显脉羊蹄甲中酚酸类成分研究

为了研究显脉羊蹄甲中抗糖尿病活性成分,采用硅胶、ODS、MCI以及Sephadex LH-20等柱色谱方法从显脉羊蹄甲95%乙醇提取物中分离得到11个酚酸类成分,其结构经多种波谱技术鉴定为6'-O-没食子酰基葡萄糖异丙苷(1)、6'-O-没食子酰基葡萄糖乙苷(2)、3,4,5-三甲氧基苯酚-1-O-β-D-(6'-O-没食子酰基)吡喃葡萄糖苷(3)、3,4,5-三甲氧基苯酚葡萄糖苷(4)、没食子酸(5)、没食子酸甲酯(6)、没食子酸乙酯(7)、原儿茶酸(8)、3,5-二甲氧基-4-羟基苯甲酸(9)、erigeside C(10)和丁香酸葡萄糖苷(11)。化合物1为新化合物,化合物2、10和11为首次从羊蹄甲属植物中分离得到,其余化合物为首次从该植物中分离得到。化合物6和8对蛋白酪氨酸磷酸酶1B(protein tyrosine phosphatase1B,PTP1B)显示较好的抑制活性,其IC50值分别为72.3和54.1μmol.L-1。     

Influence of Pseudomonas putida AF7 inoculation on soil enzymes

There has been some concern about the environmental impact of microbial agents. Pseudomonas may be used as bioremediator and as biopesticide. In this study, we report the use of soil enzyme assays as biological indicator of possible negative effects in soil functioning after the P. putida AF7 inoculation. For that, P. putida AF7 was originally isolated from the rizosphere of rice and was inoculated on three soil types: Rhodic Hapludox (RH), Typic Hapludox (TH); and Arenic Hapludult (AH). The acid phosphatase, β-glucosidase and protease enzymes activities were measured for three period of evaluation (7, 14 and 21 days). In general, the enzymatic activities presented variation among the tested soils. The highest activities of β-glucosidase and acid phosphatase were observed in the RH and AH soils, while the protease activity was higher in the TH soil. Also, the soil characteristics were measured for each plot. The activity of enzymes from the carbon cycle was positively correlated with the N and the P and the enzyme from the nitrogen cycle was negatively correlated with N and C.org. The presented data indicate that soil biochemical properties can be an useful tool for use as an indicator of soil perturbations by microbial inoculation in a risk assessment.     

Inhibition effects of the classical pathway complement of isolated compounds from Quercus glauca

Species of the Quercus species is an evergreen broadleaf tree found not only in Korea but also in China, Taiwan, and Japan. Quercus species is the most commonly occurring plant among the 50 native species of the family Fagaceae in Korea, China, and Taiwan. Quercus species have been used for diarrhea, dysentery, dermatitis, and hemorrhagia in Korean folk medicine. The present study evaluated the anticomplement effect of constituents from Quercus species (Fagaceae) in classical pathway complement system. We have evaluated leaves of five species of the Quercus genus with regard to its anticomplement activity and have identified its active principles following activity-guided isolation. Bioactivity-guided fractionation of the 80% methanol extracts of the stem barks of Quercus glauca Thunberg has led to the isolation of galloyl derivatives, displaying high anticomplement activity. Four galloyl derivatives isolated from the leaves of Q. glauca, namely 6'-O-galloyl salidroside (1), methyl gallate (2), 1,2,3,6-tetragalloylglucose (3), and 1,2,6-trigalloylglucose (4). 1, 2, 3 and 4 showed inhibitory activity against complement system with 50% inhibitory concentrations (IC(50)) values of 224 μM, 362.4 μM, 32.3 μM, and 138.3 μM. Among the compounds tested, 3 showed the most potent anticomplement activity (IC(50), 32.3 μM). This is the first report of the isolation and anticomplement activity from Q. glauca.     

