Timing of oral glutamine on DMBA-induced tumorigenesis

INTRODUCTION: A single dose of oral 7,12-dimethylbenz(a)anthracene (DMBA) in pubertal rats causes breast tumors by 11 weeks and is associated with ablation of the normal gut glutathione (GSH) production for up to 4 weeks. We hypothesized that glutamine (GLN), known to restore the gut GSH production inhibited by DMBA, given only during this 4-week period, would prevent breast cancer initiation. METHODS: 160 Female Sprague-Dawley rats were divided to 10 groups (n = 16/group): Long Term (LT): DMBA + GLN, DMBA + FA, DMBA + H2O, OIL + GLN, OIL + FA, OIL + H2O; Short Term (ST): DMBA + GLN, DMBA + FA, OIL + GLN, OIL + FA At age 50 days old, rats received a one-time dose of 100 mg/kg DMBA or sesame oil. LT rats were gavaged daily with isonitrogenous GLN, (FA), or water (H2O) the entire study. ST rats were gavaged with GLN, freamine, or H2O the first 4 weeks and then H2O the remaining 7 weeks. All rats were pair-fed defined chow. Rats were sacrificed at 11 weeks, observed for tumors, blood assayed for GLN, GSH, gut GLN and GSH and uptake or production calculated using labeled C-14-PAH. RESULTS: ST and LT GLN were equally effective in preventing tumor formation. GLN doubled gut GSH production in LT animals as compared to all other groups (P < 0.05). Control rats developed no tumors and had superior gut GSH production as compared with tumor-bearing rats. CONCLUSIONS: Oral GLN when given only during the 4 weeks of known gut GSH ablation had the same tumor prevention efficacy as prolonged GLN administration. Not previously reported, GLN appears to affect the initiation of tumor formation in this model.     

Gut glutathione metabolism and changes with 7,12-DMBA and glutamine

INTRODUCTION: The mechanism by which oral glutamine (GLN) prevents 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast cancer is unknown. While GLN triples the negative extraction of gut glutathione (GSH) in rats, DMBA significantly disrupts it. Actual gut GSH flux has not been reported. We hypothesized that the gut is a producer of GSH; DMBA blocks gut GSH production and supplemental oral GLN antagonizes this effect. MATERIALS AND METHODS: Eighty Sprague-Dawley rats were randomized to four groups (n = 20/group): DMBA + GLN, DMBA + FA, OIL + GLN, OIL + FA. Rats (age 50 days) were gavaged with a one-time dose of 100 mg/kg DMBA or oil. Rats were gavaged with AES-14 as GLN (1 gm/kg/day) or an isonitrogenous amount of Freamine (FA) from 1 week before till sacrifice at 1 week after DMBA (greatest effect on gut GSH extraction). Arterial and portal blood was taken for GLN and GSH levels, and blood flow was measured using (14)C-PAH. Gut GLN and GSH fluxes (uptake or production) were calculated. RESULTS: DMBA abrogated the normal GSH production (negative flux) in OIL + FA while not affecting GLN metabolism. GLN maintained GSH production in DMBA + GLN. CONCLUSIONS: Oral GLN restores to normal GSH production in DMBA-treated animals suggesting one of the mechanism(s) by which GLN prevents breast cancer in this model. Unchanged uptake of GLN in the DMBA-treated animals may indicate a block in GSH transport rather than actual intracellular production.     

