Anti-implantation activity of 2 derivatives of o-hydroxy naphthaquinones in rats

AIM:To search for female contraceptive agents. METHODS: 2-Hydroxy-3-methyl-1, 4-naphthoquinone monosemicarbazone ( HMNQS ) and 2-hydroxy-1, 4-naphthoquinone monothiosemicarbazone ( HNQTS ) were screened for anti-implantation activity in rats. RESULTS: Both compounds showed a dose-dependent activity, and HNQTS was more potent. An 100 % anti-implantation activity was observed with HNQTS 150 mg kg-1 ig . Its LD50 was found to be >2g kg-1 ig in mice. CONCLUSION: HNQTS was more potent than HMNQS for anti-implantation activity in rats.     

丙泊酚镇痛作用及其与阿片受体的关系

目的观察丙泊酚在亚睡眠剂量时对大鼠的抗伤害作用及其与阿片受体的关系。方法选用成年雄性Wistar大鼠,通过甩尾（TFL）、电刺激鼠尾嘶叫（TSV）和结直肠扩张（CIm）法测定动物的痛阈。观察丙泊酚20mg／kg和同时应用阿片受体拮抗剂纳洛酮1mg／kg对大鼠痛阈的影响,以等效剂量硫喷妥钠作为对照。结果丙泊酚20mg／kg显著提高TSV、CRD和TFL伤害性反应阈值。采用TSV抗伤害作用时间持续60min以上,而采用TFL和CRD抗伤害作用≤30min。等效剂量硫喷妥钠无论采用TFL、TSV或CRD都无明显提高大鼠痛阈的作用。纳洛酮1mg／kg可以拮抗或部分拮抗丙泊酚引起的抗伤害作用。结论与等效量硫喷妥钠相比,亚睡眠剂量的丙泊酚在大鼠能产生一定的镇痛效应;这种镇痛效应可能与丙泊酚间接作用于中枢阿片受体有关。     

Convulsant effect of diphenyl diselenide in rats and mice and its relationship to plasma levels

Diphenyl diselenide [(PhSe)₂], an organoselenium compound, presents pharmacological and toxicological properties in rodents. The aim of this study was to carry out the determination and quantification of (PhSe)₂ in plasma after oral administration (p.o.) of this compound (500 mg/kg), dissolved in canola oil, in rats and mice. The second objective was to verify the involvement of different routes of administration ((p.o.), intraperitoneal (i.p.) and subcutaneous (s.c.)) and vehicle solutions (canola oil and dimethyl sulfoxide (DMSO)) in the appearance of seizure episodes and in the plasmatic levels of (PhSe)₂ in rats and mice. Analysis of (PhSe)₂ in blood samples was performed by gas chromatography/flame ionized detector system (GC/FID). Rat and mouse peak plasma (PhSe)₂ levels were 13.13 and 10.11 μg/ml (C_max), respectively, and occurred at 0.5 h (T_max) post-dosing. The use of different administration routes (p.o., i.p. and s.c.) and vehicle solutions (canola oil or DMSO) in rats and mice indicated that the appearance of seizures and (PhSe)₂ plasmatic levels are dependent of administration routes (i.p. > p.o. > s.c.), vehicle solutions (DMSO > canola oil) and animal species (mice > rat).     

Immunosuppressive activity of 15-deoxyspergualin and its effect on skin allografts in rats

The immunosuppressive activity of spergualin analogues, 15-deoxyspergualin and N-30, is presented. These compounds suppressed antibody formation and establishment of delayed-type hypersensitivity to sheep red blood cells (SRBC) in mice. Among spergualin, 15-deoxyspergualin, and N-30, 15-deoxyspergualin was most effective in suppressing immune responses. It suppressed antibody formation against SRBC by spleen cell cultures in a dose-dependent fashion without reducing cell viability. The spergualins also suppressed the mixed lymphocyte culture reaction. Peritoneal exudate cells taken from mice given immunosuppressive doses of 15-deoxyspergualin were not reduced in their functions measured: Release of lysosomal enzymes and production of superoxide anions. 15-Deoxyspergualin and N-30 were markedly effective in prolonging skin graft in rats.     