Ecological and health risk assessment of heavy metals in the Hattar industrial estate,Pakistan

Abstract

This study aimed to determine the heavy metals (HMs) contaminations in soil of the Hattar industrial estate (HIE), Haripur, Khyber Pakhtunkhwa. For this purpose, various types of soils were collected in HIE and analyzed for the HMs concentrations. The HMs showed highest contamination levels in wastewater irrigated agriculture soil (WWIAS), followed by waste dump site soil (WDSS), and the lowest in range land soil (RLS). Determined HMs concentrations were used for pollution quantification factors, including contamination factors (CFs), pollution load index (PLI), ecological risk factor (ER), and potential health risk assessment, including chronic or non-cancer and cancer risk levels.     

Microbial quantities and enzyme activity in soil irrigated with sewage for different lengths of time

Sewage is widely used on agricultural soils in peri-urban areas of developing countries to meet shortages of water resource. Although sewage is a good source of plant nutrients, it also increases the heavy metals loads to soils. Microbial responses to these contaminants may serve as early warning indicators of adverse effects of sewage irrigation on soil quality. The purpose of this study was to assess the effect of time of sewage irrigation on soil microbial indicators. Soil samples were collected from seven soil sites (S1–S7) irrigated with 0 years, 16 years, 23 years, 25 years, 27 years, 32 years and 52 years, respectively in Shijiazhuang of China and analyzed. For each soil sample, we determined the quantities of bacteria, fungi and actinomycete, and enzyme activities of urease, sucrase, phosphatase, dehydrogenase and catalase. Our results showed that the soils of S2–S7 irrigated with sewage effluents for different times (ranged between 16 and 52 years) exhibited higher densities of bacteria, actinomycete, urease, sucrase and phosphatase but lower densities of fungi when compared with S1 irrigated with sewage effluents for 0 years. The soil S7 irrigated with sewage effluents for longest times (52 years) contained lowest activities of catalase when compared with the soils of S1–S6. The densities of bacteria (R = 0.877, p < 0.01), actinomycete (R = 0.875, p < 0.01), sucrase (R = 0.858, p < 0.01) and phosphatase (R = 0.804, p < 0.05) were significantly correlated in a positive manner with time of sewage irrigation. Soil fungi quantities and urease, dehydrogenase and catalase activities did not change significantly with irrigation time. This study confirms that sewage irrigation had negative effects on microbial properties including fungi, catalase and dehydrogenase in the long term, so there is a need for continuous monitoring for sustainable soil health.     

Effects of three peptidase inhibitors, amastatin, captopril and phosphoramidon, on the hydrolysis of [Met5]-enkephalin-Arg6-Phe7 and other opioid peptides

The contents of [Met⁵]-enkephalin-Arg⁶-Phe⁷ (met-enk-RF) and its six hydrolysis products: Y, YG, YGG, YGGF, YGGFM, and YGGFMR were estimated after incubating met-enk-RF with either a guinea-pig ileal or striatal membrane fraction for various times at 37° C. After 45 min incubation with either ileal or striatal membranes, met-enk-RF was completely hydrolyzed, yielding Y as the major product. Incubation with either membrane preparation for 60 min in the presence of the aminopeptidase inhibitor amastatin hydrolyzed 90 or 92% of met-enk-RF, respectively, with YGG being the major product. If the dipeptidyl carboxypeptidase I inhibitor captopril is also included in the incubation, met-enk-RF hydrolysis decreases by about half for both membranes, with YGG remaining the major product. Inclusion of three peptidase inhibitors, amastatin, captopril, and phosphoramidon (inhibition of endopeptidase-24.11) further reduced met-enk-hydrolysis, with 87% or more remaining intact. This shows that met-enk-RF was mainly hydrolyzed by three enzymes, amastatin-sensitive aminopeptidase, captopril-sensitive dipeptidyl carboxypeptidase I and phosphoramidon-sensitive endopeptidase-24.11, in both ileal and striatal membranes. Additionally, estimations of [Leu⁵]-enkephalin (leu-enk), α- and β-neoendorphins (α- and β-neoends), and dynorphin B (dyn B) contents after incubating the individual peptides with striatal membrane for 60 min in the presence of the three peptidase inhibitors showed that 98, 32, 5, and 23%, respectively, remained intact. Our previous studies together with the data obtained here show that one group of endogenous opioid peptides: met-enk, leu-enk, met-enk-RF, met-enk-RGL, and dyn A-(1-8) are largely or almost exclusively hydrolyzed by the three enzymes, amastatin-sensitive aminopeptidase, captopril-sensitive dipeptidyl carboxypeptidase I, and phosphoramidon-sensitive endopeptidase-24.11, and indicate that an unidentified fourth enzyme(s) is involved in the hydrolysis of another group of peptides: α-neoend, β-neoend, and dyn B. Received: 15 July 1997 / Accepted: 20 November 1997     