Effect of glutamine on glutathione,IGF-I,and TGF-beta 1

BACKGROUND: Our previous results have showed that oral glutamine (GLN) supplementation decreased carcinogenesis in 7,12-dimethylbenz[a]antracene (DMBA) breast cancer model. We also have found that GLN raises blood glutathione (GSH) levels in an implantable breast cancer model. The process of tumor growth was accompanied by depressed GSH production and increased levels of insulin-like growth factor-I (IGF-I) and transforming growth factor beta1 (TGF-beta 1). GSH is counter-regulatory to IGF-I. We therefore hypothesized that in DMBA model of breast cancer, the increased GSH levels seen with oral GLN would be associated with lowered levels of IGF-I &TGF-beta(1). METHODS: Time-dated pubertal Sprague-Dawley rats were gavaged at time 0 with 1 g/kg/day glutamine (GLN) (n = 18), isonitrogenous Freamine (FA) (n = 18), or water (H(2)O) (n = 18). Rats were further randomized on day 7 to 100 mg/kg DMBA or oil. After 14 days, the animals were sacrificed and blood GSH, IGF-1, TGF-beta 1, breast tissue, and gut mucosa GSH levels were measured. RESULTS: Oral GLN increased significantly blood, breast tissue, and gut mucosa levels of GSH in both DMBA and control groups in comparison with the control groups not treated with GLN. At the same time, the levels of blood IGF-I and TGF-beta 1 decreased significantly in both DMBA-treated and control groups. DMBA did not significantly affect any of these levels. CONCLUSIONS ;Oral GLN increased GSH levels and lowered IGF-I and TGF-beta 1 in a range that is considered clinically significant. However, the effect of GLN in maintaining normal gut GSH production in the presence of DMBA was much more significant. Inconsistent with our hypothesis, reduction in IGF and TGF-beta 1 levels did not correlate with DMBA's effect on gut GSH production.     

Effect of estrogen on regression of vascular calcification in rats

Objective To investigate the effect of estrogen on regression of vascular calcification in rats induced by vitamin D3 plus nicotine. Methods Ninety?six female SD rats were divided randomly into control group (n=24) and calcification group (n=72). Vascular calcification of 72 rats was induced by vitamin D3 and nicotine (VDN). On the day 1, the VDN group rats were injected with vitamin D3(300 000 U/kg, i.m), and were intragastric administrated with nicotine (25 mg/kg), after 9 hours, another dosage of nicotine was given again. After 4 weeks, the VDN group rats were subdivided randomly into 4 groups: VDN group(n=16), Sham operation group (n=16), ovariotomy group (n=16), estrogen group(after ovariotomy, 17β ?estrogen was subcutaneously injected, 50 μg•kg-1•d-1, n=16). Results After 4 weeks，the VDN group showed obvious vascular calcification, and calcium content of the vessel wall was significantly higher than that of control group (P<0.01). Extensive calcification was witnessed on the aortic tunica media of the VDN group. After 12 and 8 weeks, the calcium content of the vessel wall in each subdivided groups was significantly lower than that at 4 weeks point(P<0.01), and the lowest calcinm content was in estrogen group, meanwhile the reduction of previously accumulated arterial calcium precipitate in each group was different. Conclusions It is a reversible process that vascular calcification induced by vitamin D plus nicotine in rats. Estrogen can promote the regression of vascular calcification.     

Chemoprevention of DMBA-Induced Mammary Tumors in Rats by a Combined Regimen of Alpha-Tocopherol, Selenium, and Ascorbic Acid

Abstract: This experimental study was designed to evaluate the efficacy of associated naturally occuring antioxidants in the prevention of chemically induced breast cancer using DMBA in virgin female Wistar rats. Rats were randomly allocated to three groups: control group (CG; n = 20), induction group (IG; n = 100), and prevention group (PG; n = 70). A single dose (65 mg/kg) of DMBA was administered in the IG and PG animals at 50 days of age. PG animals also received a single dose of alpha-tocopherol (200 mg/rat) 1 hour after DMBA administration and an association of selenium (p-XSC, 40 ppm/day/rat) and ascorbic acid (540 mg/day/rat) in drinking water, daily, from carcinogenic induction until necropsy. Macroscopic study and pathology revealed a significantly lower development of neoplasms in the PG animals (p < 0.05); the number of rats with mammary tumors, breast cancer incidence, and the number of malignant breast tumors per rat as well as per tumor-bearing rat were significantly decreased in the PG animals. Other types of primary neoplasms existing in the IG animals totally disappeared in the PG animals. Immunostaining to hormone steroid receptors (ER and PR) and cathepsin D was similar in both groups. Overexpression of p53 and metallothioneine was significantly increased in the PG animals (p < 0.05) and immunostaining to bromodeoxiuridin and Ki-67 was also stronger in the remaining tumors in the PG animals. These data thus add to the accumulating evidence that those micronutrients in combination seem to be effective in reducing the incidence of malignant tumors. Nevertheless, remaining tumors seem to present more aggressive behavior and characteristics of drug resistance.     

