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Sample records for 5-fu treated rats

  1. The herbal extract, Iberogast, improves jejunal integrity in rats with 5-Fluorouracil (5-FU)-induced mucositis.

    PubMed

    Wright, Tessa H; Yazbeck, Roger; Lymn, Kerry A; Whitford, Eleanor J; Cheah, Ker Y; Butler, Ross N; Feinle-Bisset, Christine; Pilichiewicz, Amelia N; Mashtoub, Suzanne; Howarth, Gordon S

    2009-05-01

    There is an acute need for the development of effective therapies for mucositis, a debilitating side effect of cancer chemotherapy. Iberogast is a herbal extract reported to possess anti-inflammatory properties. We investigated Iberogast for its potential to reduce the severity of 5-Fluorouracil (FU)-induced mucositis in rats. Rats were allocated to three treatment groups (n = 8) and gavaged daily with a 10% solution of Iberogast or water from day 0 to day 8. Rats were injected intraperitoneally with 5-FU (150 mg/kg) or saline on day 6, and killed after 72 h. In vivo and in vitro sucrase activity was assessed by (13)C-sucrose breath test (SBT) and sucrase assay respectively. Intestinal disease severity was determined by histological assessment of villus height and crypt depth. Significant increases in villus height (277 +/- 9 microm) and crypt depth (67 +/- 3 microm) were observed in 5-FU + Iberogast-treated rats compared with 5-FU + Water (224 +/- 13 microm and 48 +/- 2 microm respectively; p < 0.05). Sucrase activity was significantly reduced in all 5-FU groups compared to control. Significant reductions in SBT and sucrase activity were observed in all 5-FU groups compared with Saline + Water controls (p < 0.05). We conclude that although Iberogast partially improved the histopathological features of 5-FU induced mucositis, it conferred no significant protection as indicated by the assessed endpoints.

  2. Absorption and distribution characteristics of 5-fluorouracil (5-FU) after an application to the liver surface in rats in order to reduce systemic side effects.

    PubMed

    Kodama, Yukinobu; Fumoto, Shintaro; Nishi, Junya; Nakashima, Mikiro; Sasaki, Hitoshi; Nakamura, Junzo; Nishida, Koyo

    2008-05-01

    The present study was undertaken to elucidate the absorption and distribution characteristics of 5-fluorouracil (5-FU) after its application to the liver surface in rats to examine the possibility of reducing the systemic side effects of this agent. 5-FU was applied to the surface of the liver by employing a cylindrical diffusion cell. Approximately 69% of the dose was absorbed in 360 min. The time course of the change in the amount of 5-FU remaining in the diffusion cell obeyed first-order kinetics. Also, a linear relationship was observed between the apparent permeability coefficient, P app, and the reciprocal of the square root of the molecular weight of several compounds including 5-FU. The estimated P app value of 5-FU was in good agreement with the experimental value. The plasma concentration of 5-FU was low (<1.2 microg/ml) until 360 min after the application. Following i.v. administration, 5-FU was rapidly eliminated from the plasma and could not be detected at 120 min. In the analysis of tissue distribution, the liver was divided into three sites; the region under the diffusion cell attachment site (site 1), the treated lobe excluding site 1 (site 2), and untreated lobes (site 3). After being administered i.v., 5-FU mainly distributed in the kidney, and the concentration in the liver was significantly lower than that in kidney, spleen, or heart. After its application to the liver surface, however, 5-FU preferentially distributed at site 1, and was not detected at the other sites or in other tissues. Thus, these results suggested the possibility of a reduction in the systemic side effect of 5-FU on its application to the liver surface.

  3. Effects of 5-FU.

    PubMed

    Wigmore, Peter M; Mustafa, Sarah; El-Beltagy, Maha; Lyons, Laura; Umka, Jariya; Bennett, Geoff

    2010-01-01

    5-fluorouracil (5-FU) is a chemotherapeutical agent used to treat cancers including breast and colorectal. Working as an antimetabolite to prevent cell proliferation, it primarily inhibits the enzyme thymidylate synthase blocking the thymidine formation required for DNA synthesis. Although having a relatively short half-life (< 30 mins) it readily enters the brain by passive diffusion. Clinically, it is used both as a single agent or in combination with other chemotherapies and has been associated with the long-term side effects of cognitive impairment, known as "chemo brain" or "chemo fog" These accounts have come primarily from patients undergoing treatment for breast cancer who report symptoms including confusion and memory impairment, which can last for months to years. Psychometric studies of patients have suffered from confounding variables, which has led to the use of rodent models to assess the cognitive effects of this drug. Researchers have used behavioral and physiological tests including the Morris water maze, novel object location/recognition tests, shock motivated T-maze, sensory gating and conditioning, to investigate the effect of this drug on cognition. The variety of cognitive tests and the difference in dosing and administration of 5-FU has led to varied results, possibly due to the different brain regions associated with each test and the subtlety of the drug's effect, but overall these studies indicates that 5-FU has a negative effect on memory, executive function and sensory gating. 5-FU has also been demonstrated to have biochemical and structural changes on specific regions of the brain. Evidence shows it can induce apoptosis and depress cell proliferation in the neurogenic regions of the adult brain including the sub granular zone (SGZ) within the hippocampus and in oligodendrocyte precursor populations within white matter tracts. Furthermore, investigations indicate levels ofdoublecortin, a marker for newly formed neurons and brain derived

  4. Pharmacogenetic Analysis of INT 0144 Trial: Association of Polymorphisms with Survival and Toxicity in Rectal Cancer Patients Treated with 5-FU and Radiation

    PubMed Central

    Bohanes, Pierre; Rankin, Cathryn J.; Blanke, Charles D.; Winder, Thomas; Ulrich, Cornelia M.; Smalley, Stephen R.; Rich, Tyvin A.; Martensen, James A.; Benson, Al B.; Mayer, Robert J.; Cripps, Christine M.; Danenberg, Kathleen; Makar, Karen W.; Zhang, Wu; Benedetti, Jacqueline K.; Lenz, Heinz-Josef

    2015-01-01

    Purpose We tested whether 18 polymorphisms in 16 genes (GSTP1, COX2, IL-10, EGFR, EGF, FGFR4, CCDN1, VEGFR2, VEGF, CXCR2, IL-8, MMP3, ICAM1, ERCC1, RAD51 and XRCC3) would predict disease-free-survival (DFS), Overall survival (OS) and toxicity in the INT0144 trial, which was designed to investigate different postoperative regimen of 5-FU-based chemoradiation in locally advanced rectal cancers: Arm1 consisted of bolus 5-FU followed by 5-FU protracted venous infusion (PVI) with radiotherapy; Arm2 was induction and concomitant PVI 5-FU with radiotherapy Arm3 was induction and concomitant bolus 5-FU with radiotherapy. Patients and Methods DNA from 746 stage II/III rectal patients enrolled in the SWOG S9304 phase III trial was analyzed. Genomic DNA was extracted from FFPE tumor tissue. The polymorphisms were analyzed using direct DNA-sequencing or PCR-RFLP. Results GSTP1-Ile105Val (rs1695) was significantly associated with DFS and OS and its effect did not vary by treatment arm. The 5-year DFS and OS were 53% and 58%, respectively, for G/G, 66% and 72% for G/A and 57% and 66% for A/A patients. In Arm2, IL8-251A/A genotype (rs4073) was associated with a lower risk of toxicities (p=0.04). The VEGFR2 H472Q Q/Q genotype (rs1870377) was associated with a higher risk of grade 3–5 proximal upper gastrointestinal tract (PUGIT) mucositis (p=0.04) in Arm 2. However, in Arm 1 this genotype was associated with a lower risk of PUGIT mucositis (p=0.004). Conclusion rs1695 may be prognostic in patients with rectal cancer treated with adjuvant chemoradiation. rs4073 and rs1870377 may exhibit different associations with toxicity, according to the 5-FU schedule. PMID:25589620

  5. Effects of Streptococcus thermophilus TH-4 on intestinal mucositis induced by the chemotherapeutic agent, 5-Fluorouracil (5-FU).