Anti-allergic activity of sesquiterpenes from the rhizomes of <Emphasis Type="Italic">Cyperus rotundus</Emphasis>

From the 70% ethanol extract of the rhizomes of Cyperus rotundus (CRE), several major constituents including the sesquiterpene derivatives (valencene, nootkatone, and caryophyllene α-oxide), monoterpenes (β-pinene, 1,8-cineole, and limonene) and 4-cymene were isolated and examined for their anti-allergic activity in vitro and in vivo. In rat basophilic leukemia (RBL)-1 cells, the sesquiterpenes strongly inhibited 5-lipoxygenase-catalyzed leukotrienes production. In addition, they inhibited β-hexosaminidase release by antigen-stimulated RBL-2H3 cells, with valencene having the highest inhibitory effect. CRE inhibited leukotrienes production and β-hexosaminidase release at 300 μg/mL. It was also found that the most active sesquiterpene (valencene) and CRE inhibited β-hexosaminidase degranulation by inhibiting the initial activation reaction, Lyn phosphorylation, in IgE-stimulated RBL-2H3 cells. Moreover, CRE, valencene and nootkatone significantly inhibited the delayed-type hypersensitivity reaction in mice when administered orally at 50–300 mg/kg. In conclusion, C. rotundus and its constituents, valencene, nootkatone, and caryophyllene α-oxide, exert anti-allergic activity in vitro and in vivo. These sesquiterpenes, but not monoterpenes, certainly contribute to the anti-allergic activity of the rhizomes of C. rotundus.     

Regulation of Complement Component C3 in Astrocytes by IL-1β and Morphine

Substances of abuse, such as opiates, and astroglial-derived proinflammatory cytokines, such as interleukin (IL)-1β, likely contribute to the neuroinflammatory and neurodegenerative processes observed in NeuroAIDS in injection drug users. Furthermore, uncontrolled synthesis and activation of complement component C3 in the brain can also lead to inflammation and neurodegeneration. We hypothesized that morphine may alter regulation of the C3 gene by IL-1β in astrocytes. Our studies demonstrate that IL-1β induces C3 promoter activity in a CAAT/enhancer-binding protein (C/EBP)-dependent manner. Inhibition of IL-1β mediated C3 promoter activation by the dominant negative mutant of p38-α mitogen-activated protein kinase suggests that IL-1β induces C3 expression through the activation of C/EBP. Morphine (0.01 μM) in combination with IL-1β further induced C3 promoter activity. Similarly, the C/EBP-β isoform liver activating protein and C/EBP-δ-induced C3 promoter activity were upregulated by morphine and IL-1β. Taken together, this study illustrates that morphine modulates IL-1β-mediated C3 expression in astrocytic cells. Part of this work was presented at the 12th SNIP Conference, April 2006, Santa Fe, NM, and HIV/AIDS and Drug Abuse, USA Caribbean Conference, Dec 2006, San Juan, PR.     

Effect of Galphimia glauca methanolic extract on neuropharmacological tests.

Galphimia glauca Cav. (Malpighiaceae) is used in Mexican traditional medicine for the treatment of nervous excitement. A methanolic extract from its aerial parts (MEGA) was tested in several neuropharmacological animal models including among others: hypothermic activity, barbiturate potentiation, protection against strychnine- and leptazol-induced convulsions. The combined data obtained from all biological models demonstrate the sedative property of this plant product.     