Protective effects of resveratrol on spleen and ileum in rats subjected to ischemia-reperfusion

Resveratrol is as an antioxidant with free radical-scavenging activity and finds its clinical application in the prevention of postischemic tissue injury following solid organ transplantation. This study investigates the effect of Resveratrol on spleen and ileum tissues subjected to hepatic ischemia-reperfusion (I/R) in rats. Twenty-four rats were recruited in the study as follows: group A: I/R (n = 8), group B: I/R + Resveratrol (n = 8), and group C: sham operation (n = 8). After intraperitonealy pretreatment of eight rats with resveratrol (15 mg/kg/d) for 5 days, 16 rats were subjected to 45 minutes of hepatic ischemia followed by 30 minutes reperfusion period. Resveratrol was given 15 minutes prior to ischemia and just before the reperfusion in rats. After reperfusion period all rats were sacrificed. Spleen and ileum tissues were examined spectrophotometrically to measure malondialdehyde (MDA), glutathione (GSH), and total nitrite, nitrate as an end product of nitric oxide (NO) levels. Concerning the spleen, statistically significant decrease of GSH and increase of MDA and NO levels were found group A when compared to groups B and C (P = .040, P = .004, and P = .001 group A vs group B; P = .05, P = .003, and P = .001 group A vs group C, respectively). Parallel results were obtained in ileum. A statistically significant decrease in GSH and an increase in MDA and NO levels in group A in respect to group B and group C was obtained (P = .048, P = .034, and P = .001 group A vs group B; P = .004, P = .001, and P = .003 group A vs group C, respectively). The result of this study shows that resveratrol has a protective effect on spleen and ileal mitochondrial oxidative stress in rats subjected to I/R.     

基于16S rRNA高通量测序技术分析I型骨质疏松大鼠肠道菌群结构变化

目的 探讨I型骨质疏松大鼠肠道菌群的结构变化。方法 采用去势法建立I型骨质疏松大鼠模型（n=24）：雌性SD大鼠随机分为4组（n=6）,实验动物自由进食水,12 h光照周期。分别在去势前和去势后4、8、12周共4个时间点,采用直接收集法采集大鼠粪便。利用16S rRNA高通量肠菌基因测序技术,在phylum（门）,class（纲）,order（目）,family（科）,genus（属）,species（种）级别分析肠道菌群的变化规律。结果 厚壁菌门与拟杆菌门是肠道菌群的主要构成肠菌,无论在去势前或去势后,二者含量之和均超过肠道菌群总量的90%。厚壁菌门含量在去势后下降并且持续到术后8周,其含量在术后12周显著增加（P<0.05）;拟杆菌门的含量变化趋势与此相反。另外,在纲、目级别的物种差异变化趋势较为一致。普雷沃氏菌属、Odoribacter 含量在术后12周明显降低（P<0.05）,而螺杆菌属与Alistipes在术后12周含量显著增多（P<0.05）。在种级别的分类中,白色瘤胃球菌在术后12周显著增多（P<0.05）,而单形拟杆菌含量显著降低（P<0.05）。结论 I型骨质疏松大鼠的肠道菌群在不同分类级别的结构组成上发生了显著性改变,为研究肠道菌群和骨质疏松症的关系提供理论依据。     

Psychological stress accelerates the onset of tumour formation and alters the type and location of tumours in a DMBA mouse carcinogenesis model

