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Sample records for 5-fu treated rats

  1. [A case of recurrent sigmoid colon cancer successfully treated with 5-FU and UFT].

    PubMed

    Otsuji, E; Yamaguchi, T; Yamane, T; Fujita, Y; Takahashi, T; Nishioka, B

    1988-03-01

    A 57-year-old female patient with recurrent sigmoid colon cancer was successfully treated with 5-FU and UFT for 8 years. The patient, with cancer recurrence in the para-aortic lymph nodes, which were palpated in the abdomen, was given oral 5-FU at a daily dose of 200 mg. During the second week of administration, the mass showed a remarkable decrease in size, and complete disappearance was achieved within one month. However, 5 years and 2 months after discontinuation of 5-FU administration, recurrence in the supra-clavicular lymph nodes and para-aortic lymph nodes was recognized. After administration of UFT at a daily dose of 600 mg, complete disappearance of para-aortic lymph node recurrence was observed. At present, the patient is under observation as an outpatient at our hospital. This case suggests the effectiveness of 5-FU and UFT for lymph node metastases of sigmoid colon cancer.

  2. The Combination of the PARP Inhibitor Rucaparib and 5FU Is an Effective Strategy for Treating Acute Leukemias.

    PubMed

    Falzacappa, Maria Vittoria Verga; Ronchini, Chiara; Faretta, Mario; Iacobucci, Ilaria; Di Rorà, Andrea Ghelli Luserna; Martinelli, Giovanni; Meyer, Lüder Hinrich; Debatin, Klaus-Michael; Orecchioni, Stefania; Bertolini, Francesco; Pelicci, Pier Giuseppe

    2015-04-01

    The existing treatments to cure acute leukemias seem to be nonspecific and suboptimal for most patients, drawing attention to the need of new therapeutic strategies. In the last decade the anticancer potential of poly ADP-ribose polymerase (PARP) inhibitors became apparent and now several PARP inhibitors are being developed to treat various malignancies. So far, the usage of PARP inhibitors has been mainly focused on the treatment of solid tumors and not too much about their efficacy on leukemias is known. In this study we test, for the first time on leukemic cells, a combined therapy that associates the conventional chemotherapeutic agent fluorouracil (5FU), used as a source of DNA damage, and a PARP inhibitor, rucaparib. We demonstrate the efficacy and the specificity of this combined therapy in killing both acute myeloid leukemia and acute lymphoid leukemia cells in vitro and in vivo. We clearly show that the inhibition of DNA repair induced by rucaparib is synthetic lethal with the DNA damage caused by 5FU in leukemic cells. Therefore, we propose a new therapeutic strategy able to enhance the cytotoxic effect of DNA-damaging agents in leukemia cells via inhibiting the repair of damaged DNA.

  3. [Improved Response to 5-FU Using Dose Adjustment and Elastomeric Pump Selection Based on Monitoring of the 5-FU Level--A Case Report].

    PubMed

    Muneoka, Katsuki; Shirai, Yoshio; Kanda, Junkichi; Sasaki, Masataka; Wakai, Toshifumi; Wakabayashi, Hiroyuki

    2015-10-01

    A 6 1-year-old man with unresectable multiple hepatic metastases after resection of sigmoid colon carcinoma was treated with irinotecan and infused 5-fluorouracil (5-FU) plus Leucovorin (FOLFIRI). Since the levels of tumor markers increased, the 5-FU dose was increased from 2,700 to 3,000 mg/m2 using a Jackson-type pump and an extended infusion time of 53 hours. The blood level of 5-FU was 507 ng/mL 16 hours after starting the infusion. The pump was then changed to a bottle-type pump with the same dose of 3,000 mg/m2. At 16 hours, the 5-FU level was 964.5 ng/mL. The areas under the concentration vs. time curve (AUC mg・h/L)were 21 and 44 mg・h/L for the Jackson- and bottle-type pumps, respectively. Owing to the development of Grade 3 stomatitis and hand-foot syndrome, 5-FU was reduced to 2,700 mg/m2 with a bottle-type pump. The AUC decreased to 27 mg・h/L, but the liver metastases were reduced and the adverse effects subsided to Grade 1. This case shows that individual dose adjustment of 5-FU to the appropriate AUC based on pharmacokinetic monitoring of the blood 5-FU level can improve the response, reduce adverse effects, and have a clinical benefit. PMID:26489552

  4. Adenovirus KH901 promotes 5-FU antitumor efficacy and S phase in LoVo cells.

    PubMed

    Peng, Wei; Li, Jin; Yin, X G; Xu, J F; Cheng, L Z

    2012-06-01

    A combination of oncolytic and chemotherapeutic agents has been used to kill cancer cells. However, the effect of oncolytic adenoviruses on the cell cycle remains to be determined. Cytotoxicity assays were performed to determine cell death in cells treated with 5-fluorouracil (5-FU) alone or in combination with the oncolytic adenovirus KH901. Dynamic changes in the cell cycle, cell proliferation, and apoptosis-related proteins including p-AKT, Bcl-2, Bax, and caspase 3 were investigated after treatment with 5-FU with or without KH901. A higher proportion of S-phase cells were observed after treatment with KH901 and 5-FU than with 5-FU alone. p-AKT, Bcl-2, and Bax expression was increased upon treatment with KH901, whereas the expression of caspase-3 was not induced upon treatment with KH901 with or without 5-FU. KH901 exhibited significant potential as an oncolytic adenovirus and increased cell death in combination with 5-FU in LoVo cells, as compared to 5-FU alone. In conclusion, KH901 stimulates LoVo cells to enter the S-phase by activation of p-AKT, which could partly explain its synergistic effect with 5-FU on LoVo cell cytotoxicity.

  5. QUANTITATIVE FLUORESCENCE OF 5-FU-TREATED FETAL RAT LIMBS USING CONFOCAL LASER SCANNING MICROSCOPY AND LYSOTRACKER RED

    EPA Science Inventory

    Background: LysoTracker Red (LT) is a paraformaldehyde fixable probe that concentrates into acidic compartments of cells and tissues. After cell death a high level of lysosomal activity (acidic enzyme) is expressed resulting from phagocytosis of apoptotic bodies by neighboring ce...

  6. Resistance of colorectal cancer cells to radiation and 5-FU is associated with MELK expression

    SciTech Connect

    Choi, Seungho; Ku, Ja-Lok

    2011-08-26

    Highlights: {yields} MELK expression significantly increased when the cells are exposed to radiation or 5-FU. {yields} Suppression of MELK caused cell cycle changes and decrease in proliferation. {yields} Radiation or 5-FU treatment after MELK suppression by siRNA induced growth inhibition. -- Abstract: It was reported that the local recurrence would be caused by cancer stem cells acquiring chemo- and radio-resistance. Recently, one of the potential therapeutic targets for colorectal and other cancers has been identified, which is maternal embryonic leucine zipper kinase (MELK). MELK is known as an embryonic and neural stem cell marker, and associated with the cell survival, cell proliferation, and apoptosis. In this study, SNU-503, which is a rectal cancer cell line, was treated with radiation or 5-fluorouracil (5-FU), and elevation of the MELK expression level was observed. Furthermore, the cell line was pre-treated with small interfering RNA (siRNA) against MELK mRNA before treatment of radiation or 5-FU and its effects on cell cycle and proliferation were observed. We demonstrated that knockdown of MELK reduced the proliferation of cells with radiation or 5-FU treatment. In addition, MELK suppression caused changes in cell cycle. In conclusion, MELK could be associated with increased resistance of colorectal cancer cells against radiation and 5-FU.

  7. White light-mediated Cu (II)-5FU interaction augments the chemotherapeutic potential of 5-FU: an in vitro study.

    PubMed

    Chibber, Sandesh; Farhan, Mohd; Hassan, Iftekhar; Naseem, Imrana

    2011-10-01

    5-Fluorouracil (5-FU) is a potent photosensitizer used in colon and rectal cancers. 5-FU on galvanostatic electrolysis or radiation-induced oxidation of aqueous solution yields N(1)-C(5)-linked dimmer hydrate of 5-FU. Copper is presently associated with chromatin; in cancer cells the concentration of copper is very high. It has been shown to be capable of mediating the action of several anticancer drugs through the production of reactive oxygen species (ROS). The objective of the present study is to determine the Cu (II)-mediated anticancer mechanism of 5-FU under photo-illumination as well as 5-FU alone. We have shown that a pro-oxidant action was enhanced when Cu (II) was used with 5-FU as compared to 5-FU alone. This may be due to the inhibition of dimerization of 5-FU when present in combination with Cu (II) under photo-illumination. It was also shown that 5-FU alone as well as in combination with Cu (II) was able to generate oxidative stress in lymphocyte which is inhibited by scavengers of ROS. Moreover, the results of Fourier-transformed infrared spectra lead to the conclusion that the dimerization of 5-FU was inhibited when used in combination with Cu (II). It was due to the interaction of 5-FU with Cu (II). Hence, we propose that during chemoradiotherapy with 5-FU, the endogenous copper is mobilized by 5-FU, leading to the generation of ROS which cause oxidative stress and possibly cancer cell death by apoptosis. PMID:21618035

  8. Pre-operative combined 5-FU, low dose leucovorin, and sequential radiation therapy for unresectable rectal cancer

    SciTech Connect

    Minsky, B.D.; Cohen, A.M.; Kemeny, N.; Enker, W.E.; Kelsen, D.P.; Schwartz, G.; Saltz, L.; Dougherty, J.; Frankel, J.; Wiseberg, J. )

    1993-04-02

    The authors performed a Phase 1 trial to determine the maximum tolerated dose of combined pre-operative radiation (5040 cGy) and 2 cycles (bolus daily [times] 5) of 5-FU and low dose LV (20 mg/m2), followed by surgery and 10 cycles of post-operative LV/5-FU in patients with unresectable primary or recurrent rectal cancer. Twelve patients were entered. The initial dose of 5-FU was 325 mg/m2. 5-FU was to be escalated while the LV remained constant at 20 mg/m2. Chemotherapy began on day 1 and radiation on day 8. The post-operative chemotherapy was not dose escalated; 5-FU: 425 mg/m2 and LV: 20 mg/m2. The median follow-up was 14 months (7--16 months). Following pre-operative therapy, the resectability rate with negative margins was 91% and the pathologic complete response rate was 9%. For the combined modality segment (preoperative) the incidence of any grade 3+ toxicity was diarrhea: 17%, dysuria: 8%, mucositis: 8%, and erythema: 8%. The median nadir counts were WBC: 3.1, HGB: 8.8, and PLT: 153000. The maximum tolerated dose of 5-FU for pre-operative combined LV/5-FU/RT was 325 mg/m2 with no escalation possible. Therefore, the recommended dose was less than 325 mg/m2. Since adequate doses of 5-FU to treat systemic disease could not be delivered until at least 3 months (cycle 3) following the start of therapy, the authors do not recommend that this 5-FU, low dose LV, and sequential radiation therapy regimen be used as presently designed. However, given the 91% resectability rate they remain encouraged with this approach. 31 refs., 1 fig., 2 tabs.

  9. Adverse effects on cardiovascular status and lipid levels of albino Wistar rats treated with cisplatin and oxaliplatin in combination with 5 Fluorouracil.

    PubMed

    Najam, Rahila; Bano, Nusrat; Mirza, Talat; Hassan, Saba

    2014-09-01

    The study was designed to comparatively assess direct damages on cardiac tissues and aorta associated with abnormalities in lipid profile and cardiac biomarkers induced by two platinum cytotoxic compounds with and without 5FU (5Fluorouracil) in rats. Albino Wistar rats were treated with 5FU (15mg/kg), cisplatin (0.8mg/kg) and oxaliplatin (0.8mg/kg) in different dosing schedules. The changes in the lipid levels, CPK and Tropinin I levels, following treatment with single and combination schedules of CDDP, 5FU and Oxaliplatin were compared with the control group maintained on normal saline. Changes in LDL and cholesterol levels were highly significant in cisplatin and oxaliplatin treated rats. Myofibrillar loss and vascular wall thickening was seen in cisplatin treatment groups in the acute model of toxicity. The damages were mild but progressive. Tropinin I levels were raised well above diagnostic risk levels in the delayed model of toxicity in the rats treated with oxaliplatin in combination of 5FU, indicative of definite cardiotoxic potential of oxaliplatin in combination of 5FU mimicking the FOLFOX regimen.

  10. Potentially functional SNPs (pfSNPs) as novel genomic predictors of 5-FU response in metastatic colorectal cancer patients.

    PubMed

    Wang, Jingbo; Wang, Xu; Zhao, Mingjue; Choo, Su Pin; Ong, Sin Jen; Ong, Simon Y K; Chong, Samuel S; Teo, Yik Ying; Lee, Caroline G L

    2014-01-01

    5-Fluorouracil (5-FU) and its pro-drug Capecitabine have been widely used in treating colorectal cancer. However, not all patients will respond to the drug, hence there is a need to develop reliable early predictive biomarkers for 5-FU response. Here, we report a novel potentially functional Single Nucleotide Polymorphism (pfSNP) approach to identify SNPs that may serve as predictive biomarkers of response to 5-FU in Chinese metastatic colorectal cancer (CRC) patients. 1547 pfSNPs and one variable number tandem repeat (VNTR) in 139 genes in 5-FU drug (both PK and PD pathway) and colorectal cancer disease pathways were examined in 2 groups of CRC patients. Shrinkage of liver metastasis measured by RECIST criteria was used as the clinical end point. Four non-responder-specific pfSNPs were found to account for 37.5% of all non-responders (P<0.0003). Five additional pfSNPs were identified from a multivariate model (AUC under ROC = 0.875) that was applied for all other pfSNPs, excluding the non-responder-specific pfSNPs. These pfSNPs, which can differentiate the other non-responders from responders, mainly reside in tumor suppressor genes or genes implicated in colorectal cancer risk. Hence, a total of 9 novel SNPs with potential functional significance may be able to distinguish non-responders from responders to 5-FU. These pfSNPs may be useful biomarkers for predicting response to 5-FU.

  11. Potentially functional SNPs (pfSNPs) as novel genomic predictors of 5-FU response in metastatic colorectal cancer patients.

    PubMed

    Wang, Jingbo; Wang, Xu; Zhao, Mingjue; Choo, Su Pin; Ong, Sin Jen; Ong, Simon Y K; Chong, Samuel S; Teo, Yik Ying; Lee, Caroline G L

    2014-01-01

    5-Fluorouracil (5-FU) and its pro-drug Capecitabine have been widely used in treating colorectal cancer. However, not all patients will respond to the drug, hence there is a need to develop reliable early predictive biomarkers for 5-FU response. Here, we report a novel potentially functional Single Nucleotide Polymorphism (pfSNP) approach to identify SNPs that may serve as predictive biomarkers of response to 5-FU in Chinese metastatic colorectal cancer (CRC) patients. 1547 pfSNPs and one variable number tandem repeat (VNTR) in 139 genes in 5-FU drug (both PK and PD pathway) and colorectal cancer disease pathways were examined in 2 groups of CRC patients. Shrinkage of liver metastasis measured by RECIST criteria was used as the clinical end point. Four non-responder-specific pfSNPs were found to account for 37.5% of all non-responders (P<0.0003). Five additional pfSNPs were identified from a multivariate model (AUC under ROC = 0.875) that was applied for all other pfSNPs, excluding the non-responder-specific pfSNPs. These pfSNPs, which can differentiate the other non-responders from responders, mainly reside in tumor suppressor genes or genes implicated in colorectal cancer risk. Hence, a total of 9 novel SNPs with potential functional significance may be able to distinguish non-responders from responders to 5-FU. These pfSNPs may be useful biomarkers for predicting response to 5-FU. PMID:25372392

  12. Synergistic anticancer effect of exogenous wild-type p53 gene combined with 5-FU in human colon cancer resistant to 5-FU in vivo

    PubMed Central

    Xie, Qi; Wu, Min-Yi; Zhang, Ding-Xuan; Yang, Yi-Ming; Wang, Bao-Shuai; Zhang, Jing; Xu, Jin; Zhong, Wei-De; Hu, Jia-Ni

    2016-01-01

    AIM To investigate the anticancer effect of a recombinant adenovirus-mediated p53 (rAd-p53) combined with 5-fluorouracil (5-FU) in human colon cancer resistant to 5-FU in vivo and the mechanism of rAd-p53 in reversal of 5-FU resistance. METHODS Nude mice bearing human colon cancer SW480/5-FU (5-FU resistant) were randomly assigned to four groups (n = 25 each): control group, 5-FU group, rAd-p53 group, and rAd-p53 + 5-FU group. At 24 h, 48 h, 72 h, 120 h and 168 h after treatment, 5 mice were randomly selected from each group and sacrificed using an overdose of anesthetics. The tumors were removed and the protein expressions of p53, protein kinase C (PKC), permeability-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1) (Western blot) and apoptosis (TUNEL) were determined. RESULTS The area ratios of tumor cell apoptosis were larger in the rAd/p53 + 5-FU group than that in the control, 5-FU and rAd/p53 groups (P < 0.05), and were larger in the rAd/p53 group than that of the control group (P < 0.05) and the 5-FU group at more than 48 h (P < 0.05). The p53 expression was higher in the rAd/p53 and the rAd/p53 + 5-FU groups than that of the control and 5-FU groups (P < 0.05), and were higher in the rAd/p53 + 5-FU group than that of the rAd/p53 group (P < 0.05). Overexpression of PKC, P-gp and MRP1 was observed in the 5-FU and control groups. In the rAd/p53 + 5-FU group, the expression of P-gp and MRP1 was lower that of the control and 5-FU groups (P < 0.05), and the expression of PKC was lower than that of the control, 5-FU and rAd/p53 groups at more than 48 h (P < 0.05). In the rAd/p53 group, the expression of P-gp and MRP1 was lower that of the control and 5-FU groups at more than 48 h (P < 0.05), and the expression of PKC was lower than that of the control and 5-FU groups at more than 120 h (P < 0.05). CONCLUSION 5-FU combined with rAd-p53 has a synergistic anticancer effect in SW480/5-FU (5-FU resistance), which contributes to reversal of 5-FU

  13. Synergistic anticancer effect of exogenous wild-type p53 gene combined with 5-FU in human colon cancer resistant to 5-FU in vivo

    PubMed Central

    Xie, Qi; Wu, Min-Yi; Zhang, Ding-Xuan; Yang, Yi-Ming; Wang, Bao-Shuai; Zhang, Jing; Xu, Jin; Zhong, Wei-De; Hu, Jia-Ni

    2016-01-01

    AIM To investigate the anticancer effect of a recombinant adenovirus-mediated p53 (rAd-p53) combined with 5-fluorouracil (5-FU) in human colon cancer resistant to 5-FU in vivo and the mechanism of rAd-p53 in reversal of 5-FU resistance. METHODS Nude mice bearing human colon cancer SW480/5-FU (5-FU resistant) were randomly assigned to four groups (n = 25 each): control group, 5-FU group, rAd-p53 group, and rAd-p53 + 5-FU group. At 24 h, 48 h, 72 h, 120 h and 168 h after treatment, 5 mice were randomly selected from each group and sacrificed using an overdose of anesthetics. The tumors were removed and the protein expressions of p53, protein kinase C (PKC), permeability-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1) (Western blot) and apoptosis (TUNEL) were determined. RESULTS The area ratios of tumor cell apoptosis were larger in the rAd/p53 + 5-FU group than that in the control, 5-FU and rAd/p53 groups (P < 0.05), and were larger in the rAd/p53 group than that of the control group (P < 0.05) and the 5-FU group at more than 48 h (P < 0.05). The p53 expression was higher in the rAd/p53 and the rAd/p53 + 5-FU groups than that of the control and 5-FU groups (P < 0.05), and were higher in the rAd/p53 + 5-FU group than that of the rAd/p53 group (P < 0.05). Overexpression of PKC, P-gp and MRP1 was observed in the 5-FU and control groups. In the rAd/p53 + 5-FU group, the expression of P-gp and MRP1 was lower that of the control and 5-FU groups (P < 0.05), and the expression of PKC was lower than that of the control, 5-FU and rAd/p53 groups at more than 48 h (P < 0.05). In the rAd/p53 group, the expression of P-gp and MRP1 was lower that of the control and 5-FU groups at more than 48 h (P < 0.05), and the expression of PKC was lower than that of the control and 5-FU groups at more than 120 h (P < 0.05). CONCLUSION 5-FU combined with rAd-p53 has a synergistic anticancer effect in SW480/5-FU (5-FU resistance), which contributes to reversal of 5-FU

  14. Concurrent cisplatin, 5-FU, paclitaxel, and radiation therapy in patients with locally advanced esophageal cancer

    SciTech Connect

    Roof, Kevin S. . E-mail: kroof@sero.net; Coen, John; Lynch, Thomas J.; Wright, Cameron; Fidias, Panos; Willett, Christopher G.; Choi, Noah C.

    2006-07-15

    Purpose: Phase I-II data regarding neoadjuvant cisplatin, 5-fluorouracil (5-FU), paclitaxel, and radiation (PFT-R) from our institution demonstrated encouraging pathologic complete response (pCR) rates. This article updates our experience with PFT-R, and compares these results to our experience with cisplatin, 5-FU, and radiation therapy (PF-R) in locally advanced esophageal cancer. Patients and Methods: We searched the Massachusetts General Hospital cancer registry for esophageal cancer patients treated with radiation therapy and chemotherapy between 1994-2002. Records of patients treated with curative, neoadjuvant therapy were examined for chemotherapeutic regimen. Outcomes of patients treated with PF-R or PFT-R were assessed for response to therapy, toxicity, and survival. Results: A total of 177 patients were treated with neoadjuvant therapy with curative intent; 164 (93%) received PF-R (n = 81) or PFT-R (n = 83). Median overall survival was 24 months. After a median follow-up of 54 months for surviving patients, 3-year overall survival was 40% with no significant difference between PF-R (39%) and PFT-R (42%). Conclusions: Our findings failed to demonstrate an improvement in pCR or survival with PFT-R vs. PF-R. These results do not support this regimen of concurrent neoadjuvant PFT-R in esophageal cancer, and suggest that further investigations into alternative regimens and novel agents are warranted.

  15. Preoperative Capecitabine and Pelvic Radiation in Locally Advanced Rectal Cancer-Is it Equivalent to 5-FU Infusion Plus Leucovorin and Radiotherapy?

    SciTech Connect

    Chan, Alexander K.; Wong, Alfred O.; Jenken, Daryl A.

    2010-04-15

    Purpose: The aim of this retrospective case-matching study was to compare the treatment outcomes and acute toxicity of preoperative radiotherapy (RT) with capecitabine vs. preoperative RT with intermittent 5-fluorouracil (5-FU) infusion, leucovorin, and mitomycin C in rectal cancer. Methods and Materials: We matched 34 patients who were treated with preoperative concurrent capecitabine and 50 Gy of RT by their clinical T stage (T3 or T4) and the tumor location (<=7 cm or >7 cm from the anal verge) with another 68 patients who were treated with preoperative intermittent 5-FU infusion, leucovorin, mitomycin C, and 50 Gy of RT for a comparison of the pathologic tumor response, local control, distant failure, and survival rates. Results: The pathologic complete response rate was 21% with capecitabine and 18% with 5-FU and leucovorin (p = 0.72). The rate of T downstaging after chemoradiation was 59% for both groups. The rate of sphincter-sparing resection was 38% after capecitabine plus RT and 43% after 5-FU plus RT (p = 0.67). At 3 years, there was no significant difference in the local control rate (93% for capecitabine and 92% for 5-FU and leucovorin), relapse-free rate (74% for capecitabine and 73% for 5-FU and leucovorin), or disease-specific survival rate (86% for capecitabine and 77% for 5-FU and leucovorin). The acute toxicity profile was comparable, with little Grade 3 and 4 toxicity. Conclusions: When administered with concurrent preoperative RT, both capecitabine and intermittent 5-FU infusion with leucovorin modulation provided comparable pathologic tumor response, local control, relapse-free survival, and disease-specific survival rates in rectal cancer.

  16. Skin cancer treatment by albumin/5-Fu loaded magnetic nanocomposite spheres in a mouse model.

    PubMed

    Misak, H; Zacharias, N; Song, Z; Hwang, S; Man, K-P; Asmatulu, R; Yang, S-Y

    2013-03-10

    Albumin/drug loaded magnetic nanocomposite spheres were fabricated using an oil-in-oil emulsion/solvent evaporation method, and tested on a mouse model (experimental squamous cell carcinoma) to determine the efficacy of the drug delivery system (DDS) on skin cancer. This novel DDS consists of human serum albumin, poly(lactic-co-glycolic acid) (PLGA), 5-fluorouracil (5-Fu), magnetic nanoparticles (10 nm) and fluorescent labeling molecule (diphenylhexatriene). One of the major purposes of using albumin is that it likely provides internal binding to and retention by the inflammatory tissues to reduce the amount of magnetic nanoparticles needed in the drug loaded microspheres (750–1100 nm). This study is aimed at reducing many negative side effects of conventionally used chemotherapy drugs by localizing the chemotherapy drug, controlling the release of the therapeutic agent and encouraging uptake of the DDS into cancerous cells. A group of mice treated with (1) the magnetic targeted DDS were compared to the other three groups, including, (2) DDS without a magnet, (3) 5-Fu local injection, and (4) untreated groups. The fluorescent tracer was ubiquitously identified inside the tumor tissue, and the DDS/tumor tissue boundary presented a leaky interface. The test results clearly showed that the magnetic targeted DDS exhibited significantly superior therapeutic effects in treating the skin cancer, with the increased efficacy to halt the tumor growth. PMID:23395619

  17. Anticancer effect of bromelain with and without cisplatin or 5-FU on malignant peritoneal mesothelioma cells.

    PubMed

    Pillai, Krishna; Ehteda, Anahid; Akhter, Javid; Chua, Terence C; Morris, David L

    2014-02-01

    Malignant peritoneal mesothelioma (MPM) is a rare neoplasm of the peritoneum, causally related to asbestos exposure. Nonspecific symptoms with a late diagnosis results in poor survival (<1 year). Treatment with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy has improved survival in some patients (median 3-5 years). Hence, new therapies are urgently needed. MUC1 is a glycosylation-dependent protein that confers tumours with invasiveness, metastasis and chemoresistance. Bromelain (cysteine proteinase) hydrolyses glycosidic bonds. Therefore, we investigated the antitumour effect of bromelain on MUC1-expressing MPM cell lines. MUC1 expressions in cells were assessed using immunofluorescent probes with cells grown on cover slips and western blot analysis on cell lysates. The cell lines were treated with various concentrations of bromelain and after 4 and 72 h, their viability was assessed using standard sulforhodamine assays. The cells were also treated with combinations of bromelain and cytotoxic drugs (cisplatin or 5-FU) and their viability was assessed at 72 h. Finally, with western blotting, the effects of bromelain on cellular survival proteins were investigated. PET cells expressed more MUC1 compared with YOU cells. The cell viability of both PET and YOU cells was adversely affected by bromelain, with PET cells being slightly resistant. The addition of bromelain increased the cytotoxicity of cisplatin significantly in both cell lines. However, 5-FU with bromelain did not show any significant increase in cytotoxicity. Bromelain-induced cell death is by apoptosis and autophagy. Bromelain has the potential of being developed as a therapeutic agent in MPM.

  18. Herb-Drug Pharmacokinetic Interaction of a Traditional Chinese Medicine Jia-Wei-Xiao-Yao-San with 5-Fluorouracil in the Blood and Brain of Rat Using Microdialysis

    PubMed Central

    Chiang, Meng-Hsuan; Chang, Li-Wen; Wang, Ju-Wen; Lin, Lie-Chwen; Tsai, Tung-Hu

    2015-01-01

    According to a survey from the National Health Insurance Research Database (NHIRD), Jia-Wei-Xiao-Yao-San (JWXYS) is the most popular Chinese medicine for cancer patients in Taiwan. 5-Fluorouracil (5-FU) is a general anticancer drug for the chemotherapy. To investigate the herb-drug interaction of JWXYS on pharmacokinetics of 5-FU, a microdialysis technique coupled with a high-performance liquid chromatography system was used to monitor 5-FU in rat blood and brain. Rats were divided into four parallel groups, one of which was treated with 5-FU (100 mg/kg, i.v.) alone and the remaining three groups were pretreated with a different dose of JWXYS (600, 1200, or 2400 mg/kg/day for 5 consecutive days) followed by a combination with 5-FU. This study demonstrates that 5-FU with JWXYS (600 mg/kg/day or 1200 mg/kg/day) has no significant effect on the pharmacokinetics of 5-FU in the blood and brain. However, JWXYS (2400 mg/kg/day) coadministered with 5-FU extends the elimination half-life and increases the volume of distribution of 5-FU in the blood. The elimination half-life of 5-FU in the brain for the pretreatment group with 2400 mg/kg/day of JWXYS is significantly longer than that for the group treated with 5-FU alone and also reduces the clearance. This study provides practical dosage information for clinical practice and proves the safety of 5-FU coadministered with JWXYS. PMID:25861367

  19. A Diet Containing Beta-Hydroxy-Beta-Methylbutyrate, L-Glutamine and L-Arginine Ameliorates Chemoradiation-Induced Gastrointestinal Injury in Rats.

    PubMed

    Alsan Cetin, Ilknur; Atasoy, Beste M; Cilaker, Serap; Alicikus, Lutfiye Zumre Arican; Karaman, Meral; Ersoy, Nevin; Demiral, Ayse Nur; Yilmaz, Osman

    2015-10-01

    The aim of this study was to investigate the effects of a specific diet, containing beta-hydroxy-beta-methylbutyrate, L-glutamine and L-arginine (HMB/Glu/Arg), on chemoradiation-induced injuries of the rat gastrointestinal mucosa. Wistar albino rats were divided into 4 groups: control (n = 5); radiation (n = 14); 5-fluorouracil treatment (5-FU; n = 14); and radiation and 5-FU treatment (n = 14). Rats were fed either a standard diet or a specific diet (SpD) containing HMB/Glu/Arg supplementation for 7 days prior to radiation exposure and/or 5-FU treatment. The irradiated groups were exposed to an 1 Gy dose of 6 MV x rays delivered to the who-abdominal. The animals receiving 5-FU treatment were given a 100 mg/kg dose of the drug. In the radiation and 5-FU treatment group, the 5-FU was administered 30 min prior to irradiation. After irradiation and/or 5-FU treatment, feeding with either the standard rat diet or specific diet continued as before. All animals were sacrificed on day 4 after irradiation and 5-FU treatment. Data collected included microbiological, histological and immunohistochemical end points. We found that bacterial colony counts in the ceca and mesenteric lymph nodes of irradiated rats treated with 5-FU were significantly lower in the specific diet (SpD) group than in the standard diet group (P = 0.002-0.05). Morphometrically, gastric, duodenal and colonic mucosal injuries were less severe in the irradiated animals fed the specific diet, as well as the 5-FU-treated animals fed the specific diet, compared to the similarly treated standard diet groups. Apoptosis, measured by TUNEL, revealed significantly lower numbers of TUNEL positive cells in irradiated animals fed the specific diet, and irradiated animals treated with 5-FU and fed the specific diet compared to irradiated animals fed the standard diet, and irradiated animals treated with 5-FU and fed the standard diet. In the 5-Fu-treated and SpD group, the extent of apoptosis was significantly lower

  20. Neuroprotective effects of intravenous transplantation of bone marrow mononuclear cells from 5-fluorouracil pre-treated rats on ischemic stroke.

    PubMed

    Li, Y; Mao, W W; Zhang, C G; Wan, L; Jing, C H; Hua, X M; Li, S T; Cheng, J

    2016-03-15

    Our previous findings showed bone marrow mononuclear cells (BMMNCs) from 5- fluorouracil (5-FU) pre-treated rats (named BMRMNCs) had a better therapeutic efficacy in ischemia/reperfusion rats as compared to BMMNCs from untreated rats. This study was undertaken to explore the potential mechanisms underlying the neuroprotective effects of BMRMNCs in middle cerebral artery occlusion (MCAO) rat model. Rats were intravenously pre-treated with 5-FU and BMRMNCs were collected at different time points. The contents of growth factors in the supernatant and CXCR4 expression were detected by ELISA and flow cytometry, respectively. MCAO was introduced to rats, and BMMNCs and BMRMNCs collected at 7 days after 5-FU pre-treatment were independently transplanted via the tail vein 24h later. The neurological function was evaluated before cell transplantation and at 24h, 7d and 14d after cell transplantation. Rats were sacrificed at 14d after cell transplantation, the brains were collected for TTC staining, infarct volume detection, NISSL staining, counting of viable cells in the CA1 region, and observation of transplanted cells. BMRMNCs had elevated expressions of growth factors as well as CXCR4 expression. Our results confirmed the better therapeutic effects of BMRMNCs in MCAO rats, demonstrated by reduction in infarct volume, improvement of neurological function and more viable cells in the hippocampus. In addition, more transplanted cells were found after BMRMNCs transplantation at 7 days and 14 days although there was no marked difference at 14 days. These findings indicate that BMRMNCs transplantation may protect ischemic stroke, at least partially, via increasing the secretion of growth factors and migration to the injured site.

  1. PUMA mediates the combinational therapy of 5-FU and NVP-BEZ235 in colon cancer.

    PubMed

    Wang, Huanan; Zhang, Lingling; Yang, Xu; Jin, Yipeng; Pei, Shimin; Zhang, Di; Zhang, Hong; Zhou, Bin; Zhang, Yingjie; Lin, Degui

    2015-06-10

    Colon cancer is the third most common cancer in humans which has a high mortality rate, and 5-Fluorouracil (5-FU) is one of the most widely used drugs in colon cancer therapy. However, acquired chemoresistance is becoming the major challenges for patients, and the molecular mechanism underlying the development of 5-FU resistance is still poorly understood. In this study, a newly designed therapy in combination with 5-FU and NVP-BEZ235 in colon cancer cells (HCT-116 and RKO) was established, to investigate the mechanism of 5-FU resistance and optimize drug therapy to improve outcome for patients. Our results show 5-FU induced cell apoptosis through p53/PUMA pathway, with aberrant Akt activation, which may well explain the mechanism of 5-FU resistance. NVP-BEZ235 effectively up-regulated PUMA expression, mainly through inactivation of PI3K/Akt and activation of FOXO3a, leading to cell apoptosis even in the p53-/- HCT-116 cells. Combination treatment of 5-FU and NVP-BEZ235 further increased cell apoptosis in a PUMA/Bax dependent manner. Moreover, significantly enhanced anti-tumor effects were observed in combination treatment in vivo. Together, these results demonstrated that the combination treatment of 5-FU and NVP-BEZ235 caused PUMA-dependent tumor suppression both in vitro and in vivo, which may promise a more effective strategy for colon cancer therapy.

  2. PX-12 inhibits the growth of hepatocelluar carcinoma by inducing S-phase arrest, ROS-dependent apoptosis and enhances 5-FU cytotoxicity

    PubMed Central

    Li, Guang-Zhen; Liang, Hui-Fang; Liao, Bo; Zhang, Lei; Ni, Ya-An; Zhou, Hong-Hao; Zhang, Er-Lei; Zhang, Bi-Xiang; Chen, Xiao-Ping

    2015-01-01

    Background: 1-methylpropyl 2-imidazolyl disulfide (PX-12), a thioredoxin 1 (Trx1) inhibitor, has been investigated in a number of ancers, but its effectiveness in the treatment of hepatocellular carcinoma (HCC) has not been reported. PX-12 has generated considerable interest in its use in a variety of solid tumors, yet most studies have confined their interests to using PX-12 as a single agent. The aim of this study is to investigate whether PX-12 inhibits cell growth and has a synergistic anti-tumor effect in combination with 5-fluorouracil (5-FU) in HCC. Methods: Cells were treated with different concentrations of PX-12 and 5-FU. Cell viability assays, colony formation assay, cell cycle assay, reactive oxygen species (ROS) assay, apoptosis analysis, western blot assay, immunohistochemistry and xenograft tumorigenicity assay were performed. Results: Treatment with PX-12 inhibited cell growth, induced S-phase arrest, and increased ROS levels. PX-12-induced apoptosis and inhibition of colony formation were associated with the generation of ROS, and inhibition of ROS attenuated PX-12-induced apoptosis and inhibition of colony formation. Treatment with PX-12 increased the expression of bax and reduced the expression of bcl-2, indicating that PX-12-mediated apoptosis is mitochondria-dependent. PX-12 also exerted a synergistic effect with 5-FU tosignificantly suppress tumorigenicity both in vitro and in vivo. Inhibition of ROS accumulation reduced the synergistic effect of PX-12 and 5-FU. Conclusions: PX-12 has anti-tumor activity and a synergistic effect in combination with 5-FU in HCC. Treatment with PX-12 alone or in combination with 5-FU may have clinical use in the treatment of HCC and other cancers. PMID:26550453

  3. UFT/leucovorin vs 5-FU/leucovorin in colon cancer.

    PubMed

    Smith, R E; Lembersky, B C; Wieand, H S; Colangelo, L; Mamounas, E P

    2000-10-01

    Adjuvant chemotherapy has been shown to alter the natural history of resected colon cancer. Two regimens (fluorouracil [5-FU] plus leucovorin and 5-FU plus levamisole) have been found to prolong disease-free survival and overall survival in affected patients. Previous comparisons of these two regimens indicate that 5-FU plus leucovorin may offer a small disease-free survival and overall survival advantage. Evidence that UFT (uracil and tegafur) plus oral leucovorin is associated with significant antitumor activity and has an acceptable toxicity profile makes this a logical formulation for the adjuvant treatment of colon cancer. The National Surgical Adjuvant Breast and Bowel Project Protocol C-06 is a randomized comparison of the relative efficacies of 5-FU plus leucovorin vs UFT plus leucovorin. Preliminary analysis of the toxicity findings among 1,530 evaluable patients indicates that both regimens are well tolerated and have similar toxicity profiles. PMID:11098486

  4. Production of immunoregulatory polysaccharides from Crassostrea hongkongensis and their positive effects as a nutrition factor in modulating the effectiveness and toxicity of 5-FU chemotherapy in mice.

    PubMed

    Cai, Bingna; Chen, Hua; Sun, Han; Wan, Peng; Sun, Huili; Pan, Jianyu

    2016-01-01

    Chemotherapy is generally accompanied by undesirable side effects, such as immunosuppression and malnutrition, which reduce tolerance to cancer therapies. Prior studies have shown that immunonutrition improves the clinical outcomes of cancer patients. In this study, immunoregulatory polysaccharides from Crassostrea hongkongensis were included in a nutrition formula that was administered to S180 tumor-bearing mice in combination with 5-fluorouracil (5-FU) treatment. The C30-60% fraction of the polysaccharides was characterized as a branched polysaccharide, with a high amount of d-glucose (96.76% of the total) and the highest uronic acid and sulfate groups' content among all of the polysaccharide fractions. The C30-60% polysaccharide fraction showed a maximal proliferative effect on RAW264.7 cells and T lymphocytes at a concentration of 0.0391 mg mL(-1) and 0.0781 mg mL(-1), respectively. Moreover, the combination treatment of the C30-60% polysaccharide-based nutrition formula (OPNF) with the administration of 5-FU effectively inhibited the growth of tumors and notably increased the leucocyte and lymphocyte counts in S180 tumor-bearing mice. In addition, a slight increase in the erythrocyte and hemoglobin values was observed in the mice treated with the combination of OPNF and 5-FU. These results suggest that supplementation with a C30-60%-based enteral formula would be beneficial for patients undergoing chemotherapy with 5-FU.

  5. Anti-tumor effect of L-methionine-deprived total parenteral nutrition with 5-fluorouracil administration on Yoshida sarcoma-bearing rats.

    PubMed

    Goseki, N; Endo, M; Onodera, T; Kosaki, G

    1991-07-01

    L-methionine-deprived total parenteral nutrition (methionine-deprived TPN), infusing amino acid solution devoid of L-methionine and L-cysteine by the method of TPN as an only protein source, showed enhancement of the effect of several anti-cancer agents. In this study the combined effect of the methionine-deprived TPN with administration of 5-fluorouracil (5-FU) was examined in Yoshida Sarcoma (YS)-bearing rats, from aspects of effects on the tumor metastasis and the host animal's life span, in the following four groups treated with: methionine-deprived TPN with administration of 5-FU, methionine-deprived TPN without administration of 5-FU, L-methionine-contained TPN plus 5-FU, and L-methionine-contained TPN without 5-FU. In the first experiment, TPN was continued for 8 days in the four groups, and the anti-cancer effect of methionine-deprived TPN and administration of 5-FU based on both the growth of the primary tumor at the implanted site and the tumor metastasis was studied from the view point of pathologic findings of animals killed immediately after these treatments. In experiment 2 the survival period was examined after these treatments for 10 days with subsequent oral feeding until death. The results were as follows: proliferation of YS, transplanted subcutaneously, was markedly suppressed; particularly hematogenous metastasis, characteristic in YS, was prominently blunted then obtained an apparent longer survival period in rats treated with the methionine-deprived TPN with administration of 5-FU.

  6. Comparative cardiac toxicity in two treatment schedules of 5-FU/LV for colorectal carcinoma.

    PubMed

    Najam, Rahila; Bano, Nusrat; Mateen, Ahmed

    2013-09-01

    The purpose of the study is evaluation and assessment of parameters of cardiac toxicity in patients subjected to 5-FU based chemotherapy. Cardiac morbidity is a reported outcome in different 5FU/LV regimens; however none of them are definite or proximate. The bimonthly regimen of high dose leucovorin is reported to be less toxic and more effective as compared to the monthly regimen of low dose leucovorin. We report the detailed assessment of few cardiac parameter of toxicity in patients of advanced colorectal carcinoma subjected to two Schedules of high and low dose Folinic Acid, 5-Fluorouracil, bolus and continuous infusion. The correlation of elevated cardiac biomarkers, angina and hypertension is comparatively assessed in patients with normal general status, hyperglycemia and known cardiac disorders subjected to two different 5FU based chemotherapeutic regimen.

  7. Autophagy in human skin squamous cell carcinoma: Inhibition by 3-MA enhances the effect of 5-FU-induced chemotherapy sensitivity.

    PubMed

    Zhang, Lili; Zhang, Jie; Chen, Li; Wang, Jianli

    2015-12-01

    Autophagy is an intracellular multi-step catabolic degradation process that involves the degradation and recycling of cellular proteins and cytoplasmic damaged organelles to maintain cellular homeostasis and reduction of metabolic stress. Numerous studies have indicated the importance of autophagy in cancer, but the role of autophagy in human skin squamous cell carcinoma (SSCC) development and response to therapy it is still unclear. In the present study, we investigated the role of autophagy in SSCC and the relationship with chemotherapy sensitivity. The present study demonstrated that autophagy related gene the microtubule-associated protein 1 light chain 3 (LC3) expression was low in SSCC. The negative correlation with Bcl2 and survivin, and the chemotherapy drug 5-FU increased the level of autophagy and the autophagy inhibitor 3-MA inhibited this effect in SSCC cells, time- and dose-dependently. When SSCC cells were treated first with 3-MA and then with 5-FU, the inhibition of proliferation, migration, invasion and apoptosis of SSCC cells was enhanced. Our results suggested the possibility of autophagy as a potential target in SSCC therapy and 3-MA and 5-FU combination treatment may be an effective SSCC therapy via autophagy modulating. PMID:26398820

  8. Clinical outcomes of amniotic membrane loaded with 5-FU PLGA nanoparticles in experimental trabeculectomy

    PubMed Central

    Hu, Fang; Zeng, Xiang-Yun; Xie, Zhao-Lian; Liu, Lin-Lin; Huang, Liang

    2015-01-01

    AIM To evaluate the effect of amniotic membrane loaded with 5-fluorouracil poly (lactic-co-glycolic acid) (PLGA) nanoparticles (5-FU-NPs) in the surgical outcomes of experimental trabeculectomy in rabbits. METHODS Thirty-two New Zealand white rabbits were randomly categorized into four groups with 8 rabbits in each group. Group 1, the control group, performed traditional trabeculectomy without adjuvant treatment. While the experimental groups performed compound trabeculectomy with different implantations including amniotic membrane (group 2), 5-FU-NPs (group 3) and amniotic membrane loaded with 5-FU-NPs (group 4). Clinical evaluations including IOP measurement and filtration bleb analysis were performed in all groups postoperatively. RESULTS There is no significant difference of mean IOP in all groups at first 7d after surgery. While at P14, mean IOPs of experimental group 2 (9.8±2.1 mm Hg), groups 3 (8.9±2.8 mm Hg) and group 4 (7.6±2.3 mm Hg) were significantly reduced compared to control group (12.4±2.6 mm Hg; n=8, P<0.05). At P21, mean IOPs of groups 3 (11.7±3.2 mm Hg) and group 4 (9.9±1.6 mm Hg) were significantly decreased compare to control group (17.9±1.6 mm Hg) and group 2 (16.6±2.8 mm Hg; n=8, P<0.05). At P28, mean IOPs of groups 3 (13.8±3.3 mm Hg) and group 4 (10.6±2.0 mm Hg) were also significantly reduced compare to control group (19.4±2.3 mm Hg) and group 2 (18.5±2.4 mm Hg; n=8, P<0.05). Meanwhile mean IOP of group 4 is significantly decreased compared to group 3 at P28 (n=8, P<0.05). Survival analysis of functional filtration blub in all groups revealed the longest survival time in group 4 (24.9±5.1d) compared to that in group 3 (20.6±4.3d), group 2 (15.0±5.2d) and control group (10.1±5.7d). CONCLUSION Amniotic membrane loaded with 5-Fu-NPs may function as an effective anti-scarring implant and provides improved long-term surgical outcomes for experimental trabeculectomy in rabbits. PMID:25709903

  9. miRNA-195 sensitizes human hepatocellular carcinoma cells to 5-FU by targeting BCL-w.

    PubMed

    Yang, Xiaoyan; Yin, Jie; Yu, Jia; Xiang, Qiong; Liu, Yunmei; Tang, Shensong; Liao, Duanfang; Zhu, Bingyang; Zu, Xuyu; Tang, Huifang; Lei, Xiaoyong

    2012-01-01

    The role of microRNA-195 in developing acquired drug resistance in hepatocellular carcinoma cells was investigated. Expression profiling of miRNAs revealed a limited set of miRNAs with altered expression in drug resistant hepatocellular carcinoma cell line BEL-7402/5-FU compared to its parental BEL-7402 cell line. Real-time PCR confirmed down-regulation of miRNA-195 in BEL-7402/5-FU cells. Overexpression of miRNA-195 sensitized BEL-7402/5-FU cells to anticancer drugs. Consistent with these findings, miR-195 antisense oligonucleotide induced drug resistance in BEL-7402/5-FU cells. Also, the basal levels of the anti-apoptotic protein Bcl-w were high in BEL-7402/5-FU cells and miR-195 overexpression repressed Bcl-w protein level and inhibited the luciferase activity of a Bcl-w 3' untranslated region-based reporter construct in both BEL-7402/5-FU and BEL-7402 cells. These results indicate that miR-195 could improve the drug sensitivity at least in part by targeting Bcl-w to increase cell apoptosis in hepatocellular carcinoma cells.

  10. Laser sclerectomy and 5-FU controlled-drug-release biodegradable implant for glaucoma therapy

    NASA Astrophysics Data System (ADS)

    Villain, Franck L.; Parel, Jean-Marie A.; Kiss, Katalin; Parrish, Richard K.; Kuhne, Francois; Takesue, Yoshiko; Hostyn, Patrick

    1993-06-01

    Laser sclerectomy, a simple filtering procedure performed to alleviate high intraocular pressure in glaucoma patients, was taught to offer longer lasting effect and therefore improve the patient's outcome when compared with the standard trabeculectomy procedure. Recent clinical trials have shown that this was not the case and pharmacologic wound healing modulation is also required with this new procedure. Five-Fluorouracil (5-FU) is useful as an adjunct treatment for glaucoma filtering surgery. However, efficacy depends upon maintaining sustained drug levels, currently achieved by repeated daily injection of the drug for several weeks. To overcome this limitation, we designed a biodegradable implant for the sustained release of 5-FU. After laser sclerectomy, the implant is inserted through the same 1 mm wide conjunctival snip incision and positioned below the open channel. Implantation takes less than a minute. The implant releases the drug for over 15 days and totally biodegrades in less than 100 days. The combined laser surgery and implantation procedure show great potentials for the treatment of glaucoma.

  11. Cell Line Derived 5-FU and Irinotecan Drug-Sensitivity Profiles Evaluated in Adjuvant Colon Cancer Trial Data

    PubMed Central

    Delorenzi, Mauro; Jensen, Thomas; Jensen, Peter Buhl; Bosman, Fred; Tejpar, Sabine; Roth, Arnaud; Brunner, Nils; Hansen, Anker; Knudsen, Steen

    2016-01-01

    Purpose This study evaluates whether gene signatures for chemosensitivity for irinotecan and 5-fluorouracil (5-FU) derived from in vitro grown cancer cell lines can predict clinical sensitivity to these drugs. Methods To test if an irinotecan signature and a SN-38 signature could identify patients who benefitted from the addition of irinotecan to 5-FU, we used gene expression profiles based on cell lines and clinical tumor material. These profiles were applied to expression data obtained from pretreatment formalin fixed paraffin embedded (FFPE) tumor tissue from 636 stage III colon cancer patients enrolled in the PETACC-3 prospective randomized clinical trial. A 5-FU profile developed similarly was assessed by comparing the PETACC-3 cohort with a cohort of 359 stage II colon cancer patients who underwent surgery but received no adjuvant therapy. Results There was no statistically significant association between the irinotecan or SN-38 profiles and benefit from irinotecan. The 5-FU sensitivity profile showed a statistically significant association with relapse free survival (RFS) (hazard ratio (HR) = 0.54 (0.41–0.71), p<1e-05) and overall survival (HR = 0.47 (0.34–0.63), p<1e-06) in the PETACC-3 subpopulation. The effect of the 5-FU profile remained significant in a multivariable Cox Proportional Hazards model, adjusting for several relevant clinicopathological parameters. No statistically significant effect of the 5-FU profile was observed in the untreated cohort of 359 patients (relapse free survival, p = 0.671). Conclusion The irinotecan predictor had no predictive value. The 5-FU predictor was prognostic in stage III patients in PETACC-3 but not in stage II patients with no adjuvant therapy. This suggests a potential predictive ability of the 5-FU sensitivity profile to identify colon cancer patients who may benefit from 5-FU, however, any biomarker predicting benefit for adjuvant 5-FU must be rigorously evaluated in independent cohorts. Given differences

  12. Phase II study of combined chemotherapy with docetaxel, CDDP and 5-FU for highly advanced esophageal cancer.

    PubMed

    Osaka, Yoshiaki; Shinohara, Motoo; Hoshino, Sumito; Ogata, Takashi; Takagi, Yu; Tsuchida, Akihiko; Aoki, Tatsuya

    2011-02-01

    Advanced esophageal cancer with widespread metastasis to lymph nodes or other organs is difficult to treat and has an extremely poor prognosis. A new combined chemotherapy of docetaxel with cisplatin (CDDP) and 5-fluorouracil (5-FU) (DPF therapy) was performed and its efficacy and safety were examined. Among those hospitalized between May 2003 and October 2009, 30 patients with stage III or stage IV unresectable, untreated advanced esophageal squamous cell carcinoma which had invaded other organs were enrolled in this study. The regimen of DPF therapy was as follows: a set of intravenous drips of 60 mg/m(2) of docetaxel (day 1), 60 mg/m(2) of CDDP (day 1) and 800 mg/m(2) of 5-FU (days 1-5) was administered twice at an interval of 3 to 4 weeks. Antitumor effects, adverse reactions and treatment outcomes were then examined. The patients included 26 men and 4 women aged 40 to 73 years (average age, 58.1 years), and the performance status (PS) was 1 in 18 cases and 2 in 12 cases. The main location of the esophageal cancer was the upper/middle/lower thoracic esophagus in 7/14/9 cases, respectively. Clinical stage was III in 5 cases and IV in 25. The effective rate of DPF therapy was 83.3% for the primary lesion (complete response, CR: 4 cases, partial response, PR: 21 cases), 72.4% for lymph node metastasis (CR: 3 cases, PR: 18 cases) and 72.0% for distant organ metastasis (CR: 3 cases, PR: 15 cases). The observed adverse reactions of grade 2 or higher of National Cancer Institute-Common Toxicity Criteria (NCI-CTC) included anemia (16.7%), leukopenia (73.3%), liver dysfunction (20.0%), anorexia (16.7%), stomatitis (33.3%), esophagitis (16.7%), alopecia (16.7%) and diarrhea (26.7%). The therapy completion rate was 96.7% and the therapy-related death rate was 3.3%. Treatments given after the completion of the DPF therapy were surgery in 6 cases, chemotherapy such as additional DPF in 12, chemoradiation in 4, esophageal stent placement in 1, and no treatment in 7. The

  13. [A case of advanced esophageal cancer with liver metastases: efficacy of combination therapy of docetaxel/cisplatin/5-FU].

    PubMed

    Ehara, Kazuhisa; Tsutsumi, Kenji; Kinoshita, Yoshihiro; Ueno, Masaki; Mine, Shinji; Udagawa, Harushi

    2008-08-01

    The combination chemotherapy with docetaxel/CDDP/5-FU(DCF)for head and neck squamous carcinoma(SCC) has been widely accepted. It seems quite natural that DCF therapy is expected to be equally effective against esophageal SCC because of their histological similarity. In this report, we present a case of unresectable advanced esophageal SCC with multiple liver metastases which showed remarkable regression by DCF therapy, with relatively slight adverse effects. The patient was a 46-year-old female, who underwent upper gastrointestinal fiber-optic endoscopy for dysphasia and was diagnosed to have upper middle thoracic esophageal SCC. Abdominal CT scan showed multiple liver metastases with para-aortic lymph node involvement. The clinical stage diagnosis was T3N4M1, Stage IVB, obviously non-resectable far-advanced esophageal SCC. Systemic chemotherapy with DCF was started as the initial treatment. The chemotherapy regimen was as follows. 5-FU 500 mg/m(2) was administered as continuous intravenous infusion through day 1 to 5, while docetaxl 60 mg/m(2) and cisplatin 50 mg/m(2) were given intravenously on day 2. Each course was followed by a 23-day drug-free period, and the entire course was repeated every 28 days. Ten cycles of this DCF chemotherapy were carried out. After 4 cycles, primary lesion was judged as complete response(CR)by endoscopy. After 8 cycles, the liver metastases were judged as CR and para-aortic lymph nodes showed a partial response(PR)by CT scan. After 10 cycles, all we could detect was a small local recurrence of the primary tumor, which was then treated with chemoradiotherapy at the outpatient clinic. Until this writing, we added 2 more cycles of DCF therapy for the recurrent para-aortic and inguinal lymph node metastasis. Three years have passed from her first visit, and the patient is still in a stable disease state. The adverse effects were grade 3 at most in both hematological and non-hematological toxicity. We conclude that DCF therapy is

  14. Moderate intensity static magnetic fields affect mitotic spindles and increase the antitumor efficacy of 5-FU and Taxol.

    PubMed

    Luo, Yan; Ji, Xinmiao; Liu, Juanjuan; Li, Zhiyuan; Wang, Wenchao; Chen, Wei; Wang, Junfeng; Liu, Qingsong; Zhang, Xin

    2016-06-01

    Microtubules are the fundamental components in mitotic spindle, which plays essential roles in cell division. It was well known that purified microtubules could be affected by static magnetic fields (SMFs) in vitro because of the diamagnetic anisotropy of tubulin. However, whether these effects lead to cell division defects was unknown. Here we find that 1T SMFs induce abnormal mitotic spindles and increase mitotic index. Synchronization experiments show that SMFs delay cell exit from mitosis and cause mitotic arrest. These mimic the cellular effects of a microtubule-targeting drug Paclitaxel (Taxol), which is frequently used in combination with 5-Fluorouracil (5-FU) and Cisplatin in cancer treatment. Using four different human cancer cell lines, HeLa, HCT116, CNE-2Z and MCF7, we find that SMFs increase the antitumor efficacy of 5-FU or 5-FU/Taxol, but not Cisplatin, which indicates that the SMF-induced combinational effects with chemodrugs are drug-specific. Our study not only reveals the effect of SMFs on microtubules to cause abnormal mitotic spindles and delay cells exit from mitosis, but also implies the potential applications of SMFs in combination with chemotherapy drugs 5-FU or 5-FU/Taxol, but not with Cisplatin in cancer treatment.

  15. Impairment of energy metabolism in cardiomyocytes caused by 5-FU catabolites can be compensated by administration of amino acids.

    PubMed

    Lischke, Julia; Lang, Christine; Sawodny, Oliver; Feuer, Ronny

    2015-01-01

    Identification of patients with increased risk of 5-fluorouracil (5-FU)-related toxicity is an important challenge for cancer treatment. Research often focus on dihydropyrimidine dehydrogenase (DPYD) deficiency in this context. However, patients with normal DPYD activity may also develop life-threatening 5-FU adverse effects. DPYD initiates the catabolic route of 5-FU generating metabolites such as fluoroacetate (FAC). The catabolite FAC is known to inhibit the TCA cycle enzyme aconitase, which is supposed to impair mitochondrial energy metabolism. Therefore, we aim for a systems understanding of the association of 5-FU-related cardiac side effects with aconitase inhibition caused by FAC. Using a mitochondrial model of cardiomyocytes we found strong depletion of ATP production and citrate accumulation as main effects of aconitase inhibition. Shadow price analysis revealed that the uptakes of valine, arginine, proline and glutamate are most effective in compensating the impairment of energy metabolism. Our findings suggest that 5-FU catabolism contributes to the occurrence of cardiac adverse effects and are the basis for further biomarker identifications and development of side effect treatment. PMID:26737503

  16. [Effect of 5-FU on the utilization of purine and pyrimidine by human gastric cancer cells (KATO III)].

    PubMed

    Usami, M; Wang, J; Yasuda, I; Saitoh, Y; Yumisashi, T; Abe, K

    1995-05-01

    Effect of utilization of purine and pyrimidine in the culture medium by human gastric cancer cells (KATO III) was evaluated. Nucleosides mixture solution (OG-VI), consisting of inosine, guanosine 5' monophosphate (5'GMP), cytidine, uridine and thymidine (4: 4: 4: 3: 1 in molar ratio) was used and their levels in the culture medium was measured by HPLC after 3 day culture. Purine, inosine and 5' GMP, in the medium almost decreased and purine base, xanthine and hypoxanthine levels increased, but changes in pyrimidine level were minimal. 5-FU decreased purine and increased pyrimidine consumption. Addition of nucleosides mixture did not enhance the cellular proliferation, but inhibited growth when given in higher concentrations. Nucleoside mixture solution enhanced growth inhibition by 5-FU and it is a potential biochemical modulator of 5-FU metabolism in human cancer cells. PMID:7755382

  17. MORPHOMETRIC ANALYSIS OF RAT HINDLIMB MALFORMATIONS DUE TO GESTATIONAL EXPOSURE TO 5-FU

    EPA Science Inventory

    SETZER1, R. W., M. D. WILLIAMS2, D. LITTON3, M.G. NAROTSKY4, 1Experimental Toxicology Division and 4Reproductive Toxicology Division, NHEERL, ORD, USEPA, Research Triangle Park, North Carolina; 2UNC School of Medicine, Chapel Hill, North Carolina; and 3Department of Aerospace E...

  18. Anticipatory vomiting in women receiving cyclophosphamide, methotrexate, and 5-FU (CMF) adjuvant chemotherapy for breast carcinoma.

    PubMed

    Wilcox, P M; Fetting, J H; Nettesheim, K M; Abeloff, M D

    1982-08-01

    To determine the incidence of anticipatory vomiting (AV) and postchemotherapy nausea and vomiting (PCNV) in women receiving cyclophosphamide, methotrexate, and 5-FU (CMF) adjuvant chemotherapy for breast carcinoma, we studied 52 women randomized to two regimens (standard-dose and low-dose) of CMF. Charts were reviewed for the cycle of onset of AV and PCNV, the severity of PCNV, and relationships of these syndromes to CMF dose and protocol compliance. Among the 52 patients, AV occurred in 17 (33%), while PCNV was experienced by 46 (88%). Severe PCNV (defined as uncontrolled nausea and/or vomiting interfering with performance of daily activities) occurred in 22 of 52 (42%) women. Eighteen of 23 (78%) women receiving standard-dose CMF experienced severe PCNV, and 13 of these had AV. Patients in whom severe PCNV began before cycle 4 were more likely to develop AV than women in whom PCNV began later (P less than 0.01). Ten of 52 (19%) patients discontinued CMF adjuvant chemotherapy because of nausea and vomiting; seven of the ten (70%) were receiving standard-dose CMF and seven had experienced AV. This study demonstrates that both AV an PCNV are significant toxic effects that not only affect the quality of life of a woman receiving CMF chemotherapy for breast cancer but also limit the ability of the clinician to provide maximum therapy to woman at high risk of recurrence of breast carcinoma.

  19. Assessment of surface concentrations in resorbable ocular implants: controlled drug delivery devices for 5-fluorouracil (5-FU)

    NASA Astrophysics Data System (ADS)

    Milne, Peter J.; Gautier, Sandrine; Parel, Jean-Marie A.; Jallet, Valerie

    1997-05-01

    The antineoplastic drug 5-fluorouracil (5-fluoro- 2,4,(1H,3H)-pyrimidinedione; 5-FU) has been used to control proliferation of penetrating fibroblasts and to prevent channel closure following glaucoma filtration surgery (trabeculectomy) or laser sclerectomy. Because of the toxicity of the drug, administration of low dosages slowly over time, at the site of the desired treatment, is indicated for optimum efficacy. Repeated injections of low dosages of the drug represent an undesirable intervention and may also result in unwanted toxicity to the corneal epithelium. A suitable biocompatible and resorbable polymer matrix composed of a poly (D,L-lactic-co-glycolic acid: PLGA) has been admixed with varying amounts of 5-FU and cast as shapes suitable for intracorneal implantation. Slow biodegradation of this polymer over a one to two week period has been shown to result in an acceptably slow drug release mechanism. An issue arising during the clinical evaluation of the efficacy of this drug delivery system was how best to quantify the concentration of 5-FU and its distribution spatially in the solid implant. FT-IR and FT-Raman spectroscopies distinguishes between the drug and the polymer matrix and were used to differentiate and quantitate the 5-FU concentration of the implants.

  20. Overcoming acquired drug resistance in colorectal cancer cells by targeted delivery of 5-FU with EGF grafted hollow mesoporous silica nanoparticles

    NASA Astrophysics Data System (ADS)

    Chen, Lijue; She, Xiaodong; Wang, Tao; He, Li; Shigdar, Sarah; Duan, Wei; Kong, Lingxue

    2015-08-01

    Acquired drug resistance (ADR) can be developed in colorectal cancer cells after 5-fluorouracil (5-FU) treatment and diminish the effectiveness of chemotherapy. In this work, acquired 5-FU resistance in the colorectal cancer cell line SW480 was obtained with the up-regulation of dihydropyrimidine dehydrogenase (DPYD) gene expression which can convert 5-FU to its inactive metabolite. To overcome ADR in colorectal cancer, hollow mesoporous silica nanoparticles (HMSNs) grafted with epidermal growth factor (EGF) were used as nanocarriers to deliver 5-FU to colorectal cancer cells with acquired drug resistance. The effect and mechanism of 5-FU loaded EGF grafted HMSNs (EGF-HMSNs-5-FU) in overcoming acquired drug resistance in SW480/ADR cells were studied. The EGF-HMSNs were demonstrated to be specifically internalized in EGFR overexpressed SW480/ADR cells via a receptor-mediated endocytosis and can escape from endo-lysosomes. The EGF-HMSNs-5-FU exhibited much higher cytotoxicity on SW480/ADR cells than HMSNs-5-FU and free 5-FU while the plain HMSNs did not show significant cytotoxicity. The mechanism of EGF-HMSNs-5-FU in overcoming drug resistance in SW480/ADR cells could be attributed to the specific internalization of EGF-HMSNs-5-FU in EGFR overexpressed cells which can lead to high intracellular drug accumulation and cause cell death through S phase arrest.Acquired drug resistance (ADR) can be developed in colorectal cancer cells after 5-fluorouracil (5-FU) treatment and diminish the effectiveness of chemotherapy. In this work, acquired 5-FU resistance in the colorectal cancer cell line SW480 was obtained with the up-regulation of dihydropyrimidine dehydrogenase (DPYD) gene expression which can convert 5-FU to its inactive metabolite. To overcome ADR in colorectal cancer, hollow mesoporous silica nanoparticles (HMSNs) grafted with epidermal growth factor (EGF) were used as nanocarriers to deliver 5-FU to colorectal cancer cells with acquired drug resistance. The

  1. Synthesis of liver-targeting dual-ligand modified GCGA/5-FU nanoparticles and their characteristics in vitro and in vivo.

    PubMed

    Cheng, Mingrong; Gao, Xiaoyan; Wang, Yong; Chen, Houxiang; He, Bing; Li, Yingchun; Han, Jiang; Zhang, Zhiping

    2013-01-01

    Nanoparticle drug delivery systems using polymers hold promise for clinical applications. We synthesized dual-ligand modified chitosan (GCGA) nanoparticles using lactic acid, glycyrrhetinic acid, and chitosan to target the liver in our previous studies. We then synthesized the GCGA/5-FU nanoparticles by conjugating 5-fluorouracil (5-FU) onto the GCGA nanomaterial, which had a mean particle size of 239.9 nm, a polydispersity index of 0.040, a zeta potential of +21.2 mV, and a drug loading of 3.90%. GCGA/5-FU nanoparticles had good slow release properties, and the release process could be divided into five phases: small burst release, gentle release, second burst release, steady release, and slow release. Inhibitory effects of GCGA/5-FU on tumor cells targeted the liver, and were time and dose dependent. GCGA nanoparticles significantly prolonged the efficacy of 5-FU on tumor cells, and alleviated the resistance of tumor cells to 5-FU. GCGA/5-FU nanoparticles were mostly concentrated in the liver, indicating that the GCGA nanoparticles were liver targeting. GCGA/5-FU nanoparticles significantly suppressed tumor growth in orthotopic liver transplantation mouse model, and improved mouse survival.

  2. Stevens-Johnson Syndrome Patient Received Combination Chemotherapy Gemcitabine, Cisplatin, and 5-FU for Biliary Tract Cancer

    PubMed Central

    Aznab, Mozaffar; Khazaei, Mansour

    2016-01-01

    Stevens-Johnson syndrome has been an acute, usually self-limiting disease of the skin and mucous membranes. This case report has presented an evidence of the development Stevens - Johnson syndrome associated with combination chemotherapy administration of 5FU, gemcitabin and cisplatin in a patient with biliary tract cancer. Our case was a 54-year-old woman patient, a case of biliary tract cancer who has developed more severe symptoms of Stevens-Johnson syndrome. Diagnosis has confirmed by skin biopsy of an affected area .The patient has improved with supportive care, and during 25 day occurred recovery. Although Stevens-Johnson syndrome has been a rare toxicity, physicians should pay a special attention to the monitoring of biliary tract cancer patients on combination chemotherapy with 5FU, cisplatin and gemcitabin.

  3. 5-fu dose-dependency in mtx/s-fu sequential therapy assessed by in-vitro assay using gastric-cancer cell-lines.

    PubMed

    Nozue, M; Todoroki, T; Fukao, K

    1995-09-01

    The sequential administration of methotrexate (MTX) and 5-fluorouracil (5-FU) (MTX/5-FU therapy) on gastric cancers has shown higher response rates than standard chemotherapy. The response rate of these cancers, however, still showed from 18 to 48%. The purpose of this study was to determine the appropriate interval time and doses of MTX/5-FU therapy using a panel of 4 cell lines originated from the poorly-differentiated gastric cancers. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used as the chemosensitivity test. The sequential administration of MTX and 5-FU inhibited the growth of 2 cell lines more than 5-FU alone. In one cell line (GCIY), it inhibited the growth 6 times, and the longest interval time (6 h) was the most effective. In the other cell line (KATOIII), it inhibited growth 3 times, and the shortest interval time (O h) was the most effective. The growth inhibition in these cases did not depend on the dose of MTX (0.01 mu g/ml to 100 mu g/ml), but on the dose of 5-FU. In conclusion, 2 out of 4 cell lines showed a synergic effect between MTX and 5-FU. While the appropriate interval time between the two drugs varied between two cell lines, 5-FU dose was more critical than that of MTX. If 5-FU dose were to be increased in future trials with MTX, its efficacy might be higher. This model should also be good to screen other anti cancer drugs combined with MTX/5-FU therapy. PMID:21597807

  4. Proliferation rate but not mismatch repair affects the long-term response of colon carcinoma cells to 5FU treatment.

    PubMed

    Choudhary, B; Hanski, M L; Zeitz, M; Hanski, C

    2012-07-01

    The role of mismatch repair (MMR) in the response of colon carcinoma cells to 5-fluorouracil (5FU) is not well understood. In most of the in vitro studies only short-term response was investigated. We focussed here on the influence of MMR status on the mechanism of the short- and long-term response to clinically relevant 5FU concentrations by using isogenic or semiisogenic cell line pairs expressing/nonexpressing the hMLH1 protein, an important component of the MMR system. We show that the lower survival of MMR-proficient than of MMR-deficient cells in the clonogenic survival assay is due to a more frequent early cell arrest and to subsequent senescence. By contrast, the long-term cell growth after treatment, which is also affected by long-term arrest and senescence, is independent from the MMR status. The overall effect on the long-term cell growth is a cumulative result of cell proliferation rate-dependent growth inhibition, apoptosis and necrotic cell death. The main long-term cytotoxic effect of 5FU is the inhibition of growth while apoptosis and the necrotic cell death are minor contributions.

  5. A feasibility study of [sup 252]Cf neutron brachytherapy, cisplatin + 5-FU chemo-adjuvant and accelerated hyperfractionated radiotherapy for advanced cervical cancer

    SciTech Connect

    Murayama, Y.; Wierzbicki, J. Univ. of Kentucky Medical Center, Lexington, KY ); Bowen, M.G.; Van Nagell, J.R.; Gallion, H.H.; DePriest, P. )

    1994-06-15

    The purpose was to evaluate the feasibility and toxicity of [sup 252]Cf neutron brachytherapy combined with hyperaccelerated chemoradiotherapy for Stage III and IV cervical cancers. Eleven patients with advanced Stage IIIB-IVA cervical cancers were treated with [sup 252]Cf neutron brachytherapy in an up-front schedule followed by cisplatin (CDDP; 50 mg/m[sup 2]) chemotherapy and hyperfractionated accelerated (1.2 Gy bid) radiotherapy given concurrently with intravenous infusion of 5-Fluorouracil (5-FU) (1000 mg/m[sup 2]/day [times] 4 days) in weeks 1 and 4 with conventional radiation (weeks 2, 3, 5, and 6). Total dose at a paracervical point A isodose surface was 80-85 Gy-eq by external and intracavitary therapy and 60 Gy at the pelvic sidewalls. Patients tolerated the protocol well. There was 91% compliance with the chemotherapy and full compliance with the [sup 252]Cf brachytherapy and the external beam radiotherapy. There were no problems with acute chemo or radiation toxicity. One patient developed a rectovaginal fistula (Grade 3-4 RTOG criteria) but no other patients developed significant late cystitis, proctitis or enteritis. There was complete response (CR) observed in all cases. With mean follow-up to 26 months, local control has been achieved with 90% actuarial 3-year survival with no evidence of disease (NED). [sup 252]Cf neutrons can be combined with cisplatin and 5-FU infusion chemotherapy plus hyperaccelerated chemoradiotherapy without unusual side effects or toxicity and with a high local response and tumor control rate. Further study of [sup 252]Cf neutron-chemoradiotherapy for advanced and bulky cervical cancer are indicated. The authors found chemotherapy was more effective with the improved local tumor control. 18 refs., 2 tabs.

  6. Methylation status at HYAL2 predicts overall and progression-free survival of colon cancer patients under 5-FU chemotherapy.

    PubMed

    Pfütze, Katrin; Benner, Axel; Hoffmeister, Michael; Jansen, Lina; Yang, Rongxi; Bläker, Hendrik; Herpel, Esther; Ulrich, Alexis; Ulrich, Cornelia M; Chang-Claude, Jenny; Brenner, Hermann; Burwinkel, Barbara

    2015-12-01

    DNA methylation variations in gene promoter regions are well documented tumor-specific alterations in human malignancies including colon cancer, which may influence tumor behavior and clinical outcome. As a subset of colon cancer patients does not benefit from adjuvant chemotherapy, predictive biomarkers are desirable. Here, we describe that DNA methylation levels at CpG loci of hyaluronoglucosaminidase 2 (HYLA2) could be used to identify stage II and III colon cancer patients who are most likely to benefit from 5-flourouracil (5-FU) chemotherapy with respect to overall survival and progression-free survival. PMID:26453961

  7. AT101 exerts a synergetic efficacy in gastric cancer patients with 5-FU based treatment through promoting apoptosis and autophagy.

    PubMed

    Wei, Xi; Duan, Wei; Li, Ying; Zhang, Sheng; Xin, Xiaojie; Sun, Lei; Gao, Ming; Li, Qing; Wang, Dong

    2016-06-01

    Gastric cancer remains a disease with a high mortality rate despite of multiple therapeutic strategies. So far, it is very important to develop new treatment approaches to improve current therapeutic efficacy in gastric cancer. Apurinic/apyrimidinic endonuclease (APE1) involves in DNA base excision repair (BER) during DNA damage pathway. APE1 was found to be associated with poor overall survival with gastric cancer patients. In the in vitro experiment, we tested APE1 inhibitor-AT101 could potently inhibit gastric cancer cell growth and further induce cancer cell apoptosis and autophagy through p53-dependent pathway. Downregulation of APE1 by AT101 has ability to suppress gastric cancer cell migration and renewal through inhibition of CD133, Nanog and LC3expression. Based on findings that Her-2 positive expression cases has poor prognosis from our dataset and TCGA database, we investigated the role of AT101 in synergetic efficacy with 5-FU treatment in Her-2 overexpression gastric cancer in vivo, indicating that AT101 is able to enhance 5-FU in the shrinkage of xenograft mice tumor and induction of cell apoptosis. In summary, the data obtained from our study showed APE1 is guided as a potential therapeutic target for gastric cancer. AT101 could be regarded as a potent inhibitor to promote chemotherapeutic sensitivity in patients with gastric cancer.

  8. AT101 exerts a synergetic efficacy in gastric cancer patients with 5-FU based treatment through promoting apoptosis and autophagy

    PubMed Central

    Wei, Xi; Duan, Wei; Li, Ying; Zhang, Sheng; Xin, Xiaojie; Sun, Lei; Gao, Ming; Li, Qing; Wang, Dong

    2016-01-01

    Gastric cancer remains a disease with a high mortality rate despite of multiple therapeutic strategies. So far, it is very important to develop new treatment approaches to improve current therapeutic efficacy in gastric cancer. Apurinic/apyrimidinic endonuclease (APE1) involves in DNA base excision repair (BER) during DNA damage pathway. APE1 was found to be associated with poor overall survival with gastric cancer patients. In the in vitro experiment, we tested APE1 inhibitor-AT101 could potently inhibit gastric cancer cell growth and further induce cancer cell apoptosis and autophagy through p53-dependent pathway. Downregulation of APE1 by AT101 has ability to suppress gastric cancer cell migration and renewal through inhibition of CD133, Nanog and LC3expression. Based on findings that Her-2 positive expression cases has poor prognosis from our dataset and TCGA database, we investigated the role of AT101 in synergetic efficacy with 5-FU treatment in Her-2 overexpression gastric cancer in vivo, indicating that AT101 is able to enhance 5-FU in the shrinkage of xenograft mice tumor and induction of cell apoptosis. In summary, the data obtained from our study showed APE1 is guided as a potential therapeutic target for gastric cancer. AT101 could be regarded as a potent inhibitor to promote chemotherapeutic sensitivity in patients with gastric cancer. PMID:27144437

  9. Resveratrol synergistically augments anti-tumor effect of 5-FU in vitro and in vivo by increasing S-phase arrest and tumor apoptosis

    PubMed Central

    Dun, Jiening; Chen, Xueyan; Gao, Haixia; Zhang, Yan; Zhang, Huajun

    2015-01-01

    Many studies have shown that natural dietary agents, in combination with chemical agents, can improve the therapeutic response of cancers to chemotherapy and reduce the associated side-effects. In the present study, we investigated the therapeutic potential and mechanisms of anticancer effects for the combination of 5-fluorouracil (5-FU) and resveratrol (Res). In these studies, we employed the cancer cell lines TE-1 and A431 and an animal model of skin cancer. The presented results provide the first evidence that Res can enhance the anti-tumor potency of 5-FU by inducing S-phase arrest. The combination of Res and 5-FU demonstrates synergistic efficacy, causing tumor regression in a two-stage model of mouse skin carcinogenesis induced by DMBA and TPA. There was clear evidence of Res augmenting the growth inhibitory effect of 5-FU on the TE-1 and A431 cancer cells in vitro. In the in vivo studies, the tumor regression rate in the combination group increased significantly after four weeks of treatment (P < 0.01). The combination of 5-FU and Res significantly increased the percentage of apoptotic cells and the level of activated caspase-3, cleaved PARP and p53 proteins as well as increased the Bax/Bcl-2 ratio. In conclusion, the 5-FU/Res combination enabled a more effective inhibition of cell growth and the induction of apoptosis in cancer cells than 5-FU alone. The results of this study suggest that chemotherapy using natural dietary agents with chemical agents represents a superior cancer treatment option. PMID:25736303

  10. Chitosan coated sodium alginate-chitosan nanoparticles loaded with 5-FU for ocular delivery: in vitro characterization and in vivo study in rabbit eye.

    PubMed

    Nagarwal, Ramesh C; Kumar, Rakesh; Pandit, J K

    2012-11-20

    The objective of the study was to develop chitosan (CH) coated sodium alginate-chitosan (SA-CH) nanoparticles, i.e. CH-SA-CH NPs loaded with 5-FU for ophthalmic delivery. Drug loaded nanoparticles (DNPs) were prepared by ionic gelation technique using sodium alginate (SA) and chitosan (CH) and then suspended in chitosan solution. The mean size of nanoparticles and morphology were characterized by dynamic light scattering, scanning electron microscopy, atomic force microscopy and zeta potential. The in vitro release was studied by dialysis membrane technique. The size and drug encapsulation efficiency were dependent on molar ratio of SA and CH. The size of SA-CH nanoparticles was significantly increased with changed morphology after CH coating. SA-CH nanoparticles did not show any interaction with mucin while an enhanced viscosity was observed on coating of nanoparticles with CH. CH-SA-CH DNPs presented a sustained release of 5-FU compared to the 5-FU solution with high burst effect. In vivo study in rabbit eye showed significantly greater level of 5-FU in aqueous humor compared to 5-FU solution. The enhanced mucoadhesiveness of CH-SA-CH DNPs results in higher bioavailability as compared to the uncoated nanoparticles. Optimized formulation was found non-irritant and tolerable when tested by modified Draize test in rabbit eye. PMID:22922098

  11. Human rpL3 plays a crucial role in cell response to nucleolar stress induced by 5-FU and L-OHP.

    PubMed

    Esposito, Davide; Crescenzi, Elvira; Sagar, Vinay; Loreni, Fabrizio; Russo, Annapina; Russo, Giulia

    2014-11-30

    Recent evidence showed that a variety of DNA damaging agents including 5-FU and L-OHP impairs ribosomal biogenesis activating a ribosomal stress pathway. Here, we demonstrate that in lung and colon cancer cell lines devoid of p53, the efficacy of 5-FU and L-OHP chemotherapy depends on rpL3 status. Specifically, we demonstrate that ribosomal stress induced by 5-FU and L-OHP is associated to up-regulation of rpL3 and its accumulation as ribosome-free form. We show that rpL3 participates in the cell response to chemotherapy acting as a critical regulator of cell cycle, apoptosis and DNA repair, by modulating p21 expression. Moreover, we demonstrate that rpL3 is able to control DNA repair also independently from p21 status of cell. It is noteworthy that silencing of rpL3 abolishes the cytotoxic effects of 5-FU and L-OH indicating that the loss of rpL3 makes chemotherapy drugs ineffective. Taking together our results shed light on 5-FU and L-OHP mechanism of action and contribute to more effective clinical use of these drugs in cancer therapy. PMID:25473889

  12. The Effects and Mechanisms of Periplaneta americana Extract Reversal of Multi-Drug Resistance in BEL-7402/5-FU Cells.

    PubMed

    Yuan, Falu; Liu, Junyong; Qiao, Tingting; Li, Ting; Shen, Qi; Peng, Fang

    2016-01-01

    The present study reports the reversing effects of extracts from P. americana on multidrug resistance of BEL-7402/5-FU cells, as well as a preliminary investigation on their mechanism of action. A methylthiazolyl tetrazolium (MTT) method was applied to determine the multidrug resistance of BEL-7402/5-FU, while an intracellular drug accumulation assay was used to evaluate the effects of a column chromatography extract (PACC) and defatted extract (PADF) from P. americana on reversing multi-drug resistance. BEL-7402/5-FU reflected high resistance to 5-FU; PACC and PADF could promote drug accumulation in BEL-7402/5-FU cells, among which PADF was more effective than PACC. Moreover, results from the immunocytochemical method showed that PACC and PADF could downregulate the expression of drug resistance-associated proteins (P-gp, MRP, LRP); PACC and PADF had no effects on the expression of multidrug resistance-associated enzymes (GST-π), but PACC could increase the expression of multidrug resistance-associated enzymes (PKC). Results of real-time fluorescence quantitative PCR revealed that PACC and PADF were able to markedly inhibit the expression of multidrug resistance-associated genes (MDR1, LRP and MRP1); PACC presented a significant impact on the gene expression of multidrug resistance-associated enzymes, which increased the gene expression of GST-π and PKC. However, PADF had little impact on the expression of multidrug resistance-associated enzymes. These results demonstrated that PACC and PADF extracted from P. americana could effectively reverse MDR in BEL-7402/5-FU cells, whose mechanism was to inhibit the expression of P-gp, MRP, and LRP, and that PADF was more effective in the reversal of MDR than did PACC. In addition, some of extracts from P. americana altered (sometimes increasing) the expression of multidrug resistance-associated enzymes. PMID:27367657

  13. Effect of green tea on pharmacokinetics of 5-fluorouracil in rats and pharmacodynamics in human cell lines in vitro.

    PubMed

    Qiao, Jinping; Gu, Chenxin; Shang, Weihu; Du, Jinglei; Yin, Wei; Zhu, Meilin; Wang, Wei; Han, Mei; Lu, Weidong

    2011-06-01

    Tea drinking is widely practiced in the world and has recently increased among cancer patients. However, the effects of concurrent consumption of tea on the bioavailability and the net therapeutic potential of co-administered chemical drugs are not clear. In this study, the effects of green tea on the pharmacokinetics of 5-fluorouracil (5-FU) in rats and the pharmacodynamics in human cell lines in vitro were studied. The pharmacokinetic experiment indicated that there was an approximately 151% increase in the maximum plasma concentration (C(max)) and an approximately 425% increase in the area under the plasma concentration curve (AUC) of 5-FU in the green tea-treated group compared with the control group. Green tea consumption increased the plasma concentration of 5-FU. In addition, the pharmacodynamics experiment showed that at the moderate dose level (equivalent to <6 cups daily in human), neither fresh green tea extract nor (-)-epigallocatechin-3-gallate (EGCG) showed significant additive effects on the cytotoxicity of 5-FU in human cell lines. The results showed that it is crucial to perform therapeutic drug monitoring (TDM) when the cancer patients have a habit of drinking green tea. PMID:21440026

  14. The anticancer effect of (1S,2S,3E,7E,11E)-3,7,11, 15-cembratetraen-17,2-olide(LS-1) through the activation of TGF-β signaling in SNU-C5/5-FU, fluorouracil-resistant human colon cancer cells.

    PubMed

    Kim, Eun-Ji; Kang, Jung-Il; Kwak, Jeon-Won; Jeon, Chan-Hee; Tung, Nguyen-Huu; Kim, Young-Ho; Choi, Cheol-Hee; Hyun, Jin-Won; Koh, Young-Sang; Yoo, Eun-Sook; Kang, Hee-Kyoung

    2015-03-16

    The anticancer effect of (1S,2S,3E,7E,11E)-3,7,11,15-cembratetraen-17,2-olide (LS-1) from Lobophytum sp. has been already reported in HT-29 human colorectal cancer cells. In this study, we examined the effect of LS-1 on the apoptosis induction of SNU-C5/5-FU, fluorouracil-resistant human colon cancer cells. Furthermore, we investigated whether the apoptosis-induction effect of LS-1 could arise from the activation of the TGF-β pathway. In SNU-C5/5-FU treated with LS-1 of 7.1 μM (IC50), we could observe the various apoptotic characteristics, such as the increase of apoptotic bodies, the increase of the sub-G1 hypodiploid cell population, the decrease of the Bcl-2 level, the increase of procaspase-9 cleavage, the increase of procaspase-3 cleavage and the increase of poly(ADP-ribose) polymerase cleavage. Interestingly, the apoptosis-induction effect of LS-1 was also accompanied by the increase of Smad-3 phosphorylation and the downregulation of c-Myc in SNU-C5/5-FU. LS-1 also increased the nuclear localization of phospho-Smad-3 and Smad-4. We examined whether LS-1 could downregulate the expression of carcinoembryonic antigen (CEA), a direct inhibitor of TGF-β signaling. LS-1 decreased the CEA level, as well as the direct interaction between CEA and TGF-βR1 in the apoptosis-induction condition of SNU-C5/5-FU. To examine whether LS-1 can induce apoptosis via the activation of TGF-β signaling, the SNU-C5/5-FU cells were treated with LS-1 in the presence or absence of SB525334, a TGF-βRI kinase inhibitor. SB525334 inhibited the effect of LS-1 on the apoptosis induction. These findings provide evidence demonstrating that the apoptosis-induction effect of LS-1 results from the activation of the TGF-β pathway via the downregulation of CEA in SNU-C5/5-FU.

  15. Immunochemoradiotherapy for patients with oral squamous cell carcinoma: augmentation of OK-432-induced helper T cell 1 response by 5-FU and X-ray irradiation.