    PubMed

    Whitford, Eleanor J; Cummins, Adrian G; Butler, Ross N; Prisciandaro, Luca D; Fauser, Jane K; Yazbeck, Roger; Lawrence, Andrew; Cheah, Ker Y; Wright, Tessa H; Lymn, Kerry A; Howarth, Gordon S

    2009-03-15

    Beneficial bacteria (probiotics) and probiotic-derived factors have the potential to ameliorate disorders of the intestine. The aim of this study was to compare live Streptococcus thermophilus TH-4 (TH-4), dead TH-4 and TH-4 supernatant in rats treated with 5-Fluorouracil. Rats were randomly allocated to five treatment groups (n=8-10): Saline+Water; 5-FU+Skim Milk; 5-FU+Live TH-4; 5-FU+Supernatant TH-4; and 5-FU+Dead TH-4. 5-FU (150mg.kg(-1)) was administered by a single intraperitoneal injection on day 0; animals were killed on day 4. Treatments were administered daily from days -2 to 3 via oro-gastric gavage. Metabolic parameters were measured daily. Blood was obtained by cardiac puncture, and intestinal tissues removed for quantitative and qualitative histological assessment, including: villous height and area; crypt depth and area, mitotic count and crypt fission; biochemical determination of sucrase and myeloperoxidase (MPO) activity; and disease severity scoring. One-way ANOVA statistical analyses were conducted for the majority of outcome measures. Live TH-4 significantly reduced disease severity score by 13% (p< 0.05), and partially normalised mitotic counts compared with 5-FU+Skim milk controls. Live and supernatant TH-4 reduced crypt fission by 69% and 48% (p< 0.05), respectively, compared to 5-FU+Skim Milk controls. No significant differences (p> 0.05) in the occurrence of bacteraemia were evident across all groups. Live TH-4 partially normalised mitotic count and histological severity score in 5-FU treated rats. The inhibitory effect of live TH-4 and TH-4 supernatant on crypt fission suggests therapeutic utility in the prevention of disorders characterised by increased crypt fission, such as colorectal carcinoma.

  6. Effects of Streptococcus thermophilus TH-4 on intestinal mucositis induced by the chemotherapeutic agent 5-Fluorouracil (5-FU).

    PubMed

    Whitford, Eleanor J; Cummins, Adrian G; Butler, Ross N; Prisciandaro, Luca D; Fauser, Jane K; Yazbeck, Roger; Lawrence, Andrew; Cheah, Ker Y; Wright, Tessa H; Lymn, Kerry A; Howarth, Gordon S

    2009-03-15

    Beneficial bacteria (probiotics) and probiotic-derived factors have the potential to ameliorate disorders of the intestine. The aim of this study was to compare live Streptococcus thermophilus TH-4 (TH-4), dead TH-4 and TH-4 supernatant in rats treated with 5-Fluorouracil. Rats were randomly allocated to five treatment groups (n = 8–10): Saline + Water; 5-FU + Skim Milk; 5-FU+ Live TH-4; 5-FU + Supernatant TH-4; and 5-FU + Dead TH-4.5-FU (150 mg.kg-1) was administered by a single intraperitoneal injection on day zero; animals were killed on day four. Treatments were administered daily from days -2 to +3 via oro-gastric gavage. Metabolic parameters were measured daily. Blood was obtained by cardiac puncture, and intestinal tissues removed for quantitative and qualitative histological assessment, including: villus height and area; crypt depth and area, mitotic count and crypt fission;biochemical determination of sucrase and myeloperoxidase (MPO)activity; and disease severity scoring. One-way ANOVA statistical analyses were conducted for the majority of outcome measures. Live TH-4 significantly reduced disease severity score by 13% (p< 0.05), and partially normalized mitotic counts compared with 5-FU + Skim Milk controls. Live and Supernatant TH-4 reduced crypt fission by 69% and 48% (p < 0.05), respectively, compared to 5-FU + Skim Milk controls. No significant differences (p > 0.05) in the occurrence of bacteraemia were evident across all groups. Live TH-4 partially normalized mitotic count and histological severity score in 5-FU treated rats. The inhibitory effect of live TH-4 and TH-4 Supernatant on crypt fission suggests therapeutic utility in the prevention of disorders characterized by increased crypt fission,such as colorectal carcinoma.

  7. 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...

  8. γ-tocotrienol prevents 5-FU-induced reactive oxygen species production in human oral keratinocytes through the stabilization of 5-FU-induced activation of Nrf2

    PubMed Central

    TAKANO, HIDEYUKI; MOMOTA, YUKIHIRO; KANI, KOUICHI; AOTA, KEIKO; YAMAMURA, YOSHIKO; YAMANOI, TOMOKO; AZUMA, MASAYUKI

    2015-01-01

    Chemotherapy-induced oral mucositis is a common adverse event in patients with oral squamous cell carcinoma, and is initiated through a variety of mechanisms, including the generation of reactive oxygen species (ROS). In this study, we examined the preventive effect of γ-tocotrienol on the 5-FU-induced ROS production in human oral keratinocytes (RT7). We treated RT7 cells with 5-FU and γ-tocotrienol at concentrations of 10 μg/ml and 10 nM, respectively. When cells were treated with 5-FU alone, significant growth inhibition was observed as compared to untreated cells. This inhibition was, in part, due to the ROS generated by 5-FU treatment, because N-acetyl cysteine (NAC), a ROS scavenger, significantly ameliorated the growth of RT7 cells. γ-tocotrienol showed no cytotoxic effect on the growth of RT7 cells. Simultaneous treatment of cells with these agents resulted in the significant recovery of cell growth, owing to the suppression of ROS generation by γ-tocotrienol. Whereas 5-FU stimulated the expression of NF-E2-related factor 2 (Nrf2) protein in the nucleus up to 12 h after treatment of RT7 cells, γ-tocotrienol had no obvious effect on the expression of nuclear Nrf2 protein. Of note, the combined treatment with both agents stabilized the 5-FU-induced nuclear Nrf2 protein expression until 24 h after treatment. In addition, expression of Nrf2-dependent antioxidant genes, such as heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase-1 (NQO-1), was significantly augmented by treatment of cells with both agents. These findings suggest that γ-tocotrienol could prevent 5-FU-induced ROS generation by stabilizing Nrf2 activation, thereby leading to ROS detoxification and cell survival in human oral keratinocytes. PMID:25625649

  9. 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.