Psychological stress is recognized as a factor that contributes to increased susceptibility to a number of diseases, including cancer. Psychological stress, via release of chemical mediators, can induce long‐term changes in the organism resulting in an altered responsiveness of the organism to external carcinogens. The present investigation sought to evaluate the impact of stress on polycyclic aromatic hydrocarbon (PAH)‐induced carcinogenesis. We utilized a repetitive restraint stress mouse model and the model PAH, 7,12‐dimethylbenz[a]anthracene (DMBA). Restraint stress was applied three times a week for 6 weeks and DMBA was administered intra‐gastrically once a week for 6 weeks and formation of skin, mammary and ovarian tumours was examined at 26 weeks by pathological analyses. The results indicate that stress accelerates the onset of tumour formation produced in response to DMBA and significantly influences the type and location of tumours. Taken together, these results demonstrate that stress enhances the carcinogenicity of DMBA. These results clearly indicate the need for further characterization of the impact of stress on carcinogen metabolism in oncology. Copyright © 2010 John Wiley & Sons, Ltd.     

Short-term effect of ovariectomy on osteoprogenitors in the healing rat mandibular incisor extraction socket

SUMMARY: OVX increased the percentage of AP-positive CFU-F in healing rat mandible. The increase of the number of osteoprogenitors was not significant in rat mandible-derived cultures but was in femur-derived ones. This suggests that the effect of OVX on osteoprogenitors is either smaller or develops later in mandible relative to femur. INTRODUCTION: Osteoprogenitors play an essential role in the regeneration process that leads to the successful integration of dental implants. However, it is unclear how systemic osteoporosis affects osteoprogenitors in oral bone. The present study was designed to determine the short-term effects of ovariectomy (OVX) on osteoprogenitors from the healing extraction socket in rat mandible. METHODS: Six-month-old rats were ovariectomized (n=8) and control rats were left intact (n=8). Two weeks post-OVX, the right mandibular incisor was extracted. Four weeks post-extraction, the basal mandibular bone between the 1st and 3rd molar in the healing extraction socket was used to determine the number of fibroblastic progenitors (CFU-F), alkaline phosphatase-positive fibroblastic progenitors (AP-positive CFU-F), Dex-dependent osteoprogenitors (CFU-O Dex) and Prog-dependent osteoprogenitors (CFU-O Prog) using colony assays (n=5). Osteocalcin mRNA expression was evaluated using in situ hybridization (n=3). Data were analyzed using two-way ANOVA or Student's t-test. RESULTS: OVX increased the percentage of AP-positive CFU-F in both mandible and femur. The number of CFU-O was increased only in femur. Osteocalcin mRNA expression in regenerating mandible was not statistically different between control and OVX animals. CONCLUSION: Our results suggest that the effect of OVX on osteoprogenitors is either smaller or develops later in mandible relative to femur.     

Alterations to the Gut Microbiome Impair Bone Strength and Tissue Material Properties

Alterations in the gut microbiome have been associated with changes in bone mass and microstructure, but the effects of the microbiome on bone biomechanical properties are not known. Here we examined bone strength under two conditions of altered microbiota: (1) an inbred mouse strain known to develop an altered gut microbiome due to deficits in the immune system (the Toll‐like receptor 5–deficient mouse [TLR5KO]); and (2) disruption of the gut microbiota (ΔMicrobiota) through chronic treatment with selected antibiotics (ampicillin and neomycin). The bone phenotypes of TLR5KO and WT (C57Bl/6) mice were examined after disruption of the microbiota from 4 weeks to 16 weeks of age as well as without treatment (n = 7 to 16/group, 39 animals total). Femur bending strength was less in ΔMicrobiota mice than in untreated animals and the reduction in strength was not fully explained by differences in bone cross‐sectional geometry, implicating impaired bone tissue material properties. Small differences in whole‐bone bending strength were observed between WT and TLR5KO mice after accounting for differences in bone morphology. No differences in trabecular bone volume fraction were associated with genotype or disruption of gut microbiota. Treatment altered the gut microbiota by depleting organisms from the phyla Bacteroidetes and enriching for Proteobacteria, as determined from sequencing of fecal 16S rRNA genes. Differences in splenic immune cell populations were also observed; B and T cell populations were depleted in TLR5KO mice and in ΔMicrobiota mice (p < 0.001), suggesting an association between alterations in bone tissue material properties and immune cell populations. We conclude that alterations in the gut microbiota for extended periods during growth may lead to impaired whole‐bone mechanical properties in ways that are not explained by bone geometry. © 2017 American Society for Bone and Mineral Research.     