    PubMed

    Tano, Tomoyuki; Okamoto, Masato; Kan, Shin; Bando, Takashi; Goda, Hiroyuki; Nakashiro, Koh-ichi; Shimodaira, Shigetaka; Koido, Shigeo; Homma, Sadamu; Fujita, Tomonobu; Sato, Mitsunobu; Yamashita, Naomi; Hamakawa, Hiroyuki; Kawakami, Yutaka

    2013-07-01

    Eighty-one patients with oral squamous cell carcinoma (OSCC) received oral fluoropyrimidine UFT and radiotherapy (RT) with or without an immunotherapeutic agent OK-432. Both overall survival and progression-free survival of patients who received RT + UFT + OK-432 were significantly longer than those of patients who received RT + UFT (P = .0075 and P = .0175, respectively). Clinical response was also more favorable in RT + UFT + OK-432 group than in RT + UFT group (P = .0066). Next, in vitro experiments were conducted to examine the effect of 5-fluorouracil (5-FU) and X-ray irradiation in OK-432-induced immunity. Human peripheral blood mononuclear cells stimulated with OK-432 produced helper T cell 1 (Th1)-type cytokines as well as interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), which are produced by Th2 and regulatory T cells (Tregs), respectively, and are inhibitory in antitumor immunity. OK-432-induced IL-10 and TGF-β but not Th1 cytokines were significantly inhibited by 5-FU and/or X-ray. 5-FU and X-ray also inhibited the expression of mRNAs for GATA-3 and Foxp3, which are transcription factors for Th2 and Tregs, respectively, but not for T-bet, a transcription factor for Th1. In addition, 5-FU and X-ray decreased the expression of mRNAs for suppressor of cytokine signaling 1 (SOCS1) and SOCS3. Antisense oligonucleotides for SOCS1 and SOCS3 markedly reduced OK-432-induced IL-10 and TGF-β. This is the first report clearly demonstrating that OK-432-based immunotherapy significantly enhanced the therapeutic effects of chemoradiotherapy in patients with OSCC as well as elucidating the mechanism of the synergistic effect of immunochemoradiotherapy in which 5-FU and radiation enhanced OK-432-induced Th1 response mediated by the inhibition of SOCS1 and SOCS3 gene expression.

  16. Neuronal lipofuscin in centrophenoxine treated rats.

    PubMed

    Tani, F; Miyoshi, K

    1977-01-01

    The diminution of neuronal lipofuscin was studied in centrophenoxine adminstered animals. In fluorescent studies, as well as in ordinary histological methods, a marked decrease of the lipofuscin was observed in the cerebral cortex, hippocampus, thalamus, basal ganglia, midbrain, medulla oblongata and spinal cord. The lipofuscin in the cenntrophenoxine animals showed fine granular structures in the perikarua of the neurones when compared to that of control rats. Electronmicroscopically, electron density of the lipofusin structures was observed. Enlargement of the vacuolar portions of the lipofuscin was seen in the neurones of the dorsal ganglia in the centrophenoxine animals. In the present studies, the diminution of the lipofuscin in the neurones was well demonstrated with fluorecent and histological methods. The characteristic ultrastructural changes of the neuronal lipofuscin are reported.

  17. Emphysema model in rats treated intratracheally with elastase

    SciTech Connect

    Yokoyama, E.; Nambu, Z.; Uchiyama, I.; Kyono, H.

    1987-04-01

    Pulmonary functions, morphology, and morphometry were examined in rats at 3, 7, and 10 weeks after a single intratracheal administration of 6.5 units of porcine pancreatic elastase in order to obtain a model of pulmonary emphysema which would be suitable for studying the responses of emphysematous lungs to atmospheric pollutants. Functional residual capacity and residual volume of the elastase-treated rats increased at all the times studied, but their total lung capacity increased only at 7 and 10 weeks compared with those of the saline-treated control rats. The increase in static lung compliance and the decrease in peak flow and maximum flow at 50% of total lung capacity during forced expiration were also observed in all except the 3-week elastase animals. The elastase-treated lungs showed morphological changes characteristic of emphysematous lesions. The increase in mean linear intercept length and the decrease in total alveolar surface area were demonstrated by these elastase-treated lungs. Based on these results, they conclude that an adequate and suitable model of pulmonary emphysemia could be obtained in rats 7-10 weeks after treatment with the present dose of elastase.

  18. Microarray analysis of thioacetamide-treated type 1 diabetic rats

    SciTech Connect

    Devi, Sachin S.; Mehendale, Harihara M. . E-mail: mehendale@ulm.edu

    2006-04-01

    It is well known that diabetes imparts high sensitivity to numerous hepatotoxicants. Previously, we have shown that a normally non-lethal dose of thioacetamide (TA, 300 mg/kg) causes 90% mortality in type 1 diabetic (DB) rats due to inhibited tissue repair allowing progression of liver injury. On the other hand, DB rats exposed to 30 mg TA/kg exhibit delayed tissue repair and delayed recovery from injury. The objective of this study was to investigate the mechanism of impaired tissue repair and progression of liver injury in TA-treated DB rats by using cDNA microarray. Gene expression pattern was examined at 0, 6, and 12 h after TA challenge, and selected mechanistic leads from microarray experiments were confirmed by real-time RT-PCR and further investigated at protein level over the time course of 0 to 36 h after TA treatment. Diabetic condition itself increased gene expression of proteases and decreased gene expression of protease inhibitors. Administration of 300 mg TA/kg to DB rats further elevated gene expression of proteases and suppressed gene expression of protease inhibitors, explaining progression of liver injury in DB rats after TA treatment. Inhibited expression of genes involved in cell division cycle (cyclin D1, IGFBP-1, ras, E2F) was observed after exposure of DB rats to 300 mg TA/kg, explaining inhibited tissue repair in these rats. On the other hand, DB rats receiving 30 mg TA/kg exhibit delayed expression of genes involved in cell division cycle, explaining delayed tissue repair in these rats. In conclusion, impaired cyclin D1 signaling along with increased proteases and decreased protease inhibitors may explain impaired tissue repair that leads to progression of liver injury initiated by TA in DB rats.

  19. Neoadjuvant Treatment With Single-Agent Cetuximab Followed by 5-FU, Cetuximab, and Pelvic Radiotherapy: A Phase II Study in Locally Advanced Rectal Cancer

    SciTech Connect

    Bertolini, Federica Chiara, Silvana; Bengala, Carmelo; Antognoni, Paolo; Dealis, Cristina; Zironi, Sandra; Malavasi, Norma; Scolaro, Tindaro; Depenni, Roberta; Jovic, Gordana; Sonaglio, Claudia; Rossi, Aldo; Luppi, Gabriele; Conte, Pier Franco

    2009-02-01

    Purpose: Preoperative chemoradiotherapy followed by surgery represents the standard of care for locally advanced rectal cancer (LARC). Cetuximab has proved activity in advanced colorectal cancer, and its incorporation in preoperative treatment may increase tumor downstaging. Methods and Materials: After biopsy and staging, uT3/uT4 N0/+ LARC received single-agent cetuximab in three doses, followed by weekly cetuximab plus 5-fluorouracil (5-FU), concomitantly with RT. Sample size was calculated according to Bryant and Day test, a two-stage design with at least 10 pathologic complete remissions observed in 60 patients (pts) able to complete the treatment plan. Results: Forty pts with LARC were entered: male/female = 34/6; median age: 61 (range, 28-77); 12 uT3N0 Ed(30%); 25 uT3N1 (62%); 3 uT4N1 (8%); all Eastern Cooperative Oncology Group = 0. Thirty-five pts completed neoadjuvant treatment; 5 (12%) withdrew therapy after one cetuximab administration: three for hypersensitivity reactions, one for rapid progression, and one for purulent arthritis. They continued 5-FU in continuous infusion in association with RT. Thirty-one pts (77%) presented with acnelike rash; dose reduction/interruption of treatment was necessary in six pts (15%): two for Grade 3 acnelike rash, two for Grade 3 gastrointestinal toxicity, and two for refusal. Thirty-eight pts were evaluable for pathological response (one patient refused surgery, and one was progressed during neoadjuvant treatment). Pathological staging was: pT0N0 three pts (8%), pT1N0 1 pt (3%); pT2N0 13 pts (34%), and pT3 19 pts (50%) (N0:9, N1:5; N2:5); pT4 2 pts (5%). Conclusions: Preoperative treatment with 5-FU, cetuximab, and pelvic RT is feasible with acceptable toxicities; however, the rate of pathologic responses is disappointingly low.

  20. Saddle pulmonary embolus and bronchiolitis obliterans with organizing pneumonia develop simultaneously after first cyclophosphamide, methotrexate, 5FU chemotherapy for breast cancer.

    PubMed

    Al-Hameed, Fahad M

    2015-06-01

    A 62-year-old woman underwent a right mastectomy with axillary node dissection for a poorly differentiated ductal carcinoma. One month later, she underwent a left nephrectomy for a renal cell carcinoma. Two weeks after, she received her first cycle of cyclophosphamide, methotrexate, and 5FU (CMF) as a part of her breast cancer treatment. We describe an unusual case of non-occlusive saddle pulmonary embolus with extensive bilateral deep vein thrombosis and severe bronchiolitis obliterans with organizing pneumonia developing simultaneously after the first CMF chemotherapy for breast cancer. PMID:25987120

  1. [Combination therapy of continuous venous infusion (CVI) of 5-FU and low dose consecutive cisplatin (CDDP), and the new oral anti-cancer drug S-1 for advanced gastro-intestinal cancer].

    PubMed

    Shirasaka, T; Aiba, K; Araki, H; Suzuki, M; Terashima, M; Mikami, Y

    1999-03-01

    Highly effective treatment is required for patients with advanced GI cancer. Returning to the starting point for reconsideration of cancer chemotherapy, with the aim of attaining a therapy (self rescuing concept: SRC) with more potential efficacy and less toxicity than current therapy, we report two kinds of chemotherapy in the present paper. They were set up preclinically using the theory of 5-FU biochemical modulation, and demonstrated their usefulness in clinical practice. S-1 is a newly developed oral anti-cancer drug which is a combination of Tegafur (FT), a prodrug of 5-FU and two modulators (CDHP, an inhibitor of 5-FU degradation and Oxo, a selective inhibitor GI toxicity by 5-FU) at a molar ratio of 1:0.4:1. In combination with CDHP, 5-FU gradually released from FT remained longer in plasma, and consequently had high anti-tumor activity, while the combined Oxo significantly suppressed GI toxicity due to 5-FU. The response rate to S-1 of stomach cancer in a phase II study was 46.5% (60/129). Toxicity at more than G3 was less than 10%. In the combination therapy employing 5-FU by CVI (5-FU: 250-350 mg/body for 24 h, 4-6 wks) and low dose consecutive CDDP, CDDP acts mainly as a modulator of 5-FU (to increase 5-FU sensitivity for tumor by inhibition of intracellular Met incorporation). For this purpose, it was found that daily consecutive administration is required, even at low dose of CDDP (3-5 mg/body/day for 5 days). A high response rate (40-60%) was obtained for advanced GI cancer. Toxicity at more than G3 was less than 10%. On the other hand, the possibility has been suggested that so far as 5-FU is concerned, CVI every other day (500-750 mg/body/day for 3 days) is more favorable than long term CVI, with regard to decreasing GI and myelotoxicities based upon the difference in generation time between normal cell (GI mucous membrane and stem cell) and tumor cell cycles. The possibility is suggested that the above-mentioned chemotherapy can become a standard

  2. Attachment of an anti-MUC1 monoclonal antibody to 5-FU loaded BSA nanoparticles for active targeting of breast cancer cells.

    PubMed

    Kouchakzadeh, Hasan; Shojaosadati, Seyed Abbas; Mohammadnejad, Javad; Paknejad, Malihe; Rasaee, Mohammad Javad

    2012-01-01

    With PR81 as a murine monoclonal antibody (mAb) that was prepared against the human breast cancer, the MUC1 receptor specific targeting is possible. In this study, PR81-conjugated bovine serum albumin (BSA) nanoparticles loaded with anticancer drug 5-fluorouracil (5-FU) were developed. Enzyme linked immunosorbant assay (ELISA) results showed high immunoreactivity of PR81 mAb conjugated to nanoparticles towards MUC1 related peptide or native cancerous MUC1 and almost no cross-reaction to non-specific proteins. In vitro experiments were performed to determine the ability of this new drug delivery system on overcoming MCF-7 breast cancer cells in comparison with four other systems. The results revealed that these cell-type specific drug loaded nanoparticles could achieve more cell death as compared to when the 5-FU was used with no carriers. Stability studies of produced drug delivery system proved high immunoreactivity of conjugated PR81 even after 11 days of storage in room temperature.

  3. Dual drug delivery of 5-fluorouracil (5-FU) and methotrexate (MTX) through random copolymeric nanomicelles of PLGA and polyethylenimine demonstrating enhanced cell uptake and cytotoxicity.

    PubMed

    Ashwanikumar, N; Kumar, Nisha Asok; Nair, S Asha; Kumar, G S Vinod

    2014-10-01

    We now report the synthesis of a random copolymer of poly-lactic-co-glycolic acid (PLGA) grafted branched polyethylenimine (BPEI) and the use of it as a multi drug delivery system (DDS). The methotrexate (MTX) was conjugated to BPEI through DCC/NHS chemistry. The copolymer-drug conjugate (PBP-MTX) was characterised by FT-IR and (1)H NMR spectroscopy. The PBP-MTX was converted into nanomicelles with entrapped 5-fluorouracil (5-FU) through nanoprecipitation technique. The size, shape, morphology and surface charge of the nanomicelles were confirmed using different techniques. The thermal behaviour and distribution of both conjugated and entrapped drug through the polymeric matrix were assessed by differential scanning calorimetry (DSC) and powder X-ray diffraction analysis (PXRD). In vitro drug release pattern of the nanomicelles was examined to ascertain the release pattern of two drugs namely 5-FU and MTX. The cellular uptake studies demonstrated higher uptake of the nanomicelles in colon cancer cell line HCT 116. Further the cytotoxicity evaluation of nanomicelles illustrated promising action which confirms the use of the system as a potential DDS to colon cancer. PMID:25108479

  4. [Changes in serum enzymes in rats treated with sodium bisulfite].

    PubMed

    Alarcón-Corredor, O M; Ramirez de Fernández, M; Bastardo de Castañeda, G; Silva, T; Alarcón, A O

    2000-01-01

    Inorganic sulfites are chemical compounds with antioxidative, antibacterial and antimycotic properties diffusely employed in agro-food and pharmaceutical industries. In spite of their continuous use there still are many questions regarding their safety, and their possible influence in several nutrients and enzymatic systems, as according to reports in the literature cited. In this study it is determined the effect of increasing doses of sodium bisulphite, 10 to 50 mg/kg/day, injected intramuscularly during seven days on the activity of the following serum enzymes: phosphohexoseisomerase (PHI), gamma-glutamyltranspeptidase (gamma-GT), cholinesterase (CHE), arginase, acid maltase (AM), alkaline phosphatase (AIP), lactic dehydrogenase (LDH), transaminases (GOT and GPT) and 5'-nucleotidase (5'-N) on male Wistar rats (treated groups). The results indicate that in rats treated with sodium bisulphite there is a significant increase (p < 0.05) in the activity of PHI, gamma-GT, arginase, AIP, GOT, GPT and 5'-N as well as an equally significant decrease (p < 0.05) in the activity of LDH, AM and CHE; these variations are proportional to the doses of the compound applied. These findings indicate there is cellular damage to rat liver, kidney or others organs as a result of bisulphite injected or by its metabolic derivatives. It is suggested that measurements of serum levels of LDH, AM and CHE are particularly helpful in the clinical assessment of pathologies caused by sulfites in allergology.

  5. [Level of blood serum lipids in rats treated with detergents].

    PubMed

    Szymaniec, J; Trzeciak, H I; Machalska, H; Turczyński, B

    1977-01-01

    Male Wistar rats were treated intraperitoneally once per week for 12 weeks with following detergents: Olbrotol-18 (nonionic detergent), a product of etheric condensation of 18 moles of ethylene oxide to 1 mole of the mixture of olein alcohol and cetyl alkohol in ratio 1:1, in a dose of 10 mg/kg; SBO (anionic detergent), sodium 2-ethylhexylsulfosuccinate, in a dose of 10 mg/kg and Sterinol (cationic detergent), benzalkonium bromide, in a dose of 0.6 mg/kg. The control rats were injected with 0.9% saline solution. The content of total cholesterol, beta-lipoproteins and total lipids in serum were estimated. The increase of total cholesterol and the decrease of beta-lipoproteins content in serum of rats after all used detergents were observed as compared with the control. The increase of total lipid content only after long-term treatment with Olbrotol-18 was found. It is concluded that long term intraperitoneal treatment with detergents changes similarly the contents of total cholesterol and of beta-lipoproteins in blood serum of rats.

  6. Perirhinal Cortex Hyperexcitability in Pilocarpine-Treated Epileptic Rats

    PubMed Central

    Benini, Ruba; Longo, Daniela; Biagini, Giuseppe; Avoli, Massimo

    2016-01-01

    The perirhinal cortex (PC), which is heavily connected with several epileptogenic regions of the limbic system such as the entorhinal cortex and amygdala, is involved in the generation and spread of seizures. However, the functional alterations occurring within an epileptic PC network are unknown. Here, we analyzed this issue by using in vitro electrophysiology and immunohistochemistry in brain tissue obtained from pilocarpine-treated epileptic rats and age-matched, nonepileptic controls (NECs). Neurons recorded intracellularly from the PC deep layers in the two experimental groups had similar intrinsic and firing properties and generated spontaneous depolarizing and hyperpolarizing postsynaptic potentials with comparable duration and amplitude. However, spontaneous and stimulus-induced epileptiform discharges were seen with field potential recordings in over one-fifth of pilocarpine-treated slices but never in NEC tissue. These network events were reduced in duration by antagonizing NMDA receptors and abolished by NMDA + non-NMDA glutamatergic receptor antagonists. Pharmacologically isolated isolated inhibitory postsynaptic potentials had reversal potentials for the early GABAA receptor-mediated component that were significantly more depolarized in pilocarpine-treated cells. Experiments with a potassium-chloride cotransporter 2 antibody identified, in pilocarpine-treated PC, a significant immunostaining decrease that could not be explained by neuronal loss. However, interneurons expressing parvalbumin and neuropeptide Y were found to be decreased throughout the PC, whereas cholecystokinin-positive cells were diminished in superficial layers. These findings demonstrate synaptic hyper-excitability that is contributed by attenuated inhibition in the PC of pilocarpine-treated epileptic rats and underscore the role of PC networks in temporal lobe epilepsy. PMID:20865722

  7. Adult Rats Treated with Risperidone during Development Are Hyperactive

    PubMed Central

    Bardgett, Mark E.; Franks-Henry, Julie M.; Colemire, Kristin R.; Juneau, Kathleen R.; Stevens, Rachel M.; Marczinski, Cecile A.; Griffith, Molly S.

    2014-01-01

    Risperidone is an antipsychotic drug approved for use in children, but little is known about the long-term effects of early-life risperidone treatment. In animals, prolonged risperidone administration during development increases forebrain dopamine receptor expression immediately upon the cessation of treatment. A series of experiments was performed to ascertain whether early-life risperidone administration altered locomotor activity, a behavior sensitive to dopamine receptor function, in adult rats. One additional behavior modulated by forebrain dopamine function, spatial reversal learning, was also measured during adulthood. In each study, Long-Evans rats received daily subcutaneous injections of vehicle or one of two doses of risperidone (1.0 and 3.0 mg/kg per day) from postnatal days 14 – 42. Weight gain during development was slightly yet significantly reduced in risperidone-treated rats. In the first two experiments, early-life risperidone administration was associated with increased locomotor activity at one week post-administration through approximately nine months of age, independent of changes in weight gain. In a separate experiment, it was found that the enhancing effect of early-life risperidone on locomotor activity occurred in males and female rats. A final experiment indicated that spatial reversal learning was unaffected in adult rats administered risperidone early in life. These results indicate that locomotor activity during adulthood is permanently modified by early-life risperidone treatment. The findings suggest that chronic antipsychotic drug use in pediatric populations (e.g., treatment for the symptoms of autism) could modify brain development and alter neural set-points for specific behaviors during adulthood. PMID:23750695

  8. Changes in the adrenals in lead treated rats

    SciTech Connect

    Chowdhury, A.R.; Gautam, A.K.; Rao, R.V.; Sathwara, N.G.; Parikh, D.J.; Chatterjee, B.B.

    1986-07-01

    That the endocrine functions of tests, ovary, thyroid, and adrenals were affected by lead are known from observations on either man or laboratory animals. In one study adrenal steroid excretion was first found to increase and then to decrease considerably during advanced stages of lead intoxication in exposed workers. No comprehensive studies on this aspect of lead poisoning seem to have been carried out. The present investigation was undertaken to contribute to a better understanding of the adrenal functions in rats treated with different dosages of lead.

  9. Nephroprotection of plantamajoside in rats treated with cadmium.

    PubMed

    Jung, Ha-Young; Seo, Dong-Won; Hong, Chung-Oui; Kim, Ji-Yeon; Yang, Sung-Yong; Lee, Kwang-Won

    2015-01-01

    Cadmium (Cd), an environmental and industrial pollutant, generates free radicals responsible for oxidative stress. Cd can also lead to various renal toxic damage such as the proximal tubules and glomerulus dysfunction. Plantamajoside (PMS), a major compound of Plantago asiatica (PA), was reported to have the antioxidant effects. In this study, we investigated the protective effects of PMS on Cd-induced renal damage in the NRK-52E cell and rat kidney tissue. Cd exposure increased the ROS generation, lipid peroxidation, serum biochemical values of renal damage, and mRNA and protein expressions of KIM-1 in vitro and in vivo. The significant reduction in glutathione (GSH)/glutathione disulfide (GSSG) ratio and activities of antioxidant enzymes were also observed in the rats treated with Cd. PMS significantly decreased the ROS generation and lipid peroxidation, thus enhancing GSH/GSSG ratio, antioxidant enzyme activities in the cells and rats, and improved histochemical appearances, indicating that PMS has protective activities against Cd-induced renal injury. PMID:25499790

  10. Behavioral deficits in adult rats treated neonatally with glutamate.

    PubMed

    Hlinák, Zdenek; Gandalovicová, Dana; Krejcí, Ivan

    2005-01-01

    The present study evaluated long-term behavioral consequences of neonatal monosodium-l-glutamate (MSG) treatment in rats. The pups received MSG (3 mg/g sc) daily from postnatal day (PD) 5-12. Data from an automatic activity monitor showed that locomotion of MSG-treated females and males aged 56 and 84 days was significantly reduced. Beginning PD 120, three behavioral tests were performed. As compared to the controls, in the elevated plus maze test, modified to evaluate the adaptive form of spatial memory, MSG-treated animals of both sex had significantly prolonged start and transfer latencies. In the social recognition test, assessing olfactory working memory, MSG-treated males displayed a reduced interest in the juvenile conspecific as the stimulus partner during both the initial exposure and re-exposure performed 30 min later. In the open field test, a significant decrease in the habituation rate was found in MSG-treated animals. Sex-dependent differences in behavioral performance were suggested in the open field and elevated plus maze tests. Behavioral changes are discussed in light of the deficits in perception and processing of visual and olfactory stimuli.

  11. Hepatotoxicity in Rats Treated with Dimethylformamide or Toluene or Both

    PubMed Central

    Chung, Yong Hyun

    2013-01-01

    The effects of toluene in dimethylformamide (DMF)-induced hepatotoxicity were investigated with respect to the induction of cytochrome P-450 (CYP) and the activities of related enzymes. The rats were treated intraperitoneally with the organic solvents in olive oil (Single treatment groups: 450 [D1], 900 [D2], 1,800 [D3] mg DMF, and 346 mg toluene [T] per kg of body weight; Combined treatment groups: D1+T, D2+T, and D3+T) once a day for three days, while the control group received just the olive oil. Each group consisted of 4 rats. The activities of the xenobiotic metabolic enzymes and the hepatic morphology were assessed. The immunoblots indicated that the expression of CYP2E1 was considerably enhanced depending on the dosage of DMF and the CYP2E1 blot densities were significantly increased after treatment with both DMF and toluene, compared to treatment with DMF alone. The activities of glutathione- S-transferase and glutathione peroxidase were either decreased or remained unaltered after treatment with DMF and toluene, whereas the lipid peroxide levels were increased with increasing dosage of DMF and toluene. The liver tissue in the D3 group (1,800 mg/kg of DMF) showed signs of microvacuolation in the central vein region and a large necrotic zone around the central vein, in rats treated with both DMF (1,800 mg/kg) and toluene (D3T). These results suggest that the expression of CYP2E1 is induced by DMF and enhanced by toluene. These changes may have facilitated the accelerated formation of Nmethylformamide (NMF) from toluene, and the generated NMF may directly induce liver damage. PMID:24386519

  12. Heterologous mesenchymal stem cells successfully treat femoral pseudarthrosis in rats

    PubMed Central

    2012-01-01

    Background This study evaluated the effectiveness of treating pseudarthrosis in rats by using bone marrow cell suspensions or cultures of bone marrow mesenchymal stromal cells Methods Thirty-eight specific pathogen-free (SPF) animals were randomly assigned to four groups: Group 1, Control, without surgical intervention; Group 2 (Placebo), experimental model of femoral pseudarthrosis treated only with saline solution; Group 3, experimental model of femoral pseudarthrosis treated with heterologous bone marrow cells suspension; Group 4, experimental model of femoral pseudarthrosis treated with cultures of heterologous mesenchymal stromal cells from bone marrow. When pseudarthrosis was confirmed by simple radiological studies, digital radiography and histopathology after a 120-day postoperative period, Groups 2, 3 and 4 were treated as above. At 30, 60 and 90 days after the treatment, all animals were evaluated by simple radiological studies, and at the end of the experiment, the animals were assessed by computed axial tomography and anatomopathological and histomorphometric examinations. Results Injected cells were detected in the areas affected by pseudarthrosis using scintigraphy within the first 24 hours after their administration. After 60 days, the animals of Group 3 showed callus formation while the animals of Group 4 presented periosteal reaction and had some consolidated areas. In contrast, Group 2 showed a predominance of fibro-osteoid tissue. After 90 days, bone consolidation and remodeling was observed in all animals from Group 3 whereas animals from Group 4 exhibited partial consolidation and those ones from Group 2 persisted with pseudarthrosis. Conclusion The treatment with heterologous bone marrow cells suspension proved to be effective in the treatment of pseudarthrosis whereas cultures of heterologous bone marrow mesenchymal stromal cells did not show the same potential to aid bone healing. PMID:22429995

  13. Triacylglycerol metabolism in the phenobarbital-treated rat

    PubMed Central

    Goldberg, David M.; Roomi, M. Waheed; Yu, Alexander; Roncari, Daniel A. K.

    1981-01-01

    1. Various aspects of triacylglycerol metabolism were compared in rats given phenobarbital at a dose of 100mg/kg body wt. per day by intraperitoneal injection; controls were injected with an equal volume of 0.15m-NaCl by the same route. Animals were killed after 5 days of treatment. 2. Rats injected with phenobarbital demonstrated increased liver weight, and increased microsomal protein per g of liver. Other evidence of microsomal enzyme induction was provided by increased activity of aminopyrine N-demethylase and cytochrome P-450 content. Increased hepatic activity of γ-glutamyltransferase (EC 2.3.2.2) occurred in male rats, but not in females, and was not accompanied by any detectable change in the activity of this enzyme in serum. 3. Phenobarbital treatment increased the hepatic content of triacylglycerol after 5 days in starved male and female rats, as well as in non-starved male rats; non-starved females were not tested in this regard. At 5 days after withdrawal of the drug, there was no difference in hepatic triacylglycerol content or in hepatic functions of microsomal enzyme induction between the treated and control rats. 4. After 5 days, phenobarbital increased the synthesis in vitro of glycerolipids in cell-free liver fractions fortified with optimal concentrations of substrates and co-substrates when results were expressed per whole liver. The drug caused a significant increment in the activity of hepatic diacylglycerol acyltransferase (EC 2.3.1.20), but did not affect the activity per liver of phosphatidate phosphohydrolase (EC 3.1.3.4) in cytosolic or washed microsomal fractions. A remarkable sex-dependent difference was observed for this latter enzyme. In female rats, the activity of the microsomal enzyme per liver was 10-fold greater than that of the cytosolic enzyme, whereas in males, the activities of phosphohydrolases per liver from both subcellular fractions were similar. 5. The phenobarbital-mediated increase in hepatic triacylglycerol content

  14. NEUROMODULATORY EFFECTS OF THYMOQUINONE IN EXTENUATING OXIDATIVE STRESS IN CHLORPROMAZINE TREATED RATS.

    PubMed

    Safhi, Mohammed Mohsin

    2016-01-01

    The present study was undertaken to evaluate the possible protective effect of thymoquinone on chlorpromazine induced catalepsy, locomotor activity and cerebral oxidative stress in rats. The rats were divided into four groups, each group containing eight animals. The animals were evaluated after repeated administration of chlorpromazine (CPZ) 30 min before the administration of thymoquinone (TQ) for 21 days. Catalepsy was assessed using block method whereas the locomotor activity was assessed using acceleratory rotarod and actophotometer. Markers of oxidative stress parameters (LPO, GSH, GPx, GR, GST and CAT) were evaluated in the brain of rats. The cataleptic scores were significantly increased in CPZ treated rats when compared with normal control rats. Oral administration of TQ (5 and 10 mg/kg) significantly decreased cataleptic scores when compared with chlorpromazine (CPZ) treated rats. The muscle coordination and spontaneous locomotor activity was significantly decreased in CPZ treated rats when compared with normal control rats. Treatment with TQ significantly improved the muscle coordination and spontaneous locomotor activity when compared with CPZ treated rats. TQ treated rats significantly reduced the elevated levels of lipid peroxidation (LPO), increased levels of antioxidant enzymes i.e., reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST) and catalase (CAT) when compared with CPZ treated rats. The results clearly suggest that supplementation with TQ can be used to preclude CPZ induced extrapyramidal side effects and may find a role in reducing the oxidative stress. PMID:27180446

  15. Copper and zinc in CCl/sub 4/ treated rats

    SciTech Connect

    Loyke, H.F.

    1984-04-01

    The role of two trace metals, copper and zinc, are important in maintaining blood pressure and the effect of carbon tetrachloride (CCl/sub 4/) has been found to be a depressor. Experimental renal hypertension has been reduced to normotension after multiple subcutaneous injections of CCl/sub 4/. By dose adjustment, the degree of liver damage has been reduced to a level of mild to moderate degree of fatty metamorphosis of the liver. It is possible that the depressor effect could be mediated by imbalance of copper and/or zinc. In the present study, copper and zinc levels were determined following CCl/sub 4/ treatment. The present work used normotensive rats treated for periods, which, in hypertensive animals, caused the blood pressure to fall.

  16. Effect of clofibrate on cholesterol metabolism in rats treated with polychlorinated biphenyls

    SciTech Connect

    Nakagawa, M.; Shimokawa, T.; Noguchi, A.; Ishihara, N.; Kojima, S.

    1986-02-01

    Serum and hepatic cholesterol content in rats treated with polychlorinated biphenyls (PCBs, KC-400) were increased compared to those of control rats. This increase of cholesterol content was reduced to control level by simultaneous administration of ethyl p-chlorophenoxyisobutyrate (CPIB). Also, when lecithin-cholesterol acyltransferase (LCAT) activity was expressed as the net cholesterol esterification, the acyltransferase activity in rats treated with PCBs was elevated, while the elevated acyltransferase activity was brought to control level by simultaneous administration of CPIB. On the other hand, the amount of bile of rats treated with CPIB, PCBs and PCBs-CPIB was increased, but free and total cholesterol content in bile of these treated rats was decreased to 40-60% of those of control rats. Moreover, cytochrome P-450 content in liver microsomes of rats treated with CPIB, PCBs and PCBs-CPIB was increased. At the same time, cholesterol-metabolizing activity in liver microsomes of rats treated with CPIB, PCBs and PCBs-CPIB also was elevated. Similar results were obtained for drug metabolizing (aniline hydroxylation and aminopyrine N-demethylation) activity. In addition, the amount of bile acids excreted from rats treated with CPIB, PCBs and PCBs-CPIB was increased compared to that of control rats. These results suggest that hypercholesterolemia induced by oral ingestion of PCBs is recovered by CPIB treatment and that this hypocholesterolemic effect of CPIB may be related partly to the elevation of hepatic mixed function oxidase activity for cholesterol catabolism.

  17. Prospective Study of Alternating Chemoradiotherapy Consisting of Extended-Field Dynamic Conformational Radiotherapy and Systemic Chemotherapy Using 5-FU and Nedaplatin for Patients in High-Risk Group With Cervical Carcinoma

    SciTech Connect

    Kodaira, Takeshi Fuwa, Nobukazu; Nakanishi, Toru; Tachibana, Hiroyuki; Nakamura, Tatsuya; Tomita, Natsuo; Nakahara, Rie; Inokuchi, Haruo

    2009-01-01

    Purpose: To assess the efficacy of alternating chemoradiotherapy combined with extended-field conformal radiotherapy for patients with high-risk cervical cancer. Methods and Materials: Patients with previously untreated cervical cancer, with Stage III/IVA disease, or Stage IB/II with high-risk factor (primary tumor diameter {>=}50 mm or positive lymph node) were entered into this study. Three cycles of chemotherapy with 3,500 mg/m{sup 2} of 5-fluorouracil (5-FU) and nedaplatin (NDP) were accompanied with pelvic irradiation of 45.6-51.3 Gy in 24-27 fractions over 6 weeks. Prophylactic (36 Gy/20 fractions) or definitive (45-56 Gy) irradiation for para-aortic region was followed by pelvic irradiation. Results: Between 1998 and 2004, 40 patients were recruited for this protocol study. Eighteen patients from Phase I setting were registered. Twenty-two patients were treated with NDP of 140 mg/m{sup 2} (the recommended dose) in the Phase II segment. Twenty-five patients had T3 disease, and 25 patients had nodal disease including para-aortic involvement (n = 5). Overall/progression-free survival rates at 5 years were 78.8 and 66.5%, respectively. The median follow-up time was 61.8 months (25.5-106.7). Hematologic and gastrointestinal Grade 3 or more toxicities were relatively high rate (27.5-45%); however, they were well manageable. Two for bladder toxicity of Grade 3 were noted. Comparing the data from historical control group evaluated by magnetic resonance imaging, alternating chemoradiotherapy revealed a significant favorable factor for survival and disease recurrence in multivariate analysis (p < 0.05). Conclusion: Acquired results from our unique protocol for cervical cancer with high-risk factor were thought to be promising, considering that the majority of our cohort consisted of high-risk population.

  18. Effect of oral administration of kefir on serum proinflammatory cytokines on 5-FU induced oral mucositis in patients with colorectal cancer.

    PubMed

    Topuz, E; Derin, D; Can, G; Kürklü, E; Cinar, S; Aykan, F; Cevikbaş, A; Dişçi, R; Durna, Z; Sakar, B; Saglam, S; Tanyeri, H; Deniz, G; Gürer, U; Taş, F; Guney, N; Aydiner, A

    2008-12-01

    In order to investigate the effect of kefir consumption on mucositis induced by 5-FU based chemotherapy (CT), we monitored the systemic immune response by measurement of the serum proinflammatory cytokine levels and we evaluated the anti-microbial effect of kefir with an agar diffusion method. Forty patients with colorectal cancer were included in this randomized prospective study. On the first 5 days of each CT cycle, the study group received oral lavage with kefir and then swallowed 250 ml of kefir while control group received oral lavage with 0.09% NaCl twice a day. Before and after every cycle of CT, the oral mucosa was assessed. Serum proinflammatory cytokine levels were evaluated before the initiation and after the third and the sixth cycle. Kefir was administered in 99 out of 205 courses. Mucositis developed in 27.3% of the courses given with kefir administration and in 21.7% of the courses given with 0.9% NaCl oral rinses. The difference between the two groups was not statistically significant (p > 0.05). When we compared the serum proinflammatory cytokine levels of the two groups at the baseline and following the third and the sixth cycles, we again found no statistically significant difference (p > 0.05). Kefir consumption at the mentioned doses made no statistically significant effect on serum proinflammatory cytokine levels and on the incidence of mucositis development in cancer patients. Under in vitro conditions, kefir inhibits only Staphylococcus epidermidis.

  19. Effect of oral administration of kefir on serum proinflammatory cytokines on 5-FU induced oral mucositis in patients with colorectal cancer.

    PubMed

    Topuz, E; Derin, D; Can, G; Kürklü, E; Cinar, S; Aykan, F; Cevikbaş, A; Dişçi, R; Durna, Z; Sakar, B; Saglam, S; Tanyeri, H; Deniz, G; Gürer, U; Taş, F; Guney, N; Aydiner, A

    2008-12-01

    In order to investigate the effect of kefir consumption on mucositis induced by 5-FU based chemotherapy (CT), we monitored the systemic immune response by measurement of the serum proinflammatory cytokine levels and we evaluated the anti-microbial effect of kefir with an agar diffusion method. Forty patients with colorectal cancer were included in this randomized prospective study. On the first 5 days of each CT cycle, the study group received oral lavage with kefir and then swallowed 250 ml of kefir while control group received oral lavage with 0.09% NaCl twice a day. Before and after every cycle of CT, the oral mucosa was assessed. Serum proinflammatory cytokine levels were evaluated before the initiation and after the third and the sixth cycle. Kefir was administered in 99 out of 205 courses. Mucositis developed in 27.3% of the courses given with kefir administration and in 21.7% of the courses given with 0.9% NaCl oral rinses. The difference between the two groups was not statistically significant (p > 0.05). When we compared the serum proinflammatory cytokine levels of the two groups at the baseline and following the third and the sixth cycles, we again found no statistically significant difference (p > 0.05). Kefir consumption at the mentioned doses made no statistically significant effect on serum proinflammatory cytokine levels and on the incidence of mucositis development in cancer patients. Under in vitro conditions, kefir inhibits only Staphylococcus epidermidis. PMID:18762864

  20. Annonaceous acetogenins reverses drug resistance of human hepatocellular carcinoma BEL-7402/5-FU and HepG2/ADM cell lines

    PubMed Central

    Qian, Jun-Qiang; Sun, Pei; Pan, Zhan-Yu; Fang, Zhi-Zhong

    2015-01-01

    Hepatocellular carcinoma (HCC) is the most common tumor in worldwide and chemotherapy resistant is a severe obstacle in HCC treatment. Annonaceous acetogenins was a nature compound from Uvaria accuminata and it has show the anti-tumor proliferation activity in many types cancer. In this study, we showed that annonaceous acetogenins is correlated with the drug resistance reversal in human hepatocellular carcinoma BEL-7402/5-FU and HepG2/ADM cell lines. We found that cell apoptosis was improved and cell cycle was arrested, further, multidrug-resistance proteins such as MDR1, MRP1, Topo-IIα, GST-π, cyclin D1, Survivin and bcl-2 are down-regulated, however, intracellular Rh-123 and caspase-3/8 was up-regulated by Annonaceous acetogenins treatment. We also found that there was a decreased activity of NF-κB and Akt in Annonaceous acetogenins treatment groups. Therefore, we demonstrate that Akt/NF-κB pathway was involved in Annonaceous acetogenins reverses drug resistance of human hepatocellular carcinoma cells. PMID:26617951

  1. Cadmium modifies the cell cycle and apoptotic profiles of human breast cancer cells treated with 5-fluorouracil.

    PubMed

    Asara, Yolande; Marchal, Juan A; Carrasco, Esther; Boulaiz, Houria; Solinas, Giuliana; Bandiera, Pasquale; Garcia, Maria A; Farace, Cristiano; Montella, Andrea; Madeddu, Roberto

    2013-01-01

    Industrialisation, the proximity of factories to cities, and human work activities have led to a disproportionate use of substances containing heavy metals, such as cadmium (Cd), which may have deleterious effects on human health. Carcinogenic effects of Cd and its relationship with breast cancer, among other tumours, have been reported. 5-Fluorouracil (5-FU) is a fluoropyrimidine anticancer drug used to treat solid tumours of the colon, breast, stomach, liver, and pancreas. The purpose of this work was to study the effects of Cd on cell cycle, apoptosis, and gene and protein expression in MCF-7 breast cancer cells treated with 5-FU. Cd altered the cell cycle profile, and its effects were greater when used either alone or in combination with 5-FU compared with 5-FU alone. Cd significantly suppressed apoptosis of MCF-7 cells pre-treated with 5-FU. Regarding gene and protein expression, bcl2 expression was mainly upregulated by all treatments involving Cd. The expression of caspase 8 and caspase 9 was decreased by most of the treatments and at all times evaluated. C-myc expression was increased by all treatments involving Cd, especially 5-FU plus Cd at the half time of treatment. Cd plus 5-FU decreased cyclin D1 and increased cyclin A1 expression. In conclusion, our results indicate that exposure to Cd blocks the anticancer effects of 5-FU in MCF-7 cells. These results could have important clinical implications in patients treated with 5-FU-based therapies and who are exposed to high levels of Cd. PMID:23941782

  2. Cadmium Modifies the Cell Cycle and Apoptotic Profiles of Human Breast Cancer Cells Treated with 5-Fluorouracil

    PubMed Central

    Asara, Yolande; Marchal, Juan A.; Carrasco, Esther; Boulaiz, Houria; Solinas, Giuliana; Bandiera, Pasquale; Garcia, Maria A.; Farace, Cristiano; Montella, Andrea; Madeddu, Roberto

    2013-01-01

    Industrialisation, the proximity of factories to cities, and human work activities have led to a disproportionate use of substances containing heavy metals, such as cadmium (Cd), which may have deleterious effects on human health. Carcinogenic effects of Cd and its relationship with breast cancer, among other tumours, have been reported. 5-Fluorouracil (5-FU) is a fluoropyrimidine anticancer drug used to treat solid tumours of the colon, breast, stomach, liver, and pancreas. The purpose of this work was to study the effects of Cd on cell cycle, apoptosis, and gene and protein expression in MCF-7 breast cancer cells treated with 5-FU. Cd altered the cell cycle profile, and its effects were greater when used either alone or in combination with 5-FU compared with 5-FU alone. Cd significantly suppressed apoptosis of MCF-7 cells pre-treated with 5-FU. Regarding gene and protein expression, bcl2 expression was mainly upregulated by all treatments involving Cd. The expression of caspase 8 and caspase 9 was decreased by most of the treatments and at all times evaluated. C-myc expression was increased by all treatments involving Cd, especially 5-FU plus Cd at the half time of treatment. Cd plus 5-FU decreased cyclin D1 and increased cyclin A1 expression. In conclusion, our results indicate that exposure to Cd blocks the anticancer effects of 5-FU in MCF-7 cells. These results could have important clinical implications in patients treated with 5-FU-based therapies and who are exposed to high levels of Cd. PMID:23941782

  3. Asporin and the mineralization process in fluoride-treated rats.

    PubMed

    Houari, Sophia; Wurtz, Tilmann; Ferbus, Didier; Chateau, Danielle; Dessombz, Arnaud; Berdal, Ariane; Babajko, Sylvie

    2014-06-01

    Microarray analysis of odontoblastic cells treated with sodium fluoride has identified the asporin gene as a fluoride target. Asporin is a member of the small leucine-rich repeat proteoglycan/protein (SLRP) family that is believed to be important in the mineralization process. In this study, asporin expression and distribution were investigated by systematic analysis of dentin and enamel, with and without fluoride treatment. Specific attention was focused on a major difference between the two mineralized tissues: the presence of a collagenous scaffold in dentin, and its absence in enamel. Normal and fluorotic, continually growing incisors from Wistar rats treated with 2.5 to 7.5 mM sodium fluoride (NaF) were studied by immunochemistry, in situ hybridization, Western blotting, and RT-qPCR. Asporin was continuously expressed in odontoblasts throughout dentin formation as expected. Asporin was also found, for the first time, in dental epithelial cells, particularly in maturation-stage ameloblasts. NaF decreased asporin expression in odontoblasts and enhanced it in ameloblasts, both in vivo and in vitro. The inverse response in the two cell types suggests that the effector, fluoride, is a trigger that elicits a cell-type-specific reaction. Confocal and ultrastructural immunohistochemistry evidenced an association between asporin and type 1 collagen in the pericellular nonmineralized compartments of both bone and dentin. In addition, transmission electron microscopy revealed asporin in the microenvironment of all cells observed. Thus, asporin is produced by collagen-matrix-forming and non-collagen-matrix-forming cells but may have different effects on the mineralization process. A model is proposed that predicts impaired mineral formation associated with the deficiency and excess of asporin.

  4. Renal extracellular matrix alterations in lead-treated rats.

    PubMed

    Sánchez, S; Pérez Aguilar, R; Genta, S; Aybar, M; Villecco, E; Sánchez Riera, A

    2001-01-01

    Although the nephrotoxic effects of lead are well documented, the subcellular mechanisms of its action on the kidney remain unclear. The aim of the present work was to investigate the effects of chronic lead exposure on the expression of laminin-1 and fibronectin in the kidney of lead-treated rats. Western immunoblotting of the kidney extracts revealed that experimental exposure to lead resulted in a marked decrease in the intensity of the bands corresponding to laminin-1 and an increase in the intensity of the band corresponding to fibronectin. Immunohistochemical studies demonstrated a weak labelling to laminin-1 and a strong labelling to fibronectin in all renal basement membranes together with a decrease in their thickness. Other ultrastructural alterations found were a diminution in the amount of endothelial fenestrae, an increased fusion of foot processes in epithelial cells of the glomerulus and the presence of intranuclear inclusion bodies in the proximal tubule cells. Lead intoxication might be responsible for the above alterations in the renal extracellular matrix that could play an important role in the pathogenesis of lead nephropathy. PMID:11746185

  5. Degradation of 5-FU by means of advanced (photo)oxidation processes: UV/H2O2, UV/Fe2+/H2O2 and UV/TiO2--Comparison of transformation products, ready biodegradability and toxicity.

    PubMed

    Lutterbeck, Carlos Alexandre; Wilde, Marcelo Luís; Baginska, Ewelina; Leder, Christoph; Machado, Ênio Leandro; Kümmerer, Klaus

    2015-09-15

    The present study investigates the degradation of the antimetabolite 5-fluorouracil (5-FU) by three different advanced photo oxidation processes: UV/H2O2, UV/Fe(2+)/H2O2 and UV/TiO2. Prescreening experiments varying the H2O2 and TiO2 concentrations were performed in order to set the best catalyst concentrations in the UV/H2O2 and UV/TiO2 experiments, whereas the UV/Fe(2+)/H2O2 process was optimized varying the pH, Fe(2+) and H2O2 concentrations by means of the Box-Behnken design (BBD). 5-FU was quickly removed in all the irradiation experiments. The UV/Fe(2+)/H2O2 and UV/TiO2 processes achieved the highest degree of mineralization, whereas the lowest one resulted from the UV/H2O2 treatment. Six transformation products were formed during the advanced (photo)oxidation processes and identified using low and high resolution mass spectrometry. Most of them were formed and further eliminated during the reactions. The parent compound of 5-FU was not biodegraded, whereas the photolytic mixture formed in the UV/H2O2 treatment after 256 min showed a noticeable improvement of the biodegradability in the closed bottle test (CBT) and was nontoxic towards Vibrio fischeri. In silico predictions showed positive alerts for mutagenic and genotoxic effects of 5-FU. In contrast, several of the transformation products (TPs) generated along the processes did not provide indications for mutagenic or genotoxic activity. One exception was TP with m/z 146 with positive alerts in several models of bacterial mutagenicity which could demand further experimental testing. Results demonstrate that advanced treatment can eliminate parent compounds and its toxicity. However, transformation products formed can still be toxic. Therefore toxicity screening after advanced treatment is recommendable.

  6. Irinotecan Plus S-1 Followed by Hepatectomy for a Patient with Initially Unresectable Colorectal Liver Metastases, Who Showed Severe Drug Rash with Oxaliplatin Plus 5-FU and Leucovorin (FOLFOX)

    PubMed Central

    Komori, Hiroyuki; Beppu, Toru; Sakamoto, Yasuo; Miyamoto, Yuji; Hayashi, Hiromitsu; Imai, Katsunori; Nitta, Hidetoshi; Watanabe, Masayuki; Baba, Hideo

    2014-01-01

    For unresectable colorectal liver metastases (CRLM), hepatic resection with or without chemotherapy is the only curative treatment that sufficiently achieves long-term survival. However, occasional severe allergic responses to anticancer drugs necessitate treatment discontinuation. A 45-year-old woman presented with metachronous unresectable colorectal liver metastases. Chemotherapy with oxaliplatin plus 5-FU and leucovorin (FOLFOX) was initiated, but severe allergic dermatitis developed after the second cycle. Although she reported no prior history of adverse reactions to tegafur-uracil, a drug lymphocyte stimulation test showed an allergic response to 5-FU. We subsequently replaced with Irinotecan plus S-1 (IRIS) chemotherapy which was well tolerated and resulted in a partial response after 3 cycles. As a result, right trisectionectomy was successfully performed and no recurrence was detected in the following 3 years. A severe allergic reaction to intravenous 5-FU-containing drug regimens can be successfully alleviated by switching to S-1-containing regimens such as IRIS or S-1 plus oxaliplatin (SOX). PMID:25031875

  7. In vivo isolated liver perfusion technique in a rat hepatic metastasis model: 5-fluorouracil concentrations in tumor tissue.

    PubMed

    de Brauw, L M; van de Velde, C J; Tjaden, U R; de Bruijn, E A; Bell, A V; Hermans, J; Zwaveling, A

    1988-02-01

    An in vivo method of isolated rat liver perfusion was developed with true vascular isolation and recirculating perfusate. This new surgical technique to temporarily isolate the liver vascularly, and the perfusion procedure are described in depth. Twelve inbred WAG/RIJ rats were subjected to 25 min of normothermic liver perfusion without chemotherapy, and all rats survived the procedure. Hepatic functional and histological integrity were not significantly altered during perfusion. To determine the role of isolated liver perfusion (ILP) as a means of improved targeting of antitumor agents, 5-fluorouracil (5-FU) concentrations were monitored in hepatic tumor and liver tissues and in systemic plasma using high-performance liquid chromatography. Fifty-one rats with hepatic tumors of colonic origin were randomly assigned to one of three dosage groups (20, 40, or 80 mg/kg) receiving 5-FU by ILP, hepatic artery infusion (HAI), or jugular vein infusion (JVI). ILP resulted in significantly increased 5-FU concentrations in liver tissue. However, no significant differences were found in tumor tissue concentrations of 5-FU between the three treatment modalities. 5-FU concentrations in tumor tissue increased as a function of the dose with ILP, HAI, and JVI. ILP was associated with the lowest systemic drug concentrations. The low systemic 5-FU concentrations with ILP suggest a higher maximum tolerable dose. This mode of treatment deserves to be studied further in our model before conclusions can be drawn regarding its therapeutic potential. PMID:3339874

  8. Protection against hyperoxia by serum from endotoxin treated rats: absence of superoxide dismutase induction

    SciTech Connect

    Berg, J.T.; Smith, R.M.

    1988-01-01

    Endotoxin greatly reduces lung injury and pleural effusions in adult rats exposed to normobaric hyperoxia (> 98% oxygen for 60 hours). This study reports that serum from endotoxin treated donor rats protects serum recipients against hyperoxic lung injury without altering lung superoxide dismutase (SOD) activity. Rats pretreated with endotoxin alone were protected and exhibited an increase in lung SOD activity as previously reported by others. Protection by serum was not due to the transfer of residual endotoxin or SOD. These results show, that protection from oxygen toxicity can occur in rats without an increase in lung SOD and suggest that a serum factor may be involved.

  9. Normal spatial and contextual learning for ketamine-treated rats in the pilocarpine epilepsy model.

    PubMed

    McKay, B E; Persinger, M A

    2004-05-01

    Cognitive impairments frequently accompany epileptic disorders. Here, we examine two neuroprotective agents, the noncompetitive NMDA antagonist ketamine and the dopaminergic antagonist acepromazine, for their efficacy in attenuating cognitive impairments in the lithium-pilocarpine (LI-PILO) model of rat limbic epilepsy. Declarative-like cognitive behaviors were assessed in a Morris water maze task that consisted successively of spatial and nonspatial (cued platform) training. Whereas the ketamine-treated (Ket) LI-PILO rats performed equally in all respects to nonseized control rats for the spatial and nonspatial components of the water maze task, the acepromazine-treated (Ace) LI-PILO rats failed to demonstrate learning in either the hidden or cued platform variants of the task and did not demonstrate any place learning in the platform-removed probe trials. We further assessed nondeclarative (associative) cognitive behaviors with a standard contextual fear-conditioning protocol. LI-PILO rats treated with acepromazine failed to learn the Pavlovian relationship; Ket LI-PILO rats performed equivalently to nonseized controls. Cumulatively, these data suggest robust cognitive sparing for LI-PILO rats with pharmacological NMDA receptor antagonism following induction of status epilepticus (SE). This cognitive sparing occurs despite earlier findings that the mean amount of total brain damage with LI-PILO is equivalent for Ket and Ace rats.

  10. Alveolar bone dynamics in osteoporotic rats treated with raloxifene or alendronate: confocal microscopy analysis

    NASA Astrophysics Data System (ADS)

    Ramalho-Ferreira, Gabriel; Faverani, Leonardo Perez; Grossi-Oliveira, Gustavo Augusto; Okamoto, Tetuo; Okamoto, Roberta

    2015-03-01

    In this study, the characteristics of the alveolar bone of rats with induced osteoporosis were examined. Thirty-two rats were divided into four groups according to the induction of osteoporosis and drugs administered: OG, osteoporotic rats without treatment (negative control); SG, rats which underwent sham surgery ovariectomy (SHAM); alendronate (AG), osteoporotic rats treated with alendronate; and RG, osteoporotic rats treated with raloxifene (RG). On the 8th day after ovariectomy and SHAM surgeries, drug therapy was started with AG or RG. On the 52nd day, 20 mg/kg calcein was administered to all of the rats, and on the 80th day, 20 mg/kg alizarin red was administered. Euthanasia was performed on the 98th day. The bone area marked by fluorochromes was calculated and data were subjected to two-way ANOVA test and Tukey's post-hoc test (p<0.05). The comparison of the induced osteoporosis groups showed no statistically significant differences in bone turnover only between RG and SG (p=0.074) and AG and OG (p=0.138). All other comparisons showed significant differences (p<0.001). The largest bone turnover was observed in RG and SG groups. RG was the medication that improved the dynamics of the alveolar bone of rats with induced osteoporosis, resembling that of healthy rats.

  11. The Effect of Eurycoma Longifolia Jack on Spermatogenesis in Estrogen-Treated Rats

    PubMed Central

    Wahab, Norhazlina Abdul; Mokhtar, Norfilza M.; Halim, Wan Nurul Heriza A; Das, Srijit

    2010-01-01

    INTRODUCTION: There is little data concerning the ability of Eurycoma longifolia Jack (EL) to reverse the inhibitory effects of estrogen on testosterone production and spermatogenesis. The aim of the present study was to determine the effect of EL on testicular histology and sperm count in estrogen-treated male rats. METHODS: Adult male Sprague-Dawley rats weighing 200–250 g were divided into four groups of six rats each. Group A (control) was given solvent in the same manner as the treated groups were given EL. Group B was treated with EL (8 mg/kg body weight) orally. Group C was treated with estradiol (E2) (intramuscular dose of 500 μg/kg body weight), and group D received a combined treatment of oral EL and intramuscular E2. After fourteen consecutive days of treatment, rats from all groups were sacrificed and subjected to spermatogenic and epididymal sperm cell counts. RESULTS: The spermatogenic cell count in the E2-treated group was significantly decreased as compared to the control (p < 0.05) and EL+E2-treated groups (p < 0.05). A similar finding was found for the epididymal sperm count; the E2-treated group had a significant decrease in the count compared to the control (p < 0.05) and EL+E2-treated groups (p < 0.05). Rats that were treated with EL alone exhibited significantly higher sperm counts and sperm motility when compared to the control group (p < 0.05). CONCLUSIONS: EL extract acts as a potential agent for reversing the effects of estrogen by increasing spermatogenesis and sperm counts in rats after fourteen consecutive days of treatment. PMID:20126351

  12. Insulin resistance in SD rats chronically treated with ethanol

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We have previously demonstrated that hepatic insulin signaling is disrupted in Sprague-Dawley (SD) rats fed EtOH-containing diets by total enteral nutrition (TEN). To determine if whole body insulin resistance could be demonstrated in the TEN model, we conducted euglycemic-hyperinsulinemic clamp st...

  13. Molecular basis of bilirubin UDP-glucuronosyltransferase induction in spontaneously diabetic rats, acetone-treated rats and starved rats.

    PubMed Central

    Braun, L; Coffey, M J; Puskás, F; Kardon, T; Nagy, G; Conley, A A; Burchell, B; Mandl, J

    1998-01-01

    The co-ordinated induction of several hepatic drug-metabolizing enzymes is a common feature in the regulation of drug biotransformation under normal and pathological conditions. In the present study the activity and expression of bilirubin UDP-glucuronosyltransferase (UGT1A1) were investigated in livers of BioBreeding/Worcester diabetic, fasted and acetone-treated rats. Bilirubin glucuronidation was stimulated by all three treatments; this was correlated with an increase in the UGT1A1 protein concentration in hepatic microsomes. Transcriptional induction of UGT1A1 was also observed in diabetes and starvation but not with acetone treatment, which apparently caused translational stabilization of the enzyme protein. The hormonal/metabolic alterations in diabetes and starvation might be a model for postnatal development. The sudden interruption of maternal glucose supply signals the enhanced expression of UGT1A1, giving a novel explanation for the physiological induction of bilirubin glucuronidation in newborn infants. PMID:9841869

  14. The endocrine status of gossypol - treated male rats.

    PubMed

    Weinbauer, G F; Rovan, E; Frick, J; Adam, H

    1983-01-01

    Male adult Wistar rats were exposed daily or every other day to oral gossypol acetic acid (GAA) concentrations of 2.5-30 mg/kg for 10-20 weeks. Controls received the GAA-suspension medium or were left completely untreated. The serum concentrations of testosterone, LH and FSH as well as the weight of testis, epididymis, prostate, seminal vesicle, coagulating gland, and pituitary were determined. The accessory sex organs were prepared for light microscopy. Significant antifertility effect in these animals was achieved at GAA-dosage of 15 mg/kg and higher. GAA-administration neither altered the serum hormonal profiles nor the reproductive organ weights in comparison to the controls. Accordingly, light microscopical examination revealed no alterations in the histological picture of prostate, seminal vesicle and coagulating gland when compared with the controls. The results indicate that GAA does not interfere with the hypothalamic-pituitary-gonadal axis in male adult rats.

  15. Carbohydrate digestibility predicts colon carcinogenesis in azoxymethane-treated rats.

    PubMed

    Jacobsen, Helene; Poulsen, Morten; Dragsted, Lars Ove; Ravn-Haren, Gitte; Meyer, Otto; Lindecrona, Rikke Hvid

    2006-01-01

    The purpose of this study was to compare the effect of carbohydrate structure and digestibility on azoxymethane (AOM)-induced colon carcinogenesis. Five groups of male Fischer 344 rats each comprising 30 animals were injected with AOM and fed a high-fat diet with 15% of various carbohydrates. The carbohydrate sources used were sucrose, cornstarch (a linear starch, reference group), potato starch (a branched starch), a short-chained oligofructose (Raftilose), and a long-chained inulin-type fructan (Raftiline). An interim sacrifice was performed after 9 wk to investigate markers of carbohydrate digestibility, including caecal fermentation (caecum weight and pH) and glucose and lipid metabolism [glucose, fructoseamine, HbA1c, triglycerides, and insulin-like growth factor (IGF) 1]. In addition potential early predictors of carcinogenicity [cell proliferation and aberrant crypt foci (ACF)] at 9 wk and their correlation to colon cancer risk after 32 wk were investigated. Tumor incidence was significantly reduced in animals fed oligofructose, and the number of tumors per animal was significantly reduced in animals fed inulin and oligofructose at 32 wk after AOM induction compared to the reference group fed sucrose. Increased caecum weight and decreased caecal pH were seen in groups fed oligofructose, inulin, and potato starch. Plasma triglyceride was decreased in rats fed oligofructose and inulin. Cell proliferation was increased in the proximal colon of rats fed sucrose, oligofructose, and inulin, and the number of cells per crypt decreased in rats fed oligofructose and inulin. The total number of ACF's was unaffected by treatment, and the size and multiplicity of ACF was unrelated to tumor development. It was concluded that less digestible carbohydrates with an early effect on caecum fermentation and plasma triglyceride decreased subsequent tumor incidence and multiplicity. This was unrelated to ACF, cell proliferation, and other markers of glucose and lipid metabolism.

  16. Heart Rate Changes in Electroacupuncture Treated Polycystic Ovary in Rats

    PubMed Central

    Ramadoss, Mukilan; Subbiah, Angelie Jessica; Natrajan, Chidambaranathan

    2016-01-01

    Introduction Polycystic Ovary Syndrome (PCOS) is a common metabolic disorder, it affects both humans and animals. It may induce coronary heart disease, obesity and hyperandrogenism. Previous studies show that Low frequency Electroacupuncture (EA) have an effect on PCOS, however the exact pathway is unclear. Aim To find the effect of EA on autonomic activity of the heart in Estradiol Valerate (EV) induced PCOS rats. Materials and Methods Heart rate variability (HRV) was assessed in 3 groups: 1) Control; 2) PCOS rats; and 3) PCOS rats after EA treatment (n=8 in each group). From the time domain analysis and frequency domain analysis (linear measures) HRV analysis was done. EA stimulation was given at low frequency of 2Hz for 15 min on alternate days for 4-5 weeks. Collected data were statistically analysed using One-Way Analysis of Variance with the application of multiple comparisons of Tukey test. Results EA treatment group shows significant reduction in Heart Rate (HR) and low frequency, high frequency ratio (LF/HF); and increase in RR interval, Total Power (TP) when compared to PCOS group. Conclusion The study concludes that EA treatment has a significant effect on reducing sympathetic tone and decreasing HR in PCOS. PMID:27134868

  17. Metabolic and neurochemical profiles in insulin-treated diabetic rats.

    PubMed

    Bellush, L L; Reid, S G

    1994-01-01

    Plasma glucose concentration was measured at 3-h intervals in streptozotocin-induced diabetic rats placed on various insulin replacement regimens using three different kinds of insulin. High insulin dosages produced at least periodic hypoglycemia, even though there were no overt signs of insulin overdose. Low- and single-dose regimens produced periods of hyperglycemia. Both high and low doses of protamine zinc insulin normalized diabetes-induced reductions in 5-hydroxyindole-3-acetic acid [5-HIAA; the principal metabolite of 5-hydroxytryptamine (5-HT)] and 5-HT turnover (5-HIAA/5-HT), despite the failure of the low-dose regimen to normalize plasma glucose. Diabetic rats evidenced continued hyperphagia and hyperdipsia during insulin treatment, and insulin treatment also induced hyperphagia and excessive weight gain in nondiabetic rats. Insulin treatment only partially normalized diabetes-induced adrenal hypertrophy. Adrenal hypertrophy is an indication of a continued stresslike physiological state in diabetes even during insulin therapy. This state may be involved in the enhanced risk in diabetic humans for development of anxiety disorders and clinical depression. PMID:7508209

  18. Antioxidant Effects of Cranberry Powder in Lipopolysaccharide Treated Hypercholesterolemic Rats

    PubMed Central

    Kim, Mi Joung; Kim, Jung Hee; Kwak, Ho-Kyung

    2014-01-01

    This study was conducted to investigate the effects of cranberry power on antioxidant defense system in rats fed an atherogenic diet and injected with lipopolysaccharide (LPS). Sprague-Dawley rats were divided into the following 5 groups: normal diet+saline (NS), atherogenic diet+saline (AS), atherogenic diet+LPS (AL), atherogenic diet with 5% cranberry powder+LPS (AL-C5), and atherogenic diet with 10% cranberry powder+LPS (AL-C10). Total antioxidant status measured by ferric reducing ability of plasma (FRAP) was significantly reduced by LPS injection (24%) and was restored by the cranberry powder treatment (P<0.05). In addition, the mean level of plasma total phenolics was significantly decreased by LPS injection (P<0.05) and tended to be increased when cranberry powder was incorporated in to the diet. Activity of serum superoxide dismutase (SOD) tended to be lowered by LPS injection and declined further in cranberry powder fortified groups. Overall results indicate that dietary cranberry powder may provide appropriate antioxidants to counter the diminished antioxidant status induced by exposing hypercholesterolemic rats to LPS. PMID:25054105

  19. Atorvastatin improves Y-maze learning behaviour in nicotine treated male albino rats.

    PubMed

    Das S, Syam; Nair, Saritha S; Kavitha, S; Febi, John; Indira, M

    2015-11-01

    Nicotine is a parasympathomimetic alkaloid present in tobacco which can induce hyperlipidemia and has a direct effect on neural functions. Statins, competitive inhibitors of 3-hydroxymethyl-3-glutaryl-coenzyme-A reductase, are cholesterol lowering drugs. It has some neuroprotective effects. Hence we analysed the combined effect of nicotine and statin on the learning behaviour of male albino rats. We employed Y-Maze conditional discrimination task. Rats were divided into 4 groups with six rats in each group. (1) Control, (2) Atorvastatin (10mg/kgb.wt), (3) Nicotine (0.6mg/kgb.wt) and (4) Atorvastatin (10mg/kgb.wt)+Nicotine (0.6mg/kgb.wt). After 30days of treatment rats from each group were selected for behavioural study and they were observed for 30days. At the end of the experimental period rats were sacrificed, and brain and liver were dissected out for further biochemical analysis. Nicotine treated group showed least performance in learning in comparison with control, atorvastatin and atorvastatin+nicotine treated groups. Co-administration of atorvastatin and nicotine improved learning behaviour compared to nicotine treated group. Reactive oxygen species level was significantly increased in nicotine group compared to control. The level of neurotransmitter serotonin which has a significant role in learning was found to be decreased in nicotine treated group compared to the control group. Activity of Na(+) K(+) ATPase, Ca(2+) ATPase and glutathione content was significantly reduced in nicotine treated group compared to control. The activity of acetylcholine esterase was significantly increased in the nicotine treated group. Expression studies showed significant decrease in N-methyl D-aspartate receptors and increase in mono amine oxidase-A and mono amine oxidase-B in nicotine treated group and was reversed in atorvastatin + nicotine treated group. It can be concluded that co-administration of nicotine with statin ameliorates the neural functional alterations caused

  20. Natural killer (NK) activity of pit cells perfused from livers of rats treated with ethanol

    SciTech Connect

    Albornoz, L.; Jones, J.M.; Crutchfield, C.; Veech, R.L. Univ. of Arkansas Medical Sciences, Little Rock )

    1991-03-11

    The liver is the major site of ethanol (ETOH) metabolism. Liver sinusoids contain lymphocytes with NK activity. The authors treated LEW rats for 2 weeks with i.p. injection of 1.25 ml 25% ETOH/kg 3 times/week and 5% ETOH in drinking water. Livers were perfused at 5-fold physiological pressure and cells obtained were banded on 1.077 density Ficoll. Their cytotoxicity was tested against {sup 51}Cr-labeled YAC-1 or U937 and compared to spleen and blood lymphocytes. In untreated rats, pit cell NK activity was 2-fold that of splenic lymphocytes and 4-fold that of blood lymphocytes. Compared to controls, ETOH-treated rats exhibited a 30 to 90% rise in pit cell NK activity detected with YAC-1 or U937 targets. The pit cell enhanced NK activity in ETOH-treated rats was further increased if polyinosinicpolycytidilic acid was injection i.p. 18 hours before the assay. Blood and spleen lymphocyte NK activity of ETOH-treated rats was also greater than in controls. There was no evidence that ETOH merely redistributed lymphocytes among the tissues. Although ETOH acutely inhibits NK activity in vitro, chronic ETOH increases in vivo.

  1. Stimulation of adrenal DNA synthesis in cadmium-treated male rats

    SciTech Connect

    Nishiyama, S.; Nakamura, K.

    1984-07-01

    Cadmium chloride (CdCl2) at a dose of 1 mg/kg body wt was injected into male rats of the Wistar strain, weighing 250 g on the average, twice a day (12-hr intervals) for 7 consecutive days. DNA and RNA contents and (/sup 3/H)-thymidine and (/sup 3/H)-uridine incorporation into the acid-insoluble fraction significantly increased in the adrenals of rats treated with Cd for 2 and 7 consecutive days. Adrenal protein content and weight also significantly increased. These results indicate that continued treatment with Cd stimulates DNA and RNA synthesis in the adrenal cortex, which in turn results in the increase of the total protein contents of the adrenal gland and subsequently in the enlargement of the gland. Serum adrenocorticotrophin (ACTH) and insulin levels in Cd-treated rats were not higher than control levels, suggesting that the stimulation of DNA synthesis in the adrenals of Cd-treated rats is due to factor(s) other than serum ACTH and insulin. Treatment with Cd inhibited DNA synthesis in cultured adrenocortical cells at concentrations of 10(-4) to 10(-8) M, suggesting that Cd does not directly stimulate DNA synthesis in the adrenal gland in vivo. Although the adrenal gland became enlarged, the total adrenal corticosterone content decreased significantly. The decrease of total adrenal corticosterone content may be due to the fall in serum ACTH level of Cd-treated rats.

  2. Beneficial Effects of American Ginseng on Epididymal Sperm Analyses in Cyclophosphamide Treated Rats

    PubMed Central

    Akram, Hosseini; Ghaderi Pakdel, Firouz; Ahmadi, Abbas; Zare, Samad

    2012-01-01

    Objective: This study aims to evaluate the protective effects of American ginseng administered by gastric intubation on sperm vital quality in adult male rats treated with cyclophosphamide (CP). Materials and Methods: In this experimental study, 28 Adult male Wistar rats were assigned to four groups, seven rats in each. The animals allocated to control, CP treated, Ginseng treated and CP-Ginseng treated groups. Rats were treated with CP (6.1 mg/kg/day, i.p) for 6 weeks. American ginseng was used at a dose of 500 mg/kg/day during treatment. Sperm analysis (motion, count, morphology and viability) were evaluated at the end of the experiments. Sperm motion was assessed by Computer-Assisted Sperm Analysis (CASA). The data were analyzed using GB stat software. Probability values of p<0.05 and p<0.01 were considered significant. Results: The epididymal sperm counts in the groups that received CP showed significant decreases compared to the control group. Also dead and abnormal sperms significantly increased following CP treatment compared with control. The motility of caudal sperm was reduced significantly with CP treatment. Therefore, according to the results of this study, co-administration of CP and American ginseng can improve these parameters. Conclusion: American ginseng can prevent the cytotoxic effects of CP on sperm quality factors. PMID:23508327

  3. Metabolic Profile of Offspring from Diabetic Wistar Rats Treated with Mentha piperita (Peppermint)

    PubMed Central

    Barbalho, Sandra M.; Damasceno, Débora C.; Spada, Ana Paula Machado; da Silva, Vanessa Sellis; Martuchi, Karla Aparecida; Oshiiwa, Marie; Machado, Flávia M. V. Farinazzi; Mendes, Claudemir Gregório

    2011-01-01

    This study aimed at evaluating glycemia and lipid profile of offspring from diabetic Wistar rats treated with Mentha piperita (peppermint) juice. Male offspring from nondiabetic dams (control group: 10 animals treated with water and 10 treated with peppermint juice) and from dams with streptozotocin-induced severe diabetes (diabetic group: 10 animals treated with water and 10 treated with peppermint juice) were used. They were treated during 30 days, and, after the treatment period, levels of glycemia, triglycerides, total cholesterol, and fractions were analyzed in the adult phase. The offspring from diabetic dams treated with peppermint showed significantly reduced levels of glucose, cholesterol, LDL-c, and triglycerides and significant increase in HDL-c levels. The use of the M. piperita juice has potential as culturally appropriate strategy to aid in the prevention of DM, dyslipidemia, and its complications. PMID:21647314

  4. Metabolic Profile of Offspring from Diabetic Wistar Rats Treated with Mentha piperita (Peppermint).

    PubMed

    Barbalho, Sandra M; Damasceno, Débora C; Spada, Ana Paula Machado; da Silva, Vanessa Sellis; Martuchi, Karla Aparecida; Oshiiwa, Marie; Machado, Flávia M V Farinazzi; Mendes, Claudemir Gregório

    2011-01-01

    This study aimed at evaluating glycemia and lipid profile of offspring from diabetic Wistar rats treated with Mentha piperita (peppermint) juice. Male offspring from nondiabetic dams (control group: 10 animals treated with water and 10 treated with peppermint juice) and from dams with streptozotocin-induced severe diabetes (diabetic group: 10 animals treated with water and 10 treated with peppermint juice) were used. They were treated during 30 days, and, after the treatment period, levels of glycemia, triglycerides, total cholesterol, and fractions were analyzed in the adult phase. The offspring from diabetic dams treated with peppermint showed significantly reduced levels of glucose, cholesterol, LDL-c, and triglycerides and significant increase in HDL-c levels. The use of the M. piperita juice has potential as culturally appropriate strategy to aid in the prevention of DM, dyslipidemia, and its complications.

  5. The cytoskeleton of digitonin-treated rat hepatocytes.

    PubMed

    Fiskum, G; Craig, S W; Decker, G L; Lehninger, A L

    1980-06-01

    Treatment of isolated rat hepatocptes with low concentrations of digitonin increases the permeability of the plsma membrane to cytosolic proteins without causing release of organelles such as mitochondria into the surrounding medium. Electron microscopy showed that treatment of the cells with increasing concentations of digitonin results in a progressive loss in the continuity of the plasma membrane, while most other aspects of cellular morphology remain normal. Depletion of background staining material from the cytosol by digitonin treatment of the cells greatly enhances the visualization of the cytoskeleton. The use of this technique, together with immunofluorescent light microscopy, has verified the presence of an actin-containing filamentous network at the hepatocyte cortex as well as intermediate filaments distributed throughout the cell. Digitonin is thus useful both for selectively permeabilizing the plasma membrane and for intensifying the appearance of intracellular structures such as microfilaments that are normally difficult to observe in cells such as hepatocytes.

  6. Arginine rich coconut kernel protein modulates diabetes in alloxan treated rats.

    PubMed

    Salil, G; Nevin, K G; Rajamohan, T

    2011-01-15

    Diabetes mellitus is a syndrome characterized by the loss of glucose homeostasis due to several reasons. In spite of the presence of known anti-diabetic medicines in the pharmaceutical market, remedies from natural resources are used with success to treat this disease. The present study was undertaken to investigate the effect of coconut kernel protein (CKP) on alloxan induced diabetes in Sprague-Dawley rats. Diabetes was induced by injecting a single dose of alloxan (150mg/kg body weight) intraperitoneally. After inducing diabetes, purified CKP isolated from dried coconut kernel was administered to rats along with a semi synthetic diet for 45 days. After the experimental period, serum glucose, insulin, activities of different key enzymes involved in glucose metabolism, liver glycogen levels and the histopathology of the pancreas were evaluated. The amount of individual amino acids of CKP was also determined using HPLC. Results showed that CKP has significant amount of arginine. CKP feeding attenuated the increase in the glucose and insulin levels in diabetic rats. Glycogen levels in the liver and the activities of carbohydrate metabolizing enzymes in the serum of treated diabetic rats were reverted back to the normal levels compared to that of control. Histopathology revealed that CKP feeding reduced the diabetes related pancreatic damage in treated rats compared to the control. These results clearly demonstrated the potent anti-diabetic activity of CKP which may be probably due to its effect on pancreatic β cell regeneration through arginine.

  7. Anti-mitotic potential of 7-diethylamino-3(2 Prime -benzoxazolyl)-coumarin in 5-fluorouracil-resistant human gastric cancer cell line SNU620/5-FU

    SciTech Connect

    Kim, Nam Hyun; Kim, Su-Nam; Oh, Joa Sub; Lee, Seokjoon; Kim, Yong Kee

    2012-02-24

    Highlights: Black-Right-Pointing-Pointer DBC exerts antiproliferative potential against 5FU-resistant human gastric cancer cells. Black-Right-Pointing-Pointer This effect is mediated by destabilization of microtubules and subsequent mitotic arrest. Black-Right-Pointing-Pointer DBC enhances apoptosis via caspase activation and downregulation of antiapoptotic genes. -- Abstract: In this study, we investigate an anti-mitotic potential of the novel synthetic coumarin-based compound, 7-diethylamino-3(2 Prime -benzoxazolyl)-coumarin, in 5-fluorouracil-resistant human gastric cancer cell line SNU-620-5FU and its parental cell SNU-620. It exerts the anti-proliferative effects with similar potencies against both cancer cells, which is mediated by destabilization of microtubules and subsequent mitotic arrest. Furthermore, this compound enhances caspase-dependent apoptotic cell death via decreased expression of anti-apoptotic genes. Taken together, our data strongly support anti-mitotic potential of 7-diethylamino-3(2 Prime -benzoxazolyl)-coumarin against drug-resistant cancer cells which will prompt us to further develop as a novel microtubule inhibitor for drug-resistant cancer chemotherapy.

  8. Tissue distribution and urinary excretion of dimethylated arsenic and its metabolites in dimethylarsinic acid- or arsenate-treated rats

    SciTech Connect

    Adair, Blakely M.; Moore, Tanya; Conklin, Sean D.; Creed, John T.; Wolf, Douglas C.; Thomas, David J. . E-mail: thomas.david@epa.gov

    2007-07-15

    Adult female Fisher 344 rats received drinking water containing 0, 4, 40, 100, or 200 parts per million of dimethylarsinic acid or 100 parts per million of arsenate for 14 days. Urine was collected during the last 24 h of exposure. Tissues were then taken for analysis of dimethylated and trimethylated arsenicals; urines were analyzed for these arsenicals and their thiolated derivatives. In dimethylarsinic acid-treated rats, highest concentrations of dimethylated arsenic were found in blood. In lung, liver, and kidney, concentrations of dimethylated arsenic exceeded those of trimethylated species; in urinary bladder and urine, trimethylated arsenic predominated. Dimethylthioarsinic acid and trimethylarsine sulfide were present in urine of dimethylarsinic acid-treated rats. Concentrations of dimethylated arsenicals were similar in most tissues of dimethylarsinic acid- and arsenate-treated rats, including urinary bladder which is the target for dimethylarsinic acid-induced carcinogenesis in the rat. Mean concentration of dimethylated arsenic was significantly higher (P < 0.05) in urine of dimethylarsinic acid-treated rats than in arsenate-treated rats, suggesting a difference between treatment groups in the flux of dimethylated arsenic through urinary bladder. Concentrations of trimethylated arsenic concentrations were consistently higher in dimethylarsinic acid-treated rats than in arsenate-treated rats; these differences were significant (P < 0.05) in liver, urinary bladder, and urine. Concentrations of dimethylthioarsinic acid and trimethylarsine sulfide were higher in urine from dimethylarsinic acid-treated rats than from arsenate-treated rats. Dimethylarsinic acid is extensively metabolized in the rat, yielding significant concentrations of trimethylated species and of thiolated derivatives. One or more of these metabolites could be the species causing alterations of cellular function that lead to tumors in the urinary bladder.

  9. Brain Pathology in Adult Rats Treated With Domoic Acid.

    PubMed

    Vieira, A C; Alemañ, N; Cifuentes, J M; Bermúdez, R; Peña, M López; Botana, L M

    2015-11-01

    Domoic acid (DA) is a neurotoxin reported to produce damage to the hippocampus, which plays an important role in memory. The authors inoculated rats intraperitoneally with an effective toxic dose of DA to study the distribution of the toxin in major internal organs by using immunohistochemistry, as well as to evaluate the induced pathology by means of histopathologic and immunohistochemical methods at different time points after toxin administration (6, 10, and 24 hours; 5 and 54 days). DA was detected by immunohistochemistry exclusively in pyramidal neurons of the hippocampus at 6 and 10 hours after dosing. Lesions induced by DA were prominent at 5 days following treatment in selected regions of the brain: hippocampus, amygdala, piriform and perirhinal cortices, olfactory tubercle, septal nuclei, and thalamus. The authors found 2 types of lesions: delayed death of selective neurons and large areas of necrosis, both accompanied by astrocytosis and microgliosis. At 54 days after DA exposure, the pathology was characterized by still-distinguishable dying neurons, calcified lesions in the thalamus, persistent astrocytosis, and pronounced microgliosis. The expression of nitric oxide synthases suggests a role for nitric oxide in the pathogenesis of neuronal degeneration and chronic inflammation induced by DA in the brain.

  10. Betanin attenuates oxidative stress and inflammatory reaction in kidney of paraquat-treated rat.

    PubMed

    Tan, Dehong; Wang, Yiheng; Bai, Bing; Yang, Xuelian; Han, Junyan

    2015-04-01

    The effects of natural pigment betanin on oxidative stress and inflammation in kidney of paraquat-treated rat were investigated. Paraquat was injected intraperitoneally into rats to induce renal damage. The rats were randomly divided into four groups: a control group, a paraquat group, and two paraquat groups that were treated with betanin at 25 and 100 mg/kg/d three days before and two days after paraquat administration. Treatment with betanin alleviated the paraquat-incurred acute kidney injury, evidenced by histological improvement, reduced serum and urine markers for kidney injury. Betanin antagonized the paraquat-induced inflammation, indicated by reduced expression of inducible nitric oxide synthase and cyclooxygenase, blunted activation of nuclear factor kappa B, and diminished lysosomal protease activities. Betanin also decreased oxidative stress elicited by paraquat. In conclusion, betanin may have a protective effect against paraquat-induced acute kidney damage. The mechanisms of the protection appear to be the inhibition of oxidative stress and inflammation.

  11. Carvacrol and Pomegranate Extract in Treating Methotrexate-Induced Lung Oxidative Injury in Rats

    PubMed Central

    Şen, Hadice Selimoğlu; Şen, Velat; Bozkurt, Mehtap; Türkçü, Gül; Güzel, Abdulmenap; Sezgi, Cengizhan; Abakay, Özlem; Kaplan, Ibrahim

    2014-01-01

    Background This study was designed to evaluate the effects of carvacrol (CRV) and pomegranate extract (PE) on methotrexate (MTX)-induced lung injury in rats. Material/Methods A total of 32 male rats were subdivided into 4 groups: control (group I), MTX treated (group II), MTX+CRV treated (group III), and MTX+PE treated (group IV). A single dose of 73 mg/kg CRV was administered intraperitoneally to rats in group III on Day 1 of the investigation. To group IV, a dose of 225 mg/kg of PE was administered via orogastric gavage once daily over 7 days. A single dose of 20 mg/kg of MTX was given intraperitoneally to groups II, III, and IV on Day 2. The total duration of experiment was 8 days. Malondialdehyde (MDA), total oxidant status (TOS), total antioxidant capacity (TAC), and oxidative stress index (OSI) were measured from rat lung tissues and cardiac blood samples. Results Serum and lung specimen analyses demonstrated that MDA, TOS, and OSI levels were significantly greater in group II relative to controls. Conversely, the TAC level was significantly reduced in group II when compared to the control group. Pre-administering either CRV or PE was associated with decreased MDA, TOS, and OSI levels and increased TAC levels compared to rats treated with MTX alone. Histopathological examination revealed that lung injury was less severe in group III and IV relative to group II. Conclusions MTX treatment results in rat lung oxidative damage that is partially counteracted by pretreatment with either CRV or PE. PMID:25326861

  12. Toxicity profiles in rats treated with tumorigenic and nontumorigenic triazole conazole fungicides: Propiconazole, triadimefon, and myclobutanil.

    PubMed

    Wolf, Douglas C; Allen, James W; George, Michael H; Hester, Susan D; Sun, Guobin; Moore, Tanya; Thai, Sheau-Fung; Delker, Don; Winkfield, Ernest; Leavitt, Sharon; Nelson, Gail; Roop, Barbara C; Jones, Carlton; Thibodeaux, Julie; Nesnow, Stephen

    2006-01-01

    Conazoles are a class of azole based fungicides used in agriculture and as pharmaceutical products. They have a common mode of antifungal action through inhibition of ergosterol biosynthesis. Some members of this class have been shown to be hepatotoxic and will induce mouse hepatocellular tumors and/or rat thyroid follicular cell tumors. The particular mode of toxic and tumorigenic action for these compounds is not known, however it has been proposed that triadimefon-induced rat thyroid tumors arise through the specific mechanism of increased TSH. The present study was designed to identify commonalities of effects across the different conazoles and to determine unique features of the tissue responses that suggest a toxicity pathway and a mode of action for the observed thyroid response for triadimefon. Male Wistar/Han rats were treated with triadimefon (100, 500, 1800 ppm), propiconazole (100, 500, 2500 ppm), or myclobutanil (100, 500, 2000 ppm) in feed for 4, 30, or 90 days. The rats were evaluated for clinical signs, body and liver weight, histopathology of thyroid and liver, hepatic metabolizing enzyme activity, and serum T3, T4, TSH, and cholesterol levels. There was a dose-dependent increase in liver weight but not body weight for all treatments. The indication of cytochrome induction, pentoxyresorufin O-dealkylation (PROD) activity, had a dose-related increase at all time points for all conazoles. Uridine diphopho-glucuronosyl transferase (UDPGT), the T4 metabolizing enzyme measured as glucuronidation of 1-naphthol, was induced to the same extent after 30 and 90 days for all three conazoles. Livers from all high dose treated rats had centrilobular hepatocyte hypertrophy after 4 days, while only triadimefon and propiconazole treated rats had hepatocyte hypertrophy after 30 days, and only triadimefon treated rats had hepatocyte hypertrophy after 90 days. Thyroid follicular cell hypertrophy, increased follicular cell proliferation, and colloid depletion were

  13. The Effects and Possible Mechanisms of Puerarin to Treat Endometriosis Model Rats

    PubMed Central

    Zhao, Li; Zhang, Danying; Zhai, Dongxia; Shen, Wei; Bai, Lingling; Liu, Yiqun; Cai, Zailong; Li, Ji; Yu, Chaoqin

    2015-01-01

    Objective. To explore the effects of puerarin to treat endometriosis (EMT) model rats and the possible regulatory mechanisms. Methods. EMT model rats were surgically induced by autotransplantion of endometrial tissues. The appropriate dosage of puerarin to treat EMT model rats was determined by observing the pathologic morphology of ectopic endometrial tissues and by detecting the levels of estradiol (E2) and prostaglandin E2 (PGE2) of both serum and ectopic endometrial tissues. The related genes and proteins of ectopic endometrial tissues were analyzed by Real-time PCR and immunohistochemistry (IHC) to explore the possible mechanisms. Results. Puerarin could reduce the levels of E2 and PGE2 and prevent the growth of ectopic endometrium tissues by inhibiting the expression of aromatase cytochrome P450 (p450arom) and cyclooxygenase-2 (cox-2); puerarin could adjust the anabolism of E2 by upregulating the expression of 17β-hydroxysteroid-2 (17β-hsd-2) and downregulating the expression of 17β-hydroxysteroid-1 (17β-hsd-1) of the ectopic endometrium tissues; puerarin could increase the expression of ERβ and improve the inflammatory microenvironment of EMT model rats. Conclusions. Our data suggest that puerarin has a therapeutic effect on EMT model rats and could be a potential therapeutic agent for the treatment of EMT in clinic. PMID:25815028

  14. Spleen-Specific Development of Germinal Centers in Rats Treated with Antithyroid Drugs

    PubMed Central

    Fukui, Motoko; Fukui, Norio; Sakai, Kuniyoshi; Hasegawa, Yuko; Nagasaki, Shuji; Shibata, Seiji; Araki, Sei-ichi; Isobe, Mitsui; Hisada, Shigeru

    2013-01-01

    The antithyroid drugs (ATDs) methimazole (MMI) and propylthiouracil (PTU) have been used for treatment of hyperthyroidism for more than several decades, despite the fact that they are associated with adverse drug reactions that are thought to be autoimmune mediated. We therefore examined histopathologic responses in the immune system in male and female rats given MMI (2, 20 and 200 mg/kg/day, p.o., in experiment 1; 200 mg/kg/day, p.o., in experiment 3) or PTU (25 and 250 mg/kg/day, p.o., in experiment 2; 200 mg/kg/day, p.o., in experiment 3) for two weeks. In experiments 1 and 2, highest doses of MMI and PTU induced histopathologic changes in the spleen consistent with those in experiment 3 without any changes in the other peripheral lymphoid organs and tissues. In experiment 3, histopathological evaluation of the spleen along with hematological and bone marrow examinations were performed. In both male and female rats, MMI or PTU induced histopathological changes in the spleen characterized by development of germinal centers and an increase in the number of IgG-positive plasma cells in the red pulp; these changes were most prevalent in the MMI-treated female rats. Total red and white blood cell counts were decreased in the MMI-treated male and female rats; lymphocytes and monocytes were lower in male and female rats, respectively. Bone marrow nucleated cells were significantly lower in the MMI-treated males. This is the first study to demonstrate that ATDs induce spleen specific B-cell reactions in rats PMID:24526810

  15. Sipa1l1 is an early biomarker of liver fibrosis in CCl4-treated rats

    PubMed Central

    Marfà, Santiago; Morales-Ruiz, Manuel; Oró, Denise; Ribera, Jordi; Fernández-Varo, Guillermo; Jiménez, Wladimiro

    2016-01-01

    ABSTRACT At present, several procedures are used for staging liver fibrosis. However, these methods may involve clinical complications and/or present diagnostic uncertainty mainly in the early stages of the disease. Thus, this study was designed to unveil new non-invasive biomarkers of liver fibrosis in an in vivo model of fibrosis/cirrhosis induction by CCl4 inhalation by using a label-free quantitative LC-MS/MS approach. We analyzed 94 serum samples from adult Wistar rats with different degrees of liver fibrosis and 36 control rats. Firstly, serum samples from 18 CCl4-treated rats were clustered into three different groups according to the severity of hepatic and the serum proteome was characterized by label-free LC-MS/MS. Furthermore, three different pooled serum samples obtained from 16 control Wistar rats were also analyzed. Based on the proteomic data obtained, we performed a multivariate analysis which displayed three main cell signaling pathways altered in fibrosis. In cirrhosis, more biological imbalances were detected as well as multi-organ alterations. In addition, hemopexin and signal-induced proliferation-associated 1 like 1 (SIPA1L1) were selected as potential serum markers of liver fibrogenesis among all the analyzed proteins. The results were validated by ELISA in an independent group of 76 fibrotic/cirrhotic rats and 20 controls which confirmed SIPA1L1 as a potential non-invasive biomarker of liver fibrosis. In particular, SIPA1L1 showed a clear diminution in serum samples from fibrotic/cirrhotic rats and a great accuracy at identifying early fibrotic stages. In conclusion, the proteomic analysis of serum samples from CCl4-treated rats has enabled the identification of SIPA1L1 as a non-invasive marker of early liver fibrosis. PMID:27230648

  16. Voluntary exercise impairs initial delayed spatial alternation performance in estradiol treated ovariectomized middle-aged rats.