Changes in urinary 6β-hydroxycortisol/cortisol ratio after birth in human neonates

Objective: Urinary 6β-hydroxycortisol/cortisol (6β-OHF/C) ratio was measured in human neonates to assess the CYP3A enzyme activity. Methods: Urinary 6β-OHF/C ratio was determined on the day of birth in 94 neonates including those born prematurely. In addition, changes in the ratios after birth were also determined in 81 neonates. Results: On the day of birth, a significant positive correlation was found between urinary 6β-OHF/C ratios and gestational age (r=0.476) and birth weight (r=0.283). There was no gender difference in the urinary 6β-OHF/C ratios in human neonates. Furthermore, delivery modes such as cesarean section and vaginal delivery did not appear to affect the urinary 6β-OHF/C ratio. The mean ratio of urinary 6β-OHF/C observed in 39 mature neonates (more than 37 weeks of gestational age) was higher than that observed in adults (16.5 vs 9.9). Within 5 days after birth, the ratio rapidly decreased to less than that in adults. In contrast, the mean ratio of urinary 6β-OHF/C observed in 42 premature neonates (under 37 weeks of gestational age) was significantly lower than that observed in mature neonates (5.3 vs 16.5) and was virtually unchanged during the 14-days after birth. Therefore, no significant difference was observed in the mean ratio of urinary 6β-OHF/C between mature and premature neonates at 5 days after birth. Conclusion: From these results, it was concluded that on the day of birth, mature neonates might possess a higher activity of CYP3A enzyme compared with premature neonates, and that the CYP3A enzyme activity in mature neonates might be promptly changed at an early stage after birth. Received: 18 March 1997 / Accepted in revised form: 16 September 1997     

The nicotinic antagonist mecamylamine has antidepressant-like effects in wild-type but not β2- or α7-nicotinic acetylcholine receptor subunit knockout mice

Rationale Increases in cholinergic transmission are linked to depression in human subjects and animal models. We therefore examined the effect of decreasing nicotinic acetylcholine receptor (nAChR) activity in tests of antidepressant efficacy using C57BL/6J mice.Objectives We determined whether the noncompetitive nAChR antagonist mecamylamine had antidepressant-like effects in the forced swim test (FST) and tail suspension test (TST). These experiments were repeated in mice lacking either the β2- or α7-nAChR subunits to identify the nAChR subunits involved in mediating the antidepressant response to mecamylamine.Materials and methods Adult mice on the C57BL/6J background were acutely administered mecamylamine i.p. 30 min before testing in the FST or TST.Results A dose–response study showed that mecamylamine significantly decreased immobility time in the TST at the 1.0-mg/kg dose but did not alter baseline locomotor activity. The competitive nAChR antagonist dihydro-β-erythroidine, but not the blood–brain barrier impermeant antagonist hexamethonium, also decreased immobility in the TST. One milligram per kilogram of mecamylamine also significantly decreased time immobile in the FST whereas both β2- and α7-knockout mice were insensitive to the effects of mecamylamine in the FST.Conclusions Decreased activity of central nAChRs has antidepressant-like effects in both the TST and FST and these effects are dependent on both β2 and α7 subunits. Therefore, compounds that decrease nAChR activity may be attractive new candidates for development as antidepressants in humans.     

Oltipraz promotion of liver regeneration after partial hepatectomy: The role of PI3-kinase-dependent C/EBPβ and cyclin E regulation