  10. [Performance of a portable continuous infusion pump (SUREFUSER A) in continuous infusion of 5-FU].

    PubMed

    Kimata, Tsukasa; Sakamoto, Eiji; Kawachi, Aya; Takahashi, Yayoi; Kuroki, Asako; Nakamura, Masashi; Kawade, Yoshihiro; Tokui, Kenji; Suzuki, Tatsuya; Oyama, Takashi; Uchida, Toshiki; Yamada, Tomonori; Kondoh, Masahiro; Ogura, Michinori

    2010-08-01

    Therapy with mFOLFOX6/FOLFIRI used in treating colorectal cancer is typical of the regimens performed in outpatient settings. In this therapy, 46-h continuous infusion of 5-fluorouracil (5-FU) with concomitant oxaliplatin and irinotecan hydrochloride is conducted. The portable continuous infusion pump that makes continuous infusion possible has a non-electric structure, so variation in the infusion rate is seen. There are known effects of 5-FU concentration and temperature, and many studies have reported on the precision. In our hospital, we have experienced many cases of incomplete infusion and delays for the above reasons. We changed the specifications of the infusion pump to correspond to the kinematic viscosity of 5-FU and made all drug solution amounts uniform. We measured the time required to administer the drug solution from the time the infusion was started (recorded by a nurse) and the time it was completed (recorded by the patient), and confirmed the precision of the pump after the changes were made. It was found that while there was a decrease in the infusion rate at which the effect of the kinematic viscosity of 5-FU is seen, the mean infusion time was kept to within 46+/-10% hours in more than 90% of patients. There were no effects from concentration differences in 5-FU, and the completion time was reduced. The management and lifestyles of individual patients are potential factors in precision errors, and it is important to explain in advance to patients the necessity of secure fixation and infusion pump problems that might occur.

  11. Probiotic factors partially improve parameters of 5-fluorouracil-induced intestinal mucositis in rats.

    PubMed

    Prisciandaro, Luca D; Geier, Mark S; Butler, Ross N; Cummins, Adrian G; Howarth, Gordon S

    2011-04-01

    Certain live bacteria have demonstrated preliminary indications of efficacy for the treatment of chemotherapy-induced intestinal mucositis. However, probiotic derived supernatants (SN) have yet to be investigated in the mucositis setting. We evaluated SN from Escherichia coli Nissle 1917 (EcN) and Lactobacillus fermentum BR11 (BR11) for their capacity to decrease 5-Fluorouracil (5-FU)-induced damage in vivo. Female Dark Agouti rats were gavaged with 1 mL of either SN or vehicle daily (days 0-8) and intraperitoneally injected with 5-FU (150 mg/kg) on day 5 to induce mucositis. On day 9, animals were culled and intestinal tissues collected. Significantly lower histological damage scores were apparent in the jejunum of 5-FU treated rats receiving SN compared to 5-FU controls. Myeloperoxidase levels in the jejunum of 5-FU treated rats were increased in vehicle and BR11 SN treatments compared to untreated controls, whereas no significant increase was observed after EcN SN treatment. 5-FU treatment significantly reduced villus height and crypt depth in the jejunum compared to normal controls; however no significant reduction in these parameters was observed in 5-FU treated rats receiving either SN. We conclude that bacterial SN, especially EcN, partially protect the intestine from 5-FU mucositis. Further studies are required to define specific mechanisms by which SN exert their beneficial effects.

  12. Zebrafish stem cell differentiation stage factors suppress Bcl-xL release and enhance 5-Fu-mediated apoptosis in colon cancer cells.

    PubMed

    D'Anselmi, F; Cucina, A; Biava, P M; Proietti, S; Coluccia, P; Frati, L; Bizzarri, M

    2011-02-01

    Stem cell differentiation stage factors (SCDSF), taken from Zebrafish embryos during the stage in which totipotent stem cells are differentiating into pluripotent stem cells, have been shown to inhibit proliferation and induce apoptosis in colon tumors. In order to ascertain if these embryonic factors could synergistically/additively interact with 5-Fluorouracil (5-Fu), whole cell-count, flow-cytometry analysis and apoptotic parameters were recorded in human colon cancer cells (Caco2) treated with Zebrafish stem cell differentiation stage factors (SCDSF 3 µg/ml) in association or not with 5-Fu in the sub-pharmacological therapeutic range (0.01 mg/ml). Cell proliferation was significantly reduced by SCDSF, meanwhile SCDSF+5-Fu leads to an almost complete growth-inhibition. SCDSF produces a significant apoptotic effect, meanwhile the association with 5-FU leads to an enhanced additive apoptotic rate at both 24 and 72 hrs. SCDSF alone and in association with 5-Fu trigger both the extrinsic and the intrinsic apoptotic pathways, activating caspase-8, -3 and -7. SCDSF and 5-Fu alone exerted opposite effects on Bax and Bcl-xL proteins, meanwhile SCDSF+5-Fu induced an almost complete suppression of Bcl-xL release and a dramatic increase in the Bax/Bcl-xL ratio. These data suggest that zebrafish embryo factors could improve chemotherapy efficacy by reducing anti-apoptotic proteins involved in drug-resistance processes.

  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. 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.

  15. 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

  16. 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.

  17. rpL3 promotes the apoptosis of p53 mutated lung cancer cells by down-regulating CBS and NFκB upon 5-FU treatment

    PubMed Central

    Russo, Annapina; Saide, Assunta; Cagliani, Roberta; Cantile, Monica; Botti, Gerardo; Russo, Giulia

    2016-01-01

    5-FU is a chemotherapy drug commonly used for the treatment of human cancers; however drug resistance represents a major challenge for its clinical application. In the present study, we reporte that rpL3 induced by 5-FU treatment in Calu-6 cells represses CBS transcription and reduces CBS protein stability leading to a decrease of CBS protein levels. rpL3 also regulates negatively the activation of NFκB by preventing NFκB nuclear translocation through IκB-α up-regulation. Furthermore, we demonstrate that rpL3 significantly enhances the apoptosis of 5-FU treated Calu-6 cells promoting the overexpression of the pro-apoptotic proteins Bax and the inhibition of the anti-apoptotic protein Bcl-2. We finally demonstrate that rpL3 potentiates 5-FU efficacy inhibiting cell migration and invasion. Our results suggest that combination of rpL3 and 5-FU is a promising strategy for chemotherapy of lung cancers lacking functional p53 that are resistant to 5-FU. PMID:27924828

  18. The potential protective role of taurine against 5-fluorouracil-induced nephrotoxicity in adult male rats.

    PubMed

    Yousef, Hany N; Aboelwafa, Hanaa R

    2017-02-08

    Nephrotoxicity is common with the use of the chemotherapeutic agent 5-Fluorouracil (5-FU). The current study aimed to investigate the probable protective effect of taurine (TAU) against 5-FU-induced nephrotoxicity in rats using biochemical, histological and ultrastructural approaches. Twenty-four rats were equally divided into control, TAU, 5-FU and 5-FU+TAU groups. 5-FU significantly elevated levels of blood urea nitrogen (BUN), creatinine, and uric acid; while it reduced activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px). Also, 5-FU induced significant elevation in malondialdehyde (MDA) levels accompanied with marked decline in γ-glutamyltranspeptidase (GGT) and alkaline phosphatase (AP) levels in kidney tissues. These biochemical alterations were accompanied by histopathological changes marked by destruction of the normal renal structure, in addition to ultrastructural alterations represented by thickened and irregular glomerular basement membranes, congested glomerular capillaries, damaged lining fenestrated endothelium, mesangial cells hyperplasia with expanded mesangial matrix, and distorted podocyte's processes. Also, the proximal (PCT) and distal (DCT) convoluted tubules showed thickened basement membranes, destructed apical microvilli and loss of basal infoldings of their epithelial cells. Administration of TAU to 5-FU-treated rats reversed most of the biochemical, histological, and ultrastructural alterations. These results indicate that TAU has a protective effect against 5-FU-induced nephrotoxicity.