    PubMed

    Neese, Steven L; Korol, Donna L; Schantz, Susan L

    2013-09-01

    Estrogens differentially modulate behavior in the adult female rodent. Voluntary exercise can also impact behavior, often reversing age associated decrements in memory processes. Our research group has published a series of papers reporting a deficit in the acquisition of an operant working memory task, delayed spatial alternation (DSA), following 17β-estradiol treatment to middle-aged ovariectomized (OVX) rats. The current study examined if voluntary exercise could attenuate the 17β-estradiol induced deficits on DSA performance. OVX 12-month old Long-Evans rats were implanted with a Silastic capsule containing 17β-estradiol (10% in cholesterol: low physiological range) or with a blank capsule. A subset of the 17β-estradiol and OVX untreated rats were given free access to a running wheel in their home cage. All rats were tested for 40 sessions on the DSA task. Surprisingly, we found running wheel access to impair initial acquisition of the DSA task in 17β-estradiol treated rats, an effect not seen in OVX untreated rats given running wheel access. This deficit was driven by an increase in perseverative responding on a lever no longer associated with reinforcement. We also report for the first time a 17β-estradiol induced impairment on the DSA task following a long intertrial delay (18-sec), an effect revealed following more extended testing than in our previous studies (15 additional sessions). Overall, running wheel access increased initial error rate on the DSA task in 17β-estradiol treated middle-aged OVX rats, and failed to prevent the 17β-estradiol induced deficits in performance of the operant DSA task in later testing sessions.

  17. Uric acid plasma level and urine pH in rats treated with ambroxol.

    PubMed

    Drewa, Tomasz; Wolski, Zbigniew; Gruszka, Marzena; Misterek, Bartosz; Lysik, Joanna

    2007-01-01

    It was a chance discovery that ambroxol parenteral administration led to urinary bladder stone formation in rats. This study was undertaken to examine the serum uric acid levels and urine pH in rats after ambroxol parenteral treatment. Ambroxol influence on the uric acid level was measured in 5 rats (Rattus sp.) treated with 60 mg/kg (dissolved in injection water, sc, daily) during 2 weeks. Ambroxol influence on urine pH was examined on 45 rats divided into 3 groups. Rats from the 1st and 2nd group received 30 and 60 mg/kg/24h ambroxol, respectively. Urine was collected once daily and measured with strip kit. All values were presented as the means with standard deviations. The Student t test was used to compare the means, p < 0.05 was considered as significant. Dynamics of pH changes was measured in 4 rats treated with 60 mg/kg/24h of ambroxol. Controls received 1 mL of injection water sc. Serum uric acid level increased up to 8.7 +/- 1.0 mg/dL vs. 5.7 +/- 1.0 mg/dL in control (p < 0.002). In the 1st and 2nd group urine pH increased up to 7.5 +/- 0.5 and 7.6 +/- 0.5 vs. 6.7 +/- 0.4 (p < 0.05). Ambroxol withdrawal resulted in sequential urine pH decrease. 11 days after interruption of ambroxol therapy pH reached the starting value. Urine pH changes and possible disturbances in uric acid metabolic pathway may influence on the stone formation in rats after ambroxol parenteral treatment. The influence of ambroxol on urinary tract GAG layer and the balance between xanthine and CaOx in the urine should be checked.

  18. Studies on organ weights in naproxen treated rats after intermittent exposure to simulated high altitude

    NASA Astrophysics Data System (ADS)

    Saha, R. C.; Biswas, H. M.

    1990-06-01

    Rats were exposed intermittently for 8h per day over 6 days at simulated high altitude of 20 000 feet. One group of altitude-exposed animals was treated with naproxen, a prostaglandin inhibiting drug. Significant reduction in body weight gain was observed in both altitude-exposed and drug-treated altitude-exposed animals compared to the control group. Right and left ventricular weights and weights of the adrenal glands were increased significantly in altitude-exposed and altitude-exposed drug-treated animals. The weight of the spleen was increased significantly in altitude-exposed animals whereas no such increase of splenic weight was observed in drug-treated altitude-exposed group of animals. On the other hand, the weight of the liver was decreased significantly in both cases. In drug-treated altitude-exposed animals, the unaltered splenic weight was thought to be due to inhibition of the erythropoietic activity.

  19. Bone morphometry and differences in bone fluorine containing compounds in rats treated with NaF and MFP.

    PubMed

    Brun, L R; Pera, L I; Rigalli, A

    2010-01-01

    Sodium fluoride (NaF) and sodium monofluorophosphate (MFP) are drugs used to increase bone mass. They have been considered equivalent but the results of the treatments were not always coincident. Most studies have been carried out in osteoporotic women or ovariectomized rats pointing to the result in bone mass rather than at the mechanism of action. Convincing evidence indicates that pharmacokinetic of NaF is different from MFP. While only fluoride is found in bones and plasma of rats treated with NaF, in MFP-treated rats, there are also fluorine (F) bound to plasma alpha-macroglobulin and bone covalently bound F. A significant increase in bone mass of rats was observed after 30 days of treatment with NaF and MFP in young rats. This increase in bone mass correlates with the increase in number and thickness of trabeculas in cancellous bone. In the femur of MFP-treated rats, there was an increase in the inertia momentum of the diaphysis without changes in bone width. In addition, bone F content of MFP-treated animals is twice of the content of NaF-treated rats. This difference is the consequence of bone covalently bound F, which is absent in NaF-treated rats. In addition, alpha-macroglobulin was detected in noncollagenous bone matrix of MFP-treated rats. Although F in feces and plasma did not differ among treatments, the urinary excretion of F was lower in MFP than in NaF-treated rats, which is consistent with the higher bone F content.

  20. [Studies on transdermal delivery of ferulic acid through rat skin treated by microneedle arrays].

    PubMed

    Yang, Bing; Du, Shou-ying; Bai, Jie; Shang, Ke-xin; Lu, Yang; Li, Peng-yue

    2014-12-01

    In order to investigate the characteristics of transdermal delivery of ferulic acid under the treated of microneedle arrays and the influence on permeability of rat skin capillaries, improved Franz-cells were used in the transdermal delivery experiment with the rat skin of abdominal wall and the length of microneedle arrays, different insertion forces, retention time were studied in the influence of characteristics of transdermal delivery of FA. The amount of FA was determined by HPLC system. Intravenous injection Evans blue and FA was added after microneedle arrays treated. Established inflammation model was built by daubing dimethylbenzene. The amount of Evans blue in the rat skin was read at 590 nm wavelength with a Multiskan Go microplate reader. Compared with passive diffusion group the skin pretreated with microneedle arrays had a remarkable enhancement of FA transport (P <0.01). The accumulation of FA increased with the enhancement of insertion force as to as the increase of retention time. Microneedle arrays with different length had a remarkable enhancement of FA transport, but was not related to the increase of the length. The research of FA on the reduce of permeability of rat skin capillaries indicated that the skin pretreated with microneedle arrays could reduce the content of Evans blue in the skins of rat significantly compared with the untreated group. The permeation rate of ferulic acid transdermal delivery had remarkable increase under the treated of microneedle arrays and the length of microneedle arrays ,the retention time so as to the insertion force were important to the transdermal delivery of ferulic acid. PMID:25898576

  1. Effect of hydroalcoholic extract of ginger on the liver of epileptic female rats treated with lamotrigine

    PubMed Central

    Poorrostami, Ameneh; Farokhi, Farah; Heidari, Reza

    2014-01-01

    Objective: Lamotrigine is an antiepileptic drug, widely used in the treatment of epilepsy; long-term use of this drug can cause hepatotoxicity. Zingiber officinale Roscoe (ginger) possesses antioxidant properties. In present research, the effect ofhydroalcoholic extract of ginger (HEG) on the liver of lamotrigine-treated epileptic rats was investigated Material and Methods: Forty-eight female Wistar rats were selected and allocated to 8 groups of 6 each. Group 1: Negative controls were treated with normal saline. Group 2: Positive controls were treated with lamotrigine (LTG) (10 mg/kg) daily by gavages for 4 consecutive weeks. Epilepsy was induced in treatment groups by i.p. injection of pentylenetetrazol (PTZ) (40 mg/kg). Group 3: Epileptic group received normal saline (10 ml/kg). Group 4: Epileptic group was treated with LTG (10 mg/kg). Groups 5 and 6: Epileptic groups received HEG (50 and 100 mg/kg). Groups 7 and 8: Epileptic groups received LTG and HEG (50 and 100 mg/kg). At the end of 28 days, blood samples were drawn and their livers were processed for light microscopy. Results: The mean values of TG, CHOL, AST, and ALT activity significantly rose (p<0.01) in groups 2, 3, and 4, while in rats treated with HEG (groups 5, 6, 7, and 8), the levels of liver enzymes significantly decreased (p<0.05) compared with epileptic group treated with lamotrigine (group 4). Histopathological changes of liver samples were comparable with respective control. Conclusion: These results suggest that hydroalcoholic extract of ginger improves liver function in lamotrigine-induced hepatotoxicity. PMID:25068142

  2. Estrogen therapy increases BDNF expression and improves post-stroke depression in ovariectomy-treated rats

    PubMed Central

    Su, Qiaoer; Cheng, Yifan; Jin, Kunlin; Cheng, Jianhua; Lin, Yuanshao; Lin, Zhenzhen; Wang, Liuqing; Shao, Bei

    2016-01-01

    The present study investigated the effect of exogenous estrogen on post-stroke depression. Rats were exposed to chronic mild stress following middle cerebral artery occlusion. The occurrence of post-stroke depression was evaluated according to the changes in preference for sucrose and performance in a forced swimming test. Estrogen therapy significantly improved these neurological symptoms, indicating that estrogen is effective in treating post-stroke depression. Increased brain-derived neurotrophic factor (BDNF) expression was reported in the hippocampus of rats that had been treated with estrogen for two weeks, suggesting that BDNF expression may be an important contributor to the improvement of post-stroke depression that is observed following estrogen therapy.

  3. Estrogen therapy increases BDNF expression and improves post-stroke depression in ovariectomy-treated rats

    PubMed Central

    Su, Qiaoer; Cheng, Yifan; Jin, Kunlin; Cheng, Jianhua; Lin, Yuanshao; Lin, Zhenzhen; Wang, Liuqing; Shao, Bei

    2016-01-01

    The present study investigated the effect of exogenous estrogen on post-stroke depression. Rats were exposed to chronic mild stress following middle cerebral artery occlusion. The occurrence of post-stroke depression was evaluated according to the changes in preference for sucrose and performance in a forced swimming test. Estrogen therapy significantly improved these neurological symptoms, indicating that estrogen is effective in treating post-stroke depression. Increased brain-derived neurotrophic factor (BDNF) expression was reported in the hippocampus of rats that had been treated with estrogen for two weeks, suggesting that BDNF expression may be an important contributor to the improvement of post-stroke depression that is observed following estrogen therapy. PMID:27602095

  4. Histological changes in testes of rats treated with testosterone, nandrolone, and stanozolol

    PubMed Central

    Mohd Mutalip, Siti Syairah; Surindar Singh, Gurmeet Kaur; Mohd Shah, Aishah; Mohamad, Mashani; Mani, Vasudevan; Hussin, Siti Nooraishah

    2013-01-01

    Background: Anabolic androgenic steroids (AAS) is being used in medical treatments, but AAS also was identified to have the risks of adverse effects towards patients and consumers health. Objective: Present study was conducted to observe the effects of testosterone, nandrolone, and stanozolol (forms of AAS) intake during onset of puberty on the rat testicular histology. Materials and Methods: Juvenile male Sprague-Dawley (SD) rats (n=42) were divided into seven groups and were injected subcutaneously with medium dose of polyethylene glycol-200 (PEG-200) (control), testosterone, nandrolone, and stanozolol for six weeks (PND 41-87). The animals were weighed daily and sacrificed on PND 88. Testes were removed, weighed, and prepared for histological assessment and finally specimens were observed under microscope. Results: The results showed an insignificant increase in mean daily body weight with highest and lowest body weight gained was of 177.6±1.69 gr and 140.0±12.26 gr respectively. There was significant decrease in the testes absolute weight (p≤0.01) in all experimental groups except in the nandrolone 2.5 mg/kg/week treated group. Testicular histology of rats treated with AAS also showed slight changes in the uniformity of arrangements of seminiferous tubules. Conclusion: Data from present study suggests that AAS have been initiating the adverse effects on testicular normal functions in rats during onset of puberty. PMID:24639803

  5. Anti-aging Effect and Gene Expression Profiling of Aged Rats Treated with G. bimaculatus Extract

    PubMed Central

    Hwang, Jae Sam; Yun, Eun Young; Kim, Min-Ji; Park, Kun-Koo

    2015-01-01

    Extract from Gryllus bimaculatus crickets inhibits oxidation at the DNA level, with reduced production of 8-hydroxy-2'-deoxyguanosine (8-OHdG). Microarray analyses were performed with a rat 28K cDNA clone set array to identify the gene expression profiles of aged (10 months old) Wistar Kyoto rats treated for one month with 100 mg/kg G. bimaculatus ethanol extract to assess the effects. The extract produced a meaningful anti-edema effect, evident by the inhibition of creatinine phosphokinase activity. The weights of abdominal and ovarian adipose tissues were reduced and the proportion of unsaturated fatty acids in adipose tissues was increased in an extract dose-dependent manner. Compared with untreated control rats, rats treated with the extract displayed the upregulation of 1053 genes including Fas (tumor necrosis factor receptor superfamily, member 6), Amigo3 (adhesion molecule with an immunoglobulin-like domain), Reticulon 4, 3-hydroxy-3-methylglutaryl-coenzyme (Hmgcr; a reductase), related anti-fatigue (enzyme metabolism), and Rtn antioxidant, and the downregulation of 73 genes including Ugt2b (UDP glycosyltransferase 2 family), Early growth response 1, and Glycoprotein m6a. Data suggest that G. bimaculatus extract may have value in lessening the effects of aging, resulting in a differential gene expression pattern indicative of a marked stress response and lower expression of metabolic and biosynthetic genes. PMID:26191384

  6. BIOCHEMICAL EFFECTS IN NORMAL AND STONE FORMING RATS TREATED WITH THE RIPE KERNEL JUICE OF PLANTAIN (MUSA PARADISIACA)

    PubMed Central

    Devi, V. Kalpana; Baskar, R.; Varalakshmi, P.

    1993-01-01

    The effect of Musa paradisiaca stem kernel juice was investigated in experimental urolithiatic rats. Stone forming rats exhibited a significant elevation in the activities of two oxalate synthesizing enzymes - Glycollic acid oxidase and Lactate dehydrogenase. Deposition and excretion of stone forming constituents in kidney and urine were also increased in these rats. The enzyme activities and the level of crystalline components were lowered with the extract treatment. The extract also reduced the activities of urinary alkaline phosphatase, lactate dehydrogenase, r-glutamyl transferase, inorganic pyrophosphatase and β-glucuronidase in calculogenic rats. No appreciable changes were noticed with leucine amino peptidase activity in treated rats. PMID:22556626

  7. Memory and hippocampal architecture following short-term midazolam in western diet-treated rats.

    PubMed

    Rosenberger, Dorothea S; Falangola, Maria F; Ledreux, Aurélie; Nie, Xingju; Suhre, Wendy M; Boger, Heather A; Granholm, Ann-Charlotte

    2016-05-16

    The impact of short-term benzodiazepine exposure on cognition in middle-aged or older patients is a highly debated topic among anesthesiologists, critical care physicians and public media. "Western diet" (WD) consumption is linked to impaired cognition as well. The combination of benzodiazepines with substantial exposure to WD might set the stage for increased hippocampal vulnerability for benzodiazepines leading to exaggerated cognitive impairment in the postoperative period. In this study, Fischer 344 rats were fed either WD or standard rodent diet from 5 to 10.5 months of age. Rats were exposed to midazolam or placebo two days prior to an MRI scan using Diffusional Kurtosis Imaging (DKI) to assess brain microstructural integrity, followed by behavioral testing using a water radial arm maze. Hippocampal tissue was collected to assess alterations in protein biochemistry in brain regions associated with learning and memory. Our results showed that rats exposed to the combination of midazolam and WD had significantly delayed time of learning and exhibited spatial memory impairment. Further, we observed an overall increase of kurtosis metrics in the hippocampus and increased expression of the mitochondrial protein VDAC2 in midazolam-treated rats. Our data suggest that both the short-acting benzodiazepine midazolam and WD contribute to negatively affect the brain in middle-aged rats. This study is the first application of DKI on the effects of midazolam and WD exposure, and the findings demonstrate that diffusion metrics are sensitive indicators of changes in the complexity of neurite architecture.

  8. Reproductive performance of rats treated with defatted jojoba meal or simmondsin before or during gestation.

    PubMed

    Cokelaere, M; Daenens, P; Decuypere, E; Flo, G; Kühn, E; Van Boven, M; Vermaut, S

    1998-01-01

    The effects on food intake, growth and reproductive performance parameters of defatted jojoba meal and pure simmondsin, an extract from jojoba meal, were compared in female Wistar rats. Rats fed 0.15% simmondsin or 3% defatted jojoba meal (equivalent to 0.15% simmondsin) for 8 weeks before conception showed a similar reduction in food intake (about 20%) and a similar growth retardation compared with controls. Both treatments induced a reduction in the number of corpora lutea on gestation day 16: this effect could be ascribed to the lower food intake before conception because it was also observed in rats pair-fed to the treated ones. Rats given feed containing 0.15% simmondsin or 3% defatted jojoba meal during days 1-16 of gestation showed a similar reduction in food intake relative to controls. Foetal and placental weights were reduced, relative to controls, to a similar extent in both groups, and the reductions were slightly greater than in the corresponding pair-fed groups. We conclude that the effects on food intake, growth and reproductive performance that were seen after feeding rats defatted jojoba meal were due to the simmondsin content of the meal. The simmondsin induced reduction in food intake and probably also a relative protein shortage.

  9. Brain energy consumption in ethanol-treated, Long-Evans rats.

    PubMed

    Viña, J R; Salus, J E; DeJoseph, M R; Pallardo, F; Towfighi, J; Hawkins, R A

    1991-06-01

    The cerebral metabolic rate of glucose utilization (CMRGlc) was measured in rats fed liquid diets containing ethanol for 8 wk, after removal of ethanol from the diet and after acute ethanol intoxication. Control rats were pair fed the liquid diets containing isoenergetic amounts of dextrin-maltose. Quantitative autogradiography using [6-14C]glucose measured CMRGlc at the level of individual structures. Digital image techniques created stereograms of brain energy consumption from the autoradiographs. These techniques provided information about CMRGlc throughout the brain. Rats given the ethanol liquid diet drank constantly throughout the day and night. Neuropathological examination of brain revealed no abnormalities from ethanol consumption. Acute ethanol administration to control rats produced a decrease in CMRGlc throughout the brain that was most prominent in structures concerning auditory, visual, memory and motor functions. Chronic ethanol consumption did not reduce CMRGlc to the same degree as acute ethanol intoxication; in fact, it affected only a few structures. The removal of ethanol from chronic ethanol-treated rats for a period of 18 h caused CMRGlc to rise above control values throughout the brain. However, there were no seizures or other evidence of brain dysfunction.

  10. Urinary concentrating mechanism and Aquaporin-2 abundance in rats chronically treated with aluminum lactate.

    PubMed

    Mahieu, Stella; Millen, Néstor; Contini, María del Carmen; Gonzalez, Marcela; Molinas, Sara M; Elías, María Mónica

    2006-06-15

    The aim of this work was to study the effects of chronic administration of aluminum (Al) on the urinary concentrating and diluting mechanisms in the distal tubules and collecting ducts. Male Wistar rats were chronically treated with aluminum lactate for 12 weeks (0.575 mg Al/100g of body weight, i.p., three times per week). After 12 weeks, renal function of control and Al-treated rats was evaluated by clearance techniques. To study urinary concentrating mechanisms, renal function was also measured in control and Al-treated rats deprived of water, after the administration of desmopressin (vasopressin agonist) and after the infusion of hypertonic saline at increasing infusion rates. Sodium and water balance were impaired. We found decreased urinary concentrating ability in situations in which endogenous (thirst or infusion of hypertonic saline) or exogenous plasma antidiuretic hormone was increased. Solute-free water formation, measured during the infusion of hypotonic saline showed normal transport in the thick ascending limb. Aquaporin-2 (AQP2) expression was measured by Western blot to evaluate water permeability in collecting ducts. We found that Al produced downregulation of AQP2 in plasma membranes and intracellular vesicles, that could account for the impaired water handling. Administration of desmopressin increased AQP2 in plasma membranes, suggesting that Al did not impair trafficking of this protein, but could interfere with AQP2 synthesis. PMID:16675087

  11. Urinary concentrating mechanism and Aquaporin-2 abundance in rats chronically treated with aluminum lactate.

    PubMed

    Mahieu, Stella; Millen, Néstor; Contini, María del Carmen; Gonzalez, Marcela; Molinas, Sara M; Elías, María Mónica

    2006-06-15

    The aim of this work was to study the effects of chronic administration of aluminum (Al) on the urinary concentrating and diluting mechanisms in the distal tubules and collecting ducts. Male Wistar rats were chronically treated with aluminum lactate for 12 weeks (0.575 mg Al/100g of body weight, i.p., three times per week). After 12 weeks, renal function of control and Al-treated rats was evaluated by clearance techniques. To study urinary concentrating mechanisms, renal function was also measured in control and Al-treated rats deprived of water, after the administration of desmopressin (vasopressin agonist) and after the infusion of hypertonic saline at increasing infusion rates. Sodium and water balance were impaired. We found decreased urinary concentrating ability in situations in which endogenous (thirst or infusion of hypertonic saline) or exogenous plasma antidiuretic hormone was increased. Solute-free water formation, measured during the infusion of hypotonic saline showed normal transport in the thick ascending limb. Aquaporin-2 (AQP2) expression was measured by Western blot to evaluate water permeability in collecting ducts. We found that Al produced downregulation of AQP2 in plasma membranes and intracellular vesicles, that could account for the impaired water handling. Administration of desmopressin increased AQP2 in plasma membranes, suggesting that Al did not impair trafficking of this protein, but could interfere with AQP2 synthesis.

  12. Neurorestorative Therapy of Stroke in Type two Diabetes Rats Treated with Human Umbilical Cord Blood Cells

    PubMed Central

    Yan, Tao; Venkat, Poornima; Chopp, Michael; Zacharek, Alex; Ning, Ruizhuo; Cui, Yisheng; Roberts, Cynthia; Kuzmin-Nichols, Nicole; Sanberg, Cyndy Davis; Chen, Jieli

    2015-01-01

    Background and Purpose Diabetes mellitus is a high risk factor for ischemic stroke. Diabetic stroke patients suffer worse outcomes, poor long term recovery, risk of recurrent strokes and extensive vascular damage. We investigated the neurorestorative effects and the underlying mechanisms of stroke treatment with human umbilical cord blood cells (HUCBCs) in Type two diabetes mellitus (T2DM) rats. Methods Adult male T2DM rats were subjected to 2 h of middle cerebral artery occlusion (MCAo). Three days after MCAo, rats were treated via tail-vein injection with: 1) phosphate-buffered-saline (PBS); 2) HUCBCs (5×106); n=10/group. Results HUCBC stroke treatment initiated 3 days after MCAo in T2DM rats did not significantly decrease blood-brain-barrier (BBB) leakage (p=0.1) and lesion volume (p=0.078), but significantly improved long term functional outcome and decreased brain hemorrhage (p<0.05) when compared to the PBS-treated T2DM-MCAo control group. HUCBC treatment significantly promoted white matter (WM) remodeling as indicated by increased expression of Bielschowsky silver (axons marker), Luxol fast blue (myelin marker), SMI-31 (neurofilament) and Synaptophysin in the ischemic border zone (IBZ). HUCBC promoted vascular remodeling, and significantly increased arterial and vascular density. HUCBC treatment of stroke in T2DM rats significantly increased M2 macrophage polarization (increased M2 macrophage CD163, CD 206; decreased M1 macrophage ED1 and iNOS expression) in the ischemic brain compared to PBS-treated T2DM-MCAo controls (p<0.05). HUCBC also significantly decreased pro-inflammatory factors i.e., matrix metalloproteinase 9 (MMP9), receptor for advanced glycation end-products (RAGE) and toll like receptor 4 (TLR4) expression in the ischemic brain. Conclusion HUCBC treatment initiated 3 days after stroke significantly increased WM and vascular remodeling in the ischemic brain as well as decreased neuroinflammatory factor expression in the ischemic brain in T2DM

  13. Cocaine responsiveness or anhedonia in rats treated with methylphenidate during adolescence.

    PubMed

    Ferguson, Sherry A; Boctor, Sherin Y

    2010-01-01

    Methylphenidate (MPH) treatment in boys diagnosed with ADHD is reported to decrease the risk of drug abuse in adulthood. Similarly, MPH treatment appears to decrease the cocaine preference of male rats during conditioned place preference (CPP) tests. However, the effects of MPH treatment on later drug use of girls/women or CPP in female rodents have not been fully examined, nor have a clinically-relevant MPH dose and/or administration route been thoroughly studied. Here, Sprague-Dawley rats (n=34/sex/treatment) were treated orally 3x/day on postnatal days (PNDs) 29-50 with water or 3mg MPH/kg, a dose producing serum levels within the human clinical range. CPP assessments to cocaine (10 mg/kg, ip) (PNDs 62-71) indicated MPH-treated rats were less active during pre- and postconditioning sessions (p<.04), but there were no significant MPH-related differences in conditioning strength. Baseline open field activity at PND 84 indicated that MPH-treated females were more active than same-sex controls (p<.05). A cocaine challenge (10 mg/kg, ip) elevated activity similarly in MPH-treated and controls of both sexes. As an anhedonia measure, saccharin solution intake on PNDs 87-90 indicated no significant MPH effects. Estrous cycle phase did not appear to affect cocaine response during CPP or open field assessments. Hormonal levels at PND 90 indicated 63% higher corticosterone levels in MPH-treated females relative to same-sex controls (p<.05), a finding that deserves further investigation. These results address some of the major issues surrounding animal models of MPH treatment and provide additional support for a lack of severe long-term behavioral effects of adolescent MPH.

  14. Methylprednisolone Protects Cardiac Pumping Mechanics from Deteriorating in Lipopolysaccharide-Treated Rats

    PubMed Central

    Ko, Ya-Hui; Tsai, Ming-Shian; Chang, Ru-Wen; Chang, Chun-Yi; Wang, Chih-Hsien; Wu, Ming-Shiou; Liang, Jin-Tung; Chang, Kuo-Chu

    2015-01-01

    It has been shown that a prolonged low-dose corticosteroid treatment attenuates the severity of inflammation and the intensity and duration of organ system failure. In the present study, we determined whether low-dose methylprednisolone (a synthetic glucocorticoid) can protect male Wistar rats against cardiac pumping defects caused by lipopolysaccharide-induced chronic inflammation. For the induction of chronic inflammation, a slow-release ALZET osmotic pump was subcutaneously implanted to infuse lipopolysaccharide (1 mg kg−1 d−1) for 2 weeks. The lipopolysaccharide-challenged rats were treated on a daily basis with intraperitoneal injection of methylprednisolone (5 mg kg−1 d−1) for 2 weeks. Under conditions of anesthesia and open chest, we recorded left ventricular (LV) pressure and ascending aortic flow signals to calculate the maximal systolic elastance (Emax) and the theoretical maximum flow (Qmax), using the elastance-resistance model. Physically, Emax reflects the contractility of the myocardium as an intact heart, whereas Qmax has an inverse relationship with the LV internal resistance. Compared with the sham rats, the cardiodynamic condition was characterized by a decline in Emax associated with the increased Qmax in the lipopolysaccharide-treated rats. Methylprednisolone therapy increased Emax, which suggests that the drug may have protected the contractile status from deteriorating in the inflamed heart. By contrast, methylprednisolone therapy considerably reduced Qmax, indicating that the drug may have normalized the LV internal resistance. In parallel, the benefits of methylprednisolone on the LV systolic pumping mechanics were associated with the reduced cardiac levels of negative inotropic molecules such as peroxynitrite, malondialdehyde, and high-mobility group box 1 protein. Based on these data, we suggested that low-dose methylprednisolone might prevent lipopolysaccharide-induced decline in cardiac intrinsic contractility and LV internal

  15. L-arginine prevents bone loss and bone collagen breakdown in cyclosporin A-treated rats.

    PubMed

    Fiore, C E; Pennisi, P; Cutuli, V M; Prato, A; Messina, R; Clementi, G

    2000-11-24

    Cyclosporin A is implicated in the pathogenesis of post-transplantation bone disease. Because of recent evidence that cyclosporin A may cause renal and cardiovascular toxicity by inhibiting nitric oxide (NO) activity, and that NO slows bone remodeling and bone loss in animal and human studies, we investigated a possible link between NO production and beneficial effects on bone health in cyclosporin A-treated rats. Thirty-six 10-week-old male rats were assigned to six groups of six animals each, and treated for 4 weeks with: vehicle; cyclosporin A; L-arginine; N(G)-nitro-L-arginine methylester (L-NAME, a general inhibitor of NO synthase activity); a combination of cyclosporin A+L-arginine; and a combination of cyclosporin A+L-NAME. Whole body and regional (spine and pelvis) bone mineral content of rats were measured under basal conditions and at the end of the treatment period by dual-energy X-ray absorptiometry (DXA) scanning. Femur weights and serum concentrations of pyridinoline, a reliable marker of bone resorption, were measured at the end of the study period. Cyclosporin A-, L-NAME-, and cyclosporin A+L-NAME-treated rats had significantly lower bone mineral content and femur weights, and significantly higher pyridinoline levels than did control animals. The administration of L-arginine appeared to prevent bone loss caused by cyclosporin A, suggesting that this amino acid, which can be converted to produce NO, might prove useful in preventing disturbed bone modeling and inhibition of bone growth associated with cyclosporin A therapy. PMID:11090650

  16. Drinking water with red beetroot food color antagonizes esophageal carcinogenesis in N-nitrosomethylbenzylamine-treated rats.

    PubMed

    Lechner, John F; Wang, Li-Shu; Rocha, Claudio M; Larue, Bethany; Henry, Cassandra; McIntyre, Colleen M; Riedl, Kenneth M; Schwartz, Steven J; Stoner, Gary D

    2010-06-01

    This study was undertaken to determine if the oral consumption of red beetroot food color would result in an inhibition of N-nitrosomethylbenzylamine (NMBA)-induced tumors in the rat esophagus. Rats were treated with NMBA and given either regular water ad libitum or water containing 78 microg/mL commercial red beetroot dye, E162. The number of NMBA-induced esophageal papillomas was reduced by 45% (P < .001) in animals that received the food color compared to controls. The treatment also resulted in reduced rates of cell proliferation in both precancerous esophageal lesions and in papillomas of NMBA-treated rats, as measured by immunohistochemical staining of Ki-67 in esophageal tissue specimens. The effects of beetroot food color on angiogenesis (microvessel density by CD34 immunostaining), inflammation (by CD45 immunostaining), and apoptosis (by terminal deoxynucleotidyl transferase dUTP nick end-labeling staining) in esophageal tissue specimens were also determined. Compared to rats treated with NMBA only, the levels of angiogenesis and inflammation in the beetroot color-consuming animals were reduced, and the apoptotic rate was increased. Thus, the mechanism(s) of chemoprevention by the active constituents of red beetroot color include reducing cell proliferation, angiogenesis, and inflammation and stimulating apoptosis. Importantly, consumption of the dye in the drinking water for a period of 35 weeks did not appear to induce any overt toxicity. Based on the fact that red beetroot color contains betanins, which have strong antioxidant activity, it is postulated that these effects are mediated through inhibition of oxygen radical-induced signal transduction. However, the sum of constituents of E162 has not been determined, and other components with other mechanisms may also be involved in antagonizing cancer development. PMID:20438319

  17. Drinking water with red beetroot food color antagonizes esophageal carcinogenesis in N-nitrosomethylbenzylamine-treated rats.

    PubMed

    Lechner, John F; Wang, Li-Shu; Rocha, Claudio M; Larue, Bethany; Henry, Cassandra; McIntyre, Colleen M; Riedl, Kenneth M; Schwartz, Steven J; Stoner, Gary D

    2010-06-01

    This study was undertaken to determine if the oral consumption of red beetroot food color would result in an inhibition of N-nitrosomethylbenzylamine (NMBA)-induced tumors in the rat esophagus. Rats were treated with NMBA and given either regular water ad libitum or water containing 78 microg/mL commercial red beetroot dye, E162. The number of NMBA-induced esophageal papillomas was reduced by 45% (P < .001) in animals that received the food color compared to controls. The treatment also resulted in reduced rates of cell proliferation in both precancerous esophageal lesions and in papillomas of NMBA-treated rats, as measured by immunohistochemical staining of Ki-67 in esophageal tissue specimens. The effects of beetroot food color on angiogenesis (microvessel density by CD34 immunostaining), inflammation (by CD45 immunostaining), and apoptosis (by terminal deoxynucleotidyl transferase dUTP nick end-labeling staining) in esophageal tissue specimens were also determined. Compared to rats treated with NMBA only, the levels of angiogenesis and inflammation in the beetroot color-consuming animals were reduced, and the apoptotic rate was increased. Thus, the mechanism(s) of chemoprevention by the active constituents of red beetroot color include reducing cell proliferation, angiogenesis, and inflammation and stimulating apoptosis. Importantly, consumption of the dye in the drinking water for a period of 35 weeks did not appear to induce any overt toxicity. Based on the fact that red beetroot color contains betanins, which have strong antioxidant activity, it is postulated that these effects are mediated through inhibition of oxygen radical-induced signal transduction. However, the sum of constituents of E162 has not been determined, and other components with other mechanisms may also be involved in antagonizing cancer development.

  18. Drinking Water with Red Beetroot Food Color Antagonizes Esophageal Carcinogenesis in N-Nitrosomethylbenzylamine-Treated Rats

    PubMed Central

    Lechner, John F.; Wang, Li-Shu; Rocha, Claudio M.; Larue, Bethany; Henry, Cassandra; McIntyre, Colleen M.; Riedl, Kenneth M.; Schwartz, Steven J.

    2010-01-01

    Abstract This study was undertaken to determine if the oral consumption of red beetroot food color would result in an inhibition of N-nitrosomethylbenzylamine (NMBA)-induced tumors in the rat esophagus. Rats were treated with NMBA and given either regular water ad libitum or water containing 78 μg/mL commercial red beetroot dye, E162. The number of NMBA-induced esophageal papillomas was reduced by 45% (P < .001) in animals that received the food color compared to controls. The treatment also resulted in reduced rates of cell proliferation in both precancerous esophageal lesions and in papillomas of NMBA-treated rats, as measured by immunohistochemical staining of Ki-67 in esophageal tissue specimens. The effects of beetroot food color on angiogenesis (microvessel density by CD34 immunostaining), inflammation (by CD45 immunostaining), and apoptosis (by terminal deoxynucleotidyl transferase dUTP nick end-labeling staining) in esophageal tissue specimens were also determined. Compared to rats treated with NMBA only, the levels of angiogenesis and inflammation in the beetroot color-consuming animals were reduced, and the apoptotic rate was increased. Thus, the mechanism(s) of chemoprevention by the active constituents of red beetroot color include reducing cell proliferation, angiogenesis, and inflammation and stimulating apoptosis. Importantly, consumption of the dye in the drinking water for a period of 35 weeks did not appear to induce any overt toxicity. Based on the fact that red beetroot color contains betanins, which have strong antioxidant activity, it is postulated that these effects are mediated through inhibition of oxygen radical-induced signal transduction. However, the sum of constituents of E162 has not been determined, and other components with other mechanisms may also be involved in antagonizing cancer development. PMID:20438319

  19. Ultra structural study of the rat cheek epithelium treated with Neem extract.

    PubMed

    Azmi, Muhammad Arshad; Khatoon, Nasira; Ghaffar, Rizwana Abdul

    2015-11-01

    The purpose of this study was to investigate the effects of neem extract (Azadirachta indica A. Juss) on the ultrastructure of the rat oral epithelium, because neem extract has been added in the tooth paste as an anti-plaque-forming substance in Asian countries. The non-toxic dose of 2000 mg/kg body weight of Neem extract (NBE) was applied daily to the surface of buccal epithelium for four weeks and controls did not receive Neem extract. After four weeks cheek epithelial tissues were excised and processed for light microscopy, scanning and transmission electron microscopy. Light microscopy did not show significant differences between NBE-treated and control epithelium. Difference between control and treated rats weight was non-significant. Moreover, time period was also non-significant. Irregular cell surfaces were noticed when compared to control specimens when examined by scanning electron microscopy. Under transmission electron microscopy, wider intercellular spaces were observed in the treated epithelial spinous cellular layers when compared to control. Further, more keratohyalin granules were present in experimental granular cells. It was concluded that present study showed differences between Neem-treated and control in epithelial tissues but these structural differences may not be related to adverse side effects of the Neem extract.

  20. Expression of Folate Pathway Genes in Stage III Colorectal Cancer Correlates with Recurrence Status Following Adjuvant Bolus 5-FU-Based Chemotherapy.

    PubMed

    Odin, Elisabeth; Sondén, Arvid; Gustavsson, Bengt; Carlsson, Göran; Wettergren, Yvonne

    2015-01-01

    Colorectal cancer is commonly treated with 5-fluorouracil and 5-formyltetrahydrofolate (leucovorin). Metabolic action of leucovorin requires several enzymatic steps that are dependent on expression of corresponding coding genes. To identify folate pathway genes with possible impact on leucovorin metabolism, a retrospective study was performed on 193 patients with stage III colorectal cancer. Relative expression of 22 genes putatively involved in leucovorin transport, polyglutamation and metabolism was determined in tumor and mucosa samples using quantitative real-time polymerase chain reaction. After surgery, patients received adjuvant 5-fluorouracil-based bolus chemotherapy with leucovorin during six months, and were followed for 3 to 5 years. Cox regression analysis showed that high tumoral expression of the genes SLC46A1/PCFT (proton-coupled folate transporter) and SLC19A1/RFC-1 (reduced folate carrier 1) correlated significantly (p < 0.001 and p < 0.01, respectively) with a decreased risk of recurrent disease, measured as disease-free survival (DFS). These two genes are involved in the transport of folates into the cells and each functions optimally at a different pH. We conclude that SLC46A1/PCFT and SLC19A1/RFC-1 are associated with DFS of patients with colorectal cancer and hypothesize that poor response to 5-fluorouracil plus leucovorin therapy in some patients may be linked to low expression of these genes. Such patients might need a more intensified therapeutic approach than those with high gene expression. Future prospective studies will determine if the expression of any of these genes can be used to predict response to leucovorin. PMID:26193446

  1. Gene expression analyses of the liver in rats treated with oxfendazole.

    PubMed

    Dewa, Yasuaki; Nishimura, Jihei; Muguruma, Masako; Matsumoto, Sayaka; Takahashi, Miwa; Jin, Meilan; Mitsumori, Kunitoshi

    2007-09-01

    The effect of oxfendazole (OX), a benzimidazole anthelmintic, on hepatic gene expression was investigated in the liver of rats as a preliminary study to elucidate the possible mechanism of its non-genotoxic hepatocarcinogenesis. The liver from a male F344/N rat given a diet containing 500 ppm of OX for 3 weeks was examined by global gene expression analysis in comparison with an untreated rat. Microarray analysis revealed that phase I and phase II detoxifying enzymes were up-regulated in an OX-treated rat. In addition to these genes, the expressions of several upregulated genes related to xenobiotic metabolism and oxidative stress [e.g. Cyp1a1; NAD(P)H dehydrogenase, quinone 1 (Nqo1); glutathione peroxidase 2 (Gpx2); glutathione S-transferase Yc2 subunit (Yc2)], were confirmed by real-time reverse transcription polymerase chain reaction (RT-PCR). Furthermore, rats were administered 500 or 1,000 ppm of OX for 9 weeks, and the effect of OX on oxidative stress responses was evaluated by real-time RT-PCR along with conventional toxicological assays, including lipid peroxidation (thiobarbituric acid-reactive substance; TBARS). A longer treatment period and/or a higher dose of OX tended to increase the gene expressions of not only phase I (Cyp1a1 and Cyp1a2) but also phase II (Nqo1, Gpx2, Yc2, and Akr7a3) drug metabolizing enzymes. Toxicological parameters, such as TBARS, serum aspartate aminotransferase (AST), and serum alkaline phosphatase (ALP), showed slight but significant increases after treatment with OX for 9 weeks. These results indicate that OX elicits adaptive responses against oxidative stress in the liver and suggest that the imbalance in redox status might be one of the factors triggering the initial step of OX-induced non-genotoxic carcinogenesis in the liver of rats.

  2. Dietary guar gum alters colonic microbial fermentation in azoxymethane-treated rats.

    PubMed

    Weaver, G A; Tangel, C; Krause, J A; Alpern, H D; Jenkins, P L; Parfitt, M M; Stragand, J J

    1996-08-01

    To assess the effects of guar gum on colonic microbial fermentation and cancer development, azoxymethane-treated rats were fed a partially hydrolyzed guar or control diet. Anaerobic fecal incubations were conducted at 8-wk intervals, either without added substrate or with cornstarch or hydrolyzed guar as substrates. Short-chain fatty acids in colonic contents and colonic carcinoma areas were measured at 27 wk. Fecal in vitro fermentation rates were higher for guar-fed rats than for control rats [three-way ANOVA (diet, time, in vitro substrates), P = 0.002]. Fecal in vitro butyrate production was greater for guar-fed rats than for control rats after 3-11 weeks of diet treatment (three-way ANOVA, P = 0.027). Butyrate concentrations of colonic contents at 27 wk were higher in guar-fed than in control rats and higher in the cecum than in the post-cecal colon (two-way ANOVA, P = 0.0001). A regression equation predicting colonic carcinoma area (r2 = 0.279) using propionate and butyrate concentrations of the contents of the post-cecal colon showed propionate as a positive predictor (P < 0.001) and butyrate as a negative predictor (P = 0.033). Our results show that patterns of short-chain fatty acid production may affect the results of fiber-carcinogenesis experiments. Dietary addition of hydrolyzed guar is associated with fecal fermentation low in propionate and high in butyrate; short-chain fatty acid concentrations are greater proximally than distally. These results suggest that butyrate protects against colonic neoplasia, whereas propionate enhances it, and demonstrate that colonic microbiota adapt to produce more butyrate if given time and the proper substrate.

  3. The influence of zinc on the blood serum of cadmium-treated rats through the rheological properties.

    PubMed

    Moussa, Sherif Aa; Alaamer, Abdulaziz; Abdelhalim, Mohamed A K

    2016-01-01

    The blood rheological properties serve as an important indicator for the early detection of many diseases. This study aimed to investigate the influence of zinc (Zn) on blood serum of cadmium (Cd) intoxication-treated male rats through the rheological properties. The rheological parameters were measured in serum of control, Cd, and Cd+Zn groups at wide range of shear rates (225-1875 s(-1)). The rat blood serum showed a non-significant change in cadmium-treated rats' %torque and shear stress at the lower shear rates (200-600 s(-1)) while a significant increase was observed at the higher shear rates (650-1875 s(-1)) compared with the control. The rat blood serum viscosity increased significantly in the Cd-treated group at each shear rate compared with the control. The viscosity and shear rate exhibited a non-Newtonian behavior for all groups. The increase in blood serum viscosity in Cd-treated male rats might be attributed to destruction or changes in the non-clotting proteins, and other blood serum components. In Cd+Zn-treated rats, the rat blood serum viscosity values returned nearer to the control values at each shear rate. Our results confirmed that Zn displaced Cd or compete with the binding sites for Cd uptake.

  4. Immunohistochemical profile of some neurotransmitters and neurotrophins in the seminiferous tubules of rats treated by lonidamine.

    PubMed

    Artico, M; Bronzetti, E; Saso, L; Felici, L M; D'Ambrosio, A; Forte, F; Grande, C; Ortolani, F

    2007-01-01

    Lonidamine (LND) or [1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid] is an anticancer and antispermatogenic drug that exerts a large number of effects on tumor cells and germ cells. Sexually mature male Sprague-Dawley rats were housed at 22 degrees C on a 12-h light/12-h dark cycle 1 week before the experiments, with free access to food and water. LND was suspended in 0.5% methylcellulose at a concentration of 10 mg/mL and administered orally at the dose of 10 mL/kg (b.w.) as a single dose. Control rats received an equal amount of vehicle. Testes were removed, fixed for 24 h in 2% glutaraldehyde and 2% paraformaldehyde in 0.1 M sodium phosphate (pH 7.2 at 22 degrees C), rinsed with the same buffer, and stored at room temperature. From each sample, a block of tissue was removed by sectioning through the organ. After dehydration in ethanol at increasing concentrations (70-100%), each block was embedded in paraffin and serial 5 mm thick sections were cut using a rotatory microtome. The immunoreactivity for NTs has been observed in spermatogonia of untreated rats, while the rats treated with LND showed an immunohistochemical localization in all the stages of germinal cells. The generally well-expressed immunoreactivity for the neurotrophins receptors in treated rats observed in our study is presumably attributable to alterations of the receptors' structure and/or expression leading to changes of the activity, affinity, localization or protein interactions that may depend on sensitization of ion channels (induced by LND). Neurotrophins (NTs) appear to be interesting proteins for the modulation of sperm maturation and motility with a prominent role for the nerve growth factor (NGF), that may exert an autocrine or paracrine role. We therefore investigated the location and distribution of immunoreactivity for some neurotransmitters (SP, VIP, CGRP, nNOS, Chat), neurotrophins (NGF, BDNF, NT-3) and their own receptors (TrKA, TrKB, TrKC, p75) in the seminiferous tubules

  5. Urinary Aminopeptidase Activities as Early and Predictive Biomarkers of Renal Dysfunction in Cisplatin-Treated Rats

    PubMed Central

    Quesada, Andrés; Vargas, Félix; Montoro-Molina, Sebastián; O'Valle, Francisco; Rodríguez-Martínez, María Dolores; Osuna, Antonio; Prieto, Isabel; Ramírez, Manuel; Wangensteen, Rosemary

    2012-01-01

    This study analyzes the fluorimetric determination of alanyl- (Ala), glutamyl- (Glu), leucyl-cystinyl- (Cys) and aspartyl-aminopeptidase (AspAp) urinary enzymatic activities as early and predictive biomarkers of renal dysfunction in cisplatin-treated rats. Male Wistar rats (n = 8 each group) received a single subcutaneous injection of either saline or cisplatin 3.5 or 7 mg/kg, and urine samples were taken at 0, 1, 2, 3 and 14 days after treatment. In urine samples we determined Ala, Glu, Cys and AspAp activities, proteinuria, N-acetyl-β-D-glucosaminidase (NAG), albumin, and neutrophil gelatinase-associated lipocalin (NGAL). Plasma creatinine, creatinine clearance and renal morphological variables were measured at the end of the experiment. CysAp, NAG and albumin were increased 48 hours after treatment in the cisplatin 3.5 mg/kg treated group. At 24 hours, all urinary aminopeptidase activities and albuminuria were significantly increased in the cisplatin 7 mg/kg treated group. Aminopeptidase urinary activities correlated (p<0.011; r2>0.259) with plasma creatinine, creatinine clearance and/or kidney weight/body weight ratio at the end of the experiment and they could be considered as predictive biomarkers of renal injury severity. ROC-AUC analysis was made to study their sensitivity and specificity to distinguish between treated and untreated rats at day 1. All aminopeptidase activities showed an AUC>0.633. We conclude that Ala, Cys, Glu and AspAp enzymatic activities are early and predictive urinary biomarkers of the renal dysfunction induced by cisplatin. These determinations can be very useful in the prognostic and diagnostic of renal dysfunction in preclinical research and clinical practice. PMID:22792302

  6. Improved metabolic status and insulin sensitivity in obese fatty (fa/fa) Zucker rats and Zucker Diabetic Fatty (ZDF) rats treated with the thiazolidinedione, MCC-555

    PubMed Central

    Upton, R; Widdowson, P S; Ishii, S; Tanaka, H; Williams, G

    1998-01-01

    We examined the effect of chronic (21 days) oral treatment with the thiazolidinedione, MCC-555 ((±)-5-[{6-(2-fluorbenzyl)-oxy-2-naphy}methyl]-2,4-thiazolidinedione) on metabolic status and insulin sensitivity in obese (fa/fa) Zucker rats and Zucker Diabetic Fatty (ZDF) rats which display an impaired glucose tolerance (IGT) or overt diabetic symptoms, respectively.MCC-555 treatment to obese Zucker rats (10 and 30 mg kg−1) and diabetic ZDF rats (10 mg kg−1) reduced non-esterified fatty acid concentrations in both rat strains and reduced plasma glucose and triglyceride concentrations in the obese Zucker rats. Liver glycogen concentrations were significantly increased by chronic MCC-555 treatment in both obese Zucker rats (30 mg kg−1 day−1) and diabetic ZDF rats (10 mg kg−1 day−1), as compared with vehicle-treated lean and obese rats and there was a significant increase in hepatic glycogen synthase activity in MCC-555-treated diabetic ZDF rats as compared to vehicle-treated controls.During a euglycaemic hyperinsulinaemic clamp, MCC-555-treated obese Zucker rats and diabetic ZDF rats required significantly higher glucose infusion rates to maintain stable glucose concentrations (2.01±0.19 mg min−1 and 6.42±1.03 mg min−1, respectively) than vehicle-treated obese controls (0.71±0.17 mg min−1 and 2.09±0.71 mg min−1; P<0.05), demonstrating improved insulin sensitivity in both Zucker and ZDF rats. MCC-555 treatment also enhanced insulin-induced suppression of hepatic glucose production in ZDF rats as measured using infusions of [6-3H]-glucose under clamp conditions.In conclusion, we have demonstrated that MCC-555 improves metabolic status and insulin sensitivity in obese Zucker and diabetic ZDF rats. MCC-555 may prove a useful compound for alleviating the metabolic disturbances and IGT associated with insulin resistance in man. PMID:9886762

  7. Identification of differentially expressed genes in aflatoxin B1-treated cultured primary rat hepatocytes and Fischer 344 rats.

    PubMed

    Harris, A J; Shaddock, J G; Manjanatha, M G; Lisenbey, J A; Casciano, D A

    1998-08-01

    Aflatoxin B1 (AFB1), a mutagen and hepatocarcinogen in rats and humans, is a contaminant of the human food supply, particularly in parts of Africa and Asia. AFB1-induced changes in gene expression may play a part in the development of the toxic, immunosuppressive and carcinogenic properties of this fungal metabolite. An understanding of the-role of AFB1 in modulating gene regulation should provide insight regarding mechanisms of AFB1-induced carcinogenesis. We used three PCR-based subtractive techniques to identify AFB1-responsive genes in cultured primary rat hepatocyte RNA: differential display PCR (DD-PCR), representational difference analysis (RDA) and suppression subtractive hybridization (SSH). Each of the three techniques identified AFB1-responsive genes, although no individual cDNA was isolated by more than one technique. Nine cDNAs isolated using DD-PCR, RDA or SSH were found to represent eight genes that are differentially expressed as a result of AFB1 exposure. Genes whose mRNA levels were increased in cultured primary rat hepatocytes after AFB1 treatment were corticosteroid binding globulin (CBG), cytochrome P450 4F1 (CYP4F1), alpha-2 microglobulin, C4b-binding protein (C4BP), serum amyloid A-2 and glutathione S-transferase Yb2 (GST). Transferrin and a small CYP3A-like cDNA had reduced mRNA levels after AFB1 exposure. Full-length CYP3A mRNA levels were increased. When liver RNA from AFB1-treated male F344 rats was evaluated for transferrin, CBG, GST, CYP3A and CYP4F1 expression, a decrease in transferrin mRNA and an increase in CBG, GST, CYP3A and CYP4F1 mRNA levels was also seen. Analysis of the potential function of these genes in maintaining cellular homeostasis suggests that their differential expression could contribute to the toxicity associated with AFB1 exposure.

  8. Neuroprotective effects of zinc on antioxidant defense system in lithium treated rat brain.

    PubMed

    Bhalla, Punita; Chadha, Vijayta Dani; Dhar, Rakesh; Dhawan, D K

    2007-11-01

    With a view to find out whether zinc affords protection against lithium toxicity the activities of antioxidant enzymes and lipid peroxidation profile were determined in the cerebrum and cerebellum of lithium treated female Sprague Dawley rats. Lipid peroxidation was significantly increased in both the cerebrum and the cerebellum of animals administered with lithium for a total duration of 4 months as compared to the normal control group. On the contrary, the activities of catalase and glutathione-s-transferase (GST) were significantly reduced after 4 months of lithium treatment. The activity of superoxide dismutase (SOD) was significantly increased in the cerebrum after 4 months lithium administration, whereas in the cerebellum the enzyme activity was unaffected. No significant change in the levels of reduced glutathione (GSH) was found in either cerebrum or cerebellum after 2 months of lithium treatment. However, 4 months lithium treatment did produce significant changes in GSH levels in the cerebrum and in the cerebellum. Zinc supplementation for 4 months in lithium-treated rats significantly increased the activities of catalase and GST in the cerebellum, showing that the treatment with zinc reversed the lithium induced depression in these enzyme activities. Though, zinc treatment tended to normalize the SOD activity in the cerebrum yet it was still significantly higher in comparison to normal levels. From the present study, it can be concluded that the antiperoxidative property of zinc is effective in reversing the oxidative stress induced by lithium toxicity in the rat brain.

  9. Immunohistochemical expression of ghrelin in capsaicin-treated rat ovaries during the different developmental periods.

    PubMed

    Tütüncü, Ş; İlhan, T; Özfiliz, N

    2016-01-01

    Red hot pepper is a plant that belongs to the Solanaceae family and is known as Capsicum annuum. Capsaicin is the active ingredient of cayenne pepper. Ghrelin is a hormone, which consists of polypeptide structure. Ghrelin also contributes to growth hormone secretion, energy balance, food intake and body weight regulator. The aim of this study was the localization and expression of ghrelin in the ovaries of rats treated with capsaicin during the postnatal development. Ninety female Sprague-Dawley rats (21 d) were used. The rats were randomly divided into 3 groups (n=30 each) as pubertal, post pubertal and adult. Each group was subdivided into three groups. The first subgroup (control) was given no injections. The second subgroup (vehicle) received only 0.3 cc solvent and the third subgroup (experiment) received subcutaneous injection of equal volume of capsaicin (1 mg/kg/d) for 42, 56, and 70 days. Ghrelin immunoreactivity was determined in ovarian follicular granulosa cells, interstitial cells and corpus luteal cells. A ghrelin immunopositive reaction located in the cytoplasm of cells in all groups. These results indicate that prolonged administration of low dose capsaicin does not affect ghrelin expression. However, follicular atresia was seen in lower rate in capsaicin treated group in comparison to other groups. PMID:27656230

  10. Immunohistochemical expression of ghrelin in capsaicin-treated rat ovaries during the different developmental periods

    PubMed Central

    Tütüncü, Ş.; İlhan, T.; Özfiliz, N.

    2016-01-01

    Red hot pepper is a plant that belongs to the Solanaceae family and is known as Capsicum annuum. Capsaicin is the active ingredient of cayenne pepper. Ghrelin is a hormone, which consists of polypeptide structure. Ghrelin also contributes to growth hormone secretion, energy balance, food intake and body weight regulator. The aim of this study was the localization and expression of ghrelin in the ovaries of rats treated with capsaicin during the postnatal development. Ninety female Sprague-Dawley rats (21 d) were used. The rats were randomly divided into 3 groups (n=30 each) as pubertal, post pubertal and adult. Each group was subdivided into three groups. The first subgroup (control) was given no injections. The second subgroup (vehicle) received only 0.3 cc solvent and the third subgroup (experiment) received subcutaneous injection of equal volume of capsaicin (1 mg/kg/d) for 42, 56, and 70 days. Ghrelin immunoreactivity was determined in ovarian follicular granulosa cells, interstitial cells and corpus luteal cells. A ghrelin immunopositive reaction located in the cytoplasm of cells in all groups. These results indicate that prolonged administration of low dose capsaicin does not affect ghrelin expression. However, follicular atresia was seen in lower rate in capsaicin treated group in comparison to other groups. PMID:27656230

  11. Efficacy of curcumin to reduce hepatic damage induced by alcohol and thermally treated oil in rats.

    PubMed

    El-Deen, Nasr A M N; Eid, Mohamed

    2010-01-01

    The authors investigated the effect of curcumin on markers of oxidative stress and liver damage in rats that chronically ingested alcohol and heated oil. Nine groups of ten Wistar male rats received combinations of curcumin 100 mg/kg body weight daily, ethanol 5 mg/kg, 15% dietary sunflower oil and 15% heated sunflower oil for 12 weeks. Serum and liver tissue were collected. Groups 4-6, which had received compounds causing oxidative stress, showed increased serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, cholesterol, triglycerides, low density lipoprotein, very low density lipoprotein and reduced high density lipoprotein, protein and albumin, compared with the controls. Reductions were observed in glutathione peroxidase and reductase gene expression, superoxide dismutase activity, glutathione peroxidase activity, glutathione reductase activity, reduced glutathione concentration and catalase enzyme activity. Groups 7, 8 and 9 which received curcumin with heated oil, ethanol or both, showed lower elevations in serum and oxidative damage markers compared with the corresponding non-curcumin treated groups. It can be concluded that curcumin reduces markers of liver damage in rats treated with heated sunflower oil or ethanol.

  12. Gene expression profiles of hepatocytes treated with La (NO3) 3 of rare earth in rats

    PubMed Central

    Zhao, Hui; Hao, Wei-Dong; Xu, Hou-En; Shang, Lan-Qin; Lu, You-Yong

    2004-01-01

    AIM: To compare the gene expression between La (NO3) 3-exposed and control rats in vivo. METHODS: Rats were fed La (NO3) 3 once daily at a dose of 20 mg/kg for one month by gavage. Gene expression of hepatocytes was detected using mRNA differential display (DD) technique and cDNA microarray and compared between treated and control groups. RESULTS: Six differentially expressed sequence tags were cloned by DD, of which five were up regulated and one was down regulated in treated rats. Two sequences were determined. One band was novel. The other shared 100% sequence homology with AU080263 Sugano mouse brain mncb Mus musculus cDNA clone MNCb-5435 5’. With DNA microarray, 136 differentially expressed genes were identified including 131 over-expressed genes and 5 under-expressed genes. Most of these differentially expressed genes were cell signal and transmission genes, genes associated with metabolism, protein translation and synthesis. CONCLUSION: La (NO3) 3 could change the expression levels of some kinds of genes. Further analysis of the differentially expressed genes would be helpful for understanding the wide biological effect spectrum of rare earth elements. PMID:15162537

  13. Immunohistochemical expression of ghrelin in capsaicin-treated rat ovaries during the different developmental periods.

    PubMed

    Tütüncü, Ş; İlhan, T; Özfiliz, N

    2016-01-01

    Red hot pepper is a plant that belongs to the Solanaceae family and is known as Capsicum annuum. Capsaicin is the active ingredient of cayenne pepper. Ghrelin is a hormone, which consists of polypeptide structure. Ghrelin also contributes to growth hormone secretion, energy balance, food intake and body weight regulator. The aim of this study was the localization and expression of ghrelin in the ovaries of rats treated with capsaicin during the postnatal development. Ninety female Sprague-Dawley rats (21 d) were used. The rats were randomly divided into 3 groups (n=30 each) as pubertal, post pubertal and adult. Each group was subdivided into three groups. The first subgroup (control) was given no injections. The second subgroup (vehicle) received only 0.3 cc solvent and the third subgroup (experiment) received subcutaneous injection of equal volume of capsaicin (1 mg/kg/d) for 42, 56, and 70 days. Ghrelin immunoreactivity was determined in ovarian follicular granulosa cells, interstitial cells and corpus luteal cells. A ghrelin immunopositive reaction located in the cytoplasm of cells in all groups. These results indicate that prolonged administration of low dose capsaicin does not affect ghrelin expression. However, follicular atresia was seen in lower rate in capsaicin treated group in comparison to other groups.

  14. Immunohistochemical expression of ghrelin in capsaicin-treated rat ovaries during the different developmental periods

    PubMed Central

    Tütüncü, Ş.; İlhan, T.; Özfiliz, N.

    2016-01-01

    Red hot pepper is a plant that belongs to the Solanaceae family and is known as Capsicum annuum. Capsaicin is the active ingredient of cayenne pepper. Ghrelin is a hormone, which consists of polypeptide structure. Ghrelin also contributes to growth hormone secretion, energy balance, food intake and body weight regulator. The aim of this study was the localization and expression of ghrelin in the ovaries of rats treated with capsaicin during the postnatal development. Ninety female Sprague-Dawley rats (21 d) were used. The rats were randomly divided into 3 groups (n=30 each) as pubertal, post pubertal and adult. Each group was subdivided into three groups. The first subgroup (control) was given no injections. The second subgroup (vehicle) received only 0.3 cc solvent and the third subgroup (experiment) received subcutaneous injection of equal volume of capsaicin (1 mg/kg/d) for 42, 56, and 70 days. Ghrelin immunoreactivity was determined in ovarian follicular granulosa cells, interstitial cells and corpus luteal cells. A ghrelin immunopositive reaction located in the cytoplasm of cells in all groups. These results indicate that prolonged administration of low dose capsaicin does not affect ghrelin expression. However, follicular atresia was seen in lower rate in capsaicin treated group in comparison to other groups.

  15. Acetylcholine content in the brain of rats treated with paraoxon and obidoxime

    PubMed Central

    Milošević, M. P.

    1970-01-01

    1. The effect of obidoxime on the rise in brain acetylcholine caused by the anticholinesterase paraoxon was studied in the rat. 2. In animals poisoned with a sublethal dose of paraoxon and thereafter treated with obidoxime the levels of both “free” and total brain acetylcholine were practically the same as those in rats injected with paraoxon only. 3. After poisoning with doses of paraoxon which are lethal unless an oxime is also given, the total acetylcholine in the brain of obidoxime-protected rats continued to accumulate, reaching a peak 2 h after injection of paraoxon. At this time no signs of central effects such as convulsions or tremor were seen. 4. Atropine, given 30 min before paraoxon, markedly reduced the rise in total brain acetylcholine seen when the anticholinesterase is given alone. 5. In rats pretreated with atropine and obidoxime excessive doses of paraoxon which are lethal in the absence of the antidotes produced a rise in total brain acetylcholine which was directly proportional to the dose of paraoxon administered. PMID:5485148

  16. Analysis of proteome changes in doxorubicin-treated adult rat cardiomyocyte

    PubMed Central

    Kumar, Suresh N.; Konorev, Eugene A.; Aggarwal, Deepika; Kalyanaraman, Balaraman

    2011-01-01

    Doxorubicin-induced cardiomyopathy in cancer patients is well established. The proposed mechanism of cardiac damage includes generation of reactive oxygen species, mitochondrial dysfunction and cardiomyocyte apoptosis. Exposure of adult rat cardiomyocytes to low levels of DOX for 48 h induced apoptosis. Analysis of protein expression showed a differential regulation of several key proteins including the voltage dependent anion selective channel protein 2 and methylmalonate semialdehyde dehydrogenase. In comparison, proteomic evaluation of DOX-treated rat heart showed a slightly different set of protein changes that suggests nuclear accumulation of DOX. Using a new solubilization technique, changes in low abundant protein profiles were monitored. Altered protein expression, modification and function related to oxidative stress response may play an important role in DOX cardiotoxicity. PMID:21338723

  17. The concentration and biosynthesis of nicotinamide nucleotides in the livers of rats treated with carcinogens

    PubMed Central

    Clark, J. B.; Greenbaum, A. L.; McLean, Patricia

    1966-01-01

    1. The oxidoreduction state and concentration of both NAD and NADP as well as the maximum potential activities of NMN adenylyltransferase and NAD+ kinase have been measured in the livers of rats treated for 14–28 days with 4-dimethylamino-3′-methylazobenzene, 4-dimethylamino-4′-fluoroazobenzene, α-naphthyl isothiocyanate or ethionine and in primary hepatomas induced by 4-dimethylamino-3′-methylazobenzene. 2. The total NAD and total NADP both decreased in the livers of rats treated with either azo-dyes or α-naphthyl isothiocyanate but not in those treated with ethionine. The activities of NMN adenylyltransferase and NAD+ kinase did not alter appreciably after such treatments. 3. In the primary hepatomas the concentrations of both NAD and NADP fell drastically and the activities of NMN adenylyltransferase and NAD+ kinase fell to about 50% of the control activities. 4. No correlation could be established between the concentrations of the nucleotides and the activities of the enzymes synthesizing them. It appears, however, that a relationship exists between the NAD content of the tissue and the amount of NADP present. 5. The results are discussed with respect to the control of NAD and NADP synthesis by ATP. At the concentrations of NAD normally present in the cell it is suggested that NAD may be a rate-limiting substrate in NADP synthesis. PMID:4380162

  18. Plasma levels of corticosterone and testosterone after sexual activity in male rats treated neonatally with clomipramine.

    PubMed

    Bonilla-Jaime, H; Retana-Márquez, S; Vazquez-Palacios, G; Velázquez-Moctezuma, J

    2003-07-01

    Neonatal treatment with clomipramine (CMI) in rats, induces alterations of pleasure-seeking behaviors during adulthood. Alterations of hormonal responses to stressful situations have also been reported. In this study, the levels of corticosterone and testosterone in response to sexual activity were assessed in rats treated neonatally with CMI. Male pups received subcutaneous injections of CMI (15 mg/kg, 0.1 ml), twice a day (09.00 hours and 18.00 hours) from 8 to 21 days of age. A control group received saline in the same number of injections. Four months after CMI treatment, subjects (Ss) were submitted to the forced swim test to verify the effect of CMI. Thereafter, they were tested to assess their spontaneous sexual activity. Plasma levels of corticosterone and testosterone were assessed under different conditions. Results of sexual behavior and the forced swim test corroborate the depressive-like effect of CMI. The sole presence of an estrogenized stimulus female caused an increase in plasma levels of testosterone in both control and CMI-treated Ss. The same was true for corticosterone; however, this increase was significantly lower in the CMI-treated group. There is a discrepancy between the normal hypothalamus-pituitary-gonadal (HPG) response and the decreased sexual behavior. The data suggest that CMI induces permanent changes in the reactivity of the hypothalamic-pituitary-adrenal axis.

  19. Butyrate delivered by butyrylated starch increases distal colonic epithelial apoptosis in carcinogen-treated rats.

    PubMed

    Clarke, Julie M; Young, Graeme P; Topping, David L; Bird, Anthony R; Cobiac, Lynne; Scherer, Benjamin L; Winkler, Jessica G; Lockett, Trevor J

    2012-01-01

    Animal studies show that increasing large bowel butyrate concentration through ingestion of butyrylated or resistant starches opposes carcinogen-induced tumorigenesis, which is consistent with population data linking greater fiber consumption with lowered colorectal cancer (CRC) risk. Butyrate has been shown to regulate the apoptotic response to DNA damage. This study examined the impact of increasing large bowel butyrate concentration by dietary butyrylated starch on the colonic epithelium of rats treated with the genotoxic carcinogen azoxymethane (AOM). Four groups of 10 male rats were fed AIN-93G based-diets containing either low amylose maize starch (LAMS), LAMS with 3% tributyrin, 10% high amylose maize starch (HAMS) or 10% butyrylated HAMS (HAMSB). HAMS and HAMSB starches were cooked by heating in water. After 4 weeks, rats were injected once with AOM and killed 6 h later. Rates of apoptosis and proliferation were measured in colonic epithelium. Short-chain fatty acid concentrations in large bowel digesta and hepatic portal venous plasma were higher in HAMSB than all other groups. Apoptotic rates in the distal colon were increased by HAMSB and correlated with luminal butyrate concentrations but cellular proliferation rates were unaffected by diet. The increase in apoptosis was most marked in the base and proliferative zone of the crypt. Regulation of luminal butyrate using HAMSB increases the rates of apoptotic deletion of DNA-damaged colonocytes. We propose this pro-apoptotic function of butyrate plays a major role reducing tumour formation in the AOM-treated rat and that these data support a potential protective role of butyrate in CRC.

  20. Comparison of hemihypoglossal- and accessory-facial neurorrhaphy for treating facial paralysis in rats.

    PubMed

    Li, Dezhi; Wan, Hong; Feng, Jie; Wang, Shiwei; Su, Diya; Hao, Shuyu; Schumacher, Michael; Liu, Song

    2014-12-15

    The aim of this study was to determine the effectiveness of hypoglossal-facial nerve "side"-to-end (HemiHN-FN) and accessory-facial nerve end-to-end (AN-FN) neurorrhaphy using a predegenerated nerve graft (PNG) for reanimating facial paralysis in a rat FN injury model. A total of 25 rats with complete unilateral facial paralysis resulting from section of the right FN were divided into 5 groups (n=5 each) that were submitted to immediate, delayed (3 months after FN injury) or no (control) FN reconstruction procedures involving HemiHN-FN or AN-FN neurorrhaphy. Approximately 3 months after FN reconstruction, cholera toxin subunit B conjugate Alexa 555 (CTB-Alexa 555) was injected into the ipsilateral whisker pad muscle and CTB-Alexa 555-labeled neurons were observed in the hypoglossal or accessory nuclei of all the FN reconstruction rats, but none of these neurons were found in the controls. There were numerous myelinated and nonmyelinated axons in both PNG and repaired FN of the FN reconstruction rats. No differences were found for these numbers between the two neurorrhaphy methods for each of the treatment time points, indicating the equal effectiveness of axon regeneration. However, a significantly higher number of CTB-Alexa 555-labeled neurons was observed in the hypoglossal nucleus of the immediate HemiHN-FN neurorrhaphy-treated rats when compared to that in the accessory nucleus of the immediate AN-FN neurorrhaphy-treated rats, consistent with the surface values of the recorded MAPs at the whisker pad muscle while electro-stimulating the FN. These results suggest that HemiHN-FN neurorrhaphy produces more efficient innervation of the paralyzed facial muscles than AN-FN neurorrhaphy without sacrificing ipsilateral hypoglossal function. Taking into consideration the clinical relevance of these findings for postoperative complications and functional reanimation in relation to the central plasticity, we suggest that HemiHN-FN neurorrhaphy may be the preferable facial

  1. Lipid Profile and Electrolyte Composition in Diabetic Rats Treated With Leaf Extract of Musa sapientum.

    PubMed

    Adewoye, E O; Ige, A O

    2016-01-01

    Diabetes mellitus affects lipid levels resulting in diabetic dyslipidemia as well as electrolyte loss from the body. Musa sapientum has been reported to possess antidiabetic properties. This study assessed the lipid profile and electrolyte composition in alloxan-induced diabetic rats treated with methanol leaf extract of M. sapientum (cMEMSL). Diabetes was induced with alloxan (120 mg/kg i.p.). Seventy-five male albino rats were divided into 5 groups of 15 rats each. Group 1 was control; groups 2-5 were made diabetic and treated with 0.2 ml 0.9% NaCl, cMEMSL (250 mg/kg and 500 mg/kg), and glibenclamide (5 mg/kg), respectively, for 14 days. Blood samples were obtained from the retro orbital sinus after light anesthesia from 5 animals in each group on days 2, 7, and 14 for lipids and electrolyte analysis. Lipid profile of diabetic treated (cMEMSL and glibenclamide) animals showed significant reduction (p < .05) in total cholesterol, triglyceride, and low density lipoprotein (LDL) levels. The high density lipoprotein (HDL) level in the treatment groups increased significantly (p < .05) compared with diabetic untreated. Sodium, potassium, and phosphate ions significantly increased in all diabetic treatment groups while chloride ion significantly decreased compared with diabetic untreated. There was no significant difference in calcium and bicarbonate ion concentration in all the groups. This study has showed additional properties of Musa sapientum to include its ability to restore electrolyte balance, reduce cholesterol, triglyceride, LDL, and increase the HDL levels in diabetic animals.

  2. Lipid Profile and Electrolyte Composition in Diabetic Rats Treated With Leaf Extract of Musa sapientum.

    PubMed

    Adewoye, E O; Ige, A O

    2016-01-01

    Diabetes mellitus affects lipid levels resulting in diabetic dyslipidemia as well as electrolyte loss from the body. Musa sapientum has been reported to possess antidiabetic properties. This study assessed the lipid profile and electrolyte composition in alloxan-induced diabetic rats treated with methanol leaf extract of M. sapientum (cMEMSL). Diabetes was induced with alloxan (120 mg/kg i.p.). Seventy-five male albino rats were divided into 5 groups of 15 rats each. Group 1 was control; groups 2-5 were made diabetic and treated with 0.2 ml 0.9% NaCl, cMEMSL (250 mg/kg and 500 mg/kg), and glibenclamide (5 mg/kg), respectively, for 14 days. Blood samples were obtained from the retro orbital sinus after light anesthesia from 5 animals in each group on days 2, 7, and 14 for lipids and electrolyte analysis. Lipid profile of diabetic treated (cMEMSL and glibenclamide) animals showed significant reduction (p < .05) in total cholesterol, triglyceride, and low density lipoprotein (LDL) levels. The high density lipoprotein (HDL) level in the treatment groups increased significantly (p < .05) compared with diabetic untreated. Sodium, potassium, and phosphate ions significantly increased in all diabetic treatment groups while chloride ion significantly decreased compared with diabetic untreated. There was no significant difference in calcium and bicarbonate ion concentration in all the groups. This study has showed additional properties of Musa sapientum to include its ability to restore electrolyte balance, reduce cholesterol, triglyceride, LDL, and increase the HDL levels in diabetic animals. PMID:25320868

  3. [Progression of the mechanism study on experimental migraine treated with acupuncture in rat model].

    PubMed

    Liu, Lu; Pei, Pei; Wang, Linpeng

    2016-03-01

    In the paper, by taking acupuncture and migraine as the key words to retrieve CNKI and PubMed database, the literature analysis was done on the mechanism study on experimental migraine treated with acupuncture in rat model. The results showed that acupuncture mechanism study focused on the regulation and control of the relevant neurotransmitters/neuromodulators of migraine, such as calcitonin gene-related peptide (CGRP), serotonin (5-HT), nitric oxide (NO), etc. Moreover, in the paper, the review had been done on the neurotransmitters/neuromodulators involved in the study.

  4. Adjuvant intrahepatic chemotherapy with mitomycin and 5-FU combined with hepatic irradiation in high-risk patients with carcinoma of the colon: a Southwest Oncology Group phase II pilot study

    SciTech Connect

    McCracken, J.D.; Weatherall, T.J.; Oishi, N.; Janaki, L.; Boyer, C.

    1985-01-01

    The Southwest Oncology Group conducted a pilot study in patients who had had total clinical resection of cancer of the colon and had a high risk of recurrence (Duke's C); the purpose of the study was to determine the toxic effects of intra-arterial chemotherapy combined with hepatic radiotherapy, in anticipation of their potential use in an adjuvant groupwide protocol. The treatment plan included intra-arterial chemotherapy with mitomycin (3 mg/m2) on Days 1, 4, 35, and 38 by slow intra-arterial push and 5-FU (1000 mg/m2) on Days 1-4 and 35-38 by continuous 96-hour infusion. Radiation therapy was begun on Day 8 of therapy and consisted of 1950 rads in 13 fractions over 2 1/2 weeks. Nineteen patients have been studied. Of 13 fully evaluable patients, two have relapsed in the liver. Eleven patients have developed significant, persistent liver enzyme elevations, and one patient has died from therapy-related liver failure. Combined radiotherapy and intra-arterial chemotherapy may result in significant chronic liver damage, and caution should be exercised in future adjuvant trials.

  5. Role of endothelin receptor antagonist; bosentan in cisplatin-induced nephrotoxicity in ovariectomized estradiol treated rats

    PubMed Central

    Zahedi, Alieh; Nematbakhsh, Mehdi; Moeini, Maryam; Talebi, Ardeshir

    2015-01-01

    Background: Endothelin-1 (ET-1) is a vasoconstrictor peptide that mediates cell proliferation, fibrosis, and inflammation. ET-1 has 2 receptors A and B. Objectives: The present study investigated whether administration of ET-1 receptor type A antagonist leads to protect cisplatin (CP) induced nephrotoxicity in ovariectomized-estradiol (Es) treated rats. Materials and Methods: Thirty-six ovariectomized Wistar rats were divided into 6 groups. Group 1 received CP (2.5 mg/kg/day) for one week. Groups 2 and 3 received 2 different doses of Es (0.25 and 0.5 mg/kg/week) for 3 weeks, but CP was started in the third week. Group 4 was treated as group 1, but bosentan (BOS, 30 mg/kg/day) was also added. Groups 5 and 6 treated similar to groups 2 and 3 but CP and BOS were added in the third week. At the end of the experiment, blood samples were obtained, and the animals were sacrificed for histopathological investigation of kidney tissue. Results: The serum levels of creatinine (Cr) and blood urea nitrogen (BUN) increased by CP; however, BOS significantly elevated the BUN and Cr levels that were increased by CP administration (P < 0.05). Co-treatment of Es, BOS, and CP decreased the serum levels of BUN, Cr, and malondialdehyde (MDA) when compared with the group treated with BOS plus CP (P < 0.05). Such finding was obtained for kidney tissue damage score (KTDS). As expected, Es significantly increased uterus weight (P < 0.05). The groups were not significantly different in terms of serum and kidney nitrite, kidney weight (KW), and bodyweight Conclusions: According to our findings, BOS could not protect renal functions against CP-induced nephrotoxicity. In contrast, Es alone or accompanied with BOS could protect the kidney against CP-induced nephrotoxicity via reduction of BUN, Cr, and KTDS. PMID:26457261

  6. Simultaneous gene expression signature of heart and peripheral blood mononuclear cells in astemizole-treated rats.

    PubMed

    Lee, Eun-Hee; Oh, Jung-Hwa; Park, Han-Jin; Kim, Do-Geun; Lee, Jong-Hwa; Kim, Choong-Yong; Kwon, Myung-Sang; Yoon, Seokjoo

    2010-08-01

    We investigated the effects of astemizole, a second-generation antihistamine, on the heart and peripheral blood mononuclear cells (PBMCs) and identified the early markers of its cardiotoxicity using gene expression profiling. Astemizole causes torsades de pointes, which is a type of ventricular tachycardia. We administered astemizole (dosage: 20, 60 mg/kg) to male Sprague-Dawley rats, using an oral gavage. Cardiac tissue and PBMCs were collected from the rats 4 h after treatment. Gene expression profiles were obtained using an Affymetrix GeneChip. The most deregulated genes were associated with energy metabolism pathways and calcium ion homeostasis in the heart of astemizole-treated rats. The most altered genes in the PBMCs were those involved in developmental processes and cardiotoxicity. Genes related to the response to oxidative stress, reactive oxygen species, heat shock proteins, hypoxia, immunity, and inflammation were also deregulated in the heart and PBMCs. These data provide further insight into the genetic pathways affected by astemizole. In addition, the simultaneously deregulated genes identified herein may be further studied. It will be interesting to find out whether single genes or certain sets of these genes could finally serve as biomarkers for cardiotoxicity of astemizole or other similar antihistamine drugs. PMID:20221588

  7. Brewers' rice attenuated aberrant crypt foci developing in colon of azoxymethane-treated rats.

    PubMed

    Tan, Bee Ling; Norhaizan, Mohd Esa; Pandurangan, Ashok Kumar; Hazilawati, Hamzah; Roselina, Karim

    2016-01-01

    Brewers' rice is one of abundant agricultural waste products in the rice industry. The present study is designed to investigate the potential of brewers' rice to inhibit the development of aberrant crypt foci (ACF) in colon of azoxymethane (AOM)-treated rats. The effects on the attenuation of hepatic toxicity and kidney function enzymes were also evaluated. Male Sprague-Dawley rats were randomly divided into five groups: (G1) normal; (G2) AOM alone; and (G3), (G4), and (G5), which were AOM fed with 10%, 20%, and 40% (w/w) of brewers' rice, respectively. The rats in group 2-5 were injected intraperitoneally with AOM (15 mg/kg body weight) once weekly for two weeks. After 8 weeks of treatment,the total number of ACF/colon and the number of ACF in the distal and middle colon were significantly reduced in all treatment groups compared to G2 (p<0.05). Brewers' rice decreased the number of ACF with dysplastic morphology in a dose-dependent manner. Alkaline phosphatase (ALP) level in G5 was significantly lower compared to the G2 (p<0.05). In conclusion, this study found the potential value of brewers' rice in reducing the risk of cancer susceptibility in colon. PMID:26826813

  8. Glutathione S-transferase localization in aflatoxin B1-treated rat livers.

    PubMed

    Harrison, D J; May, L; Hayes, J D; Neal, G E

    1990-06-01

    Overexpression of detoxication enzymes is associated with the development of drug-resistant, preneoplastic nodules in the carcinogen-treated rat liver. The most consistent marker of preneoplasia in many experimental models is increased expression of the pi-class glutathione S-transferase (GST) YfYf. We have confirmed by immunostaining that the pi-class GST is overexpressed in aflatoxin B1-induced preneoplastic nodules and liver tumours in rats. However, pi-class GST YfYf has low activity against aflatoxin B1-8,9-epoxide, and most activity against this cytotoxic and genotoxic metabolite is associated with the alpha-class GSTs YaYa, YaYc and YcYc. We have demonstrated that there is also a consistent increase in the alpha-class GSTs in this model. It seems likely that the overexpression of the Ya and Yc subunits, rather than increased levels of the pi-class GST YfYf, is responsible for the acquisition of a drug-resistant phenotype in rat liver preneoplastic nodules and tumours induced by aflatoxin B1. PMID:2112061

  9. Spinal cord injury in rats treated using bone marrow mesenchymal stem-cell transplantation

    PubMed Central

    Chen, Yu-Bing; Jia, Quan-Zhang; Li, Dong-Jun; Sun, Jing-Hai; Xi, Shuang; Liu, Li-Ping; Gao, De-Xuan; Jiang, Da-Wei

    2015-01-01

    The aim of this study was to observe the effects of bone marrow mesenchymal stem-cell transplantation (BMSCs) in repairing acute spinal cord damage in rats and to examine the potential beneficial effects. 192 Wistar rats were randomized into 8 groups. Spinal cord injury was created. Behavior and limb functions were scored. Repairing effects of BMSCs transplantation was evaluated and compared. In vitro 4’,6-diamidino-2-phenylindole (DAPI)-tagged BMSCs were observed, and whether they migrated to the area of spinal cord injury after intravenous tail injection was investigated. The expression of neuron-specific protein (NSE) on BMSCs was examined. Fifteen days after transplantation, the BMSCs-treated groups scored significantly higher in limb function tests than the untreated group. Pathological sections of the bone marrow after operation showed significant recovery in treated groups in comparison to the control group. After transplantation, small amounts of fluorescent-tagged BMSCs can be found in the blood vessels in the area of spinal cord injury, and fluorescent-tagged BMSCs were diffused in extravascular tissues, whereas the DAPI-tagged BMSCs could not be detected,and BrdU/NSE double-labeled cells were found in the injured marrow. BMSCs improve behavioral responses and can repair spinal cord injuries by migrating to the injured area, where they can differentiate into neurons. PMID:26309595

  10. Insular neural system controls decision-making in healthy and methamphetamine-treated rats

    PubMed Central

    Mizoguchi, Hiroyuki; Katahira, Kentaro; Inutsuka, Ayumu; Fukumoto, Kazuya; Nakamura, Akihiro; Wang, Tian; Nagai, Taku; Sato, Jun; Sawada, Makoto; Ohira, Hideki; Yamanaka, Akihiro; Yamada, Kiyofumi

    2015-01-01

    Patients suffering from neuropsychiatric disorders such as substance-related and addictive disorders exhibit altered decision-making patterns, which may be associated with their behavioral abnormalities. However, the neuronal mechanisms underlying such impairments are largely unknown. Using a gambling test, we demonstrated that methamphetamine (METH)-treated rats chose a high-risk/high-reward option more frequently and assigned higher value to high returns than control rats, suggestive of changes in decision-making choice strategy. Immunohistochemical analysis following the gambling test revealed aberrant activation of the insular cortex (INS) and nucleus accumbens in METH-treated animals. Pharmacological studies, together with in vivo microdialysis, showed that the insular neural system played a crucial role in decision-making. Moreover, manipulation of INS activation using designer receptor exclusively activated by designer drug technology resulted in alterations to decision-making. Our findings suggest that the INS is a critical region involved in decision-making and that insular neural dysfunction results in risk-taking behaviors associated with altered decision-making. PMID:26150496

  11. Insular neural system controls decision-making in healthy and methamphetamine-treated rats.

    PubMed

    Mizoguchi, Hiroyuki; Katahira, Kentaro; Inutsuka, Ayumu; Fukumoto, Kazuya; Nakamura, Akihiro; Wang, Tian; Nagai, Taku; Sato, Jun; Sawada, Makoto; Ohira, Hideki; Yamanaka, Akihiro; Yamada, Kiyofumi

    2015-07-21

    Patients suffering from neuropsychiatric disorders such as substance-related and addictive disorders exhibit altered decision-making patterns, which may be associated with their behavioral abnormalities. However, the neuronal mechanisms underlying such impairments are largely unknown. Using a gambling test, we demonstrated that methamphetamine (METH)-treated rats chose a high-risk/high-reward option more frequently and assigned higher value to high returns than control rats, suggestive of changes in decision-making choice strategy. Immunohistochemical analysis following the gambling test revealed aberrant activation of the insular cortex (INS) and nucleus accumbens in METH-treated animals. Pharmacological studies, together with in vivo microdialysis, showed that the insular neural system played a crucial role in decision-making. Moreover, manipulation of INS activation using designer receptor exclusively activated by designer drug technology resulted in alterations to decision-making. Our findings suggest that the INS is a critical region involved in decision-making and that insular neural dysfunction results in risk-taking behaviors associated with altered decision-making.