Oltipraz, a representative cancer chemopreventive agent, regenerates cirrhotic liver via CCAAT/enhancer binding protein β (C/EBPβ). This study examined the effect of oltipraz on liver regeneration after partial hepatectomy (PH) and explored the role of phosphatidylinositol 3-kinase (PI3K) pathway responsible in liver regeneration. Oltipraz treatment (30 mg/kg/day, for 3 days) promoted liver regeneration in PH rats, but did not increase hepatocyte growth factor production. Subcellular fractionation and electrophoretic mobility shift assays showed that oltipraz treatment increased C/EBPβ-DNA binding activity in the liver of sham control rats and further enhanced PH-mediated nuclear translocation of C/EBPβ. The expression of cyclin E and the activity of cyclin E-dependent kinase were both enhanced by oltipraz treatment of PH rats. The signaling pathway that controls C/EBPβ and cyclin E were studied in H4IIE cells, a rat-derived hepatocyte cell line. Oltipraz potentiated the nuclear accumulation of C/ EBPβ and C/EBPβ-DNA binding activity in cells incubated in a medium containing serum. PI3K and its downstream kinase, p70S6 kinase, were both required for C/EBPβ-dependent induction of cyclin E by oltipraz, as shown by chemical inhibition and plasmid transfection experiments. The results of this study demonstrate that oltipraz treatment enhances liver regeneration after PH, which involves activation of C/EBPβ and C/EBPβ-dependent cyclin E expression via the PI3K-p70S6 kinase pathway.     

骨髓间充质干细胞/骨基质明胶复合体修复大鼠桡骨缺损的放射学研究

目的构建骨髓间充质干细胞/骨基质明胶复合体修复大鼠桡骨节段骨缺损,为骨组织工程中制备组织化骨提供理论依据。方法制备成MSCs/BMG复合体和桡骨缺损模型。实验组为A组：MSCs/BMG组;对照组：B组：BMG组;C组：MSCs 1×10^6/ml组。每组都设置2、4、8、12周四个时间点进行取材。观察术肢X射线放射学、免疫组织化学等检测骨缺损的修复情况。结果X射线放射学评分4、8、12周各组均有明显差异（P〈0.01）。Ⅰ型胶原蛋白表达各组随着时间的延长均有明显增强,各组均有明显差异（P〈0.01）。结论骨髓间充质干细胞与骨基质明胶复合修复桡骨缺损效果优,可以用于组织化骨。     

Alpha1-and beta2-adrenoceptors in the human liver with mass-forming intrahepatic cholangiocarcinoma: density and coupling to adenylate cyclase and phospholipase C

Besides the regulation of hepatic metabolic pathways in which adrenoceptors are mainly involved, their effect on the second messenger cAMP is thought to be related to the growth and differentiation of neoplastic cells. However, few studies have been done on the status of these structures in the human liver affected by cholangiocarcinoma (CC). Thus, in this study, changes in densities of α₁- and β₂-adrenoceptors (α₁-and β₂-ARs) were investigated in membranes of human liver with cholangiocarcinoma, and for comparison, in membranes of non-adjacent non-tumour liver using the potent antagonists [³H]-prazosin and [¹I]-iodocyanopindolol (ICYP) respectively. In addition, the activity of membrane-bound phospholipase C (PLC) and adenylate cyclase (AC) was also studied. In CC liver, the density of α₁-and β₂-ARs was significantly reduced, compared with non-tumour liver tissues (α₁-ARs: 23.38±4.69 vs 80.35±10.52, P=0.0002 β₂-ARs: 14.27±2.93 vs 33.22±4.32 fmol/mg protein, P=0.03), whereas the ligand affinities (K_D) remained unchanged. The β₂-selective antagonist ICI 118,551 was about 100 times more potent in inhibiting ICYP binding than the β₁-selective antagonist CGP 20712A; thus, more than 98% of the β-ARs were of the β₂-subtypes. The AC activity upon stimulants acting on β-AR (isoprenaline), G-protein (GTP, NaF) and AC (forskolin) was decreased in CC liver. Similarly, noradrenaline-stimulated PLC activity was significantly reduced in tumour tissues. In conclusion, in CC liver the α₁- and β₂-ARs density was down-regulated and the neoplastic invasion blunted AC and PLC activity. These quantitative changes may help to elucidate not fully understood pathogenetic mechanisms of disturbed hepatic metabolic processes, such as hypoglycemia during cancer in human liver.     