  19. Dosimetric study of photobiomodulation therapy in 5-FU-induced oral mucositis in hamsters

    NASA Astrophysics Data System (ADS)

    Cotomacio, Claudia Carrara; Campos, Luana; Nesadal de Souza, Douglas; Arana-Chavez, Victor Elias; Simões, Alyne

    2017-01-01

    Oral mucositis (OM) is a debilitating consequence of cancer treatment that could be treated with photobiomodulation therapy (PBMT); however, there is no consensus about its dosimetric parameters for OM healing. The aim of this study was to compare different PBMT protocols on OM treatment, through clinical and histological analysis. Thirty hamsters were used, in an induced model of OM by 5-fluorouracil (5-FU) and superficial scratching, in seven days of follow-up. The animals were divided into five groups: control (C), which received only anesthesia and chemotherapeutic vehicle; chemotherapy (Ch), which received anesthesia, 5-FU, and scratches; laser 1 (L1), the same as Ch group, PBMT 6 J/cm2 and 0.24 J (one point); laser 2 (L2), the same as Ch group, PBMT 25 J/cm2 and 1 J (one point); and laser 3 (L3), the same as Ch group, PBMT 4 points of 0.24 J and 6 J/cm2 each. The laser used has λ=660 nm, 0.04 cm2 of spot area, and 40 mW. The best PBMT protocol to maintain lowest OM levels compared to Ch group was L1, followed by L2 and L3. Our results suggest that the application mode of PBMT and the energy delivered per area could interfere with the OM healing.

  20. PAK6 increase chemoresistance and is a prognostic marker for stage II and III colon cancer patients undergoing 5-FU based chemotherapy

    PubMed Central

    Yan, Dongwang; Cui, Feifei; Wang, Xiaoliang; Yu, Fudong; Xue, Yingming; Feng, Xiaodong; Wang, Jingtao; Wang, Xiao; Jiang, Tao; Zhang, Meng; Zhao, Senlin; Yu, Yang; Tang, Huamei; Peng, Zhihai

    2015-01-01

    p21-Activated kinase 6 (PAK6) has been implicated in radiotherapy and docetaxel resistance. We have further evaluated PAK6 as a predictor of 5-fluorouracil (5-FU) treatment response in colon cancer. Here we report that in colon cancer PAK6 promotes tumor progression and chemoresistance both in vitro and in vivo. In the clinical analysis, PAK6 was overexpressed in 104 of 147 (70.75%) stage II and III patients who received 5-FU based chemotherapy after surgery. Multivariate Cox regression analysis indicated that PAK6 was an independent prognostic factor for overall survival (P < 0.001) and disease-free survival (P < 0.001). Colon cancer cell lines showed increased PAK6 expression upon 5-FU treatment. In PAK6-knockdown cells treated with 5-FU, cell viability and phosphorylation of BAD decreased, and the number of apoptotic cells, levels of cleaved caspase 3 and PARP increased compared to control cells. The opposite was observed in PAK6 overexpressing cells. Short hairpin RNA knockdown of PAK6 blocked cells in G2-M phase. Furthermore, Animal experiments results in vivo are consistent with outcomes in vitro. This study demonstrates that PAK6 is an independent prognostic factor for adjuvant 5-FU-based chemotherapy in patients with stage II and stage III colon cancer. PMID:25426562

  1. Layered inorganic nanocomposites: a promising carrier for 5-fluorouracil (5-FU).

    PubMed

    Kevadiya, Bhavesh D; Patel, Tapan A; Jhala, Devendrasinh D; Thumbar, Rahul P; Brahmbhatt, Harshad; Pandya, Maharshi P; Rajkumar, Shalini; Jena, Prasant K; Joshi, Ghanshyam V; Gadhia, Pankaj K; Tripathi, C B; Bajaj, Hari C

    2012-05-01

    We report here the intercalation of 5-fluorouracil (5-FU), an anticancer drug in interlayer gallery of Na(+) clay (Montmorillonite, MMT), with the assistance of biopolymer (chitosan, CS). The X-ray diffraction patterns, thermal and spectroscopic analyses indicated the drug intercalation into the clay interlayer space in support of CS and stabilized in the longitudinal monolayer by electrostatic interaction. In vitro drug release showed controlled release pattern. The genotoxic effect of drug was in vitro evaluated in human lymphocyte cell culture by comet assay, and results indicated significant reduction in DNA damage when drug was intercalated with clay and formulated in composites. The results of in vitro cell viability assay in cancer cells pointed at decreased toxicity of drug when encapsulated in Na(+)-clay plates than the pristine drug. In vivo pharmacokinetics, biodistribution, hepatotoxicity markers, e.g., SGPT and SGOT, and liver/testicular histology in rats showed plasma/tissue drug levels were within therapeutic window as compared to pristine drug. Therefore, drug-clay hybrid and composites can be of considerable value in chemotherapy of cancer with reduced side effects.

  2. [Effects of intravenous alimentation on adjuvant chemotherapy--an experimental study on the distribution of 5-FU after injection of tegafur (2)].

    PubMed

    Kimoto, M; Nagano, H; Sano, K

    1987-10-01

    The stomach, small and large intestines, heart, lungs, bone and kidneys were removed from 48 Sato lung cancer-bearing rats used in the previous experiments and given 90 mg/kg of tegafur (FT-207) by single intravenous administration and tissue 5-FU and FT-207 concentrations were measured. FT-207 concentration in the alimentary canal was somewhat lower than the blood concentration, but both were lowered in parallel. 5-FU concentration in the stomach and large intestines showed virtually identical changes in both IVH and PO groups, but IVH group tended to have higher concentration. IVH group showed higher values than PO group anytime, particularly in the large intestines. A reduction of the side effects on the digestive system via intravenous alimentation was thought due to the elimination of mechanical stimulation via a cessation of oral feeding. 5-FU concentration in the bone was highest in PO group at six hours after administration and blood concentration changes were parallel, but there was virtually no change in IVH group. Maximum values were found one hour after administration and slowly declined thereafter; at 24 hrs the values were 0.059 +/- 0.013 microgram/g, relatively high compared to the PO group at 0.041 +/- 0.022 microgram/g. In the present study under intravenous alimentation, the concentration changes were slight in spite of 5-FU maximum concentration being lower than that by oral feeding and the long-term high concentration which was maintained; this is thought to be a disadvantageous action with regard to the bone marrow. FT-207 concentration in the kidney, heart and lungs was the same as that for the blood, with a gradual reduction in IVH group. 5-FU concentration was the same for the kidneys and IVH group quickly reached to the high levels compared to PO group with only slight changes thereafter. Effects of continuous water load might be involved but not clear.