  12. Spinal cord injury in rats treated using bone marrow mesenchymal stem-cell transplantation.

    PubMed

    Chen, Yu-Bing; Jia, Quan-Zhang; Li, Dong-Jun; Sun, Jing-Hai; Xi, Shuang; Liu, Li-Ping; Gao, De-Xuan; Jiang, Da-Wei

    2015-01-01

    The aim of this study was to observe the effects of bone marrow mesenchymal stem-cell transplantation (BMSCs) in repairing acute spinal cord damage in rats and to examine the potential beneficial effects. 192 Wistar rats were randomized into 8 groups. Spinal cord injury was created. Behavior and limb functions were scored. Repairing effects of BMSCs transplantation was evaluated and compared. In vitro 4',6-diamidino-2-phenylindole (DAPI)-tagged BMSCs were observed, and whether they migrated to the area of spinal cord injury after intravenous tail injection was investigated. The expression of neuron-specific protein (NSE) on BMSCs was examined. Fifteen days after transplantation, the BMSCs-treated groups scored significantly higher in limb function tests than the untreated group. Pathological sections of the bone marrow after operation showed significant recovery in treated groups in comparison to the control group. After transplantation, small amounts of fluorescent-tagged BMSCs can be found in the blood vessels in the area of spinal cord injury, and fluorescent-tagged BMSCs were diffused in extravascular tissues, whereas the DAPI-tagged BMSCs could not be detected,and BrdU/NSE double-labeled cells were found in the injured marrow. BMSCs improve behavioral responses and can repair spinal cord injuries by migrating to the injured area, where they can differentiate into neurons.

  13. Gene expression profiling in rat liver treated with compounds inducing phospholipidosis

    SciTech Connect

    Hirode, Mitsuhiro |; Ono, Atsushi |; Miyagishima, Toshikazu; Nagao, Taku; Ohno, Yasuo; Urushidani, Tetsuro |

    2008-06-15

    We have constructed a large-scale transcriptome database of rat liver treated with various drugs. In an effort to identify a biomarker for diagnosis of hepatic phospholipidosis, we extracted 78 probe sets of rat hepatic genes from data of 5 drugs, amiodarone, amitriptyline, clomipramine, imipramine, and ketoconazole, which actually induced this phenotype. Principal component analysis (PCA) using these probes clearly separated dose- and time-dependent clusters of treated groups from their controls. Moreover, 6 drugs (chloramphenicol, chlorpromazine, gentamicin, perhexiline, promethazine, and tamoxifen), which were reported to cause phospholipidosis but judged as negative by histopathological examination, were designated as positive by PCA using these probe sets. Eight drugs (carbon tetrachloride, coumarin, tetracycline, metformin, hydroxyzine, diltiazem, 2-bromoethylamine, and ethionamide), which showed phospholipidosis-like vacuolar formation in the histopathology, could be distinguished from the typical drugs causing phospholipidosis. Moreover, the possible induction of phospholipidosis was predictable by the expression of these genes 24 h after single administration in some of the drugs. We conclude that these identified 78 probe sets could be useful for diagnosis of phospholipidosis, and that toxicogenomics would be a promising approach for prediction of this type of toxicity.

  14. Insular neural system controls decision-making in healthy and methamphetamine-treated rats.

    PubMed

    Mizoguchi, Hiroyuki; Katahira, Kentaro; Inutsuka, Ayumu; Fukumoto, Kazuya; Nakamura, Akihiro; Wang, Tian; Nagai, Taku; Sato, Jun; Sawada, Makoto; Ohira, Hideki; Yamanaka, Akihiro; Yamada, Kiyofumi

    2015-07-21

    Patients suffering from neuropsychiatric disorders such as substance-related and addictive disorders exhibit altered decision-making patterns, which may be associated with their behavioral abnormalities. However, the neuronal mechanisms underlying such impairments are largely unknown. Using a gambling test, we demonstrated that methamphetamine (METH)-treated rats chose a high-risk/high-reward option more frequently and assigned higher value to high returns than control rats, suggestive of changes in decision-making choice strategy. Immunohistochemical analysis following the gambling test revealed aberrant activation of the insular cortex (INS) and nucleus accumbens in METH-treated animals. Pharmacological studies, together with in vivo microdialysis, showed that the insular neural system played a crucial role in decision-making. Moreover, manipulation of INS activation using designer receptor exclusively activated by designer drug technology resulted in alterations to decision-making. Our findings suggest that the INS is a critical region involved in decision-making and that insular neural dysfunction results in risk-taking behaviors associated with altered decision-making. PMID:26150496

  15. Estrogen administration modulates hippocampal GABAergic subpopulations in the hippocampus of trimethyltin-treated rats

    PubMed Central

    Corvino, Valentina; Di Maria, Valentina; Marchese, Elisa; Lattanzi, Wanda; Biamonte, Filippo; Michetti, Fabrizio; Geloso, Maria Concetta

    2015-01-01

    Given the well-documented involvement of estrogens in the modulation of hippocampal functions in both physiological and pathological conditions, the present study investigates the effects of 17-beta estradiol (E2) administration in the rat model of hippocampal neurodegeneration induced by trimethyltin (TMT) administration (8 mg/kg), characterized by loss of pyramidal neurons in CA1, CA3/hilus hippocampal subfields, associated with astroglial and microglial activation, seizures and cognitive impairment. After TMT/saline treatment, ovariectomized animals received two doses of E2 (0.2 mg/kg intra-peritoneal) or vehicle, and were sacrificed 48 h or 7 days after TMT-treatment. Our results indicate that in TMT-treated animals E2 administration induces the early (48 h) upregulation of genes involved in neuroprotection and synaptogenesis, namely Bcl2, trkB, cadherin 2 and cyclin-dependent-kinase-5. Increased expression levels of glutamic acid decarboxylase (gad) 67, neuropeptide Y (Npy), parvalbumin, Pgc-1α and Sirtuin 1 genes, the latter involved in parvalbumin (PV) synthesis, were also evident. Unbiased stereology performed on rats sacrificed 7 days after TMT treatment showed that although E2 does not significantly influence the extent of TMT-induced neuronal death, significantly enhances the TMT-induced modulation of GABAergic interneuron population size in selected hippocampal subfields. In particular, E2 administration causes, in TMT-treated rats, a significant increase in the number of GAD67-expressing interneurons in CA1 stratum oriens, CA3 pyramidal layer, hilus and dentate gyrus, accompanied by a parallel increase in NPY-expressing cells, essentially in the same regions, and of PV-positive cells in CA1 pyramidal layer. The present results add information concerning the role of in vivo E2 administration on mechanisms involved in cellular plasticity in the adult brain. PMID:26594149

  16. Modifications in bone matrix of estrogen-deficient rats treated with intermittent PTH.

    PubMed

    Pacheco-Costa, Rafael; Campos, Jenifer Freitas; Katchburian, Eduardo; de Medeiros, Valquíria Pereira; Nader, Helena Bonciani; Nonaka, Keico Okino; Plotkin, Lilian Irene; Reginato, Rejane Daniele

    2015-01-01

    Bone matrix dictates strength, elasticity, and stiffness to the bone. Intermittent parathyroid hormone (iPTH), a bone-forming treatment, is widely used as a therapy for osteoporosis. We investigate whether low doses of intermittent PTH (1-34) change the profile of organic components in the bone matrix after 30 days of treatment. Forty 6-month-old female Wistar rats underwent ovariectomy and after 3 months received low doses of iPTH administered for 30 days: daily at 0.3 µg/kg/day (PTH03) or 5 µg/kg/day (PTH5); or 3 times per week at 0.25 µg/kg/day (PTH025). After euthanasia, distal femora were processed for bone histomorphometry, histochemistry for collagen and glycosaminoglycans, biochemical quantification of sulfated glycosaminoglycans, and hyaluronan by ELISA and TUNEL staining. Whole tibiae were used to estimate the bone mineral density (BMD). Histomorphometric analysis showed that PTH5 increased cancellous bone volume by 6% over vehicle-treated rats. In addition, PTH5 and PTH03 increased cortical thickness by 21% and 20%, respectively. Tibial BMD increased in PTH5-treated rats and this group exhibited lower levels of chondroitin sulfate; on the other hand, hyaluronan expression was increased. Hormonal administration in the PTH5 group led to decreased collagen maturity. Further, TUNEL-positive osteocytes were decreased in the cortical compartment of PTH5 whereas administration of PTH025 increased the osteocyte death. Our findings suggest that daily injections of PTH at low doses alter the pattern of organic components from the bone matrix, favoring the increase of bone mass. PMID:25695082

  17. Enduring attentional deficits in rats treated with a peripheral nerve injury.

    PubMed

    Higgins, Guy A; Silenieks, Leo B; Van Niekerk, Annalise; Desnoyer, Jill; Patrick, Amy; Lau, Winnie; Thevarkunnel, Sandy

    2015-06-01

    The present study investigated the impact of a spared nerve injury (SNI) on the daily performance of rats tested in two instrumental conditioning procedures: the progressive ratio (PR) schedule of food reinforcement to study motivation for an appetitive stimulus, and the 5-choice serial reaction time task (5-CSRTT), a test of attention and reaction time. Separate groups of male, Sprague-Dawley rats of age 8-10 months were trained to asymptotic performance in either task, before undergoing either SNI or sham surgery. After a recovery period of 3-4 days the animals were run 5 days/week for 3 months in either task. Tests of responsivity to evoked tactile (Von Frey) and thermal (acetone) stimuli were also conducted over this period to check integrity of the model. Post SNI surgery, rats showed equivalent responding to sham controls for food available under a PR schedule throughout the test period, implying a similar level of motivation for a food reward. In contrast, a performance deficit emerged in SNI treated rats run in the 5-CSRTT, consistent with an attentional deficit. This deficit emerged during the second month post-surgery and was characterized by slower response speed, reduced accuracy and increased trial omissions. Both SNI groups showed equivalent hypersensitivity to evoked sensory stimuli compared to controls. Since attention based deficits have been reported in individuals with clinical forms of neuropathic pain, the present studies suggest a novel approach to study this phenomena and a means to study the effect of treatments against this cognitive endpoint. PMID:25746510

  18. Does Swimming Exercise Affect Experimental Chronic Kidney Disease in Rats Treated with Gum Acacia?

    PubMed Central

    Ali, Badreldin H.; Al-Salam, Suhail; Al Za'abi, Mohammed; Al Balushi, Khalid A.; Ramkumar, Aishwarya; Waly, Mostafa I.; Yasin, Javid; Adham, Sirin A.; Nemmar, Abderrahim

    2014-01-01

    Different modes of exercise are reported to be beneficial in subjects with chronic kidney disease (CKD). Similar benefits have also been ascribed to the dietary supplement gum acacia (GA). Using several physiological, biochemical, immunological, and histopathological measurements, we assessed the effect of swimming exercise (SE) on adenine –induced CKD, and tested whether SE would influence the salutary action of GA in rats with CKD. Eight groups of rats were used, the first four of which were fed normal chow for 5 weeks, feed mixed with adenine (0.25% w/w) to induce CKD, GA in the drinking water (15% w/v), or were given adenine plus GA, as above. Another four groups were similarly treated, but were subjected to SE during the experimental period, while the first four groups remained sedentary. The pre-SE program lasted for four days (before the start of the experimental treatments), during which the rats were made to swim for 5 to 10 min, and then gradually extended to 20 min per day. Thereafter, the rats in the 5th, 6th, 7th, and 8th groups started to receive their respective treatments, and were subjected to SE three days a week for 45 min each. Adenine induced the typical signs of CKD as confirmed by histopathology, and the other measurements, and GA significantly ameliorated all these signs. SE did not affect the salutary action of GA on renal histology, but it partially improved some of the above biochemical and physiological analytes, suggesting that addition of this mode of exercise to GA supplementation may improve further the benefits of GA supplementation. PMID:25048380

  19. Zinc improves antioxidative enzymes in red blood cells and hematology in lithium-treated rats.

    PubMed

    Malhotra, Anshoo; Dhawan, Devinder K

    2008-01-01

    The present study was designed to evaluate the protective role of zinc in attenuating the adverse effects induced by lithium in blood of female Wistar rats. Female Wistar rats received lithium in the form of lithium carbonate in diet at a dose level of 1.1 g/kg diet, zinc alone in the form of zinc sulfate in drinking water at a dose level of 227 mg/L drinking water, or lithium plus zinc treatments in the combined group for a total duration of 2 months. Effects of the treatments were studied on antioxidant defense system, various hematologic parameters, and percentage of (65)Zn-specific activity. Lithium treatment resulted in a significant increase in lipid peroxidation levels but caused a significant decrease in reduced glutathione levels and the activities of catalase, glutathione S-transferase, and superoxide dismutase. Lithium treatment also caused a significant decrease in the activities of aminolevulinic acid dehydratase and Na(+) K(+) adenosine triphosphatase. However, it resulted in a significant increase in total leukocyte counts, neutrophils, and lymphocyte counts as well as zinc protoporphyrin levels, whereas a significant decrease in counts of monocytes, eosinophils, and percentage specific activity of (65)Zn in blood and its various fractions was noticed. Furthermore, lithium treatment caused a significant decrease in serum zinc levels. However, zinc supplementation to lithium-treated rats effectively raised the reduced glutathione levels and also normalized lipid peroxidation and the activities of antioxidative enzymes, which included catalase, glutathione S-transferase, and superoxide dismutase. Moreover, zinc supplementation could raise the activities of the enzymes aminolevulinic acid dehydratase and Na(+) K(+) adenosine triphosphatase as well as the percentage uptake values of (65)Zn in blood and its fractions. The study suggests that zinc, as a nutritional supplement, has the potential in attenuating most of the adverse effects induced by lithium

  20. DNA microarray unravels rapid changes in transcriptome of MK-801 treated rat brain

    PubMed Central

    Kobayashi, Yuka; Kulikova, Sofya P; Shibato, Junko; Rakwal, Randeep; Satoh, Hiroyuki; Pinault, Didier; Masuo, Yoshinori

    2015-01-01

    AIM: To investigate the impact of MK-801 on gene expression patterns genome wide in rat brain regions. METHODS: Rats were treated with an intraperitoneal injection of MK-801 [0.08 (low-dose) and 0.16 (high-dose) mg/kg] or NaCl (vehicle control). In a first series of experiment, the frontoparietal electrocorticogram was recorded 15 min before and 60 min after injection. In a second series of experiments, the whole brain of each animal was rapidly removed at 40 min post-injection, and different regions were separated: amygdala, cerebral cortex, hippocampus, hypothalamus, midbrain and ventral striatum on ice followed by DNA microarray (4 × 44 K whole rat genome chip) analysis. RESULTS: Spectral analysis revealed that a single systemic injection of MK-801 significantly and selectively augmented the power of baseline gamma frequency (30-80 Hz) oscillations in the frontoparietal electroencephalogram. DNA microarray analysis showed the largest number (up- and down- regulations) of gene expressions in the cerebral cortex (378), midbrain (376), hippocampus (375), ventral striatum (353), amygdala (301), and hypothalamus (201) under low-dose (0.08 mg/kg) of MK-801. Under high-dose (0.16 mg/kg), ventral striatum (811) showed the largest number of gene expression changes. Gene expression changes were functionally categorized to reveal expression of genes and function varies with each brain region. CONCLUSION: Acute MK-801 treatment increases synchrony of baseline gamma oscillations, and causes very early changes in gene expressions in six individual rat brain regions, a first report. PMID:26629322

  1. Protective effect of heat-treated cucumber (Cucumis sativus L.) juice on alcohol detoxification in experimental rats.

    PubMed

    Bajpai, Vivek K; Kim, Na-Hyung; Kim, Ji-Eun; Kim, Kangmin; Kang, Sun Chul

    2016-05-01

    In this study, heat-treated cucumber juice was assessed for its protective effect on blood alcohol levels and hepatic alcohol metabolic enzyme system in experimental rats. Initially, during detoxification of alcohol, all groups were orally dosed to 22% alcohol (6ml/kg body weight) along with different concentrations of heat-treated cucumber juice (10, 100 and 500mg/kg) and commercial goods for hangover-removal on sale (2ml/kg). Cucumber juice was dosed before 30 min, and simultaneously after 30min of alcohol administration, and its hepatoprotective effect on blood alcohol levels and hepatic alcohol metabolic enzyme system in experimental rats was evaluated. As a result, after 7h, remarkable reduction was found in the blood alcohol levels for all concentrations of cucumber juice treatment. Treatment with cucumber juice resulted in increasing dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) enzymatic activities in rat liver at 9h after alcohol administration thereby stimulated blood alcohol metabolism as compared with control group. The effect of heat-treated cucumber juice on alcohol detoxification was observed only in the rats treated before 30min from alcohol administration. These findings indicate that heat-treated cucumber juice has significant protective effect on alcohol detoxification in experimental rats, suggesting its usefulness in the treatment of liver injury caused by alcohol consumption.

  2. Protective effect of heat-treated cucumber (Cucumis sativus L.) juice on alcohol detoxification in experimental rats.

    PubMed

    Bajpai, Vivek K; Kim, Na-Hyung; Kim, Ji-Eun; Kim, Kangmin; Kang, Sun Chul

    2016-05-01

    In this study, heat-treated cucumber juice was assessed for its protective effect on blood alcohol levels and hepatic alcohol metabolic enzyme system in experimental rats. Initially, during detoxification of alcohol, all groups were orally dosed to 22% alcohol (6ml/kg body weight) along with different concentrations of heat-treated cucumber juice (10, 100 and 500mg/kg) and commercial goods for hangover-removal on sale (2ml/kg). Cucumber juice was dosed before 30 min, and simultaneously after 30min of alcohol administration, and its hepatoprotective effect on blood alcohol levels and hepatic alcohol metabolic enzyme system in experimental rats was evaluated. As a result, after 7h, remarkable reduction was found in the blood alcohol levels for all concentrations of cucumber juice treatment. Treatment with cucumber juice resulted in increasing dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) enzymatic activities in rat liver at 9h after alcohol administration thereby stimulated blood alcohol metabolism as compared with control group. The effect of heat-treated cucumber juice on alcohol detoxification was observed only in the rats treated before 30min from alcohol administration. These findings indicate that heat-treated cucumber juice has significant protective effect on alcohol detoxification in experimental rats, suggesting its usefulness in the treatment of liver injury caused by alcohol consumption. PMID:27383492

  3. Anti-inflammatory Effect of Isaria sinclairii Glycosaminoglycan in an Adjuvant-treated Arthritis Rat Model

    PubMed Central

    Jee, Sang Duck; Hwang, Jae Sam; Yun, Eun Young; Ahn, Kwang Seok; Kim, Yeong Shik

    2013-01-01

    The anti-inflammatory effects of glycosaminoglycan (GAG) derived from Isaria sinclairii (IS) and of IS extracts were investigated in a complete Freund’s adjuvant (CFA)-treated chronic arthritis rat model. Groups of rats were treated orally with 30 mg/kg one of the following: [1] saline control, extracts of [2] water-IS, [3] methanol-IS, [4] butanol-IS, [5] ethyl acetate-IS, or [6] Indomethacin® as the positive control for a period of two weeks. The anti-paw edema effects of the individual extracts were in the following order: water-IS ex. > methanol ex. > butanol ex. > ethyl acetate ex. The water/methanol extract from I. sinclairii remarkably inhibited UV-mediated upregulation of NF-κB activity in transfected HaCaT cells. GAG as a water-soluble alcohol precipitated fraction also produced a noticeable anti-edema effect. This GAG also inhibited the pro-inflammatory cytokine levels of prostaglandin E2-stimulated lipopolysaccharide in LAW 264.7 cells, cytokine TNF-α production in splenocytes, and atherogenesis cytokine levels of vascular endothelial growth factor (VEGF) production in HUVEC cells in a dose-dependent manner. In the histological analysis, the LV dorsal root ganglion, including the articular cartilage, and linked to the paw-treated IS GAG, was repaired against CFA-induced cartilage destruction. Combined treatment with Indomethacin® (5 mg/kg) and IS GAG (10 mg/kg) also more effectively inhibited CFA-induced paw edema at 3 hr, 24 hr, and 48 hr to levels comparable to the anti-inflammatory drug, indomethacin. Thus, the IS GAG described here holds great promise as an anti-inflammatory drug in the future. PMID:24386520

  4. Locomotion, physical development, and brain myelination in rats treated with ionizing radiation in utero

    SciTech Connect

    Zaman, M.S.

    1989-01-01

    Effects of ionizing radiation on the emergence of locomotion skill and some physical development parameters were studied in laboratory rats (Fisher F-344 inbred strain). Rats were treated with 3 different doses of radiation (150 R, 15 R, and 6.8 R) delivered on the 20th day of the prenatal life. Results indicated that relatively moderate (15 R) to high (150 R) doses of radiation have effects on certain locomotion and physical development parameters. Exposure to 150 R affected pivoting, cliff-avoidance, upper jaw tooth eruption, body weight, and organs, such as brain, cerebral cortex, ovary, kidney, heart and spleen weights. Other parameters, such as negative geotaxis, eye opening, and lower jaw tooth eruption appeared to be affected in the 150 R treated animals. Exposure to 15 R affected pivoting and cliff-avoidance parameters. The cerebral cortex weight of the 15 R treated animals was found to be reduced at the age of day 30. Exposure to 6.8 R had no adverse effects on these parameters. Prenatal exposure to 150 R of radiation reduced the cerebral cortex weight by 22.07% at 30 days of age, and 20.15% at 52 days of age which caused a reduction in cerebral cortex myelin content by 20.16, and 22.89% at the ages of day 30 and day 52 respectively. Exposure to 150 R did not affect the myelin content of the cerebellum or the brain stem; or the myelin concentration (mg myelin/g brain tissue weight) of the cerebral cortex, cerebellum, and the brain stem. Exposure to 15 R, and 6.8 R did not affect either the myelin content or the myelin concentration of these brain areas.

  5. Increased nuclear ploidy, not cell proliferation, is sustained in the peroxisome proliferator-treated rat liver.

    PubMed

    Lalwani, N D; Dethloff, L A; Haskins, J R; Robertson, D G; de la Iglesia, F A

    1997-01-01

    Peroxisome proliferators are believed to induce liver tumors in rodents due to sustained increase in cell proliferation and oxidative stress resulting from the induction of peroxisomal enzymes. The objective of this study was to conduct a sequential analysis of the early changes in cell-cycle kinetics and the dynamics of rat liver DNA synthesis after treatment with a peroxisome proliferator. Immunofluorescent detection of proliferating cell nuclear antigen (PCNA) and bromodeoxyuridine (BrdU) incorporation into DNA during S phase we used to assess rat hepatocyte proliferation in vivo during dietary administration of Wy-14,643, a known peroxisome proliferator and hepatocarcinogen in rodents. Rats were placed on diet containing 0.1% WY-14,643 and implanted subcutaneously with 5-bromo-2'deoxyuridine containing osmotic pumps 4 days prior to being sacrificed on days 4, 11, and 25 of treatment. Isolated liver nuclei labeled with fluorscein isothiocyanate (FITC)-anti-BrdU/PI and FITC-anti-PCNA/PI were analyzed for S-phase kinetics using flow cytometry. Morphometric analysis was performed to evaluate nuclear and cell size and enumeration of BrdU labeled cells, binucleated hepatocytes, and mitotic index. The BrdU labeling index increased 2-fold in livers of Wy-14,643-treated rats at day 4, but distribution of cells in G1, S phase, and G2-M did not differ significantly from controls. PCNA-positive cells decreased from 36% on day 4 to 17% on day 25, whereas the percentage of PCNA-positive cells in controls increased 2-fold from day 4 to day 11 and remained unchanged up to day 25. The differences in the number of PCNA-positive nuclei between control and Wy-14,643-treated groups were statistically significant only on day 4. Binucleated hepatocytes, determined by morphometric analysis, increased slightly on day 25 in treated rats parallel to an increase in the percentage of cells in G2-M phase. Significant shifts were noted in nuclear diameter and nuclear area after 11 and 25

  6. Glutamate co-transmission from developing medial nucleus of the trapezoid body - Lateral superior olive synapses is cochlear dependent in kanamycin-treated rats

    SciTech Connect

    Lee, Jae Ho; Pradhan, Jonu; Maskey, Dhiraj; Park, Ki Sup; Hong, Sung Hwa; Suh, Myung-Whan; Kim, Myeung Ju; Ahn, Seung Cheol

    2011-02-11

    Research highlights: {yields} Glutamate co-transmission is enhanced in kanamycin-treated rats. {yields} VGLUT3 expression is increased in kanamycin-treated rats. {yields} GlyR expression is decreased in kanamycin-treated rats. {yields} GlyR, VGLUT3 expression patterns are asymmetric in unilaterally cochlear ablated rat. -- Abstract: Cochlear dependency of glutamate co-transmission at the medial nucleus of the trapezoid body (MNTB) - the lateral superior olive (LSO) synapses was investigated using developing rats treated with high dose kanamycin. Rats were treated with kanamycin from postnatal day (P) 3 to P8. A scanning electron microscopic study on P9 demonstrated partial cochlear hair cell damage. A whole cell voltage clamp experiment demonstrated the increased glutamatergic portion of postsynaptic currents (PSCs) elicited by MNTB stimulation in P9-P11 kanamycin-treated rats. The enhanced VGLUT3 immunoreactivities (IRs) in kanamycin-treated rats and asymmetric VGLUT3 IRs in the LSO of unilaterally cochlear ablated rats supported the electrophysiologic data. Taken together, it is concluded that glutamate co-transmission is cochlear-dependent and enhanced glutamate co-transmission in kanamycin-treated rats is induced by partial cochlear damage.

  7. In vitro inhibition of proliferation of vascular smooth muscle cells by serum of rats treated with Dahuang Zhechong pill.

    PubMed

    Zhang, Yuan-Hui; Liu, Jun-Tian; Wen, Bin-Yu; Xiao, Xiang-Hua

    2007-06-13

    Dahuang Zhechong pill (DHZCP) is a famous and classical Chinese herbal prescription, which is clinically used to treat hepatic, gynecological and cardiovascular diseases in China. The aim of this study was to observe the effects of the serum of rats treated with DHZCP on the proliferation of cultured rat vascular smooth muscle cells (VSMCs) stimulated by platelet-derived growth factor (PDGF), oxidized low density lipoprotein (ox-LDL) and hyperlipidemic serum (HLS), and on DNA, protein and collagen syntheses of VSMCs induced by PDGF in vitro. VSMCs proliferation was assayed by measuring the cell viability with MTT method, and syntheses of DNA, protein and collagen were evaluated by detecting [(3)H]-thymidine, [(3)H]-leucine and [(3)H]-proline incorporations, respectively. The results showed that PDGF, ox-LDL and HLS stimulated the proliferation of rat VSMCs in vitro. The serum of rats treated with DHZCP significantly inhibited the proliferation of rat VSMCs induced by the above stimulants and the incorporations of [(3)H]-thymidine, [(3)H]-leucine and [(3)H]-proline into rat VSMCs induced by PDGF in comparison with the model control group (P<0.01). The data suggest that DHZCP is able to obviously inhibit VSMCs proliferation via interfering with syntheses of DNA and protein, and to decrease production of extracellular matrix by VSMCs through antagonizing collagen synthesis.

  8. Influence of mRNA expression of epiregulin and amphiregulin on outcome of patients with metastatic colorectal cancer treated with 5-FU/LV plus irinotecan or irinotecan plus oxaliplatin as first-line treatment (FIRE 1-trial).

    PubMed

    Stahler, A; Heinemann, V; Giessen-Jung, C; Crispin, A; Schalhorn, A; Stintzing, S; Fischer von Weikersthal, L; Vehling-Kaiser, U; Stauch, M; Quietzsch, D; Held, S; von Einem, J C; Holch, J; Neumann, J; Kirchner, T; Jung, A; Modest, D P

    2016-02-01

    Our aim was to investigate the impact of EREG and AREG mRNA expression (by RT-qPCR) in patients with metastatic colorectal cancer (mCRC). In addition, epidermal growth factor receptor (EGFR) expression (by immunohistochemistry) as well as RAS-and PIK3CA-mutations (by pyrosequencing) were assessed. Tumors of 208 mCRC patients receiving 5-fluorouracil/leucovorin plus irinotecan (FUFIRI) or irinotecan plus oxaliplatin (mIROX) within the FIRE-1 trial were analyzed for mutations. Molecular characteristics were correlated with response, progression-free survival (PFS), overall survival (OS). mRNA expression was evaluated using ROC-analysis in 192 tumors (AREG high n = 31 vs. low n = 161; EREG high n = 89 vs. low n = 103). High versus low AREG expression was associated with PFS of 10.0 versus 8.0 months (HR = 0.62, 95% CI: 0.402-0.940, p = 0.03) and OS of 24.6 versus 18.7 months (HR = 0.72, 95% CI: 0.476-1.078, p = 0.11). High versus low EREG expression correlated with prolonged PFS (9.4 vs. 6.8 months, HR = 0.62, 95% CI: 0.460-0.846, p = 0.002) and OS (25.8 vs. 15.5 months, HR = 0.48, 95% CI: 0.351-0.657, p < 0.001). The positive prognostic effect of high EREG expression was confirmed in a multivariate analysis and was neither affected by EGFR expression nor by mutations of RAS- and PIK3CA-genes. EREG expression appears as an independent prognostic marker in patients with mCRC receiving first-line irinotecan-based chemotherapy. PMID:26284333

  9. Contribution of the endothelin and renin–angiotensin systems to the vascular changes in rats chronically treated with ouabain

    PubMed Central

    Xavier, Fabiano E; Yogi, Álvaro; Callera, Gláucia E; Tostes, Rita C; Alvarez, Yolanda; Salaices, Mercedes; Alonso, María J; Rossoni, Luciana V

    2004-01-01

    Renin–angiotensin and endothelin systems are involved in the cardiovascular effects produced by treatment with ouabain. We recently demonstrated that the contractile response to phenylephrine is decreased in ouabain-treated rats. The present study investigated whether endothelin-1 (ET-1) and angiotensin II (Ang II) contributes to the vascular changes observed in rats chronically treated with ouabain. Wistar rats were treated with ouabain (8.0 μg day−1, s.c. pellets for 5 weeks) alone or in combination with an endothelin type A receptor (ETA) antagonist, BMS182874 (40 mg kg−1 day−1, per gavage) or an angiotensin type 1 (AT1) receptor antagonist, losartan (15 mg kg−1 day−1, p.o.). Treatment with ouabain increased systolic blood pressure and treatment with either losartan or BMS182874 prevented the development of ouabain-induced hypertension. The sensitivity and maximal response for phenylephrine were reduced in aortic rings from ouabain-treated rats. Removal of the endothelium or in vitro exposure to an inhibitor of nitric oxide synthase (NOS), N-nitro-L-arginine methyl ester (L-NAME, 100 μM) increased the responses to phenylephrine, an effect that was more pronounced in aortas from ouabain-treated rats. Endothelial NOS protein (eNOS) expression was increased after ouabain treatment. Treatment with BMS182874, but not with losartan, prevented the effects of ouabain on the reactivity of phenylephrine and in eNOS protein expression. Gene expression of pre–pro-ET-1 and ETA receptors was increased in aortic rings from ouabain-treated rats. ETB receptor gene expression was not altered by ouabain treatment. In conclusion, our results suggest that endothelin and angiotensin systems play an important role in the development of ouabain-induced hypertension. However, ET-1, by activation of ETA receptors, but not Ang II, contributes to changes in vascular reactivity to phenylephrine induced by chronic treatment with ouabain. PMID:15477225

  10. Microvesicles from brain-extract—treated mesenchymal stem cells improve neurological functions in a rat model of ischemic stroke

    PubMed Central

    Lee, Ji Yong; Kim, Eiru; Choi, Seong-Mi; Kim, Dong-Wook; Kim, Kwang Pyo; Lee, Insuk; Kim, Han-Soo

    2016-01-01

    Transplantation of mesenchymal stem cells (MSCs) was reported to improve functional outcomes in a rat model of ischemic stroke, and subsequent studies suggest that MSC-derived microvesicles (MVs) can replace the beneficial effects of MSCs. Here, we evaluated three different MSC-derived MVs, including MVs from untreated MSCs (MSC-MVs), MVs from MSCs treated with normal rat brain extract (NBE-MSC-MVs), and MVs from MSCs treated with stroke-injured rat brain extract (SBE-MSC-MVs), and tested their effects on ischemic brain injury induced by permanent middle cerebral artery occlusion (pMCAO) in rats. NBE-MSC-MVs and SBE-MSC-MVs had significantly greater efficacy than MSC-MVs for ameliorating ischemic brain injury with improved functional recovery. We found similar profiles of key signalling proteins in NBE-MSC-MVs and SBE-MSC-MVs, which account for their similar therapeutic efficacies. Immunohistochemical analyses suggest that brain-extract—treated MSC-MVs reduce inflammation, enhance angiogenesis, and increase endogenous neurogenesis in the rat brain. We performed mass spectrometry proteomic analyses and found that the total proteomes of brain-extract—treated MSC-MVs are highly enriched for known vesicular proteins. Notably, MSC-MV proteins upregulated by brain extracts tend to be modular for tissue repair pathways. We suggest that MSC-MV proteins stimulated by the brain microenvironment are paracrine effectors that enhance MSC therapy for stroke injury. PMID:27609711

  11. Microvesicles from brain-extract-treated mesenchymal stem cells improve neurological functions in a rat model of ischemic stroke.

    PubMed

    Lee, Ji Yong; Kim, Eiru; Choi, Seong-Mi; Kim, Dong-Wook; Kim, Kwang Pyo; Lee, Insuk; Kim, Han-Soo

    2016-01-01

    Transplantation of mesenchymal stem cells (MSCs) was reported to improve functional outcomes in a rat model of ischemic stroke, and subsequent studies suggest that MSC-derived microvesicles (MVs) can replace the beneficial effects of MSCs. Here, we evaluated three different MSC-derived MVs, including MVs from untreated MSCs (MSC-MVs), MVs from MSCs treated with normal rat brain extract (NBE-MSC-MVs), and MVs from MSCs treated with stroke-injured rat brain extract (SBE-MSC-MVs), and tested their effects on ischemic brain injury induced by permanent middle cerebral artery occlusion (pMCAO) in rats. NBE-MSC-MVs and SBE-MSC-MVs had significantly greater efficacy than MSC-MVs for ameliorating ischemic brain injury with improved functional recovery. We found similar profiles of key signalling proteins in NBE-MSC-MVs and SBE-MSC-MVs, which account for their similar therapeutic efficacies. Immunohistochemical analyses suggest that brain-extract-treated MSC-MVs reduce inflammation, enhance angiogenesis, and increase endogenous neurogenesis in the rat brain. We performed mass spectrometry proteomic analyses and found that the total proteomes of brain-extract-treated MSC-MVs are highly enriched for known vesicular proteins. Notably, MSC-MV proteins upregulated by brain extracts tend to be modular for tissue repair pathways. We suggest that MSC-MV proteins stimulated by the brain microenvironment are paracrine effectors that enhance MSC therapy for stroke injury. PMID:27609711

  12. Microvesicles from brain-extract-treated mesenchymal stem cells improve neurological functions in a rat model of ischemic stroke.

    PubMed

    Lee, Ji Yong; Kim, Eiru; Choi, Seong-Mi; Kim, Dong-Wook; Kim, Kwang Pyo; Lee, Insuk; Kim, Han-Soo

    2016-09-09

    Transplantation of mesenchymal stem cells (MSCs) was reported to improve functional outcomes in a rat model of ischemic stroke, and subsequent studies suggest that MSC-derived microvesicles (MVs) can replace the beneficial effects of MSCs. Here, we evaluated three different MSC-derived MVs, including MVs from untreated MSCs (MSC-MVs), MVs from MSCs treated with normal rat brain extract (NBE-MSC-MVs), and MVs from MSCs treated with stroke-injured rat brain extract (SBE-MSC-MVs), and tested their effects on ischemic brain injury induced by permanent middle cerebral artery occlusion (pMCAO) in rats. NBE-MSC-MVs and SBE-MSC-MVs had significantly greater efficacy than MSC-MVs for ameliorating ischemic brain injury with improved functional recovery. We found similar profiles of key signalling proteins in NBE-MSC-MVs and SBE-MSC-MVs, which account for their similar therapeutic efficacies. Immunohistochemical analyses suggest that brain-extract-treated MSC-MVs reduce inflammation, enhance angiogenesis, and increase endogenous neurogenesis in the rat brain. We performed mass spectrometry proteomic analyses and found that the total proteomes of brain-extract-treated MSC-MVs are highly enriched for known vesicular proteins. Notably, MSC-MV proteins upregulated by brain extracts tend to be modular for tissue repair pathways. We suggest that MSC-MV proteins stimulated by the brain microenvironment are paracrine effectors that enhance MSC therapy for stroke injury.

  13. Effects of pramipexole on the duration of immobility during the forced swim test in normal and ACTH-treated rats.

    PubMed

    Kitagawa, Kouhei; Kitamura, Yoshihisa; Miyazaki, Toshiaki; Miyaoka, Junya; Kawasaki, Hiromu; Asanuma, Masato; Sendo, Toshiaki; Gomita, Yutaka

    2009-07-01

    The dopamine D2/D3 receptor agonist pramipexole has clinically been proven to improve depression or treatment-resistant depression. However, the involvement of the dopamine receptor system on the effect of pramipexole on depression remains unclear. We examined the influence of pramipexole on the duration of immobility during the forced swim test in normal and adrenocorticotropic hormone (ACTH)-treated rats and further analyzed the possible role of dopamine receptors in this effect. Additionally, the mechanism by which pramipexole acts in this model was explored specifically in relation to the site of action through the use of microinjections into the intramedial prefrontal cortex and nucleus accumbens. Pramipexole (0.3-1 mg/kg) significantly decreased the duration of immobility in normal and ACTH-treated rats. This effect was blocked by L-741,626, a D2 receptor antagonist, and nafadotride, a D3 receptor antagonist, in normal rats. Furthermore, infusions of pramipexole into the intranucleus accumbens, but not the medial prefrontal cortex, decreased the immobility of normal and ACTH-treated rats during the forced swim test. Taken together, the results of these experiments suggested that pramipexole, administered into the intranucleus accumbens rather than the medial prefrontal cortex, exerted an antidepressant-like effect on ACTH-treated rats via the dopaminergic system. The immobility-decreasing effect of pramipexole may be mediated by dopamine D2 and D3 receptors.

  14. Voluntary exercise improves metabolic profile in high-fat fed glucocorticoid-treated rats

    PubMed Central

    Beaudry, Jacqueline L.; Dunford, Emily C.; Leclair, Erwan; Mandel, Erin R.; Peckett, Ashley J.; Haas, Tara L.

    2015-01-01

    Diabetes is rapidly induced in young male Sprague-Dawley rats following treatment with exogenous corticosterone (CORT) and a high-fat diet (HFD). Regular exercise alleviates insulin insensitivity and improves pancreatic β-cell function in insulin-resistant/diabetic rodents, but its effect in an animal model of elevated glucocorticoids is unknown. We examined the effect of voluntary exercise (EX) on diabetes development in CORT-HFD-treated male Sprague-Dawley rats (∼6 wk old). Animals were acclimatized to running wheels for 2 wk, then given a HFD, either wax (placebo) or CORT pellets, and split into 4 groups: placebo-sedentary (SED) or -EX and CORT-SED or -EX. After 2 wk of running combined with treatment, CORT-EX animals had reduced visceral adiposity, and increased skeletal muscle type IIb/x fiber area, oxidative capacity, capillary-to-fiber ratio and insulin sensitivity compared with CORT-SED animals (all P < 0.05). Although CORT-EX animals still had fasting hyperglycemia, these values were significantly improved compared with CORT-SED animals (14.3 ± 1.6 vs. 18.8 ± 0.9 mM). In addition, acute in vivo insulin response to an oral glucose challenge was enhanced ∼2-fold in CORT-EX vs. CORT-SED (P < 0.05) which was further demonstrated ex vivo in isolated islets. We conclude that voluntary wheel running in rats improves, but does not fully normalize, the metabolic profile and skeletal muscle composition of animals administered CORT and HFD. PMID:25792713

  15. Voluntary exercise improves metabolic profile in high-fat fed glucocorticoid-treated rats.

    PubMed

    Beaudry, Jacqueline L; Dunford, Emily C; Leclair, Erwan; Mandel, Erin R; Peckett, Ashley J; Haas, Tara L; Riddell, Michael C

    2015-06-01

    Diabetes is rapidly induced in young male Sprague-Dawley rats following treatment with exogenous corticosterone (CORT) and a high-fat diet (HFD). Regular exercise alleviates insulin insensitivity and improves pancreatic β-cell function in insulin-resistant/diabetic rodents, but its effect in an animal model of elevated glucocorticoids is unknown. We examined the effect of voluntary exercise (EX) on diabetes development in CORT-HFD-treated male Sprague-Dawley rats (∼6 wk old). Animals were acclimatized to running wheels for 2 wk, then given a HFD, either wax (placebo) or CORT pellets, and split into 4 groups: placebo-sedentary (SED) or -EX and CORT-SED or -EX. After 2 wk of running combined with treatment, CORT-EX animals had reduced visceral adiposity, and increased skeletal muscle type IIb/x fiber area, oxidative capacity, capillary-to-fiber ratio and insulin sensitivity compared with CORT-SED animals (all P < 0.05). Although CORT-EX animals still had fasting hyperglycemia, these values were significantly improved compared with CORT-SED animals (14.3 ± 1.6 vs. 18.8 ± 0.9 mM). In addition, acute in vivo insulin response to an oral glucose challenge was enhanced ∼2-fold in CORT-EX vs. CORT-SED (P < 0.05) which was further demonstrated ex vivo in isolated islets. We conclude that voluntary wheel running in rats improves, but does not fully normalize, the metabolic profile and skeletal muscle composition of animals administered CORT and HFD.

  16. Cannabidiol-treated rats exhibited higher motor score after cryogenic spinal cord injury.

    PubMed

    Kwiatkoski, Marcelo; Guimarães, Francisco Silveira; Del-Bel, Elaine

    2012-04-01

    Cannabidiol (CBD), a non-psychoactive constituent of cannabis, has been reported to induce neuroprotective effects in several experimental models of brain injury. We aimed at investigating whether this drug could also improve locomotor recovery of rats submitted to spinal cord cryoinjury. Rats were distributed into five experimental groups. Animals were submitted to laminectomy in vertebral segment T10 followed or not by application of liquid nitrogen for 5 s into the spinal cord at the same level to cause cryoinjury. The animals received injections of vehicle or CBD (20 mg/kg) immediately before, 3 h after and daily for 6 days after surgery. The Basso, Beattie, and Bresnahan motor evaluation test was used to assess motor function post-lesion one day before surgery and on the first, third, and seventh postoperative days. The extent of injury was evaluated by hematoxylin-eosin histology and FosB expression. Cryogenic lesion of the spinal cord resulted in a significant motor deficit. Cannabidiol-treated rats exhibited a higher Basso, Beattie, and Bresnahan locomotor score at the end of the first week after spinal cord injury: lesion + vehicle, day 1: zero, day 7: four, and lesion + Cannabidiol 20 mg/kg, day 1: zero, day 7: seven. Moreover, at this moment there was a significant reduction in the extent of tissue injury and FosB expression in the ventral horn of the spinal cord. The present study confirmed that application of liquid nitrogen to the spinal cord induces reproducible and quantifiable spinal cord injury associated with locomotor function impairments. Cannabidiol improved locomotor functional recovery and reduced injury extent, suggesting that it could be useful in the treatment of spinal cord lesions.

  17. Effects of diallyl sulfide and zinc on testicular steroidogenesis in cadmium-treated male rats.

    PubMed

    Sadik, Nermin A H

    2008-01-01

    Cadmium (Cd) is one of the environmental pollutants that affect various tissues and organs including testis. Harmful effect of cadmium on testis is known to be germ cell degeneration and impairment of testicular steroidogenesis. In the present study, the effect of diallyl sulfide (DAS), a sulfur-containing volatile compound present in garlic, and zinc (Zn) was investigated on cadmium-induced testicular toxicity in rats. Male adult Wistar rats treated with cadmium (2.5 mg/kg body wt, five times a week for 4 weeks) showed decreased body weight, paired testicular weight, relative testicular weight, serum testosterone, luteinizing hormone, follicle-stimulating hormone, and testicular total antioxidant capacity (TAC) and protein levels. Testicular steroidogenic enzymes, such as 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and 17beta-hydroxysteroid dehydrogenase (17beta-HSD), and marker enzymes, such as sorbitol dehydrogenase (SDH), lactate dehydrogenase (LDH), acid phosphatase (ACP), alkaline phosphatase (ALP), and glucose-6-phosphate dehydrogenase (G6PD), showed a significant decrease in activities whereas that of gamma-glutamyl transferase was significantly increased after cadmium exposure. The results have revealed that concurrent treatment with DAS or zinc restored key steroidogenic enzymes, SDH, LDH, and G6PD and increased testicular weight significantly. DAS restored the TAC level and increased testosterone level and relative testicular weight significantly. Zinc restored testicular protein level and body weight. It can be concluded that cadmium causes testicular toxicity and inhibits androgen production in adult male rats probably by affecting pituitary gonadotrophins and that concurrent administration of DAS or zinc provides protection against cadmium-induced testicular toxicity. PMID:18972399

  18. BQ123 Stimulates Skeletal Muscle Antioxidant Defense via Nrf2 Activation in LPS-Treated Rats

    PubMed Central

    Jeleń, Agnieszka; Żebrowska, Marta; Balcerczak, Ewa; Gorąca, Anna

    2016-01-01

    Little is understood of skeletal muscle tissue in terms of oxidative stress and inflammation. Endothelin-1 is an endogenous, vasoconstrictive peptide which can induce overproduction of reactive oxygen species and proinflammatory cytokines. The aim of this study was to evaluate whether BQ123, an endothelin-A receptor antagonist, influences the level of TNF-α, IL-6, SOD-1, HO-1, Nrf2 mRNA, and NF-κB subunit RelA/p65 mRNA in the femoral muscle obtained from endotoxemic rats. Male Wistar rats were divided into 4 groups (n = 6) and received iv (1) saline (control), (2) LPS (15 mg/kg), (3) BQ123 (1 mg/kg), (4) BQ123 (1 mg/kg), and LPS (15 mg/kg, resp.) 30 min later. Injection of LPS led to significant increase in levels of RelA/p65 mRNA, TNF-α, and IL-6, while content of SOD-1, HO-1, and Nrf2 mRNA was unchanged. Administration of BQ123 prior to LPS challenge resulted in a significant reduction in RelA/p65 mRNA, TNF-α, and IL-6 levels, as well as markedly elevated concentrations of SOD-1, HO-1, and Nrf2 mRNA. BQ123 appears to enhance antioxidant defense and prevent production of TNF-α and IL-6 in skeletal muscle of LPS-treated rat. In conclusion, endothelin-A receptor antagonism exerts significant impact on the skeletal muscle favouring anti-inflammatory effects and protection against oxidative stress. PMID:26823945

  19. Hypophagic and hypolocomotive effects of metachloro phenyl piperazine in rats treated with theophylline and caffeine.

    PubMed

    Alam, Nausheen; Haleem, Darakshan Jabeen; Najam, Rahila; Haider, Syeda; Ahmed, Shahida Perveen

    2011-07-01

    Long term intake of coffee is known to produce anxiety and suppression of appetite. 5- hydroxytryptamine (5-HT) acting via 5-HT-2C receptors elicits anorexia and anxiety. The present study is design to monitor metachloro phenyl piperazine (m-CPP) at a dose of 3mg/ml/kg, induces hypophagia and hypolocomotion in rats taking a solution of caffeine (a component of coffee and tea) or theophylline (a component of tea) as a sole source of water. We found that hypophagic and hypolocomotive effects of m-CPP were attenuated in theophylline but not in caffeine treated animals suggesting that long term intake of theophylline may attenuate anorexiogenic and anxiogenic effects of 5-HT. A possible role of 5-HT-2C receptors in the modulation of anxiety and appetite in people drinking coffee or tea discussed.

  20. Cofactor metals and antioxidant enzymes in cisplatin-treated rats: effect of antioxidant intervention.

    PubMed

    Sabuncuoglu, Suna; Eken, Ayse; Aydin, Ahmet; Ozgunes, Hilal; Orhan, Hilmi

    2015-10-01

    We explored the association between the activities of antioxidant enzymes and their metallic cofactors in rats treated with cisplatin. The antioxidant effects of aminoguanidine, and a combination of vitamins E and C were investigated. Plasma platin was significantly lower than liver and kidney. Cisplatin treatment caused significant increase in plasma Se-glutathione peroxidase activity. Activities of Se-glutathione peroxidase, glutathione S-transferase, catalase and Cu,Zn-superoxide dismutase have been found to be significantly decreased in liver and kidney compared to controls. Zn levels in these organs were diminished upon cisplatin treatment, while levels of Cu were unaffected. Interestingly, levels of iron, the cofactor of catalase, were found to be significantly increased in liver and kidney. Intervention with aminoguanidine or vitamins was generally prevented cisplatin-caused changes in the activity of enzymes and in the tissue levels of cofactor metals. These observations suggest that relation between activities of enzymes and levels of cofactor metals is multifactorial.

  1. Efficacy of exogenous gonadotropins on the maintenance of spermatogenesis in pethidine treated albino rats.

    PubMed

    Patil, S R; Sonar, A; Londonkar, R; Patil, S R; Patil, S B

    1998-10-01

    An attempt is made to induce the pethidine suppressed gonadal activities by the administration of exogenous gonadotropins (hCG, PMSG, hCG + PMSG). Administration of 5 IU gonadotropins either separately or in combination to the rats treated with pethidine for 30 days resulted in the significant increase in the weight of testis, diameter of testis and seminiferous tubules. Gonadotropin(s) treatment stimulated the spermatogenic activity which was inhibited by pethidine. Therefore the number of spermatogonia, spermatocytes, spermatids in the seminiferous tubules and spermatozoa in cauda epididymis is increased significantly. Decreased testicular cholesterol, increased protein content and weight of accessory sex organs indicate the rejuvenation of steroidogenesis. Combination of both the gonadotropins is more effective in bringing all these activities.

  2. Absence of organ specific toxicity in rats treated with Tonica, an aqueous herbal haematinic preparation.

    PubMed

    Martey, Orleans Nii-Korley; Armah, George; Okine, Laud K N-A

    2010-01-01

    The sub-chronic toxicity of Tonica, an aqueous herbal haematinic prepared from the stem barks of Khaya senegalensis, Mitragyna stipulosa and Kigelia africana, was investigated in male Sprague-Dawley rats at 28, 280 and 560 mg kg(-1) day(-1), representing the normal human dose, 10x and 20x that dose, respectively for 6 weeks. The growth rate of animals over the period of treatment and certain serum biochemical and haematological indices as well as urinalysis and weight of selected organs at termination, were determined. Results show that the extract did not affect the weight gain of the animals with time or the mean wet weights of selected organs. Although there were slight but insignificant (p>0.05) elevations in WBC (16-27%) and PLT (8-11%) counts in Tonica-treated animals compared to controls at 10x and 20x the normal dose, most serum biochemical, haematological and urinalysis data indicated no significant differences (p>0.05) between tests and control rats. There were also no changes in the morphology of liver, kidney, lung and heart tissues as a result of Tonica treatment. These findings suggest that Tonica is safe at the dosage regimens administered to the animals in this study, and there appears to be no overt organ specific toxicity associated with it. PMID:21461151

  3. Effect of retinyl acetate on transglutaminase 2 activity in carcinogen treated rat liver.

    PubMed

    Aydin, O; Akyuz, F; Tekin, N; Ustuner, Mc; Degirmenci, I; Burukoglu, D; Ozden, H

    2016-07-01

    Transglutaminase 2 (TG2) has been implicated in wound healing, cellular differentiation, apoptosis and cell survival. TG2 activity increases following acute and chronic liver injury; however, the role of TG2 in tumors, is controversial. TG2 is a retinoid-inducible enzyme. We investigated the effects of retinyl acetate (RA) on the activity and levels of TG2 during the initiation and promotion stages of liver cancer. p-Dimethylaminoazobenzene (p-DAB) was used as initiator and 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) was used as promoter in our model of carcinogenesis. Rats were divided into four groups of 24: control, corn oil control, p-DAB + TCDD, and p-DAB + TCDD + RA. Six rats from each group were sacrificed at days 30, 60, 90 and 120. TG2 activity decreased in the p-DAB + TCDD treated group, but TG2 immunostaining scores did not change by days 90 and 120. Neither TG2 enzyme activity nor the immunostaining score of TG2 protein changed in the tissues of the p-DAB + TCDD + RA group by days 90 and 120. TG2 activity was not be ameliorated by RA during the initiation or promotion stages of carcinogen induced liver cancer. PMID:27089473

  4. Effects of fermented Cordyceps sinensis on oxidative stress in doxorubicin treated rats

    PubMed Central

    Wu, Rong; Gao, Jian-Ping; Wang, Hui-Lin; Gao, Yan; Wu, Qian; Cui, Xiao-Hua

    2015-01-01

    Background: Cordyceps sinensis (CS) is one of the rare traditional Chinese herbs, only a very limited amount of natural CS is produced. Fermented CS, as a substitute for natural CS, is widely used in the field of supplementary medical treatment and health products. Its antagonistic effect on oxidative stress (OS) in vivo has not been investigated. Objective: Our aim was to investigate the antagonistic effect of fermented CS on OS in doxorubicin (DOX) treated rats and to compare the anti-OS effects in heart and liver tissues. Materials and Methods: OS rats were induced by tail-intravenous injection of DOX (total of 7.5 mg/kg), and then administered intragastrically with fermented CS (1.5 g/kg) for 4 weeks. At the end of the experiment, heart, liver and serum samples were taken for and biochemical analyses. Results: Fermented CS significantly increased the activities of glutathione peroxidase and catalase and the scavenging activity of O2− in serum, and the total superoxide dismutase activity in cardiac tissue; reduced the malondialdehyde content in liver and cardiac tissues. Conclusion: Fermented CS can inhibit DOX-induced OS reactions, and the anti-OS effects have high selectivity to heart and liver, especially to heart. Thus, fermented CS may be a candidate used for the prevention against various cardiac diseases induced by OS. PMID:26600716

  5. Abnormal expression of vesicular transport proteins in pulmonary arterial hypertension in monocrotaline-treated rats.

    PubMed

    Zhang, Hongliang; Luo, Qin; Liu, Zhihong; Wang, Yong; Zhao, Zhihui

    2015-03-01

    Intracellular vesicular transport is shown to be dysfunctional in pulmonary arterial hypertension (PAH). However, the expression of intracellular vesicular transport proteins in PAH remains unclear. To elucidate the possible role of these proteins in the development of PAH, the changes in the expressions of N-ethyl-maleimide-sensitive factor (NSF), α-soluble NSF attachment protein (α-SNAP), synaptosome-associated membrane protein 23 (SNAP23), type 2 bone morphogenetic receptor (BMPR2), caveolin-1 (cav-1), and endothelial nitric oxide synthase (eNOS) were examined in lung tissues of monocrotaline (MCT)-treated rats by real-time polymerase chain reaction and western blot analysis. In addition, caspase-3, also examined by western blot analysis, was used as an indicator of apoptosis. Our data showed that during the development of PAH, the expressions of NSF, α-SNAP, and SNAP23 were significantly increased before pulmonary arterial pressure started to increase and then significantly decreased after PAH was established. The expressions of BMPR2 and eNOS were similar to those of NSF, α-SNAP, and SNAP23; however, the expression of cav-1 was down-regulated after MCT treatment. Caspase-3 expression was increased after exposure to MCT. In conclusion, the expressions of NSF, α-SNAP, and SNPA23 changed greatly during the onset of PAH, which was accompanied by abnormal expressions of BMPR2, cav-1, and eNOS, as well as an increase in apoptosis. Thus, changes in NSF, α-SNAP, and SNAP23 expressions appear to be mechanistically associated with the development of PAH in MCT-treated rats. PMID:25630652

  6. Histomorphological and morphometric studies of the pancreatic islet cells of diabetic rats treated with extracts of Annona muricata.

    PubMed

    Adeyemi, D O; Komolafe, O A; Adewole, O S; Obuotor, E M; Abiodun, A A; Adenowo, T K

    2010-05-01

    Microanatomical changes in the pancreatic islet cells of streptozotocin induced diabetic Wistar rats were studied after treatment with methanolic extracts of Annona muricata leaves. Thirty adult Wistar rats were randomly assigned into three groups (control, untreated diabetic group, and A. muricata-treated diabetic group) of ten rats each. Diabetes mellitus was experimentally induced in groups B and C by a single intra-peritoneal injection of 80 mg/kg streptozotocin dissolved in 0.1 M citrate buffer. The control rats were intraperitoneally injected with an equivalent volume of citrate buffer. Daily intra peritoneal injections of 100 mg/kg A. muricata were administered to group C rats for two weeks. Post sacrifice the pancreases of the rats were excised and fixed in Bouin's fluid. The tissues were processed for paraffin embedding and sections of 5 mum thickness were produced and stained with H & E, Gomori aldehyde fuchsin, and chrome alum haematoxylin-phloxine for demonstration of the beta-cells of islets of pancreatic islets. Histomorphological and morphometric examination of the stained pancreatic sections showed a significant increase in the number, diameter, and volume of the beta-cells of pancreatic islets of the A. muricata-treated group (5.67 +/- 0.184 N/1000 mum(2), 5.38 +/- 0.093 mum and 85.12 +/- 4.24 mum(3), respectively) when compared to that of the untreated diabetic group of rats (2.85 +/- 0.361 N/1000 mum(2), 2.85 +/- 0.362 mum and 69.56 +/- 5.216 mum(3), respectively). The results revealed regeneration of the beta-cells of islets of pancreatic islet of rats treated with extract of A. muricata.

  7. Potential fat-lowering and prebiotic effects of enzymatically treated okara in high-cholesterol-fed Wistar rats.

    PubMed

    Villanueva-Suárez, María-José; Pérez-Cózar, María-Luisa; Mateos-Aparicio, Inmaculada; Redondo-Cuenca, Araceli

    2016-11-01

    This study evaluates the effect of the lipid profile on serum, liver and faeces, and the potential prebiotic effect of diets supplemented with enzymatically treated okara (okara(ET)) in high-cholesterol fed Wistar rats. Triglyceride levels were significantly reduced in the serum (p < 0.01) and liver (p < 0.01) of okara(ET) treated rats. Total lipids, triglycerides and bile acids were significantly higher (p < 0.001) in the faeces of rats fed the okara(ET) diet. The pH of faecal contents from treated okara(ET) rats was lower (p < 0.001), probably due to the significantly higher (p < 0.001) production of short-chain fatty acids (SCFA). Okara(ET), therefore, reduced triglycerides in serum and liver, and increased the excretion of total lipids, triglycerides and bile acids, improving the lipid profile in rats fed with high-cholesterol diets. Okara(ET) fibre can improve intestinal transit by increasing faecal bulk. The decreased pH and increased SCFA production indicated that okara(ET) fibre fermentation occurred, suggesting a potential prebiotic effect.

  8. Requirements of glycerol and fatty acid for triglyceride synthesis and ketogenesis by hepatocytes from normal and triiodothyronine-treated rats

    SciTech Connect

    Olubadewo, J.O.; Heimberg, M.

    1985-11-15

    Hepatocytes from T3-treated rats synthesized less triglyceride and more ketone bodies from (1-/sup 14/C)oleate at all concentrations from 0-2 mM, than did hepatocytes from euthyroid animals; addition of 1.0 mM glycerol increased triglyceride synthesis and reduced ketogenesis in hepatocytes from T3-treated rats to the rates observed in euthyroid hepatocytes in the absence of added glycerol. Glycerol did not alter triglyceride synthesis, but reduced ketogenesis genesis by euthyroid hepatocytes. It is probable from these and other data that, in the hyperthyroid rat, glycero-3-P, and not fatty acid, is rate limiting for synthesis of triglyceride, and, secondarily for reducing rates of ketogenesis in the hepatocyte.

  9. Cancellous bone healing around strontium-doped hydroxyapatite in osteoporotic rats previously treated with zoledronic acid.

    PubMed

    Li, Yunfeng; Shui, Xueping; Zhang, Li; Hu, Jing

    2016-04-01

    Bisphosphonates (BPs) are potent anti-osteoporotic agents. Strontium-doped hydroxyapatite (HA) (SrHA) has been reported to increase bone density and improve trabecular microarchitecture in osteoporotic animals. But information about the effect of SrHA on the surrounding bone tissue in osteoporotic animals previously on BPs treatment is limited. We hypothesize that SrHA will induce increased bone density in the vicinity of the material when compared to HA, even in osteoporotic animals previously treated with BPs. HA and 10%SrHA (HA with 10 mol % calcium substituted by strontium) implants were prepared and characterized by scanning electronic microscopy (SEM), X-ray photoemission spectroscopy (XPS), and X-ray diffraction (XRD). Osteoporotic animal model was established by bilateral ovariectomy. Twelve weeks later, all OVX rats accepted subcutaneous injection of zoledronic acid (ZOL) at the dose of 1.5 μg/kg weekly for another twelve weeks. Subsequently, rod-shaped HA and SrHA implants were inserted in the distal femur of the OVX animals previously treated with ZOL. Eight weeks after implantation, specimens were harvested for histological and micro-computed tomography (micro-CT) analysis. Compared to HA, 10%SrHA raised the percent bone volume by 32.7%, the mean trabecular thickness by 36.5%, the mean trabecular number by 34.3%, the mean connectivity density by 38.4%, while the mean trabecular separation showed no significant difference. 10%SrHA also increased the bone area density by 36.3% in histological analysis. Results from this study indicated that 10%SrHA increased bone density and improved trabecular microarchitecture around implants in osteoporotic animals previously treated with ZOL when compared to HA. PMID:25891947

  10. Interaction of central Angiotensin II and estrogen on systolic blood pressure in female DOCA-salt treated rats

    PubMed Central

    Kafami, Marzieh; Hosseini, Mahmoud; Niazmand, Saeed; Hadjzadeh, Mousa Alreza; Farrokhi, Esmaeil; Mazloum, Tahereh; Shafei, Mohammad Naser

    2016-01-01

    Background: There is a probable interaction of central angiotensin II (Ang II) and estrogen (Est) on blood pressure in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Therefore, in the present study, the interaction between Ang II and Est in ovariectomized (Ovx) and Sham rats that were treated with DOCA- salt was evaluated. Materials and Methods: The female rats were divided into 10 groups as follows: Sham, Ovx, Sham-DOCA, Ovx-DOCA, Sham-DOCA-estrogen (E), Ovx DOCA-E, Sham-DOCA-losartan (L), Ovx-DOCA-L, Sham–DOCA-L-E, and Ovx-DOCA-L-E. The Est groups received estradiol valerate (2 mg/kg; daily; subcutaneously (s.c)) for four weeks. Following that, several doses of Ang II (0.5, 5, 50, 500, 5000 ng/5 μl) were injected via the intracerebroventricular (i.c.v) route and the changes in systolic blood pressure (SBP) were evaluated. In the losartan groups, 200 μg losartan was injected (i.c.v) 15 minutes after the Ang II injection and the blood pressure was recorded. Treatment by DOCA was performed by removal of one kidney, injection of DOCA (45 mg/kg i.p), and adding of sodium chloride (NaCl) (1%) and potassium chloride (KCl) (0.1%) in the drinking water. Results: The SBP was increased by Ang II and this effect in DOCA-salt treated rat was higher than in the untreated groups. The effect of Ang II on SBP in groups that were treated with Est and L was lower than that in the DOCA-salt groups. Increase in SBP was strongly attenuated by Ang II in groups that were co-treated with both Est and L compared to the DOCA-treated rats. These results showed that Est significantly attenuated the effect of central Ang II on SBP in the DOCA-salt treated rats. Conclusion: We suggest that there are interactions between E and Ang II in the control of blood pressure in DOCA-salt treated rats. PMID:27195251

  11. Postweaning housing conditions and partner preference and sexual behavior of neonatally ATD-treated male rats.

    PubMed

    Bakker, J; van Ophemert, J; Slob, A K

    1995-01-01

    Male rats were neonatally treated with cholesterol or a substance that blocks the aromatization of testosterone to estradiol (1,4,6-androstatriene-3,17-dione: ATD). At weaning (21 days) they were either housed alone or in small groups (2-3 animals) and tested for partner preference behavior (PPB) in adulthood. Choice was between an estrous female and an active male (Part I) and between an estrous female and an ATD-male (Part II). Tests were carried out in a 3-compartment box. Social isolation did not have major effects on PPB except when sexual interaction with the stimulus animals was prevented (Part I). In this case, isolates (ATD and control) showed higher preference scores (PS) for the estrous female and spent less time in the empty middle compartment. When the choice was between an estrous female and an ATD-male, partner PS decreased in all males, most clearly in ATD-males. The latter animals spent more time with the stimulus ATD-male than they had done in previous PPB tests with the normal stimulus male. In contrast to partner preference behaviors, sexual behavior was clearly affected by social isolation. Isolates (ATD and control) displayed lower frequencies of mounts and intromissions. These effects persisted over consecutive tests. Ejaculation was not affected. In conclusion, the present results confirm earlier findings about the significance of neonatal endocrine conditions for the organization of adult PPB in male rats. The presence or absence of social conspecifics after weaning appears to have little influence on adult PPB.

  12. Charge effect of a liposomal delivery system encapsulating simvastatin to treat experimental ischemic stroke in rats

    PubMed Central

    Campos-Martorell, Mireia; Cano-Sarabia, Mary; Simats, Alba; Hernández-Guillamon, Mar; Rosell, Anna; Maspoch, Daniel; Montaner, Joan

    2016-01-01

    Background and aims Although the beneficial effects of statins on stroke have been widely demonstrated both in experimental studies and in clinical trials, the aim of this study is to prepare and characterize a new liposomal delivery system that encapsulates simvastatin to improve its delivery into the brain. Materials and methods In order to select the optimal liposome lipid composition with the highest capacity to reach the brain, male Wistar rats were submitted to sham or transitory middle cerebral arterial occlusion (MCAOt) surgery and treated (intravenous [IV]) with fluorescent-labeled liposomes with different net surface charges. Ninety minutes after the administration of liposomes, the brain, blood, liver, lungs, spleen, and kidneys were evaluated ex vivo using the Xenogen IVIS® Spectrum imaging system to detect the load of fluorescent liposomes. In a second substudy, simvastatin was assessed upon reaching the brain, comparing free and encapsulated simvastatin (IV) administration. For this purpose, simvastatin levels in brain homogenates from sham or MCAOt rats at 2 hours or 4 hours after receiving the treatment were detected through ultra-high-protein liquid chromatography. Results Whereas positively charged liposomes were not detected in brain or plasma 90 minutes after their administration, neutral and negatively charged liposomes were able to reach the brain and accumulate specifically in the infarcted area. Moreover, neutral liposomes exhibited higher bioavailability in plasma 4 hours after being administered. The detection of simvastatin by ultra-high-protein liquid chromatography confirmed its ability to cross the blood–brain barrier, when administered either as a free drug or encapsulated into liposomes. Conclusion This study confirms that liposome charge is critical to promote its accumulation in the brain infarct after MCAOt. Furthermore, simvastatin can be delivered after being encapsulated. Thus, simvastatin encapsulation might be a promising

  13. Mucosal acid causes gastric mucosal microcirculatory disturbance in nonsteroidal anti-inflammatory drug-treated rats.

    PubMed

    Funatsu, Toshiyuki; Chono, Koji; Hirata, Takuya; Keto, Yoshihiro; Kimoto, Aishi; Sasamata, Masao

    2007-01-01

    The mechanism by which nonsteroidal anti-inflammatory drugs (NSAIDs) suppress gastric mucosal blood flow is not fully understood, although the depletion of mucosal prostaglandin E2 has been proposed as one possible explanation. We investigated the role of gastric acid on gastric mucosal blood flow in NSAID-treated rats. A rat stomach was mounted in an ex vivo chamber, and gastric mucosal blood flow was measured sequentially in a 5-mm2 area of the gastric corpus using a scanning laser Doppler perfusion image system. Results showed that diclofenac (5 mg/kg s.c.) and indomethacin (10 mg/kg s.c.) did not affect gastric mucosal blood flow, although both strongly decreased mucosal prostaglandin E2 when saline was instilled into the gastric chamber. On replacement of the saline in the chamber with 100 mM hydrochloric acid, these drugs caused a decrease in gastric mucosal blood flow levels within 30 min. The specific cyclooxygenase (COX)-2 inhibitors celecoxib (50 mg/kg s.c.) and rofecoxib (25 mg/kg s.c.) did not affect mucosal prostaglandin E2 level, nor did they decrease gastric mucosal blood flow, even when hydrochloric acid was added to the chamber. Furthermore, measurement of vasoconstrictive factors present in the mucosa showed that endothelin-1 levels increased after administration of diclofenac s.c. in the presence of intragastric hydrochloric acid. This indicates that the presence of mucosal hydrochloric acid plays an important role in the NSAID-induced decrease in gastric mucosal blood flow, while the COX-1-derived basal prostaglandin E2, which is unlikely to control gastric mucosal blood flow itself, protects microcirculatory systems from mucosal hydrochloric acid.

  14. Structural and biochemical changes in lungs of 3-methylindole-treated rats.

    PubMed Central

    Woods, L. W.; Wilson, D. W.; Schiedt, M. J.; Giri, S. N.

    1993-01-01

    Effects of a single dose of 3-methylindole (3-MI) (250 mg/kg intraperitoneally) were studied at different times ranging from 12 hours to 2 weeks post-treatment (PT). Microscopic study revealed mild Clara cell injury 24 hours PT and mucus hyperplasia 24 hours to 2 weeks PT. Diffuse type I alveolar epithelial cell necrosis occurred at 48 hours, followed by type II cell hyperplasia. Septal edema and accumulation of interstitial and capillary polymorphonuclear leukocytes and perivascular mixed mononuclear inflammatory cells accompanied the injury and repair. A gradual resolution of lesions with persistent mononuclear inflammatory cellular clusters at septal junctions, focal septal fibrosis, and accumulation of alveolar macrophages was evident at 1 and 2 weeks PT. Collagen, measured as hydroxyproline, in 3-MI-treated rats was significantly increased to 130% and 139% of control (3.0 mg/lung) at 1 and 2 weeks PT, respectively. Biphasic peaks of plasma 6-keto-prostaglandin F1 alpha occurred at 12 to 24 hours and at 96 hours PT with 3-MI and thromboxane B2 was elevated 12, 48, and 96 hours PT. Right ventricular/left ventricular and septal weight was increased to 120% and 140% of the control 1 and 2 weeks PT. We concluded that 3-MI induces alveolar septal injury in the rat with relatively complete repair of the alveolar epithelium and residual mild focal septal fibrosis and pulmonary hypertension 2 weeks PT. Arachidonic acid-derived mediators and inflammation are associated with 3-MI-induced lung injury. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 PMID:8424451

  15. Experimental erythrocyte autoantibodies. V. Induction and suppression of red blood cell autoantibodies in mice injected with rat bromelain-treated red blood cells.

    PubMed

    Cox, K O; McAuliffe, A

    1983-10-01

    Mice injected with rat red blood cells (RBC), or rat bromelain-treated (brom) RBC, produce RBC autoantibodies and suppressor cells that specifically inhibit the autoimmune response without inhibiting the net production of antibodies against rat RBC. It has been investigated whether suppressor cells induced by injections of rat RBC are effective in preventing autoantibody production induced by rat brom RBC and vice versa. Autoantibodies were induced in C3H mice by weekly ip injections, each 0.2 ml, of a 6% suspension of rat RBC or rat brom RBC. Autoantibody production was assayed using Coombs' test. Suppressor cells were present in the spleens of mice positive in Coombs' tests and were shown by intravenous injections of 40 X 10(6) viable cells per mouse into untreated syngeneic mice 18 hr before the first injection of rat RBC or rat brom RBC. Autoantibodies eluted from mice positive in Coombs' tests after injections of rat RBC or brom RBC were absorbed by either type of rat RBC but not by RBC from sheep. This suggests that rat RBC and rat brom RBC display antigens that are similar, if not identical, to autoantigens on the mouse RBC. Spleen cells from mice injected with rat RBC suppressed autoantibodies induced by both rat RBC and rat brom RBC. In contrast, spleen cells from mice injected with rat brom RBC suppressed autoantibodies induced by rat brom RBC but not those induced by unmodified rat RBC. This differential suppression may be due to the removal from rat RBC, by bromelain, of a suppressor site and/or autoantigens of some specificities. Thus rat brom RBC may not induce the total range of specificities of autoantibodies, and of suppressor cells, induced by rat RBC.

  16. Effects of puffer (Sphoeroides rubripes) supplementation on disruption of antioxidant defense systems in ethanol-treated rats.

    PubMed

    Joo, Jong-Chan; Park, Jae-Hee; Kim, Rae-Young; Jeon, Kyoung-Im; Lee, Hyun-Jung; Seo, Bo-Young; Park, Eunju

    2011-01-01

    We investigated the effects of puffer (Sphoeroides rubripes) supplementation on antioxidant metabolism in ethanol-treated rats. Sprague-Dawley rats were randomly assigned into 4 groups of 7 rats each and fed (1) an AIN-93G diet (NC), (2) 25% ethanol (E), (3) 25% ethanol and an AIN-93G diet containing 1% puffer flesh (E+F), or (4) 25% ethanol and an AIN-93G diet containing 1% puffer skin (E+S) for 5 wk. At the end of the experimental period, the rats were sacrificed and their blood and organs were collected. To evaluate the effect of puffer supplementation, lipid-soluble antioxidant vitamin and conjugated diene (CD) levels, DNA damage, and mRNA expression of heme oxygenase-1 (HO-1) were assessed. Animals that were fed ethanol showed reduced plasma levels of lipid-soluble antioxidant vitamin and significantly increased levels of lipid peroxides, DNA damage, and HO-1 expression. Dietary supplementation with puffer conferred an antioxidant effect by significantly increasing the levels of γ-tocopherol, a lipid-soluble antioxidant vitamin, and by significantly decreasing the plasma levels of CD, DNA damage, and HO-1 expression. These results suggest that consumption of puffer improves the antioxidant status of ethanol-treated rats.

  17. Induction of thymidine phosphorylase as a pharmacodynamic end-point in patients with advanced carcinoma treated with 5-fluorouracil, folinic acid and interferon alpha

    PubMed Central

    Braybrooke, J P; Propper, D J; O’Byrne, K J; Koukourakis, M I; Patterson, A V; Houlbrook, S; Love, S D; Varcoe, S; Taylor, M; Ganesan, T S; Talbot, D C; Harris, A L

    2000-01-01

    Thymidine phosphorylase (TP) is an essential enzyme for the biochemical activation of 5-fluorouracil (5-FU). Interferon upregulates TP in vivo, although the dose and schedule of interferon for optimal biomodulation of 5-FU is not known. In this study, TP activity was measured in peripheral blood lymphocytes (PBLs) from patients with advanced carcinoma receiving treatment with 5-FU and folinic acid. Cohorts of patients were treated with interferon alpha (IFNα), immediately prior to 5-FU/folinic acid, at doses of 3 MIU m–2, 9 MIU m–2and 18 MIUm–2. IFNα was administered on day 0 cycle two, day –1 and day 0 cycle three and day –2, day –1 and day 0 cycle four. A fourth cohort was treated with IFNα 9 MIU m–2three times per week from cycle 2 onwards. Twenty-one patients were entered into the study with 19 evaluable for response. Six patients (32%) had stable disease and 13 (68%) progressive disease. There were no grade-IV toxicities. TP activity was detected in PBLs from all patients with wide interpatient variability in constitutive TP activity prior to chemotherapy, and in response to IFNα. 5-FU/folinic acid alone did not induce TP activity but a single dose of IFNα led to upregulation of TP within 2 h of administration with a further increase by 24 h (signed rank test, P = 0.006). TP activity remained elevated for at least 13 days (signed rank test, P = 0.02). There were no significant differences in TP activity between schedules or with additional doses of IFNα. A single dose of IFNα as low as 3 MIU m–2can cause sustained elevation of PBL TP activity in vivo indicating that biochemical markers are important pharmacodynamic endpoints for developing optimal schedules of IFNα for biomodulation of 5-FU. © 2000 Cancer Research Campaign PMID:10901374

  18. Role of Mas receptor in renal blood flow response to angiotensin-(1-7) in ovariectomized estradiol treated rats

    PubMed Central

    Saberi, Shadan; Dehghani, Aghdas; Nematbakhsh, Mehdi

    2016-01-01

    The angiotensin 1-7 (Ang 1-7), is abundantly produced in kidneys and antagonizes the function of angiotensin II through Mas receptor (MasR) or other unknown mechanisms. In the current study, the role of MasR and steroid hormone estrogen on renal blood flow response to Ang 1-7 administration was investigated in ovariectomized (OV) female rats. OV female Wistar-rats received estradiol (500 μg/kg/week) or vehicle for two weeks. In the day of the experiment, the animals were anesthetized, cannulated, and the responses including mean arterial pressure, renal blood flow (RBF), and renal vascular resistance at the constant level of renal perfusion pressure to graded infusion of Ang 1-7 at 0, 100 and 300 ng/kg/min were determined in OV and OV estradiol-treated (OVE) rats, treated with vehicle or MasR antagonist; A779. RBF response to Ang 1-7 infusion increased dose-dependently in vehicle (Pdose<0.001) and A779-treated (Pdose<0.01) animals. However, when MasR was blocked, the RBF response to Ang 1-7 significantly increased in OV animals compared with OVE rats (P<0.05). When estradiol was limited by ovariectomy, A779 increased RBF response to Ang 1-7 administration, while this response was attenuated in OVE animals. PMID:27051434

  19. Role of Mas receptor in renal blood flow response to angiotensin-(1-7) in ovariectomized estradiol treated rats.

    PubMed

    Saberi, Shadan; Dehghani, Aghdas; Nematbakhsh, Mehdi

    2016-01-01

    The angiotensin 1-7 (Ang 1-7), is abundantly produced in kidneys and antagonizes the function of angiotensin II through Mas receptor (MasR) or other unknown mechanisms. In the current study, the role of MasR and steroid hormone estrogen on renal blood flow response to Ang 1-7 administration was investigated in ovariectomized (OV) female rats. OV female Wistar-rats received estradiol (500 μg/kg/week) or vehicle for two weeks. In the day of the experiment, the animals were anesthetized, cannulated, and the responses including mean arterial pressure, renal blood flow (RBF), and renal vascular resistance at the constant level of renal perfusion pressure to graded infusion of Ang 1-7 at 0, 100 and 300 ng/kg/min were determined in OV and OV estradiol-treated (OVE) rats, treated with vehicle or MasR antagonist; A779. RBF response to Ang 1-7 infusion increased dose-dependently in vehicle (Pdose <0.001) and A779-treated (Pdose <0.01) animals. However, when MasR was blocked, the RBF response to Ang 1-7 significantly increased in OV animals compared with OVE rats (P<0.05). When estradiol was limited by ovariectomy, A779 increased RBF response to Ang 1-7 administration, while this response was attenuated in OVE animals. PMID:27051434

  20. Evaluation of glycemic and lipid profile of offspring of diabetic Wistar rats treated with Malpighia emarginata juice.

    PubMed

    Barbalho, Sandra M; Damasceno, Débora C; Spada, Ana Paula Machado; Palhares, Miréia; Martuchi, Karla Aparecida; Oshiiwa, Marie; Sazaki, Viviane; da Silva, Vanessa Sellis

    2011-01-01

    Knowing that maternal diabetes is related to hyperglycemia and fetal hyperinsulinemia, which affect the lipid metabolism, the aim of this study was to evaluate the effects of Malpighia emarginata (acerola) juice on the glycemic and lipid profile of offspring of diabetic and nondiabetic Wistar rats. The adult offspring of non-diabetic dams and of dams with severe streptozotocin-induced diabetes were divided into groups: G1, offspring (of control dams) treated with water, G2, offspring (of diabetic dams) treated with water, G3, male offspring (of control dams) treated with acerola juice, and G4, male offspring (of diabetic dams) treated with acerola juice. The offspring of diabetic dams treated with acerola juice showed significantly decreased levels of glucose, cholesterol, triglycerides, and increased HDL-c. The use of acerola juice is a potential strategy to aid in the prevention of DM and dyslipidemia and its complications or to act as an auxiliary in the treatment of these diseases.

  1. Quantitative analysis of hindlimbs locomotion kinematics in spinalized rats treated with Tamoxifen plus treadmill exercise.

    PubMed

    Osuna-Carrasco, L P; López-Ruiz, J R; Mendizabal-Ruiz, E G; De la Torre-Valdovinos, B; Bañuelos-Pineda, J; Jiménez-Estrada, I; Dueñas-Jiménez, S H

    2016-10-01

    Locomotion recovery after a spinal cord injury (SCI) includes axon regeneration, myelin preservation and increased plasticity in propriospinal and descending spinal circuitries. The combined effects of tamoxifen and exercise after a SCI were analyzed in this study to determine whether the combination of both treatments induces the best outcome in locomotion recovery. In this study, the penetrating injury was provoked by a sharp projectile that penetrates through right dorsal and ventral portions of the T13-L1 spinal segments, affecting propriospinal and descending/ascending tracts. Intraperitoneal application of Tamoxifen and a treadmill exercise protocol, as rehabilitation therapies, separately or combined, were used. To evaluate the functional recovery, angular patterns of the hip, knee and ankle joints as well as the leg pendulum-like movement (PLM) were measured during the unrestricted gait of treated and untreated (UT) animals, previously and after the traumatic injury (15 and 30days post-injury (dpi)). A pattern (curve) comparison analysis was made by using a locally designed Matlab script that determines the Frechet dissimilarity. The SCI magnitude was assessed by qualitative and quantitative histological analysis of the injury site 30days after SCI. Our results showed that all treated groups had an improvement in hindlimbs kinematics compared to the UT group, which showed a poor gait locomotion recovery throughout the rehabilitation period. The group with the combined treatment (tamoxifen+exercise (TE)) presented the best outcome. In conclusion, tamoxifen and treadmill exercise treatments are complementary therapies for the functional recovery of gait locomotion in hemi-spinalized rats. PMID:27450566

  2. Morphological study of rat skin flaps treated with subcutaneous dimethyl sulfoxide combined with hyperbaric oxygen therapy.

    PubMed

    Almeida, K G; Oliveira, R J; Dourado, D M; Filho, E A; Fernandes, W S; Souza, A S; Araújo, F H S

    2015-01-01

    This study investigated the effects of hyperbaric oxygen therapy (HBOT) and dimethyl sulfoxide (DMSO) in tissue necrosis, genotoxicity, and cell apoptosis. Random skin flaps were made in 50 male Wistar rats, randomly divided into the following groups. Control group (CT), wherein a rectangular skin section (2 x 8 cm) was dissected from the dorsal muscle layer, preserving the cranial vessels, lifted, and refixed to the bed; distilled water (DW) group, in which DW was injected into the distal half of the skin flap; DMSO group, wherein 5% DMSO was injected; HBOT group, comprising animals treated only with HBOT; and HBOT + DMSO group, comprising animals treated with 100% oxygen at 2.5 atmospheres absolute for 1 h, 2 h after the experiment, daily for 10 consecutive days. A skinflap specimen investigated by microscopy. The percentage of necrosis was not significantly different between groups. The cell viability index was significantly different between groups (P < 0.001): 87.40% (CT), 86.20% (DW), 84.60% (DMSO), 86.60% (DMSO + HBO), and 91% (HBO) (P < 0.001), as was the cell apoptosis index of 12.60 (CT), 12.00 (DW), 15.40 (DMSO), 9.00 (HBO), and 12.00 (DMSO + HBO) (P < 0.001). The genotoxicity test revealed the percentage of cells with DNA damage to be 22.80 (CT), 22.60 (DW), 26.00 (DMSO), 8.80 (DMSO + HBO), and 7.20 (HBO) (P < 0.001). Although the necrotic area was not different between groups, there was a significant reduction in the cellular DNA damage and apoptosis index in the HBOT group. PMID:26782463

  3. Morphological study of rat skin flaps treated with subcutaneous dimethyl sulfoxide combined with hyperbaric oxygen therapy.