17β-Estradiol attenuates vascular contraction through inhibition of RhoA/Rho kinase pathway

We hypothesized that 17β-estradiol attenuates vascular contraction through inhibition of RhoA/Rho kinase pathway. Rat aortic rings were contracted with cumulative addition of U46619, NaF, KCl or PDBu 30 min after pretreatment with 17β-estradiol (10, 30, and 100 μM) or vehicle. We measured the amount of GTP RhoA and the level of phosphorylation of the myosin light chain (MLC₂₀), myosin phosphatase targeting subunit 1 (MYPT1) and PKC-potentiated inhibitory protein for heterotrimeric MLCP of 17 kDa (CPI17). Pretreatment with 17β-estradiol dose-dependently inhibited the concentration-response curves in response to U46619, NaF or KCl, but not to PDBu. 17β-Estradiol decreased not only the level of phosphorylation of MYPT1^Thr855 and CPI17^Thr38 as well as MLC₂₀, but also the activity of RhoA induced by U46619 or NaF. However, 17β-estradiol did not affect the level of phosphorylation of CPI17 induced by PDBu. 17β-Estradiol attenuates vascular contraction through inhibition of RhoA/Rho kinase pathway.     

Chronic Ingestion of Uranium in Drinking Water: A Study of Kidney Bioeffects in Humans

A study was conducted of the chemical effects on the human kidneyinduced by the chronic ingestion of uranium in drinking water.Subjects were divided into two groups: The low-exposure group,whose drinking water was obtained from a municipal water systemand contained <1 µg uranium/L, and the high-exposuregroup, whose drinking water was obtained from private drilledwells and contained uranium levels that varied from 2 to 781µg/L. Years of residence varied from 1 to 33 years inthe low-exposure group and from 3 to 59 years in the high-exposuregroup. The indicators of kidney function measured in this studyincluded glucose, creatinine, protein, and ß₂-microglobulin(BMG). The markers for cell toxicity studied were alkaline phosphatase(ALP),     

Therapeutic effect of Kalpaamruthaa,a herbal preparation on adjuvant induced arthritis in wistar rats

The present study was performed in order to establish the efficacy of Kalpaamruthaa (KA), a modified indigenous Siddha preparation in adjuvant induced arthritic rat (AIA) model with reference to mediators of inflammation (lysosomal enzymes) and its effect on proteoglycans. Albino rats of Wistar strain were divided into seven Groups of six animals each. Arthritis was induced to rats by subcutaneous injection of 0.1 ml of Complete Freund’s Adjuvant into the plantar surface of the left hind paw. Group I served as normal control rats receiving 0.5 ml of olive oil as vehicle, Group II arthritic rats served as induced-untreated and Group III (50 mg/kg), Group IV (100 mg/kg), Group V (150 mg/kg), Group VI (200 mg/kg) and Group VII (250 mg/kg) were KA treated rats at different dose levels orally in 0.5 ml of olive oil from 14^th day of adjuvant injection and was terminated on day 28. Animals were then sacrificed on the day 29, blood was collected, liver and kidney were dissected out, washed and 10% homogenates were prepared. The activities of lysosomal enzymes (β-glucuronidase, β-galactosidase, acid phosphatase, β-N-acetyl glucosaminidase and cathepsin-D), aminotransferases (alkaline phosphatase, aspartate and aminotransferases) and levels of plasma protein bound carbohydrate components of glycoproteins were determined and were found to be elevated in arthritic rats when compared to control animals. After administration of KA, the activities of lysosomal enzymes, aminotransferases and protein-bound carbohydrate component levels were significantly normalized. The data obtained evidently indicate that Kalpaamruthaa is effective at the dose of 150 mg/kg b.wt. in AIA and plays an important role in lysosomal membrane stabilization. This was further confirmed by radiological, histological and electron microscopic studies. Received 21 November 2006; revised 6 April 2007; accepted 13 April 2007     

α4β2 Nicotinic receptor stimulation contributes to the effects of nicotine in the DBA/2 mouse model of sensory gating