Antidiabetic activity of Aegle marmelos and its relationship with its antioxidant properties

Oxidative stress induced by alloxan has been shown to damage pancreatic beta-cell and produce hyperglycemia in rats. Aegle marmelos leaf extract is being used in Ayurveda as a medicine for diabetes. The present study examined the action of Aegle marmelos against experimental diabetes as well as the antioxidant potential of the drug. A methanolic extract of Aegle marmelos was found to reduce blood sugar in alloxan diabetic rats. Reduction in blood sugar could be seen from 6th day after continuous administration of the extract and on 12th day sugar levels were found to be reduced by 54%. Oxidative stress produced by alloxan was found to be significantly lowered by the administration of Aegle marmelos extract. This was evident from a significant decrease in lipid peroxidation, conjugated diene and hydroperoxide levels in serum as well as in liver induced by alloxan. Catalase and glutathione peroxidase activity in blood and liver were found to be increased from 9th day onwards after drug administration. Superoxide dismutase and glutathione levels were found to be increased only on 12th day. These results indicate that Aegle marmelos extract effectively reduced the oxidative stress induced by alloxan and produced a reduction in blood sugar.     

卡托普利对蛋氨酸所致血管内皮功能损伤的保护作用与对氧磷酶1的关系

目的探讨卡托普利对高蛋氨酸饮食所致大鼠血管内皮功能损伤的保护作用及其机制。方法将蛋氨酸通过灌胃的方法,1次.d-1,连续4周,诱导大鼠血管功能损伤,治疗组同时给予卡托普利、依那普利、N-乙酰半胱氨酸灌胃。4周后处死动物,检测血清一氧化氮(nitric oxide,NO)、丙二醛(malondialdehyde,MDA)含量、对氧磷酶(paraoxonase 1,PON1)、超氧化物歧化酶(superoxide dismutase enzyme,SOD)、血管紧张素转换酶(an-giotensin-converting enzyme,ACE)活性。取胸主动脉检测由乙酰胆碱(acetylcysteine,Ach)诱导的血管内皮依赖性舒张反应。结果高蛋氨酸损伤组大鼠血管内皮依赖性舒张反应显著减弱,血清中MDA浓度升高,PON1活性、血浆NO浓度与SOD活性降低;卡托普利、N-乙酰半胱氨酸和依那普利能显著改善血管内皮依赖性舒张反应、降低MDA浓度、提高血清中的PON1活性、SOD活性和NO浓度。结论卡托普利能够改善高蛋氨酸引起的血管内皮功能的损伤,该作用可能与保护PON1活性及其抗氧化作用、促进内皮细胞释放NO有关。     

利奈唑胺对大鼠血细胞的影响及与氧化应激间的关系

目的研究利奈唑胺对大鼠血细胞的影响及与氧化应激间的关系。方法将80只大鼠分为4组:空白对照组、利奈唑胺50、100、250 mg/kg组,连续给药15 d,监测血细胞及血清超氧化物歧化酶(SOD)、过氧化氢酶(CAT)、还原型谷胱甘肽(GSH)、谷胱甘肽过氧化物酶(GSH-Px)、还原型辅酶Ⅱ(NADPH)、丙二醛(MDA)的变化。结果 250 mg/kg利奈唑胺可引起大鼠血细胞减少,血清SOD、CAT活性下降,MDA含量增加;100、250mg/kg利奈唑胺可引起大鼠血清NADPH含量升高,与空白对照组比较差异有统计学意义;各组利奈唑胺对大鼠血清GSH、GSH-Px活性无显著性影响。结论高剂量利奈唑胺较长时程给药后可引起大鼠血细胞减少,其机制可能与引起机体氧化应激后诱导脂质过氧化产生有关。     

The effect of piroxicam on locomotor activity in rats with adjuvant-induced arthritis