Long-term Impairment of Acquisition of a Spatial Memory Task following Isoflurane-Nitrous Oxide Anesthesia in Rats

Background: The authors demonstrated previously that isoflurane-nitrous oxide anesthesia attenuates performance improvement on an already-learned spatial memory task and that the effect persists for weeks. This experiment was designed to test the hypothesis that learning of new information is particularly susceptible to prolonged disruption after general anesthesia.

Methods: Six- (n = 5) and 20- (n = 5) month-old male Fischer 344 rats were anesthetized for 2 h with 1.2% isoflurane, 70% nitrous oxide, and 30% oxygen. Age-matched control rats received 30% oxygen and 70% nitrogen (n = 5 per group). Rats breathed spontaneously, and anesthetic and oxygen concentrations were measured. Spatial learning was assessed daily for 21 days on a 12-arm radial maze (RAM) beginning 48 h after anesthesia. In a post hoc experiment to examine locomotion, swim speed was assessed in a separate group of identically treated rats (n = 3 per group) for 4 days beginning 48 h after anesthesia.

Results: Aged rats were slower to complete the maze, made fewer correct choices before first error, and made more errors at baseline than young rats (P < 0.05). Anesthesia worsened maze performance in both age groups, as evidenced by increased time to complete the maze and a decreased number of correct choices before first error (P < 0.05), but there were no statistically significant differences in total number of errors. Interestingly, there were no age-by-anesthesia interactions. Aged rats swam slower than adult rats (P < 0.001), but there were no differences between the control and anesthesia groups.     

Photodynamic therapy for the treatment of induced mammary tumor in rats

The objective of this work was to evaluate photodynamic therapy (PDT) by using a hematoporphyrin derivative as a photosensitizer and light-emitting diodes (LEDs) as light source in induced mammary tumors of Sprague–Dawley (SD) rats. Twenty SD rats with mammary tumors induced by DMBA were used. Animals were divided into four groups: control (G1), PDT only (G2), surgical removal of tumor (G3), and submitted to PDT immediately after surgical removal of tumor (G4). Tumors were measured over 6 weeks. Lesions and surgical were LEDs lighted up (200 J/cm² dose). The light distribution in vivo study used two additional animals without mammary tumors. In the control group, the average growth of tumor diameter was approximately 0.40 cm/week. While for PDT group, a growth of less than 0.15 cm/week was observed, suggesting significant delay in tumor growth. Therefore, only partial irradiation of the tumors occurred with a reduction in development, but without elimination. Animals in G4 had no tumor recurrence during the 12 weeks, after chemical induction, when compared with G3 animals that showed 60 % recurrence rate after 12 weeks of chemical induction. PDT used in the experimental model of mammary tumor as a single therapy was effective in reducing tumor development, so the surgery associated with PDT is a safe and efficient destruction of residual tumor, preventing recurrence of the tumor.     