  3. [A case of liver metastasis of rectal cancer demonstrating complete response to 5-FU + Leucovorin + UFT].

    PubMed

    Ishida, Hideyuki; Ohsawa, Tomonori; Takeuchi, Ikuya; Nakada, Hiroshi; Inokuma, Shigehisa; Hoshino, Takanobu; Daijo, Hashimoto

    2002-04-01

    Dihydropyrimidine dehydrogenase (DPD) is a rate-limiting enzyme that metabolizes 5-fluorouracil (5-FU). We report a patient with metachronous liver metastasis from rectal cancer with low expression of DPD, who demonstrated complete response to chemotherapy comprising 5-FU, Leucovorin, and UFT. A 53-year-old man underwent macroscopically curative proctectomy with coloanal anastomosis for lower rectal cancer (Curability B). The DPD level in the primary tumor determined by an enzyme-linked immunosorbent assay was extremely low (10.3 U/mg.protein). Three months postoperatively, 5-FU (333 mg/m2) + Leucovorin (200 mg/m2) therapy (once a week for 3 weeks with a one-week rest interval, repeatedly) was started as an adjuvant therapy. However, computed tomography demonstrated a solitary liver metastasis 3 cm in size 1 month later. Chemotherapy was continued with dose escalation of 5-FU (500 mg/m2) and with oral administration of UFT-E (400 mg/body, daily). Five months later, computed tomography did not detect the liver metastasis, and this finding was maintained for two months (complete response). This case provides evidence that a low expression of DPD in the primary lesion is related to a favorable response of liver metastasis to 5-FU-based systemic chemotherapy.

  4. Regorafenib with a fluoropyrimidine for metastatic colorectal cancer after progression on multiple 5-FU-containing combination therapies and regorafenib monotherapy

    PubMed Central

    Marks, Eric I.; Tan, Carlyn; Zhang, Jun; Zhou, Lanlan; Yang, Zhaohai; Scicchitano, Angelique; El-Deiry, Wafik S.

    2015-01-01

    We present 2 patients with metastatic colorectal cancer who had progressed despite treatment with first-line FOLFOX and second-line FOLFIRI combination chemotherapy regimens. After failing these fluoropyrimidine-based regimens, both patients received additional cytotoxic and targeted therapies with eventual disease progression. These therapies included capecitabine plus dabrafenib and trametinib, regorafenib monotherapy, and regorafenib with panitumumab. After exhausting available options, both patients were offered regorafenib with either 5-fluorouracil (5-FU) or capecitabine. These therapies are individually approved for the treatment of colorectal cancer but have not yet been studied in combination. This regimen produced stable disease in both patients with acceptable toxicity. One patient continued therapy for 17 months. Although these patients previously progressed during treatment with regorafenib, capecitabine or 5-FU, the combination had some activity in both cases of refractory metastatic colorectal cancer and may be considered in the palliative setting. In bedside-to-bench cell culture experiments performed after the clinical observations, we observed sensitivity of human colorectal cancer cell lines (N = 4) to single agent regorafenib or 5-FU and evidence of synergy with the combination therapy. Synergistic effects were noted in colorectal cancer cells with KRAS mutation, BRAF mutation, and p53 mutation, as well as mismatch repair deficient cells. Regorafenib suppressed Mcl-1 and Bcl-XL in treated cancer cells that may have contributed to the anticancer efficacy including in combination with 5-FU. The safety and efficacy of regorafenib with 5-FU or capecitabine in combination should be further investigated as a therapy for patients with refractory metastatic colorectal cancer, including individuals who had progressed on regorafenib monotherapy. PMID:26561209

  5. Effects of American ginseng on pharmacokinetics of 5-fluorouracil in rats.

    PubMed

    He, Yi-Sheng; Sun, Wei; Wang, Chong-Zhi; Qi, Lian-Wen; Yang, Jie; Li, Ping; Wen, Xiao-Dong; Yuan, Chun-Su

    2015-05-01

    The pharmacokinetics of 5-fluorouracil (5-FU) in combination with or without American ginseng (seven-consecutive days oral dose) in rats were evaluated using liquid chromatography-electrospray ionization-mass spectrometry (LC-MS). Chromatographic separation was performed on a reverse LC column within a total run time of 6.5 min, which allowed for a relatively quick analysis. The limit of quantification for 5-FU was 15 ng/mL and this method was linear over 15-50,000 ng/mL. This method supported stabilizing determination of the plasma concentration of 5-FU over a period of 24 h. Precision both interday and intraday (coefficient of variation) was within 14% and accuracy (relative error) ranged from -5 to 14%. In view of the observed pharmacokinetic parameters, including maximum concentration, time to maximum concentration, area under the concentration-time curve (AUC), mean residence time, elimination half-life and clearance, our results showed no significant differences in all of the pharmacokinetic parameters between the ginseng co-treated group and 5-FU alone group. Some increase in AUC was observed in 5-FU plus ginseng group; however, the difference did not reach statistical significance compared with 5-FU alone. It appeared that American ginseng administration did not significantly alter the kinetics of 5-FU. More studies are still needed to confirm our results.

  6. [Postoperative adjuvant chemotherapy using NCS (neocarzinostatin) and 5-FU in the treatment of gastric cancer. First report--A comparison with the 5-year survival rate of patients undergoing combined therapy with MMC and 5-FU].

    PubMed

    Yokomori, T; Taniguchi, T; Iesato, H; Sakata, Y; Watanabe, T; Kawabe, K

    1987-11-01

    As a postoperative adjuvant chemotherapy for gastric cancer, we have administered a combination of NCS (Neocarzinostatin) and 5-FU (NF treatment method) and in this paper we have compiled the results obtained in patients who were treated for 5 years in an attempt to compare the 5-year survival rate with that of patients administered a combination of MMC and 5-FU (MF treatment group) and a control group administered no anticancer agents. As the selection of either NF or MF treatment was conducted on an annual basis, this study can be considered an historical controlled study. The results obtained are summarized as follows. On comparing the survival rate of the NF treatment group and the control group, the 5-year survival rate for all patients who underwent curative resection and all patients with histological stage III cancers and the curative resection PS (+) group, as well as the survival period of the non-resected patients, showed a statistically significant difference, indicating that the survival rate was higher in the NF group. On comparing the NF group and the MF group, although no statistically significant difference was observed between then based on a stratified analysis of all resected cases, histological stage differences and n.ps factors, etc., certain values tended to indicate a higher survival rate for the NF group. Moreover, the survival rate of the non-resected patients was more favorable in the NF group. These results confirm that NCS is useful for the treatment of stomach cancer and compares favorably with MMC. The appearance of side-effects was significantly lower in the NF group in comparison with the MF group and the number of patients who had to discontinue therapy was extremely low.