To evaluate the effectiveness of piroxicam, a clinically effective, long-acting, nonsteroidal antiinflammatory drug, in a potential animal model of chronic nociception, the locomotor activity of arthritic rats was monitored over long periods of time by computer. Rats injected with complete Freund's adjuvant (CFA) displayed locomotor deficits as measured by both horizontal and vertical activity. In experiment 1, to test the effectiveness of piroxicam therapy in severely arthritic animals, administration of piroxicam (1--10 mg/kg/day) was initiated 14 days after CFA injection and activity was recorded for 5 days. It was found that a single treatment significantly increased the mobility of the arthritic animals and the 4 additional days of treatment induced continued improvement in mobility and reduction in paw swelling. In experiment 2, to assess the effect of piroxicam on the development of the immobility associated with CFA-induced arthritis, piroxicam administration (0.3--3.3 mg/kg/day) was initiated prior to CFA injection and locomotor activity was monitored for 16 days. It was demonstrated that the activity of CFA-injected rats severely and progressively decreased and that piroxicam significantly increased the activity of the arthritic rats, while having no effect on the activity of the nonarthritic control animals. These studies demonstrate the efficacy of piroxicam in arthritic rats and, although further investigation is necessary, demonstrate that the measurement of locomotor activity in arthritic rodents may be an important tool for the identification and evaluation of antiinflammatory/analgetic agents.     

Antiestrogenic and antitumor effects of droloxifene in experimental breast carcinoma

The pharmacological effects of droloxifene [E)-a [p-[2-(dimethylamino)ethoxy]phenyl]-a'-ethyl-3-stilbenol, FK435), a new antiestrogen drug, were studied and compared with those of tamoxifen in animals and in vitro cultured cells. Droloxifene showed about 20-fold and 3-fold higher affinity to estrogen receptors (ER) in the rat uterus and human ER positive MCF-7 breast carcinoma cells, respectively, than tamoxifen, and was more active in decreasing uterine weight of mature rats and 17 beta-estradiol-treated immature rats. Tamoxifen increased uterus growth in immature rats, but droloxifene did not, suggesting that droloxifene has no estrogenic effects. Both drugs inhibited the growth of in vitro cultured MCF-7 cells, with droloxifene being the more active agent, but this effect of both drugs was countered by 17 beta-estradiol. Neither drug, however, had effects on the in vitro growth of human ER negative MDA-MB-231 breast carcinoma cells. In vivo, both drugs inhibited the growth of MCF-7 carcinoma implanted subcutaneously in BALB/c nu/nu mice, but not the growth of human ER negative MX-1 breast carcinoma. The results suggest that droloxifene has antitumor effects on human ER positive breast cancers, and would be useful for the treatment of estrogen-dependent breast cancers.     

High-dose clastogenic activity of aniline in the rat bone marrow and its relationship to the carcinogenicity in the spleen of rats

To clarify the question of clastogenicity of aniline in rats two studies were performed: a bone marrow micronucleus test and a bone marrow metaphase test. In the micronucleus test aniline (as aniline hydrochloride) was administered to groups of seven male PVG rats at single oral doses of 0, 300, 400, or 500 mg/kg body weight. Bone marrow was obtained 24 and 48 h after oral treatment. Smears of bone marrow were stained with acridine orange and erythrocytes were examined for the presence of micronuclei. Animals receiving cyclophosphamide (1x7.5 mg/kg) served as positive controls. Clinical signs observed in animals dosed at 300 mg/kg and above included cyanosis, light brown coloured urine and cold to touch. Small, but statistically significant and dose-related increases in the incidence of micronulei over the vehicle control values were observed at the 24-h sampling time only. Cyclophosphamide induced a significant and comparably much higher increase in micronuclei than aniline. In the bone marrow metaphase test aniline (as aniline hydrochloride) was administered to groups of seven male PVG rats at single oral dose levels of 0, 300, 400, or 500 mg/kg body weight. Bone marrow was sampled 18 and 30 h after dosing. A group treated with cyclophosphamide (1x40 mg/kg) served as positive control. A small increase in the percentage of aberrant cells above solvent control values was recorded in one rat at 400 mg/kg and four rats at 500 mg/kg at the 18-h sampling time only. The positive control cyclophosphamide induced a much higher rate of aberrant cells in all animals. Several lines of evidences are presented against a causal relationship between the clastogenic activity in male PVG rats at 400 and 500 mg/kg and the carcinogenicity in the spleen of Fischer 344 rats starting at 30 mg/kg in males. Among these are the dose-response relationship of the tumour incidence, the close correlation between degree of spleen damage and tumour induction, the lack of carcinogenic effects in mice even at higher dose levels, or in rats at dose levels inducing only slight haematotoxicity and spleen toxicity, and the available data on the mode of action of other chemicals inducing spleen tumours.     