    PubMed

    Almeida, K G; Oliveira, R J; Dourado, D M; Filho, E A; Fernandes, W S; Souza, A S; Araújo, F H S

    2015-12-28

    This study investigated the effects of hyperbaric oxygen therapy (HBOT) and dimethyl sulfoxide (DMSO) in tissue necrosis, genotoxicity, and cell apoptosis. Random skin flaps were made in 50 male Wistar rats, randomly divided into the following groups. Control group (CT), wherein a rectangular skin section (2 x 8 cm) was dissected from the dorsal muscle layer, preserving the cranial vessels, lifted, and refixed to the bed; distilled water (DW) group, in which DW was injected into the distal half of the skin flap; DMSO group, wherein 5% DMSO was injected; HBOT group, comprising animals treated only with HBOT; and HBOT + DMSO group, comprising animals treated with 100% oxygen at 2.5 atmospheres absolute for 1 h, 2 h after the experiment, daily for 10 consecutive days. A skinflap specimen investigated by microscopy. The percentage of necrosis was not significantly different between groups. The cell viability index was significantly different between groups (P < 0.001): 87.40% (CT), 86.20% (DW), 84.60% (DMSO), 86.60% (DMSO + HBO), and 91% (HBO) (P < 0.001), as was the cell apoptosis index of 12.60 (CT), 12.00 (DW), 15.40 (DMSO), 9.00 (HBO), and 12.00 (DMSO + HBO) (P < 0.001). The genotoxicity test revealed the percentage of cells with DNA damage to be 22.80 (CT), 22.60 (DW), 26.00 (DMSO), 8.80 (DMSO + HBO), and 7.20 (HBO) (P < 0.001). Although the necrotic area was not different between groups, there was a significant reduction in the cellular DNA damage and apoptosis index in the HBOT group.

  4. Statin-induced myotoxicity is exacerbated by aging: A biophysical and molecular biology study in rats treated with atorvastatin.

    PubMed

    Camerino, Giulia Maria; De Bellis, Michela; Conte, Elena; Liantonio, Antonella; Musaraj, Kejla; Cannone, Maria; Fonzino, Adriano; Giustino, Arcangela; De Luca, Annamaria; Romano, Rossella; Camerino, Claudia; Laghezza, Antonio; Loiodice, Fulvio; Desaphy, Jean-Francois; Conte Camerino, Diana; Pierno, Sabata

    2016-09-01

    Statin-induced skeletal muscle damage in rats is associated to the reduction of the resting sarcolemmal chloride conductance (gCl) and ClC-1 chloride channel expression. These drugs also affect the ClC-1 regulation by increasing protein kinase C (PKC) activity, which phosphorylate and close the channel. Also the intracellular resting calcium (restCa) level is increased. Similar alterations are observed in skeletal muscles of aged rats, suggesting a higher risk of statin myotoxicity. To verify this hypothesis, we performed a 4-5-weeks atorvastatin treatment of 24-months-old rats to evaluate the ClC-1 channel function by the two-intracellular microelectrodes technique as well as transcript and protein expression of different genes sensitive to statins by quantitative real-time-PCR and western blot analysis. The restCa was measured using FURA-2 imaging, and histological analysis of muscle sections was performed. The results show a marked reduction of resting gCl, in agreement with the reduced ClC-1 mRNA and protein expression in atorvastatin-treated aged rats, with respect to treated adult animals. The observed changes in myocyte-enhancer factor-2 (MEF2) expression may be involved in ClC-1 expression changes. The activity of PKC was also increased and further modulate the gCl in treated aged rats. In parallel, a marked reduction of the expression of glycolytic and mitochondrial enzymes demonstrates an impairment of muscle metabolism. No worsening of restCa or histological features was found in statin-treated aged animals. These findings suggest that a strong reduction of gCl and alteration of muscle metabolism coupled to muscle atrophy may contribute to the increased risk of statin-induced myopathy in the elderly. PMID:27377005

  5. Effect of tocotrienol on the activities of cytosolic glutathione-dependent enzymes in rats treated with 2-acetylaminofluorene.

    PubMed

    Shamaan, N A; Wan Ngah, W Z; Ibrahim, R; Jarien, Z; Top, A G; Abdul Kadir, K

    1993-04-01

    The effect of tocotrienol on the activities of glutathione S-transferases (GSTs), glutathione reductase (GR) and glutathione peroxidase (GPx) in rats given 2-acetylaminofluorene (AAF) was investigated over a 20 week period. Liver and kidney GST and liver GR activities were significantly increased after AAF administration. Kidney GPx activities were significantly affected; activity assayed with cumene hydroperoxide (cu-OOH) was increased but activity assayed with H2O2 was reduced. Supplementation of the diet with tocotrienol in the AAF-treated rats reduced the increase in enzyme activities. Tocotrienol on its own had no effect on the enzyme activities.

  6. The regulatory mechanisms of myogenin expression in doxorubicin-treated rat cardiomyocytes

    PubMed Central

    Yen, Li-Chen; Huang, Chi-Jung; Lin, Wei-Shiang; Chan, James Yi-Hsin

    2015-01-01

    Doxorubicin, an anthracycline antibiotic, has been used as an anti-neoplastic drug for almost 60 years. However, the mechanism(s) by which anthracyclines cause irreversible myocardial injury remains unclear. In order to delineate possible molecular signals involved in the myocardial toxicity, we assessed candidate genes using mRNA expression profiling in the doxorubicin-treated rat cardiomyocyte H9c2 cell line. In the study, it was confirmed that myogenin, an important transcriptional factor for muscle terminal differentiation, was significantly reduced by doxorubicin in a dose-dependent manner using both RT-PCR and western blot analyses. Also, it was identified that the doxorubicin-reduced myogenin gene level could not be rescued by most cardio-protectants. Furthermore, it was demonstrated how the signaling of the decreased myogenin expression by doxorubicin was altered at the transcriptional, post-transcriptional and translational levels. Based on these findings, a working model was proposed for relieving doxorubicin-associated myocardial toxicity by down-regulating miR-328 expression and increasing voltage-gated calcium channel β1 expression, which is a repressor of myogenin gene regulation. In summary, this study provides several lines of evidence indicating that myogenin is the target for doxorubicin-induced cardio-toxicity and a novel therapeutic strategy for doxorubicin clinical applications based on the regulatory mechanisms of myogenin expression. PMID:26452256

  7. Estradiol affects liver mitochondrial function in ovariectomized and tamoxifen-treated ovariectomized female rats

    SciTech Connect

    Moreira, Paula I.; Custodio, Jose B.A.; Nunes, Elsa; Moreno, Antonio; Seica, Raquel; Oliveira, Catarina R.; Santos, Maria S. . E-mail: mssantos@ci.uc.pt

    2007-05-15

    Given the tremendous importance of mitochondria to basic cellular functions as well as the critical role of mitochondrial impairment in a vast number of disorders, a compelling question is whether 17{beta}-estradiol (E2) modulates mitochondrial function. To answer this question we exposed isolated liver mitochondria to E2. Three groups of rat females were used: control, ovariectomized and ovariectomized treated with tamoxifen. Tamoxifen has antiestrogenic effects in the breast tissue and is the standard endocrine treatment for women with breast cancer. However, under certain circumstances and in certain tissues, tamoxifen can also exert estrogenic agonist properties. We observed that at basal conditions, ovariectomy and tamoxifen treatment do not induce any statistical alteration in oxidative phosphorylation system and respiratory chain parameters. Furthermore, tamoxifen treatment increases the capacity of mitochondria to accumulate Ca{sup 2+} delaying the opening of the permeability transition pore. The presence of 25 {mu}M E2 impairs respiration and oxidative phosphorylation system these effects being similar in all groups of animals studied. Curiously, E2 protects against lipid peroxidation and increases the production of H{sub 2}O{sub 2} in energized mitochondria of control females. Our results indicate that E2 has in general deleterious effects that lead to mitochondrial impairment. Since mitochondrial dysfunction is a triggering event of cell degeneration and death, the use of exogenous E2 must be carefully considered.

  8. Oxidative damages in isolated rat hepatocytes treated with the organochlorine fungicides captan, dichlofluanid and chlorothalonil.

    PubMed

    Suzuki, Toshihide; Nojiri, Hisao; Isono, Hideo; Ochi, Takafumi

    2004-11-15

    The cytotoxicity and lipid peroxidative potency of the organochlorine fungicides captan (N-(trichloromethylthio)-4-cyclohexene-1,2-dicarboximide), dichlofluanid (N-dichlorofluoromethylthio-N'N'-dimethyl-N-phenylsulfamide) and chlorothalonil (2,4,5,6-tetrachloro-isophthalonitrile) were studied in isolated rat hepatocytes. These fungicides induced cytotoxicity and lipid peroxidation in a dose- and time-dependent manner. Considerable cytotoxicity and lipid peroxidation occurred after cells were treated with 25 microM and more of fungicide. The phosphatidylcholine hydroperoxide (PCOOH) content increased more than 300 times by captan (250-1000 microM), 400 times by dichlofluanid (250-1000 microM) and 20 times by chlorothalonil (25-1000 microM) after 1h of incubation, as compared with untreated control. Significant cytotoxicity occurred after 20 min (captan), 30 min (dichlofluanid) and 60 min (chlorothalonil) of incubation and lipid peroxidation was induced prior to cytotoxicity. The antioxidant alpha-tocopherol and cytochrome P450 inhibitor SKF-525A effectively prevented cytotoxicity and lipid peroxidation. Our results suggest that metabolites of these fungicides produced by the microsomal cytochrome P450 system, induced membrane phospholipid peroxidation that caused cytotoxicity.

  9. Protective Effect of Sodium Ferulate on Acetaldehyde-Treated Precision-Cut Rat Liver Slices

    PubMed Central

    Guo, Yu; Wu, Xiao-Qian; Zhang, Chun; Liao, Zhang-Xiu; Wu, Yong

    2012-01-01

    Abstract Activated hepatic stellate cells (HSCs) play a key role in hepatic fibrogenesis, and inhibition of HSC activation may prevent liver fibrosis. Acetaldehyde, the most deleterious metabolite of alcohol, triggers HSC activation in alcoholic liver injury. In the present study, we investigated the protective effect of sodium ferulate (SF), a sodium salt of ferulic acid that is rich in fruits and vegetables, on acetaldehyde-stimulated HSC activation using precision-cut liver slices (PCLSs). Rat PCLSs were co-incubated with 350 μM acetaldehyde and different concentrations of SF. Hepatotoxicity was assessed by measuring enzyme leakage and malondialdehyde content in tissue. α-Smooth muscle actin, transforming growth factor-β1, and hydroxyproline were determined to assess the activation of HSCs. In addition, matrix metalloproteinase (MMP)-1 and the tissue inhibitor of metalloproteinase (TIMP-1) were determined to evaluate collagen degradation. SF prominently prevented the enzyme leakage in acetaldehyde-treated slices and also inhibited HSC activation and collagen production stimulated by acetaldehyde. In addition, SF increased MMP-1 expression and decreased TIMP-1 expression. These results showed that SF protected PCLSs from acetaldehyde-stimulated HSC activation and liver injury, which may be associated with the attenuation of oxidative injury and acceleration of collagen degradation. PMID:22404575

  10. Testicular histomorphometry and ultrastructure of rats treated with cadmium and Ginkgo biloba.

    PubMed

    de Souza Predes, Fabrícia; Monteiro, Juliana Castro; Matta, Sérgio Luis Pinto; Garcia, Márcia C; Dolder, Heidi

    2011-06-01

    The aim of this study is to investigate the association of a single low dose of Cd and daily doses of Ginkgo biloba extract (GbE) on the testis and accessory glands of rats. The animals were treated with a single dose of 3 µmol/kg body weight of cadmium chloride (CdCl₂) and/or 100 mg/kg body weight of GbE. The plasma testosterone levels; corporal, testicular, and accessory glands weight; gonadosomatic index, volumetric proportion; and absolute volume of testicular components did not change after the treatments. CdCl₂ caused significant reduction in Leydig cells volume and altered Leydig cell morphology, as well as vacuolated Sertoli cells cytoplasm, irregular chromatin condensation of late spermatids, and modified acrosome formation. However, animals that received GbE did not show these alterations. The reversal of Cd-induced alterations by the extract is a strong indication that G. biloba is helpful in diminishing the effect of Cd toxicity. PMID:20428964

  11. Isolation and characterization of three endosomal fractions from the liver of estradiol-treated rats

    SciTech Connect

    Belcher, J.D.; Hamilton, R.L.; Brady, S.E.; Hornick, C.A.; Jaeckle, S.; Schneider, W.J.; Havel, R.J.

    1987-10-01

    Three distinct endosomal fractions were isolated in high purity from livers of estradiol-treated rats. Each fraction had characteristic physical and ultrastructural properties, but the lipid composition and major proteins of their membranes were similar and differed from those derived from the Golgi apparatus. Injected radioiodinated low density lipoproteins accumulated first in the fraction of intermediate density and later in the low density fraction. The latter was composed almost exclusively of lipoprotein-filled multivesicular bodies, most of which had a single membranous appendage. The fraction of intermediate density was composed of lipoprotein-filled vesicles that were smaller than multivesicular bodies and also had membranous appendages. The high density fraction was composed of membranes resembling the appendages of the two vesicular fractions. All three fractions were enriched in receptors for low density lipoproteins and asialoglycoproteins, but receptor concentrations were considerably reduced in multivesicular bodies. The fraction of intermediate density may represent the compartment of uncoupling of receptor and ligand (CURL) described by Geuze et al. CURL vesicles may lose some of their appendages as multivesicular bodies are formed. The high density fraction than may represent a receptor-recycling compartment.

  12. Metabolic changes in the urine of andrographolide sodium bisulfite-treated rats.

    PubMed

    Xu, J D; Xing, W M; Yuan, T J; Chen, J; Lu, H

    2016-02-01

    In recent years, andrographolide sodium bisulfite (ASB) has been reported to cause acute renal failure frequently in clinical practice. We hypothesized that changes in metabolic profile could have occurred after administration of ASB. To investigate the metabolic changes caused by ASB-induced nephrotoxicity, metabonomics method was utilized to depict the urine metabolic characteristics and find the specific urine biomarkers associated with ASB-induced nephrotoxicity. Sprague-Dawley rats were randomly assigned into three experimental groups. They received a single daily injection of vehicle (0.9% sodium chloride solution) or ASB at a dose of 100 or 600 mg kg(-1) day(-1) for 7 days. Twelve-hour urine was collected after the last administration. The routine urinalysis was measured by a urine automatic analyzer while urinary metabolites were evaluated using gas chromatography/mass spectrometry. The acquired data were processed by multivariate principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and orthogonal PLS-DA. After 7-day administration of ASB, the positive urine samples in protein, occult blood, and ketones were increased, presenting dose dependence. The PCA and PLS-DA models were capable of distinguishing the difference between ASB-treated group and control. Biomarkers such as 1,5-anhydroglucitol, d-erythro-sphingosine, and 2-ketoadipate were identified as the most influential factors in ASB-induced nephrotoxicity.

  13. Role of fatty acyl coenzyme A oxidase in the efflux of oxidized glutathione from perfused livers of rats treated with the peroxisome proliferator nafenopin.

    PubMed

    Conway, J G; Neptun, D A; Garvey, L K; Popp, J A

    1987-09-15

    The diffusion of H2O2 into the cytoplasm from peroxisomes during high rates of peroxisomal beta oxidation of fatty acids was studied in perfused livers from rats treated with the hepatocarcinogenic peroxisome proliferator, nafenopin. Efflux of oxidized glutathione (GSSG) into the bile was used as a measure of increased H2O2 supply for cytoplasmic glutathione peroxidase. Male F-344 rats were given methylcellulose vehicle or nafenopin (80 mg/kg/day) by gavage for 5-8 days and livers perfused in situ with Krebs-Henseleit buffer containing 50 microM taurocholate and 0.75 g/100 ml albumin. In livers from fed, vehicle-treated or fed, nafenopin-treated rats basal rates of GSSG efflux were about 60 nmol/g/h. Subsequent infusion of 350 microM lauric acid, an excellent substrate for peroxisomal beta-oxidation, had no effect on GSSG efflux. To maximize fatty acid oxidation rats were fasted 16-20 h. In livers from fasted, nafenopin-treated rats the basal rate of GSSG efflux was 384 +/- 85 (SE) nmol/g/h (n = 8). Subsequent infusion of lauric acid increased the rate to 940 +/- 138 nmol/g/h. In livers from fasted, vehicle-treated rats lauric acid caused GSSG efflux to increase slightly from 104 +/- 14 to 286 +/- 37 nmol/g/h (n = 9). Efflux of reduced glutathione in bile was similar in livers from fasted, vehicle-treated (163 +/- 15 nmol/g/h) and fasted, nafenopin-treated rats (135 +/- 17 nmol/g/h) and decreased about 30% with lauric acid infusion. N-Octanoyl and oleoyl coenzyme A were excellent substrates for cyanide-insensitive NAD+ reduction in liver homogenates from fasted, nafenopin-treated rats whereas n-butyl, linoleoyl, and arachidonyl coenzyme A were poor substrates. Infusion of octanoate and oleate caused large increases in GSSG efflux from perfused livers from fasted, nafenopin-treated rats. In contrast, butyrate, linoleate, and arachidonate had no effect on GSSG efflux from livers from fasted, nafenopin-treated rats. Octanoate, oleate, linoleate, butyrate, and

  14. Chemotherapeutic effect of Berberis integerrima hydroalcoholic extract on colon cancer development in the 1,2-dimethyl hydrazine rat model.

    PubMed

    Malayeri, Mohammad R Mohammadi; Dadkhah, Abolfazl; Fatemi, Faezeh; Dini, Salome; Torabi, Fatemeh; Tavajjoh, Mohammad M; Rabiei, Javad

    2016-01-01

    The aim of this study was to investigate the efficacy of a Berberis integerrima hydroalcoholic extract as a chemotherapeutic agent in colon carcinogenesis in the rat induced by 1,2-dimethyl hydrazine (DMH). Male Wistar rats were divided into five groups: a negative control group without DMH treatment; a control group injected DMH (20 mg/kg b.w); two groups receiving B. integerrima extract (50 and 100 mg/kg b.w), concomitant with injected DMH, as chemotherapeutic groups; a positive control group receiving 5-fluorouracil (5-FU) along with DMH. The effects of the extracts were determined by assessment of hepatic malondialdehyde (MDA), glutathione (GSH), ferric reducing ability of plasma (FRAP), and the activities of hepatic glutathione S-transferase and cytochrome P450 (GST and CYP450). Additionally, colon tissues were assessed for colonic β-catenin and histopathological analysis. In DMH-treated rats, the extracts partially normalized the levels of FRAP, CYP450, β-catenin, and GST. Likewise, formation of aberrant crypt foci (ACF) in colon tissue of DMH-treated was reduced by the extracts. Thus, the extracts possess chemotherapeutic activity against colon carcinogenesis.

  15. Blood glucose level and lipid profile of alloxan-induced hyperglycemic rats treated with single and combinatorial herbal formulations

    PubMed Central

    Ojiako, Okey A.; Chikezie, Paul C.; Ogbuji, Agomuo C.

    2015-01-01

    The current study sought to investigate the capacities of single and combinatorial herbal formulations of leaf extracts of Acanthus montanus, Asystasia gangetica, Emilia coccinea, and Hibiscus rosasinensis to reverse hyperglycemia and dyslipidemia in alloxan-induced diabetic male rats. Phytochemical composition of the herbal extracts, fasting plasma glucose concentration (FPGC), and serum lipid profile (SLP) of the rats were measured by standard methods. The relative abundance of phytochemicals in the four experimental leaf extracts was in the following order: flavonoids > alkaloids > saponins > tannins. Hyperglycemic rats (HyGR) treated with single and combinatorial herbal formulations showed evidence of reduced FPGC compared with the untreated HyGR and were normoglycemic (FPGC < 110.0 mg/dL). Similarly, HyGR treated with single and combinatorial herbal formulations showed evidence of readjustments in their SLPs. Generally, HyGR treated with triple herbal formulations (THfs) exhibited the highest atherogenic index compared with HyGR treated with single herbal formulations (SHfs), double herbal formulations (DHfs), and quadruple herbal formulation (QHf). The display of synergy or antagonism by the composite herbal extracts in ameliorating hyperglycemia and dyslipidemia depended on the type and number of individual herbal extract used in constituting the experimental herbal formulations. Furthermore, the capacities of the herbal formulations (SHfs, DHfs, THfs, and QHf) to exert glycemic control and reverse dyslipidemia did not follow predictable patterns in the animal models. PMID:27114943

  16. Liver growth factor induces testicular regeneration in EDS-treated rats and increases protein levels of class B scavenger receptors.

    PubMed

    Lobo, M V T; Arenas, M I; Huerta, L; Sacristán, S; Pérez-Crespo, M; Gutiérrez-Adán, A; Díaz-Gil, J J; Lasunción, M A; Martín-Hidalgo, A

    2015-01-15

    The aim of the present work was to determine the effects of liver growth factor (LGF) on the regeneration process of rat testes after chemical castration induced by ethane dimethanesulfonate (EDS) by analyzing some of the most relevant proteins involved in cholesterol metabolism, such as hormone sensitive lipase (HSL), 3β-hydroxysteroid dehydrogenase (3β-HSD), scavenger receptor SR-BI, and other components of the SR family that could contribute to the recovery of steroidogenesis and spermatogenesis in the testis. Sixty male rats were randomized to nontreated (controls) and LGF-treated, EDS-treated, and EDS + LGF-treated groups. Testes were obtained on days 10 (T1), 21 (T2), and 35 (T3) after EDS treatment, embedded in paraffin, and analyzed by immunohistochemistry and Western blot. LGF improved the recovery of the seminiferous epithelia, the appearance of the mature pattern of Leydig cell interstitial distribution, and the expression of mature SR-BI. Moreover, LGF treatment resulted in partial recovery of HSL expression in Leydig cells and spermatogonia. No changes in serum testosterone were observed in control or LGF-treated rats, but in EDS-castrated animals LGF treatment induced a progressive increase in serum testosterone levels and 3β-HSD expression. Based on the pivotal role of SR-BI in the uptake of cholesteryl esters from HDL, it is suggested that the observed effects of LGF would facilitate the provision of cholesterol for sperm cell growth and Leydig cell recovery.

  17. Blood glucose level and lipid profile of alloxan-induced hyperglycemic rats treated with single and combinatorial herbal formulations.

    PubMed

    Ojiako, Okey A; Chikezie, Paul C; Ogbuji, Agomuo C

    2016-04-01

    The current study sought to investigate the capacities of single and combinatorial herbal formulations of leaf extracts of Acanthus montanus, Asystasia gangetica, Emilia coccinea, and Hibiscus rosasinensis to reverse hyperglycemia and dyslipidemia in alloxan-induced diabetic male rats. Phytochemical composition of the herbal extracts, fasting plasma glucose concentration (FPGC), and serum lipid profile (SLP) of the rats were measured by standard methods. The relative abundance of phytochemicals in the four experimental leaf extracts was in the following order: flavonoids > alkaloids > saponins > tannins. Hyperglycemic rats (HyGR) treated with single and combinatorial herbal formulations showed evidence of reduced FPGC compared with the untreated HyGR and were normoglycemic (FPGC < 110.0 mg/dL). Similarly, HyGR treated with single and combinatorial herbal formulations showed evidence of readjustments in their SLPs. Generally, HyGR treated with triple herbal formulations (THfs) exhibited the highest atherogenic index compared with HyGR treated with single herbal formulations (SHfs), double herbal formulations (DHfs), and quadruple herbal formulation (QHf). The display of synergy or antagonism by the composite herbal extracts in ameliorating hyperglycemia and dyslipidemia depended on the type and number of individual herbal extract used in constituting the experimental herbal formulations. Furthermore, the capacities of the herbal formulations (SHfs, DHfs, THfs, and QHf) to exert glycemic control and reverse dyslipidemia did not follow predictable patterns in the animal models. PMID:27114943

  18. Increase in oxidative stress and mitochondrial impairment in hypothalamus of streptozotocin treated diabetic rat: Antioxidative effect of Withania somnifera.

    PubMed

    Parihar, P; Shetty, R; Ghafourifar, P; Parihar, M S

    2016-01-22

    Hypothalamus, the primary brain region for glucose sensing, is severely affected by oxidative stress in diabetes mellitus. Oxidative stress in this region of brain may cause severe impairment in neuronal metabolic functions. Mitochondria are prominent targets of oxidative stress and the combination of increased oxidative stress and mitochondrial dysfunctions may further decline hypothalamic neuronal functions. In the present study we examined the oxidative damage response, antioxidative responses and mitochondrial membrane permeability transition in hypothalamus of streptozotocin-treated diabetic rats. Our results show that streptozotocin significantly increases hypothalamic lipid peroxidation, protein carbonyl content while glutathione peroxidase and reduced glutathione were declined. Mitochondrial impairment marked by an increase in mitochondrial membrane permeabilization was seen following streptozotocin treatment in the hypothalamus. The oral administration of Withania somnifera root extract stabilized mitochondrial functions and prevented oxidative damage in the hypothalamus of diabetic rat. These findings suggest an increase in the oxidative stress and decline in antioxidative responses in the hypothalamus of streptozotocin treated diabetic rats. Withania somnifera root extract was found useful in reducing oxidative stress and mitochondrial impairment in hypothalamus of diabetic rat.

  19. Uptake of barbituric acid derivatives in small intestinal brush border membrane vesicles from retinyl palmitate-treated rats.

    PubMed

    Tanii, H; Horie, T

    2000-08-01

    Brush border membrane was prepared from the small intestinal (jejunum) cells along the crypt-villus axis. The fluorescence spectra of 1,8-anilinonaphthalene sulfonic acid and the steady-state fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene were measured in the brush border membrane vesicle suspension. The hydrophobicity of brush border membrane was found to be in the order villus tip >mid villus >lower villus. The fluidity of brush border membrane was in the order villus tip rats, the fluidity of brush border membrane was found to be higher in the retinyl palmitate-treated rats than in the control rats. However, no significant difference in the uptake of hexobarbital by brush border membrane vesicles was observed between the retinyl palmitate-administered rats and the control rats. Thus, the retinyl palmitate treatment seems unlikely to affect the passively transported ligands like barbituric acid derivatives in brush border membrane vesicles. PMID:10989945

  20. Immunocytochemical study of amelogenin deposition during the early odontogenesis of molars in alendronate-treated newborn rats.

    PubMed

    Massa, Luciana F; Bradaschia-Correa, Vivian; Arana-Chavez, Victor E

    2006-06-01

    Newborn rats were treated with sodium alendronate to study how enamel is formed and the effect of alendronate during early odontogenesis. Ultrastructural analysis combined with high-resolution immunocytochemistry for amelogenin was carried out. Twelve rats were subjected to daily SC injections of sodium alendronate (2.5 mg/kg/day) for 3 days on their dorsal region, whereas three rats were daily injected with saline solution as a control. Molar tooth germs from 3-day-old rats were fixed under microwave irradiation in 0.1% glutaraldehyde + 4% formaldehyde buffered at pH 7.2 with 0.1 M sodium cacodylate. The specimens were left undecalcified, postfixed with osmium tetroxide, dehydrated, and embedded in LR White resin. Ultrathin sections were incubated with a chicken anti-24-kDa rat amelogenin antibody, a secondary antibody, and finally with a protein A-gold complex. Large patches of amelogenin were present over the unmineralized mantle dentin and at early secretory ameloblasts. At more advanced stages, they were also detected at the enamel matrix, as well as in the mineralized dentin, at the periodontoblastic space of the dentinal tubules, and at the predentin. It is likely that the main effect of alendronate at early stages of odontogenesis is the increase of synthesis/secretion of amelogenin, promoting its deposition within the forming dentin and enamel.

  1. Role of oxidative stress in disrupting the function of negative glucocorticoid response element in daily amphetamine-treated rats.

    PubMed

    Chu, Shu-Chen; Yu, Ching-Han; Chen, Pei-Ni; Hsieh, Yih-Shou; Kuo, Dong-Yih

    2016-09-01

    Amphetamine (AMPH)-induced appetite suppression is associated with changes in hypothalamic reactive oxygen species (ROS), antioxidants, neuropeptides, and plasma glucocorticoid. This study explored whether ROS and glucocorticoid response element (GRE), which is the promoter site of corticotropin-releasing hormone (CRH) gene, participated in neuropeptides-mediated appetite control. Rats were treated daily with AMPH for four days, and changes in food intake, plasma glucocorticoid and expression levels of hypothalamic neuropeptide Y (NPY), proopiomelanocortin (POMC), superoxide dismutase (SOD), CRH, and glucocorticoid receptor (GR) were examined and compared. Results showed that food intake decreased and NPY gene down-regulated, while POMC, SOD, and CRH gene up-regulated during AMPH treatment. GR and GRE-DNA bindings were disrupted on Day 1 and Day 2 when glucocorticoid levels were still high. Pretreatment with GR inhibitor or ROS scavenger modulated mRNA levels in NPY, POMC, SOD and CRH in AMPH-treated rats. We suggest that disruptions of negative GRE (nGRE) on Day 1 and Day 2 are associated with an increase in oxidative stress during the regulation of NPY/POMC-mediated appetite control in AMPH-treated rats. These results advance the understanding of molecular mechanism in regulating AMPH-mediated appetite suppression. PMID:27235634

  2. Involvement of oxidative stress in the regulation of NPY/CART-mediated appetite control in amphetamine-treated rats.

    PubMed

    Hsieh, Yih-Shou; Chen, Pei-Ni; Yu, Ching-Han; Chen, Chia-Hui; Tsai, Tsung-Ta; Kuo, Dong-Yih

    2015-05-01

    Amphetamine (AMPH) treatment can suppress appetite and increase oxidative stress in the brain. AMPH-induced appetite suppression is associated with the regulation of neuropeptide Y (NPY) and cocaine- and amphetamine-regulated transcript (CART) in the hypothalamus. The present study explored whether antioxidants, including glutathione S-transferase (GST) and glutathione peroxidase (GP), were involved in this NPY/CART-mediated appetite control. Rats were treated daily with AMPH for four days. Changes in food intake and expression levels of hypothalamic NPY, CART, GST, and GP were examined and compared. Results showed that, in AMPH-treated rats, (1) food intake and NPY expression decreased, while CART, GST, and GP expression increased; (2) NPY knockdown in the brain enhanced the decrease in NPY and the increases in CART, GST, and GP expression; and (3) central inhibition of reactive oxygen species production decreased GST and GP and modulated AMPH anorexia and the expression levels of NPY and CART. The present results suggest that oxidative stress in the brain participates in regulating NPY/CART-mediated appetite control in AMPH-treated rats. These results may advance the knowledge regarding the molecular mechanism of AMPH-evoked or NPY/CART-mediated appetite suppression.

  3. Pectinase-treated Panax ginseng extract (GINST) rescues testicular dysfunction in aged rats via redox-modulating proteins.

    PubMed

    Won, Yu-Jin; Kim, Bo-Kyung; Shin, Yong-Kyu; Jung, Seung-Hyo; Yoo, Sung-Kwang; Hwang, Seock-Yeon; Sung, Jong-Hwan; Kim, Si-Kwan

    2014-05-01

    The root of Panax ginseng improves testicular function both in humans and animals. However, the molecular mechanism by which ginseng exerts this effect has not been elucidated. Changes in protein expression in the rat testis in response to a pectinase-treated P. ginseng extract (GINST) were identified using 2-dimensional electrophoresis (2-DE) and MALDI-TOF/TOF MS. Number of sperm, Sertoli cells and germ cells, and the Sertoli Cell Index decrease in the testis of aged rats (AR) relative to young control rats (YCR). However, those parameters were completely restored in GINST-treated AR (GINST-AR). A proteomic analysis identified 14 proteins that were differentially expressed between vehicle-treated AR (V-AR) and GINST-AR. Out of these, the expression of glutathione-S-transferase (GST) mu5 and phospholipid hydroperoxide (PH) glutathione peroxidase (GPx) was significantly up-regulated in GINST-AR compared to V-AR. The activity of GPx and GST, as well as the expression of glutathione, in the testis of GINST-AR was higher than that in V-AR. The levels of lipid peroxidation (LPO) increased in AR compared with YCR, but this change was reversed by GINST-AR. These results suggest that the administration of GINST enhances testicular function by elevating GPx and GST activity, thus resulting in increased glutathione, which prevents LPO in the testis.

  4. Decreased expression of alpha-2-HS glycoprotein in the sera of rats treated with Eurycoma longifolia extract

    PubMed Central

    Chen, Yeng; Phang, Wai-Mei; Mu, Alan K.-W.; Chan, Choon-Keat; Low, Bin-Seng; Sasidharan, Sreenivasan; Chan, Kit-Lam

    2015-01-01

    Eurycoma longifolia is a Malaysian native herb that has been widely used as an aphrodisiac and a remedy for andropause. Although the physiological effects of the plant extract were predicted as a result of the alterations in protein expression, the key protein(s) involved in these alterations are still unclear. In the present study, we have investigated the effect of standardized E. longifolia extract on serum protein expression up to 28 days following oral administration in rats. Serum protein profiles were analyzed by 2-dimensional electrophoresis, and altered proteins were identified via mass spectrometry. We observed that alpha-2-HS glycoprotein (AHS) was significantly decreased in the serum of experimentally treated rats compared to pre-treated animals. Moreover, reduction in AHS was confirmed using competitive enzyme-linked immunosorbent assay. AHS expression is known to be associated with insulin resistance and diabetes. Our data indicated that serum AHS was reduced in rats treated with standardized E. longifolia extract, and therefore form a prelude for further investigation into the effects of this natural extract in animal models involving infertility and diabetes. PMID:26441666

  5. Factors affecting mammary tumor incidence in chlorotriazine-treated female rats: hormonal properties, dosage, and animal strain.

    PubMed Central

    Eldridge, J C; Tennant, M K; Wetzel, L T; Breckenridge, C B; Stevens, J T

    1994-01-01

    Chlorotriazines are widely used in agriculture as broadleaf herbicides. The compounds specifically inhibit photosynthesis, and, as such, display little interaction with animal systems. However, a 24-month feeding study with atrazine (ATR) revealed a significant dose-related increase of mammary tumors in female Sprague-Dawley (SD) rats. Because numerous studies indicated that ATR had a low mutagenic and oncogenic potential, it was decided to test a hypothesis that the herbicide possessed endocrine activity. Among tests for estrogenic action, oral dosing of ATR up to 300 mg/kg did not stimulate uterine weight of ovariectomized rats. However, ATR administration did reduce estrogen-stimulated uterine weight gain. Further evidence of inhibition came from measures of [3H]-thymidine incorporation into uterine DNA of ATR-treated immature rats. Again, no intrinsic estrogenic activity was observed up to a 300-mg/kg dose. In vitro, ATR competed poorly against estradiol binding to cytosolic receptors, with an approximate IC50 of 10(-5) M. Atrazine administration to SD and Fischer-344 (F-344) rats for 12 months, up to 400 ppm in food, was correlated with significant alterations of estrous cycling activity; but there was a divergent strain response. SD rats showed an increased number of days in vaginal estrus, increased plasma estradiol, and decreased plasma progesterone by 9 to 12 months of treatment. F-344 rats did not demonstrate treatment-related affects. A study of ultrastructure in the hypothalamic arcuate nucleus of female SD rats that were fed diaminochlorotriazine (DACT), an ATR metabolite, suggested that age-associated glial pathology was enhanced by treatment.(ABSTRACT TRUNCATED AT 250 WORDS) Images Figure 8. PMID:7737039

  6. Relaxant and contractile responses of detrusor muscle strips obtained from bladder outlet-obstructed rats treated with doxazosin enantiomers.

    PubMed

    Wang, Miao; Ren, Xue-Jiao; Zhao, Qing-Hua; Lin, Li-Xin; Wang, Xue; Zhao, Yan; Ren, Lei-Ming

    2011-12-01

    (-)Doxazosin, one of (±)doxazosin enantiomers, was speculated to have a pharmacological enantioselectivity between the cardiovascular system and the urinary system by comparison with (+)doxazosin. Therefore, to evaluate the potential benefits of (-)doxazosin in the treatment of benign prostate hyperplasia, we compared the effects of the 3 agents, using rat mesenteric artery preparations and obstructed bladder strips. Concentration-response curves for carbachol (contractile response) and isoprenaline (relaxant response) in detrusor muscle strips of the bladder outlet obstruction (BOO) rats were shifted to the left, with significant increases in the Emax values, and significant decreases in the EC50 values by comparison with the sham-operated rats (P < 0.05, n = 10). The enhanced responses in detrusor muscle strips of the BOO rats treated with (±)doxazosin and its enantiomers at 3 mg·(kg body mass)(-1)·day(-1) for 2 weeks returned to normal levels, and the 3 agents inhibited the enhanced responses to carbachol and isoprenaline to the same extent. On the other hand, the 3 agents uncompetitively inhibited the vasoconstrictive response curves for NA in the rat isolated mesenteric artery, and the pKB value of (-)doxazosin at vascular α1-adrenoceptors was significantly smaller (P < 0.05, n = 6) than that of (+)doxazosin or (±)doxazosin. In conclusion, although (-)doxazosin inhibits vascular functional α1-adrenoceptors more weakly than (+)doxazosin, both agents equally ameliorate the enhanced responses in detrusor muscle of BOO rats, suggesting that the chiral carbon atom in the molecular structure of doxazosin does not affect its beneficial effects in the bladder smooth muscle of BOO rats.

  7. Anti-inflammatory effects of propofol on lipopolysaccharides-treated rat hepatic Kupffer cells.

    PubMed

    Li, Sen; Wang, Chun-xia; Liu, Nai-Zheng; Liu, Ping

    2015-03-01

    This study is set to explore the role of commonly used intravenous anesthetic propofol on the inflammatory response of rat liver Kupffer cells (KCs) induced by lipopolysaccharides (LPS). The isolated KCs were cultured at the density of 1 × 10(5)/ml, divided into five groups randomly after 48 h culture: group C, control group; group L, KCs were treated with 1 μg/ml LPS for 24 h; groups P1, P2, P3, KCs were pretreated with propofol at low (25 μM), medium (50 μM), high (100 μM) concentration for 2 h, respectively, and then were stimulated with 1 μg/ml LPS for 24 h. The expressions of tumor necrosis factor-α (TNF-α) mRNA and interleukin-1β (IL-1β) mRNA of every group were measured by RT-PCR. Nuclear NF-ΚB p65 was determined by Western blot. The concentrations of IL-1β and TNF-α in supernatant were measured by ELISA. Compared with the group C, TNF-α mRNA and IL-1β mRNA in group L were significantly up-regulated and NF-ΚB p65 was significantly up-regulated after LPS treatment (P < 0.05). Meanwhile, TNF-α and IL-1β were also significantly increased (P < 0.05). With propofol the mRNA expressions of aforementioned inflammatory mediators were significantly down-regulated and NF-ΚB p65 was significantly inhibited in group P2 and P3 (P < 0.05), compared with group L. However, low propofol concentration did not exhibit any effect (group P1, P > 0.05). Propofol at medium and high concentration can counteract the LPS-induced inflammatory response in KCs by regulating NF-ΚB p65 protein expression. PMID:25296958

  8. Alteration in lung particle translocation, macrophage function, and microfilament arrangement in monocrotaline-treated rats.

    PubMed

    Madl, A K; Wilson, D W; Segall, H J; Pinkerton, K E

    1998-11-01

    Individuals with preexisting cardiopulmonary disease are thought to be more susceptible to acute episodes of particulate pollution resulting in increased morbidity and mortality. Our study was designed to evaluate particle fate and macrophage function in an animal model of monocrotaline (MCT)-induced pulmonary hypertension. Two weeks following a single MCT injection, Sprague-Dawley rats were exposed sequentially to two different colored fluorescent microspheres 1.0 micron in diameter by aerosolization. Morphometric evaluation of lung sections was performed 0 and 24 h following the final particle exposure to determine the intrapulmonary location of inhaled microspheres. A decrease in the number of particles phagocytized by alveolar macrophages and an increase of free particles overlying the epithelium were found in MCT-treated animals compared with control. Pulmonary macrophages recovered by bronchoalveolar lavage were evaluated for chemotactic and phagocytic ability. Macrophage chemotaxis was significantly impaired following MCT treatment compared with controls, whereas phagocytic activity of macrophages lavaged from MCT and control treatment groups was similar. Macrophages were stained for filamentous (F) and globular (G) actin using Texas-Red-labeled phalloidin and Oregon-green-labeled DNase I, respectively. The area of microfilament staining for F and G actin increased, but the ratio of F/G actin was significantly decreased in animals with MCT treatment compared with control. While the responses observed with MCT treatment, such as pulmonary edema, polymorphonuclear leukocytes influx, and unique macrophage morphology may contribute to impaired macrophage function, the change in microfilament arrangement suggests that MCT may inhibit macrophage chemotaxis and impair particle clearance from the lungs. PMID:9875297

  9. Alterations of p75 neurotrophin receptor and Myelin transcription factor 1 in the hippocampus of perinatal phencyclidine treated rats.

    PubMed

    Andrews, Jessica L; Newell, Kelly A; Matosin, Natalie; Huang, Xu-Feng; Fernandez-Enright, Francesca

    2015-12-01

    Postnatal administration of phencyclidine (PCP) in rodents causes major disturbances to neurological processes resulting in severe modifications to normal behavioral traits into adulthood. It is routinely used to model psychiatric disorders such as schizophrenia, producing many of the dysfunctional processes in the brain that are present in this devastating disorder, including elevated levels of apoptosis during neurodevelopment and disruptions to myelin and plasticity processes. Lingo-1 (or Leucine-rich repeat and immunoglobulin domain-containing protein) is responsible for negatively regulating neurite outgrowth and the myelination of axons. Recent findings using a postmortem human brain cohort showed that Lingo-1 signaling partners in the Nogo receptor (NgR)/p75/TNF receptor orphan Y (TROY) signaling complex, and downstream signaling partners With No Lysine (K) (WNK1) and Myelin transcription factor 1 (Myt1), play a significant part in schizophrenia pathophysiology. Here we have examined the implication of Lingo-1 and its signaling partners in a neurodevelopmental model of schizophrenia using PCP to determine if these pathways are altered in the hippocampus throughout different stages of neurodevelopment. Male Sprague-Dawley rats were injected subcutaneously with PCP (10mg/kg) or saline solution on postnatal days (PN) 7, 9, and 11. Rats (n=6/group) were sacrificed at PN12, 5weeks, or 14weeks. Relative expression levels of Lingo-1 signaling proteins were examined in the hippocampus of the treated rats. p75 and Myt1 were decreased (0.001≤p≤0.011) in the PCP treated rats at PN12. There were no significant changes in any of the tested proteins at 5weeks (p>0.05). At 14weeks, p75, TROY, and Myt1 were increased in the PCP treated rats (0.014≤p≤0.022). This is the first report of an alteration in Lingo-1 signaling proteins in the rat hippocampus, both directly after PCP treatment in early development and in adulthood. Based on our results, we propose that

  10. Alterations of p75 neurotrophin receptor and Myelin transcription factor 1 in the hippocampus of perinatal phencyclidine treated rats.

    PubMed

    Andrews, Jessica L; Newell, Kelly A; Matosin, Natalie; Huang, Xu-Feng; Fernandez-Enright, Francesca

    2015-12-01

    Postnatal administration of phencyclidine (PCP) in rodents causes major disturbances to neurological processes resulting in severe modifications to normal behavioral traits into adulthood. It is routinely used to model psychiatric disorders such as schizophrenia, producing many of the dysfunctional processes in the brain that are present in this devastating disorder, including elevated levels of apoptosis during neurodevelopment and disruptions to myelin and plasticity processes. Lingo-1 (or Leucine-rich repeat and immunoglobulin domain-containing protein) is responsible for negatively regulating neurite outgrowth and the myelination of axons. Recent findings using a postmortem human brain cohort showed that Lingo-1 signaling partners in the Nogo receptor (NgR)/p75/TNF receptor orphan Y (TROY) signaling complex, and downstream signaling partners With No Lysine (K) (WNK1) and Myelin transcription factor 1 (Myt1), play a significant part in schizophrenia pathophysiology. Here we have examined the implication of Lingo-1 and its signaling partners in a neurodevelopmental model of schizophrenia using PCP to determine if these pathways are altered in the hippocampus throughout different stages of neurodevelopment. Male Sprague-Dawley rats were injected subcutaneously with PCP (10mg/kg) or saline solution on postnatal days (PN) 7, 9, and 11. Rats (n=6/group) were sacrificed at PN12, 5weeks, or 14weeks. Relative expression levels of Lingo-1 signaling proteins were examined in the hippocampus of the treated rats. p75 and Myt1 were decreased (0.001≤p≤0.011) in the PCP treated rats at PN12. There were no significant changes in any of the tested proteins at 5weeks (p>0.05). At 14weeks, p75, TROY, and Myt1 were increased in the PCP treated rats (0.014≤p≤0.022). This is the first report of an alteration in Lingo-1 signaling proteins in the rat hippocampus, both directly after PCP treatment in early development and in adulthood. Based on our results, we propose that

  11. Transcriptional responses in thyroid tissues from rats treated with a tumorigenic and a non-tumorigenic triazole conazole fungicide

    SciTech Connect

    Hester, Susan D. Nesnow, Stephen

    2008-03-15

    Conazoles are azole-containing fungicides that are used in agriculture and medicine. Conazoles can induce follicular cell adenomas of the thyroid in rats after chronic bioassay. The goal of this study was to identify pathways and networks of genes that were associated with thyroid tumorigenesis through transcriptional analyses. To this end, we compared transcriptional profiles from tissues of rats treated with a tumorigenic and a non-tumorigenic conazole. Triadimefon, a rat thyroid tumorigen, and myclobutanil, which was not tumorigenic in rats after a 2-year bioassay, were administered in the feed to male Wistar/Han rats for 30 or 90 days similar to the treatment conditions previously used in their chronic bioassays. Thyroid gene expression was determined using high density Affymetrix GeneChips (Rat 230{sub 2}). Gene expression was analyzed by the Gene Set Expression Analyses method which clearly separated the tumorigenic treatments (tumorigenic response group (TRG)) from the non-tumorigenic treatments (non-tumorigenic response group (NRG)). Core genes from these gene sets were mapped to canonical, metabolic, and GeneGo processes and these processes compared across group and treatment time. Extensive analyses were performed on the 30-day gene sets as they represented the major perturbations. Gene sets in the 30-day TRG group had over representation of fatty acid metabolism, oxidation, and degradation processes (including PPAR{gamma} and CYP involvement), and of cell proliferation responses. Core genes from these gene sets were combined into networks and found to possess signaling interactions. In addition, the core genes in each gene set were compared with genes known to be associated with human thyroid cancer. Among the genes that appeared in both rat and human data sets were: Acaca, Asns, Cebpg, Crem, Ddit3, Gja1, Grn, Jun, Junb, and Vegf. These genes were major contributors in the previously developed network from triadimefon-treated rat thyroids. It is

  12. Emu Oil Combined with Lyprinol™ Reduces Small Intestinal Damage in a Rat Model of Chemotherapy-Induced Mucositis.

    PubMed

    Mashtoub, Suzanne; Lampton, Lorrinne S; Eden, Georgina L; Cheah, Ker Y; Lymn, Kerry A; Bajic, Juliana E; Howarth, Gordon S

    2016-10-01

    Chemotherapy-induced mucositis is characterized by inflammation and ulcerating lesions lining the alimentary tract. Emu Oil and Lyprinol™ have independently demonstrated their therapeutic potential in intestinal inflammatory disorders, including mucositis. We investigated Emu Oil and Lyprinol™ in combination for their further potential to alleviate chemotherapy-induced mucositis in rats. Rats were gavaged with (1 ml) water, Olive Oil, Emu Oil + Olive Oil, Lyprinol™ + Olive Oil or Emu Oil + Lyprinol™ from Days 0 to 7, injected with saline (control) or 5-Fluorouracil (5-FU) on Day 5 and euthanized on Day 8. Myeloperoxidase (MPO) activity (indicative of acute inflammation), histological severity scores, and intestinal architecture were quantified. Myeloperoxidase activity was significantly increased in the jejunum and ileum following 5-FU, compared to saline controls. Both Olive Oil and Emu Oil + Lyprinol™ significantly reduced jejunal MPO levels (1.8-fold and 1.7-fold, respectively), whereas only Emu Oil + Lyprinol™ significantly decreased ileal MPO levels, relative to 5-FU controls. All oil treatments decreased histological severity scores in the jejunum and ileum, and normalized crypt depth in the mid small intestine, relative to 5-FU controls. Emu Oil combined with Lyprinol™ partially reduced acute small intestinal inflammation. Isolating bioactive constituents of these naturally sourced oils could provide a more targeted strategy to protect against intestinal mucositis. PMID:27618153

  13. Nerve growth factor affects defense-related behaviors, but not lordosis, in ovariectomized, estrogen-treated rats.

    PubMed

    Gibbs, R B; McCarthy, M M; Pfaff, D W

    1993-05-01

    Effects of NGF and anti-NGF on estrogen-sensitive behaviors were examined in ovariectomized, estrogen-treated rats. Intracerebroventricular (i.c.v.) administration of NGF resulted in a significant decrease in body weight. Daily treatment with low levels of estradiol resulted in a steady increase in lordosis behavior as reflected by average lordosis quotient and lordosis score. No effects of NGF or anti-NGF on lordosis behavior were detected. Estrogen treatment also resulted in a significant increase in the number of vocalizations elicited from female controls by male contact during sex behavior. NGF-treatment enhanced this effect, resulting in significantly more vocalizations elicited earlier in the course of estrogen treatment than were elicited from non-NGF-treated controls. These effects were blocked by progesterone. An increase in the number of rejections elicited by male contact during sex behavior was also observed in NGF-treated animals relative to controls. In addition, i.c.v. infusions of anti-NGF prevented the estrogen-mediated increase in elicited vocalizations, suggesting that NGF may have a physiological role in regulating this behavior. These data implicate NGF in the regulation of specific defense-related behaviors in estrogen-treated rats. Effects of NGF and anti-NGF on immunocytochemical staining for p75NGFR-, and ChAT-like immunoreactivity were also analyzed and are discussed.

  14. Effect of omega-3 fatty acids on haemostatic functions in urocortin-treated obese rats.

    PubMed

    El-Gendy, Ahmed A; Abbas, Amr M

    2014-09-01

    Urocortin 1 (UCN1) decreases food intake. We investigated the effects of UCN1 and omega-3 fatty acids (FA) on metabolic and coagulation parameters in high fat diet (HFD)-fed rats. Fifty male Sprague Dawley rats were divided into five groups; control, HFD, HFD with omega-3 FA, HFD with UCN1, and HFD with UCN1 and omega-3 FA. Food intake, body weight (BW), body mass index (BMI), Lee index, glucose, insulin, HOMA-IR, triglycerides, cholesterol, low (LDL) and high (HDL) density lipoproteins, fibrinogen, plasminogen activator inhibitor 1 (PAI-1), fibrin degradation product (FDP), clotting time, bleeding time, prothrombin time (PT), activated partial thromboplastin time (aPTT), and platelet aggregation were measured. Food intake, BW, BMI, Lee index, glucose, insulin, HOMA-IR, triglycerides, cholesterol, LDL, fibrinogen, platelet aggregation, PAI-1, and FDP increased while bleeding and clotting times, PT, and aPTT decreased in HFD rats. UCN1 decreased food intake, BW, BMI, Lee index, bleeding and clotting times, PT, and aPTT and increased fibrinogen, PAI-1, FDP, and platelet aggregation in HFD rats. Omega-3 FA decreased food intake, BW, BMI, Lee index, platelet aggregation, glucose, insulin, HOMA-IR, triglycerides, and increased HDL and bleeding time in HFD rats. We concluded that UCN1 worsens the hypercoagulable state in HFD rats while omega-3 FA improve the insulin resistance and decrease the platelet aggregation in those rats. PMID:25062615

  15. Decreased neuron loss and memory dysfunction in pilocarpine-treated rats pre-exposed to hypoxia.

    PubMed

    Do Val-da Silva, Raquel Araujo; Peixoto-Santos, José Eduardo; Scandiuzzi, Renata Caldo; Balista, Priscila Alves; Bassi, Mirian; Glass, Mogens Lesner; Romcy-Pereira, Rodrigo Neves; Galvis-Alonso, Orfa Yineth; Leite, João Pereira

    2016-09-22

    Preconditioning can induce a cascade of cellular events leading to neuroprotection against subsequent brain insults. In this study, we investigated the chronic effects of hypoxic preconditioning on spontaneous recurrent seizures (SRS), neuronal death, and spatial memory performance in rats subjected to pilocarpine (Pilo)-induced status epilepticus (SE). Rats underwent a short hypoxic episode (7% O2+93% N2; 30min on two consecutive days) preceding a 4-h SE (HSE group). Control groups were rats submitted to SE only (SE), rats subjected to hypoxia only (H) or normoxia-saline (C). Animals were monitored for the occurrence of SRS, and spatial memory performance was evaluated in the radial-arm maze. Hippocampal sections were analyzed for cell death and mossy fiber sprouting at 1 or 60days after SE. Compared to SE group, HSE had increased SE latency, reduced number of rats with SRS, reduced mossy fiber sprouting at 60days, and reduced cell death in the hilus and the CA3 region 1 and 60days after SE. Additionally, HSE rats had better spatial memory performance than SE rats. Our findings indicated that short hypoxic preconditioning preceding SE promotes long-lasting protective effects on neuron survival and spatial memory.

  16. Transplantation of Achilles Tendon Treated With Bone Morphogenetic Protein 7 Promotes Meniscus Regeneration in a Rat Model of Massive Meniscal Defect

    PubMed Central

    Ozeki, Nobutake; Muneta, Takeshi; Koga, Hideyuki; Katagiri, Hiroki; Otabe, Koji; Okuno, Makiko; Tsuji, Kunikazu; Kobayashi, Eiji; Matsumoto, Kenji; Saito, Hirohisa; Saito, Tomoyuki; Sekiya, Ichiro

    2013-01-01

    Objective This study was undertaken to examine whether bone morphogenetic protein 7 (BMP-7) induces ectopic cartilage formation in the rat tendon, and whether transplantation of tendon treated with BMP-7 promotes meniscal regeneration. Additionally, we analyzed the relative contributions of host and donor cells on the healing process after tendon transplantation in a rat model. Methods BMP-7 was injected in situ into the Achilles tendon of rats, and the histologic findings and gene profile were evaluated. Achilles tendon injected with 1 μg of BMP-7 was transplanted into a meniscal defect in rats. The regenerated meniscus and articular cartilage were evaluated at 4, 8, and 12 weeks. Achilles tendon from LacZ-transgenic rats was transplanted into the meniscal defect in wild-type rats, and vice versa. Results Injection of BMP-7 into the rat Achilles tendon induced the fibrochondrocyte differentiation of tendon cells and changed the collagen gene profile of tendon tissue to more closely approximate meniscal tissue. Transplantation of the rat Achilles tendon into a meniscal defect increased meniscal size. The rats that received the tendon treated with BMP-7 had a meniscus matrix that exhibited increased Safranin O and type II collagen staining, and showed a delay in articular cartilage degradation. Using LacZ-transgenic rats, we determined that the regeneration of the meniscus resulted from contribution from both donor and host cells. Conclusion Our findings indicate that BMP-7 induces ectopic cartilage formation in rat tendons. Transplantation of Achilles tendon treated with BMP-7 promotes meniscus regeneration and prevents cartilage degeneration in a rat model of massive meniscal defect. Native cells in the rat Achilles tendon contribute to meniscal regeneration. PMID:23897174

  17. Morphometric study on the uterine horn and thyroid gland in hypothyroid, and thyroxine treated hypothyroid rats.

    PubMed Central

    Inuwa, I; Williams, M A

    1996-01-01

    A wide range of reproductive disorders such as irregular menstruation and frank infertility is found in women with hypothyroidism. Most research done on these patients has focused on steroid and gonadotropin hormone profiles, whilst there has been little work on uterine morphology. Studies on hypothyroid animals have also demonstrated increases in fetal wastage, but there have been few studies of uterine structure in the hypothyroid rat. The present study has used hypothyroid Wistar rats as a model for investigating the effects of hypothyroidism on uterine structure. Three groups of Wistar rats were studied. One was made hypothyroid with methimazole (MMI), the 2nd was also made hypothyroid with methimazole but in addition the rats were simultaneously given daily thyroxine intraperitoneally (MMI + T4), and the 3rd was an untreated euthyroid group (control). Daily vaginal smears were obtained from rats in all 3 groups. All rats were aged 6 wk at the start of treatment and were killed after a further 6 wk. Uterine horns were removed and studied. Systematic random transverse sections were obtained from the proximal, middle, and distal regions of the horn and subjected to morphometric analysis. Difference between regions was assessed using 2-way analysis of variance. Absolute volume of endometrium in the uteri of hypothyroid rats was reduced by 45.1% (P < 0.05), whilst that of the muscle layer was decreased by 33.6% (P < 0.05). The cross-sectional area and absolute volume of the uterine horns were also reduced in hypothyroid animals (P < 0.05). In hypothyroid rats given thyroxine (MMI + T4) all variables increased significantly above those of hypothyroid rats. These changes suggest that hypothyroidism has an effect on uterine structure, which demonstrably improves under exogenous thyroxine administration. The observed structural changes might well play a significant role in the reproductive difficulties observed during hypothyroidism. Images Fig. 1 Fig. 2 (cont.) Fig. 2

  18. The effect of social learning on a conditioned avoidance response of rats treated prenatally with aluminum lactate.

    PubMed

    Gonda, Z; Miklósi, A; Lehotzky, K

    1997-01-01

    Aluminum (Al) has been proven to be a behavioral teratogenic agent in a number of experimental studies. Prenatal exposures to Al lactate have been shown to cause cognitive deficits in a variety of species. The present experiment was carried out on SPRD rat pups treated prenatally with Al lactate to determine whether observational conditioning (social learning) would reverse the impairment in learning described previously following such treatment. A conditioned avoidance response was used as an observational learning task. The results provide evidence that Al-treated pups are capable of social learning (i.e., the performance of the avoidance response improved as a result that Al-treated learning); however, the response latency of the avoidance response was not different in these animals from those that were not exposed to such facilitation, suggesting that additional factors are involved in the effects of prenatal aluminum intoxication on cognitive processes. PMID:9088011

  19. Iron bioavailability and utilization in rats are lower from lime-treated corn flour than from wheat flour when they are fortified with different sources of iron.

    PubMed

    Hernández, Miguel; Sousa, Virginia; Moreno, Ambar; Villapando, Salvador; López-Alarcón, Mardya

    2003-01-01

    Although iron bioavailability from wheat flour fortified with iron has been widely studied, the bioavailability of lime-treated corn flour has not been evaluated sufficiently. We compared iron bioavailability and utilization of lime-treated corn flour and wheat flour supplemented with various iron sources. Bioavailability and utilization were determined in Sprague-Dawley rats using the iron balance and hemoglobin depletion-repletion methods. Rats were iron depleted by feeding them a low iron, casein diet for 10 d. During the repletion period, the rats were fed diets based on lime-treated corn flour or wheat flour, both supplemented with ferrous fumarate, ferrous sulfate, ferric citrate and reduced iron for 14 d. Hemoglobin was determined at the end of depletion and repletion periods. The phytate concentration was lower in wheat flour (114 mg/100g) than in lime-treated corn flour (501 mg/100g). Iron bioavailability and utilization by rats were higher from fortified and unfortified wheat flour than from the lime-treated corn flour counterparts. Iron utilization was greater in rats fed wheat flour supplemented with ferrous sulfate, followed by fumarate and citrate than in rats fed reduced iron. In lime-treated corn flour, iron utilization by rats fed unfortified flour and flour fortified with reduced iron did not differ, but utilization was higher in rats fed corn flour fortified with iron sulfate, fumarate and citrate than with reduced iron. We conclude that fortification of lime-treated corn flour with reduced iron has no effect on iron bioavailability or utilization, probably due to the high phytate content. Other iron compounds must be selected to fortify lime-treated corn flour when intended for public nutrition programs.

  20. Potassium transport in cortical collecting tubules from mineralocorticoid-treated rat

    SciTech Connect

    Schafer, J.A.; Troutman, S.L.

    1987-07-01

    Unidirectional fluxes of /sup 86/Rb/sup +/ were used to examine the stimulation of K/sup +/ secretion produced by arginine vasopressin (ADH) in isolated perfused cortical collecting tubules from rats treated with desoxycorticosterone. ADH at 100 ..mu..U/ml in the bathing solution increased the bath-to-lumen flux (J/sub b..-->..1/; pmol /center dot/ min/sup -1/ /center dot/ mm/sup -1/) from 16.9 /plus minus/ 2.3 to 43.2 /plus minus/ 4.6. The lumen-to-bath flux (J/sub 1..-->..b/) fell from 3.2 /plus minus/ 0.7 to 1.3 /plus minus/ 0.4 with ADH due to hyperpolarization of the transepithelial voltage from -12.6 /plus minus/ 1.3 to /minus/39.3 /plus minus/ 2.0 mV, but the calculated Rb/sup +/ permeability was unaltered at 0.20-0.26 ..mu..m/s. Although 2 mM lumen Ba/sup 2 +/ inhibited J/sub b..-->..1/ by 55 /plus minus/ 6%, the flux ratio (J/sub b..-->..1//J/sub 1..-->..b/) of 28 /plus minus/ 8 was larger than predicted for passive exchange. In the absence of ADH 2 mM Ba/sup 2 +/ reduced J/sub b..-->..1/ to the level predicted for passive movement, but addition of ADH with Ba/sup 2 +/ still present increased J/sub 1..-->..1/ by an amount identical to that observed without Ba/sup 2 +/, although the absolute J/sub b..-->..1/ was less. Simultaneous addition of 2 mM luminal and 4 mM bath Ba/sup 2 +/ also inhibited J/sub 1..-->..b/ for /sup 22/Na/sup +/ but not to passive levels. These results indicate either that the concentrations of Ba/sup 2 +/ used were insufficient to block K/sup +/ conductances completely or that K/sup +//Rb/sup +/ secretion can occur through a Ba/sup 2 +/-insensitive pathway.

  1. Amelioration of endotoxin-induced uveitis treated with the sea urchin pigment echinochrome in rats

    PubMed Central

    Kitaichi, Nobuyoshi; Noda, Kousuke; Mizuuchi, Kazuomi; Ando, Ryo; Dong, Zhenyu; Fukuhara, Junichi; Kinoshita, Satoshi; Namba, Kenichi; Ohno, Shigeaki; Ishida, Susumu

    2014-01-01

    Purpose Echinochrome is a pigment present in the shells and spines of sea urchins. It has been reported to have several biologic protective effects, including in experimental models of myocardial ischemia/reperfusion injury, for which the proposed mechanisms are scavenging reactive oxygen species (ROS) and chelating iron. Endotoxin-induced uveitis (EIU) is an animal model of acute anterior segment intraocular inflammation that is induced by the injection of lipopolysaccharide (LPS). In this study, the therapeutic effect of echinochrome was examined in uveitis using the EIU model. Methods EIU was induced in Lewis rats via 200 μg subcutaneous injections of LPS from Escherichia coli. Echinochrome was administered intravenously in 10, 1, or 0.1 mg/kg doses suspended in PBS (controls were injected with PBS only). Twenty-four hours after LPS injection, the number of infiltrating cells and the protein concentration in aqueous humor were determined. Aqueous tumor necrosis factor α (TNF-α) concentration was quantified with enzyme-linked immunosorbent assay, eyes were stained with nuclear factor (NF) κB antibodies, and ROS production was determined by dihydroethidium staining in fresh frozen samples. Results The number of inflammatory aqueous cells and protein levels were lower in the groups treated with 10 and 1 mg/kg of echinochrome than in the untreated LPS group (p<0.01). Treatment with 10 and 1 mg/kg of echinochrome significantly reduced TNF-α concentrations in aqueous humor (p<0.01). The numbers of NFκB-positive cells and ROS signals were also reduced by echinochrome administration (p<0.05). Conclusions Echinochrome ameliorated intraocular inflammation caused by EIU by reducing ROS production, thereby also decreasing the expression of NFκB and TNF-α. As a natural pigment, echinochrome may therefore be a promising candidate for the safe treatment of intraocular inflammation. The use of sea urchin shells and spines in health foods and medical products is thus

  2. Latent inhibition in rats neonatally treated chronically with MK-801: differential effects on conditioned taste aversion and conditioned emotional response.

    PubMed

    Niikura, Ryo; Nozawa, Takashi; Yamada, Kazuo; Kato, Katsunori; Ichitani, Yukio

    2015-04-15

    Chronic neonatal blockade of N-methyl-d-aspartate (NMDA) receptors produces various abnormal behaviors in adulthood animals. This study investigated the effects of neonatal treatment chronically with MK-801 in rats on the preexposure-induced retardation of CS-US association, i.e. latent inhibition (LI), of two aversive classical conditioning tasks in adulthood. In conditioned taste aversion (CTA) using sucrose taste and LiCl, neonatal chronic MK-801 (0.4 mg/kg twice/day) treatment attenuated the inhibitory effect of sucrose preexposure on the aversive conditioning, although the treatment did not affect CTA conditioning itself. On the other hand, in conditioned emotional response (CER) using tone and electrical foot shock, rats neonatally treated with MK-801 showed the same degree of inhibitory effect of tone preexposure on the aversive conditioning compared with neonatally vehicle-treated rats, and also showed the same level of CER conditioning itself. Thus, the effect of chronic neonatal blockade of NMDA receptors on the LI of classical conditioning in adulthood was differentiated by the task employed. Results suggest that LI of CTA paradigm compared with that of CER is more sensitive to abnormal development after chronic neonatal blockade of NMDA receptors as an index of cognitive/attentional deficits caused by the treatment.

  3. Oxygen nano-bubble water reduces calcium oxalate deposits and tubular cell injury in ethylene glycol-treated rat kidney.

    PubMed

    Hirose, Yasuhiko; Yasui, Takahiro; Taguchi, Kazumi; Fujii, Yasuhiro; Niimi, Kazuhiro; Hamamoto, Shuzo; Okada, Atsushi; Kubota, Yasue; Kawai, Noriyasu; Itoh, Yasunori; Tozawa, Keiichi; Sasaki, Shoichi; Kohri, Kenjiro

    2013-08-01

    Renal tubular cell injury induced by oxalate plays an important role in kidney stone formation. Water containing oxygen nano-bubbles (nanometer-sized bubbles generated from oxygen micro-bubbles; ONB) has anti-inflammatory effects. Therefore, we investigated the inhibitory effects of ONB water on kidney stone formation in ethylene glycol (EG)-treated rats. We divided 60 rats, aged 4 weeks, into 5 groups: control, the water-fed group; 100 % ONB, the 100 % ONB water-fed group; EG, the EG treated water-fed group; EG + 50 % ONB and EG + 100 % ONB, water containing EG and 50 % or 100 % ONB, respectively. Renal calcium oxalate (CaOx) deposition, urinary excretion of N-acetyl-β-D-glucosaminidase (NAG), and renal expression of inflammation-related proteins, oxidative stress biomarkers, and the crystal-binding molecule hyaluronic acid were compared among the 5 groups. In the control and 100 % ONB groups, no renal CaOx deposits were detected. In the EG + 50 % ONB and EG + 100 % ONB groups, ONB water significantly decreased renal CaOx deposits, urinary NAG excretion, and renal monocyte chemoattractant protein-1, osteopontin, and hyaluronic acid expression and increased renal superoxide dismutase-1 expression compared with the EG group. ONB water substantially affected kidney stone formation in the rat kidney by reducing renal tubular cell injury. ONB water is a potential prophylactic agent for kidney stones.

  4. Sepsis progression to multiple organ dysfunction in carotid chemo/baro-denervated rats treated with lipopolysaccharide.

    PubMed

    Nardocci, Gino; Martin, Aldo; Abarzúa, Sebastián; Rodríguez, Jorge; Simon, Felipe; Reyes, Edison P; Acuña-Castillo, Claudio; Navarro, Cristina; Cortes, Paula P; Fernández, Ricardo

    2015-01-15

    Sepsis progresses to multiple organ dysfunction (MOD) due to the uncontrolled release of inflammatory mediators. Carotid chemo/baro-receptors could play a protective role during sepsis. In anesthetized male rats, we measured cardiorespiratory variables and plasma TNF-α, glucocorticoids, epinephrine, and MOD marker levels 90min after lipopolysaccharide (LPS) administration in control (SHAM surgery) and bilateral carotid chemo/baro-denervated (BCN) rats. BCN prior to LPS blunted the tachypneic response and enhanced tachycardia and hypotension. BCN-LPS rats also showed blunted plasma glucocorticoid responses, boosted epinephrine and TNF-α responses, and earlier MOD onset with a lower survival time compared with SHAM-LPS rats. Consequently, the complete absence of carotid chemo/baro-sensory function modified the neural, endocrine and inflammatory responses to sepsis. Thus, carotid chemo/baro-receptors play a protective role in sepsis.

  5. Toxicity of zinc oxide nanoparticles in rats treated by two different routes: single intravenous injection and single oral administration.

    PubMed

    Choi, Jonghye; Kim, Heyjin; Kim, Pilje; Jo, Eunhye; Kim, Hyun-Mi; Lee, Moo-Yeol; Jin, Seon Mi; Park, Kwangsik

    2015-01-01

    Toxicokinetics of zinc oxide nanoparticles (ZnONP) was studied in rats via a single intravenous (iv) injection and a single oral administration (3 mg/kg or 30 mg/kg), respectively. Blood concentrations of zinc (Zn) were monitored for 7 d and tissue distribution were determined in liver, kidneys, lung, spleen, thymus, brain, and testes. To ascertain the excretion of ZnONP, Zn levels in urine and feces were measured for 7 d. ZnONP were not readily absorbed from the gastrointestinal tract (GIT) after oral administration and were excreted mostly in feces. When the nanoparticles were injected iv to rats at a dose of 30 mg/kg, peak concentration appeared at 5 min but returned to normal range by d 2 (48 h after injection). ZnONP were distributed mainly to liver, kidneys, lung, and spleen, but not to thymus, brain, and testes. The distribution level was significantly decreased to normal by d 7. Feces excretion levels after iv injection supported biliary excretion of ZnONP. In rats injected iv with 30 mg/kg, mitotic figures in hepatocytes were significantly increased and multifocal acute injuries with dark brown pigment were noted in lungs, while no significant damage was observed in rats treated orally with the same dosage.

  6. Alteration in the fatty acid composition of liver, kidney and plasma from diethylhexyl phthalate-treated rats

    SciTech Connect

    Okita, J.R.; Okita, R.T. )

    1990-02-26

    Cytochromes P-450 are induced in rat liver microsomes by a number of compounds which cause peroxisome proliferation. One such compound, diethylhexyl phthalate (DEHP), induces P-450 IVA1 which catalyzes {omega}- and ({omega}-1)-hydroxylation of fatty acids. In liver of rats fed DEHP, there is a 10-fold induction of {omega}-hydroxylation of laurate and ({omega}-1)-hydroxylation of palmitate, as compared to control rat liver. There is a 3-fold induction of other hydroxylations, such as W-hydroxylation of palmitate and {omega}- ({omega}-1)-hydroxylation of syristate. Despite these increases in hydroxylase activity, the authors have not been able to demonstrate increases in hydroxy fatty acids or dicarboxylic acids in liver or plasma of rats fed DEHP. However, alterations in the fatty acid composition of lipids in liver, kidney cortex and plasma were observed. They consistently observed increases in oleate (expressed as mol% of total fatty acid) in liver (11% in control increased to 24% in DEHP-treated), kidney cortex (12% to 16%) and plasma (13% to 24%). This increase in oleate was quite striking when expressed as ug/gm tissue or ug/al plasma. DEHP treatment resulted in increased oleate in mitochondrial, microsomal and cytosolic fractions of liver.

  7. Identification of mucin-depleted foci in the unsectioned colon of azoxymethane-treated rats: correlation with carcinogenesis.

    PubMed

    Caderni, Giovanna; Femia, Angelo Pietro; Giannini, Augusto; Favuzza, Alessandro; Luceri, Cristina; Salvadori, Maddalena; Dolara, Piero

    2003-05-15

    We tested the association between aberrant crypt foci (ACF) and tumor induction by feeding azoxymethane-induced rats (15 mg/kg x 2, s.c.) with synbiotics (Raftilose Synergy 1, a derivative of inulin, 10% of the diet, along with lactobacilli and bifidobacteria). After 16 weeks of feeding, synbiotics significantly increased ACF multiplicity. On the contrary, after 32 weeks, synbiotics significantly decreased intestinal tumors. When the same unsectioned colon used for ACF determination was stained with high-iron diamine Alcian blue, foci of crypts with scarce or absent mucins were identified. We defined these lesions as mucin-depleted foci (MDF), and they were visible in all azoxymethane-treated rats and correlated with tumor induction (MDF/colon: 8.2 +/- 0.9 and 3.8 +/- 0.9 in controls and synbiotic-fed rats, respectively, P < 0.01; crypts/MDF: 12.2 +/- 2 and 6.4 +/- 1 in controls and synbiotic-fed rats, respectively, P < 0.05, means +/- SE, n = 7). There were fewer MDF/colon than ACF, and they were histologically more dysplastic than mucinous lesions identified as ACF in high-iron diamine Alcian blue-stained colon. In conclusion, MDF may be premalignant lesions that predict colon carcinogenesis.

  8. Elevated expression of transforming growth factor β3 in carbon tetrachloride-treated rat liver and involvement of retinoid signaling.

    PubMed

    Mezaki, Yoshihiro; Morii, Mayako; Yoshikawa, Kiwamu; Yamaguchi, Noriko; Satoyoshi, Kiyofumi; Miura, Mitsutaka; Imai, Katsuyuki; Hebiguchi, Tatsuzo; Habuchi, Tomonori; Senoo, Haruki

    2012-01-01

    Transforming growth factor (TGF) β is a pro-fibrotic cytokine. While three isoforms (TGF-β1, 2 and 3) are known, the functional differences between them are obscure. To investigate the roles of TGF-β isoforms during liver fibrogenesis, male Wistar rats were administrated carbon tetrachloride (CCl4) subcutaneously twice a week for two months. Livers were excised and sectioned for histochemical examinations. These livers were also used to quantitate the expression of genes associated with fibrogenesis, including TGF-β isoforms, as well as those associated with retinoid metabolism. Expression levels of Tgfb1 and Tgfb3 were up-regulated in CCl4-treated rat livers while that of Tgfb2 was not changed. The mRNAs for lecithin-retinol acyltransferase (Lrat) and retinoic acid hydroxylase, Cyp26a1, were also elevated. By immunohistochemical staining, TGF-β3 protein was found to be localized mainly in liver parenchymal cells (hepatocytes). These results indicate that retinoid mobilization likely takes place within the rat's liver following CCl4 treatment, and suggest the possibility that the expression of Tgfb mRNA is regulated by retinoic acid receptors. Reporter analyses of a region of the Tgfb3 gene were performed using the rat liver parenchymal cell line, RLC-16, and a positively responsive region was identified within its intron.

  9. Histopathological changes in retinas and F-ERG features of streptozotocin-induced diabetic rats treated with ozone

    PubMed Central

    Xie, Ting-Yu; Li, Qin; Chen, Xue-Yi

    2016-01-01

    AIM To study the histopathological changes in the retina and flash electroretinogram (F-ERG) features of ozone-treated streptozotocin (STZ)-induced diabetic rats. METHODS Seventy male Sprague Dawley rats were grouped as follows: blank group (GB, n=10), model control group (GM, n=18), ozone group (GO3, n=19), and oxygen group (GO2, n=18). The model was induced by single intraperitoneal injection of STZ. Ozone or oxygen enteroclysm was given twice per week for 4wk. F-ERG and histopathological examinations were performed one month after treatment. RESULTS Under dark adaption, as compared to GB, the other groups each had differential decreases in the a-wave amplitudes (P<0.05); the latencies were delayed in GM, GO2, and GO3 rats (P<0.05). Similar results were observed under light adaption, with the exception that the a-wave of the amplitudes (F=0.28, P>0.05). There were significant differences in the apoptosis index among the groups (P<0.05). Under ozone treatment, apoptosis was decreased in GO3 as compared to GM and GO2. CONCLUSION Ozone administration alleviates nerve damage and reduces pathology and apoptosis in the retinas of diabetic rats. PMID:27366680

  10. Spatial working memory is preserved in rats treated with anabolic-androgenic steroids.

    PubMed

    Smith, S T; Stackman, R W; Clark, A S

    1996-10-21

    The effects of anabolic-androgenic steroid (AAS) compounds on spatial working memory were evaluated in male rats. Thirty days of administration of a high dose of three individual AAS compounds (17 alpha-methyltestosterone, methandrostenolone, or testosterone cypionate) had no effects on spatial memory or motivation as tested on a delayed non-match-to-sample radial arm maze task. Administration of these AAS compounds at doses within the human abuse range does not impair spatial working memory in rats. PMID:8930382

  11. Enhanced oral bioavailability of vancomycin in rats treated with long-term parenteral nutrition.

    PubMed

    Fukushima, Keizo; Okada, Akira; Hayashi, Yoriko; Ichikawa, Hideki; Nishimura, Asako; Shibata, Nobuhito; Sugioka, Nobuyuki

    2015-01-01

    Long-term parenteral nutrition (PN) can induce intestinal atrophy, leading to a loss of epithelial integrity in the small intestines. This change may alter the intestinal permeability of vancomycin (VCM), a non-absorbable antibiotic. The aim of the present study was to investigate the effect of PN on the pharmacokinetics of VCM in rats. VCM was intravenously (5 mg/kg) or intraduodenally (20 mg/kg) administered to control and PN rats, which were prepared by administration of PN for 9 days. After intravenous administration, there were no significant differences in any of the VCM pharmacokinetic parameters between the control and PN rats. However, after intraduodenal administration, the maximum concentration and area under the plasma concentration-time curve of VCM in PN rats was approximately 2.4- and 2.6-fold higher, respectively, than in the control rats; the calculated bioavailability was approximately 0.5 and 1.3 % in control and PN rats, respectively. These results indicated that PN administration did not affect VCM disposition, but enhanced VCM absorption; however, the enhanced oral VCM bioavailability was statistically, not clinically, significant. Therefore, while long-term PN administration may play a role in the enhancement of VCM bioavailability, this effect may be negligible without any complications.

  12. Housing influences exploration and social interaction of control and DSP-4-treated rats.

    PubMed

    Cornwell-Jones, C A; Palfai, T; Krasenbaum, D; Byer, E; Clark, R; Kinnard, K

    1992-08-01

    Exploratory behavior and social interaction were investigated in rats that were reared in different social environments following neonatal injection with either water vehicle or the norepinephrine neurotoxin, DSP-4. At weaning, they were placed in a familiar or novel bedding type and were housed in either vehicle control-only, DSP-4-only, or mixed vehicle control and DSP-4 groups for 10 days. They were then observed in three different situations: the home cage, the cage of an unfamiliar rat, and an open field. Compared to rats housed in vehicle control-only or DSP-4-only groups, rats housed in mixed DSP-4 and vehicle control groups showed elevated exploration behavior in the home cage. Also, rats housed in mixed groups in the familiar bedding, but not the novel one, showed abnormally low levels of rearing in an open field test and reduced social interaction with unfamiliar rats. The implications of these results for a new animal model of anxiety are discussed. PMID:1381838

  13. Marked reduction in gonadal steroid hormone levels in rats treated neonatally with monosodium L-glutamate: further evidence for disruption of hypothalamic-pituitary-gonadal axis regulation.

    PubMed

    Nemeroff, C B; Lamartiniere, C A; Mason, G A; Squibb, R E; Hong, J S; Bondy, S C

    1981-11-01

    Serum levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin, estradiol-17 beta and testosterone were determined in adult rats that were treated in the neonatal period with monosodium L-glutamate (MSG) which has previously been shown to reliably produce destruction of arcuate nucleus perikarya. MSG-treated males had significantly smaller accessory sexual organs (seminal vesicles and ventral prostate) and tests and had significantly lower serum concentrations of FSH and testosterone than sex-matched controls. MSG-treated females had significantly lower serum concentrations of LH, FSH and estradiol-17 beta. Prolactin levels of MSG-treated rats were no different than sex-matched controls. This marked reduction in gonadal steroid levels (decreases 68%) and inappropriately low gonadotropin levels further characterizes the deficit of feedback regulation in the hypothalamic-pituitary-gonadal axis in MSG-treated rats.

  14. Nobiletin protects dopaminergic neurons in the 1-methyl-4-phenylpyridinium-treated rat model of Parkinson's disease.

    PubMed

    Jeong, Kyoung Hoon; Jeon, Min-Tae; Kim, Heung Deok; Jung, Un Ju; Jang, Min Cheol; Chu, Jin Woo; Yang, Seung Jun; Choi, Il Yoon; Choi, Myung-Sook; Kim, Sang Ryong

    2015-04-01

    This study investigated the effect of nobiletin, a flavonoid found in citrus fruits, on the degeneration of dopaminergic (DA) neurons in a neurotoxin model of Parkinson's disease (PD). 1-Methyl-4-phenylpyridinium (MPP(+)) was unilaterally injected into the median forebrain bundle of rat brains (to generate a neurotoxin model of PD) with or without daily intraperitoneal injection of nobiletin. Our results showed that nobiletin treatment at 10 mg/kg bw, but not at 1 or 20 mg/kg bw, significantly protected DA neurons in the substantia nigra (SN) of MPP(+)-treated rats. In parallel to the neuroprotection, nobiletin treatment at 10 mg/kg inhibited microglial activation and preserved the expression of the glial cell line-derived neurotrophic factor, which is a therapeutic agent against PD, in the SN. These results suggest that the proper supplementation with nobiletin may protect against the neurodegeneration involved in PD.

  15. Nobiletin protects dopaminergic neurons in the 1-methyl-4-phenylpyridinium-treated rat model of Parkinson's disease.

    PubMed

    Jeong, Kyoung Hoon; Jeon, Min-Tae; Kim, Heung Deok; Jung, Un Ju; Jang, Min Cheol; Chu, Jin Woo; Yang, Seung Jun; Choi, Il Yoon; Choi, Myung-Sook; Kim, Sang Ryong

    2015-04-01

    This study investigated the effect of nobiletin, a flavonoid found in citrus fruits, on the degeneration of dopaminergic (DA) neurons in a neurotoxin model of Parkinson's disease (PD). 1-Methyl-4-phenylpyridinium (MPP(+)) was unilaterally injected into the median forebrain bundle of rat brains (to generate a neurotoxin model of PD) with or without daily intraperitoneal injection of nobiletin. Our results showed that nobiletin treatment at 10 mg/kg bw, but not at 1 or 20 mg/kg bw, significantly protected DA neurons in the substantia nigra (SN) of MPP(+)-treated rats. In parallel to the neuroprotection, nobiletin treatment at 10 mg/kg inhibited microglial activation and preserved the expression of the glial cell line-derived neurotrophic factor, which is a therapeutic agent against PD, in the SN. These results suggest that the proper supplementation with nobiletin may protect against the neurodegeneration involved in PD. PMID:25325362

  16. Paricalcitol Enhances the Chemopreventive Efficacy of 5-Fluorouracil on an Intermediate-Term Model of Azoxymethane-Induced Colorectal Tumors in Rats.

    PubMed

    El-Shemi, Adel Galal; Refaat, Bassem; Kensara, Osama Adnan; Mohamed, Amr Mohamed; Idris, Shakir; Ahmad, Jawwad

    2016-06-01

    Colorectal cancer is a common cancer with high mortality rate. Despite being the standard anti-colorectal cancer drug, 5-fluorouracil (5-FU) exhibits only limited therapeutic benefits. Herein, we investigated whether paricalcitol, a synthetic vitamin D analogue with potential antitumor properties, would enhance the chemopreventive efficacy of 5-FU on an intermediate-term (15 weeks) model of colorectal tumors induced by azoxymethane (AOM) in rats. After AOM injection, 5-FU was administered during the 9th and 10th weeks (12 mg/kg/day for 4 days, then 6 mg/kg every other day for another 4 doses), whereas paricalcitol (2.5 μg/kg/day; 3 days/week) was given from the 7th to the 15th week. At week 15, the animals were euthanized and their resected colons were examined macroscopically and microscopically. Quantitative RT-PCR was used to measure the transcription activities of Wnt, β-catenin, DKK-1, CDNK-1A, NF-κB, and COX-2 genes, and ELISA was used to quantify the protein levels of β-catenin, COX-2, HSP90, and VEGF. IHC was additionally used to measure β-catenin, HSP90, and inducible nitric oxide synthase (iNOS). Compared with their individual therapy, combination of 5-FU and paricalcitol showed more significant reducing effect on numbers of grown tumors and large aberrant crypts foci. Mechanistically, paricalcitol and 5-FU had cooperated together to repress the expression of procancerous Wnt, β-catenin, NF-κB, COX-2, iNOS, VEGF, and HSP-90 more, and to upregulate the expression of antitumorigenesis DKK-1 and CDNK-1A, compared with their monotherapies. Our findings suggest that combined use of paricalcitol with 5-FU exhibits an augmenting chemopreventive effect against colorectal tumors, and might potentially be useful for chemoprevention in colorectal cancer patients. Cancer Prev Res; 9(6); 491-501. ©2016 AACR. PMID:27020656

  17. Vitamin E, glutathione S-transferase and gamma-glutamyl transpeptidase activities in cultured hepatocytes of rats treated with carcinogens.

    PubMed

    Ong, F B; Wan Ngah, W Z; Top, A G; Khalid, B A; Shamaan, N A

    1994-03-01

    1. The effects of alpha-tocopherol and gamma-tocotrienol on glutathione S-transferase (GST) and gamma-glutamyl transpeptidase (gamma-GT) activities in cultured hepatocytes prepared from rats treated with diethylnitrosamine (DEN) and 2-acetylaminofluorene (AAF) were investigated. 2. Both the alpha-tocopherol and gamma-tocotrienol treated hepatocytes showed significantly higher (P < 0.05) GST activities than untreated hepatocytes prepared from the carcinogen treated rats in the first 3 days of culture. Treatment with alpha-tocopherol and gamma-tocotrienol generally resulted in a tendency to increase the GST activities above that in the untreated hepatocytes. 3. Treatment with high doses (125-250 microM) of alpha-tocopherol and low doses (12.5-25 microM) of gamma-tocotrienol generally resulted in a significant reduction in gamma-GT activities at 1-3 days. gamma-GT activities are reduced as the dose of alpha-tocopherol and gamma-tocotrienol are increased.

  18. Urinary folate excretion in chronic ethanol- and diet-treated rats

    SciTech Connect

    Collins, T.D.; McMartin, K.E.; Bairnsfather, L.

