotective activity in vivo. In in vitro studies, capillarisin and genipin, an intestinal metabolite of geniposide that is contained in Sanshishi, were examined. IFN-γ production was significantly suppressed by capillarisin and genipin in con A-stimulated splenocyte culture. Genipin also suppressed IL-1β, IL-6, and IL-12p70 synthesis. Capillarisin and genipin decreased nitrite release from IFN-γ-stimulated macrophages. Conclusions: These results suggested that both Inchinko and Sanshishi may contribute to the protective effects of ICKT against con A hepatitis. Capillarisin was found to be potently hepatoprotective, and genipin may also contribute, especially via modulation of cytokine production. [Copyright &y& Elsevier]

Abstract: The aim of the present study was to determine the influence of acute estrogen deficiency induced by administration of a gonadotropin-releasing hormone (GnRH) agonist on circulating levels of cytokines and chemokines. Eighty-three women with uterine leiomyoma were assigned in open, parallel-group fashion to a no-treatment (control) group and a GnRH-agonist group. Serum levels of nine cytokines and chemokines as well as vascular inflammatory markers were measured. Serum levels of monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor-α (TNFα) in the GnRH-agonist group were increased significantly at 6 months. There were also significant differences in percentage changes in interleukin (IL)-6, IL8, MCP1, and macrophage inflammatory protein-1β (MIP1β) between the control and GnRH agonist groups. Soluble intercellular adhesion molecule-1 (sICAM1) and E-selectin levels showed significant increases in the GnRH agonist group at 6 months. Serum MCP1 concentrations showed weak correlations with levels of sICAM and E-selectin. We conclude that a hypo-estrogenic state due to administration of a GnRH agonist increases circulating levels of cytokines and chemokines, especially MCP1. [Copyright &y& Elsevier]

Abstract: Aim of study: Luteinizing hormone-releasing hormone (LH-RH) has been suggested as an inducer of centrally mediated elevation of skin temperature, and calcitonin gene-related peptide (CGRP) is one of the potent vasodilator neuropeptides that has been suggested as an inducer of peripherally mediated elevation of skin temperature. We investigate the effect of the Japanese herbal medicine Tokaku-jyoki-to using two rat-models for menopausal hot flash. Materials and methods: Tokaku-jyoki-to used in present study was prepared as a spray-dried powder from hot-water extract. Skin temperature was measured by thermister thermometer. Estrogen receptor (ER) binding assay of Tokaku-jyoki-to extract was performed using human recombinant ERα or ERβ. Results: Oral Tokaku-jyoki-to (1000mg/kg) restored skin temperature rise induced by LH-RH or CGRP in ovariectomized (OVX) rats as well as subcutaneous 17β-estradiol (0.010mg/kg) did. Tokaku-jyoki-to did not affect the lower concentration of plasma estradiol and the decreased uterine weight due to ovariectomy, although the hormone replacement of 17β-estradiol restored them. In estrogen receptor ligand-binding study, Tokaku-jyoki-to extract bound to human ERα poorly and did not bound to human ERβ. Conclusions: These results suggest that Tokaku-jyoki-to, which appears to contain organ-specific selective estrogen receptor modulator, may be useful for the treatment of hot flashes in patients for whom estrogen replacement therapy is contraindicated as well as menopausal women. [Copyright &y& Elsevier]