The anti-estrogenic activity of sediments from agriculturally intense watersheds: assessment using in vivo and in vitro assays

The goal of the current study was to determine whether sediments from agriculturally intense watersheds can act as a potential source of anti-estrogenic endocrine-disrupting compounds. The specific objectives of the current study were to determine (1) whether female fathead minnows (Pimephales promelas) experience alterations in endocrine function when exposed to sediments collected from agriculturally intense watersheds and (2) if these sediments display anti-estrogenic activity in an in vitro assay. In addition, sediment samples were analyzed for the presence of steroid hormones and pesticides associated with local agricultural practices. To accomplish this, sediments and water were collected from three sites within two agriculturally intense Nebraska watersheds (Bow Creek and the Elkhorn River). In 2009, minnows were exposed to sediment and/or water collected from the two Bow Creek sites (East Bow Creek and the Confluence) in the laboratory, while in 2010, minnows were exposed to sediment and/or water from East Bow Creek, the Confluence and the Elkhorn River. Following the 7-day exposure period, the hepatic mRNA expression of two-estrogen responsive genes, estrogen receptor α (ERα) and vitellogenin (Vtg) was determined. In 2009, females exposed to Confluence sediments, in the presence of laboratory water or Confluence water, experienced significant reductions in ERα expression relative to unexposed and Confluence water-exposed females. The defeminization of these females suggests the presence of a biologically available anti-estrogenic compound in sediments collected from this site. In 2010, sediments were assessed for anti-estrogenic activity on days 0 and 7 of the exposure period using a 4-h yeast estrogen screen. Lipophilic extracts (LEs) of day 0 sediments collected from the Confluence and the Elkhorn River induced significant reductions in the estrogenic reporter activity of treated yeast cultures suggesting the presence of a lipophilic anti-estrogenic compound in these extracts. Chemical analysis revealed the presence of a variety of steroid hormones, including those associated with the production of beef cattle (i.e. β-trenbolone, α-zearalanol and α-zearalenol), in sediments indicating that compounds utilized by local beef cattle operations are capable of entering nearby watersheds. Overall, the results of this study indicate that an environmentally relevant anti-estrogenic compound is present in sediments from agriculturally intense watersheds and that this compound is bioavailable to fish. Furthermore, the presence of steroid hormones in sediments from these watersheds provides evidence indicating that steroids are capable of sorbing to sediments.     

The quinine-haemin interaction and its relationship to antimalarial activity

Benzene-soluble complexes of quinine and related antimalarial drugs with haemin (ferriprotoporphyrin IX) were examined spectrophotometrically and gave evidence for coordination of haemin iron with the nitrogen atom of the quinuclidine or piperidine group. The antimalarially inactive 9-epimer of quinine did not show evidence of coordination with haemin. A model of the interaction is presented.     

Analgesic and antioxidant activity of mangiferin and its derivatives: the structure activity relationship

Mangiferin, 2-beta-D-glucopyranosyl-1,3,6,7-tetrahydroxy-9H-xanthen-9-one, obtained directly from methanolic extracts of Bombax ceiba leaves in substantial amounts demonstrated strong antioxidant activity (EC(50) 5.8+/-0.96 mug/ml or 13.74 muM) using DPPH assay comparable to rutin, commonly used as antioxidant for medical purposes. The acetyl and cinnamoyl derivatives were found to be less active than mangiferin whereas, methyl and 3,6,7-trimethylether tetraacetate derivatives were inactive implying that for antioxidant activity, free hydroxyl groups and catechol moiety are essential. Moreover, mangiferin showed hepatoprotective activity against carbon tetrachloride induced liver injury further supporting the free radical scavenging property in the in vivo system. Additionally, plant extracts and mangiferin failed to exhibit acute anti-inflammatory activity whereas, it displayed significant analgesic effect in acetic acid-induced writhing and hot plate tests in mice. Using naloxone, it was revealed that plant extracts induced analgesia was independent of opioid receptor, whereas, mangiferin demonstrated significant interaction with it at peripheral site with a slight contribution at the neuronal level.     