Effects of reflux of bile and/or pancreaticoduodenal juice on gastric carcinogenesis in rats

The present study was designed to investigate which fraction of duodenal contents was responsible for gastric carcinogenesis, bile or pancreaticoduodenal juice. A series of 61 male Wistar rats were subjected to one of following four operative procedures: total reflux (TR, n = 17), bile reflux (BR, n = 8), or pancreaticoduodenal reflux (PDR, n = 16), and simple laparotomy (control, n = 20). Fifty weeks after operations the animals were sacrificed. The incidence of gastric adenocarcinoma was 7/17 (41%) in TR group, 2/8 (25%) in BR group, 0/16 (0%) in PDR group, and 0/20 (0%) in control group. The incidence of cancer in the both TR and BR groups were significantly higher than PDR and control groups, respectively. Histologically, lesions of gastric cancers showed tubular adenocarcinoma or mucinous adenocarcinoma. There was a significant difference in the intragastric pH between the first three reflux groups and control group. The concentrations of the total bile acids of the both TR and BR groups were significantly higher than PDR and control groups, respectively. These results suggested that duodenogastric reflux induces adenocarcinoma in the rat gastric mucosa and bile rather than pancreatico-duodenal juice is related to increased risk for gastric cancer.     

TNF-α在实验性胰腺癌模型发生发展中的作用

目的:研究实验性胰腺癌发生过程中血清AMS和TNF-α含量的变化及其意义。方法:将二甲基苯并蒽（DMBA）直接置入SD大鼠胰腺被膜下实质内建立胰腺癌模型组（A）组，在制模过程中每周腹腔注射曲古霉素（TSA）定为干预组（B）组，A，B组于3～5个月内处死。手术对照组（C组）除未置入DMBA外，余同A组，于第5个月处死。肉眼检查及HE染色观察胰腺癌发生情况。血清AMS含量由全自动生化分析仪测定，TNF-α含量由ELISA法测定。结果:（1）A组3～5个月癌发生率为48.7%(18/37),17例为胰腺导管癌。1例为纤维肉瘤。B组5个月癌发生率为33.3%（12/36）；11例为胰腺导管癌，1例为纤维肉瘤；A组胰腺癌最大径均值大于B组（P＜0.05）；C组胰腺及A，B组胰腺外主要脏器均无明显病理改变。（2）A，B组大鼠血清AMS和TNF-α含量明显高于C组（P＜0.05或P＜0.01），但A组和B组之间差异无显著性（P＜0.05）。A，B组中的胰腺癌组和非癌胰腺组大鼠血清AMS和TNF-α含量均明显高于C组（P＜0.05），但胰腺癌亚组和非癌胰腺亚组间差异无显著性（P＞0.05）。结论:较大剂量DMBA置入胰实质内，可在短期内获得较高胰腺癌发生率，TSA能干预胰腺癌的生长；在胰腺癌发生过程中血清AMS和TNF-α含量有明显升高，TNF-α可能在胰腺癌发生中发挥作用。     

Induced mammary cancer in rat models: pathogenesis,genetics, and relevance to female breast cancer

Mammary cancer, or breast cancer in women, is a polygenic disease with a complex etiopathogenesis. While much remains elusive regarding its origin, it is well established that chemical carcinogens and endogenous estrogens contribute significantly to the initiation and progression of this disease. Rats have been useful models to study induced mammary cancer. They develop mammary tumors with comparable histopathology to humans and exhibit differences in resistance or susceptibility to mammary cancer depending on strain. While some rat strains (e.g., Sprague-Dawley) readily form mammary tumors following treatment with the chemical carcinogen, 7,12-dimethylbenz[a]-anthracene (DMBA), other strains (e.g., Copenhagen) are resistant to DMBA-induced mammary carcinogenesis. Genetic linkage in inbred strains has identified strain-specific quantitative trait loci (QTLs) affecting mammary tumors, via mechanisms that act together to promote or attenuate, and include 24 QTLs controlling the outcome of chemical induction, 10 QTLs controlling the outcome of estrogen induction, and 4 QTLs controlling the outcome of irradiation induction. Moreover, and based on shared factors affecting mammary cancer etiopathogenesis between rats and humans, including orthologous risk regions between both species, rats have served as useful models for identifying methods for breast cancer prediction and treatment. These studies in rats, combined with alternative animal models that more closely mimic advanced stages of breast cancer and/or human lifestyles, will further improve our understanding of this complex disease.

