Endocrine-disrupting chemicals, i.e., endocrine disruptors (EDs), are exogenous compounds that have the potential to interfere with hormonal regulation and the normal endocrine system and consequently cause side effects on human health. Environmental estrogens, i.e., xenoestrogens, are a diverse group of chemicals that bind to estrogen receptors, mimic estrogenic actions, and may have side effects on human health. Bisphenol A (BPA), which is produced by the acid-catalyzed reaction of acetone and phenol and is widely used in the manufacture of polycarbonate plastics and epoxy resins, is classified into xenoestrogens. Food allergy is caused by individual intolerance towards commonly tolerated foods, and this event derived from an immunological mechanism. Allergic diseases such as urticaria, asthma and anaphylaxis, are known to be connected with the production of specific immunoglobulin (Ig)E to allergens of environmental sources. In this paper, we discuss the relationship of EDs between xenoestrogenic reaction and immune responses in human and animals.
Nuclear receptors (NRs) and the aryl hydrocarbon receptor (AhR) form a ligand-dependent transcription factor that regulates the genes involved in key physiological functions such as cell growth and differentiation, development, homeostasis, and metabolism. These receptors are potential targets of endocrine-disrupting chemicals (EDCs). To date, many studies have shown that EDCs, such as plasticizers, pesticides, and dioxins, can function as ligands of NRs and AhR. In this review, we focus on recent studies showing that a variety of pesticides, intentionally released into the environment, have agonistic and/or antagonistic activity against NRs and AhR, and present our transactivation assay-based screening results for 200 pesticides against estrogen receptors (ERs), androgen receptor (AR), thyroid hormone receptors (TRs), pregnane X receptor (PXR), peroxisome proliferator-activated receptors (PPARs), and AhR. Our studies have shown that a number of pesticides possess ERα, ERβ, and PXR agonistic activity as well as AR antagonistic activity, whereas none of the pesticides affect the TRα1, TRβ1, and PPARγ-mediated signaling pathways. In addition, several of the 200 tested pesticides were found to have PPARα and AhR agonistic, and ERα and ERβ antagonistic activity. Although the activities of each of these compounds were weak compared to those of endogenous hormone or dioxins, the endocrine-disrupting potential of pesticides, particularly those which function against ERα/β, AR, and PXR, may reflect that of numerous environmental chemicals.
Cerium oxide nanoparticles have a high thermodynamic affinity for oxygen and sulfur, which makes them useful in applications such as catalysts, solar cells, and gas sensors. In this study, we investigated the effects of intratracheal instillation of cerium oxide nanoparticles on the inflammatory responses in mice. The number of neutrophils in bronchoaveolar lavage (BAL) fluids was significantly elevated on day 1 after instillation. Inflammatory cytokines, such as interleukin (IL)-1, tumor necrosis factor (TNF)-α, and IL-6, were also increased in BAL fluid and the cytokine increase initiated the differentiation of naive T cells, followed by the induction of Th1-type cytokines [IL-12 and interferon (IFN)-γ] and Th2-type cytokines (IL-4, IL-5, and IL-10). The secretion of Th1-type cytokines was more dominant than that of Th2-type cytokines. The inflammatory responses were maintained for 28 days by a positive feedback stimulation of IFN-γ and IL-10. In the lung, the expression of inflammatory genes was increased in a time-dependent manner, and granuloma formation appeared on day 14 after instillation. This suggests that intratracheal instillation of cerium oxide nanoparticles causes a delayed-type hypersensitivity reaction and lung fibrosis in mice.