屈洛昔芬对假孕大鼠黄体细胞凋亡和Bax、Bcl-2蛋白表达的影响(英文)

目的:研究屈洛昔芬对假孕大鼠黄体细胞凋亡和Bax、Bcl-2蛋白表达的影响。方法:HE染色观察大鼠卵巢黄体组织学变化,TUNEL法检测黄体中凋亡细胞的存在,免疫组织化学方法观察假孕大鼠卵巢黄体中Bax和Bcl-2蛋白的表达。结果:成年假孕大鼠卵巢黄体自然退化中黄体细胞凋亡出现在假孕第13天,15天时可观察到凋亡细胞的显著增加。Bax和Bcl-2蛋白在黄体细胞中的表达在整个黄体自然退化中无显著改变。20mg·kg~(-1)假孕大鼠第2天口服给予20mg·kg~(-1)屈洛昔芬后,第8天观察时黄体中出现凋亡细胞,且假孕期从(15.5±1.1)天缩短至(12.8±1.6)天。经屈洛昔芬作用后,假孕大鼠黄体中Bax蛋白的表达增加而Bcl-2蛋白表达下降。结论:成年假孕大鼠卵巢黄体自然退化中有细胞凋亡的发生,屈洛昔芬可加速假孕大鼠黄体细胞凋亡的出现并可缩短假孕期。Bax和Bcl-2蛋白的表达在假孕不同时间时无明显改变,而屈洛昔芬所诱导的Bax/Bcl-2的增加可能与该药物对黄体细胞凋亡的促进作用有关。     

Correlation of lithium effects on motor activity with its brain concentrations in rats

Effects of lithium (Li) on motor activity have been investigated at different post-drug intervals (0.5–72 hr) after adminstration of 1, 2 and 3 mequiv/kg of lithium cholride (LiCl) to rats. The activity gradually decreased until the maximum effects of these doses were observed at 8 hr, after which the activity returned to control levels (48–72 hr). Lithium concentrations were estimated in various brain areas (cortex, caudate nucleus, hypothalmus, rest of the diencephalon, midbrain, ponsmedulla and cerebellum) following administration of a 3 mequiv/kg dose of LiCl to rats at different post-drug intervals (0.5–48 hr). Lithium concentrations increased gradually reaching their peak at 8 hr in almost all brain areas except for the caudate nucleus where the peak level was achieved at 12 hr. The time-course of the depressant effect of Li on motor activity correlated with the changes in Li concentrations in the brain areas related to emotion and psychomotor activity.     

Assessing the relationship between latent inhibition and the partial reinforcement extinction effect in autoshaping with rats

Results from a variety of independently run experiments suggest that latent inhibition (LI) and the partial reinforcement extinction effect (PREE) share underlying mechanisms. Experiment 1 tested this LI=PREE hypothesis by training the same set of rats in situations involving both nonreinforced preexposure to the conditioned stimulus (LI stage) and partial reinforcement training (PREE stage). Control groups were also included to assess both LI and the PREE. The results demonstrated a significant, but negative correlation between the size of the LI effect and that of the PREE. Experiment 2 extended this analysis to the effects on LI and the PREE of the anxiolytic benzodiazepine chlordiazepoxide (5 mg/kg, i.p.). Whereas chlordiazepoxide had no effect on LI, it delayed the onset of the PREE. No evidence in support of the LI=PREE hypothesis was obtained when these two learning phenomena were compared within the same experiment and under the same general conditions of training.