     

雌激素对雌性大鼠心肌蛋白激酶A活力的影响

为了探索雌激素对心肌β受体后信息传递的作用，观察切除双侧卵巢及补充雌激素对心肌胞浆蛋白激酶Ａ（ＰＫＡ）活力的影响。结果：成年对照雌鼠心肌胞浆ＰＫＡ活力为１０９±２ｌｐｍｏｌ·ｍｉｎ￣(－１)／mｇ（ｎ＝７），显著高于切除双侧卵巢鼠（５６±１６ｐｍｏｌ·ｍｉｎ￣(－１)／ｍｇ，ｎ＝６）（Ｐ＜０．０１）。去卵巢鼠经补充笨甲酸雌二醇，每次肌注２００μｇ，３天１次，连续５周后，心肌胞浆ＰＫＡ活力升至１０９±１６ｐmｏｌ·ｍｉｎ￣(－１)／ｍｇ（ｎ＝７）。老年鼠心肌胞浆ＰＫＡ活力为３２±４ｐｍｏｌ·ｍｉｎ￣(－１)／ｍｇ（ｎ＝１０）也明显低于成年早期鼠（７５±ｌｌｐｍｏｌ·ｍｉｎ￣(－１)／ｍｇ，ｎ＝４），老年鼠双侧卵巢切除后心肌胞浆ＰＫＡ活力进一步下降（２４±４ｐｍｏｌ·ｍｉｎ￣(－１)／ｍｇ，ｎ＝１１），以上表明卵巢激素（雌激素）参与了维持雌性大鼠心肌蛋白激酶Ａ的正常活力，而对成年鼠的维持作用（占４９％）比老年鼠（占２５％）更明显。     

Protective effect of resveratrol against renal oxidative stress in cholestasis

BACKGROUND/AIMS: This experimental study was designed to evaluate histological changes of the kidney and renal tissue levels of malondialdehyde (MDA), reduced glutathione (GSH), and nitric oxide (NO) and the effect of resveratrol on these metabolites after bile duct ligation in rats. METHODS: Secondary biliary cirrhosis was induced by bile duct ligation for 28 days. Swiss albino rats were divided into three groups. Group 1: Sham (n=7), Group 2: Bile duct ligation (n=7), Group 3: Bile duct ligation plus resveratrol (n=7). Bile duct ligation (BDL) plus resveratrol group received 10 mgr/kg dose of resveratrol intraperitoneally daily throughout 28 days. Kidney tissues were harvested to determine the tissue levels of MDA, GSH, and NO activity. Liver and kidney tissues were removed for light microscopic evaluation. RESULTS: Cholestasis was determined by biochemical and pathologic examination. In the resveratrol-treated rats, levels of MDA were significantly lower than those of the BDL group (p < 0.04). The levels of GSH in the resveratrol-treated rats were significantly higher than those in the BDL group (p < 0.01). The levels of NO in the resveratrol group were significantly lower than those in the BDL group (p < 0.01). CONCLUSION: The present study demonstrates that intraperitoneal administration of resveratrol in bile duct ligated rats maintains antioxidant defenses and reduces kidney oxidative damage. This effect of resveratrol may be useful in the preservation of renal oxidative stress in cholestasis.     

Long-term impairment of acquisition of a spatial memory task following isoflurane-nitrous oxide anesthesia in rats