Abstract: Interleukin (IL-7), which is a regulator of development and homeostatic maintenance of T and B cells, is implicated in the induction of leukocyte-endothelial cell adhesion during inflammatory events. We hypothesized that circulating IL-7 is associated with cytokines and chemokines, vascular inflammatory markers and lipid profiles involved in regulating cell adhesion in post-menopausal women. Serum levels of 8 cytokines and chemokines were simultaneously measured in 200 post-menopausal women using a multiplexed human cytokine assay. C-reactive protein, soluble vascular cell adhesion molecule, soluble intercellular adhesion molecule and soluble E-selectin were measured as inflammatory markers. Serum IL-7 concentration was significantly correlated with serum MCP-1 concentration and the correlation remained after adjustment for age and body mass index (BMI). Serum IL-7 levels also showed significant positive correlations with serum levels of IL-10 and IL-6. In addition, the serum IL-7 concentration showed significant positive correlations with levels of soluble E-selectin and triglyceride after adjustment for age and BMI. We conclude that there is a relationship between circulating IL-7, MCP-1 and soluble E-selectin, and that IL-7 may be involved in regulating inflammatory cell adhesion together with MCP-1 and E-selectin in post-menopausal women. [Copyright &y& Elsevier]

Abstract: Objective: The aim of the present study was to determine the effects of raloxifene on changes in circulating levels of cytokines and chemokines in relation to changes in lipid profiles and markers of inflammation in postmenopausal women. Methods: Fifty-three postmenopausal women aged 45–65 years old were randomly assigned in open, parallel-group fashion to a control group or raloxifene group. Twenty-six women received oral administration of 60mg raloxifene every day and 27 women did not receive any drugs for 12 months. Serum cytokines levels were simultaneously measured using a multiplexed human cytokine assay. Results: Serum IL-7 concentrations in women who received raloxifene were decreased significantly (p =0.014), and serum monocyte chemoattractant protein (MCP)-1 concentrations in women who received raloxifene were decreased significantly (p =0.0003) at 12 months. In the control group, serum levels of MCP-1 and IL-7 did not show significant changes. There were significant differences (p =0.032 and p =0.0024, respectively) in percentage changes in IL-7 and MCP-1 in the control group and in the raloxifene group. Levels of low-density lipoprotein cholesterol (LDL-C) and E-selectin were decreased significantly in women who received raloxifene, but the percentage changes in LDL-C and E-selectin over a period of 12 months were not significantly correlated with percentage changes in IL-7 and MCP-1 over the same period. Conclusion: Circulating levels of IL-7 and MCP-1 decrease in postmenopausal women who received raloxifene. [Copyright &y& Elsevier]

Abstract: Objective: The aim of the present study was to compare the effects on serum cytokine concentrations of paroxetine, a selective serotonin re-uptake inhibitor, and kamishoyosan, a Japanese traditional medicine, in midlife women with psychological symptoms. Methods: Seventy-six women with psychological symptoms such as anxiety and mild depression as menopausal symptoms were enrolled in this study. Thirty-eight women received oral administration of 10mg paroxetine every day, and 38 women received oral administration of kamshoyosan every day for 6 months. Overall climacteric symptoms were assessed using Greene''s climacteric scale. Serum levels of cytokines were measured using a multiplexed human cytokine assay. Results: Greene''s total scores in both women treated with paroxetine and in women treated with kamishoyosan decreased significantly. Percentage decreases in Greene''s total, psychological and vasomotor scores during the 6-month period in the paroxetine group were significantly greater than those in the kamishoyosan group. Serum IL-6 concentration in women treated with paroxetine decreased significantly. Serum concentrations of IL-8, IL-10, macrophage inflammatory protein (MIP)-1β and monocyte chemoattractant protein-1 in women treated with paroxetine decreased significantly. On the other hand, serum IL-6 concentration in women treated with kamishoyosan decreased significantly, but other serum concentrations did not change significantly. Conclusion: Decrease in IL-6 concentration may be involved in the mechanism of the actions of both paroxetine and kamishoyosan in women with psychological symptoms, and IL-6 may therefore be useful as a marker of treatment. The action of paroxetine may also be associated with decreases in IL-8, IL-10, MIP-1β. [Copyright &y& Elsevier]