  7. [Evaluation of combination chemotherapy with 5-FU, CDDP and CPT-11 for human gastric carcinoma transplanted into nude mice - comparative study of in vivo chemosensitivity test].

    PubMed

    Kanamori, Noriaki; Fujii, Masashi; Kochi, Mitsugu; Kaiga, Teruo; Takahashi, Tohru; Takayama, Tadatoshi

    2007-06-01

    We performed in vivo chemosensitivity tests on human gastric carcinoma. To evaluate the efficacy of some combined chemotherapy for human gastric carcinoma maintained in the subcutaneous space in nude mice, we designed the following six experimental groups: 1) 5-FU group, 2) CDDP group, 3) CPT-11 group, 4) combined therapy group of 5-FU and CDDP, 5) combined therapy group of 5-FU and CPT-11, and 6) combined therapy group of CPT-11 and CDDP. An in vivo nude mice assay was performed. Histopathological changes of the tumors in nude mice, treated with anti-cancer agents,were also evaluated and compared to the results of the nude mice assay. Based on histopathological grading,the true positive rate of the nude mice assay was 0%, the true negative rate was 83.3%, and the accuracy rate was 83.3%. CPT-11 appeared to be highly efficacious when given in combination with CDDP in human gastric cancer cell lines. These results suggest that combination chemotherapy with CPT-11 and CDDP is clinically effective for gastric cancer patients.

  8. New Perspectives in the Treatment of Advanced Gastric Cancer: S-1 as a Novel Oral 5-FU Therapy in Combination with Cisplatin.

    PubMed

    Mahlberg, Rolf; Lorenzen, Sylvie; Thuss-Patience, Peter; Heinemann, Volker; Pfeiffer, Per; Möhler, Markus

    2017-01-01

    Oral fluoropyrimidines have been available for more than 10 years. Capecitabine is well established in treating solid tumors in Europe. S-1 (Teysuno®), an oral formulation containing the 5-fluorouracil (5-FU) prodrug tegafur and the two enzyme modulators gimeracil and oteracil, has not been available in non-Asia countries until recently. In Japan, S-1 in combination with cisplatin is the recommended first-line treatment in patients with gastric cancer. In Europe, the first trials with S-1 were disappointing due to high unacceptable incidences of adverse events. Pharmacokinetic studies showed differences in Asian and Caucasian patients; therefore, a new non-Asian study program was initiated, which led to the pivotal phase 3 trial First-Line Advanced Gastric Cancer Study (FLAGS). In FLAGS, 1,053 patients with advanced gastric cancer from 24 non-Asian countries were enrolled. S-1 plus cisplatin showed no overall survival (OS) benefit when compared to 5-FU plus cisplatin. The primary endpoint superior OS was not met but better tolerability was shown. A post hoc noninferiority OS and safety analysis showed that S-1 plus cisplatin has the same efficacy as 5-FU plus cisplatin but a more favorable safety profile. This led to the approval of S-1 in combination with cisplatin in gastric cancer in Europe in 2011. This article reviews the mode of action of S-1, pivotal study results from an EU point of view, and future perspectives.

  9. Neuroprotection by intravenous transplantation of bone marrow mononuclear cells from 5-fluorouracil pre-treated rats in a model of ischemic stroke.

    PubMed

    Li, Yi; Chen, Chun-Hua; Yin, Yu; Mao, Wen-Wei; Hua, Xu-Ming; Cheng, Juan

    2016-10-01

    Our previous studies showed that 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 further explore the potential mechanisms underlying the neuroprotective effects of BMRMNCs in the same model. Rats were intravenously pre-treated with 5-FU, and BMRMNCs were collected 7 days later and subjected to flow cytometry for detection of CD34, CD45 and CD90. Middle cerebral artery occlusion (MCAO) was induced in rats, and BMMNCs and BMRMNCs were independently transplanted via the tail vein at 24 h after MCAO. NISSL staining was performed 14 days after cell transplantation and the viable cells in the hippocampus were counted. Stromal cell-derived factor 1 (SDF-1) mRNA expression was detected in the penumbra at 7 and 14 days after treatment. The contents of pro-inflammatory cytokines and growth factors as well as microvessel density (MVD) were determined at 14 days. Results showed more BMRMNCs were positive for CD34, CD45 and CD90. After transplantation, more viable cells were observed in the hippocampus of BMRMNCs treated rats. In addition, BMRMNCs transplantation significantly increased MVD, reduced pro-inflammatory cytokines and raised growth factors in the penumbra. However, the SDF-1 mRNA expression was comparable between BMRMNCs group and BMMNCs group. Our results indicate that BMRMNCs are likely to more effectively improve the local microenvironment to increase viable cells and elevate angiogenesis, exerting neuroprotective effects on cerebral ischemia in rats.

  10. CTGF enhances resistance to 5-FU-mediating cell apoptosis through FAK/MEK/ERK signal pathway in colorectal cancer

    PubMed Central

    Yang, Kai; Gao, Kai; Hu, Gui; Wen, Yanguang; Lin, Changwei; Li, Xiaorong

    2016-01-01

    Colorectal cancer (CRC) is one of the most commonly diagnosed cancers among both males and females; the chemotherapy drug 5-fluorouracil (5-FU) is one of a doctors’ first lines of defense against CRC. However, therapeutic failures are common because of the emergence of drug resistance. Connective tissue growth factor (CTGF) is a secreted protein that binds to integrins, and regulates the invasiveness and metastasis of certain carcinoma cells. Here, we found that CTGF was upregulated in drug-resistant phenotype of human CRC cells. Overexpression of CTGF enhanced the resistance to 5-FU-induced cell apoptosis. Moreover, downregulating the expression of CTGF promoted the curative effect of chemotherapy and blocked the cell cycle in the G1 phase. We also found that CTGF facilitated resistance to 5-FU-induced apoptosis by increasing the expression of B-cell lymphoma-extra large (Bcl-xL) and survivin. Then we pharmacologically blocked MEK/ERK signal pathway and assessed 5-FU response by MTT assays. Our current results indicate that the expression of phosphorylated forms of MEK/ERK increased in high CTGF expression cells and MEK inhibited increases in 5-FU-mediated apoptosis of resistant CRC cells. Therefore, our data suggest that MEK/ERK signaling contributes to 5-FU resistance through upstream of CTGF, and supports CRC cell growth. Comprehending the molecular mechanism underlying 5-FU resistance may ultimately aid the fight against CRC. PMID:27942222

  11. [Pharmacokinetics and distribution of 5-Fu magnetic albumin deuto-microsphere in normal and tumor-bearing mice].