    1986-03-05

    Acute ethanol treatment of rats produces a marked increase in urinary folate excretion, which accumulates in correlation with the duration of ethanol treatment. In order to study the role of excess urinary folate excretion in the development of folate deficiency by chronic ethanol feeding, groups of male Sprague-Dawley rats were maintained for four months on one of the following liquid diets: ethanol, pair-fed control, ethanol minus folic acid, and pair-fed control minus folic acid. A fifth group was provided a control chow diet ad libitum. Blood ethanol levels were generally maintained between 80-150 mg/dl at various times of the day. Decrease in plasma and tissue folate levels occurred within four weeks in all liquid diet groups compared to chow rats and within two weeks for urinary folate levels. Greater effects were generally observed in both folate-deficient groups than in the control or ethanol group. Acute ethanol treatment of rats from the various diet groups produced increases in urinary folate excretion in all groups except the ethanol minus folic acid diet group. When the folate system of rats are compromised by dietary deprivation and/or chronic ethanol treatment, these results suggest that urinary folate excretion is greatly reduced as a conservation measure.

  19. Analysis of the Ki-67 index in the vaginal epithelium of castrated rats treated with tamoxifen

    PubMed Central

    Nery-Aguiar, Afif Rieth; Aguiar, Yousef Qathaf; Júnior, Airton Mendes Conde; Alencar, Airlane Pereira; Tavares, Cleciton Braga; Lopes-Costa, Pedro Vitor; Nazário, Afonso Celso; da Silva, Benedito Borges

    2016-01-01

    OBJECTIVES: Vaginal atrophy and breast cancer are common conditions in postmenopausal women and tamoxifen is the standard endocrine treatment for hormone-sensitive tumors. The present study aimed to assess the effect of tamoxifen on Ki-67 protein expression in the vaginal epithelium of castrated rats. MATERIAL AND METHODS: Forty Wistar-Hannover adult, virgin, castrated rats were randomly divided into two groups, group I (control, n=20) and group II (tamoxifen, n=20), receiving 0.5 ml of propylene glycol and 250 µg of tamoxifen diluted in 0.5 ml of propylene glycol, respectively, daily by gavage for 30 days. On the 31st day, the rats were euthanized and their vaginas were removed and fixed in 10% buffered formalin for the immunohistochemical study of Ki-67 protein expression. Data were analyzed by the Levene and Student's t tests (p<0.05). RESULTS: The mean index of Ki-67 expression in the rat vagina of groups I and II was 4.04±0.96 and 26.86±2.19, respectively (p<0.001). CONCLUSIONS: According to the results of the present study, tamoxifen, at the dose and treatment length used, induced a significant increase in the cell proliferation of the vaginal mucosa in castrated rats, as evaluated by Ki-67 protein expression. PMID:26934238

  20. Protective effect of pumpkin seed extract on sperm characteristics, biochemical parameters and epididymal histology in adult male rats treated with cyclophosphamide.

    PubMed

    Aghaei, S; Nikzad, H; Taghizadeh, M; Tameh, A A; Taherian, A; Moravveji, A

    2014-10-01

    Cancer treatment with cyclophosphamide (CP) may result in reproductive toxicity as one of its side effects. The pumpkin seed is a rich natural source of antioxidant. We have assessed the possible protective efficacy of pumpkin seed extract on sperm characteristics, biochemical parameters and epididymal histology of CP-treated rats. Male adult Wistar rats were categorised into four groups. Group 1 served as control and received intraperitoneal (IP) injection of isotonic saline solution. Group 2 rats were treated with CP by IP injection in a single dose of 100 mg/kg body weight, only once. Group 3 and 4 received CP plus 300 and 600 mg/kg pumpkin seed extract respectively. Six weeks after treatment, sperm characteristics, biochemical parameters and histopathological changes were examined. Results showed that, sperm characteristics in CP-treated rats were significantly decreased. Biochemical analysis results showed that the co-administration of 300 mg pumpkin seed extract could increase the total antioxidant capacity (TAC) level significantly. In CP-treated rats, histopathological changes such as vacuolisation, disorganisation and separation of epididymal epithelium were observed as well. Interestingly, pumpkin seed extract could improve the above-mentioned parameters remarkably in CP-treated rats. Our findings indicated that pumpkin seed extract might be used as protective agent against CP-induced reproductive toxicity.

  1. Effects of (+)-8-OH-DPAT on the duration of immobility during the forced swim test and hippocampal cell proliferation in ACTH-treated rats.

    PubMed

    Miyake, Ayaka; Kitamura, Yoshihisa; Miyazaki, Ikuko; Asanuma, Masato; Sendo, Toshiaki

    2014-07-01

    In the present study, we examined the effect of ACTH on the immobilization of rats in the forced swim test and hippocampal cell proliferation after administration of the 5-HT1A receptor agonist, R-(+)-8-hydroxy-2-di-n-propylamino tetralin ((+)-8-OH-DPAT). Chronic treatment with (+)-8-OH-DPAT (0.01-0.1 mg/kg, s.c.) significantly decreased the duration of immobility in saline- and ACTH-treated rats. Chronic administration of ACTH caused a significant decrease in hippocampal cell proliferation. However, (+)-8-OH-DPAT significantly normalized cell proliferation in ACTH-treated rats. We then investigated the effects of (+)-8-OH-DPAT on the expression of brain-derived neurotrophic factor (BDNF) and cyclin D1 (elements of cyclic adenosine monophosphate response element-binding protein (CREB)-BDNF and Wnt signaling pathways, respectively) in the hippocampus of saline- and ACTH-treated rats. ACTH treatment significantly decreased the expression of cyclin D1, while treatment with (+)-8-OH-DPAT normalized the expression of cyclin D1 in ACTH-treated rats. However, the expression of BDNF did not change in either saline- or ACTH-treated rats. These findings suggest that the antidepressant effects of (+)-8-OH-DPAT in treatment-resistant animals may be attributed to an enhancement of hippocampal cell proliferation, at least in part due to an enhancement of cyclin D1 expression.

  2. Effect of combination therapy consisting of enalapril, α-lipoic acid, and menhaden oil on diabetic neuropathy in a high fat/low dose streptozotocin treated rat.

    PubMed

    Davidson, Eric P; Holmes, Amey; Coppey, Lawrence J; Yorek, Mark A

    2015-10-15

    We have previously demonstrated that treating diabetic rats with enalapril, an angiotensin converting enzyme (ACE) inhibitor, α-lipoic acid, an antioxidant, or menhaden oil, a natural source of omega-3 fatty acids can partially improve diabetic peripheral neuropathy. In this study we sought to determine the efficacy of combining these three treatments on vascular and neural complications in a high fat fed low dose streptozotocin treated rat, a model of type 2 diabetes. Rats were fed a high fat diet for 8 weeks followed by a 30 mg/kg dose of streptozotocin. Eight weeks after the onset of hyperglycemia diabetic rats were treated with a combination of enalapril, α-lipoic acid and menhaden oil. Diabetic rats not receiving treatment were continued on the high fat diet. Glucose clearance was impaired in diabetic rats and significantly improved with treatment. Diabetes caused steatosis, elevated serum lipid levels, slowing of motor and sensory nerve conduction, thermal hypoalgesia, reduction in intraepidermal nerve fiber profiles, decrease in cornea sub-basal nerve fiber length and corneal sensitivity and impairment in vascular relaxation to acetylcholine and calcitonin gene-related peptide in epineurial arterioles of the sciatic nerve. Treating diabetic rats with the combination of enalapril, α-lipoic acid and menhaden oil reversed all these deficits to near control levels except for motor nerve conduction velocity which was also significantly improved compared to diabetic rats but remained significantly decreased compared to control rats. These studies suggest that a combination therapeutic approach may be most effective for treating vascular and neural complications of type 2 diabetes.

  3. Metabolic and biochemical changes in streptozotocin induced obese-diabetic rats treated with Phyllanthus niruri extract.

    PubMed

    Mediani, Ahmed; Abas, Faridah; Maulidiani, M; Khatib, Alfi; Tan, Chin Ping; Ismail, Intan Safinar; Shaari, Khozirah; Ismail, Amin; Lajis, N H

    2016-09-01

    Herbal medicine has been proven to be an effective therapy offering a variety of benefits, such as moderate reduction in hypoglycemia, in the treatment and prevention of obesity and diabetes. Phyllanthus niruri has been used as a treatment for diabetes mellitus. Herein, the induction of type 2 diabetes in Sprague-Dawley rats was achieved by a low dose of streptozotocin (STZ) (25mg/kgbw). Here, we evaluated the in vivo antidiabetic properties of two concentrations (250 and 500mg/kg bw) of P. niruri via metabolomics approach. The administration of 500mg/kgbw of P. niruri extract caused the metabolic disorders of obese diabetic rats to be improved towards the normal state. The extract also clearly decreased the serum glucose level and improved the lipid profile in obese diabetic rats. The results of this study may contribute towards better understanding the molecular mechanism of this medicinal plant in managing diabetes mellitus. PMID:27318080

  4. Effects of mesenchymal stem cells on interleukin-1β-treated chondrocytes and cartilage in a rat osteoarthritic model

    PubMed Central

    TANG, JILEI; CUI, WEIDING; SONG, FANGLONG; ZHAI, CHENJUN; HU, HANSHENG; ZUO, QIANG; FAN, WEIMIN

    2015-01-01

    In the present study, the effects and mechanisms of mesenchymal stem cells (MSCs) on interleukin (IL)-1β-stimulated rat chondrocytes, as well as cartilage from a rat model of osteoarthritis (OA) induced by anterior cruciate ligament transection and medial meniscectomy were investigated. Confluent rat chondrocytes were treated with IL-1β (10 ng/ml), then cultured indirectly with or without MSCs at a ratio of 2:1. Total RNA and protein were collected at various time-points, and western blot and reverse transcription-quantitative polymerase chain reaction analyses were used to investigate the expression of type II collagen (Col2), aggrecan, matrix metalloproteinase-13 (MMP-13) and cyclooxygenase-2 (COX-2). The activation of extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), nuclear factor-κB (NF-κB) p65 and inhibitory-κ-B-α (IκBα) were also assessed by western blotting. In addition, the in vivo effects of MSCs in a rat OA model were assessed by histology and western blot analysis. The results indicated that in vitro, IL-1β markedly upregulated the expression of MMP-13, COX-2, phosphorylated ERK1/2, JNK, p38 MAPK and NF-κB p65, and inhibited the expression of Col2, aggrecan and IκBα. Conversely, MSCs enhanced the expression of Col2, aggrecan and IκBα, and inhibited the expression of MMP-13 and NF-κB p65 in IL-1β-stimulated rat chondrocytes. In vivo histological and western blot analyses revealed analogous results to the in vitro findings. The results of the present study demonstrated that MSCs suppressed the inflammatory response and extracellular matrix degradation in IL-1β-induced rat chondrocytes, as well as cartilage in a osteoarthritic rat model, in part via the NF-κB signaling pathway. PMID:25892273

  5. OXIDATIVE DNA DAMAGE AND REPAIR IN RATS TREATED WITH POTASSIUM BROMATE AND A MIXTUE OF DRINKING WATER DISINFECTION BY-PRODUCTS

    EPA Science Inventory

    Oxidative DNA Damage and Repair in Rats Treated with Potassium Bromate and a Mixture of Drinking Water Disinfection By-Products

    Public drinking water treated with chemical disint'ectants contains a complex mixture of disinfection by-products (D BPs). There is a need for m...

  6. Hypothalamic neuropeptide Y (NPY) and the attenuation of hyperphagia in streptozotocin diabetic rats treated with dopamine D1/D2 agonists.

    PubMed

    Kuo, Dong-Yih

    2006-07-01

    1. Dopamine is an appetite suppressant, while neuropeptide Y (NPY), an appetite stimulant in the brain, is reported to be involved in anorectic action induced by a combined administration of D1/D2 agonists in normal rats. In diabetic rats, however, these factors have not been studied. 2. Rats (including normal, diabetic and insulin-treated diabetic rats) were given daily injections of saline or D1/D2 agonists for 6 days. Changes in food intake and hypothalamic NPY content of these rats were assessed and compared. 3. The D1/D2 agonist-induced anorectic responses were altered in diabetic rats compared to normal rats treated similarly. Both the anorectic response on the first day of dosing and the tolerant response on the subsequent days were attenuated. 4. This alteration was independent of the neuroendocrine disturbance on feeding behavior since the basic pattern of food intake during the time course of a 24-h day/night cycle was similar in normal and diabetic rats; the decrease of food intake following drug treatment was only shown at the initial interval of 0-6 h in both groups of rats. 5. However, this alteration coincided with changes in NPY content following D1/D2 coadministration. The replacement of insulin in diabetic rats could normalize both NPY content and D1/D2 agonist-induced anorexia. 6. It is demonstrated that the response of D1/D2 agonist-induced appetite suppression is attenuated in diabetic rats compared to normal rats and that elevated hypothalamic NPY content may contribute to this alteration.

  7. Hypothalamic neuropeptide Y (NPY) and the attenuation of hyperphagia in streptozotocin diabetic rats treated with dopamine D1/D2 agonists

    PubMed Central

    Kuo, Dong-Yih

    2006-01-01

    Dopamine is an appetite suppressant, while neuropeptide Y (NPY), an appetite stimulant in the brain, is reported to be involved in anorectic action induced by a combined administration of D1/D2 agonists in normal rats. In diabetic rats, however, these factors have not been studied. Rats (including normal, diabetic and insulin-treated diabetic rats) were given daily injections of saline or D1/D2 agonists for 6 days. Changes in food intake and hypothalamic NPY content of these rats were assessed and compared. The D1/D2 agonist-induced anorectic responses were altered in diabetic rats compared to normal rats treated similarly. Both the anorectic response on the first day of dosing and the tolerant response on the subsequent days were attenuated. This alteration was independent of the neuroendocrine disturbance on feeding behavior since the basic pattern of food intake during the time course of a 24-h day/night cycle was similar in normal and diabetic rats; the decrease of food intake following drug treatment was only shown at the initial interval of 0–6 h in both groups of rats. However, this alteration coincided with changes in NPY content following D1/D2 coadministration. The replacement of insulin in diabetic rats could normalize both NPY content and D1/D2 agonist-induced anorexia. It is demonstrated that the response of D1/D2 agonist-induced appetite suppression is attenuated in diabetic rats compared to normal rats and that elevated hypothalamic NPY content may contribute to this alteration. PMID:16702993

  8. The neurochemical profile of the hippocampus in isoflurane-treated and unanesthetized rat pups

    PubMed Central

    Akulov, Andrey E.

    2015-01-01

    In vivo study of cerebral metabolism in neonatal animals by high-resolution magnetic resonance spectroscopy (MRS) is an important tool for deciphering the developmental origins of adult diseases. Up to date, all in vivo spectrum acquisition procedures have been performed in neonatal rodents under anesthesia. However, it is still unknown if the inhaled anesthetic isoflurane, which is commonly used in magnetic resonance imaging studies, could affect metabolite levels in the brain of neonatal rats. Moreover, the unanesthetized MRS preparation that uses neonatal rodent pups is still lacking. Here, a novel restraint protocol was developed for neonatal rats in accordance with the European Directive 2010/63/EU. This protocol shares the same gradation of severity as the protocol for non-invasive magnetic resonance imaging of animals with appropriate sedation or anesthesia. Such immobilization of neonatal rats without anesthesia can be implemented for MRS studies when an interaction between anesthetic and target drugs is expected. Short-term isoflurane treatment did not affect the levels of key metabolites in the hippocampi of anesthetized pups and, in contrast to juvenile and adult rodents, it is suitable for MRS studies in neonatal rats when the interaction between anesthetic and target drugs is not expected. PMID:27486369

  9. COMPARISON OF GENE EXPRESSION IN KIDNEY AND URINARY BLADDER FROM RATS TREATED WITH DIMETHYLARSINIC ACID

    EPA Science Inventory

    Arsenic is widespread in the environment and a human carcinogen. A major metabolite of inorganic arsenic (iAs) in most species, including humans, is dimethylarsinic acid (DMA), which is also used as a pesticide. Unlike iAs, DMA induces urinary bladder tumors in rats. DMA is belie...

  10. [Comparative metabonomics study on urine in rat treated by Angelica sinensis volatile oil].

    PubMed

    Li, Jin-Xia; Zhang, Man; Sun, Li-Bo; Zhang, Ling; Zhang, Wen-Quan; Zhao, Hai-Fu; Li, Peng-Ling; Hua, Yong-Li; Ji, Peng; Wei, Yan-Ming

    2014-04-01

    Metabonomics was employed to investigate the effect of Angelica sinensis volatile oil (ASVO) to the endogenous metabolites of normal rats, and to reveal the possible ways of metabolism in rats caused by ASVO. The fifty male Waster rats were randomly divided into five groups (each consists of 10 rats), such as control group, high dose group of ASVO, middle dose group of ASVO, low dose group of ASVO, and Aspirin group. They were given 0.9% saline, 0.352 mL x kg(-1) ASVO, 0.176 mL x kg(-1) ASVO, 0.088 mL x kg(-1) ASVO and ASP respectively with the equal volume of 0.2 mL. Drugs and vehicle were given for 3 successive days. The urine was collected at 12, 24, 36, 48 h after modeling with metabolic cages. Rat urine metabolic fingerprint in different stages was analyzed using GC-MS, based on which the principal component analysis (PCA)and orthogonal partial least-squares discriminant analysis (OPLS-DA) models were established for metabonomic analysis. Potential biomarkers were screened by using variable importance in the projection (VIP) and T test. It was revealed that the middle dose of ASVO at 36 h induces a substantial change in rat urine. Compared with control group, seven kinds of endogenous metabolites in ASP group and ASVO group change significantly (P < 0.05), among which aconitic acid, succinic acid, citric acid, alpha-ketone glutaric acid, glycine and malic acid content had an upward trend (P < 0.05) and prostaglandin content had a downward trend (P < 0.01). The mechanism of ASVO and ASP have the similarity. It is likely that ASVO intervenes the metabolic process by affecting the energy, amino acid and lipid metabolism. Our work also indicates that rats administrated with ASVO can increase the energy metabolism of the body, induce the production of inflammatory substances and strengthen the body's immune ability. The result has also provide a proof for futher interpret ASVO pharmacological effects. PMID:25011271

  11. P6 Electroacupuncture Improved QTc Interval Prolongation by Upregulation of Connexin43 in Droperidol Treated Rats

    PubMed Central

    Zhao, Feng; Cui, Suyang; Huang, Libing

    2014-01-01

    Aim. This study investigated the effect of P6 EA on droperidol-induced QTc interval prolongation and Cx43 expression in ventricular muscle of rats. Methods. Twenty-four rats were randomly divided into control group (C), droperidol group (D), or EA group (E). C group rats were injected with normal saline. D group rats were injected with droperidol 0.13 mg/kg. E group rats were pretreated with EA at left P6 acupoint for 30 min and then injected with droperidol (0.13 mg/kg). QTc intervals were recorded at lead II in ECG within 120 min. Cx43 expression was measured by RT-PCR and western blotting. Result. Droperidol significantly prolonged QTc intervals compared with controls at 5 min, 10 min, 15 min, and 30 min (P < 0.05). P6 EA could significantly abbreviate the prolongation of QTc interval compared with droperidol group at 5 min, 10 min, 15 min, and 30 min (P < 0.05). Cx43 mRNA and proteins were significantly increased by P6 EA compared with droperidol group at 120 min (P < 0.05). There were no significant differences in Cx43 mRNA and protein expression between droperidol and control group at 120 min (P > 0.05). Conclusion. P6 EA could improve QTc interval prolongation induced by droperidol, which may relate to upregulation of Cx43 mRNA and protein. Antiemetic dose of droperidol had minor effects on Cx43 mRNA and protein expression at 120 min. PMID:25371698

  12. Disruption of estrogen homeostasis as a mechanism for uterine toxicity in Wistar Han rats treated with tetrabromobisphenol A.

    PubMed

    Sanders, J Michael; Coulter, Sherry J; Knudsen, Gabriel A; Dunnick, June K; Kissling, Grace E; Birnbaum, Linda S

    2016-05-01

    Chronic oral treatment of tetrabromobisphenol A (TBBPA) to female Wistar Han rats resulted in increased incidence of cell proliferation at 250mg/kg and tumor formation in the uterus at higher doses. The present study was designed to test the hypothesis that disruption of estrogen homeostasis was a major mode-of-action for the observed effects. Biological changes were assessed in serum, liver, and the proximal (nearest the cervix) and distal (nearest the ovaries) sections of the uterine horn of Wistar Han rats 24h following administration of the last of five daily oral doses of 250mg/kg. Expression of genes associated with receptors, biosynthesis, and metabolism of estrogen was altered in the liver and uterus. TBBPA treatment also resulted in changes in expression of genes associated with cell division and growth. Changes were also observed in the concentration of thyroxine in serum and in expression of genes in the liver and uterus associated with thyroid hormone receptors. Differential expression of some genes was tissue-dependent or specific to tissue location in the uterus. The biological responses observed in the present study support the hypothesis that perturbation of estrogen homeostasis is a major mode-of-action for TBBPA-mediated cell proliferation and tumorigenesis previously observed in the uterus of TBBPA-treated Wistar Han rats. PMID:26988606

  13. Amelioration of Hyperglycaemia, Oxidative Stress and Dyslipidaemia in Alloxan-Induced Diabetic Wistar Rats Treated with Probiotic and Vitamin C

    PubMed Central

    Aluwong, Tagang; Ayo, Joseph O.; Kpukple, Alkali; Oladipo, Olusola Olalekan

    2016-01-01

    Clinical and experimental evidence suggests that hyperglycaemia is responsible for the oxidative stress in diabetes mellitus. The study was designed to investigate the comparative effects of probiotic and vitamin C (Vit-C) treatments on hyperglycaemia, oxidative stress and dyslipidaemia in alloxan-induced diabetic rats. Type 1 diabetes (T1DM) was induced in male Wistar rats by a single intraperitoneal (i.p.) injection of alloxan (150 mg/kg). Six groups of the animals received the following treatment regimens for four weeks: (1) Normal saline, per os; (2) alloxan (150 mg/kg, i.p.); (3) alloxan (150 mg/kg) + insulin (4 U/kg, subcutaneously); (4) alloxan (150 mg/kg) + probiotic (4.125 × 106 CFU/100 mL per os); (5) alloxan (150 mg/kg) + Vit-C (100 mg/kg, i.m.); (6) alloxan (150 mg/kg) + probiotic (4.125 × 106 CFU/100 mL per os) + Vit-C (100 mg/kg, intramuscularly). Probiotic + Vit-C decreased (p < 0.05) blood glucose concentration in diabetic treated group, when compared with the untreated diabetic group. Probiotic + Vit-C reduced malondialdehyde concentration, in the serum, brain and kidneys, respectively, but increased the activity of antioxidant enzymes. Probiotic and Vit-C may be more effective than Vit-C alone, in ameliorating hyperglycaemia, oxidative stress and dyslipidaemia in alloxan-induced diabetic rats. PMID:27164129

  14. Hepatoprotective, antioxidant, and ameliorative effects of ginger (Zingiber officinale Roscoe) and vitamin E in acetaminophen treated rats.

    PubMed

    Abdel-Azeem, Amal S; Hegazy, Amany M; Ibrahim, Khadiga S; Farrag, Abdel-Razik H; El-Sayed, Eman M

    2013-09-01

    Ginger is a remedy known to possess a number of pharmacological properties. This study investigated efficacy of ginger pretreatment in alleviating acetaminophen-induced acute hepatotoxicity in rats. Rats were divided into six groups; negative control, acetaminophen (APAP) (600 mg/kg single intraperitoneal injection); vitamin E (75 mg/kg), ginger (100 mg/kg), vitamin E + APAP, and ginger + APAP. Administration of APAP elicited significant liver injury that was manifested by remarkable increase in plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), arginase activities, and total bilirubin concentration. Meanwhile, APAP significantly decreased plasma total proteins and albumin levels. APAP administration resulted in substantial increase in each of plasma triacylglycerols (TAGs), malondialdhyde (MDA) levels, and total antioxidant capacity (TAC). However, ginger or vitamin E treatment prior to APAP showed significant hepatoprotective effect by lowering the hepatic marker enzymes (AST, ALT, ALP, and arginase) and total bilirubin in plasma. In addition, they remarkably ameliorated the APAP-induced oxidative stress by inhibiting lipid peroxidation (MDA). Pretreatment by ginger or vitamin E significantly restored TAGs, and total protein levels. Histopathological examination of APAP treated rats showed alterations in normal hepatic histoarchitecture, with necrosis and vacuolization of cells. These alterations were substantially decreased by ginger or vitamin E. Our results demonstrated that ginger can prevent hepatic injuries, alleviating oxidative stress in a manner comparable to that of vitamin E. Combination therapy of ginger and APAP is recommended especially in cases with hepatic disorders or when high doses of APAP are required. PMID:23927622

  15. Amelioration of Hyperglycaemia, Oxidative Stress and Dyslipidaemia in Alloxan-Induced Diabetic Wistar Rats Treated with Probiotic and Vitamin C.

    PubMed

    Aluwong, Tagang; Ayo, Joseph O; Kpukple, Alkali; Oladipo, Olusola Olalekan

    2016-01-01

    Clinical and experimental evidence suggests that hyperglycaemia is responsible for the oxidative stress in diabetes mellitus. The study was designed to investigate the comparative effects of probiotic and vitamin C (Vit-C) treatments on hyperglycaemia, oxidative stress and dyslipidaemia in alloxan-induced diabetic rats. Type 1 diabetes (T1DM) was induced in male Wistar rats by a single intraperitoneal (i.p.) injection of alloxan (150 mg/kg). Six groups of the animals received the following treatment regimens for four weeks: (1) Normal saline, per os; (2) alloxan (150 mg/kg, i.p.); (3) alloxan (150 mg/kg) + insulin (4 U/kg, subcutaneously); (4) alloxan (150 mg/kg) + probiotic (4.125 × 10⁶ CFU/100 mL per os); (5) alloxan (150 mg/kg) + Vit-C (100 mg/kg, i.m.); (6) alloxan (150 mg/kg) + probiotic (4.125 × 10⁶ CFU/100 mL per os) + Vit-C (100 mg/kg, intramuscularly). Probiotic + Vit-C decreased (p < 0.05) blood glucose concentration in diabetic treated group, when compared with the untreated diabetic group. Probiotic + Vit-C reduced malondialdehyde concentration, in the serum, brain and kidneys, respectively, but increased the activity of antioxidant enzymes. Probiotic and Vit-C may be more effective than Vit-C alone, in ameliorating hyperglycaemia, oxidative stress and dyslipidaemia in alloxan-induced diabetic rats. PMID:27164129

  16. Disruption of estrogen homeostasis as a mechanism for uterine toxicity in Wistar Han rats treated with tetrabromobisphenol A.

    PubMed

    Sanders, J Michael; Coulter, Sherry J; Knudsen, Gabriel A; Dunnick, June K; Kissling, Grace E; Birnbaum, Linda S

    2016-05-01

    Chronic oral treatment of tetrabromobisphenol A (TBBPA) to female Wistar Han rats resulted in increased incidence of cell proliferation at 250mg/kg and tumor formation in the uterus at higher doses. The present study was designed to test the hypothesis that disruption of estrogen homeostasis was a major mode-of-action for the observed effects. Biological changes were assessed in serum, liver, and the proximal (nearest the cervix) and distal (nearest the ovaries) sections of the uterine horn of Wistar Han rats 24h following administration of the last of five daily oral doses of 250mg/kg. Expression of genes associated with receptors, biosynthesis, and metabolism of estrogen was altered in the liver and uterus. TBBPA treatment also resulted in changes in expression of genes associated with cell division and growth. Changes were also observed in the concentration of thyroxine in serum and in expression of genes in the liver and uterus associated with thyroid hormone receptors. Differential expression of some genes was tissue-dependent or specific to tissue location in the uterus. The biological responses observed in the present study support the hypothesis that perturbation of estrogen homeostasis is a major mode-of-action for TBBPA-mediated cell proliferation and tumorigenesis previously observed in the uterus of TBBPA-treated Wistar Han rats.

  17. Thymoquinone subdues tumor growth and potentiates the chemopreventive effect of 5-fluorouracil on the early stages of colorectal carcinogenesis in rats.

    PubMed

    Kensara, Osama Adnan; El-Shemi, Adel Galal; Mohamed, Amr Mohamed; Refaat, Bassem; Idris, Shakir; Ahmad, Jawwad

    2016-01-01

    Colorectal cancer (CRC) is one of the most prevalent cancers and has a high mortality rate. Insensitivity and the limited therapeutic efficacy of its standard chemotherapeutic drug, 5-fluorouracil (5-FU), represents an important challenge in CRC treatment. The robust antitumor properties of thymoquinone (TQ), the main bioactive constituent of Nigella sativa, have recently been demonstrated on different cancers. We investigated whether TQ could potentiate the chemopreventive effect of 5-FU to eradicate the early stages of CRC and elucidated its underlying mechanisms. An intermediate-term (15 weeks) model of colorectal tumorigenesis was induced in male Wistar rats by azoxymethane (AOM), and the animals were randomly and equally divided into five groups: control, AOM, AOM/5-FU, AOM/TQ, and AOM/5-FU/TQ. TQ (35 mg/kg/d; 3 d/wk) was given during the seventh and 15th weeks post-AOM injection, while 5-FU was given during the ninth and tenth weeks (12 mg/kg/d for 4 days; then 6 mg/kg every other day for another four doses). At week 15, the resected colons were subjected to macroscopic, histopathological, molecular, and immunohistochemical examinations. Interestingly, 5-FU/TQ combination therapy resulted in a more significant reduction on AOM-induced colorectal tumors and large aberrant crypts foci than treatment with the individual drugs. Mechanistically, 5-FU and TQ remarkably cooperated to repress the expression of procancerous Wnt, β-catenin, NF-κB, COX-2, iNOS, VEGF, and TBRAS and upregulate the expression of anti-tumorigenesis DKK-1, CDNK-1A, TGF-β1, TGF-βRII, Smad4, and GPx. Overall, our findings present the first report describing the in vivo enhancement effect of combined TQ and 5-FU against early stages of CRC; however, further studies are required to determine the value of this combination therapy in an advanced long-term model of CRC and also to realize its clinical potential. PMID:27468227

  18. Thymoquinone subdues tumor growth and potentiates the chemopreventive effect of 5-fluorouracil on the early stages of colorectal carcinogenesis in rats

    PubMed Central

    Kensara, Osama Adnan; El-Shemi, Adel Galal; Mohamed, Amr Mohamed; Refaat, Bassem; Idris, Shakir; Ahmad, Jawwad

    2016-01-01

    Colorectal cancer (CRC) is one of the most prevalent cancers and has a high mortality rate. Insensitivity and the limited therapeutic efficacy of its standard chemotherapeutic drug, 5-fluorouracil (5-FU), represents an important challenge in CRC treatment. The robust antitumor properties of thymoquinone (TQ), the main bioactive constituent of Nigella sativa, have recently been demonstrated on different cancers. We investigated whether TQ could potentiate the chemopreventive effect of 5-FU to eradicate the early stages of CRC and elucidated its underlying mechanisms. An intermediate-term (15 weeks) model of colorectal tumorigenesis was induced in male Wistar rats by azoxymethane (AOM), and the animals were randomly and equally divided into five groups: control, AOM, AOM/5-FU, AOM/TQ, and AOM/5-FU/TQ. TQ (35 mg/kg/d; 3 d/wk) was given during the seventh and 15th weeks post-AOM injection, while 5-FU was given during the ninth and tenth weeks (12 mg/kg/d for 4 days; then 6 mg/kg every other day for another four doses). At week 15, the resected colons were subjected to macroscopic, histopathological, molecular, and immunohistochemical examinations. Interestingly, 5-FU/TQ combination therapy resulted in a more significant reduction on AOM-induced colorectal tumors and large aberrant crypts foci than treatment with the individual drugs. Mechanistically, 5-FU and TQ remarkably cooperated to repress the expression of procancerous Wnt, β-catenin, NF-κB, COX-2, iNOS, VEGF, and TBRAS and upregulate the expression of anti-tumorigenesis DKK-1, CDNK-1A, TGF-β1, TGF-βRII, Smad4, and GPx. Overall, our findings present the first report describing the in vivo enhancement effect of combined TQ and 5-FU against early stages of CRC; however, further studies are required to determine the value of this combination therapy in an advanced long-term model of CRC and also to realize its clinical potential. PMID:27468227

  19. Distribution profile of gadolinium in gadolinium chelate-treated renally-impaired rats: role of pharmaceutical formulation.

    PubMed

    Fretellier, Nathalie; Salhi, Mariem; Schroeder, Josef; Siegmund, Heiko; Chevalier, Thibaut; Bruneval, Patrick; Jestin-Mayer, Gaëlle; Delaloge, Francette; Factor, Cécile; Mayer, Jean-François; Fabicki, Jean-Michel; Robic, Caroline; Bonnemain, Bruno; Idée, Jean-Marc; Corot, Claire

    2015-05-25

    While not acutely toxic, chronic hepatic effect of certain gadolinium chelates (GC), used as contrast agent for magnetic resonance imaging, might represent a risk in renally-impaired patients due to free gadolinium accumulation in the liver. To answer this question, this study investigated the consequences of the presence of small amounts of either a soluble gadolinium salt ("free" Gd) or low-stability chelating impurity in the pharmaceutical solution of gadoteric acid, a macrocyclic GC with high thermodynamic and kinetic stabilities, were investigated in renally-impaired rats. Renal failure was induced by adding 0.75% adenine in the diet for three weeks. The pharmaceutical and commercial solution of gadoteric acid was administered (5 daily intravenous injections of 2.5 mmol Gd/kg) either alone or after being spiked with either "free" gadolinium (i.e., 0.04% w/v) or low-stability impurity (i.e., 0.06 w/v). Another GC, gadodiamide (low thermodynamic and kinetic stabilities) was given as its commercial solution at a similar dose. Non-chelated gadolinium was tested at two doses (0.005 and 0.01 mmol Gd/kg) as acetate salt. Gadodiamide induced systemic toxicity (mortality, severe epidermal and dermal lesions) and substantial tissue Gd retention. The addition of very low amounts of "free", non-chelated gadolinium or low thermodynamic stability impurity to the pharmaceutical solution of the thermodynamically stable GC gadoteric acid resulted in substantial capture of metal by the liver, similar to what was observed in "free" gadolinium salt-treated rats. Relaxometry studies strongly suggested the presence of free and soluble gadolinium in the liver. Electron microscopy examinations revealed the presence of free and insoluble gadolinium deposits in hepatocytes and Kupffer cells of rats treated with gadoteric acid solution spiked with low-stability impurity, free gadolinium and gadodiamide, but not in rats treated with the pharmaceutical solution of gadoteric acid. The

  20. Effects of bupropion and pramipexole on cell proliferation in the hippocampus of adrenocorticotropic hormone-treated rats.

    PubMed

    Onoue, Yuka; Kuwatsuka, Keiko; Miyazaki, Ikuko; Asanuma, Masato; Kitamura, Yoshihisa; Sendo, Toshiaki

    2014-01-01

    The dopamine reuptake inhibitor bupropion and dopamine D2/3 receptor agonist pramipexole have been clinically proven to improve both depression and treatment-resistant depression. We examined its influence on the duration of immobility during the forced swim test in adrenocorticotropic hormone (ACTH)-treated rats and further analyzed the possible role of the dopamine nerve system in this effect. Bupropion and pramipexole significantly decreased the duration of immobility in normal and ACTH-treated rats. We previously demonstrated that the chronic administration of ACTH caused a significant decrease in hippocampal cell proliferation and neurogenesis. In this study, we used the mitotic marker 5-bromo-2'-deoxyridine to investigate the effects of bupropion and pramipexole on cell proliferation in the subgranular zone of the hippocampal dentate gyrus following chronic treatment with ACTH. The ACTH treatment for 14 d decreased adult hippocampal cell proliferation. The chronic administration of bupropion for 14 d blocked the loss of cell proliferation resulting from the chronic treatment with ACTH, whereas pramipexole did not. The administration of bupropion may have treatment-resistant antidepressive properties, which may be partly attributed to the normalization of hippocampal cell proliferation.

  1. Evaluation of Osseointegration around Tibial Implants in Rats by Ibandronate-Treated Nanotubular Ti-32Nb-5Zr Alloy

    PubMed Central

    Nepal, Manoj; Li, Liang; Bae, Tae Sung; Kim, Byung Il; Soh, Yunjo

    2014-01-01

    Materials with differing surfaces have been developed for clinical implant therapy in dentistry and orthopedics. This study was designed to evaluate bone response to titanium alloy containing Ti-32Nb-5Zr with nanostructure, anodic oxidation, heat treatment, and ibandronate coating. Rats were randomly assigned to two groups for implantation of titanium alloy (untreated) as the control group and titanium alloy group coated with ibandronate as the experimental group. Then, the implants were inserted in both tibiae of the rats for four weeks. After implantation, bone implant interface, trabecular microstructure, mechanical fixation was evaluated by histology, micro-computed tomography (μCT) and the push-out test, respectively. We found that the anodized, heat-treated and ibandronate-coated titanium alloy triggered pronounced bone implant integration and early bone formation. Ibandronate-coated implants showed elevated values for removal torque and a higher level of BV/TV, trabecular thickness and separation upon analysis with μCT and mechanical testing. Similarly, higher bone contact and a larger percentage bone area were observed via histology compared to untreated alloy. Furthermore, well coating of ibandronate with alloy was observed by vitro releasing experiment. Our study provided evidences that the coating of bisphosphonate onto the anodized and heat-treated nanostructure of titanium alloy had a positive effect on implant fixation. PMID:25489426

  2. Uncoupling Protein-2 is an Antioxidant that is Up-Regulated in the Enamel Organ of Fluoride-Treated Rats*

    PubMed Central

    Suzuki, Maiko; Sierant, Megan L.; Antone, Jerry V.; Everett, Eric T.; Whitford, Gary M.; Bartlett, John D.

    2014-01-01

    Dental fluorosis is characterized by subsurface hypomineralization and retention of enamel matrix proteins. Fluoride (F−) exposure generates reactive oxygen species (ROS) that can cause ER-stress. We therefore screened oxidative stress arrays to identify genes regulated by F− exposure. Vitamin E is an antioxidant so we asked if a diet high in vitamin E would attenuate dental fluorosis. Maturation stage incisor enamel organs (EO) were harvested from F− treated rats and mice were assessed to determine if vitamin E ameliorates dental fluorosis. Uncoupling protein-2 (Ucp2) was significantly up-regulated by F− (~1.5 & 2.0 fold for the 50 or 100 ppm F− treatment groups respectively). Immunohistochemical results on maturation stage rat incisors demonstrated that UCP2 protein levels increased with F− treatment. UCP2 down-regulates mitochondrial production of ROS, which decreases ATP production. Thus, in addition to reduced protein translation caused by ER-stress, a reduction in ATP production by UCP2 may contribute to the inability of ameloblasts to remove protein from the hardening enamel. Fluoride treated mouse enamel had significantly higher quantitative fluorescence (QF) than the untreated controls. No significant QF difference was observed between control and vitamin E enriched diets within a given F− treatment group. Therefore, a diet rich in vitamin E did not attenuate dental fluorosis. We have identified a novel oxidative stress response gene that is up-regulated in vivo by F− and activation of this gene may adversely affect ameloblast function. PMID:25158175

  3. Effects of Palm Vitamin E on Bone-Formation-Related Gene Expression in Nicotine-Treated Rats

    PubMed Central

    Abukhadir, Seham Salem Ahmed; Mohamed, Norazlina; Makpol, Suzana; Muhammad, Norliza

    2012-01-01

    The study determines the effects of palm vitamin E on the gene expression of bone-formation-related genes in nicotine-treated rats. Male rats were divided into three groups: normal saline olive oil (NSO), nicotine olive oil (NO), and nicotine palm vitamin E (NE). The treatment was carried out in 2 phases. During the first 2 months, the NSO group received normal saline while the NO and NE groups received nicotine 7 mg/kg, 6 days a week, intraperitoneally. The following 2 months, normal saline and nicotine administration was stopped and was replaced with oral supplementation of olive oil for the NSO and NO groups and oral supplementation of palm vitamin E (60 mg/kg) for the NE group. Both femurs were harvested to determine the gene expression of bone morphogenetic protein-2 (BMP-2), Osterix (OSX), and Runt-related transcription factor 2 (RUNX2). Nicotine significantly downregulated the gene expression. This effect was reversed by palm vitamin E treatment. In conclusion, palm vitamin E may play a role in osteoblast differentiation and can be considered as an anabolic agent to treat nicotine-induced osteoporosis. PMID:23049610

  4. Orchidectomy selectively increases follicle-stimulating hormone secretion in gonadotropin-releasing hormone antagonist-treated male rats.

    PubMed

    Tena-Sempere, M; Pinilla, L; Aguilar, E

    1995-03-01

    The pituitary component of the feedback mechanisms exerted by testicular factors on gonadotropin secretion was analyzed in adult male rats treated with a potent gonadotropin-releasing hormone (GnRH) antagonist. In order to discriminate between androgens and testicular peptides, groups of males were orchidectomized (to eliminate androgens and non-androgenic testicular factors) or injected with ethylene dimethane sulfonate (EDS), a selective toxin for Leydig cells (to eliminate selectively androgens) and treated for 15 days with vehicle or the GnRH antagonist Ac-D-pClPhe-D-pClPhe-D-Trp-Ser-Tyr-D-Arg-Leu-Arg-Pro-D-Ala-+ ++NH2CH3COOH (Org.30276, 5 mg/kg/72 hours). Serum concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were measured 7 and 14 days after the beginning of treatment. We found that: in males treated with GnRH antagonist, orchidectomy or EDS treatment did not induce any increase in LH secretion; and orchidectomy, but not EDS treatment, increased FSH secretion in GnRH-treated males. The present results show that negative feedback of testicular factors on LH secretion is mediated completely through changes in GnRH actions. In contrast, a part of the inhibitory action of the testis on FSH secretion is exerted directly at the pituitary level. It can be hypothesized that non-Leydig cell testicular factor(s) inputs at different levels of the hypothalamic-pituitary axis in controlling LH and FSH secretion.

  5. The effect of arbutin on lipid peroxidation and antioxidant capacity in the serum of cyclosporine-treated rats

    PubMed Central

    Khadir, Fatemeh; Pouramir, Mahdi; Joorsaraee, Seyyed Gholamali; Feizi, Farideh; Sorkhi, Hadi; Yousefi, Fatemeh

    2015-01-01

    Background: Cyclosporine A (CsA) is a potent immunosuppressant drug with therapeutic and toxic actions. The use of CsA is limited by its toxicity. Several researchers had proposed that oxidative stress could play an important role in CsA-induced toxicity. Arbutin has recently been shown to possess antioxidative and free radical scavenging abilities. The present study was designed to investigate the in vivo effects of arbutin on lipid peroxidation and antioxidant capacity in the serum of cyclosporine treated rats. Methods: Adult male Wistar rats were divided into six groups (n=8/group): (I) control (no CsA and arbutin administration), (II and III) were treated subcutaneously (Sc) with arbutin (50,100 mg/kg/bw), respectively, (IV) administered CsA (25 mg/kg/bw) intraperitoneally (IP), (V and VI) received the combination of CsA (25 mg/kg/bw) i.p and arbutin (50,100 mg/kg/bw) Sc daily, respectively. At the end of the treatment (after3 weeks), serum lipid peroxidation was measured by thiobarbituric acid-reacting substances (TBARS) and serum total antioxidant capacity (ferric reducing ability of plasma [FRAP]) was assayed based on spectrophotometric method. Results: TBARS had been significantly increased by CsA administration compared with control rats. Arbutin (50mg/kg/bw) completely prevented this effect, but arbutin (100 mg/kg/bw) alone or in combination with CsA significantly increased lipid peroxidation compared with controls. Conclusion: Our data indicate that arbutin (50mg/kg/bw) had protective effect in the CsA-induced toxicity but high concentration of arbutin (100mg/kg/bw) showed meaningful oxidative and lipoperoxidative effects. PMID:26644892

  6. All-Trans-Retinoic Acid Improves Cholestasis in α-Naphthylisothiocyanate–Treated Rats and Mdr2−/− Mice

    PubMed Central

    Mennone, Albert; Soroka, Carol J.

    2014-01-01

    Chronic cholestasis results in liver injury and eventually liver failure. Although ursodeoxycholic acid (UDCA) showed limited benefits in primary biliary cirrhosis, there is an urgent need to develop alternative therapy for chronic cholestatic disorders. Previous studies from our laboratory demonstrated that all-trans-retinoic acid (atRA) is a potent suppressor of CYP7A1, the rate-limiting enzyme in bile acid synthesis. atRA also repressed the expression of tumor growth factor-β and collagen 1A1 in activated primary human stellate cells and LX2 cells. When administered together with UDCA to bile duct–ligated rats, this combined therapy significantly reduced the bile acid pool size and improved liver conditions. To further examine whether atRA alone or in combination with UDCA has greater beneficial effects than UDCA treatment alone, we assessed this treatment in two additional chronic cholestatic rodent models: α-naphthylisothiocyanate (ANIT)–treated rats and the Mdr2−/− (Abcb4−/−) knockout mouse. atRA alone significantly reduced bile duct proliferation, inflammation, and hydroxyproline levels in ANIT-treated rats, whereas the combination of atRA and UDCA significantly reduced plasma bile salt level compared with UDCA treatment. atRA alone or in combination with UDCA significantly reduced plasma levels of alkaline phosphatase and bile salts in 12-week-old Mdr2−/− mice. Reduced bile duct proliferation and inflammation were also observed in the livers of these mice. Together, atRA alone or in combination with UDCA significantly reduced the severity of liver injury in these two animal models, further supporting the combination treatment of atRA and UDCA as a potential new therapy for patients with chronic cholestatic liver disease who have not responded fully to UDCA. PMID:24492652

  7. Cardiac energy metabolism and oxidative stress biomarkers in diabetic rat treated with resveratrol.

    PubMed

    Carolo dos Santos, Klinsmann; Pereira Braga, Camila; Octavio Barbanera, Pedro; Seiva, Fábio Rodrigues Ferreira; Fernandes Junior, Ary; Fernandes, Ana Angélica Henrique

    2014-01-01

    Resveratrol (RSV), polyphenol from grape, was studied to evaluate its effects on calorimetric parameters, energy metabolism, and antioxidants in the myocardium of diabetic rats. The animals were randomly divided into four groups (n = 8): C (control group): normal rats; C-RSV: normal rats receiving RSV; DM: diabetic rats; and DM-RSV: diabetics rats receiving RSV. Type 1 diabetes mellitus was induced with administration of streptozotocin (STZ; 60 mg(-1) body weight, single dose, i.p.). After 48 hours of STZ administration, the animals received RSV (1.0 mg/kg/day) for gavage for 30 days. Food, water, and energy intake were higher in the DM group, while administration of RSV caused decreases (p<0.05) in these parameters. The glycemia decreased and higher final body weight increased in DM-RSV when compared with the DM group. The diabetic rats showed higher serum-free fatty acid, which was normalized with RSV. Oxygen consumption (VO2) and carbon dioxide production (VCO2) decreased (p<0.05) in the DM group. This was accompanied by reductions in RQ. The C-RSV group showed higher VO2 and VCO2 values. Pyruvate dehydrogenase activity was lower in the DM group and normalizes with RSV. The DM group exhibited higher myocardial β-hydroxyacyl coenzyme-A dehydrogenase and citrate synthase activity, and RSV decreased the activity of these enzymes. The DM group had higher cardiac lactate dehydrogenase compared to the DM-RSV group. Myocardial protein carbonyl was increased in the DM group. RSV increased reduced glutathione in the cardiac tissue of diabetic animals. The glutathione reductase activity was higher in the DM-RSV group compared to the DM group. In conclusion, diabetes is accompanied by cardiac energy metabolism dysfunction and change in the biomarkers of oxidative stress. The cardioprotective effect may be mediated through RVS's ability to normalize free fatty acid oxidation, enhance utilization glucose, and control the biomarkers' level of oxidative stress under

  8. Cardiac Energy Metabolism and Oxidative Stress Biomarkers in Diabetic Rat Treated with Resveratrol

    PubMed Central

    Carolo dos Santos, Klinsmann; Pereira Braga, Camila; Octavio Barbanera, Pedro; Rodrigues Ferreira Seiva, Fábio; Fernandes Junior, Ary; Fernandes, Ana Angélica Henrique

    2014-01-01

    Resveratrol (RSV), polyphenol from grape, was studied to evaluate its effects on calorimetric parameters, energy metabolism, and antioxidants in the myocardium of diabetic rats. The animals were randomly divided into four groups (n = 8): C (control group): normal rats; C-RSV: normal rats receiving RSV; DM: diabetic rats; and DM-RSV: diabetics rats receiving RSV. Type 1 diabetes mellitus was induced with administration of streptozotocin (STZ; 60 mg−1 body weight, single dose, i.p.). After 48 hours of STZ administration, the animals received RSV (1.0 mg/kg/day) for gavage for 30 days. Food, water, and energy intake were higher in the DM group, while administration of RSV caused decreases (p<0.05) in these parameters. The glycemia decreased and higher final body weight increased in DM-RSV when compared with the DM group. The diabetic rats showed higher serum-free fatty acid, which was normalized with RSV. Oxygen consumption (VO2) and carbon dioxide production (VCO2) decreased (p<0.05) in the DM group. This was accompanied by reductions in RQ. The C-RSV group showed higher VO2 and VCO2 values. Pyruvate dehydrogenase activity was lower in the DM group and normalizes with RSV. The DM group exhibited higher myocardial β-hydroxyacyl coenzyme-A dehydrogenase and citrate synthase activity, and RSV decreased the activity of these enzymes. The DM group had higher cardiac lactate dehydrogenase compared to the DM-RSV group. Myocardial protein carbonyl was increased in the DM group. RSV increased reduced glutathione in the cardiac tissue of diabetic animals. The glutathione reductase activity was higher in the DM-RSV group compared to the DM group. In conclusion, diabetes is accompanied by cardiac energy metabolism dysfunction and change in the biomarkers of oxidative stress. The cardioprotective effect may be mediated through RVS's ability to normalize free fatty acid oxidation, enhance utilization glucose, and control the biomarkers' level of oxidative stress under

  9. Evaluation of the antidepressant, anxiolytic and memory-improving efficacy of aripiprazole and fluoxetine in ethanol-treated rats.

    PubMed

    Burda-Malarz, Kinga; Kus, Krzysztof; Ratajczak, Piotr; Czubak, Anna; Hardyk, Szymon; Nowakowska, Elżbieta

    2014-07-01

    Some study results indicate a positive effect of aripiprazole (ARI) on impaired cognitive functions caused by brain damage resulting from chronic EtOH abuse. However, other research shows that to manifest itself, an ARI antidepressant effect requires a combined therapy with another selective serotonin reuptake inhibitor antidepressant, namely, fluoxetine (FLX). The aim of this article was to assess antidepressant and anxiolytic effects of ARI as well as its effect on spatial memory in ethanol-treated (alcoholized) rats. On the basis of alcohol consumption pattern, groups of (1) ethanol-preferring rats, with mean ethanol intake above 50%, and (2) ethanol-nonpreferring rats (EtNPRs), with mean ethanol intake below 50% of total daily fluid intake, were formed. The group of EtNPRs was used for this study, subdivided further into three groups administered ARI, FLX and a combination of both, respectively. Behavioral tests such as Porsolt's forced swimming test, the Morris water maze test and the two-compartment exploratory test were employed. Behavioral test results demonstrated (1) no antidepressant effect of ARI in EtNPRs in subchronic treatment and (2) no procognitive effect of ARI and FLX in EtNPRs in combined single administration. Combined administration of both drugs led to an anxiogenic effect and spatial memory deterioration in study animals. ARI had no antidepressant effect and failed to improve spatial memory in rats. However, potential antidepressant, anxiolytic and procognitive properties of the drug resulting from its mechanism of action encourage further research aimed at developing a dose of both ARI and FLX that will prove such effects in alcoholized EtNPRs. PMID:24215604

  10. Memory-improving activity of Melissa officinalis extract in naïve and scopolamine-treated rats.

    PubMed

    Soodi, M; Naghdi, N; Hajimehdipoor, H; Choopani, S; Sahraei, E

    2014-01-01

    Melissa officinalis L. (Labiatae) traditionally used in treating neurological disorders has also been identified as a memory-enhancing herb. The extract of M. officinalis has a cholinergic property. The role of basal forebrain cholinergic neurons, the neurons that are destroyed in Alzheimer's disease (AD), in learning and memory, is also well known. The aim of this study is to investigate the role of cholinergic system on the memory improving activity of M. officinalis extract. The leaves of M. officinalis were extracted with ethanol 80% using the maceration method. Rats received intra-peritoneal injections of M. officinalis extract in different doses (50-400 mg/kg) alone or in combination with scopolamine (1 mg/kg) before being trained in a Morris water maze (MWM) in a single-day training protocol. After training, the acetylcholinesterase enzyme (AChE) activity was measured in the hippocampus. Administration of M. officinalis extract (200 mg/kg) could significantly enhance learning and memory of naïve rats (p<0.001) and significantly ameliorate scopolamine-induced learning deficit, but the effect of the extract was not dose dependent, and doses above 200 mg/kg could neither enhance memory in naïve rats nor reverse scopolamine-induced memory impairment. Also, inhibition of AChE activity was observed in both naïve and scopolamine-induced memory-impaired rats. These results suggest that M. officinalis can improve memory and that the cholinergic property of the extract may contribute to the memory-improving effects observed in this study. Then M. officinalis extract has potential therapeutic value in alleviating certain memory impairment observed in AD.

  11. Partial attenuation of hydroxyurea-induced embryotoxicity by deoxyribonucleotides in mouse and rat embryos treated in vitro.

    PubMed

    Hansen, D K; Grafton, T F; Cross, D R; James, S J

    1995-02-01

    Hydroxyurea (HU) is a well known developmental toxicant in all animal species tested. It inhibits DNA synthesis, and addition of deoxycytidine monophosphate (dCMP) has been shown previously to attenuate the developmental toxicant effects of HU in vivo. The purpose of the present investigation was to determine whether addition of deoxyadenosine monophosphate (dAMP) or dCMP would attenuate HU-induced embryotoxicity using a rodent whole embryo culture system. Rat embryos were removed on the morning of day 10 of gestation, and mouse embryos were removed on day 8 of gestation (day 0 = the day a vaginal plug was found). Embryos were treated with various concentrations of HU (up to 500 mug/ml) for 1 hr at 37 degrees C before being washed and cultured for 43 hr in rat serum containing dAMP or dCMP. At the end of the culture period, six endpoints were evaluated for each viable embryo: morphological score; number of somite pairs; crown-rump and head lengths, DNA and protein contents. HU (300 mug/ml) significantly decreased values for all endpoints in embryos from both mice and rats; however, mouse embryos appeared to be more sensitive to the effects of the drug. dAMP and dCMP alone produced some embryotoxicity at high concentrations. The combination of HU + dAMP had no consistent beneficial effect in rat embryos and no effect on mouse embryos. The combination of HU + dCMP improved growth and development slightly. As determined by HPLC analysis, HU treatment (300 mug/ml for 1 hr) decreased all nucleotide pools. Subsequent treatment with dAMP increased all pool levels, although these levels remained below those of control embryos. These results suggest that the developmental toxicant effects of HU are not due solely to alterations in deoxyribonucleotide pool levels.

  12. Evaluation of the antidepressant, anxiolytic and memory-improving efficacy of aripiprazole and fluoxetine in ethanol-treated rats.

    PubMed

    Burda-Malarz, Kinga; Kus, Krzysztof; Ratajczak, Piotr; Czubak, Anna; Hardyk, Szymon; Nowakowska, Elżbieta

    2014-07-01

    Some study results indicate a positive effect of aripiprazole (ARI) on impaired cognitive functions caused by brain damage resulting from chronic EtOH abuse. However, other research shows that to manifest itself, an ARI antidepressant effect requires a combined therapy with another selective serotonin reuptake inhibitor antidepressant, namely, fluoxetine (FLX). The aim of this article was to assess antidepressant and anxiolytic effects of ARI as well as its effect on spatial memory in ethanol-treated (alcoholized) rats. On the basis of alcohol consumption pattern, groups of (1) ethanol-preferring rats, with mean ethanol intake above 50%, and (2) ethanol-nonpreferring rats (EtNPRs), with mean ethanol intake below 50% of total daily fluid intake, were formed. The group of EtNPRs was used for this study, subdivided further into three groups administered ARI, FLX and a combination of both, respectively. Behavioral tests such as Porsolt's forced swimming test, the Morris water maze test and the two-compartment exploratory test were employed. Behavioral test results demonstrated (1) no antidepressant effect of ARI in EtNPRs in subchronic treatment and (2) no procognitive effect of ARI and FLX in EtNPRs in combined single administration. Combined administration of both drugs led to an anxiogenic effect and spatial memory deterioration in study animals. ARI had no antidepressant effect and failed to improve spatial memory in rats. However, potential antidepressant, anxiolytic and procognitive properties of the drug resulting from its mechanism of action encourage further research aimed at developing a dose of both ARI and FLX that will prove such effects in alcoholized EtNPRs.

  13. Ultrastructural changes in the parenchymal liver cells of rats treated with high doses of rifampicin.

    PubMed Central

    Piriou, A.; Maissiat, R.; Jacqueson, A.; Warnet, J. M.; Claude, J. R.

    1987-01-01

    Ultrastructural study of hepatic parenchyma was carried out in female Wistar rats after they had received high doses (400 mg X kg-1) of rifampicin for 1, 2, 4, 6 and 8 days. Morphological changes in the endoplasmic reticulum, Golgi apparatus and mitochondria were observed as early as day 1 of intoxication. These changes corroborate the biochemical data available regarding RFP-induced fatty liver. Images Fig. 1 Fig. 2 Fig. 3 & 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 PMID:3580280

  14. ATP metabolism in rat liver chronically treated with ethanol and high fat

    SciTech Connect

    Miyamoto, K.; French, S.W.

    1986-03-01

    Five pairs of Wistar male rats weighing about 350 g were continuously infused with a liquid diet in which 25-35% of total calories was derived from fat, plus ethanol or isocaloric dextrose through gastrostomy cannulas for 3 wks to 3.5 mos. Mean ethanol intake was 12.9 +/- 0.7 g/kg B.W. (55% of total calories). High blood alcohol levels (BAL, 342 +/- 151 mg/dl) were maintained. The liver showed severe steatosis (4+) in all the ethanol-fed rats (ER). Two had mild focal mononuclear cell infiltration, one had mild fibrosis and one had spotty necrosis. Mild steatosis (1+) was seen in 4 out of 5 pair-fed control rats (CR). Serum ALT was significantly higher in ER (129 +/- 44 U) compared with Cr (59 +/- 30 U) or rats fed chow ad lib (NR) (48 +/- 26 U). Biopsied liver tissue was used to measure the concentration of adenine nucleotides by HPLC (6 pairs). There was a significant decrease of ATP in ER (1.7 +/- 0.3 ..mu..mol/g liver) as compared to CR (2.5 +/- 0.5 ..mu..mol/g) or NR (2.8 +/- 0.2 ..mu..mol/g, n = 6). There was no significant change in the ADP or AMP content, however. The total adenylate pool of the liver was also significantly reduced in ER when compared to that of CR or NR (3.2 +/- 0.4, 4.0 +/- 0.5 and 4.3 +/- 0.2 ..mu..mol/g liver, respectively). Adeynlate energy charge (E.C.) of the ER livers (0.71 +/- 0.05) was significantly reduced compared to NR (0.77 +/- 0.02) but not with CR (0.75 +/- 0.06). The results indicate that ethanol decreases the level of ATP as well as the biological mechanism to compensate for the lowered level.

  15. Use of Ozone to Treat Ileostomy Dermatitis in an Experimental Rat Model

    PubMed Central

    Biçer, Şenol; Sayar, İlyas; Gürsul, Cebrail; Işık, Arda; Aydın, Merve; Peker, Kemal; Demiryilmaz, İsmail

    2016-01-01

    Background Dermatitis associated with ileostomy is an important problem that affects many people, especially children. The aim of this study was to investigate the therapeutic effects of ozone on dermatitis due to ileostomy, and to develop an alternative treatment option. Material/Methods A total of 28 rats were divided into 4 groups: control, ileostomy, ozone, and zinc oxide. Ileostomy was performed in all rats except the control group. After a 1-week waiting time, the ozone group was administered ozone therapy and the zinc oxide group was administered zinc oxide cream locally once a day for a total of 7 days. All rats were sacrificed at the end of this period. The efficacy of treatment was examined by biochemical, histopathological, and immunohistochemical parameters. The levels of malondialdehyde (MDA), total glutathione (tGSH), total antioxidant capacity (TAC), and total oxidant status (TOS) were measured from tissue. Vascular endothelial growth factor (VEGF) and proliferating cell nuclear antigen (PCNA) were examined immunohistochemically. Results Dermatitis occurred pathologically in all rats that underwent ileostomy surgery. The lowest dermatitis score was in the ozone treatment group (p<0.05). Ileostomy dermatitis caused increased levels of MDA and TOS. Ozone treatment resulted in reduced MDA and TOS levels, while the levels of tGSH and TAC were increased (p<0.05). Both VEGF and PCNA immunostaining were augmented in the ozone treatment group (p<0.05). Conclusions Local ozone application may be a good alternative compared to the conventional treatment methods for the prevention of skin lesions that develop after ileostomy. PMID:26947591

  16. In vivo genotoxicity and DNA adduct levels in the liver of rats treated with safrole.

    PubMed

    Daimon, H; Sawada, S; Asakura, S; Sagami, F

    1998-01-01

    The induction of chromosome aberrations, sister chromatid exchanges (SCEs), and the formation of DNA adducts was studied in hepatocytes of F344 rats exposed in vivo to safrole. Hepatocytes were isolated 24 h after a single dose of safrole or five repeated doses (once a day) by gastric intubation and allowed to proliferate in Williams' medium E supplemented with epidermal growth factor. Cells were fixed after 48 h in culture. Safrole-DNA adducts were detected by a nuclease P1-enhanced 32P-post-labeling assay in isolated hepatocytes from the rats. While a single dose was not sufficient to induce detectable levels of chromosome aberrations at the time of assay, five repeated doses induced these changes with a maximum frequency of 13.4%, compared with the control value of 1.8%. Both a single dose and five repeated doses induced significant SCEs, to a maximum frequency of 0.81 SCEs per chromosome, while the control value was 0.59 SCEs per chromosome. Two major and two minor DNA adducts were detected after treatment with either a single dose or five repeated doses. The maximum amount of total DNA adducts was 89.8 DNA adducts/10(7) nucleotides. These results show that safrole is a genotoxic carcinogen in the rat liver in vivo and suggest that the cytogenetic effects of this compound may result from covalent DNA modification in the rat liver. This in vivo cytogenetic assay should provide a useful means of evaluation of the genotoxicity of hepatocarcinogens.

  17. Metallothionein and antioxidant enzymes in Long-Evans Cinnamon rats treated with zinc.

    PubMed

    Medici, Valentina; Santon, Alessandro; Sturniolo, Giacomo Carlo; D'Incà, Renata; Giannetto, Sabrina; Albergoni, Vincenzo; Irato, Paola

    2002-09-01

    The Long-Evans Cinnamon (LEC) rat is a mutant animal model for Wilson's disease. It is known that an abnormal accumulation of Cu and Fe in the liver and low concentrations of both ceruloplasmin and Cu in the serum occur in these rats. The accumulation of Cu is explained by the defective expression of the Cu-transporting P-type ATPase gene, homologous to the gene for Wilson's disease (ATP7B). The aim of this work was to clarify the action mechanism of Zn, and to verify the role that this metal plays in LEC rats in short-term treatment experiments (1 and 2 weeks) on concentrations of Cu, Zn, Fe, metallothionein (MT), 8-hydroxy-2'-deoxyguanosine (oh(8)dG) and on the activity of antioxidant enzymes. It is well known that Zn induces MT and has the ability to prevent redox-active metals, Cu and Fe, binding to and causing oxidative damage at active sites of Zn metalloenzymes and nonspecific binding sites on proteins. Zn administration reduces Cu and Fe transport from mucosal to serosal intestinal sides through competitive mechanisms. Our findings show that treatment with zinc acetate increases tissue Zn and MT contents and decreases Cu and Fe concentrations in the liver and kidneys, even if hepatic Zn and MT concentrations decrease with treatment period. Induction of MT synthesis by Zn contributes to the reduction in free radicals produced by Cu and Fe. We also observed that the superoxide dismutase (SOD)activity in liver decreases with treatment duration in association with the Cu and Fe liver decrease. However, the SOD activity in kidney increases in untreated rats at 2 weeks relative to those untreated for 1 week.

  18. Ovarian development in Wistar rat treated prenatally with single dose diisobutyl phthalate.

    PubMed

    Ray, B; D'Souza, A S; Kumar, V; Pugazhandhi, B; D'Souza, M R; Nayak, D; Sushma, R K; Shetty, P; Singh, H; Krishna, L; Bhat, K M; Rao, A C; Chakraborti, S; Kumar, N; Saxena, A

    2012-01-01

    Phthalates are a class of industrial compounds with an array of toxicological properties used in day to day life. Diisobutyl phthalate on (DIBP) is used as an additive to keep the plastics soft or flexible (plasticizer) in nitrocellulose plastic, nail polish, explosives, lacquer manufacturing etc. Although DIBP exposure in humans is generally low, people in adhesive industries and pharmaceutical industries are exposed to higher levels. The aim of this study was to determine the effect of single dose of DIBP on developing ovary of Wistar rat. One hundred and eight adult pregnant Wistar rats were divided into control and experimental groups. Rats in experimental group were given DIBP on day 10, 12 and 14 of gestation at 0.375, 0.75 and 1.25 ml/kg body weight dose intraperitoneally in a single dose. Sections of ovaries collected on day 21 of gestation were stained with hematoxylin and eosin and examined and Masson's trichrome histologically. Sections belonging to the control group showed the presence of oocytes in clusters separated by thin fibrous septa. Degeneration oocytes, empty follicles surrounded by follicular cells without gonocytes in the center were observed in ovarian stroma. Blood vessels in the ovarian stroma were prominent and congested. Around a bunch of follicles total architectural disarray was observed although on special staining fibrosis was not evident. As pregnant women are constantly exposed, effect of DIBP on ovary of a developing fetus would denote the long term consequence in future generations (Fig. 5, Ref. 39). PMID:23094893

  19. Histopathology and cytotoxicity as biomarkers in treated rats with cadmium and some therapeutic agents.

    PubMed

    El-Refaiy, Amal I; Eissa, Fawzy I

    2013-07-01

    The present study aimed to investigate the protective role of ascorbic acid (vitamin C) and zinc (Zn) against cadmium (Cd) induced histopathological changes in tissues of liver, kidney, lung and testis of rats as well as chromosomal aberrations. For this purpose, 60 male albino rats were divided into six groups; each group contained 10 animals. The first group served as control and was given only distilled water. The second and third groups received distilled water supplemented with 2 g ascorbic acid/l and 500 mg Zn/l, respectively. The fourth group received a daily oral dose containing 3 mg Cd/kg b.w. (1/30 LD50). The fifth group received Cd + ascorbic acid (3 mg Cd/kg b.w. + 2 g ascorbic acid/l), while the sixth group received Cd + Zn (3 mg Cd/kg b.w. +500 mg Zn/l). The treatment in all groups lasted for 90 consecutive days. Rats exposed to cadmium showed severe histopathological changes in the liver, kidney, lung and testicular tissues as well as chromosomal aberrations such as: break, ring, centromeric separation and polyploidy. Co-treatment with zinc partially improved the histopathological changes and chromosomal aberrations while co-treatment with vitamin C exhibited a more protective role and markedly reduced tissues damage induced by Cd. PMID:23961244

  20. Exogenous Angiotensin I Metabolism in Aorta Isolated from Streptozotocin Treated Diabetic Rats

    PubMed Central

    Bujak-Giżycka, B.; Jawień, J.; Olszanecki, R.; Madej, J.; Rutowski, J.; Korbut, R.

    2016-01-01

    Purpose. Products of angiotensin (ANG) I metabolism may predispose to vascular complications of diabetes mellitus. Methods. Diabetes was induced with streptozotocin (75 mg/kg i.p.). Rat aorta fragments, isolated 4 weeks later, were pretreated with perindoprilat (3 μM), thiorphan (3 μM), or vehicle and incubated for 15 minutes with ANG I (1 μM). Products of ANG I metabolism through classical (ANG II, ANG III, and ANG IV) and alternative (ANG (1–9), ANG (1–7), and ANG (1–5)) pathways were measured in the buffer, using liquid chromatography-mass spectrometry. Results. Incubation with ANG I resulted in higher concentration of ANG II (P = 0.02, vehicle pretreatment) and lower of ANG (1–9) (P = 0.048, perindoprilat pretreatment) in diabetes. Preference for the classical pathway is suggested by higher ANG III/ANG (1–7) ratios in vehicle (P = 0.03), perindoprilat (P = 0.02), and thiorphan pretreated (P = 0.02) diabetic rat. Within the classical pathway, ratios of ANG IV/ANG II (P = 0.01) and of ANG IV/ANG III (P = 0.049), but not of ANG III/ANG II are lower in diabetes. Conclusions. Diabetes in rats led to preference toward deleterious (ANG II, ANG III) over protective (ANG IV, ANG (1–9), and ANG (1–7)) ANG I metabolites. PMID:27803936

  1. Morphological Analysis of the Enamel Organ in Rats Treated with Fluoxetine

    PubMed Central

    Silva, Igor Henrique Morais; Leão, Jair Carneiro; Evêncio, Liriane Baratella; Porter, Stephen Ross; de Castro, Raul Manhães

    2010-01-01

    PURPOSE: Previous studies have evaluated the presence of serotonin in the dental epithelia and mesenchyme during odontogenesis, suggesting its participation in tooth development. MATERIALS AND METHODS: Here, we used fluoxetine, a selective serotonin re-uptake inhibitor, at a dose of 10 mg/kg, administered for 20 days during pregnancy in 12 Wistar rats to examine the influence of this drug on the development of the enamel organ of the upper first molars of rat fetuses at 17 days of intra-uterine life (i.u.l.), and at one, five and ten days postpartum. The pregnant rats were anesthetized with xylazine at 10 mg/kg and ketamine at 25 mg/kg. The fetuses were removed and beheaded; their jaws were removed, and the upper jaws were exposed. The tissues were fixed in Bouin’s fixative, decalcified in 5% nitric acid for 4 – 12 h, conventionally processed for microscopy, and embedded in paraffin. Serial sections of approximately 5 μm were obtained and stained with hematoxylin and eosin, as well as periodic acid-Schiff. RESULTS AND CONCLUSION: Morphological analysis showed no structural changes in the experimental group compared to the controls, suggesting that, at the dose used, fluoxetine does not interfere with serotonin-mediated development of the enamel organ or the process of amelogenesis. PMID:20126347

  2. Long-term cognitive impairments in adult rats treated neonatally with beta-N-Methylamino-L-Alanine.

    PubMed

    Karlsson, Oskar; Roman, Erika; Brittebo, Eva B

    2009-11-01

    Most cyanobacteria (blue-green algae) can produce the neurotoxin beta-N-methylamino-L-alanine (BMAA). Dietary exposure to BMAA has been suggested to be involved in the etiology of the neurodegenerative disease amyotrophic lateral sclerosis/Parkinsonism-dementia complex (ALS/PDC). Little is known about BMAA-induced neurotoxicity following neonatal administration. Our previous studies have revealed an uptake of BMAA in the hippocampus and striatum of neonatal mice. Furthermore, rats treated with BMAA during the neonatal period displayed acute but transient motoric disturbances and failed to show habituation at juvenile age suggesting impairments in learning functions. In the present study, the aim was to investigate long-term behavioral effects of BMAA administration in neonatal rats. BMAA was administered on postnatal days 9-10 (200 or 600 mg/kg; subcutaneous injection). Spatial learning and memory was investigated in adulthood using the radial arm maze test. The results revealed impaired learning but not memory in BMAA-treated animals. The observed impairments were not due to alterations in motoric capacity, general activity, or behavioral profiles, as assessed in the multivariate concentric square field (MCSF) and open field tests. An aversive stimulus in the MCSF test revealed impairments in avoidance learning and/or memory. There was no difference in basal serum corticosterone levels in BMAA-treated animals, indicating that the observed long-term effects were not secondary to an altered basal hypothalamic-pituitary-adrenal axis function. The present data demonstrated long-term learning impairments following neonatal BMAA administration. Further studies on biochemical effects in various brain regions and subsequent behavioral alterations are needed to elucidate the mechanisms of BMAA-induced developmental neurotoxicity.

  3. Protocol of a randomised phase III clinical trial of sequential capecitabine or 5-fluorouracil plus bevacizumab (Cape/5-FU-Bmab) to capecitabine or 5-fluorouracil plus oxaliplatin plus bevacizumab (CapeOX/mFOLFOX6-Bmab) versus combination CapeOX/mFOLFOX6-Bmab in advanced colorectal cancer: the C-cubed (C3) study

    PubMed Central

    Mishima, Hideyuki; Sawaki, Akira; Shimokawa, Mototsugu; Inukai, Michio; Shinozaki, Katsunori; Tanioka, Hiroaki; Nasu, Junichiro; Nishina, Tomohiro; Hazama, Shoichi; Okajima, Masazumi; Yamaguchi, Yoshiyuki

    2016-01-01

    Introduction Results from several randomised trials suggest that the sequential use of cytotoxic agents in patients with metastatic colorectal cancer (mCRC) has the potential to improve overall survival compared with combination chemotherapy. This study is designed to investigate whether sequential treatment with bevacizumab-based first-line treatment with oxaliplatin is superior to combination treatment of mCRC. Methods and analysis The C-cubed (C3) study is a two-arm, multicentre, open-label, randomised phase III trial in Japan comparing the efficacy and safety of sequential capecitabine or 5-fluorouracil plus bevacizumab (Cape/5-FU-Bmab) with escalation to capecitabine or 5-fluorouracil plus oxaliplatin plus bevacizumab (CapeOX/mFOLFOX6-Bmab) versus combination CapeOX/mFOLFOX6-Bmab as the first-line treatment of mCRC. In the sequential arm (Arm A: oxaliplatin ‘wait-and-go’), treatment escalation from Cape/5-FU-Bmab to CapeOX/mFOLFOX6-Bmab is recommended in the case of progressive disease. In the combination arm (Arm B: oxaliplatin ‘stop-and-go’), de-escalation from CapeOX/mFOLFOX6-Bmab to Cape/5-FU-Bmab is possible after 12 weeks of treatment. Re-escalation to CapeOX/mFOLFOX6-Bmab after progressive disease is considered only for patients who received de-escalation of oxaliplatin after 12 weeks of treatment not caused by oxaliplatin-associated toxicity. A target sample size of 304 evaluable patients is considered sufficient to validate an expected HR for time to failure of strategy of the sequential approach ‘wait-and-go’ compared to the combination approach ‘stop-and go’ with 80% power and 2-sided 5% α in case of a true HR<0.69. Ethics and dissemination This study is conducted according to the standards of Good Clinical Practice and in compliance with the Declaration of Helsinki 2013 and local regulations, and has been submitted and approved by the Ethical Committee of the Non-Profit Organization MINS Institutional Review Board. The protocol

  4. Postmortem Attraction of Sarcosaprophagous Diptera to Tramadol-Treated Rats and Morphometric Aspects of the Developed Larvae.

    PubMed

    AbouZied, E M

    2016-06-01

    The presence of some specific drugs in animal tissues may affect the time of minimal postmortem intervals estimated during forensic entomological investigations. To test the effects of a specific drug on decomposition, a field study was conducted at Fayoum University campus, Egypt, from March to May 2013, using tramadol, a synthetic analgesic opioid used to treat moderate to severe pain in humans. Albino rats were used as the animal model during this study. The duration of the fresh stage of tramadol treated rat (Ttr) carcasses was significantly shorter (2.4 ± 0.27 days) compared to tramadol free rat (Tfr) carcasses (6.4 ± 0.49 days). The dry carcass stage of Ttr lasted longer (10.3 ± 0.99 days) as compared to (7.4 ± 0.18 days) the Tfr carcass. The decomposition process of the (Ttr) carcass was not significantly faster (24.9 ± 1.58 days) as compared to (Tfr) carcasses (29.5 ± 1.69). Lucilia cuprina (Wiedemann), Chrysomya albiceps (Wiedemann), and Musca domestica L. were less attracted to Ttr carcass-baited traps than traps with Tfr carcasses. However, females of Sarcophaga spp. showed a greater attraction to Ttr carcasses. Females of another sarcophagid fly, Wohlfahrtia spp. exhibited similar attraction tendencies to both types of trap baits. Larvae of S. argyrostoma (Robineau-Desvoidy) collected from Ttr carcasses developed to a significantly longer total body length (10.4 ± 0.04 mm) as compared to the average length of the larvae collected from Tfr carcasses (8.9 ± 0.34 mm). During days 9-13 after rat death, the relative lengths of larvae from Ttr carcasses were not significantly different from Tfr carcasses. Larvae fed on Ttr carcasses pupated 2 days later than the control larvae.

  5. Estrous cycle affects the neurochemical and neurobehavioral profile of carvacrol-treated female rats

    SciTech Connect

    Trabace, L.; Zotti, M.; Morgese, M.G.; Tucci, P.; Colaianna, M.; Schiavone, S.; Avato, P.; Cuomo, V.

    2011-09-01

    Carvacrol is the major constituent of essential oils from aromatic plants. It showed antimicrobial, anticancer and antioxidant properties. Although it was approved for food use and included in the chemical flavorings list, no indication on its safety has been estimated. Since the use of plant extracts is relatively high among women, aim of this study was to evaluate carvacrol effects on female physiology and endocrine profiles by using female rats in proestrus and diestrus phases. Serotonin and metabolite tissue content in prefrontal cortex and nucleus accumbens, after carvacrol administration (0.15 and 0.45 g/kg p.o.), was measured. Drug effects in behavioral tests for alterations in motor activity, depression, anxiety-related behaviors and endocrine alterations were also investigated. While in proestrus carvacrol reduced serotonin and metabolite levels in both brain areas, no effects were observed in diestrus phase. Only in proestrus phase, carvacrol induced a depressive-like behavior in forced swimming test, without accompanying changes in ambulation. The improvement of performance in FST after subchronic treatment with fluoxetine (20 mg/kg) suggested a specific involvement of serotonergic system. No differences were found across the groups with regard to self-grooming behavior. Moreover, in proestrus phase, carvacrol reduced only estradiol levels without binding hypothalamic estradiol receptors. Our study showed an estrous-stage specific effect of carvacrol on depressive behaviors and endocrine parameters, involving serotonergic system. Given the wide carvacrol use not only as feed additive, but also as cosmetic essence and herbal remedy, our results suggest that an accurate investigation on the effects of its chronic exposure is warranted. - Highlights: > Carvacrol induced a depressive-like phenotype in rats, depending on ovarian cyclicity. > Carvacrol selectively reduced serotonin content in female rats in proestrus phase. > Carvacrol reduced serotonin levels

  6. Lack of reversal of oxidative damage in renal tissues of lead acetate-treated rats.

    PubMed

    Oyagbemi, Ademola Adetokunbo; Omobowale, Temidayo Olutayo; Akinrinde, Akinleye Stephen; Saba, Adebowale Bernard; Ogunpolu, Blessing Seun; Daramola, Oluwabusola

    2015-11-01

    Removal of lead from the environment of man or otherwise, the movement of man from lead-contaminated areas has been employed as a means of abatement of the toxic effects of lead. Whether toxic effects in already-exposed individuals subside after lead withdrawal remains unanswered. To understand the reversibility of nephrotoxicity induced by lead acetate, male Wistar rats were orally exposed to 0.25, 0.5, and 1.0 mg/mL of lead acetate for 6 weeks. Activities of glutathione-s-transferase, catalase (CAT), superoxide dismutase (SOD) and the concentrations of hydrogen peroxide (H2 O2 ), and malondialdehyde increased significantly (p < 0.05) in a dose-dependent manner, whereas reduced glutathione (GSH) level and glutathione peroxidase activity were significantly reduced. The pattern of alterations in most of the oxidative stress and antioxidant parameters remained similar in rats from the withdrawal period, although CAT and SOD activities reduced, in contrast to their elevation during the exposure period. Serum creatinine levels were significantly elevated in both exposure and withdrawal experiments whereas serum blood urea nitrogen levels were not significantly different from the control in both exposure and withdrawal periods. The histological damage observed include multifocal areas of inflammation, disseminated tubular necrosis, and fatty infiltration of the kidney tubules both at exposure and withdrawal periods. The results suggest that lead acetate-induced nephrotoxicity by induction of oxidative stress and disruption of antioxidant. The aforementioned alterations were not reversed in the rats left to recover within the time course of study.

  7. Seizure frequency in pilocarpine-treated rats is independent of circadian rhythm.

    PubMed

    Bajorat, Rika; Wilde, Marleen; Sellmann, Tina; Kirschstein, Timo; Köhling, Rüdiger

    2011-09-01

    Pilocarpine-induced status epilepticus (SE) results in chronic spontaneous recurrent seizures resembling human temporal lobe epilepsy. In this and other experimental models, behaviorally monitored seizure frequency was suggested to vary in a circadian fashion, and to increase with time. We re-addressed those hypotheses using continuous video-electroencephalography (EEG) telemetry in rats with SE at 30 days of age. In 11 chronically epileptic animals monitored up to 300 days after SE in a fixed 12 h light/dark cycle, we found that seizure frequency did not correlate with circadian rhythm.

  8. Classical and Alternative Activation of Cyanobacterium Oscillatoria sp. Lipopolysaccharide-Treated Rat Microglia in vitro.

    PubMed

    Mayer, Alejandro M S; Murphy, Joseph; MacAdam, David; Osterbauer, Christopher; Baseer, Imaan; Hall, Mary L; Feher, Domonkos; Williams, Phillip

    2016-02-01

    The purpose of this investigation was to test the hypothesis that an in vitro exposure to cyanobacterium Oscillatoria sp. Lipopolysaccharide (LPS) might result in classical and alternative activation of rat neonatal microglia. Using Escherichia coli LPS-primed microglia as a positive control, this study revealed that treatment of rat microglia with Oscillatoria sp. LPS for 17 h in vitro resulted in both classical and alternative activation as well as concomitant pro-inflammatory and anti-inflammatory mediator release, in a concentration-dependent manner: (1) treatment with 0.1-10 000 ng/ml Oscillatoria sp. LPS resulted in minimal lactic dehydrogenase (LDH) release, induced concentration-dependent and statistically significant O2 (-) generation, matrix metalloproteinase-9 (MMP-9) release, generation of the cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and the chemokines macrophage inflammatory protein-2 (MIP-2/CXCL2), interferon γ-induced protein 10 kDa (IP-10/CXCL-10), (MIP-1α/CCL3), monocyte chemotactic protein-1 (MCP-1/CCL2), regulated on activation, normal T cell expressed and secreted (RANTES/CCL5), and the alternative activation cytokine IL-10; (3) in contrast, treatment with 100 000 ng/ml Oscillatoria sp. LPS appeared to damage the microglia cell membrane, because it resulted in minimal O2 (-) generation, statistically significant LDH release, and a decrease in the generation of all the cytokines and chemokines investigated, with the exception of IL-1α and cytokine-induced neutrophil chemoattractant 1 (CINC-1/CXCL1) generation, which was increased. Thus, our results provide experimental support for our working hypothesis, namely that Oscillatoria sp. LPS induces classical and alternative activation of rat brain microglia in vitro in a concentration-dependent manner, namely 0.1-10 000 ng/ml Oscillatoria sp. LPS, when microglia cells were shown to be viable. Furthermore, should cyanobacterium Oscillatoria sp. LPS gain

  9. Transplacental and mammary passage of radioactivity in rats treated vaginally and orally with (/sup 14/C)propranolol

    SciTech Connect

    Buttar, H.S.; Moffatt, J.H.; Bura, C.

    1988-01-01

    Single doses (10 mg/kg) of an aqueous solution of (14C)propranolol were administered either orally (po) or intravaginally (ivg) on gestational d 15, or on postpartum d 7-10. Upon ivg administration, (14C)propranolol was quickly transferred to systemic circulation and the mean blood (14C) concentrations were significantly greater during the first 0.25-2 h than in po dosed counterparts. About 98% of the ivg applied dose was absorbed after 6 h in gravid rats, and the combined 6-h excretions of radioactivity in the urine (ivg = 24.6%; po = 22.9%) and feces (ivg = 16.8%; po = 14.6%) were equivalent in both groups. At the end of 6 h, the levels of (14C) in the urinary bladder, adrenal, uterus, ovary, spleen, skeletal muscle, brain, heart, lung and fat were significantly higher in ivg treated rats than po dosed animals. Compared with the maternal plasma (ivg = 0.76; po = 0.88 microgram/ml), the mean concentrations of (14C) in the placentas were similar in both groups, while the amounts of (14C) were three to five times lower in the amniotic fluids and the fetuses of both po and ivg treated dams. In lactating rats, over 99% of the administered radioactivity was absorbed from the vagina within 6 h. The blood concentrations of (14C) were significantly elevated at 0.5 and 1 h in the per vaginam treated animals, and afterward the disappearance rate of (14C) followed a similar course in both groups. Following ivg application, the milk radioactivity peaked at 0.5 h and declined rapidly. However, the appearance of (14C) in milk was rather slow after oral dosing: the milk (14C) peaked between 2 and 3 h posttreatment and remained steady thereafter. The milk to blood (M/B) (14C) concentration ratios were markedly greater during 0.5 to 1 h in the ivg group than in their po dosed counterparts.

  10. Role of thirst and visual barriers in the differential behavior displayed by streptozotocin-treated rats in the elevated plus-maze and the open field test.

    PubMed

    Rebolledo-Solleiro, Daniela; Crespo-Ramírez, Minerva; Roldán-Roldán, Gabriel; Hiriart, Marcia; Pérez de la Mora, Miguel

    2013-08-15

    Conflicting results have been obtained by several groups when studying the effects of streptozotocin (STZ)-treated rats in the elevated plus-maze (EPM). Since thirst is a prominent feature in STZ-induced diabetic-like condition, we studied whether the walls of the closed arms of the EPM, by limiting the search for water in the environment, may contribute to the observed differential behavioral outcomes. The aim of this study was to ascertain whether visual barriers within the EPM have an influence on the behavior of STZ-treated rats in this test of anxiety. A striking similarity between STZ-treated (50 mg/kg, i.p., in two consecutive days) and water deprived rats (72 h) was found in exploratory behavior in the EPM, showing an anxiolytic-like profile. However the anxiolytic response of STZ-treated rats exposed to the EPM shifts into an anxiogenic profile when they are subsequently tested in the open-field test, which unlike the EPM is devoid of visual barriers. Likewise, water deprived rats (72 h) also showed an anxiogenic profile when they were exposed to the open-field test. Our results indicate that experimental outcomes based on EPM observations can be misleading when studying physiological or pathological conditions, e.g. diabetes, in which thirst may increase exploratory behavior.