Abstract: Objective: The purpose of the present study was to clarify the association of serum cytokine concentrations, determined using a multiplexed cytokine assay, with psychological symptoms in midlife women. Methods: Fifty-three peri- and post-menopausal women with and without psychological symptoms in Greene''s climacteric scale were enrolled in this study. Levels of 17 cytokines in serum samples were measured simultaneously using a multiplexed human cytokine assay. Results: Serum interleukin (IL)-6 concentration in women with psychological symptoms (2.71±047pg/ml) was significantly (p =0.009) higher than that in women without psychological symptoms (0.98±0.18pg/ml). Serum IL-8 concentration in women with psychological symptoms (33.4±8.17pg/ml) was also significantly (p =0.022) higher than that in women without psychological symptoms (7.87±1.64pg/ml). In addition, serum IL-10 concentration in women with psychological symptoms (0.74±0.26pg/ml) was significantly (p =0.048) higher than that in women without psychological symptoms (0.07±0.04pg/ml). Tumor necrosis factor (TNF)-α in serum was detected only in women with psychological symptoms. Serum IL-2 concentration in women with psychological symptoms tended (p =0.066) to be higher than that in women without psychological symptoms. No significant differences were found between levels of other cytokines in women with and without psychological symptoms. Conclusion: Psychological stress manifested as climacteric symptoms in midlife women may be associated with increases in serum concentrations of IL-6, IL-8, IL-10, and TNF-α. [Copyright &y& Elsevier]

Abstract: Objective: The purpose of the present study was to clarify the changes in serum concentrations of 17 cytokines in healthy women during the menopausal transition by using a multiplexed cytokine assay and to clarify the associations of these cytokines with serum estradiol concentration. Methods: Sixteen premenopausal, 54 perimenopausal and 52 postmenopausal women were enrolled in this study. Seventeen cytokines in serum samples were measured simultaneously using a Bio-Plex human cytokine 17-Plex assay. Results: Serum IL-6 concentration showed a weak positive correlation with age (r =0.196, p <0.05). Postmenopausal women for whom less than 5 years had passed since menopause showed significant (p <0.05) increase in serum concentrations of IL-2, GM-CSF and G-CSF, while serum IL-4 concentration was significantly (p <0.05) increased in postmenopausal women for whom more than 5 years had passed since menopause. Serum estradiol concentration showed a significant negative correlation with serum IL-6 concentration and weak negative correlations with serum concentrations of IL-2, IL-8 and GM-CSF. Conclusion: We were able to simultaneously measure the levels of 17 cytokines using a highly sensitive cytokine assay, and we found that the changes in serum cytokine concentrations during the menopausal transition differed. We also found that serum IL-6 concentration during the menopausal transition was negatively correlated with serum estradiol concentration. [Copyright &y& Elsevier]

Abstract: Glycyrrhizin (GL), a major ingredient of Glycyrrhiza Radix (licorice), is widely used to treat various disorders or as a sweetener. It is also known that GL occasionally induces pseudoaldosteronism. It is conceivable that the active form of GL in pseudoaldosteronism induction is glycyrrhetinic acid (GA). Although it is reported that 3-monoglucuronyl-glycyrrhetinic acid (3MGA) is detectable specifically in the plasma of patients with GL-induced hypokalemia, pharmacokinetics and a hypokalemia induction mode of action for 3MGA have not been clarified. We investigated the toxicokinetics of GL, GA and 3MGA in a single or multiple oral administration of GL. The results suggested that higher blood concentrations of 3MGA were maintained by the multiple administration compared to the single dose, whereas the concentrations of GA and GL showed no difference. We injected 3MGA intravenously and found that it can decrease the plasma potassium level (PPL) in vivo. It is clinically recommended to avoid a combination treatment of GL and furosemide. While treatment with a low dosage of furosemide had no effect on PPL, the multiple administration of GL and furosemide markedly decreased PPL compared to the effect of administering GL alone. In the single dosage regime, there was no difference between PPL after the combination treatment and after administering GL alone. Collectively, these findings suggested that accumulation of 3MGA may be involved in the pathogenesis of pseudoaldosteronism induced by chronic GL treatment. [Copyright &y& Elsevier]