BACKGROUND: The authors demonstrated previously that isoflurane-nitrous oxide anesthesia attenuates performance improvement on an already-learned spatial memory task and that the effect persists for weeks. This experiment was designed to test the hypothesis that learning of new information is particularly susceptible to prolonged disruption after general anesthesia. METHODS: Six- (n = 5) and 20- (n = 5) month-old male Fischer 344 rats were anesthetized for 2 h with 1.2% isoflurane, 70% nitrous oxide, and 30% oxygen. Age-matched control rats received 30% oxygen and 70% nitrogen (n = 5 per group). Rats breathed spontaneously, and anesthetic and oxygen concentrations were measured. Spatial learning was assessed daily for 21 days on a 12-arm radial maze (RAM) beginning 48 h after anesthesia. In a post hoc experiment to examine locomotion, swim speed was assessed in a separate group of identically treated rats (n = 3 per group) for 4 days beginning 48 h after anesthesia. RESULTS: Aged rats were slower to complete the maze, made fewer correct choices before first error, and made more errors at baseline than young rats (P < 0.05). Anesthesia worsened maze performance in both age groups, as evidenced by increased time to complete the maze and a decreased number of correct choices before first error (P < 0.05), but there were no statistically significant differences in total number of errors. Interestingly, there were no age-by-anesthesia interactions. Aged rats swam slower than adult rats (P < 0.001), but there were no differences between the control and anesthesia groups. CONCLUSIONS: Isoflurane-nitrous oxide anesthesia is associated with a persistent deficit in RAM performance that is not explained by impaired locomotion. This impairment occurs in adult and aged rats, indicating that it is not an age-specific phenomenon. Thus, RAM performance is altered after general anesthesia for longer than predicted by the pharmacology of the drugs used, which, by inference, suggests a long-term deficit in learning/memory.     

大鼠胰腺癌CHK1和PLK1表达及曲古霉素A的干预作用

目的 建立SD大鼠胰腺癌模型,研究胰腺癌和非癌胰腺组织中细胞周期检测点激酶1(CHK1)和polo样激酶1(PLK1)表达水平及其意义.方法 实验动物随机分成3组:胰腺癌模型组(A组),曲古霉素A(TSA)干预组(B组)和对照组(C组),将二甲基苯茾蒽(DMBA)直接置入胰腺实质内(A组+B组),B组每周腹腔注射TSA...     

Natriuretic peptides stimulate cyclic guanosine monophosphate production in human saphenous vein and internal mammary artery.

OBJECTIVE: It has been shown previously that the internal mammary artery releases more cyclic guanosine monophosphate after stimulation with atrial natriuretic peptide than the saphenous vein, and that C-type natriuretic peptide possesses a cyclic guanosine monophosphate stimulating potential on saphenous vein bypass grafts. The present study was undertaken to investigate intracellular content and extracellular release of cyclic guanosine monophosphate, by the internal mammary artery and saphenous vein, after challenge with further members of the natriuretic peptide family. METHODS: Specimens of human internal mammary artery and saphenous vein from 29 patients were cut into segments and stimulated with 10(-6) M concentrations of atrial natriuretic peptide (internal mammary artery n=8, saphenous vein n=10), brain natriuretic peptide (internal mammary artery n=9, saphenous vein n=13), C-type natriuretic peptide (internal mammary artery n=12, saphenous vein n=15), and urodilatin (internal mammary artery n=8, saphenous vein n=12). Intracellular content and extracellular release of cyclic guanosine monophosphate were determined using an (125)I radioimmunoassay. RESULTS: The following median stimulated intracellular cyclic guanosine monophosphate concentrations were measured in the internal mammary artery and saphenous vein: 35358 and 8672 fmol/cm(2) (P<0.001) after atrial natriuretic peptide, 45632 and 7830 fmol/cm(2) (P=0.003) after brain natriuretic peptide, 10144 and 13216 fmol/cm(2) (P=NS for intergraft comparison) after C-type natriuretic peptide, and 20949 and 6690 fmol/cm(2) (P=0.001) after urodilatin. Stimulation with atrial natriuretic peptide, brain natriuretic peptide and urodilation also led to a significant increase of extracellular cyclic guanosine monophosphate release by the internal mammary artery. CONCLUSIONS We conclude that brain natriuretic peptide and urodilatin exhibit a similarly effective cyclic guanosine monophosphate-stimulating potential on the internal mammary artery as atrial natriuretic peptide. In contrast, C-type natriuretic peptide shows comparable effects on the internal mammary artery and saphenous vein.