  11. Tissue distribution of residual antimony in rats treated with multiple doses of meglumine antimoniate.

    PubMed

    Coelho, Deise Riba; Miranda, Elaine Silva; Saint'Pierre, Tatiana Dillenburg; Paumgartten, Francisco José Roma

    2014-07-01

    Meglumine antimoniate (MA) and sodium stibogluconate are pentavalent antimony (SbV) drugs used since the mid-1940s. Notwithstanding the fact that they are first-choice drugs for the treatment of leishmaniases, there are gaps in our knowledge of their toxicological profile, mode of action and kinetics. Little is known about the distribution of antimony in tissues after SbV administration. In this study, we evaluated the Sb content of tissues from male rats 24 h and three weeks after a 21-day course of treatment with MA (300 mg SbV/kg body wt/d, subcutaneous). Sb concentrations in the blood and organs were determined by inductively coupled plasma-mass spectrometry. In rats, as with in humans, the Sb blood levels after MA dosing can be described by a two-compartment model with a fast (t1/2 = 0.6 h) and a slow (t1/2 > 24 h) elimination phase. The spleen was the organ that accumulated the highest amount of Sb, while bone and thyroid ranked second in descending order of tissues according to Sb levels (spleen > bone, thyroid, kidneys > liver, epididymis, lungs, adrenals > prostate > thymus, pancreas, heart, small intestines > skeletal muscle, testes, stomach > brain). The pathophysiological consequences of Sb accumulation in the thyroid and Sb speciation in the liver, thyroid, spleen and bone warrant further studies.

  12. CONJUGATED LINOLEIC ACIDS (CLA) DECREASE THE BREAST CANCER RISK IN DMBA-TREATED RATS.

    PubMed

    Białek, Agnieszka; Tokarz, Andrzej; Zagrodzki, Paweł

    2016-01-01

    The aim of this study was to investigate how supplementation of diet of female Sprague-Dawley rats with different doses of conjugated linoleic acids and for a varied period of time influences breast cancer risk, fatty acids profile and lipids peroxidation in chemically induced mammary tumors. Animals were divided into nine groups with different modifications of diet (vegetable oil, 1.0 or 2.0% of CLA) and period of supplementation, which lasted after (A), before (B) and before and after (BA) carcinogenic agent--7,12-dimethylbenz[a]anthracene administration at 50th day of life. Mammary adenocarcinomas occurred in all groups, but CLA supplementation decreased the cancer morbidity. Two percent CLA seems to be excessive because of the coexisting cachexia. Two CLA isomers (9-cis, 11-trans and 10-trans, 12-cis) were detected in tumors but content of rumenic acid was higher. Dietary supplementation significantly influenced some unsaturated fatty acids content (C18:2 n-6 trans, C20:1, C20:5 n-3, C22:2), but the anti- or prooxidant properties of CLA were not confirmed. CLA can inhibit chemically induced mammary tumors development in female rats, but their cytotoxic action seems not to be connected with lipids peroxidation. CLA isomers differ with their incorporation into cancerous tissues and they influence the content of some other fatty acids. PMID:27180424

  13. Tissue distribution of residual antimony in rats treated with multiple doses of meglumine antimoniate.

    PubMed

    Coelho, Deise Riba; Miranda, Elaine Silva; Saint'Pierre, Tatiana Dillenburg; Paumgartten, Francisco José Roma

    2014-07-01

    Meglumine antimoniate (MA) and sodium stibogluconate are pentavalent antimony (SbV) drugs used since the mid-1940s. Notwithstanding the fact that they are first-choice drugs for the treatment of leishmaniases, there are gaps in our knowledge of their toxicological profile, mode of action and kinetics. Little is known about the distribution of antimony in tissues after SbV administration. In this study, we evaluated the Sb content of tissues from male rats 24 h and three weeks after a 21-day course of treatment with MA (300 mg SbV/kg body wt/d, subcutaneous). Sb concentrations in the blood and organs were determined by inductively coupled plasma-mass spectrometry. In rats, as with in humans, the Sb blood levels after MA dosing can be described by a two-compartment model with a fast (t1/2 = 0.6 h) and a slow (t1/2 > 24 h) elimination phase. The spleen was the organ that accumulated the highest amount of Sb, while bone and thyroid ranked second in descending order of tissues according to Sb levels (spleen > bone, thyroid, kidneys > liver, epididymis, lungs, adrenals > prostate > thymus, pancreas, heart, small intestines > skeletal muscle, testes, stomach > brain). The pathophysiological consequences of Sb accumulation in the thyroid and Sb speciation in the liver, thyroid, spleen and bone warrant further studies. PMID:25075781

  14. Tissue distribution of residual antimony in rats treated with multiple doses of meglumine antimoniate

    PubMed Central

    Coelho, Deise Riba; Miranda, Elaine Silva; Saint’Pierre, Tatiana Dillenburg; Paumgartten, Francisco José Roma

    2014-01-01

    Meglumine antimoniate (MA) and sodium stibogluconate are pentavalent antimony (SbV) drugs used since the mid-1940s. Notwithstanding the fact that they are first-choice drugs for the treatment of leishmaniases, there are gaps in our knowledge of their toxicological profile, mode of action and kinetics. Little is known about the distribution of antimony in tissues after SbV administration. In this study, we evaluated the Sb content of tissues from male rats 24 h and three weeks after a 21-day course of treatment with MA (300 mg SbV/kg body wt/d, subcutaneous). Sb concentrations in the blood and organs were determined by inductively coupled plasma-mass spectrometry. In rats, as with in humans, the Sb blood levels after MA dosing can be described by a two-compartment model with a fast (t1/2 = 0.6 h) and a slow (t1/2 >> 24 h) elimination phase. The spleen was the organ that accumulated the highest amount of Sb, while bone and thyroid ranked second in descending order of tissues according to Sb levels (spleen >> bone, thyroid, kidneys > liver, epididymis, lungs, adrenals > prostate > thymus, pancreas, heart, small intestines > skeletal muscle, testes, stomach > brain). The pathophysiological consequences of Sb accumulation in the thyroid and Sb speciation in the liver, thyroid, spleen and bone warrant further studies. PMID:25075781

  15. Ergosteroids: induction of thermogenic enzymes in liver of rats treated with steroids derived from dehydroepiandrosterone.

    PubMed Central

    Lardy, H; Partridge, B; Kneer, N; Wei, Y

    1995-01-01

    Dehydroepiandrosterone (DHEA), an intermediate in the biosynthesis of testosterone and estrogens, exerts several physiological effects not involving the sex hormones. When fed to rats it induces the thermogenic enzymes mitochondrial sn-glycerol-3-phosphate dehydrogenase and cytosolic malic enzyme in their livers. Animals and humans, and their excised tissues, are known to hydroxylate DHEA at several positions and to interconvert 7 alpha-hydroxy-DHEA, 7 beta-hydroxy-DHEA, 7-oxo-DHEA, and the corresponding derivatives of androst-5-enediol. We report here that these 7-oxygenated derivatives are active inducers of these thermogenic enzymes in rats and that the 7-oxo derivatives are more active than the parent steroids. We postulate that the 7 alpha-hydroxy and 7-oxo derivatives are on a metabolic pathway from DHEA to more active steroid hormones. These 7-oxo steroids have potential as therapeutic agents because of their increased activity and because they are not convertible to either testosterone or estrogens. PMID:7604042

  16. Voluntary alcohol consumption and plasma beta-endorphin levels in alcohol preferring rats chronically treated with lamotrigine.

    PubMed

    Zalewska-Kaszubska, Jadwiga; Bajer, Bartosz; Gorska, Dorota; Andrzejczak, Dariusz; Dyr, Wanda; Bieńkowski, Przemysław

    2015-02-01

    Several recent studies have indicated that lamotrigine, similarly to other antiepileptic drugs, may be useful in the therapy of alcohol dependence. The rationale for using lamotrigine in the treatment of alcohol addiction is based on its multiple mechanisms of action which include inhibition of voltage-sensitive sodium channels, modulation voltage-gated calcium currents and transient potassium outward current. However, the known mechanism of lamotrigine does not fully explain its efficacy in alcohol addiction therapy. For this reason we have decided to examine the effect of lamotrigine on the opioid system. Our previous studies showed that topiramate and levetiracetam (antiepileptic drugs) as well as the most effective drugs in alcohol addiction therapy i.e. naltrexone and acamprosate, when given repeatedly, all increased plasma beta endorphin (an endogenous opioid peptide) level, despite operating through different pharmacological mechanisms. It is known that low beta-endorphin level is often associated with alcohol addiction and also that alcohol consumption elevates the level of this peptide. This study aims to assess the effect of repeated treatment with lamotrigine on voluntary alcohol intake and beta-endorphin plasma level in alcohol preferring rats (Warsaw high preferring (WHP) rats). We observed a decrease in alcohol consumption in rats treated with lamotrigine. However we didn't observe significant changes in beta-endorphin level during withdrawal of alcohol, which may indicate that the drug does not affect the opioid system. We suppose that lamotrigine may be useful in alcohol dependence therapy and presents a potential area for further study. PMID:25449391

  17. Evaluation of Sphingolipids in Wistar Rats Treated to Prolonged and Single Oral Doses of Fumonisin B1

    PubMed Central

    Direito, Glória M.; Almeida, Adriana P.; Aquino, Simone; dos Reis, Tatiana Alves; Pozzi, Claudia Rodrigues; Corrêa, Benedito

    2009-01-01

    The objective of the present study was to evaluate sphingolipid levels (sphingosine-So and sphinganine-Sa) and to compare the Sa/So ratio in liver, serum and urine of Wistar rats after prolonged administration (21 days) of fumonisin B1 (FB1). In parallel, the kinetics of sphingolipid elimination in urine was studied in animals receiving a single dose of FB1. Prolonged exposure to FB1 caused an increase in Sa levels in urine, serum and liver. The most marked effect on sphingolipid biosynthesis was observed in animals treated with the highest dose of FB1. Animals receiving a single dose of FB1 presented variations in Sa and So levels and in the Sa/So ratio. PMID:19333435

  18. Nociceptive and Neuronal Evaluation of the Sciatic Nerve of Wistar Rats Subjected to Compression Injury and Treated with Resistive Exercise

    PubMed Central

    Antunes, Juliana Sobral; Lovison, Keli; Karvat, Jhenifer; Peretti, Ana Luiza; Vieira, Lizyana; Higuchi, Guilherme Hideaki; Ribeiro, Lucinéia de Fátima Chasko

    2016-01-01

    Background. To investigate the climb stairs resistance exercise on nociception and axonal regeneration in the sciatic nerve of rats. Methods. 24 Wistar rats were divided: control group (CG—no injury), exercise group (EG—no injury with physical exercise), lesion group (LG—injury, but without exercise), and treated group (LEG—injury and physical exercise). LG and LEG were subjected to sciatic nerve compression with hemostat. From the 3rd day after injury began treatment with exercise, and after 22 days occurs the removal of a nerve fragment for morphological analysis. Results. Regarding allodynia, CG obtained values less than EG (p = 0.012) and larger than LG and LEG (p < 0.001). Histological results showed that CG and EG had normal appearance, as LG and LEG showed up with large amounts of inflammatory infiltration, degeneration and disruption of nerve fibers, and reduction of the myelin sheath; however LEG presented some regenerated fibers. From the morphometric data there were significant differences, for nerve fiber diameter, comparing CG with LG and LEG and comparing axon diameter and the thickness of the myelin of the CG to others. Conclusion. Climb stairs resistance exercise was not effective to speed up the regenerative process of axons.

  19. Nociceptive and Neuronal Evaluation of the Sciatic Nerve of Wistar Rats Subjected to Compression Injury and Treated with Resistive Exercise.

    PubMed

    Antunes, Juliana Sobral; Lovison, Keli; Karvat, Jhenifer; Peretti, Ana Luiza; Vieira, Lizyana; Higuchi, Guilherme Hideaki; Brancalhão, Rose Meire Costa; Ribeiro, Lucinéia de Fátima Chasko; Bertolini, Gladson Ricardo Flor

    2016-01-01

    Background. To investigate the climb stairs resistance exercise on nociception and axonal regeneration in the sciatic nerve of rats. Methods. 24 Wistar rats were divided: control group (CG-no injury), exercise group (EG-no injury with physical exercise), lesion group (LG-injury, but without exercise), and treated group (LEG-injury and physical exercise). LG and LEG were subjected to sciatic nerve compression with hemostat. From the 3rd day after injury began treatment with exercise, and after 22 days occurs the removal of a nerve fragment for morphological analysis. Results. Regarding allodynia, CG obtained values less than EG (p = 0.012) and larger than LG and LEG (p < 0.001). Histological results showed that CG and EG had normal appearance, as LG and LEG showed up with large amounts of inflammatory infiltration, degeneration and disruption of nerve fibers, and reduction of the myelin sheath; however LEG presented some regenerated fibers. From the morphometric data there were significant differences, for nerve fiber diameter, comparing CG with LG and LEG and comparing axon diameter and the thickness of the myelin of the CG to others. Conclusion. Climb stairs resistance exercise was not effective to speed up the regenerative process of axons. PMID:27594795

  20. Toxicological assessment of enzyme-treated asparagus extract in rat acute and subchronic oral toxicity studies and genotoxicity tests.

    PubMed

    Ito, Tomohiro; Ono, Tomoko; Sato, Atsuya; Goto, Kazunori; Miura, Takehito; Wakame, Koji; Nishioka, Hiroshi; Maeda, Takahiro

    2014-03-01

    The safety of enzyme-treated asparagus extract (ETAS) developed as a novel anti-stress functional material was assessed in acute and subchronic studies and genotoxicity assays. In the acute oral dose toxicity study, all rats survived during the test period and ETAS did not influence clinical appearance, body weight gain and necropsy findings at a dosage of 2000mg/kg body weight. Thus, the 50% lethal dose (LD50) of ETAS was determined to be greater than 2000mg/kg. The 90-day subchronic study (500, 1000 and 2000mg/kg body weight, delivered by gavage) in rats reported no significant adverse effects in food consumption, body weight, mortality, urinalysis, hematology, biochemistry, necropsy, organ weight and histopathology. In the micronucleus test of mice, the incidence of micronuclei in ETAS-administered groups (500, 1000 and 2000mg/kg/day, injected twice) was equivalent to that of the negative control group, while the positive control group receiving mitomycin C showed a high incidence. The potential of ETAS to induce gene mutation was tested using four Salmonella typhimurium strains and Escherichia coli WP2uvrA. The test sample was not mutagenic to the test strains. These results support the safety of ETAS as food and dietary supplement.

  1. Evidence for a blood - uterine lumen permeability barrier in rats treated with hormones to mimic early pseudopregnancy.

    PubMed

    McRae, A C; Kennedy, T G

    1982-12-01

    Experiments have been carried out to investigate whether a blood - uterine lumen permeability barrier exists in rats treated with hormones to mimic the implantation period of gestation. Levels of radioactivity in fluid from the uterine lumen and in serum of rats at the equivalent of day 4, 5, or 6 of pseudopregnancy (day 1 = day of induced ovulation) were determined either 20 or 60 min after intravenous injection of a radiolabelled test substance. Following injection of [14C]urea or [3H]sucrose, uterine fluid (UF) radioactivity concentrations did not differ significantly between 20 and 60 min irrespective of day of pseudopregnancy. With [14C]urea, UF radioactivity concentrations were significantly less than those in serum in all groups except at the equivalent of day 6 of pseudopregnancy. After injection of [3H]sucrose, the UF radioactivity concentrations were significantly less than those in serum in all groups except at 60 min at the equivalent of day 6 of pseudopregnancy. Additionally, the UF radioactivity concentrations after injection of either [14C]urea or [3H]sucrose were significantly higher on the equivalent of day 6 of pseudopregnancy than on day 4. By contrast, when tritiated water was injected, the UF radioactivity concentrations were not markedly different from those in serum in all groups.

  2. Nourishing Yin and Promoting Blood Circulation of TCM to Treat Hemorheologic Disorder Induced by Diabetes Mellitus in Rats

    PubMed Central

    Huang, Ping; Shao, Guo-ming

    2007-01-01

    Diabetes mellitus, DM, is commonly accompanied with various stages of hemorheologic disturbances that are the main causes of the development of chronic DM. In this study, simple Chinese material medica [yang-yin jiang-tang preparation (YYJT)] was given to alloxan-induced DM rats and analyzed to compare the changes of fasting blood glucose (FBG), fasting insulin (FINS), hemorheologic parameters and insulin-like growth factor II (IGF-II) before and after administration. The results suggested that YYJT can significantly downregulate FBG (P < 0.005), improve insulin resistance and beta-cell secretion (P < 0.05), decrease whole blood viscosity at low and high shear rates, gathering of blood index test (GIT) and fibrinogen (FIB) (P < 0.05), and enlarge the function of IGF-II (P < 0.05). We concluded that YYJT could prevent and treat hemorheologic disorder in DM rats by means of reducing glucose, improving insulin resistance and elevating IGF-II. PMID:17549237

  3. Hormone replacement with 17β-estradiol plus dihydrotestosterone restores male sexual behavior in rats treated neonatally with clomipramine.

    PubMed

    Limón-Morales, Ofelia; Soria-Fregozo, Cesar; Arteaga-Silva, Marcela; González, Marisela Hernández; Vázquez-Palacios, Gonzalo; Bonilla-Jaime, Herlinda

    2014-11-01

    Male sexual behavior (MSB) in rodents, in both its consummatory and motivational components, is regulated by hormones such as testosterone, 17β-estradiol and 5-α-dihydrotestosterone. In experiments, neonatal treatment with clomipramine (CMI; a serotonin reuptake inhibitor) reproduces some of the signs of depression in adult age, including reduced sexual behavior manifested in a lower percentage of subjects that mount, intromit and ejaculate, although their testosterone levels were not altered. However, the effect of this treatment on estrogen levels and the consequences of hormone substitution using 17β-estradiol and 5-α-dihydrotestosterone on the expression of male sexual behavior are still unknown. Therefore, the objective of the present study was to analyze the effect of neonatal treatment with CMI on plasma testosterone and 17β-estradiol levels, and the role of testosterone, 17β-estradiol and 5-α-dihydrotestosterone in altering the consummatory and motivational components of sexual behavior in male rats. To this end, it analyzed the copulatory parameters and sexual incentive motivation (SIM) of rats treated with CMI under two conditions: basal and post-hormone replacements. Neonatal treatment with CMI did not affect plasma testosterone or 17β-estradiol concentrations, but did decrease both the consummatory component and sexual motivation according to the results of the SIM test. These aspects were recovered after administering 17β-estradiol +5-α-dihydrotestosterone, but not testosterone.

  4. Nociceptive and Neuronal Evaluation of the Sciatic Nerve of Wistar Rats Subjected to Compression Injury and Treated with Resistive Exercise

    PubMed Central

    Antunes, Juliana Sobral; Lovison, Keli; Karvat, Jhenifer; Peretti, Ana Luiza; Vieira, Lizyana; Higuchi, Guilherme Hideaki; Ribeiro, Lucinéia de Fátima Chasko

    2016-01-01

    Background. To investigate the climb stairs resistance exercise on nociception and axonal regeneration in the sciatic nerve of rats. Methods. 24 Wistar rats were divided: control group (CG—no injury), exercise group (EG—no injury with physical exercise), lesion group (LG—injury, but without exercise), and treated group (LEG—injury and physical exercise). LG and LEG were subjected to sciatic nerve compression with hemostat. From the 3rd day after injury began treatment with exercise, and after 22 days occurs the removal of a nerve fragment for morphological analysis. Results. Regarding allodynia, CG obtained values less than EG (p = 0.012) and larger than LG and LEG (p < 0.001). Histological results showed that CG and EG had normal appearance, as LG and LEG showed up with large amounts of inflammatory infiltration, degeneration and disruption of nerve fibers, and reduction of the myelin sheath; however LEG presented some regenerated fibers. From the morphometric data there were significant differences, for nerve fiber diameter, comparing CG with LG and LEG and comparing axon diameter and the thickness of the myelin of the CG to others. Conclusion. Climb stairs resistance exercise was not effective to speed up the regenerative process of axons. PMID:27594795

  5. Prevention of hepatorenal toxicity with Sonchus asper in gentamicin treated rats

    PubMed Central

    2011-01-01

    Background Sonchus asper possesses antioxidant capacity and is used in liver and kidney disorders. We have investigated the preventive effect of methanolic extract of Sonchus asper (SAME) on the gentamicin induced alterations in biochemical and morphological parameters in liver and kidneys of Sprague-Dawley male rat. Methods Acute oral toxicity studies were performed for selecting the therapeutic dose of SAME. 30 Sprague-Dawley male rats were equally divided into five groups with 06 animals in each. Group I received saline (0.5 ml/kg bw; 0.9% NaCl) while Group II administered with gentamicin 0.5 ml (100 mg/kg bw; i.p.) for ten days. Animals of Group III and Group IV received gentamicin and SAME 0.5 ml at a dose of 100 mg/kg bw and 200 mg/kg bw, respectively while Group V received only SAME at a dose of 200 mg/kg bw. Biochemical parameters including aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), γ-glutamyltransferase (γ-GT), total cholesterol, triglycerides, total protein, albumin, creatinine, blood urea nitrogen (BUN), total bilirubin and direct bilirubin were determined in serum collected from various groups. Urinary out puts were measured in each group and also assessed for the level of protein and glucose. Lipid peroxides (TBARS), glutathione (GSH), DNA injuries and activities of antioxidant enzymes; catalase (CAT), peroxidase (POD) and superoxide dismutase (SOD) were determined in liver and renal samples. Histopathological studies of liver and kidneys were also carried out. Results On the basis of acute oral toxicity studies, 2000 mg/kg bw did not induce any toxicity in rats, 1/10th of the dose was selected for preventive treatment. Gentamicin increased the level of serum biomarkers; AST, ALT, ALP, LDH, γ-GT, total cholesterol, triglycerides, total protein, albumin, creatinine, BUN, total and direct bilirubin; as were the urinary level of protein, glucose, and urinary output. Lipid

  6. Treating NAFLD in OLETF Rats with Vigorous-Intensity Interval Exercise Training

    PubMed Central

    Linden, Melissa A.; Fletcher, Justin A.; Morris, E. Matthew; Meers, Grace M.; Laughlin, M. Harold; Booth, Frank W.; Sowers, James R.; Ibdah, Jamal A.; Thyfault, John P.; Rector, R. Scott

    2014-01-01

    Background There is increasing use of high intensity, interval type exercise training in the management of many lifestyle-related diseases. Purpose To test the hypothesis that vigorous-intensity, interval exercise is as effective as traditional, moderate-intensity aerobic exercise training on nonalcoholic fatty liver disease (NAFLD) outcomes in obese, Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Methods OLETF rats (age 20 wks; n= 8–10/group) were assigned to sedentary (O-SED), moderate-intensity exercise training (O-MOD EX; 20 meters/min, 15% incline, 60 min/d, 5 d/wk treadmill running), or vigorous-intensity interval exercise training (O-VIG EX; 40 meters/min, 15% incline, 6×2.5 min bouts/d, 5 d/wk treadmill running) groups for 12 weeks. Results Both MOD EX and VIG EX effectively lowered hepatic triglycerides (TGs), serum ALTs, perivenular fibrosis, and hepatic collagen 1α1 mRNA expression (vs. O-SED, p<0.05). In addition, both interventions increased hepatic mitochondrial markers (citrate synthase activity and fatty acid oxidation) and suppressed markers of de novo lipogenesis (FAS, ACC, Elovl6, and SCD-1); whereas, only MOD EX increased hepatic mitochondrial β-HAD activity and hepatic TG export marker apoB100 and lowered fatty acid transporter CD36 compared with O-SED. Moreover, while total hepatic macrophage population markers (CD68 and F4/80 mRNA) did not differ among groups, MOD EX and VIG EX lowered M1 macrophage polarization markers (CD11c, IL-1β, and TNFα mRNA) and MOD EX increased M2 macrophage marker, CD206 mRNA, compared with O-SED. Conclusions The accumulation of 15 min/day of VIG EX for 12 weeks had similar effectiveness as 60 min/day of MOD EX in the management of NAFLD in OLETF rats. These findings may have important health outcome implications as we work to design better exercise training programs for NAFLD patients. PMID:24983336

  7. Normalization of periodontal tissues in osteopetrotic mib mutant rats, treated with CSF-1

    NASA Technical Reports Server (NTRS)

    Wojtowicz, A.; Yamauchi, M.; Sotowski, R.; Ostrowski, K.

    1998-01-01

    The osteopetrotic mib mutation in rats causes defects in the skeletal bone tissue in young animals. These defects, i.e. slow bone remodelling, changes in both crystallinity and mineral content, are transient and undergo normalization, even without any treatment in 6-wk-old animals. Treatment with CSF-1 (colony stimulating factor-1) accelerates the normalization process in skeletal bones. The periodontal tissues around the apices of incisors show abnormalities caused by the slow remodelling process of the mandible bone tissue, the deficiency of osteoclasts and their abnormal morphology, as well as the disorganization of periodontal ligament fibres. In contrast to the skeletal tissues, these abnormalities would not undergo spontaneous normalization. Under treatment with colony stimulating factor 1 (CSF-1), the primitive bone trabeculae of mandible are resorbed and the normalization of the number of osteoclasts and their cytology occurs. The organization of the periodontal ligament fibres is partially restored, resembling the histological structure of the normal one.

  8. Biocompatibility of supercritical CO2-treated titanium implants in a rat model.

    PubMed

    Hill, C M; Kang, Q K; Wahl, C; Jimenez, A; Laberge, M; Drews, M; Matthews, M A; An, Y H

    2006-04-01

    Supercritical phase CO2 is a promising method for sterilizing implantable devices and tissue grafts. The goal of this study is to evaluate the biocompatibility of titanium implants sterilized by supercritical phase CO2 in a rat subcutaneous implantation model. At 5 weeks post implantation titanium implants sterilized by supercritical phase CO2 produce a soft tissue reaction that is comparable to other methods of sterilization (steam autoclave, ultraviolet light radiation, ethylene oxide gas, and radio-frequency glow-discharge), as indicated by the thickness and density of the foreign body capsule, although there were some differences on the capillary density. Overall the soft tissue response to the implants was similar among all methods of sterilization, indicating supercritical phase CO2 treatment did not compromise the biocompatibility of the titanium implant.

  9. Biocompatibility of supercritical CO2-treated titanium implants in a rat model.

    PubMed

    Hill, C M; Kang, Q K; Wahl, C; Jimenez, A; Laberge, M; Drews, M; Matthews, M A; An, Y H

    2006-04-01

    Supercritical phase CO2 is a promising method for sterilizing implantable devices and tissue grafts. The goal of this study is to evaluate the biocompatibility of titanium implants sterilized by supercritical phase CO2 in a rat subcutaneous implantation model. At 5 weeks post implantation titanium implants sterilized by supercritical phase CO2 produce a soft tissue reaction that is comparable to other methods of sterilization (steam autoclave, ultraviolet light radiation, ethylene oxide gas, and radio-frequency glow-discharge), as indicated by the thickness and density of the foreign body capsule, although there were some differences on the capillary density. Overall the soft tissue response to the implants was similar among all methods of sterilization, indicating supercritical phase CO2 treatment did not compromise the biocompatibility of the titanium implant. PMID:16705612

  10. Increased contraction frequency in rat uterine strips treated in vitro with o,p prime -DDT

    SciTech Connect

    Juberg, D.R.; Loch-Caruso, R. )

    1991-05-01

    Elevated levels of DDT and other organochlorine pesticides have been associated with spontaneous abortion and preterm birth in several species, including humans. Despite the prevalence of organochlorine pesticides in the environment, a mechanistic basis for this association has not been explored. Furthermore, while DDT has been associated with inhibition of calcium ATPases, altered gap junctional communication and electrophysiological changes, all of which could affect the excitation-contraction process characteristic of smooth muscle, direct effects of DDT on uterine smooth muscle have not been reported. This study was initiated to assess the direct effects of o,p{prime}-DDT (an estrogenic isomer present in the technical grade preparation) on pregnant rat uterine tissue.

  11. Nephrotoxic effects on offspring of rats chronically treated with mercuric chloride

    SciTech Connect

    Rusk, T.L.

    1983-08-01

    Repeated subcutaneous injections of HgCl/sub 2/ at a dose of either 4.0 or 2.0 mg/kg produced toxic effects in rats when administered during the last 9 days of gestation. Females exhibited diarrhea, anorexia and weight loss of varying severity. Maternal renal function was monitored by urinalysis and was shown to be impaired during the early days of treatment but returned to normal later. Histological evaluation of adult kidneys after 2 days of treatment demonstrated the nephrotoxic effects of HgCl/sub 2/. Evidence of the regenerative process was found in tubules lined with densely packed, flattened cuboidal epithelial cells. Pup birth weight among HgCl/sub 2/-exposed litters was significantly lower than that of control litters. Nephrotoxic effects were not identifiable in pups though the presence of mercury was confirmed in fetal kidneys. 93 refs., 7 figs., 3 tabs.

  12. Transplantation of insulin-producing cells to treat diabetic rats after 90% pancreatectomy

    PubMed Central

    Yu, Ya-Bin; Bian, Jian-Min; Gu, Dian-Hua

    2015-01-01

    AIM: To investigate the effects of transplantation of insulin-producing cells (IPCs) in the treatment of diabetic rats after 90% pancreatectomy. METHODS: Human umbilical cord mesenchymal stem cells (UCMSCs) were isolated and induced into IPCs using differentiation medium. Differentiated cells were examined by dithizone (DTZ) staining, reverse transcription-polymerase chain reaction (RT-PCR), and real-time RT-PCR. C-peptide release, both spontaneously and after glucose challenge, was measured by ELISA. IPCs were then transplanted into Sprague-Dawley rats after 90% pancreatectomy and blood glucose levels and body weight were measured. RESULTS: The differentiated cells were positive for DTZ staining and expressed pancreatic β-cell related genes. C-peptide release by the differentiated cells increased after glucose challenge (380.6 ± 15.32 pmol/L vs 272.4 ± 15.32 pmol/L, P < 0.05). Further, in the cell transplantation group, blood sugar levels were significantly lower than in the sham group 2 wk after transplantation (18.7 ± 2.5 mmol/L vs 25.8 ± 1.25 mmol/L, P < 0.05). Glucose tolerance tests showed that 45 min after intraperitoneal glucose injection, blood glucose levels were significantly lower on day 56 after transplantation of IPCs (12.5 ± 4.7 mmol/L vs 42.2 ± 9.3 mmol/L, P < 0.05). CONCLUSION: Our results show that UCMSCs can differentiate into islet-like cells in vitro under certain conditions, which can function as IPCs both in vivo and in vitro. PMID:26074696

  13. Modification of biliary tree permeability in rats treated with a manganese-bilirubin combination

    SciTech Connect

    Ayotte, P.; Plaa, G.L.

    1986-06-30

    Previous studies in this laboratory demonstrated incorporation of manganese (Mn) and bilirubin (BR) in rat liver bile canalicular membrane (BCM) following a cholestatic regimen composed sequentially of Mn plus BR. The present study investigates biliary tree permeability using segmented retrograde intrabiliary injection (SRII) with (/sup 3/H)mannitol and (3H)inulin as marker substances. Male Sprague-Dawley rats were given the following iv: (a) Mn (high and low dose), (b) BR, (c) sulfobromophthalein (BSP), (d) Mn-BSP-BR, (e) MnBR. Results obtained with mannitol showed a approximately 63% decrease (p less than 0.05) in marker recovery following administration of MnBR combination. While BSP alone had no effect on mannitol recovery, BSP abolished the MnBR response when administered in the Mn-BSP-BR sequence. With inulin, Mn (high dose), MnBR, and Mn-BSP-BR all produced a approximately 45% decrease (p less than 0.05) in recovery, while BSP or BR alone caused a approximately 25% decrease (p less than 0.05). Mn (low dose) was without effect. These results and others obtained when the time pattern of the MnBR treatment was modified suggest: (1) MnBR treatment increases biliary tree permeability by altering both BCM and the junctional complex; (2) BCM alteration is probably the more critical event, since BSP, which protects against MnBR cholestasis, protected against the MnBR-induced change in mannitol recovery, but exerted no effect on inulin recovery.

  14. Proteomic study of periovarian adipose tissue in 17β-estradiol-treated and untreated ovariectomized rats.

    PubMed

    Amengual-Cladera, Emilia; Capllonch-Amer, Gabriela; Lladó, Isabel; Gianotti, Magdalena; Proenza, Ana M

    2016-04-01

    Taking into account the sexual dimorphism previously found in white adipose tissue (WAT) regarding mitochondrial function and biogenesis, as well as insulin sensitivity, the aim of this study was to go further into the role of sex hormones in this dimorphism. To achieve this objective, we used ovariectomized rats and performed a screening by means of proteomic analyses of the periovarian WAT, combined with a study of the protein levels of specific factors involved in mitochondrial function. Rats were ovariectomized at 5 weeks of age and subcutaneously injected every 48 h with corn-oil (OVX group) or with 17β-estradiol (E2, 10 μg/kg body mass; OVX + E2 group) for 4 weeks prior to sacrifice. Beside proteomic analysis, protein levels of Transcription Factor A, Mitochondrial (TFAM), cytochrome oxidase (COX)II, and COXIV were determined by Western blot, and mRNA levels of peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α, ERα, ERβ, lipoprotein lipase (LPL), peroxisome proliferator-activated receptor-γ (PPARγ), and adiponectin were quantified by real-time PCR. Our results show that ovariectomy leads to an increase in anabolic processes and inflammatory protein levels as well as to a decrease in some of the markers of mitochondrial function, which are restored, at least in part, by E2 supplementation. Indeed, this E2 supplementation seems to be counteracted by a decline in ERα and in the ERα to ERβ ratio values that could be directed to avoid an over-stimulation of the E2 signaling pathway, given the possibility of an activation of extra-gonadal steroid biosynthetic pathways.

  15. Nitric oxide-releasing flurbiprofen reduces formation of proinflammatory hydrogen sulfide in lipopolysaccharide-treated rat

    PubMed Central

    Anuar, Farhana; Whiteman, Matthew; Siau, Jia Ling; Kwong, Shing Erl; Bhatia, Madhav; Moore, Philip K

    2006-01-01

    The biosynthesis of both nitric oxide (NO) and hydrogen sulfide (H2S) is increased in lipopolysaccharide (LPS)-injected mice and rats but their interaction in these models is not known. In this study we examined the effect of the NO donor, nitroflurbiprofen (and the parent molecule flurbiprofen) on NO and H2S metabolism in tissues from LPS-pretreated rats. Administration of LPS (10 mg kg−1, i.p.; 6 h) resulted in an increase (P<0.05) in plasma TNF-α, IL-1β and nitrate/nitrite (NOx) concentrations, liver H2S synthesis (from added cysteine), CSE mRNA, inducible nitric oxide synthase (iNOS), myeloperoxidase (MPO) activity (marker for neutrophil infiltration) and nuclear factor-kappa B (NF-κB) activation. Nitroflurbiprofen (3–30 mg kg−1, i.p.) administration resulted in a dose-dependent inhibition of the LPS-mediated increase in plasma TNF-α, IL-1β and NOx concentration, liver H2S synthesis (55.00±0.95 nmole mg protein−1, c.f. 62.38±0.47 nmole mg protein−1, n=5, P<0.05), CSE mRNA, iNOS, MPO activity and NF-κB activation. Flurbiprofen (21 mg kg−1, i.p.) was without effect. These results show for the first time that nitroflurbiprofen downregulates the biosynthesis of proinflammatory H2S and suggest that such an effect may contribute to the augmented anti-inflammatory activity of this compound. These data also highlight the existence of ‘crosstalk' between NO and H2S in this model of endotoxic shock. PMID:16491094

  16. Rosiglitazone ameliorates abnormal expression and activity of protein tyrosine phosphatase 1B in the skeletal muscle of fat-fed, streptozotocin-treated diabetic rats

    PubMed Central

    Wu, Yong; Ouyang, Jing Ping; Wu, Ke; Wang, Shi Shun; Wen, Chong Yuan; Xia, Zheng Yuan

    2005-01-01

    Protein tyrosine phosphatase 1B (PTP1B) acts as a physiological negative regulator of insulin signaling by dephosphorylating the activated insulin receptor (IR). Here we examine the role of PTP1B in the insulin-sensitizing action of rosiglitazone (RSG) in skeletal muscle and liver. Fat-fed, streptozotocin-treated rats (10-week-old), an animal model of type II diabetes, and age-matched, nondiabetic controls were treated with RSG (10 μmol kg−1 day−1) for 2 weeks. After RSG treatment, the diabetic rats showed a significant decrease in blood glucose and improved insulin sensitivity. Diabetic rats showed significantly increased levels and activities of PTP1B in the skeletal muscle (1.6- and 2-fold, respectively) and liver (1.7- and 1.8-fold, respectively), thus diminishing insulin signaling in the target tissues. We found that the decreases in insulin-stimulated glucose uptake (55%), tyrosine phosphorylation of IRβ-subunits (48%), and IR substrate-1 (IRS-1) (39%) in muscles of diabetic rats were normalized after RSG treatment. These effects were associated with 34 and 30% decreases in increased PTP1B levels and activities, respectively, in skeletal muscles of diabetic rats. In contrast, RSG did not affect the increased PTP1B levels and activities or the already reduced insulin-stimulated glycogen synthesis and tyrosine phosphorylation of IRβ-subunits and IRS-2 in livers of diabetic rats. RSG treatment in normal rats did not significantly change PTP1B activities and levels or protein levels of IRβ, IRS-1, and -2 in diabetic rats. These data suggest that RSG enhances insulin activity in skeletal muscle of diabetic rats possibly by ameliorating abnormal levels and activities of PTP1B. PMID:15997237

  17. Salvianolic Acid B Prevents Bone Loss in Prednisone-Treated Rats through Stimulation of Osteogenesis and Bone Marrow Angiogenesis

    PubMed Central

    Cui, Liao; Li, Ting; Liu, Yuyu; Zhou, Le; Li, Pinghua; Xu, Bilian; Huang, Lianfang; Chen, Yan; Liu, Yanzhi; Tian, Xiaoyan; Jee, Webster S. S.; Wu, Tie

    2012-01-01

    Glucocorticoid (GC) induced osteoporosis (GIO) is caused by the long-term use of GC for treatment of autoimmune and inflammatory diseases. The GC related disruption of bone marrow microcirculation and increased adipogenesis contribute to GIO development. However, neither currently available anti-osteoporosis agent is completely addressed to microcirculation and bone marrow adipogenesis. Salvianolic acid B (Sal B) is a polyphenolic compound from a Chinese herbal medicine, Salvia miltiorrhiza Bunge. The aim of this study was to determine the effects of Sal B on osteoblast bone formation, angiogenesis and adipogenesis-associated GIO by performing marrow adipogenesis and microcirculation dilation and bone histomorphometry analyses. (1) In vivo study: Bone loss in GC treated rats was confirmed by significantly decreased BMD, bone strength, cancellous bone mass and architecture, osteoblast distribution, bone formation, marrow microvessel density and diameter along with down-regulation of marrow BMPs expression and increased adipogenesis. Daily treatment with Sal B (40 mg/kg/d) for 12 weeks in GC male rats prevented GC-induced cancellous bone loss and increased adipogenesis while increasing cancellous bone formation rate with improved local microcirculation by capillary dilation. Treatment with Sal B at a higher dose (80 mg/kg/d) not only prevented GC-induced osteopenia, but also increased cancellous bone mass and thickness, associated with increase of marrow BMPs expression, inhibited adipogenesis and further increased microvessel diameters. (2) In vitro study: In concentration from 10−6 mol/L to 10−7 mol/L, Sal B stimulated bone marrow stromal cell (MSC) differentiation to osteoblast and increased osteoblast activities, decreased GC associated adipogenic differentiation by down-regulation of PPARγ mRNA expression, increased Runx2 mRNA expression without osteoblast inducement, and, furthermore, Sal B decreased Dickkopf-1 and increased β-catenin mRNA expression with

  18. Effects of bupropion on the forced swim test and release of dopamine in the nucleus accumbens in ACTH-treated rats.

    PubMed

    Kitamura, Yoshihisa; Yagi, Takahiko; Kitagawa, Kouhei; Shinomiya, Kazuaki; Kawasaki, Hiromu; Asanuma, Masato; Gomita, Yutaka

    2010-08-01

    The dopamine reuptake inhibitor bupropion has clinically been proven to improve depression and treatment-resistant depression. We examined its influence on the duration of immobility during the forced swim test in adrenocorticotropic hormone (ACTH)-treated rats and further analyzed the possible role of dopamine receptors in this effect. Additionally, the mechanism by which bupropion acts in this model was explored specifically in relation to the site of action through the use of microinjections into the medial prefrontal cortex and nucleus accumbens. Bupropion significantly decreased the duration of immobility in normal and ACTH-treated rats. This effect was blocked by D2 and D3 receptor antagonists in normal rats. Furthermore, infusions of bupropion into the nucleus accumbens, but not medial prefrontal cortex, decreased the immobility of normal and ACTH-treated rats during the forced swim test. Bupropion treatment plus repeated ACTH treatment significantly increased the extracellular dopamine concentration. These findings suggest the antidepressant-like effect of bupropion to be related to levels of dopamine in the rat nucleus accumbens.

  19. Increased strontium uptake in trabecular bone of ovariectomized calcium-deficient rats treated with strontium ranelate or strontium chloride.

    PubMed

    Pemmer, Bernhard; Hofstaetter, Jochen G; Meirer, Florian; Smolek, Stephan; Wobrauschek, Peter; Simon, Rolf; Fuchs, Robyn K; Allen, Matthew R; Condon, Keith W; Reinwald, Susan; Phipps, Roger J; Burr, David B; Paschalis, Eleftherios P; Klaushofer, Klaus; Streli, Christina; Roschger, Paul

    2011-11-01

    Based on clinical trials showing the efficacy to reduce vertebral and non-vertebral fractures, strontium ranelate (SrR) has been approved in several countries for the treatment of postmenopausal osteoporosis. Hence, it is of special clinical interest to elucidate how the Sr uptake is influenced by dietary Ca deficiency as well as by the formula of Sr administration, SrR versus strontium chloride (SrCl(2)). Three-month-old ovariectomized rats were treated for 90 days with doses of 25 mg kg(-1) d(-1) and 150 mg kg(-1) d(-1) of SrR or SrCl(2) at low (0.1% Ca) or normal (1.19% Ca) Ca diet. Vertebral bone tissue was analysed by confocal synchrotron-radiation-induced micro X-ray fluorescence and by backscattered electron imaging. Principal component analysis and k-means clustering of the acquired elemental maps of Ca and Sr revealed that the newly formed bone exhibited the highest Sr fractions and that low Ca diet increased the Sr uptake by a factor of three to four. Furthermore, Sr uptake in bone of the SrCl(2)-treated animals was generally lower compared with SrR. The study clearly shows that inadequate nutritional calcium intake significantly increases uptake of Sr in serum as well as in trabecular bone matrix. This indicates that nutritional calcium intake as well as serum Ca levels are important regulators of any Sr treatment.

  20. Endothelial, renal and hepatic variables in Wistar rats treated with Vancomycin.

    PubMed

    Bruniera, Felipe R; Ferreira, Felipe M; Savioli, Luiz R M; Bacci, Marcelo R; Feder, David; Pereira, Edimar C; Pedreira, Mavilde L G; Peterlini, Maria A S; Perazzo, Fábio F; Azzalis, Ligia A; Rosa, Paulo C P; Junqueira, Virginia B C; Sato, Monica A; Fonseca, Fernando L A

    2014-12-01

    Vancomycin (VCM) is indicated in combat against Gram-positive infections, but it is not considered a first-choice drug because of its adverse effects. It is believed that oxidative stress is the primary mechanism of endothelial injury and the consequent VCM toxicity, which varies from phlebitis to nephrotoxicity. Moreover, dose recommendations, dilution, rates and types of infusion are still controversial. The aim of this study was to determine the effect of different VCM dilutions in endothelial, liver and kidney injuries by biochemical parameters and histopathological analysis. Wistar rats were randomly divided into six groups and subjected to femoral vein cannulation for drug administration. Control groups received 0.9 ml of saline and the others received VCM (10mg/Kg/day) at dilutions of 5.0 and 10.0 mg/mL for 3 and 7 days. Homocysteine, hs-CRP, AST, ALT, GGT, urea, creatinine, lycopene, alpha-tocopherol, beta-carotene and retinol were analyzed. Kidney, liver and cannulated femoral vein fragments were collected.This study showed alterations in ALT which featured hepatotoxicity. However, drug dilutions were not able to show changes in other biochemical parameters. In contrast, kidney and endothelium pathological changes were observed. More studies are needed to characterize VCM induced kidney and endothelium toxicity and biochemical markers able to show such morphological modifications.

  1. Behavioral changes and cholinesterase activity of rats acutely treated with propoxur.

    PubMed

    Thiesen, F V; Barros, H M; Tannhauser, M; Tannhauser, S L

    1999-01-01

    Early assessment of neurological and behavioral effects is extremely valuable for early identification of intoxications because preventive measures can be taken against more severe or chronic toxic consequences. The time course of the effects of an oral dose of the anticholinesterase agent propoxur (8.3 mg/kg) was determined on behaviors displayed in the open-field and during an active avoidance task by rats and on blood and brain cholinesterase activity. Maximum inhibition of blood cholinesterase was observed within 30 min after administration of propoxur. The half-life of enzyme-activity recovery was estimated to be 208.6 min. Peak brain cholinesterase inhibition was also detected between 5 and 30 min of the pesticide administration, but the half-life for enzyme activity recovery was much shorter, in the range of 85 min. Within this same time interval of the enzyme effects, diminished motor and exploratory activities and decreased performance of animals in the active avoidance task were observed. Likewise, behavioral normalization after propoxur followed a time frame similar to that of brain cholinesterase. These data indicate that behavioral changes that occur during intoxication with low oral doses of propoxur may be dissociated from signs characteristic of cholinergic over-stimulation but accompany brain cholinesterase activity inhibition.

  2. Acetylcholine receptors and sodium channels in denervated and botulinum-toxin-treated adult rat muscle.

    PubMed Central

    Bambrick, L; Gordon, T

    1987-01-01

    1. The number of acetylcholine (ACh) receptors and Na channels was measured in adult rat hind-limb muscles after denervation or injection of botulinum toxin type A (BoTX), using specific binding of radiolabelled neurotoxins. 2. Denervation by sciatic nerve section increased the number of [125I]iodo-alpha-bungarotoxin ([125I]BTX) binding sites from low, unmeasurable levels to 39 +/- 3 fmol of toxin bound per milligram muscle protein at 21 days. 3. Subcutaneous injection of BoTX produced complete neuromuscular blockade for 11-14 days over which time the number of [125I]BTX binding sites increased with the same time course and to the same extent as following denervation. 4. Neither denervation nor BoTX treatment significantly altered the number of tritiated saxitoxin ([3H]STX) binding sites from normal values of 7.8 fmol/mg muscle weight or 57 +/- 3 fmol/mg homogenate protein. This may, however, correspond to a lower density of [3H]STX sites in the muscle membrane. 5. It was concluded that neuromuscular blockade with BoTX is equivalent to denervation in its effects on synthesis of ACh receptors. Numbers of Na channels are more stable than ACh receptors but may also be modulated by neuromuscular activity. PMID:2442368

  3. Protective effect of vitamin E on sperm motility and oxidative stress in valproic acid treated rats.

    PubMed

    Ourique, Giovana M; Saccol, Etiane M H; Pês, Tanise S; Glanzner, Werner G; Schiefelbein, Sun Hee; Woehl, Viviane M; Baldisserotto, Bernardo; Pavanato, Maria A; Gonçalves, Paulo B D; Barreto, Kátia P

    2016-09-01

    Long-term administration of valproic acid (VPA) is known to promote reproductive impairment mediated by increase in testicular oxidative stress. Vitamin E (VitE) is a lipophilic antioxidant known to be essential for mammalian spermatogenesis. However, the capacity of this vitamin to abrogate the VPA-mediated oxidative stress has not yet been assessed. In the current study, we evaluated the protective effect of VitE on functional abnormalities related to VPA-induced oxidative stress in the male reproductive system. VPA (400 mg kg(-1)) was administered by gavage and VitE (50 mg kg(-1)) intraperitoneally to male Wistar rats for 28 days. Analysis of spermatozoa from the cauda epididymides was performed. The testes and epididymides were collected for measurement of oxidative stress biomarkers. Treatment with VPA induced a decrease in sperm motility accompanied by an increase in oxidative damage to lipids and proteins, depletion of reduced glutathione and a decrease in total reactive antioxidant potential on testes and epididymides. Co-administration of VitE restored the antioxidant potential and prevented oxidative damage on testes and epididymides, restoring sperm motility. Thus, VitE protects the reproductive system from the VPA-induced damage, suggesting that it may be a useful compound to minimize the reproductive impairment in patients requiring long-term treatment with VPA.

  4. Protective effect of vitamin E on sperm motility and oxidative stress in valproic acid treated rats.

    PubMed

    Ourique, Giovana M; Saccol, Etiane M H; Pês, Tanise S; Glanzner, Werner G; Schiefelbein, Sun Hee; Woehl, Viviane M; Baldisserotto, Bernardo; Pavanato, Maria A; Gonçalves, Paulo B D; Barreto, Kátia P

    2016-09-01

    Long-term administration of valproic acid (VPA) is known to promote reproductive impairment mediated by increase in testicular oxidative stress. Vitamin E (VitE) is a lipophilic antioxidant known to be essential for mammalian spermatogenesis. However, the capacity of this vitamin to abrogate the VPA-mediated oxidative stress has not yet been assessed. In the current study, we evaluated the protective effect of VitE on functional abnormalities related to VPA-induced oxidative stress in the male reproductive system. VPA (400 mg kg(-1)) was administered by gavage and VitE (50 mg kg(-1)) intraperitoneally to male Wistar rats for 28 days. Analysis of spermatozoa from the cauda epididymides was performed. The testes and epididymides were collected for measurement of oxidative stress biomarkers. Treatment with VPA induced a decrease in sperm motility accompanied by an increase in oxidative damage to lipids and proteins, depletion of reduced glutathione and a decrease in total reactive antioxidant potential on testes and epididymides. Co-administration of VitE restored the antioxidant potential and prevented oxidative damage on testes and epididymides, restoring sperm motility. Thus, VitE protects the reproductive system from the VPA-induced damage, suggesting that it may be a useful compound to minimize the reproductive impairment in patients requiring long-term treatment with VPA. PMID:27424124

  5. Krill Oil Ameliorates Mitochondrial Dysfunctions in Rats Treated with High-Fat Diet.

    PubMed

    Ferramosca, Alessandra; Conte, Annalea; Zara, Vincenzo

    2015-01-01

    In recent years, several studies focused their attention on the role of dietary fats in the pathogenesis of hepatic steatosis. It has been demonstrated that a high-fat diet is able to induce hyperglycemia, hyperinsulinemia, obesity, and nonalcoholic fatty liver disease. On the other hand, krill oil, a novel dietary supplement of n-3 PUFAs, has the ability to improve lipid and glucose metabolism, exerting possible protective effects against hepatic steatosis. In this study we have investigated the effects of krill oil on mitochondrial energetic metabolism in animals fed a high-fat diet. To this end, male Sprague-Dawley rats were divided into three groups and fed for 4 weeks with a standard diet (control group), a diet with 35% fat (HF group), or a high-fat diet supplemented with 2.5% krill oil (HF+KO group). The obtained results suggest that krill oil promotes the burning of fat excess introduced by the high-fat diet. This effect is obtained by stimulating mitochondrial metabolic pathways such as fatty acid oxidation, Krebs cycle, and respiratory chain complexes activity. Modulation of the expression of carrier proteins involved in mitochondrial uncoupling was also observed. Overall, krill oil counteracts the negative effects of a high-fat diet on mitochondrial energetic metabolism.

  6. Krill Oil Ameliorates Mitochondrial Dysfunctions in Rats Treated with High-Fat Diet

    PubMed Central

    Ferramosca, Alessandra; Conte, Annalea; Zara, Vincenzo

    2015-01-01

    In recent years, several studies focused their attention on the role of dietary fats in the pathogenesis of hepatic steatosis. It has been demonstrated that a high-fat diet is able to induce hyperglycemia, hyperinsulinemia, obesity, and nonalcoholic fatty liver disease. On the other hand, krill oil, a novel dietary supplement of n-3 PUFAs, has the ability to improve lipid and glucose metabolism, exerting possible protective effects against hepatic steatosis. In this study we have investigated the effects of krill oil on mitochondrial energetic metabolism in animals fed a high-fat diet. To this end, male Sprague-Dawley rats were divided into three groups and fed for 4 weeks with a standard diet (control group), a diet with 35% fat (HF group), or a high-fat diet supplemented with 2.5% krill oil (HF+KO group). The obtained results suggest that krill oil promotes the burning of fat excess introduced by the high-fat diet. This effect is obtained by stimulating mitochondrial metabolic pathways such as fatty acid oxidation, Krebs cycle, and respiratory chain complexes activity. Modulation of the expression of carrier proteins involved in mitochondrial uncoupling was also observed. Overall, krill oil counteracts the negative effects of a high-fat diet on mitochondrial energetic metabolism. PMID:26301251

  7. [Mutagenicity of the urine of rats treated with benzidine dyes (author's transl)].

    PubMed

    Tanaka, K

    1980-05-01

    Today industrial use of benzidine is restricted in many countries. However, little attention is paid to those substances which may decompose themselves in the body and release benzidine or benzidine-like substances. I investigated the mutagenicity of urinary ingredients of rats to which benzidine and three kinds of azo dyes were separately administered through the alimentary tract. The azo dyes were Direct Black EX(EX), Direct Green BK(BK), and Direct Bordeaux BK(BK), all having 4,4'-diazobiphenyl group in each structure. The mutagenicity of the urine extract with ether was tested on Salmonella typhimurium TA 98 and TA 100. Urinary metabolites of benzidine showed stronger mutagenicity than benzidine itself on both TA 98 and TA 100 in the presence of S9 mix. EX itself showed mutagenicity only on TA 98, whereas B and BK were nonmutagens. Nevertheless, the urine extract of each azo dye showed strong mutagenicity of the same pattern as benzidine. As a result it is suggested that benzidine might be released in the intestine of experimental animals after the administration of each azo dye. Mutagenic activity of urine sample is important and full of suggestions from the viewpoint of carcinogenicity of aromatic amines.

  8. EFFECTS OF ACUTE EXPOSURE TO CONCENTRATED AMBIENT PARTICULATES ON CARDIOPULMONARY, THERMOREGULATORY, AND BIOCHEMICAL PARAMETERS HEALTHY AND MONOCROTALINE-TREATED SPRAGUE-DAWLEY RATS

    EPA Science Inventory


    EFFECTS OF ACUTE EXPOSURE TO CONCENTRATED AMBIENT PARTICULATES ON CARDIOPULMONARY, THERMOREGULATORY, AND BIOCHEMICAL PARAMETERS IN HEALTHY AND MONOCROTALINE-TREATED SPRAGUE-DAWLEY RATS. LB Wichers1, JP Nolan2, DW Winsett2, UP Kodavanti2, MCJ Schladweiler2, DL Costa2, and WP ...

  9. EFFECTS OF EXPOSURE TO CONCENTRATED AMBIENT PARTICULATES ON INDICES OF CARDIOPULMONARY AND THERMOREGULATORY FUNCTION IN HEALTHY AND MONOCROTALINE-TREATED SPRAGUE-DAWLEY RATS

    EPA Science Inventory


    EFFECTS OF EXPOSURE TO CONCENTRATED AMBIENT PARTICULATES ON INDICES OF CARDIOPULMONARY AND THERMOREGULATORY FUNCTION IN HEALTHY AND MONOCROTALINE-TREATED SPRAGUE-DAWLEY RATS. LB Wichers1, JP Nolan2, UP Kodavanti2, MCJ Schladweiler2, DW Winsett2, DL Costa2, and WP Watkinson2....

  10. Potent and Selective Inhibitors of Long Chain l-2-Hydroxy Acid Oxidase Reduced Blood Pressure in DOCA Salt-Treated Rats

    PubMed Central

    2011-01-01

    l-2-Hydroxy acid oxidase (Hao2) is a peroxisomal enzyme with predominant expression in the liver and kidney. Hao2 was recently identified as a candidate gene for blood pressure quantitative trait locus in rats. To investigate a pharmacological role of Hao2 in the management of blood pressure, selective Hao2 inhibitors were developed. Optimization of screening hits 1 and 2 led to the discovery of compounds 3 and 4 as potent and selective rat Hao2 inhibitors with pharmacokinetic properties suitable for in vivo studies in rats. Treatment with compound 3 or 4 resulted in a significant reduction or attenuation of blood pressure in an established or developing model of hypertension, deoxycorticosterone acetate-treated rats. This is the first report demonstrating a pharmacological benefit of selective Hao2 inhibitors in a relevant model of hypertension. PMID:24900281

  11. The Protective Effect of γ-aminobutyric Acid on Kidney Injury Induced by Renal Ischemia-reperfusion in Ovariectomized Estradiol-treated Rats

    PubMed Central

    Talebi, Nahid; Nematbakhsh, Mehdi; Monajemi, Ramesh; Mazaheri, Safoora; Talebi, Ardeshir; Vafapour, Marzieh

    2016-01-01

    Background: Renal ischemia-reperfusion injury (IRI) is one of the most important causes of kidney injury, which is possibly gender-related. This study was designed to investigate the role of γ-aminobutyric acid (GABA) against IRI in ovariectomized estradiol-treated rats. Methods: Thirty-five ovariectomized Wistar rats were used in six experimental groups. The first three groups did not subject to estradiol treatment and assigned as sham-operated, control, and GABA-treated groups. GABA (50 μmol/kg) and saline were injected in the treated and control groups 30 min before the surgery, respectively. The second three groups received the same treatments but received estradiol valerate (500 μg/kg, intramuscularly) 3 days prior to the surgery. The IRI was induced in the control and treated groups by clamping the renal artery for 45 min and then 24 h of reperfusion. All animals were sacrificed for the measurements. Results: The serum levels of creatinine and blood urea nitrogen, kidney weight, and kidney tissue damage score significantly increased in the IRI rats (P < 0.05). GABA significantly decreased the aforementioned parameters (P < 0.05). The uterus weight increased significantly in rats that received estradiol (P < 0.05). Serum and kidney levels of nitrite (nitric oxide metabolite) did not alter significantly. Serum level of malondialdehyde increased significantly in the ovariectomized rats exposed to IRI (P < 0.05). Conclusions: It seems that GABA improved IRI in ovariectomized rats. Estradiol was also nephroprotective against IRI. However, co-administration of estradiol and GABA could not protect the kidney against IRI. PMID:26941907

  12. Monensin Improves the Effectiveness of meso-Dimercaptosuccinate when Used to Treat Lead Intoxication in Rats

    PubMed Central

    Hamidinia, Shawn A.; Erdahl, Warren L.; Chapman, Clifford J.; Steinbaugh, Gregory E.; Taylor, Richard W.; Pfeiffer, Douglas R.

    2006-01-01

    Among divalent cations, the ionophore monensin shows high activity and selectivity for the transport of lead ions (Pb2+) across phospholipid membranes. When coadministered to rats that were receiving meso-dimercaptosuccinate for treatment of Pb intoxication, monensin significantly increased the amount of Pb removed from femur, brain, and heart. It showed a tendency to increase Pb removal from liver and kidney but had no effect of this type in skeletal muscle. Tissue levels of several physiologic (calcium, cobalt, copper, iron, magnesium, manganese, molybdenum, zinc) and nonphysiologic (arsenic, cadmium, chromium, nickel, strontium) elements were also determined after the application of these compounds. Among the physiologic elements, a number of significant changes were seen, including both rising and falling values. The size of these changes was typically around 20% compared with control values, with the largest examples seen in femur. These changes often tended to reverse those of similar size that had occurred during Pb administration. Among the nonphysiologic elements, which were present in trace amounts, the changes were smaller in number but larger in size. None of these changes appears likely to be significant in terms of toxicity, and there were no signs of overt toxicity under any of the conditions employed. Monensin may act by cotransporting Pb2+ and OH– ions out of cells, in exchange for external sodium ions. The net effect would be to shuttle intracellular Pb2+ to extracellular dimercaptosuccinic acid thereby enhancing its effectiveness. Thus, monensin may be useful for the treatment of Pb intoxication when applied in combination with hydrophilic Pb2+ chelators. PMID:16581534

  13. DNA breakage in asbestos-treated normal and transformed (TSV40) rat pleural mesothelial cells.

    PubMed

    Levresse, V; Renier, A; Levy, F; Broaddus, V C; Jaurand, M

    2000-05-01

    Asbestos has been shown to induce cell cycle arrest, DNA repair and some abnormalities consistent with DNA damage but not DNA breakage. The purpose of the study was to investigate DNA breakage in asbestos-exposed rat pleural mesothelial cells (RPMC). RPMC were compared with their transformed counterparts, RPMC-TSV40 (i.e. p53-inactivated by infection with a retroviral recombinant encoding the SV40 large T antigen), as in the latter cells the cell cycle does not arrest and DNA repair is deficient due to ineffective p53-dependent cell cycle control. RPMC and RPMC-TSV40 were exposed to chrysotile and crocidolite asbestos and also to camptothecin for comparison. The presence of DNA breakage was determined using the single cell gel (Comet) assay with alkaline electrophoresis and quantified by measuring comet tail length (TL) and the percentage of total DNA in the tail and calculating tail moment (TM). We found that comets were generated by both types of asbestos in RPMC and in RPMC-TSV40 as well as by camptothecin in RPMC. On a per weight basis, chrysotile induced more abnormalities in comet parameters than did crocidolite. The comet TL and TM increased with fibre concentration, although less so with crocidolite than with chrysotile. When exposed to chrysotile at similar concentrations, RPMC consistently showed more abnormal comet parameters than did RPMC-TSV40. We concluded that asbestos causes DNA breakage and suggest that some of the DNA breakage measured was due to repair mechanisms in the normal RPMC. PMID:10792017

  14. Antioxidant activities of celery and parsley juices in rats treated with doxorubicin.

    PubMed

    Kolarovic, Jovanka; Popovic, Mira; Zlinská, Janka; Trivic, Svetlana; Vojnovic, Matilda

    2010-09-03

    We have examined the influence of diluted pure celery and parsley leaf and root juices and their combinations with doxorubicin on the antioxidant status [as measured by the content of reduced glutathione (GSH) and ferric reducing antioxidant power (FRAP)] in liver homogenate and hemolysate and on the contents of cytochrome P450 in liver homogenate. It was found that doxorubicin significantly decreased the content of reduced glutathione and the total antioxidative status (FRAP) in liver homogenate and hemolysate, while celery and parsley juices alone and in combination with doxorubicin had different actions. Doxorubicin and celery juice had no effect on content of cytochrome P450. However, in combination with doxorubicin, parsley root juice significant increased, and parsley leaves juice decreased the cytochrome P450 content (compared to doxorubicin treated animals). Only parsley root juice significantly increased the content of cytochrome P450.

  15. Blueberry treatment attenuated cirrhotic and preneoplastic lesions and oxidative stress in the liver of diethylnitrosamine-treated rats.

    PubMed

    Bingül, İlknur; Başaran-Küçükgergin, Canan; Aydın, A Fatih; Soluk-Tekkeşin, Merva; Olgaç, Vakur; Doğru-Abbasoğlu, Semra; Uysal, Müjdat

    2016-09-01

    Diethylnitrosamine (DEN)-induced liver cancer normally develops in stages that progress from cirrhosis and carcinoma. Increased oxidative stress is suggested to play a role in DEN-induced carcinogenicity. Blueberries (BB) contain high antioxidant capacity. We investigated the effect of BB supplementation on development of DEN-induced cirrhosis and neoplastic lesions in the liver. Rats were injected with DEN (200 mg/kg; i.p.) three times with an interval of 15 days at 4, 6, and 8 weeks and sacrificed 8 weeks after the last DEN injection. They were also fed on 8% BB (w/w) containing chow for 16 weeks. Hepatic damage markers in serum were determined together with hepatic histopathological examinations. Hydroxyproline (HYP), malondialdehyde (MDA), diene conjugate (DC), protein carbonyl (PC), and glutathione (GSH) levels, and CuZn-superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities, and their mRNA expressions were measured. Protein and mRNA expressions of glutathione transferase-pi (GST-pi) were evaluated as a marker of preneoplastic lesions. BB supplementation decreased hepatic damage markers in serum and hepatic MDA, DC, and PC levels, but SOD, CAT, and GSH-Px activities and their mRNA expressions remained unchanged in DEN-treated rats. BB attenuated cirrhotic changes and decreased hepatic HYP levels and GST-pi expressions. Our results indicate that BB is effective in decreasing development of DEN-induced hepatic cirrhosis and preneoplastic lesions by acting as an antioxidant (radical scavenger) itself without affecting activities and mRNA expressions of antioxidant enzymes. PMID:26684621

  16. [The mechanism of potentiation of the antitumor effect of 5-fluorouracil by methionine-free intravenous amino acid solution (AO-90) in rats].

    PubMed

    Hibino, Y; Kawarabayashi, Y; Kohri, H; Ueda, N; Tsukagoshi, S

    1994-09-01

    AO-90, a methionine-free intravenous amino acid solution (7.43%) showed to potentiate the antitumor effect of 5-fluorouracil (5-FU) when concomitantly used as the nitrogen source in total parenteral nutrition (TPN) in Yoshida sarcoma (YS)-bearing rats. In the present experiment, this potentiation mechanism was studied by determining the serum methionine level and tumor methylenetetrahydrofolate (CH2FH4) content in YS-bearing Donryu rats given AO-90 (nitrogen 0.73g/kg on the 1st day and 1.46g/kg for the remaining 6 days) by TPN for 1 week. The rats were subcutaneously inoculated with 10(4) YS cells in the dorsum 3 days before the start of TPN. Inhibition of thymidylate synthase activity in tumor tissue after dosing of AO-90 (nitrogen 0.68g/kg on the 1st day and 1.36 g/kg for the remaining 6 days) by TPN along with daily intraperitoneal dosing of 5-FU (10 mg/kg) was also evaluated with the inoculation of 10(6) tumor cells. The results were compared with those in tumor-bearing rats given TPN with a commercially available amino acid solution containing methionine. On day 5 of TPN, the tumor-bearing rats given AO-90 showed a significantly lower serum methionine level than the control rats: 101 +/- 11 mumol/l versus 29 +/- 14 mumol/l (p < 0.01); and a higher CH2FH4 content in tumor: 7.0 +/- 2.8 pmol/g protein versus 23.7 +/- 16.6 pmol/g protein (p < 0.05). Thymidylate synthase inhibition was 81.2 +/- 5.1% in the AO-90 group and 30.9 +/- 26.3% in the control group (p < 0.01). The results of the present study suggest that AO-90 potentiate the antitumor effect of 5-FU by biochemical modulation. AO-90 concomitantly given with 5-FU for 7 days was effective not only in the allogeneic tumor model, but also in WKAH and SHR rats previously inoculated with 10(6) of syngeneic KDH-8 hepatoma cells and SST-2 adenocarcinoma cells, respectively. Weight of SST-2 adenocarcinoma in SHR rats after the TPN period was significantly smaller in the AO-90 group than in the control rats given

  17. Effects of alendronate and strontium ranelate on cancellous and cortical bone mass in glucocorticoid-treated adult rats.

    PubMed

    Sun, P; Cai, D H; Li, Q N; Chen, H; Deng, W M; He, L; Yang, L

    2010-06-01

    We studied the effects of alendronate (Aln) and strontium ranelate (SrR) administration on cancellous and cortical bone in glucocorticoid (GC)-treated rats. Thirty-two 3.5-month male Sprague-Dawley rats were randomized into four groups: age-matched normal control (Nrm), methylprednisolone (Met; 5.0 mg/kg/day, sc, for 5 days/week), Met plus Aln orally (1.0 mg/kg/day), and Met plus SrR orally (900 mg/kg/day). The study period was 9 weeks. DXA was used to evaluate the femoral diaphysis and fifth lumbar vertebra (L5). Histomorphometry was performed in the proximal tibial metaphysis and tibial diaphysis. Met significantly decreased body weight and bone mineral density (BMD) compared with Nrm. Aln and SrR significantly increased body weight and BMD compared with Met. SrR resulted in significantly higher BMD than Aln. Met markedly decreased BV/TV, Tb.Th, and Tb.N and increased Tb.Sp compared with Nrm. Aln and SrR showed significantly increased of BV/TV, Tb.Th, and Tb.N and improved bone architecture. Moreover, Met reduced %Ct.Ar, enlarged %Ma.Ar, and decreased bone formation indices in the periosteum as well as increased ES/BS in the endosteum compared with Nrm. Aln significantly decreased endosteal ES/BS compared with Met. SrR significantly increased %Ct.Ar and bone formation indices in the periosteum as well as the endosteum and decreased endosteal ES/BS compared with Met. Furthermore, SrR led to a significantly higher cancellous and endocortical MS/BS and endocortical bone formation compared with Aln. Our findings suggest SrR at a dose of 900 mg/kg has a greater effect than Aln at 1.0 mg/kg, according to BMD and histomorphometric analysis, in preventing GC-induced osteopenia. Therefore, SrR might be applicable as a bone therapeutic agent to treat secondary osteoporosis in the clinic. PMID:20390406

  18. Improvement in nutrient handling in STZ induced diabetic rats treated with Ocimum gratissimum

    PubMed Central

    Okon, Uduak Akpan; Davies, Koofreh Godwin; Olubobokun, Titilope Helen

    2015-01-01

    Objective: Alteration in digestive and absorptive enzymatic activities has been reported in diabetes mellitus (DM), but not with Ocimum gratissimum (OG) treatment. This study was, therefore, designed to indirectly assess the effect of DM and treatment with OG on nutrient digestion and absorption, through estimation of their fecal excretion. Materials and Methods: Animals were randomly assigned into three groups of six per group for control, DM and diabetic mellitus treated (DMT). Diabetes was induced by single intraperitoneal injection of 65 mg/kg streptozotocin in the test groups. OG was administered to the DMT group at dose of 1500 mg/kg once daily for 28 days. Fecal glucose, protein and cholesterol were determined. Results: Fecal glucose was significantly (P < 0.001) lower in the DM group compared to the control and DMT groups, with the DMT groups significantly (P < 0.001) lower than the control. Fecal protein was significantly (P < 0.001) lower in the DM group than the control whereas it was significantly lower in the DMT groups than the DM. Fecal cholesterol was significantly (P < 0.001) higher in the DM than the DMT and control groups with DMT significantly (P < 0.01) higher than the control. Conclusion: This result indicates the propensity of OG to reverse impairment of nutrient digestion and absorption in DM. PMID:25664269

  19. Changes in Iron Metabolism and Oxidative Status in STZ-Induced Diabetic Rats Treated with Bis(maltolato) Oxovanadium (IV) as an Antidiabetic Agent

    PubMed Central

    Sánchez-González, Cristina; López-Chaves, Carlos; Trenzado, Cristina E.; Aranda, Pilar; López-Jurado, María; Gómez-Aracena, Jorge; Montes-Bayón, María; Sanz-Medel, Alfredo; Llopis, Juan

    2014-01-01

    The role of vanadium as a micronutrient and hypoglycaemic agent has yet to be fully clarified. The present study was undertaken to investigate changes in the metabolism of iron and in antioxidant defences of diabetic STZ rats following treatment with vanadium. Four groups were examined: control; diabetic; diabetic treated with 1 mgV/day; and Diabetic treated with 3 mgV/day. The vanadium was supplied in drinking water as bis(maltolato) oxovanadium (IV) (BMOV). The experiment had a duration of five weeks. Iron was measured in food, faeces, urine, serum, muscle, kidney, liver, spleen, and femur. Superoxide dismutase, catalase, NAD(P)H: quinone-oxidoreductase-1 (NQO1) activity, and protein carbonyl group levels in the liver were determined. In the diabetic rats, higher levels of Fe absorbed, Fe content in kidney, muscle, and femur, and NQO1 activity were recorded, together with decreased catalase activity, in comparison with the control rats. In the rats treated with 3 mgV/day, there was a significant decrease in fasting glycaemia, Fe content in the liver, spleen, and heart, catalase activity, and levels of protein carbonyl groups in comparison with the diabetic group. In conclusion BMOV was a dose-dependent hypoglycaemic agent. Treatment with 3 mgV/day provoked increased Fe deposits in the tissues, which promoted a protein oxidative damage in the liver. PMID:24511298

  20. Alterations of the renal function and oxidative stress in renal tissue from rats chronically treated with aluminium during the initial phase of hepatic regeneration.

    PubMed

    Mahieu, Stella; Millen, Néstor; González, Marcela; Contini, María del Carmen; Elías, María Mónica

    2005-09-01

    Various indices of renal functions during the early stage of hepatic injury were studied in rats chronically treated with aluminum (Al) lactate. Tubular and hemodynamic parameters were analyzed four days after producing a 65% partial hepatectomy (PH). Water and sodium balances were also studied. Oxidative stress and the activity of Na-K-ATPase were determined in renal tissue. The rats were distributed in four groups: control, Al, PH, Al+PH. Al did not modify the hemodynamic renal functions and the PH-group reduced the glomerular filtrate rate (GFR). The Al + PH group presented a decrease in the renal blood flow and accentuated the GFR fall as compared with PH. The fractional excretion (FE) of water and sodium increased in the PH group. The rats chronically treated with Al and then submitted to the PH protocol developed a further increase in FE of water but a reduction in FE of sodium. Both PH and Al promoted an increase in the aldosterone. PH and Al induced a similar increase of the lipoperoxidation status with reduction of glutathione (GSH) and the activity of glutathione peroxidase (GSH-Px). The data indicated that Al is an inhibitor of catalase. The GSH and GSH-Px activity in the Al + PH group demonstrated a synergic effect of Al and PH. This work demonstrates that rats treated chronically with Al and submitted to another injury (such as hepatic damage) can aggravate renal functions, probably by increasing the oxidative state, at least in kidneys. PMID:16129492

  1. Amelioration Effect of Zinc and Iron Supplementation on Selected Oxidative Stress Enzymes in Liver and Kidney of Cadmium-Treated Male Albino Rat

    PubMed Central

    Jamakala, Obaiah; Rani, Usha A.

    2015-01-01

    Cadmium (Cd) is a highly toxic, nonessential heavy metal with many industrial uses that can contribute to a well-defined spectrum of diseases in animals as well as in humans. The present study examines the effect of zinc (Zn) and iron (Fe) supplementation on oxidative stress enzymes in Cd-treated rats. Wistar strain male albino rats were treated with cadmium chloride (CdCl2) at a dose of 1/10th LD50/48 h, that is, 22.5 mg/kg body weight for 7, 15, and 30 days (d) time intervals. The 15d Cd-treated rats were divided into three groups. The first group received Zn (12 mg/kg), second group Fe (40 mg/kg) alone, and third group supplemented with both Zn and Fe and observed for 7, 15, and 30d. After the specific time intervals, rats were decapitated and oxidative stress enzymes like catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione S-transferase (GST) were assayed in liver and kidney. Simultaneously lipid peroxidation (LPO) levels were also measured. A significant elevation in LPO levels with decreased activity levels of CAT, SOD, GPx, and GST were observed during Cd intoxication. With Zn and/or Fe supplementation, a significant reversal in the oxidative stress enzymes was observed. Our study reveals that combination of Zn and Fe supplementation is effective in detoxifying the Cd body burden from the test tissues. PMID:26862254

  2. Amelioration Effect of Zinc and Iron Supplementation on Selected Oxidative Stress Enzymes in Liver and Kidney of Cadmium-Treated Male Albino Rat.

    PubMed

    Jamakala, Obaiah; Rani, Usha A

    2015-01-01

    Cadmium (Cd) is a highly toxic, nonessential heavy metal with many industrial uses that can contribute to a well-defined spectrum of diseases in animals as well as in humans. The present study examines the effect of zinc (Zn) and iron (Fe) supplementation on oxidative stress enzymes in Cd-treated rats. Wistar strain male albino rats were treated with cadmium chloride (CdCl2) at a dose of 1/10(th) LD50/48 h, that is, 22.5 mg/kg body weight for 7, 15, and 30 days (d) time intervals. The 15d Cd-treated rats were divided into three groups. The first group received Zn (12 mg/kg), second group Fe (40 mg/kg) alone, and third group supplemented with both Zn and Fe and observed for 7, 15, and 30d. After the specific time intervals, rats were decapitated and oxidative stress enzymes like catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione S-transferase (GST) were assayed in liver and kidney. Simultaneously lipid peroxidation (LPO) levels were also measured. A significant elevation in LPO levels with decreased activity levels of CAT, SOD, GPx, and GST were observed during Cd intoxication. With Zn and/or Fe supplementation, a significant reversal in the oxidative stress enzymes was observed. Our study reveals that combination of Zn and Fe supplementation is effective in detoxifying the Cd body burden from the test tissues.

  3. Alterations of the renal function and oxidative stress in renal tissue from rats chronically treated with aluminium during the initial phase of hepatic regeneration.

    PubMed

    Mahieu, Stella; Millen, Néstor; González, Marcela; Contini, María del Carmen; Elías, María Mónica

    2005-09-01

    Various indices of renal functions during the early stage of hepatic injury were studied in rats chronically treated with aluminum (Al) lactate. Tubular and hemodynamic parameters were analyzed four days after producing a 65% partial hepatectomy (PH). Water and sodium balances were also studied. Oxidative stress and the activity of Na-K-ATPase were determined in renal tissue. The rats were distributed in four groups: control, Al, PH, Al+PH. Al did not modify the hemodynamic renal functions and the PH-group reduced the glomerular filtrate rate (GFR). The Al + PH group presented a decrease in the renal blood flow and accentuated the GFR fall as compared with PH. The fractional excretion (FE) of water and sodium increased in the PH group. The rats chronically treated with Al and then submitted to the PH protocol developed a further increase in FE of water but a reduction in FE of sodium. Both PH and Al promoted an increase in the aldosterone. PH and Al induced a similar increase of the lipoperoxidation status with reduction of glutathione (GSH) and the activity of glutathione peroxidase (GSH-Px). The data indicated that Al is an inhibitor of catalase. The GSH and GSH-Px activity in the Al + PH group demonstrated a synergic effect of Al and PH. This work demonstrates that rats treated chronically with Al and submitted to another injury (such as hepatic damage) can aggravate renal functions, probably by increasing the oxidative state, at least in kidneys.

  4. Amelioration Effect of Zinc and Iron Supplementation on Selected Oxidative Stress Enzymes in Liver and Kidney of Cadmium-Treated Male Albino Rat.

    PubMed

    Jamakala, Obaiah; Rani, Usha A

    2015-01-01

    Cadmium (Cd) is a highly toxic, nonessential heavy metal with many industrial uses that can contribute to a well-defined spectrum of diseases in animals as well as in humans. The present study examines the effect of zinc (Zn) and iron (Fe) supplementation on oxidative stress enzymes in Cd-treated rats. Wistar strain male albino rats were treated with cadmium chloride (CdCl2) at a dose of 1/10(th) LD50/48 h, that is, 22.5 mg/kg body weight for 7, 15, and 30 days (d) time intervals. The 15d Cd-treated rats were divided into three groups. The first group received Zn (12 mg/kg), second group Fe (40 mg/kg) alone, and third group supplemented with both Zn and Fe and observed for 7, 15, and 30d. After the specific time intervals, rats were decapitated and oxidative stress enzymes like catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione S-transferase (GST) were assayed in liver and kidney. Simultaneously lipid peroxidation (LPO) levels were also measured. A significant elevation in LPO levels with decreased activity levels of CAT, SOD, GPx, and GST were observed during Cd intoxication. With Zn and/or Fe supplementation, a significant reversal in the oxidative stress enzymes was observed. Our study reveals that combination of Zn and Fe supplementation is effective in detoxifying the Cd body burden from the test tissues. PMID:26862254

  5. Nitric oxide-related cyclic GMP-independent relaxing effect of N-acetylcysteine in lipopolysaccharide-treated rat aorta

    PubMed Central

    Muller, Bernard; Kleschyov, Andrei L; Malblanc, Sophie; Stoclet, Jean-Claude

    1998-01-01

    We have recently demonstrated the formation of protein-bound dinitrosyl-iron complexes (DNIC) in rat aortic rings exposed to lipopolysaccharide (LPS) and shown that N-acetylcysteine (NAC) can promote vasorelaxation in these arteries, possibly via the release of nitric oxide (NO) as low molecular weight DNIC from these storage sites. The aim of the present study was to investigate further the mechanism of the relaxation induced by NAC in LPS-treated vessels.In rings incubated with LPS (10 μg ml−1 for 18 h) and precontracted with noradrenaline (NA, 3 μM) plus Nω-nitro-L-arginine methylester (L-NAME, 3 mM), the relaxation evoked by NAC (0.1 to 10 mM) was abolished by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 1 μM, a selective inhibitor of soluble guanylyl cyclase) but not affected by Rp-8-bromoguanosine 3′5′-cyclic monophosphorothioate (Rp-8BrcGMPS, 60 μM a selective inhibitor of cyclic GMP-dependent protein kinase). Tetrabutylammonium (TBA, 3 mM, as a non selective K+ channels blocker) or elevated concentration of external KCl (25 or 50 mM) significantly attenuated the NAC-induced relaxation. Selective K+ channels blockers (10 μM glibenclamide, 0.1 μM charybdotoxin, 0.5 μM apamin or 3 mM 4-aminopyridine) did not affect the NAC-induced relaxation. The relaxing effect of NAC (10 mM) was not associated with an elevation of guanosine 3′ : 5′ cyclic monophosphate (cyclic GMP) in LPS-treated rings.In aortic rings precontracted with NA (0.1 μM), low molecular weight DNIC (with thiosulphate as ligand, 1 nM to 10 μM) evoked a concentration-dependent relaxation which was antagonized by ODQ (1 μM) and Rp-8BrcGMPS (150 μM) but not significantly affected by TBA (3 mM) or by the use of KCl (50 mM) as preconstricting agent. The relaxation produced by DNIC (0.1 μM) was associated with an 11 fold increase in aortic cyclic GMP content, which was completely abolished by ODQ (1 μM).Taken together with

  6. Coenzyme Q10 remarkably improves the bio-energetic function of rat liver mitochondria treated with statins.

    PubMed

    Mohammadi-Bardbori, Afshin; Najibi, Asma; Amirzadegan, Najmeh; Gharibi, Raziyeh; Dashti, Ayat; Omidi, Mahmoud; Saeedi, Arastoo; Ghafarian-Bahreman, Ali; Niknahad, Hossein

    2015-09-01

    CoQ10 shares a biosynthetic pathway with cholesterol therefore it can be a potential target of the widely available lipid-lowering agents such as statins. Statins are the most widely prescribed cholesterol-lowering drugs with the ability to inhibit HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase. Preclinical and clinical safety data have shown that statins do not cause serious adverse effects in humans. However, their long-term administration is associated with a variety of myopatic complaints. The aim of this study was to investigate whether CoQ10 supplementation of animals under high fat diet (HFD) treated with statins is able to bypass the mitochondrial metabolic defects or not? Animals were divided into 7 groups and fed with either regular (RD) or HFD during experiments. The first group considered as regular control and fed with a RD. Groups 2-7 including HFD control, CoQ10 (10mg/kg), simvastatin (30mg/kg), atorvastatin (30mg/kg), simvastatin+CoQ10 or atorvastatin+CoQ10 treated orally for 30 days and fed with HFD. At the end of treatments, the animals were killed and blood samples were collected for biochemical examinations. The rat liver mitochondria were isolated and several mitochondrial indices including succinate dehydrogenase activity (SDA), ATP levels, mitochondrial membrane potential (MMP) and mitochondrial permeability transition pore (MPP) were determined. We found that triglyceride (Tg), cholesterol (Chol) and low-density lipoprotein (LDL) were augmented with HFD compared to RD and treatment with statins remarkably lowered the Tg, Chol and LDL levels. Mitochondrial parameters including, SDA, ATP levels, MMP and MPP were reduced with statin treatment and improved by co-administration with CoQ10. PMID:26007644

  7. Coenzyme Q10 remarkably improves the bio-energetic function of rat liver mitochondria treated with statins.

    PubMed

    Mohammadi-Bardbori, Afshin; Najibi, Asma; Amirzadegan, Najmeh; Gharibi, Raziyeh; Dashti, Ayat; Omidi, Mahmoud; Saeedi, Arastoo; Ghafarian-Bahreman, Ali; Niknahad, Hossein

    2015-09-01

    CoQ10 shares a biosynthetic pathway with cholesterol therefore it can be a potential target of the widely available lipid-lowering agents such as statins. Statins are the most widely prescribed cholesterol-lowering drugs with the ability to inhibit HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase. Preclinical and clinical safety data have shown that statins do not cause serious adverse effects in humans. However, their long-term administration is associated with a variety of myopatic complaints. The aim of this study was to investigate whether CoQ10 supplementation of animals under high fat diet (HFD) treated with statins is able to bypass the mitochondrial metabolic defects or not? Animals were divided into 7 groups and fed with either regular (RD) or HFD during experiments. The first group considered as regular control and fed with a RD. Groups 2-7 including HFD control, CoQ10 (10mg/kg), simvastatin (30mg/kg), atorvastatin (30mg/kg), simvastatin+CoQ10 or atorvastatin+CoQ10 treated orally for 30 days and fed with HFD. At the end of treatments, the animals were killed and blood samples were collected for biochemical examinations. The rat liver mitochondria were isolated and several mitochondrial indices including succinate dehydrogenase activity (SDA), ATP levels, mitochondrial membrane potential (MMP) and mitochondrial permeability transition pore (MPP) were determined. We found that triglyceride (Tg), cholesterol (Chol) and low-density lipoprotein (LDL) were augmented with HFD compared to RD and treatment with statins remarkably lowered the Tg, Chol and LDL levels. Mitochondrial parameters including, SDA, ATP levels, MMP and MPP were reduced with statin treatment and improved by co-administration with CoQ10.