    PubMed

    Xu, Rong; Shi, Shao-Jun; Zhou, Shun-Chang; Zheng, Jian-Wei; Chen, Hui; Zou, Sheng-Quan; Zeng, Fan-Dian

    2007-01-01

    To observe the pharmacokinetic and tissue-distribution characters of 5-flourouracil magnetic albumin deuto-microsphere (5-Fu-MAD) in normal and tumor-bearing mice, HPLC method for the determination of 5-Fu in plasma and tissues was established and applied to determine 5-Fu in mouse plasma and tissue samples. A Flame atomic absorption spectrometer was used to detect the iron concentration in mouse tissue. Plasma concentration-time curves of free 5-Fu, 5-Fu-MAD and 5-Fu-MAD plus the magnetic frame (MF) conformed to two compartment model of first order absorption and they had C(max) of 34.9, 7.95 and 5.97 mg x L(-1); T1/2 (Ke) of 22.26, 76.0 and 124.6 min, V(d) of 3.28, 30.7 and 66.1 L x kg; AUC(0-t), of 233.9, 78.3 and 50.2 mg x min x L(-1); AUC(0-infinity) of 237.2, 89.3 and 68.1 mg x min x L(-1), respectively. The distribution of 5-Fu and iron was the highest in the plenty blood perfusion organs like the liver, tumor, spleen and lung, while lower in the kidney and heart and lowest in brain and muscle. The tissue distribution of muscle and tumor increased significantly when a magnetic frame was inserted there. The pharmacokinetics and tissue distribution of 5-Fu-MAD exhibited sustained-release and target characteristics.

  12. Synergetic effect of SLN-curcumin and LDH-5-Fu on SMMC-7721 liver cancer cell line.

    PubMed

    Zhu, Rongrong; Wu, Xianzheng; Xiao, Yu; Gao, Bo; Xie, Qian; Liu, Hui; Wang, Shilong

    2013-10-01

    Curcumin and 5-Fluorouracil (5-Fu) have been reported to have anticancer potentials and show certain synergetic effect on some cancer cell lines. However, the poor bioavailability and rapid metabolism limited their medical application. In this study, we encapsulated curcumin with solid lipid nanoparticles (SLN), 5-Fu with Layered double hydroxides (LDHs) separately and tested its properties and anticancer potentials. SLN-curcumin and LDH-5-Fu were determined to be 100 and 60 nm by Transmission Electron Microscopy detection, and the loading efficiency were 28%±2.5% and 16.7%±1.8%, individually. Furthermore, SLN-curcumin and LDH-5-Fu showed a significantly synergetic effect on SMMC-7721 cell stronger than plain drugs together, of which the Idrug loaded nano-carriers was only 0.315. FACS analysis revealed that the combination of SLN-curcumin and LDH-5-Fu induced 80.1% apoptosis in SMMC-7721 cells, which were 1.7-folds of the sum of the two plain drug loaded carriers. The results demonstrated the significant synergetic anticancer potentials of nano-encapsulated curcumin and 5-Fu, which could be further explored for the treatment of other carcinoma.

  13. Synergetic Effect of SLN-Curcumin and LDH-5-Fu on SMMC-7721 Liver Cancer Cell Line

    PubMed Central

    Zhu, Rongrong; Wu, Xianzheng; Xiao, Yu; Gao, Bo; Xie, Qian

    2013-01-01

    Abstract Curcumin and 5-Fluorouracil (5-Fu) have been reported to have anticancer potentials and show certain synergetic effect on some cancer cell lines. However, the poor bioavailability and rapid metabolism limited their medical application. In this study, we encapsulated curcumin with solid lipid nanoparticles (SLN), 5-Fu with Layered double hydroxides (LDHs) separately and tested its properties and anticancer potentials. SLN-curcumin and LDH-5-Fu were determined to be 100 and 60 nm by Transmission Electron Microscopy detection, and the loading efficiency were 28%±2.5% and 16.7%±1.8%, individually. Furthermore, SLN-curcumin and LDH-5-Fu showed a significantly synergetic effect on SMMC-7721 cell stronger than plain drugs together, of which the Idrug loaded nano-carriers was only 0.315. FACS analysis revealed that the combination of SLN-curcumin and LDH-5-Fu induced 80.1% apoptosis in SMMC-7721 cells, which were 1.7-folds of the sum of the two plain drug loaded carriers. The results demonstrated the significant synergetic anticancer potentials of nano-encapsulated curcumin and 5-Fu, which could be further explored for the treatment of other carcinoma. PMID:23808828

  14. L-arginine pretreatment reduces intestinal mucositis as induced by 5-FU in mice.

    PubMed

    Leocádio, Paola C L; Antunes, Maísa M; Teixeira, Lílian G; Leonel, Alda J; Alvarez-Leite, Jacqueline I; Machado, Denise C C; Generoso, Simone V; Cardoso, Valbert N; Correia, Maria Isabel T D

    2015-01-01

    Beneficial effects of L-arginine on immune responses and bowel function have been reported. Mucositis is a side effect of chemotherapy treatment that affects approximately 40% of patients. This complication is characterized by inflammation that affects the gastrointestinal tract, increasing permeability and causing abdominal pain, nausea, vomiting, and diarrhea, which worsen the patient's nutritional status and increases morbimortality. The aim of this study was to evaluate the effect of pretreating with 2% L-arginine supplementation in water on mucositis as induced by 5-fluorouracil (5-FU; a single dose of 200 mg/kg body weight) in Swiss male mice. The effect of L-arginine on weight, intestinal permeability, morphology, and the histopathological score of the small intestine (from 0 to 12), oxidative stress, myeloperoxidase (MPO), and N-acetylglucosaminidase (NAG) activities were evaluated. Intestinal length improvement was observed, in addition to the partial recovery of the mucosal architecture. L-arginine attenuated the histopathological score and MPO activity. There was also an improvement in intestinal permeability, despite weight loss after 5-FU administration. In conclusion, L-arginine can positively impact intestinal mucositis by promoting partial mucosal recovery, reducing inflammation and improving intestinal permeability.

  15. 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

  16. Development and Characterization of Novel Site Specific Hollow Floating Microspheres Bearing 5-Fu for Stomach Targeting

    PubMed Central

    Bhardwaj, Peeyush; Singh, Ranjit; Swarup, Anoop

    2014-01-01

    Multiple-unit-type oral floating hollow microspheres of 5-fluorouracil (5-Fu) were developed using modified solvent evaporation technique to prolong gastric residence time, to target stomach cancer, and to increase drug bioavailability. The prepared microspheres were characterized for micromeritic properties, floating behavior, entrapment efficiency, and scanning electron microscopy (SEM). The in vitro drug release and floating behavior were studied in simulated gastric fluid (SGF) at pH 1.2. The yield of microspheres was obtained up to 84.46 ± 6.47%. Microspheres showed passable flow properties. Based on optical microscopy, particle size was found to be ranging from 158.65 ± 12.02 to 198.67 ± 17.45 μm. SEM confirmed spherical size, perforated smooth surface, and a hollow cavity inside the microspheres. Different kinetic models for drug release were also applied on selected batches. PMID:25383377

  17. 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.

  18. [Evaluation of a combination chemotherapy with nedaplatin and 5-FU for oral cancers].