The purpose of this study was to investigate the relationship between lumbar bone mineral density (BMD) and insulin-like growth factor binding protein-3 (IGFBP-3) level in 55 collegiate women. In univariate analyses, body weight, body mass index (BMI), waist circumference, maximal oxygen uptake (VO2max) in L·min-1, and IGFBP-3 level were significantly positively correlated, while serum calcium (Ca) level was significantly negatively correlated with lumbar BMD. Multiple regression analysis was performed with lumbar BMD as a dependent variable and body weight, BMI, waist circumference, VO2max in L·min-1, and serum levels of IGFBP-3 and Ca as independent variables. Lumbar BMD was significantly positively correlated with body weight, VO2max in L·min-1, and IGFBP-3 level, while negatively correlated with serum Ca level. The subjects were divided into 3 groups in accordance with IGFBP-3 level. After adjusting for body weight, VO2max in L·min-1, and serum Ca level in the analysis of covariance, the group with the highest IGFBP-3 had significantly higher lumbar BMD than the lowest group. The results indicate that the known association of IGFBP-3 with lumbar BMD in older adults is already apparent in young women.
Dietary polyunsaturated fatty acids (PUFA) increase liver injury in response to ethanol feeding. We tested the hypothesis that diets rich in linoleic acid (18:2 n-6) would also affect acute liver injury after acetaminophen injection. To determine whether the types and quantity of dietary fats were important, we examined the effects of feeding diets with either 7 or 15 g per 100 g soybean oil or beef tallow. After the feeding period, animals were unfed and injected either with 600 mg/kg body weight acetaminophen suspended in gum arabic-based vehicle, or with vehicle alone. Samples of plasma and liver were taken for analyses of liver-specific enzymes, [glutamate-pyruvate transaminase (GPT) and glutamate-oxaloacetate transaminase (GOT)] and hepatic glutathione (GSH) and thiobarbituric reactive substances (TBARS) levels, respectively. Treatment with acetaminophen significantly elevated levels of plasma GOT and GPT as well as hepatic TBARS but reduced hepatic GSH levels in groups fed diets with soybean oil compared to beef tallow. The feeding regimens changed the ratio of 18:2 n-6 to oleic acid (18:1 n-9) in liver membrane phospholipid approximately 4- to 6-fold, and produced modest changes in arachidonic acid (20:4 n-6). We conclude that acetaminophen-induced hepatotoxicity can be protected with more saturated fatty acids (SFA)-rich diet but can be exacerbated with PUFA-rich diet by modulating the tissue fatty acid composition.
Placental/umbilical cord blood (CB) contains multipotent hematopoietic stem/progenitor cells and has been utilized worldwide both clinically and experimentally. Neonatal birth weight is positively correlated with CB volume and with the total number of nucleated cells associated with engraftment and survival after CB transplantation. Considering the recent increase in the frequency of low birth weight (<2500 g) and the decline in body mass index (BMI) among Japanese women of childbearing age, the present study investigated the combined impact of the prepregnancy BMI and the gestational weight gain on CB volume. From 1998 to 2007, CB samples were obtained from 579 healthy women with singleton vaginal deliveries. The prepregnancy BMI was classified into the underweight, normal, overweight, or obese groups. According to the current gestational weight gain recommendations or other new optimum recommendations, the gestational weight gain was classified into below, within, or above recommendations in each prepregnancy BMI group. The neonatal weight and placental weight had significantly positive effects on the CB volume. Underweight pregnant women demonstrated significantly lower neonatal and placental weight. According to the current recommendations, no significant difference in the CB volume was observed. According to the new optimum recommendations for underweight pregnant women, a significantly higher CB volume was obtained from the group within the recommended weight gain range than from the group below the recommended range. In the underweight group, a higher CB volume could be obtained if the upper limit of the gestational weight gain increases by a few kilograms more than the current gestational weight gain recommendations.