  8. Bioinformatics investigation of therapeutic mechanisms of Xuesaitong capsule treating ischemic cerebrovascular rat model with comparative transcriptome analysis

    PubMed Central

    Liao, Jiangquan; Wei, Benjun; Chen, Hengwen; Liu, Yongmei; Wang, Jie

    2016-01-01

    Background: Xuesaitong soft capsule (XST) which consists of panax notoginseng saponin (PNS) has been used to treat ischemic cerebrovascular diseases in China. The therapeutic mechanism of XST has not been elucidated yet from prospective of genomics and bioinformatics. Methods: A transcriptome analysis was performed to review series concerning middle cerebral artery occlusion (MCAO) rat model and XST intervention after MCAO from Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were compared between blank group and model group, model group and XST group. Functional enrichment and pathway analysis were performed. Protein-Protein interaction network was constructed. The overlapping genes from two DEGs sets were screened out and profound analysis was performed. Results: Two series including 22 samples were obtained. 870 DEGs were identified between blank group and model group, and 1189 DEGs were identified between model group and XST group. GO terms and KEGG pathways of MCAO and XST intervention were significantly enriched. PPI networks were constructed to demonstrate the gene-gene interactions. The overlapping genes from two DEGs sets were highlighted. ANTXR2, FHL3, PRCP, TYROBP, TAF9B, FGFR2, BCL11B, RB1CC1 and MBNL2 were the pivotal genes and possible action sites of XST therapeutic mechanisms. Conclusion: MCAO is a pathological process with multiple. PMID:27347353

  9. Maternal immune activation produces neonatal excitability defects in offspring hippocampal neurons from pregnant rats treated with poly I:C

    PubMed Central

    Patrich, Eti; Piontkewitz, Yael; Peretz, Asher; Weiner, Ina; Attali, Bernard

    2016-01-01

    Maternal immune activation (MIA) resulting from prenatal exposure to infectious pathogens or inflammatory stimuli is increasingly recognized to play an important etiological role in neuropsychiatric disorders with neurodevelopmental features. MIA in pregnant rodents induced by injection of the synthetic double-stranded RNA, Poly I:C, a mimic of viral infection, leads to a wide spectrum of behavioral abnormalities as well as structural and functional defects in the brain. Previous MIA studies using poly I:C prenatal treatment suggested that neurophysiological alterations occur in the hippocampus. However, these investigations used only juvenile or adult animals. We postulated that MIA-induced alterations could occur earlier at neonatal/early postnatal stages. Here we examined the neurophysiological properties of cultured pyramidal-like hippocampal neurons prepared from neonatal (P0-P2) offspring of pregnant rats injected with poly I:C. Offspring neurons from poly I:C-treated mothers exhibited significantly lower intrinsic excitability and stronger spike frequency adaptation, compared to saline. A similar lower intrinsic excitability was observed in CA1 pyramidal neurons from hippocampal slices of two weeks-old poly I:C offspring. Cultured hippocampal neurons also displayed lower frequency of spontaneous firing, higher charge transfer of IPSCs and larger amplitude of miniature IPSCs. Thus, maternal immune activation leads to strikingly early neurophysiological abnormalities in hippocampal neurons. PMID:26742695

  10. In vitro and in vivo evaluation of cubosomes containing 5-fluorouracil for liver targeting

    PubMed Central

    Nasr, Mohamed; Ghorab, Mohamed K.; Abdelazem, Ahmed

    2014-01-01

    The objective of this study was to prepare cubosomal nanoparticles containing a hydrophilic anticancer drug 5-fluorouracil (5-FU) for liver targeting. Cubosomal dispersions were prepared by disrupting a cubic gel phase of monoolein and water in the presence of Poloxamer 407 as a stabilizer. Cubosomes loaded with 5-FU were characterized in vitro and in vivo. In vitro, 5-FU-loaded cubosomes entrapped 31.21% drug and revealed nanometer-sized particles with a narrow particle size distribution. In vitro 5-FU release from cubosomes exhibited a phase of rapid release of about half of the entrapped drug during the first hour, followed by a relatively slower drug release as compared to 5-FU solution. In vivo biodistribution experiments indicated that the cubosomal formulation significantly (P<0.05) increased 5-FU liver concentration, a value approximately 5-fold greater than that observed with a 5-FU solution. However, serum serological results and histopathological findings revealed greater hepatocellular damage in rats treated with cubosomal formulation. These results demonstrate the successful development of cubosomal nanoparticles containing 5-FU for liver targeting. However, further studies are required to evaluate hepatotoxicity and in vivo antitumor activity of lower doses of 5-FU cubosomal formulation in treatment of liver cancer. PMID:26579429

  11. m-Trifluoromethyl-diphenyldiselenide as a pharmacological tool to treat preference symptoms related to AMPH-induced dependence in rats.

    PubMed

    Segat, H J; Martini, F; Barcelos, R C S; Brüning, C A; Nogueira, C W; Burger, M E

    2016-04-01

    Amphetamine (AMPH) abuse is a world concern and a serious public health problem. Repeated administration of high doses of AMPH induces neuropsychiatric consequences, including addiction, reward and psychosis, whose pharmacological treatment has shown limited effectiveness. The m-trifluoromethyl-diphenyldiselenide [(m-CF3-PhSe)2] has been documented as a promising pharmacological agent in different animal models related to oxidative damage. In this study, we examined the influence of (m-CF3-PhSe)2 on withdrawal following re-exposure to AMPH. Wistar rats received d,l-AMPH or saline in the conditioned place preference (CPP) paradigm for 8days. Then, half of each initial (AMPH or saline) experimental group was treated with (m-CF3-PhSe)2 or vehicle, resulting in four final groups: i) Saline/vehicle; ii) (m-CF3-PhSe)2/saline; iii) AMPH/vehicle; and iv) AMPH/(m-CF3-PhSe)2. After fourteen days of (m-CF3-PhSe)2 treatment, animals were re-exposed to AMPH or vehicle in the CPP paradigm for three more days in order to assess drug re-conditioning and memory/locomotor activity, performed 24h after AMPH re-exposure in the CPP and the Y maze, respectively. Subsequently, ex-vivo assays were carried out in samples of the prefrontal cortex (PFC) of the animals. The (m-CF3-PhSe)2 treatment was able to prevent AMPH-induced re-conditioning symptoms in rats. Behavioral observations in the Y maze task showed no significant changes. AMPH exposure was able to increase 5-HT uptake as well as oxidative damage in the PFC, whereas (m-CF3-PhSe)2 treatment exerted a preventative effect against these alterations. The current findings suggest that (m-CF3-PhSe)2 might be considered a promising therapeutic tool for AMPH-induced addiction. PMID:26555614

  12. Hepatotoxicity or hepatoprotection? Pattern recognition for the paradoxical effect of the Chinese herb Rheum palmatum L. in treating rat liver injury.

    PubMed

    Wang, Jia-bo; Zhao, Hai-ping; Zhao, Yan-ling; Jin, Cheng; Liu, Dao-jian; Kong, Wei-jun; Fang, Fang; Zhang, Lin; Wang, Hong-juan; Xiao, Xiao-he

    2011-01-01

    The hepatotoxicity of some Chinese herbs has been a cause for concern in recent years. However, some herbs, such as rhubarb, have been documented as having both therapeutic and toxic effects on the liver, leading to the complex problem of distinguishing the benefits from the risks of using this herb. To comparatively analyze the dose-response relationship between rhubarb and hepatic health, we administrated total rhubarb extract (RE) to normal and carbon tetrachloride (CCl(4))-treated rats for 12 weeks at 4 dosage levels (2.00, 5.40, 14.69 and 40.00 g·kg(-1), measured as the quantity of crude material), followed by biochemical and histopathological tests of the rats' livers. A composite pattern was extracted by factor analysis, using all the biochemical indices as variables, into a visual representation of two mathematically obtained factors, which could be interpreted as the fibrosis factor and the cellular injury factor, according to the values of the variable loadings. The curative effect of administering the two lowest dosages of RE to CCl(4)-treated rats was mainly expressed as a decrease in the extent of cellular injury. The hepatoprotective mechanism of RE might be related to its antioxidant effect, the antagonism of the free radical damage to hepatocytes caused by CCl(4). By contrast, the RE-induced liver damage was mainly expressed as a significant increase in the amount of fibrosis in both normal rats at all dosage levels and CCl(4)-treated rats at the two highest dosage levels. Therefore, the hepatotoxic potential of RE could be attributable to the liver cell fibrosis induced by high doses of the herb. This study illustrates the bidirectional potential of rhubarb and demonstrates the feasibility of using factor analysis to study the dose-response relationships between herbal medicines and hepatotoxicity or the healing effects of these herbs by extracting the underlying interrelationships among a number of functional bio-indices in a holistic manner.

  13. Administration of microparticles from blood of the lipopolysaccharide-treated rats serves to induce pathologic changes of acute respiratory distress syndrome

    PubMed Central

    Li, Hongxia; Meng, Xiangyu; Liang, Xiaoyan; Gao, Yue

    2015-01-01

    This study was conducted to investigate the effect of intratracheal and intravenous administration of microparticles (MPs) on developing acute respiratory distress syndrome (ARDS). The blood MPs from lipopolysaccharide-treated rats were collected and examined by transmission electron microscopy (TEM). Cellular source of the MPs was identified by fluorescent-labeled antibodies after the circulating MPs were delivered to naïve rats. Levels of myeloperoxidase (MPO), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-10 productions in bronchoalveolar lavage fluid (BALF) and plasma were determined 24 h after the rats received intratracheal and intravenous administration of the MPs. Histopathologic examination of lungs was performed by light microscope. A TEM image of MPs showed spherical particles at a variable diameter from 0.1 to 0.5 µm. Endothelial- and leukocyte-derived vesicles were abundant in the investigated samples. Treatment with MPs may lead to significant increases in MPO, TNF-α, IL-1β, and IL-10 productions in BALF and plasma of the rats (all P < 0.001). Morphological observation indicated that alveolar structures were destroyed with a large amount of neutrophil infiltration in the lungs of the MP-treated rats. Perivascular and/or intra-alveolar hemorrhage were serious and hyaline membrane formed in the alveoli. Intratracheal and intravenous approaches to delivery of the circulating MPs to naïve recipient rats may induce ARDS. This presents an inducer of the onset of ARDS and provides potential therapeutic targets for attenuating lung injury. PMID:26088862

  14. Muscle protein turnover in rats treated with corticosterone (CC) or/and nandrolone decanoate (ND) and fed an adequate or a low-protein diet

    SciTech Connect

    Santidrian, S.; Cuevillas, F.; Goena, M.; Larralde, J.

    1986-03-01

    In order to investigate the possible antagonistic effect between glucocorticoids and androgens on muscle protein turnover, the authors have measured the fractional rates of gastrocnemius muscle protein synthesis (k/sub s/) and degradation (k/sub d/) by the constant-intravenous-infusion method using L-//sup 14/C/-tyrosine in rats receiving via s.c. per 100 g b.wt. 10 mg of CC, or 2 mg of ND or CC+ND at the indicated doses, and fed either an 18% or 5% protein diets over a period of 5 days. As an additional index of protein synthesis, RNA activity (g of synthesized protein/day/g RNA) was determined as well. Results showed that as compared to vehicle-injected animals fed the adequate diet, CC-treated rats exhibited a reduction of muscle k/sub d/, while ND-treated rats had an outstanding increase of muscle k/sub s/. However, rats receiving CC+ND showed k/sub s/ and k/sub d/ values similar to those displayed by control animals. Nevertheless, when the steroids were injected to rats fed the low-protein diet, CC has a catabolic effect on muscle protein but by reducing k/sub s/, while the anabolic action of ND is still displayed but by a significant reduction of muscle k/sub d/. CC+ND given to these protein-deficient rats caused an increase in muscle k/sub s/ and a reduction in k/sub d/. These results might indicate that, at least in part, ND antagonizes the catabolic action of high doses of CC on muscle protein metabolism.

  15. Effect of Nifedipine and S-Adenosylmethionine in the liver of rats treated with CCl[sub 4] and ethanol for one month

    SciTech Connect

    Cutrin, C.; Menino, J.M.; Otero, X.; Miguez, J.; Perez-becerra, E.; Barrio, E. )

    1992-01-01

    An experimental model of toxic liver injury in rats was employed to assay the effect of Nifedipine (a calcium antagonist blocker) and S-Adenosylmethionine. An important decrease in both perivenular fibrosis and cirrhosis was found. Furthermore, a significant decrease in lactic acid levels was found in the group of animals treated with pharmacologic therapy, although no correlation was seen between lactic acid levels and the different degrees of perivenular fibrosis. No significant variations in ALT and AST enzymes were observed between both groups, as opposed to a significant decrease in LDH enzyme in the Nifedipine+S-Adenosylmethionine group. The results indicate an improvement in the histologic picture of the liver in rats treated by means of pharmacological association, without any change in inflammatory infiltrate and with a slight decrease in necrosis, indicating an action mechanism via creeping fibrosis.

  16. Effects of Aqueous Extracts of Chicory and Milk Thistle on Serum Concentrations of Copper, Zinc, and Manganese in Tamoxifen-Treated Rats.

    PubMed

    Abbasalipourkabir, Roghayeh; Ziamajidi, Nasrin; Nasiri, Abolfazl; Behrouj, Hamid

    2016-09-01

    Some medications may change trace element levels in the body. Extracts of various plants, due to having the several elements, can have beneficial effects. Consumption of herbal extracts with chemical drugs may reduce adverse effects of medication. The goal of this study was to evaluate copper (Cu), zinc (Zn), and manganese (Mn) concentrations in serum of rats treated with tamoxifen, chicory, and/or milk thistle extracts. Therefore, 36 adult female Wistar rats were divided into six groups: normal control, chicory control, milk thistle control, tamoxifen, tamoxifen-chicory, and tamoxifen-milk thistle. At the end of the study, the blood samples were collected and sera isolated by centrifugation and analyzed by the atomic absorption spectrophotometry for Cu, Zn, and Mn levels. The Zn concentration increased in milk thistle-supplemented groups. The Cu level increased in the chicory control group only. Tamoxifen had no affect on Cu, Zn, and Mn levels, but seed extract of milk thistle increased Zn concentration, and chicory root extract increased Cu concentration. Although elevated levels of Cu in rats receiving tamoxifen-chicory were milder than rats treated only with chicory, it seems that the extract and tamoxifen impact on the Cu are in conflict with each other. PMID:26875177

  17. Effect of bicuculline and angiotensin II fragment 3-7 on learning and memory processes in rats chronically treated with ethanol.

    PubMed

    Kuziemka-Leska, M; Car, H; Wiśniewski, K

    1998-01-01

    The aim of this study was to determine the possible influence of bicuculline, the antagonist of GABA-A receptor on behavioral activity (recall, acquisition of conditioned reflexes) of angiotension II fragment 3-7 (A II 3-7) in rats chronically treated with ethanol. Long term (9 weeks) ethanol intoxication profoundly impaired learning and memory processes in all testes used. The GABA-A receptor antagonist bicuculline (0.5 mg/kg ip) did not influence exploratory and motor activity in the control rats, but we observed tendency (without significance) to decrease the locomotor activity, in the alcohol-intoxicated groups of animals, when the drug was injected together with A II 3-7 (2 microgram icv). Bicuculline did not influence retrieval process in passive avoidance recall in both investigated groups, and when the drug was given together with AII 3-7 significantly enhanced its action in the control group and in rats chronically treated with ethanol. Bicuculline significantly improved acquisition in the active avoidance test in the control and alcohol-intoxicated groups. Bicuculline injected together with A II 3-7 significantly decreased its action in the control group. Coadministration of bicuculline with A II 3-7 did not significantly change the activity of A II 3-7 in the acquisition of active avoidance test in the alcohol-intoxicated groups of rats.

  18. Percutaneous Absorption of Salicylic Acid after Administration of Trolamine Salicylate Cream in Rats with Transcutol® and Eucalyptus Oil Pre-Treated Skin

    PubMed Central

    Sajjadi, Paniz; Khodayar, Mohammad Javad; Sharif Makhmalzadeh, Behzad; Rezaee, Saeed

    2013-01-01

    Purpose: This study was conducted to assess the effect of skin pre-treatment with Transcutol® and eucalyptus oil on systemic absorption of topical trolamine salicylate in rat. Methods: Pharmacokinetic parameters of salicylic acid following administration of trolamine salicylate on rat skin pre-treated with either Transcutol® or eucalyptus oil were determined using both non-compartmental and non-linear mixed effect modeling approaches and compared with those of control group. Results: Median (% of interquartile range/median) of salicylic acid AUC0-8hr (ng/mL/hr) values in Transcutol® or eucalyptus oil treated rats were 2522(139%) and 58976(141%), respectively as compared to the 3023(327%) of the control group. Skin pre-treatment with eucalyptus oil could significantly decrease extravascular volume of distribution (V/F) and elimination rate constant (k) of salicylic acid. Conclusion: Unlike Transcutol®, eucalyptus oil lead to enhanced transdermal absorption of trolamine salicylate through rat skin. PMID:24312851

  19. Quercetin and Allopurinol Ameliorate Kidney Injury in STZ-Treated Rats with Regulation of Renal NLRP3 Inflammasome Activation and Lipid Accumulation

    PubMed Central

    Zhang, Qing-Yu; Wang, Fu-Meng; Kong, Ling-Dong

    2012-01-01

    Hyperuricemia, hyperlipidemia and inflammation are associated with diabetic nephropathy. The NLRP3 inflammasome-mediated inflammation is recently recognized in the development of kidney injury. Urate and lipid are considered as danger signals in the NLRP3 inflammasome activation. Although dietary flavonoid quercetin and allopurinol alleviate hyperuricemia, dyslipidmia and inflammation, their nephroprotective effects are currently unknown. In this study, we used streptozotocin (STZ)-induced diabetic nephropathy model with hyperuricemia and dyslipidemia in rats, and found over-expression of renal inflammasome components NLRP3, apoptosis-associated speck-like protein and Caspase-1, resulting in elevation of IL-1β and IL-18, with subsequently deteriorated renal injury. These findings demonstrated the possible association between renal NLRP3 inflammasome activation and lipid accumulation to superimpose causes of nephrotoxicity in STZ-treated rats. The treatment of quercetin and allopurinol regulated renal urate transport-related proteins to reduce hyperuricemia, and lipid metabolism-related genes to alleviate kidney lipid accumulation in STZ-treated rats. Furthermore, quercetin and allopurinol were found to suppress renal NLRP3 inflammasome activation, at least partly, via their anti-hyperuricemic and anti-dyslipidemic effects, resulting in the amelioration of STZ-induced the superimposed nephrotoxicity in rats. These results may provide a basis for the prevention of diabetes-associated nephrotoxicity with urate-lowering agents such as quercetin and allopurinol. PMID:22701621

  20. Effects of Aqueous Extracts of Chicory and Milk Thistle on Serum Concentrations of Copper, Zinc, and Manganese in Tamoxifen-Treated Rats.

    PubMed

    Abbasalipourkabir, Roghayeh; Ziamajidi, Nasrin; Nasiri, Abolfazl; Behrouj, Hamid

    2016-09-01

    Some medications may change trace element levels in the body. Extracts of various plants, due to having the several elements, can have beneficial effects. Consumption of herbal extracts with chemical drugs may reduce adverse effects of medication. The goal of this study was to evaluate copper (Cu), zinc (Zn), and manganese (Mn) concentrations in serum of rats treated with tamoxifen, chicory, and/or milk thistle extracts. Therefore, 36 adult female Wistar rats were divided into six groups: normal control, chicory control, milk thistle control, tamoxifen, tamoxifen-chicory, and tamoxifen-milk thistle. At the end of the study, the blood samples were collected and sera isolated by centrifugation and analyzed by the atomic absorption spectrophotometry for Cu, Zn, and Mn levels. The Zn concentration increased in milk thistle-supplemented groups. The Cu level increased in the chicory control group only. Tamoxifen had no affect on Cu, Zn, and Mn levels, but seed extract of milk thistle increased Zn concentration, and chicory root extract increased Cu concentration. Although elevated levels of Cu in rats receiving tamoxifen-chicory were milder than rats treated only with chicory, it seems that the extract and tamoxifen impact on the Cu are in conflict with each other.

  1. Anophthalmia in litters of female rats treated with the food-derived carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine.

    PubMed

    Ikeda, Y; Takahashi, S; Kimura, J; Cho, Y M; Imaida, K; Shirai, S; Shirai, T

    1999-01-01

    Anophthalmia in litters of pregnant rats treated with 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a food-derived carcinogen, was incidentally encountered in a risk-assessment study with 2-generation exposure to PhIP. Female Fischer 344 animals were given 200 ppm PhIP in the diet for 4 wk before mating with nontreated males and also during gestation and lactation periods. Mean numbers of newborn rats per litter in control and PhIP-treated groups were 7.9 +/- 2.9 and 7.1 +/- 1.6 in trial 1 and 8.3 +/- 1.9 and 6.1 +/- 2.4 in trial 2. Among 49 (trial 1) and 63 (trial 2) offspring from PhIP-treated dams, 9 (18.4%) and 32 (50.8%) demonstrated anophthalmia, and 1 (2.0%) and 8 (12.7%) demonstrated hydrocephaly. Five of 7 (71.4%) and 13 of 14 (92.9%) dams delivered pups with malformations in trials 1 and 2, respectively. Also, in a previous study that was carried out with the same protocol and that used the Sprague-Dawley strain of rats, anophthalmia and hydrocephaly were observed in 2 and 1 out of 175 pups, respectively, from 100 ppm PhIP-treated dams. No congenital malformations were found in control groups of the same size in either experiment. In addition to having been previously identified as a cause of carcinogenic activity, our findings suggest that PhIP is capable of causing anophthalmia in rats when administered during the gestational period.

  2. Enhanced expression of endothelial nitric oxide synthase in the myocardium ameliorates the progression of left ventricular hypertrophy in L-arginine treated Wistar-Kyoto rats.

    PubMed

    Ahmad, A; Sattar, M A; Rathore, H A; Abdulla, M H; Khan, S A; Abdullah, N A; Johns, E J

    2016-02-01

    The present study investigated the role of endothelial nitric oxide synthase (eNOS) enzyme in the development of left ventricular hypertrophy (LVH) in Wistar-Kyoto rats. The effect of L-arginine administration on cardiac structure, arterial stiffness, renal and systemic hemodynamic parameters was studied and the change in expression of eNOS and cystathione γ lyase (CSE) in the myocardium of LVH rats was evaluated. LVH was induced using isoprenaline (5 mg/kg, S.C.) and caffeine (62 mg/L in drinking water) for 14 days. Following to that, L-arginine (1.25 g/L in drinking water) was given for 5 weeks as a donor of NO. eNOS and CSE gene expressions were down regulated in the LVH group by about 35% and 67% respectively when compared to control. However, in the LVH group treated with L-arginine there was up regulation of eNOS by almost 27% and down regulation in CSE by 24% when compared to control (all P < 0.05). Heart index and H2S plasma levels were reduced by almost 53% in the L-arginine treated LVH group compared to the control (all P < 0.05). Mean arterial pressure, heart rate and pulse wave velocity were reduced while renal blood perfusion increased in L-arginine treated LVH rats compared to their untreated counterparts (all P < 0.05). The enhanced expression of eNOS in L-arginine treated LVH rats resulted in the amelioration of oxidative and haemodynamic parameters suggesting that NO system is an important therapeutic target in cardiac and LV hypertrophies. PMID:27010893

  3. A novel 4 S [3H]beta-naphthoflavone-binding protein in liver cytosol of female Sprague-Dawley rats treated with aryl hydrocarbon receptor agonists.

    PubMed Central

    Brauze, D; Malejka-Giganti, D

    2000-01-01

    beta-Naphthoflavone (beta-NF) is a widely used inducer of phase-I and phase-II enzymes controlled by aryl hydrocarbon receptor (AhR). Studies of competitive binding with (3)H-labelled 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD), 3-methylcholanthrene (3-MC) and benzo[a]pyrene (B[a]P) have shown that beta-NF is a high-affinity ligand for AhR and also for polycyclic aromatic hydrocarbon (PAH)-binding protein, both soluble proteins of rat liver in 8 S and 4 S fractions, respectively, of sucrose gradients. This study examined binding of [(3)H]beta-NF to liver cytosolic proteins of female Sprague-Dawley rats. Treatment of rats with beta-NF, 3-MC, TCDD or alpha-naphthoflavone (alpha-NF) increased the specific [(3)H]beta-NF binding to liver cytosol up to 125-fold that of vehicle (corn oil)-treated rats (<100 fmol/mg of protein). Sucrose gradients revealed a large 4 S and a small 8 S peak of radioactivity from [(3)H]beta-NF binding to cytosols of beta-NF-, 3-MC-, TCDD- or alpha-NF-treated rats. Whereas co-incubation with the unlabelled beta-NF eliminated both peaks, co-incubation with 2,3, 7,8-tetrachlorodibenzofuran (TCDF) eliminated only the 8 S peak. The sucrose density gradient from [(3)H]TCDD binding to cytosol of beta-NF- or TCDD-treated rats yielded a small 4 S and a larger 8 S peak; only the latter was abolished by co-incubation with TCDF. Thus, the patterns of sedimentation, distribution and elimination of radioactivity from the 8 S fraction of the liver cytosols from beta-NF-, 3-MC-, TCDD- or alpha-NF-treated rats were characteristic for the AhR, whereas those from the 4 S fraction appeared specific for [(3)H]beta-NF binding. The data indicate that potent AhR agonists, TCDD, 3-MC and beta-NF, and to a lesser extent alpha-NF, a weak AhR agonist, induce a 4 S [(3)H]beta-NF-binding protein in liver cytosol of female rats. alpha-NF, beta-NF and 3-MC were effective competitors (80-85% inhibition) of the [(3)H]beta-NF-specific binding to the beta-NF-, 3 MC- or TCDD

  4. Transcriptomic Analysis of Insulin-Sensitive Tissues from Anti-Diabetic Drug Treated ZDF Rats, a T2DM Animal Model

    PubMed Central

    Kim, Il-Yong; Shin, Jae Hoon; Cho, Sooyoung; Yi, Sun Shin; Kim, Wan Kyu; Kim, Kyung-Sub; Lee, Sanghyuk; Seong, Je Kyung

    2013-01-01

    Gene expression changes have been associated with type 2 diabetes mellitus (T2DM); however, the alterations are not fully understood. We investigated the effects of anti-diabetic drugs on gene expression in Zucker diabetic fatty (ZDF) rats using oligonucleotide microarray technology to identify gene expression changes occurring in T2DM. Global gene expression in the pancreas, adipose tissue, skeletal muscle, and liver was profiled from Zucker lean control (ZLC) and anti-diabetic drug treated ZDF rats compared with those in ZDF rats. We showed that anti-diabetic drugs regulate the expression of a large number of genes. We provided a more integrated view of the diabetic changes by examining the gene expression networks. The resulting sub-networks allowed us to identify several biological processes that were significantly enriched by the anti-diabetic drug treatment, including oxidative phosphorylation (OXPHOS), systemic lupus erythematous, and the chemokine signaling pathway. Among them, we found that white adipose tissue from ZDF rats showed decreased expression of a set of OXPHOS genes that were normalized by rosiglitazone treatment accompanied by rescued blood glucose levels. In conclusion, we suggest that alterations in OXPHOS gene expression in white adipose tissue may play a role in the pathogenesis and drug mediated recovery of T2DM through a comprehensive gene expression network study after multi-drug treatment of ZDF rats. PMID:23922760

  5. Effect of tocopherol on biochemical blood parameters in pleuritis-induced rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin.

    PubMed

    Całkosiński, Ireneusz; Rosińczuk-Tonderys, Joanna; Bronowicka-Szydełko, Agnieszka; Dzierzba, Katarzyna; Bazan, Justyna; Dobrzyński, Maciej; Majda, Jacek; Gamian, Andrzej

    2015-06-01

    The aim of this study was to evaluate the effect of tocopherol on pleuritis-induced rats exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Rats were treated with a single TCDD dose of 5 μg/kg body weight (b.w.) and then for 3 weeks they were daily supplemented with tocopherol at a dose of 30 mg/kg b.w. The inflammation was initiated by intrapleural injection of a single dose of 1% carrageenin solution in a volume of 0.15 ml. Changes in biochemical blood parameters were measured three times at the 24th, 72nd and 120th hour of pleuritis and the blood was collected from 20 animals of each group of rats (group with the control inflammation; group treated with TCDD and with control inflammation; group treated with TCDD, supplemented with tocopherol and with the inflammation). The following biochemical parameters were measured: tumor necrosis factor (TNF), interleukin-1 (IL-1), IL-2, IL-4, IL-6, procollagen, telopeptide, fibrinogen, cholesterol, urea, creatinine, aspartate aminotransferase (AspAT) and alanine aminotransferase (AlAT). Daily supplementation of tocopherol caused significant changes in the level of TNF, IL-1, IL-4, IL-6, urea, creatinine, AspAT and AlAT. According to the results of these studies, we suggest that tocopherol supplementation in high doses could act as a protective treatment to improve liver metabolism.

  6. Locomotor recovery in spinal cord-injured rats treated with an antibody neutralizing the myelin-associated neurite growth inhibitor Nogo-A.

    PubMed

    Merkler, D; Metz, G A; Raineteau, O; Dietz, V; Schwab, M E; Fouad, K

    2001-05-15

    The limited plastic and regenerative capabilities of axons in the adult mammalian CNS can be enhanced by the application of a monoclonal antibody (mAb), IN-1, raised against the myelin-associated neurite growth inhibitor Nogo-A. The aim of the present study was to investigate the effects of this treatment on the functional recovery of adult rats with a dorsal over-hemisection of the spinal cord. Directly after injury, half of the animals were implanted with mAb IN-1-secreting hybridoma cells, whereas the others received cells secreting a control antibody (anti-HRP). A broad spectrum of locomotor tests (open field locomotor) score, grid walk, misstep withdrawal response, narrow-beam crossing) was used to characterize locomotor recovery during the 5 weeks after the injury. In all behavioral tests, the recovery in the mAb IN-1-treated group was significantly augmented compared with the control antibody-treated rats. EMG recordings of flexor and extensor muscles during treadmill walking confirmed the improvement of the locomotor pattern in the mAb IN-1-treated rats; step-cycle duration, rhythmicity, and coupling of the hindlimbs were significantly improved. No differences between the two groups with regard to nociception were observed in the tail flick test 5 weeks after the operation. These results indicating improved functional recovery suggest that the increased plastic and regenerative capabilities of the CNS after Nogo-A neutralization result in a functionally meaningful rewiring of the motor systems. PMID:11331396

  7. Disrupted G{sub 1} to S phase clearance via cyclin signaling impairs liver tissue repair in thioacetamide-treated type 1 diabetic rats

    SciTech Connect

    Devi, Sachin S.; Mehendale, Harihara M. . E-mail: mehendale@ulm.edu

    2005-09-01

    Previously we reported that a nonlethal dose of thioacetamide (TA, 300 mg/kg) causes 90% mortality in type 1 diabetic (DB) rats because of irreversible acute liver injury owing to inhibited hepatic tissue repair, primarily due to blockage of G{sub 0} to S phase progression of cell division cycle. On the other hand, DB rats receiving 30 mg TA/kg exhibited equal initial liver injury and delayed tissue repair compared to nondiabetic (NDB) rats receiving 300 mg TA/kg, resulting in a delay in recovery from liver injury and survival. The objective of the present study was to test the hypothesis that impaired cyclin-regulated progression of G{sub 1} to S phase of the cell cycle may explain inhibited liver tissue repair, hepatic failure, and death, contrasted with delayed liver tissue repair but survival observed in the DB rats receiving 300 in contrast to 30 mg TA/kg. In the TA-treated NDB rats sustained MAPKs and cyclin expression resulted in higher phosphorylation of retinoblastoma (pRb), explaining prompt tissue repair and survival. In contrast, DB rats receiving the same dose of TA (300 mg/kg) exhibited suppressed MAPKs and cyclin expression that led to inhibition of pRb, inhibited tissue repair, and death. On the other hand, DB rats receiving 30 mg TA/kg exhibited delayed up regulation of MAPK signaling that delayed the expression of CD1 and pRb, explaining delayed stimulation of tissue repair observed in this group. In conclusion, the hepatotoxicant TA has a dose-dependent adverse effect on cyclin-regulated pRb signaling: the lower dose causes a recoverable delay, whereas the higher dose inhibits it with corresponding effect on the ultimate outcomes on hepatic tissue repair; this dose-dependent adverse effect is substantially shifted to the left of the dose response curve in diabetes.

  8. Time course of cholinesterase inhibition in adult rats treated acutely with carbaryl, carbofuran, formetanate, methomyl, methiocarb, oxamyl or propoxur.

    PubMed

    Padilla, S; Marshall, R S; Hunter, D L; Lowit, A

    2007-03-01

    To compare the toxicity of seven N-methyl carbamates, time course profiles for brain and red blood cell (RBC) cholinesterase (ChE) inhibition were established for each. Adult, male, Long Evans rats (n=4-5 dose group) were dosed orally with either carbaryl (30 mg/kg in corn oil); carbofuran (0.5 mg/kg in corn oil); formetanate HCl (10 mg/kg in water); methomyl (3 mg/kg in water); methiocarb (25 mg/kg in corn oil); oxamyl (1 mg/kg in water); or propoxur (20 mg/kg in corn oil). This level of dosing produced at least 40% brain ChE inhibition. Brain and blood were taken from 0.5 to 24 h after dosing for analysis of ChE activity using two different methods: (1) a radiometric method which limits the amount of reactivation of ChE activity, and (2) a spectrophotometric method (Ellman method using traditional, unmodified conditions) which may encourage reactivation. The time of peak ChE inhibition was similar for all seven N-methyl carbamate pesticides: 0.5-1.0 h after dosing. By 24 h, brain and RBC ChE activity in all animals returned to normal. The spectrophotometric method underestimated ChE inhibition. Moreover, there was a strong, direct correlation between brain and RBC ChE activity (radiometric assay) for all seven compounds combined (r(2)=0.73, slope 1.1), while the spectrophotometric analysis of the same samples showed a poor correlation (r(2)=0.09). For formetanate, propoxur, methomyl, and methiocarb, brain and RBC ChE inhibitions were not different over time, but for carbaryl, carbofuran and oxamyl, the RBC ChE was slightly more inhibited than brain ChE. These data indicate (1) the radiometric method is superior for analyses of ChE activity in tissues from carbamate-treated animals (2) that animals treated with these N-methyl carbamate pesticides are affected rapidly, and recover rapidly, and (3) generally, assessment of RBC ChE is an accurate predictor of brain ChE inhibition for these seven pesticides.

  9. Time course of cholinesterase inhibition in adult rats treated acutely with carbaryl, carbofuran, formetanate, methomyl, methiocarb, oxamyl or propoxur

    SciTech Connect

    Padilla, S. . E-mail: Padilla.Stephanie@epa.gov; Marshall, R.S. . E-mail: Marshall.renee@epa.gov; Hunter, D.L. . E-mail: Hunter.deborah@epa.gov; Lowit, A. . E-mail: Lowit.anna@epa.gov

    2007-03-15

    To compare the toxicity of seven N-methyl carbamates, time course profiles for brain and red blood cell (RBC) cholinesterase (ChE) inhibition were established for each. Adult, male, Long Evans rats (n = 4-5 dose group) were dosed orally with either carbaryl (30 mg/kg in corn oil); carbofuran (0.5 mg/kg in corn oil); formetanate HCl (10 mg/kg in water); methomyl (3 mg/kg in water); methiocarb (25 mg/kg in corn oil); oxamyl (1 mg/kg in water); or propoxur (20 mg/kg in corn oil). This level of dosing produced at least 40% brain ChE inhibition. Brain and blood were taken from 0.5 to 24 h after dosing for analysis of ChE activity using two different methods: (1) a radiometric method which limits the amount of reactivation of ChE activity, and (2) a spectrophotometric method (Ellman method using traditional, unmodified conditions) which may encourage reactivation. The time of peak ChE inhibition was similar for all seven N-methyl carbamate pesticides: 0.5-1.0 h after dosing. By 24 h, brain and RBC ChE activity in all animals returned to normal. The spectrophotometric method underestimated ChE inhibition. Moreover, there was a strong, direct correlation between brain and RBC ChE activity (radiometric assay) for all seven compounds combined (r {sup 2} = 0.73, slope 1.1), while the spectrophotometric analysis of the same samples showed a poor correlation (r {sup 2} = 0.09). For formetanate, propoxur, methomyl, and methiocarb, brain and RBC ChE inhibitions were not different over time, but for carbaryl, carbofuran and oxamyl, the RBC ChE was slightly more inhibited than brain ChE. These data indicate (1) the radiometric method is superior for analyses of ChE activity in tissues from carbamate-treated animals (2) that animals treated with these N-methyl carbamate pesticides are affected rapidly, and recover rapidly, and (3) generally, assessment of RBC ChE is an accurate predictor of brain ChE inhibition for these seven pesticides.

  10. Bypassing hazard of housekeeping genes: their evaluation in rat granule neurons treated with cerebrospinal fluid of multiple sclerosis subjects

    PubMed Central

    Mathur, Deepali; Urena-Peralta, Juan R.; Lopez-Rodas, Gerardo; Casanova, Bonaventura; Coret-Ferrer, Francisco; Burgal-Marti, Maria

    2015-01-01

    Gene expression studies employing real-time PCR has become an intrinsic part of biomedical research. Appropriate normalization of target gene transcript(s) based on stably expressed housekeeping genes is crucial in individual experimental conditions to obtain accurate results. In multiple sclerosis (MS), several gene expression studies have been undertaken, however, the suitability of housekeeping genes to express stably in this disease is not yet explored. Recent research suggests that their expression level may vary under different experimental conditions. Hence it is indispensible to evaluate their expression stability to accurately normalize target gene transcripts. The present study aims to evaluate the expression stability of seven housekeeping genes in rat granule neurons treated with cerebrospinal fluid of MS patients. The selected reference genes were quantified by real time PCR and their expression stability was assessed using GeNorm and NormFinder algorithms. GeNorm identified transferrin receptor (Tfrc) and microglobulin beta-2 (B2m) the most stable genes followed by ribosomal protein L19 (Rpl19) whereas β-actin (ActB) and glyceraldehyde-3-phosphate-dehydrogenase (Gapdh) the most fluctuated ones in these neurons. NormFinder identified Tfrc as the best invariable gene followed by B2m and Rpl19. ActB and Gapdh were the least stable genes as analyzed by NormFinder algorithm. Both methods reported Tfrc and B2m the most stably expressed genes and Gapdh the least stable one. Altogether our data demonstrate the significance of pre-validation of housekeeping genes for accurate normalization and indicates Tfrc and B2m as best endogenous controls in MS. ActB and Gapdh are not recommended in gene expression studies related to current one. PMID:26441545

  11. Identical changes in Bax expression, but not Fas ligand expression, occur in structural luteolysis in gonadotropin releasing hormone agonist- and prolactin-treated superovulated rats.

    PubMed

    Endo, Toshiaki; Kiya, Tamotsu; Kitajima, Yoshimitsu; Honnma, Hiroyuki; Chida, Manabu; Hayashi, Takumi; Henmi, Hirofumi; Yamazaki, Kiyohiro; Hayashi, Takuhiro; Manase, Kengo; Kudo, Ryuichi

    2005-03-25

    Structural luteolysis induced by gonadotropin releasing hormone agonist (GnRHa) or prolactin (PRL) is defined as histological involution of the corpus luteum. We reported that one of the mechanisms of structural luteolysis induced by PRL was tissue remodeling by matrix metalloproteinase (MMP) and also apoptosis in superovulated rats. We also reported that GnRHa induced structural luteolysis with elevation of MMP. In this study, we investigated whether GnRHa caused apoptosis in mature corpus luteum of superovulated rats and also examined the expression of apoptosis-related molecules (Fas, Fas ligand (FasL), Bcl-2, Bax). We gave 4-day GnRHa treatment 5 days after hCG injection to immature female rats treated with pregnant mare surum gonadotrophin (PMSG) and hCG to induce structural involution of mature corpus luteum. PMSG-hCG-treated rats without GnRHa treatment, rats treated with bromocryptine (Brom) to induce functional luteolysis and rats treated with Brom followed by PRL (Brom+PRL) to mimic the PRL surge to induce structural luteolysis as we previously reported were used for comparison. GnRHa treatment caused structural luteolysis characterized by structural involution, a decrease in the serum progestin level, and apoptotic bodies as well as structural luteolysis induced by Brom+PRL. FasL expression in corpora lutea was elevated after Brom treatment, but there was no elevation of FasL after GnRHa treatment started. FasL expression decreased and Bax expression increased in structural luteolysis induced by GnRHa as well as Brom+PRL treatment, although Fas and Bcl-2 expression did not change throughout the luteal phase. In summary, both GnRHa and Brom+PRL caused structural luteolysis, one of whose mechanisms was apoptosis with an increase in Bax expression, but not with an identical change in FasL expression. It is speculated that the significance in alteration of FasL may involve some mechanism other than apoptosis. PMID:15733931

  12. Effect of Nd:YAG laser light on post-extractive socket healing in rats treated with zoledronic acid and dexamethasone

    NASA Astrophysics Data System (ADS)

    Mergoni, Giovanni; Merigo, Elisabetta; Passerini, Pietro; Corradi, Domenico; Maestri, Roberta; Bussolati, Ovidio; Bianchi, Massimiliano; Sala, Roberto; Govoni, Paolo; Namour, Samir; Vescovi, Paolo

    2016-03-01

    Introduction The effect of low level laser therapy (LLLT) on the healing process could be useful for the prevention of post-extractive Bisphosphonate-related Osteonecrosis of the Jaws (BRONJ). The aim of the study was to investigate the effect of LLLT on the post-extractive socket healing in rats treated with zoledronic acid and dexamethasone. Material and Methods Thirty male Sprague-Dawley rats were divided in 4 groups: control group (C, n = 5), laser group (L, n = 5), treatment group (T, n = 10) and treatment plus laser group (T+L, n = 10). Rats of group T and T+L received zoledronate 0,1 mg/Kg and dexamethasone 1 mg/Kg every 2 days for 10 weeks. Rats of group C and L were infused with vehicle. After 9 weeks the first maxillary molars were extracted in all rats. Rats of groups L and T+L received laser therapy (Nd:YAG, 1064 nm, 1.25W, 15Hz, 5 min, 14.37 J/cm2) in the socket area at days 0, 2, 4 and 6 after surgery. At 8 days from extraction, the sockets were clinically assessed with a grading score and the wound area was measured with a dedicate software. Histomorphometric evaluation and western blot analysis of osteopontin and osteocalcin expression were performed. Results Group T+L showed a trend toward a better clinical grading score compared to group T (grade I 22% Vs 28 % - grade II 56% Vs 28% - grade III 22% Vs 44%, respectively). The average wound area was similar among the groups. Inhibition of osteoclastic alveolar bone resorption was found in groups T and T+L (P<0.001). Rats of groups L and T+L showed a significant higher expression of osteocalcin compared to rats of groups C and T (C=0.3993; L=1.394; T=0.2922; T+L=1.156; P=0.0001). The expression of osteopontin did not show significant differences in the groups treated with Nd:YAG compared to the ones that did not receive laser irradiation. Conclusion Our findings suggest that laser irradiation after tooth extraction can promote osteoblast differentiation, as demonstrated by the higher expression of

  13. Use of serial analysis of gene expression to reveal the specific regulation of gene expression profile in asthmatic rats treated by acupuncture

    PubMed Central

    Yin, Lei-Miao; Jiang, Gong-Hao; Wang, Yu; Wang, Yan; Liu, Yan-Yan; Jin, Wei-Rong; Xu, Yu-Dong; Zhang, Qing-Hua; Yang, Yong-Qing

    2009-01-01

    Background Asthma has become an important public health issue and approximately 300 million people have suffered from the disease worldwide. Nowadays, the use of acupuncture in asthma is increasing. This study intended to systematically analyze and compare the gene expression profiles between the asthmatic and acupuncture-treated asthmatic rat lung, and tried to gain insight into the molecular mechanism underlying the early airway response (EAR) phase of asthma treated by acupuncture. Methods Four tag libraries of serial analysis of gene expression (SAGE) were established from lung tissues of control rats (CK), asthmatic rats (AS), asthmatic rats treated by acupuncture (ASAC), and control rats treated by acupuncture (CKAC). Bioinformatic analyses were carried out by using the methods including unsupervised hierarchical clustering, functional annotation tool of the database for annotation, visualization, and integrated discovery (DAVID), gene ontology (GO) tree machine, and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis. Results There were totally 186 differentially expressed tags (P < 0.05, PCK/AS) between the libraries of CK and AS, 130 differentially expressed tags between libraries of AS/ASAC (P < 0.05, PAS/ASAC), and 144 differentially expressed tags between libraries of CK/CKAC (P < 0.05, PCK/CKAC). The gene expression profiles of AS and ASAC were more similar than other libraries via unsupervised SAGE clustering. By comparison of PCK/AS and PAS/ASAC, the DAVID genes functional classification was found to be changed from "immune response" to "response to steroid hormone stimulus", and the GO term "antigen processing and presentation of peptide antigen" disappeared in PAS/ASAC. Totally 3 same KEGG pathways were found among the three groups. Moreover, 21 specific tags of the acupuncture in treating asthma were detected using Venn diagrams. Conclusion Our SAGE research indicates that the gene expression profile of the EAR phase of asthma could be

  14. iTRAQ-Based Proteomics Analysis of Serum Proteins in Wistar Rats Treated with Sodium Fluoride: Insight into the Potential Mechanism and Candidate Biomarkers of Fluorosis

    PubMed Central

    Wei, Yan; Zeng, Beibei; Zhang, Hua; Chen, Cheng; Wu, Yanli; Wang, Nanlan; Wu, Yanqiu; Shen, Liming

    2016-01-01

    Fluorosis induced by exposure to high level fluoride is quite widespread in the world. The manifestations of fluorosis include dental mottling, bone damage, and impaired malfunction of soft tissues. However, the molecular mechanism of fluorosis has not been clarified until now. To explore the underlying mechanisms of fluorosis and screen out serum biomarkers, we carried out a quantitative proteomics study to identify differentially expressed serum proteins in Wistar rats treated with sodium fluoride (NaF) by using a proteomics approach of isobaric tagging for relative and absolute quantitation (iTRAQ). We fed Wistar rats drinking water that had 50, 150, and 250 mg/L of dissolved NaF for 24 weeks. For the experimental duration, each rat was given an examination of the lower incisors to check for the condition of dental fluorosis (DF). By the end of the treatment, fluoride ion concentration in serum and lower incisors were detected. The results showed that NaF treatment can induce rat fluorosis. By iTRAQ analysis, a total of 37 differentially expressed serum proteins were identified between NaF-treated and control rats. These proteins were further analyzed by bioinformatics, out of which two proteins were validated by enzyme-linked immunoadsorbent assays (ELISA). The major proteins were involved in complement and coagulation cascade, inflammatory response, complement activation, defense response, and wound response, suggesting that inflammation and immune reactions may play a key role in fluorosis pathogenesis. These proteins may contribute to the understanding of the mechanism of fluoride toxicity, and may serve as potential biomarkers for fluorosis. PMID:27690006

  15. Alkaline comet assay in liver and stomach, and micronucleus assay in bone marrow, from rats treated with 2-acetylaminofluorene, azidothymidine, cisplatin, or isobutyraldehyde.

    PubMed

    Kraynak, A R; Barnum, J E; Cunningham, C L; Ng, A; Ykoruk, B A; Bennet, B; Stoffregen, D; Merschman, M; Freeland, E; Galloway, S M

    2015-07-01

    As part of the Japanese Center for the Validation of Alternative Methods (JaCVAM) initiative international validation study of the in vivo rat alkaline comet assay (comet assay), we examined the ability of the assay to determine the genotoxicity of 2-acetylaminofluorene (AAF), azidothymidine (AZT), cisplatin (CPN), and isobutyraldehyde (IBA) in liver and glandular stomach of male Sprague-Dawley rats. Rats were given oral doses of test compound or control once daily for three days. High dose levels were approximately maximum tolerated doses and were based on preliminary range-finding studies. Tissues were harvested 3h after the final dose (48h after the initial dose). A bone marrow micronucleus assay (MN) was also conducted on the rats treated with AZT, CPN, and IBA. Acute toxic effects of treatment were determined primarily through histomorphologic analysis of liver and stomach but also by body weight and serum liver enzyme changes. The comet assay was conducted on fresh tissue preparations but frozen samples from two studies were also assayed. Statistically significant dose-related differences in comet % DNA in tail were found in liver and stomach for the genotoxin AZT and in liver for the genotoxin CPN, but not in liver or stomach for the non-genotoxin IBA. Statistically significant differences in % DNA in tail were measured in liver for the low and mid dose of the genotoxin AAF, but not the high dose. The comet assays of frozen liver suspensions from CPN- and AAF-treated rats yielded comparable results to the assays of fresh preparations. There were no indications of significant toxicity induced by any treatment. The micronucleus assay was positive for CPN and AZT and negative for IBA. In conclusion, the in vivo comet assay is capable of detecting genotoxic effects of a variety of chemicals and may fill an important role in the genotoxicity test battery.

  16. Protective effect of combined pumpkin seed and ginger extracts on sperm characteristics, biochemical parameters and epididymal histology in adult male rats treated with cyclophosphamide.

    PubMed

    Aghaie, Somaieh; Nikzad, Hossein; Mahabadi, Javad Amini; Taghizadeh, Mohsen; Azami-Tameh, Abolfazl; Taherian, Aliakbar; Sajjadian, Seyyed Mohammad Sajjad; Kamani, Mehran

    2016-09-01

    Reproductive toxicity is one of the side effects of cyclophosphamide (CP) in cancer treatment. Pumpkin seeds and Zingiber officinale are natural sources of antioxidants. We investigated the possible protective effect of combined pumpkin seed and Zingiber officinale extracts on sperm characteristics, epididymal histology and biochemical parameters of CP-treated rats. Male adult Wistar rats were divided randomly into six groups. Group 1, as a control, received an isotonic saline solution injection intraperitoneally (IP). Group 2 were injected IP with a single dose of CP (100 mg/kg) once. Groups 3 and 4 received CP plus 300 and 600 mg/kg combined pumpkin seed and Zingiber officinale extract (50:50). Groups 5 and 6 received only 300 and 600 mg/kg combined pumpkin seed and Zingiber officinale extract. Six weeks after treatment, sperm characteristics, histopathological changes and biochemical parameters were assessed. In CP-treated rats, motile spermatozoa were decreased, and abnormal or dead spermatozoa increased significantly (P < 0.001) but administration of the mixed extract improved sperm parameters. Epididymal epithelium and fibromascular thickness were also improved in extract-treated rats compared to control or CP groups. Biochemical analysis showed that the administration of combined extracts could increase the total antioxidant capacity (TAC) level significantly in groups 3, 4, 5 and 6. Interestingly, the mixed extract could decrease most of the side effects of CP such as vacuolization and separation of epididymal tissue. Our findings indicated that the combined extracts might be used as a protective agent against CP-induced reproductive toxicity.

  17. Role of Mas Receptor Antagonist A799 in Renal Blood Flow Response to Ang 1-7 after Bradykinin Administration in Ovariectomized Estradiol-Treated Rats

    PubMed Central

    Dehghani, Aghdas; Saberi, Shadan; Nematbakhsh, Mehdi

    2015-01-01

    Background. The accompanied role of Mas receptor (MasR), bradykinin (BK), and female sex hormone on renal blood flow (RBF) response to angiotensin 1-7 is not well defined. We investigated the role of MasR antagonist (A779) and BK on RBF response to Ang 1-7 infusion in ovariectomized estradiol-treated rats. Methods. Ovariectomized Wistar rats received estradiol (OVE) or vehicle (OV) for two weeks. Catheterized animals were subjected to BK and A799 infusion and mean arterial pressure (MAP), RBF, and renal vascular resistance (RVR) responses to Ang 1-7 (0, 100, and 300 ng kg−1 min−1) were determined. Results. Percentage change of RBF (%RBF) in response to Ang1-7 infusion increased in a dose-dependent manner. In the presence of BK, when MasR was not blocked, %RBF response to Ang 1-7 in OVE group was greater than OV group significantly (P < 0.05). Infusion of 300 ng kg−1 min−1 Ang 1-7 increased RBF by 6.9 ± 1.9% in OVE group versus 0.9 ± 1.8% in OV group. However when MasR was blocked, %RBF response to Ang 1-7 in OV group was greater than OVE group insignificantly. Conclusion. Coadministration of BK and A779 compared to BK alone increased RBF response to Ang 1-7 in vehicle treated rats. Such observation was not seen in estradiol treated rats. PMID:26421009

  18. Effect of adenosine A(2A) receptor antagonists and L-DOPA on hydroxyl radical, glutamate and dopamine in the striatum of 6-OHDA-treated rats.

    PubMed

    Gołembiowska, Krystyna; Dziubina, Anna

    2012-02-01

    A(2A) adenosine receptor antagonists have been proposed as a new therapy of PD. Since oxidative stress plays an important role in the pathogenesis of PD, we studied the effect of the selective A(2A) adenosine receptor antagonists 8-(-3-chlorostyryl)caffeine (CSC) and 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385) on hydroxyl radical generation, and glutamate (GLU) and dopamine (DA) extracellular level using a microdialysis in the striatum of 6-OHDA-treated rats. CSC (1 mg/kg) and ZM 241385 (3 mg/kg) given repeatedly for 14 days decreased the production of hydroxyl radical and extracellular GLU level, both enhanced by prior 6-OHDA treatment in dialysates from the rat striatum. CSC and ZM 241385 did not affect DA and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA) extracellular levels in the striatum of 6-OHDA-treated rats. L-DOPA (6 mg/kg) given twice daily for two weeks in the presence of benserazide (3 mg/kg) decreased striatal hydroxyl radical and glutamate extracellular level in 6-OHDA-treated rats. At the same time, L-DOPA slightly but significantly increased the extracellular levels of DOPAC and HVA. A combined repeated administration of L-DOPA and CSC or ZM 241385 did not change the effect of L-DOPA on hydroxyl radical production and glutamate extracellular level in spite of an enhancement of extracellular DA level by CSC and elevation of extracellular level of DOPAC and HVA by ZM 241385. The data suggest that the 6-OHDA-induced damage of nigrostriatal DA-terminals is related to oxidative stress and excessive release of glutamate. Administration of L-DOPA in combination with CSC or ZM 241385, by restoring striatal DA-glutamate balance, suppressed 6-OHDA-induced overproduction of hydroxyl radical.

  19. Is a highly linear relationship between the dose of quercetin and the pharmacological effect possible? - a comment on Liu, et al. Evaluation of antioxidant and immunity activities of quercetin in isoproterenol-treated rats. Molecules 2012, 17, 4281-4291.

    PubMed

    Mladěnka, Přemysl; Hrdina, Radomír; Filipský, Tomáš; Ríha, Michal; Palicka, Vladimir

    2014-07-07

    We wish to offer some comments on the article by H. Liu et al. entitled "Evaluation of antioxidant and immunity activities of quercetin in isoproterenol-treated rats", published in Molecules in 2012 [1]. [...].

  20. The role of visfatin on the regulation of inflammation and apoptosis in the spleen of LPS-treated rats.

    PubMed

    Xiao, Ke; Zou, Wei-Hua; Yang, Zhi; Zia ur Rehman; Ansari, Abdur Rahman; Yuan, Huai-Rui; Zhou, Ying; Cui, Lu; Peng, Ke-Mei; Song, Hui

    2015-02-01

    The purpose of the present study is to determine if visfatin is involved in inflammation or apoptosis induced by LPS in rat. Forty Wistar rats were divided into four groups: saline group, LPS group, visfatin group and Visfatin + LPS co-stimulated group. Spleen samples from each group of rats were collected for study. The spleen structure was examined by histological imaging. Apoptosis was evaluated with TUNEL reaction. Caspase-3 was detected with immunohistochemistry and western blot. The apoptosis-related genes were detected by qPCR and inflammatory cytokines were tested by ELISA. Our main findings were as follows. (1) Macrophages were markedly increased in the visfatin group compared with the saline group. This finding was confirmed when spleen samples were examined with western blot using CD68 antibody. (2) Visfatin promoted the expression of CD68 and caspase-3 in rat spleen, whereas visfatin could inhibit the expression of CD68 and activated caspase-3 in spleen of LPS-induced acute inflammation. (3) Visfatin had a pro-apoptotic effect on normal rat spleen, whereas it exerted an anti-apoptotic effect during LPS-induced lymphocytes apoptosis in rat spleen. Moreover, the effect of visfatin on cell apoptosis was mediated by the mitochondrial pathway. (4) Visfatin could modulate both the anti-inflammatory cytokines and pro-inflammatory cytokines in rat spleen, such as IL-10, IL-4, IL-6, TNF-α and IL-1β. Taken together, we demonstrate that visfatin could participate in the inflammatory process in rat spleen by modulating the macrophages and inflammatory cytokines. Also, visfatin plays a dual role in the apoptosis in rat spleen, which is mediated by the mitochondrial pathway.

  1. Effects of freeze-dried cranberry powder on serum lipids and inflammatory markers in lipopolysaccharide treated rats fed an atherogenic diet

    PubMed Central

    Kim, Mi Joung; Ohn, Jeong; Kim, Jung Hee

    2011-01-01

    This study investigated the effects of freeze-dried cranberry powder on anti-inflammation and lipid profiles of lipopolysaccharide (LPS)-treated rats fed an atherogenic diet for 6 weeks. Forty Sprague-Dawley male rats (6-weeks-old) were equally divided into the following five groups: 1) normal diet group + saline (NC); 2) atherogenic diet + saline (HFC); 3) atherogenic diet + LPS (HL); 4) atherogenic diet with 5% cranberry power + LPS (C5); 5) atherogenic diet with 10% cranberry power + LPS (C10). LPS (0.5 mg/kg) was injected into the abdominal cavities of rats 18 hours prior to sacrifice. At the end of the experimental period, we measured serum lipid profiles as well as levels of serum C-reactive protein (CRP), nitric oxide (NO), and pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and IL-10 as an anti-inflammatory cytokine. The mean serum high density lipoprotein (HDL)-cholesterol level in C5 rats was significantly higher than that in NC and HL rats (P < 0.05). The mean serum levels of CRP and IL-1β were significantly lower (P < 0.05) in the cranberry powder groups compared to those in HL rats. Additionally, mean serum IL-6 levels tended to be lower in the cranberry groups than that in the HL group, whereas serum IL-10 and NO showed 29% and 88% higher mean values in the C5 group and 49% and 24% higher in the C10 group than those in the HL group, respectively. These results suggest that freeze-dried cranberry powder may have beneficial effects on cardiovascular diseases by modifying serum lipids and the early inflammatory response. PMID:22125677

  2. Rapid postexposure decay of. cap alpha. /sub 2u/-globulin and hyaline droplets in the kidneys of gasoline-treated male rats

    SciTech Connect

    Garg, B.D.; Olson, M.J.; Demyan, W.F.; Roy, A.K.

    1988-01-01

    Renal ..cap alpha../sub 2u/-globulin content increased to 210% of control within 18 h of a single oral dose of gasoline (2.0 ml/kg) in male rats; maximal levels (320% of control) were attained following gasoline administration for 3 d. Increases in renal ..cap alpha../sub 2u/-globulin caused by gasoline were accompanied by concurrent proliferation of hyaline droplets. However, within 3 d of terminating gasoline administration renal ..cap alpha../sub2u/-globulin content decreased to the same level as that in unexposed rats, although renal hyaline droplet number returned to pretreatment levels somewhat more slowly. The conjoint effect of postexposure recovery and estradiol (an inhibitor of hepatic ..cap alpha../sub 2u/-globulin synthesis) administration was also determined in male rats. On postexposure of 3, 6, and 9, estradiol treatment (1 mg/kg, sc, 4 d, starting on d 9 of gasoline treatment) decreased renal ..cap alpha../sub 2u/-globulin content to 75%, 59%, and 48%, respectively, of that in rats allowed to recover from gasoline with no hormone treatment. Hepatic ..cap alpha../sub 2u/-globulin content in estradiol-treated rats was decreased by 74%, 97%, and 96% at the same intervals. Estradiol treatment during recovery from gasoline also appeared to increase the removal of accumulated hyaline droplets from the renal cortex. Thus, accumulation of ..cap alpha../sub 2u/-globulin-containing hyaline droplets after subacute exposure of male rats to gasoline is rapidly reversible, dependent on continuous exposure to gasoline and maintenance of the normal rate of hepatic ..cap alpha../sub 2u/-globulin synthesis. These results emphasize the dynamic state of renal cortical hyaline droplets and suggest strongly that gasoline hydrocarbons cause hyaline droplet accumulation by prolonging the half-time degradation of ..cap alpha../sub 2u/-globulin.

  3. Protective effects of Annona muricata Linn. (Annonaceae) leaf aqueous extract on serum lipid profiles and oxidative stress in hepatocytes of streptozotocin-treated diabetic rats.

    PubMed

    Adewole, Stephen O; Ojewole, John A O

    2008-10-25

    Extracts from various morphological parts of Annona muricata Linn. (Annonaceae) are widely used medicinally in many parts of the world for the management, control and/or treatment of a plethora of human ailments, including diabetes mellitus (DM). The present study was undertaken to investigate the possible protective effects of A. muricata leaf aqueous extract (AME) in rat experimental paradigms of DM. The animals used were broadly divided into four (A, B, C and D) experimental groups. Group A rats served as 'control' animals and received distilled water in quantities equivalent to the administered volumes of AME and reference drugs' solutions intraperitoneally. Diabetes mellitus was induced in Groups B and C rats by intraperitoneal injections of streptozotocin (STZ, 70 mg kg(-1)). Group C rats were additionally treated with AME (100 mg kg(-1) day(-1), p.o.) as from day 3 post STZ injection, for four consecutive weeks. Group D rats received AME (100 mg kg(-1) day(-1) p.o.) only for four weeks. Post-euthanization, hepatic tissues were excised and processed biochemically for antioxidant enzymes and lipid profiles, such as catalase (CAT), reactive oxygen species (ROS), glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), thiobarbituric acid reactive substances (TBARS), triglycerides (TG), total cholesterol (TC), high density lipoprotein (HDL) and low density lipoprotein (LDL), respectively. Treatment of Groups B and C rats with STZ (70 mg kg(-1) i. p.) resulted in hyperglycaemia, hypoinsulinaemia, and increased TBARS, ROS, TC, TG and LDL levels. STZ treatment also significantly decreased (p<0.05) CAT, GSH, SOD, GSH-Px activities, and HDL levels. AME-treated Groups C and D rats showed significant decrease (p<0.05) in elevated blood glucose, ROS, TBARS, TC, TG and LDL. Furthermore, AME treatment significantly increased (p<0.05) antioxidant enzymes' activities, as well as serum insulin levels. The findings of this laboratory animal study

  4. Hyperfractionated Accelerated Radiation Therapy (HART) of 70.6 Gy With Concurrent 5-FU/Mitomycin C Is Superior to HART of 77.6 Gy Alone in Locally Advanced Head and Neck Cancer: Long-term Results of the ARO 95-06 Randomized Phase III Trial

    SciTech Connect

    Budach, Volker; Stromberger, Carmen; Poettgen, Christoph; Baumann, Michael; Budach, Wilfried; Grabenbauer, Gerhard; Marnitz, Simone; Olze, Heidi; Wernecke, Klaus-Dieter; Ghadjar, Pirus

    2015-04-01

    Purpose: To report the long-term results of the ARO 95-06 randomized trial comparing hyperfractionated accelerated chemoradiation with mitomycin C/5-fluorouracil (C-HART) with hyperfractionated accelerated radiation therapy (HART) alone in locally advanced head and neck cancer. Patients and Methods: The primary endpoint was locoregional control (LRC). Three hundred eighty-four patients with stage III (6%) and IV (94%) oropharyngeal (59.4%), hypopharyngeal (32.3%), and oral cavity (8.3%) cancer were randomly assigned to 30 Gy/2 Gy daily followed by twice-daily 1.4 Gy to a total of 70.6 Gy concurrently with mitomycin C/5-FU (C-HART) or 16 Gy/2 Gy daily followed by twice-daily 1.4 Gy to a total dose of 77.6 Gy alone (HART). Statistical analyses were done with the log-rank test and univariate and multivariate Cox regression analyses. Results: The median follow-up time was 8.7 years (95% confidence interval [CI]: 7.8-9.7 years). At 10 years, the LRC rates were 38.0% (C-HART) versus 26.0% (HART, P=.002). The cancer-specific survival and overall survival rates were 39% and 10% (C-HART) versus 30.0% and 9% (HART, P=.042 and P=.049), respectively. According to multivariate Cox regression analysis, the combined treatment was associated with improved LRC (hazard ratio [HR]: 0.6 [95% CI: 0.5-0.8; P=.002]). The association between combined treatment arm and increased LRC appeared to be limited to oropharyngeal cancer (P=.003) as compared with hypopharyngeal or oral cavity cancer (P=.264). Conclusions: C-HART remains superior to HART in terms of LRC. However, this effect may be limited to oropharyngeal cancer patients.

  5. Novel receptor-derived cyclopeptides to treat heart failure caused by anti-β1-adrenoceptor antibodies in a human-analogous rat model.

    PubMed

    Boivin, Valérie; Beyersdorf, Niklas; Palm, Dieter; Nikolaev, Viacheslav O; Schlipp, Angela; Müller, Justus; Schmidt, Doris; Kocoski, Vladimir; Kerkau, Thomas; Hünig, Thomas; Ertl, Georg; Lohse, Martin J; Jahns, Roland

    2015-01-01

    Despite recent therapeutic advances the prognosis of heart failure remains poor. Recent research suggests that heart failure is a heterogeneous syndrome and that many patients have stimulating auto-antibodies directed against the second extracellular loop of the β1 adrenergic receptor (β1EC2). In a human-analogous rat model such antibodies cause myocyte damage and heart failure. Here we used this model to test a novel antibody-directed strategy aiming to prevent and/or treat antibody-induced cardiomyopathy. To generate heart failure, we immunised n = 76/114 rats with a fusion protein containing the human β1EC2 (amino-acids 195-225) every 4 weeks; n = 38/114 rats were control-injected with 0.9% NaCl. Intravenous application of a novel cyclic peptide mimicking β1EC2 (β1EC2-CP, 1.0 mg/kg every 4 weeks) or administration of the β1-blocker bisoprolol (15 mg/kg/day orally) was initiated either 6 weeks (cardiac function still normal, prevention-study, n = 24 (16 treated vs. 8 untreated)) or 8.5 months after the 1st immunisation (onset of cardiomyopathy, therapy-study, n = 52 (40 treated vs. 12 untreated)); n = 8/52 rats from the therapy-study received β1EC2-CP/bisoprolol co-treatment. We found that β1EC2-CP prevented and (alone or as add-on drug) treated antibody-induced cardiac damage in the rat, and that its efficacy was superior to mono-treatment with bisoprolol, a standard drug in heart failure. While bisoprolol mono-therapy was able to stop disease-progression, β1EC2-CP mono-therapy -or as an add-on to bisoprolol- almost fully reversed antibody-induced cardiac damage. The cyclo¬peptide acted both by scavenging free anti-β1EC2-antibodies and by targeting β1EC2-specific memory B-cells involved in antibody-production. Our model provides the basis for the clinical translation of a novel double-acting therapeutic strategy that scavenges harmful anti-β1EC2-antibodies and also selectively depletes memory B-cells involved in the production of such antibodies

  6. Novel Receptor-Derived Cyclopeptides to Treat Heart Failure Caused by Anti-β1-Adrenoceptor Antibodies in a Human-Analogous Rat Model

    PubMed Central

    Boivin, Valérie; Beyersdorf, Niklas; Palm, Dieter; Nikolaev, Viacheslav O.; Schlipp, Angela; Müller, Justus; Schmidt, Doris; Kocoski, Vladimir; Kerkau, Thomas; Hünig, Thomas; Ertl, Georg; Lohse, Martin J.; Jahns, Roland

    2015-01-01

    Despite recent therapeutic advances the prognosis of heart failure remains poor. Recent research suggests that heart failure is a heterogeneous syndrome and that many patients have stimulating auto-antibodies directed against the second extracellular loop of the β1 adrenergic receptor (β1EC2). In a human-analogous rat model such antibodies cause myocyte damage and heart failure. Here we used this model to test a novel antibody-directed strategy aiming to prevent and/or treat antibody-induced cardiomyopathy. To generate heart failure, we immunised n = 76/114 rats with a fusion protein containing the human β1EC2 (amino-acids 195–225) every 4 weeks; n = 38/114 rats were control-injected with 0.9% NaCl. Intravenous application of a novel cyclic peptide mimicking β1EC2 (β1EC2-CP, 1.0 mg/kg every 4 weeks) or administration of the β1-blocker bisoprolol (15 mg/kg/day orally) was initiated either 6 weeks (cardiac function still normal, prevention-study, n = 24 (16 treated vs. 8 untreated)) or 8.5 months after the 1st immunisation (onset of cardiomyopathy, therapy-study, n = 52 (40 treated vs. 12 untreated)); n = 8/52 rats from the therapy-study received β1EC2-CP/bisoprolol co-treatment. We found that β1EC2-CP prevented and (alone or as add-on drug) treated antibody-induced cardiac damage in the rat, and that its efficacy was superior to mono-treatment with bisoprolol, a standard drug in heart failure. While bisoprolol mono-therapy was able to stop disease-progression, β1EC2-CP mono-therapy -or as an add-on to bisoprolol- almost fully reversed antibody-induced cardiac damage. The cyclo¬peptide acted both by scavenging free anti-β1EC2-antibodies and by targeting β1EC2-specific memory B-cells involved in antibody-production. Our model provides the basis for the clinical translation of a novel double-acting therapeutic strategy that scavenges harmful anti-β1EC2-antibodies and also selectively depletes memory B-cells involved in the production of such antibodies

  7. Enhanced healing of mitomycin C-treated healing-impaired wounds in rats with hydrosheets composed of chitin/chitosan, fucoidan, and alginate as wound dressings.

    PubMed

    Murakami, Kaoru; Ishihara, Masayuki; Aoki, Hiroshi; Nakamura, Shingo; Nakamura, Shin-Ichiro; Yanagibayashi, Satoshi; Takikawa, Megumi; Kishimoto, Satoko; Yokoe, Hidetaka; Kiyosawa, Tomoharu; Sato, Yasunori

    2010-01-01

    To create a moist environment for rapid wound healing, a hydrosheet composed of alginate, chitin/chitosan, and fucoidan (ACF-HS) has been developed as a functional wound dressing. The aim of this study was to evaluate the accelerating effect of ACF-HS on wound healing for rat mitomycin C-treated healing-impaired wounds. Full-thickness skin defects were made on the back of rats and mitomycin C was applied onto the wound for 10 minutes to prepare a healing-impaired wound. After thoroughly washing out the mitomycin C, ACF-HS was applied to the healing-impaired wounds. The rats were later euthanized and histological sections of the wounds were prepared. The histological examinations showed significantly advanced granulation tissue and capillary formations in the healing-impaired wounds treated with ACF-HS on days 7 and 14, in comparison with that in alginate fiber (Kaltostat), hydrogel wound dressing (DuoACTIVE), and nontreatment (negative control). Furthermore, in cell culture studies, ACF-HS-absorbed serum and fibroblast growth factor-2 was found to be proliferative for fibroblasts and endothelial cells, respectively, and ACF-HS-absorbed serum was found to be chemoattractive for fibroblasts. However, our results may not be strictly comparable with general healing-impaired wound models in humans because of the cell damage by mitomycin C. In addition, more biocompatibility studies of fucoidan are essential due to the possibility of renal toxicity.

  8. Induction of mitochondrial biogenesis and respiration is associated with mTOR regulation in hepatocytes of rats treated with the pan-PPAR activator tetradecylthioacetic acid (TTA).

    PubMed

    Hagland, Hanne R; Nilsson, Linn I H; Burri, Lena; Nikolaisen, Julie; Berge, Rolf K; Tronstad, Karl J

    2013-01-11

    The hypolipidemic effect of peroxisome proliferator-activated receptor (PPAR) activators has been explained by increasing mitochondrial fatty acid oxidation, as observed in livers of rats treated with the pan-PPAR activator tetradecylthioacetic acid (TTA). PPAR-activation does, however, not fully explain the metabolic adaptations observed in hepatocytes after treatment with TTA. We therefore characterized the mitochondrial effects, and linked this to signalling by the metabolic sensor, the mammalian target of rapamycin (mTOR). In hepatocytes isolated from TTA-treated rats, the changes in cellular content and morphology were consistent with hypertrophy. This was associated with induction of multiple mitochondrial biomarkers, including mitochondrial DNA, citrate synthase and mRNAs of mitochondrial proteins. Transcription analysis further confirmed activation of PPARα-associated genes, in addition to genes related to mitochondrial biogenesis and function. Analysis of mitochondrial respiration revealed that the capacity of both electron transport and oxidative phosphorylation were increased. These effects coincided with activation of the stress related factor, ERK1/2, and mTOR. The protein level and phosphorylation of the downstream mTOR actors eIF4G and 4E-BP1 were induced. In summary, TTA increases mitochondrial respiration by inducing hypertrophy and mitochondrial biogenesis in rat hepatocytes, via adaptive regulation of PPARs as well as mTOR. PMID:23228666

  9. Enhanced healing of mitomycin C-treated healing-impaired wounds in rats with hydrosheets composed of chitin/chitosan, fucoidan, and alginate as wound dressings.

    PubMed

    Murakami, Kaoru; Ishihara, Masayuki; Aoki, Hiroshi; Nakamura, Shingo; Nakamura, Shin-Ichiro; Yanagibayashi, Satoshi; Takikawa, Megumi; Kishimoto, Satoko; Yokoe, Hidetaka; Kiyosawa, Tomoharu; Sato, Yasunori

    2010-01-01

    To create a moist environment for rapid wound healing, a hydrosheet composed of alginate, chitin/chitosan, and fucoidan (ACF-HS) has been developed as a functional wound dressing. The aim of this study was to evaluate the accelerating effect of ACF-HS on wound healing for rat mitomycin C-treated healing-impaired wounds. Full-thickness skin defects were made on the back of rats and mitomycin C was applied onto the wound for 10 minutes to prepare a healing-impaired wound. After thoroughly washing out the mitomycin C, ACF-HS was applied to the healing-impaired wounds. The rats were later euthanized and histological sections of the wounds were prepared. The histological examinations showed significantly advanced granulation tissue and capillary formations in the healing-impaired wounds treated with ACF-HS on days 7 and 14, in comparison with that in alginate fiber (Kaltostat), hydrogel wound dressing (DuoACTIVE), and nontreatment (negative control). Furthermore, in cell culture studies, ACF-HS-absorbed serum and fibroblast growth factor-2 was found to be proliferative for fibroblasts and endothelial cells, respectively, and ACF-HS-absorbed serum was found to be chemoattractive for fibroblasts. However, our results may not be strictly comparable with general healing-impaired wound models in humans because of the cell damage by mitomycin C. In addition, more biocompatibility studies of fucoidan are essential due to the possibility of renal toxicity. PMID:20731799

  10. Effects of 5-Amyno-4-(1,3-benzothyazol-2-yn)-1-(3-methoxyphenyl)-1,2-dihydro-3H-pyrrol-3-one Intake on Digestive System in a Rat Model of Colon Cancer

    PubMed Central

    Kuznietsova, Halyna M.; Luzhenetska, Valentyna K.; Kotlyar, Iryna P.; Rybalchenko, Volodymyr K.

    2015-01-01

    Introduction. Pyrrol derivate 5-amyno-4-(1,3-benzothyazol-2-yn)-1-(3-methoxyphenyl)-1,2-dihydro-3H-pyrrol-3-one (D1) has shown antiproliferative activities in vitro, so investigation of the impact of D1 intake on gut organs in rats that experienced colon cancer seems to be necessary. Materials and Methods. D1 at the dose of 2.3 mg/kg was administered per os daily for 27 (from the 1st day of experiment) or 7 (from the 21st week of experiment) weeks to rats that experienced 1,2-dimethylhydrazine (DMH)-induced colon cancer for 20 weeks. 5-Fluorouracil (5FU) was chosen as reference drug and was administered intraperitoneally weekly for 7 weeks (from the 21st week of experiment) at the dose of 45 mg/kg. Results. Antitumor activity of D1 comparable with the 5FU one against DMH-induced colon cancer in rats was observed (decrease of tumor number and tumor total area up to 46%). D1 attenuated the inflammation of colon, gastric and jejunal mucosa, and the liver, caused by DMH, unlike 5FU, aggravating the latter. In addition, D1 partially normalized mucosa morphometric parameters suggesting its functional restore. Conclusions. D1 possesses, comparable with 5-fluorouracil antitumor efficacy, less damaging effects on the tissues beyond cancerous areas and contributes to partial morphological and functional gut organs recovery. PMID:26504896

  11. [Blood oxygen transport, prooxidant -- antioxidant status, and vasoactive characteristics of vascular endothelium in rats treated with endotoxin and taurine].

    PubMed

    Milosh, T S; Maksimovich, N E

    2014-01-01

    Experiments on a group of 74 pregnant rats upon intramuscular introduction of E. coli lipopolysaccharides during pregnancy revealed the correction effect of taurine on the blood oxygen transport function, prooxidant - antioxidant status, and vasoactive characteristics of vascular endothelium.

  12. Promoting effects of potassium dibasic phosphate on early-stage renal carcinogenesis in unilaterally nephrectomized rats treated with N-ethyl-N-hydroxyethylnitrosamine.

    PubMed

    Hiasa, Y; Konishi, N; Nakaoka, S; Nakamura, T; Nishii, K; Ohshima, M

    1992-07-01

    The effects of potassium dibasic phosphate (PDP), potassium aluminum sulfate (PAS) and copper sulfate (CS) on early-stage renal carcinogenesis were investigated in unilaterally nephrectomized male Wistar rats after N-ethyl-N-hydroxyethylnitrosamine (EHEN) administration. After feeding 1,000 ppm EHEN, or basal diet for 2 weeks and removal of the left kidney at week 3, male Wistar rats were divided into 8 groups of 20 rats each. These groups received the following dietary treatments: 50,000 ppm PDP, 50,000 ppm PAS, 5,000 ppm CS or basal diet, respectively, for 18 weeks from weeks 3 to 20. The average numbers of adenomatous hyperplasias counted as preneoplastic lesions in the EHEN with 50,000 ppm PDP group were significantly higher than in the EHEN alone group or the EHEN followed by 50,000 ppm PAS or 5,000 ppm CS group. The treatment with 50,000 ppm PDP induced renal calcification and promoted the development of preneoplastic lesions in unilaterally nephrectomized rats treated with EHEN, but that with 50,000 ppm PAS or 5,000 ppm CS did not.

  13. Reduced synthesis of pp60src and expression of the transformation-related phenotype in interferon-treated Rous sarcoma virus-transformed rat cells.

    PubMed

    Lin, S L; Garber, E A; Wang, E; Caliguiri, L A; Schellekens, H; Goldberg, A R; Tamm, I

    1983-09-01

    Treatment of Rous sarcoma virus-transformed rat cells with rat interferon-alpha (specific activity, 10(6) U/mg of protein) for 24 h caused a 50% reduction in intracellular pp60src-associated protein kinase activity. Staphylococcus aureus V8 protease digestion of pp60src, derived from 32P-labeled monolayer cultures incubated with or without interferon, revealed no differences either in the phosphopeptide pattern or in the phosphoserine-phosphotyrosine ratio. However, [3H]leucine pulse-labeling experiments showed that the synthesis of pp60src was reduced by 42 to 48%, relative to the level of bulk protein synthesis, in the interferon-treated cultures. Rat interferon-alpha also reduced the growth rate of Rous sarcoma virus-transformed rat cells in a dose-dependent manner over a 72-h period. The decrease in growth rate was accompanied by increases in the thickness and number of actin fibers per cell and by a decline in intracellular tyrosine phosphorylation by pp60src. The results suggest that interferon can inhibit the expression of the transformation-related phenotype by selectively reducing the synthesis of the Rous sarcoma virus transforming gene product. However, the interferon effects on the cytoskeletal organization and proliferation of Rous sarcoma virus-transformed cells may be due at least in part to the predominance of interferon-induced phenotypic changes over those caused by pp60src. PMID:6314124

  14. Inhibition of lipopolysaccharide-induced liver injury in rats treated with a hepatic drug-metabolizing enzyme inducer p,p'-DDT.

    PubMed

    Shimada, Yuko; Tomita, Mariko; Yoshida, Toshinori; Fukuyama, Tomoki; Katoh, Yoshitaka; Ohnuma-Koyama, Aya; Takahashi, Naofumi; Soma, Katsumi; Kojima, Sayuri; Ohtsuka, Ryoichi; Takeda, Makio; Kuwahara, Maki; Harada, Takanori

    2015-03-01

    Hepatocellular hypertrophy in association with drug-metabolizing enzyme induction is considered to be an adaptive change associated with drug metabolism. To improve our understanding of liver hypertrophy, we determined the effect of a single ip injection of either lipopolysaccharide (LPS) or vehicle in male F344 rats with hepatocellular hypertrophy induced by oral delivery of p,p'-DDT for 2 weeks. The rats were sacrificed 3h or 24h after LPS or vehicle injection. LPS induced a focal hepatocellular necrosis in rats fed the control diet. When rats pre-treated with p,p'-DDT were injected with LPS, necrotic foci surrounded by ballooned hepatocytes were observed in the liver. The change was consistent with reduced LPS-mediated increases in plasma hepatic biomarkers, neutrophil influx, and apoptosis, and also associated with hepatic mRNA levels of TNF-α, CYPs, and NOS2. By contrast, when combined with p,p'-DDT and LPS, faint hepatocellular fatty change was extended, together with a synergistic increase in total blood cholesterol. These results suggest that hepatocytes exposed to p,p'-DDT are protected from the cell-lethal toxic effects of an exogenous stimulus, resulting in cell ballooning rather than necrosis in association with reduced inflammation and apoptosis, but compromised by an adverse effect on lipid metabolism.

  15. Pentadecapeptide BPC 157 reduces bleeding time and thrombocytopenia after amputation in rats treated with heparin, warfarin or aspirin.

    PubMed

    Stupnisek, Mirjana; Franjic, Sandra; Drmic, Domagoj; Hrelec, Masa; Kolenc, Danijela; Radic, Bozo; Bojic, Davor; Vcev, Aleksandar; Seiwerth, Sven; Sikiric, Predrag

    2012-05-01

    Recently, in rat abdominal aorta terminoterminal-anastomosis the stable gastric pentadecapeptide BPC 157 prevents obstructive thrombus formation and rapidly destroys already formed obstructive thrombus. Also, BPC 157 wound healing may signify the clot as conductive matrix or "scaffold" to speed up wound healing process, and decrease bleeding. Here, in rats, BPC 157 (10 μg/kg, 10 ng/kg) improved always reduced bleeding time and amount of bleeding after (tail) amputation only, heparin (250 mg/kg, 25mg/kg, 10mg/kg i.v.), warfarin (1.5mg/kg i.g. once daily for 3 consecutive days), aspirin (0.1g/kg i.g. (once daily/3 consecutive days) or 1.0 g/kg i.p. once), and amputation associated with those agents application. BPC 157 counteracting regimens (i.v., i.p., i.g. (immediately after any challenge)) correspondingly follow the route of bleeding-agents application. All heparin-, warfarin-, and aspirin-rats and normal-rats that received BPC 157 exhibited lesser fall in platelets count. BPC 157 attenuated over-increased APTT-, TT-values in 10mg/kg heparin-rats, but did not influence heparin activity (anti-Xa test). Indicatively, unless counteracted in BPC 157 rats, excessive bleeding-acute thrombocytopenia (<20% of initial values in heparin-rats) approaches substantial fall in platelets count known in type II HIT. Also, BPC 157 markedly prolongs the survival time (heparin-rats, 25mg/kg, right foot amputation). PMID:21840572

  16. The Efficiency of Barley (Hordeum vulgare) Bran in Ameliorating Blood and Treating Fatty Heart and Liver of Male Rats

    PubMed Central

    Abulnaja, Khalid O.; El Rabey, Haddad A.

    2015-01-01

    The current study focused on testing the hypolipidemic activity of two doses of barley bran on hypercholesterolemic male rats. Twenty-four male albino rats weighing 180–200 gm were divided into four groups. The first group (G1) was the negative control, the second group (G2) was the positive control group fed 2% cholesterol in the diet, and rats of the third and the fourth groups were fed 2% cholesterol and were cosupplemented with 5% and 10% barley bran, respectively, for 8 weeks. The hypercholesterolemic rats of (G2) showed an increase in lipid profile, liver enzymes, lactate dehydrogenase, creatine kinase-MB, and lipid peroxide and a decrease in antioxidant enzymes, whereas kidney function, fasting blood sugar, glycated hemoglobin total protein, and total bilirubin were not significantly affected compared with the negative control group in G1. Moreover, histology of heart, liver, and kidney of G2 rats showed histopathological changes compared with the negative control. Administration of the two doses of barley bran in G3 and G4 to the hypercholesterolemic rats ameliorated the level of lipids, liver enzymes, lactate dehydrogenase, and creatine kinase-MB. In addition, the histology of heart, liver, and kidney tissues nearly restored the normal state as in G1. PMID:25866539

  17. Activation of K{sup +} channels and Na{sup +}/K{sup +} ATPase prevents aortic endothelial dysfunction in 7-day lead-treated rats

    SciTech Connect

    Fiorim, Jonaina; Ribeiro Júnior, Rogério Faustino; Azevedo, Bruna Fernades; Simões, Maylla Ronacher; Padilha, Alessandra Simão; Stefanon, Ivanita; Alonso, Maria Jesus; Salaices, Mercedes; Vassallo, Dalton Valentim

    2012-07-01

    Seven day exposure to a low concentration of lead acetate increases nitric oxide bioavailability suggesting a putative role of K{sup +} channels affecting vascular reactivity. This could be an adaptive mechanism at the initial stages of toxicity from lead exposure due to oxidative stress. We evaluated whether lead alters the participation of K{sup +} channels and Na{sup +}/K{sup +}-ATPase (NKA) on vascular function. Wistar rats were treated with lead (1st dose 4 μg/100 g, subsequent doses 0.05 μg/100 g, im, 7 days) or vehicle. Lead treatment reduced the contractile response of aortic rings to phenylephrine (PHE) without changing the vasodilator response to acetylcholine (ACh) or sodium nitroprusside (SNP). Furthermore, this treatment increased basal O{sub 2}{sup −} production, and apocynin (0.3 μM), superoxide dismutase (150 U/mL) and catalase (1000 U/mL) reduced the response to PHE only in the treated group. Lead also increased aortic functional NKA activity evaluated by K{sup +}-induced relaxation curves. Ouabain (100 μM) plus L-NAME (100 μM), aminoguanidine (50 μM) or tetraethylammonium (TEA, 2 mM) reduced the K{sup +}-induced relaxation only in lead-treated rats. When aortic rings were precontracted with KCl (60 mM/L) or preincubated with TEA (2 mM), 4-aminopyridine (4-AP, 5 mM), iberiotoxin (IbTX, 30 nM), apamin (0.5 μM) or charybdotoxin (0.1 μM), the ACh-induced relaxation was more reduced in the lead-treated rats. Additionally, 4-AP and IbTX reduced the relaxation elicited by SNP more in the lead-treated rats. Results suggest that lead treat