Rationale Nicotine improves the deficiencies of sensory gating function in schizophrenic patients and in dilute brown non-Agouti (DBA/2) mice. This effect of nicotine has been attributed to activation of the α₇ nicotinic acetylcholine receptor (nAChR) subtype.Objective The aim of this study was to determine whether the activation of another nAChR subtype, the central nervous system (CNS) prominent α₄β₂ receptor, also contributes to the effects of nicotine on sensory gating in DBA/2 mice.Methods Unanesthetized DBA/2 mice were treated either with nicotine, the α₄β₂ antagonist dihydro-β-erythroidine, the noncompetitive nAChR antagonist mecamylamine, or a combination of an antagonist and nicotine. Thereafter, gating was assessed by recording hippocampal evoked potentials (EP), which were elicited by pairs of auditory clicks. The EP response to the second click, or test amplitude (TAMP), was divided by the EP response to the first click, or condition amplitude (CAMP), to derive gating T:C ratios.Results Nicotine significantly (p<0.05) lowered T:C ratios by 42%, while significantly increasing CAMP by 55%. After a pretreatment with dihydro-β-erythroidine, nicotine still significantly lowered T:C ratios by 28%; however, the nicotine-induced increase of CAMP was blocked. Mecamylamine blocked the effect of nicotine on both T:C ratios and CAMP.Conclusions Activation of α₄β₂ receptors by nicotine increases CAMP. However, under conditions where α₄β₂ receptors are blocked, nicotine still lowers T:C ratios and may improve sensory gating, possibly through the activation of other nAChR subtypes such as α₇. These effects of nicotine on auditory EPs may be indicative of a profile that would improve information processing in schizophrenia and other CNS diseases.     

Protein phosphatase 2A, a key player in Alzheimer’s disease

Protein phosphatase 2A (PP2A) is the predominant serine/threonine phosphatase in eukaryotic cells. In the brains of patients with Alzheimer’s disease (AD), decreased PP2A activities were observed, which is suggested to be involved in neuro.brillary tangle (NFT) formation, disturbed amyloid precursor protein (APP) secretion and neurodegeneration in AD brain. Based on our research and other previous findings, decreased PP2Ac level, decreased PP2A holoenzyme composition, increased level of PP2A inhibitors, increased PP2Ac Leu309 demethylation and Tyr307 phosphorylation underlie PP2A inactivation in AD. β-amyloid (Aβ) overproduction, estrogen deficiency and impaired homocysteine metabolism are the possible up-stream factors that inactivate PP2A in AD neurons. Further studies are required to disclose the role of PP2A in Alzheimer’s disease.     

Hormonal activity of combinations of genistein, bisphenol A and 17β-estradiol in the female Wistar rat

Phytoestrogens have been described as weak estrogens,selective estrogen receptor mediators (SERMs) or to exhibit antiestrogenic properties. However, information about their activity in combination with xenoestrogens and 17β-estradiol in vivo, is limited. Therefore, the combinatory activity of the phytoestrogen genistein (Gen), the industrial chemical bisphenol A (BPA), and ethinylestradiol (EE) in ovariectomized Wistar rats was analyzed in this study. All compounds were administered orally on three consecutive days (EE at 30 μg, Gen at 100 mg and BPA at 200 mg per kg body weight per day). The pure antiestrogen fulvestrant (3 mg/kg) served as estrogen receptor (ER) antagonist control. Effects on uterine wet weight, height of the uterine epithelium, uterine clusterin (Clu) and complement C3 expression, and the height of the vaginal epithelium were examined. Treatment with Gen alone resulted in a moderate stimulation of uterine weight; in the vagina the height of the epithelium was strongly stimulated. BPA did not stimulate any of the above-mentioned parameters significantly. In combination with EE, Gen acted on most of the analyzed parameters in an additive manner, whereas BPA significantly antagonized the effects of EE on the uterine epithelium and uterine Clu expression. Given in combination with Gen, BPA was also able to antagonize the stimulatory effect of Gen on the uterine epithelium. In summary, our results demonstrate that Gen, in contrast to BPA, does not exhibit any antiestrogenic properties, even if given at high concentrations. The results of this study characterize BPA as a functional antiestrogen, very likely the result of a lack of ability to activate ER-mediated transactivation after binding to the receptor. This is not the case for Gen. Our results point to the involvement of complex molecular mechanisms in the action of Gen. These mechanisms, especially the role of ERβ have to be characterized in further investigations.