The anti-osteoporotic effects of aqueous extracts of Gastrodiae Rhizoma (GR) were observed in vitro and in vivo. The effects on proliferation and alkaline phosphatase activity of primary osteoblasts, bone nodule formation, pit formation of osteoclasts and osteoclastogenesis were observed in vitro, and to observe the in vivo efficacy GR were orally administered once a day for 28 days to bilateral ovariectomy-induced osteoporosis mice at 125, 250 and 500 mg/kg. GR extracts enhanced the proliferation, differentiation, and bone nodule formation of primary cultured osteoblasts, but they inhibited the pit formation and the number of multinucleated osteoclast-like cells, osteoclastogenesis in vitro. As results of ovariectomy-induced osteoporotic process, dramatical decreases of bone weights and thickness of bone at epiphyseal regions, bone Ca and P contents, bone mineral density and failure load, serum Ca and P levels with increase of serum osteocalcin level. At histopathology-histomorphometry, dramatical decreases of trabecular and cortical bone masses were detected with classic histomorphometrical changes of bones including decrease of trabecular bone volume, thickness, length and number and cortical bone thickness and increase of osteoclast/bone perimeter. Hoevere, these estrogen-deficient osteoporotic changes were also dramatically and dose-dependently inhibited by treatment of all three different dosages of GR extracts. It was concluded that GR extracts has relatively good favorable effect to prevention and/or treatment of ovariectomy (OVX)-induced osteoporosis through osteoblast activation and inhibition of osteoclastogenesis and osteoclast activity.
Hepatotoxic and immunotoxic effects of 1-bromohexane (1-BH) and its conjugation with glutathione (GSH) were investigated in female BALB/c mice. The animals were treated once orally with 1-BH at 500, 1000, and 2000 mg/kg in corn oil for a dose-response study or treated orally with 1-BH at 2000 mg/kg for 6, 12, 24, and 48 hr for a time-course study. Treatment with 1-BH increased serum activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) dose dependently. The hepatic contents of thiobarbituric acid reactive substances were significantly increased at 2000 mg/kg of 1-BH from 12 to 24 hr after the treatment. Oral 1-BH at 2000 mg/kg significantly suppressed production of splenic intracellular interleukin (IL)-2 in response to concanavalin A. Following treatment with 1-BH, three GSH conjugates such as S-hexyl GSH, S-hexyl cysteine, and hydroxyhexyl mercapturic acid were identified in livers by liquid chromatography-electrospray ionization tandem mass spectrometry. The hepatic contents of GSH were maximally decreased 6 hr after treatment with 1-BH. GSH conjugates were also detected maximally in livers 6 hr after treatment. These results suggest that 1-BH could cause hepatotoxicity and immunotoxicity as well as depletion of GSH content due to the formation of GSH conjugates with 1-BH in female BALB/c mice.
Recent studies have shown that integrons play a major role in spreading antibiotic resistance genes in clinical settings, as antibiotic resistance genes are frequently found located at gene cassettes. Polymerase chain reaction (PCR) analyses were carried out for the detection of the integrase genes of the three classes of integrons, and their gene cassettes were characterized in 118 clinical strains, including both gram-positive and gram-negative bacteria, isolated from a hospital in Guangzhou, China during 2004. Class 1 and 2 integrons were detected in 76.3% (90/118) and 0.8% (1/118) of the tested clinical isolates, respectively. Moreover four isolates were positive for both the integrons and no class 3 was detected. Some of them were first reported, such as Enterococcus faecalis, Enterococcus faecium, Alcaligenes sp., and Flavobacterium sp. Seven different arrays of gene cassettes of class 1 integron were found, and a high prevalence of dfrA12-orfF-aadA2 genes was observed. In addition, we identified a new none-open reading frame (ORF) cassette in a class 1 integron positive clinical coagulase-negative Staphylococcus strain GH69. The none-ORF cassette, a 700 bp sequence containing a 441 bp ORF and a 59-base element, is first characterized in this study. All class 2 integrons carried an array of gene cassettes dfrA1-sat2-aadA1. Moreover bacteria contain more than one integrons were also found in this study. Resistance to trimethoprim-sulfamethoxazole was frequently found to be encoded within integrons. Therefore, it is important that guidelines for the prudent use of antimicrobial agents are adopted and surveillance programs are established.
The 50% ethanol extracts from Resina Pini of Pinus sp. (Pinaceae) showed more potent inhibitory activity against testosterone 5α-reductase prepared from rat prostate than those from several medicinal plants used for the treatment of androgen-dependent diseases such as benign prostatic hyperplasia. The fraction responsible for this activity was purified, and the active constituent was isolated and identified as abietic acid, a diterpene resin acid, which exhibited potent testosterone 5α-reductase inhibitory activity. Methyl abietate was substantially inactive against testosterone 5α-reductase, whereas other diterpene resin acids, pimaric acid and neoabietic acid, were as active as abietic acid against testosterone 5α-reductase, indicating that the negatively charged anionic carboxyl group on the molecule is an important structural moiety for the inhibitory activity. These findings suggest that a nonsteroidal anionic diterpene compound of natural origin may have the potential to act as a transition state analogue inhibitor of testosterone 5α-reductase in the treatment of androgen-dependent diseases.
There has been much interest in mutanases, α-1,3-glucanases, as they have the potential for preventive agents in the oral cavity. Mutanases have been reported in some bacteria and fungi but remain a relatively uncharacterized family of enzymes. We screened bacterial mutanase in fermented food for the application of the enzyme to preventive medicine. Immersed solutions of fermented soybeans, natto, on mutan-containing agar plates exhibited mutan-hydrolyzing activity after incubation. We isolated a microorganism that hydrolyzed mutan from the fermented soybeans and named it Paenibacillus humicus strain NA1123. The gene for the mutanase was cloned, and the nucleotide sequence of the gene consisted of 3441-bp open reading frame that encoded a predicted 1146-amino acid polypeptide including a 33-amino acid signaling peptide. The predicted molecular mass of the matured enzyme was 115399. The protein is composed of an N-terminal domain and a C-terminal domain, that are connected by a sequence composed of proline and threonine repeats. The deduced amino acid sequence of the present enzyme showed similarity to that of the mutanase MuC1 of strain KSM-M126 and the mutanase MuE of strain KSM-M318 of Paenibacillus sp. with 77.2% and 73.5% identity, respectively. We confirmed that the recombinant mutanase exhibited mutan hydrolyzing activity.
Prazosin is an alpha 1 adrenoceptor antagonist, and it is used as an antihypertensive agent. The effects of prazosin on the activity of hepatic triacylglycerole lipase (HTGL) are not fully understood. In this study, we demonstrated that prazosin stimulates the release of HTGL activity from primary cultures of rat hepatocytes in a time- and dose-dependent manner. U-73122, a phopholipase C (PLC) inhibitor, suppresses prazosin's stimulation of the release of HTGL activity. Moreover, prazosin stimulated the increase of PLC activity in the hepatocytes in a time- and dose-dependent manner. In addition, the prazosin-stimulated release of HTGL activity was reduced by Quin2/AM (an intracellular Ca2+-chelator), W-7 (a Calmodulin inhibitor), and KN-93 [an inhibitor of Ca2+/Calmodulin dependent protein kinase (CaMK)-II]. These results suggest that the prazosin-stimulated release of HTGL activity is partly due to the activation of CaMK-II that is associated with the elevation of PLC activity in the hepatocytes.
Since the role of endothelin (ET)-1 in lipoprotein metabolism in tumor cells is unclear, we investigated the effect of ET-1 on the secretion of lipoprotein lipase (LPL) from mouse Ehrlich ascites tumor cells. ET-1 increased the secretion of LPL from these cells in a time-dependent manner. Two antagonists of ET-receptor type A (ET-A), namely, BQ123 and FR139317, inhibited the stimulatory effect of ET-1 on the secretion of LPL. However, an antagonist of ET-receptor type B (ET-B), BQ788, did not have any effect. Neomycin, a phospholipase C (PLC) inhibitor, and H-7, a protein kinase C (PKC) inhibitor, also suppressed the ET-1-stimulated secretion of LPL. ET-1 also increased PKC activity in tumor cells in a dose-dependent manner. These results imply that ET-1 stimulates secretion of LPL from tumor cells by stimulating the PLC-PKC signaling pathway through the ET-A receptor rather than the ET-B receptor.
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