    PubMed

    Yamamoto, G; Shimada, T; Nishida, T; Ishida, Y; Iba, T; Nakata, T; Ohtsuki, T; Takigami, K; Yamaguchi, Y; Yoshitake, K; Tanaka, A; Tsuda, Y

    2001-08-01

    Nedaplatin (cis-diammine-glycolato platinum: CDGP) is a platinum compound with a molecular weight of 303.18 that was recently developed in Japan. There have been reports of the antineoplastic effects of Nedaplatin on cancers in the cranio-cervical region, lung, esophagus, urinary bladder, testis, ovary, and uterus. In this study, we performed combined therapy of CDGP and fluorouracil (5-FU) for 8 patients with oral cancers, and evaluated the results to elucidate the clinical effect and adverse side effects. The subjects were 8 patients with squamous cell carcinoma (5 males and 3 females aged 33-65 years). The primary carcinoma regions were the tongue in 5 patients, oral floor in 2 patients, and mandibular gingiva in 1 patient. The T-classification was T2 in 6 patients and T4 in 2 patients, and the clinical staging was Stage II in 5 patients, Stage III in 1 patient and Stage IV in 2 patients. We first administered 700 mg/m2 5-FU per day from day 1 to day 5 (total dose 3,500 mg/m2), then 90 mg/m2 CDGP on day 5. The clinical effect was evaluated as a partial response in all cases, showing a 100% success rate. The histopathological findings of resected tumors were evaluated by Ohboshi and Shimozato's classification. One patient was Grade IIA, 5 patients Grade IIB, and 2 patients Grade III. The adverse side effects were slight myelotoxicity, gagging, nausea, alopecia, and stomatitis less than Grade II. Although the oral cancers in this study were extroverted superficial ulcerative cancers, and the number of patients was low at 8, this combined therapy is considered useful and worth evaluating in further accumulated cases.

  19. Factors predicting efficacy of oxaliplatin in combination with 5-fluorouracil (5-FU) ± folinic acid in a compassionate-use cohort of 481 5-FU-resistant advanced colorectal cancer patients

    PubMed Central

    Bensmaïne, M A; Marty, M; Gramont, A de; Brienza, S; Lévi, F; Ducreux, M; François, E; Gamelin, E; Bleiberg, H; Cvitkovic, E

    2001-01-01

    A statistical analysis was performed on the patient data collected from two compassionate-use programmes using oxaliplatin (Eloxatin®) + 5-fluorouracil (5-FU) ± folinic acid (FA), to identify predictive factors for oxaliplatin-based salvage treatment in patients with 5-FU-resistant advanced colorectal cancer (ACRC). 481 5-FU-resistant ACRC patients, most with performance status ≤ 2, ≥ 3 involved sites, and ≥ 2 prior lines of chemotherapy, received oxaliplatin + 5-FU ± FA. Prognostic factors associated with overall response rate (ORR), time to progression (TTP) and overall survival (OS) were identified using univariate and multivariate logistic and/or Cox proportional hazards analyses. The ORR was 16% (95% CI: 13–20), the median TTP was 4.2 months (95% CI: 3.4–4.6), and the median OS was 9.6 months (95% CI: 8.6–10.6). The multivariate analysis indicated poor (≥ 2 WHO) performance status (PS), a large number of prior chemotherapy regimens (≥ 3), a low baseline haemoglobin level (< 10 g/dl), and a triweekly (vs biweekly) treatment administration schedule as significantly associated (P< 0.05) with a lower ORR. Sex (male), number of organs involved (≥3) and alkaline phosphatase (AP) level (≥ 2 × the upper limit of normal) were associated (P< 0.05) with shorter TTP. Poor PS, a large number of organs involved, and elevated AP were independently and significantly correlated with shorter OS. Our analysis identified a relationship between efficacy results of oxaliplatin + 5-FU ± FA treatment in 5-FU-resistant ACRC patients and baseline prognostic factors related to PS, extent of disease and number of prior regimens. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11506488

  20. Antitumor and immunomodulatory effects of low-dose 5-FU on hepatoma 22 tumor-bearing mice

    PubMed Central

    CAO, ZHIYUN; ZHANG, ZHIDENG; HUANG, ZHENGRONG; WANG, RONGPING; YANG, AILIAN; LIAO, LIANMING; DU, JIAN

    2014-01-01

    Low-dose 5-fluorouracil (5-FU), a widely used chemotherapeutic, has been reported to have immunomodulatory effects. This study aimed to evaluate the optimal dose of 5-FU that produces antitumor and immunomodulatory effects. In a hepatoma 22 tumor-bearing mouse model, 0, 10, 20 and 40 mg/kg 5-FU (i.p.) was administered for 10 days. Tumor weight and volume were measured, thymus index (TI) and spleen index (SI) were calculated, and the number of white blood cells (WBCs) and lymphocytes (LYs) were counted following treatment. The percentages of CD3+, CD4+, CD8+ and natural killer (NK) cells were measured by flow cytometry. In addition, the body weights of the mice were measured and the average diet consumption was calculated. Administration of 5-FU produced a potent antitumor effect in a dose-dependent manner (P<0.01). At 20 and 40 mg/kg, a significant reduction of body weight and food consumption was observed. TI and SI decreased in the 20- and 40-mg/kg groups (P<0.01) for 10 days. The number of WBCs significantly decreased in each group (P<0.01); however, the number of LYs only decreased in the 40-mg/kg group (P<0.01). Percentages of CD3+ and CD4+ cells were increased in the 10- and 20-mg/kg groups (P<0.01). Thus, 5-FU at 10 mg/kg inhibits tumor growth while maintaining the immune function of the mice. 5-FU may exert its antitumor effect at a low dose with low toxicity and stimulate the host immune system. Future clinical trials taking into account the immunostimulatory capacity of chemotherapeutic agents are desirable for certain patients. PMID:24660037

  1. 5-FU targets rpL3 to induce mitochondrial apoptosis via cystathionine-β-synthase in colon cancer cells lacking p53

    PubMed Central

    Pagliara, Valentina; Saide, Assunta; Mitidieri, Emma; Roberta d'Emmanuele di Villa, Bianca; Sorrentino, Raffaella; Russo, Giulia; Russo, Annapina

    2016-01-01

    Recent findings revealed in cancer cells novel stress response pathways, which in response to many chemotherapeutic drugs causing nucleolar stress, will function independently from tumor protein p53 (p53) and still lead to cell cycle arrest and/or apoptosis. Since it is known that most cancers lack functional p53, it is of great interest to explore these emerging molecular mechanisms. Here, we demonstrate that nucleolar stress induced by 5-fluorouracil (5-FU) in colon cancer cells devoid of p53 leads to the activation of ribosomal protein L3 (rpL3) as proapoptotic factor. rpL3, as ribosome-free form, is a negative regulator of cystathionine-β-synthase (CBS) expression at transcriptional level through a molecular mechanism involving Sp1. The rpL3-CBS association affects CBS stability and, in addition, can trigger CBS translocation into mitochondria. Consequently apoptosis will be induced through the mitochondrial apoptotic cell death pathway characterized by an increased ratio of Bax to Bcl-2, cytochrome c release and subsequent caspase activation. It is noteworthy that silencing of CBS is associated to a strong increase of 5-FU-mediated inhibition of cell migration and proliferation. These data reveal a novel mechanism to accomplish p53-independent apoptosis and suggest a potential therapeutic approach aimed at upregulating rpL3 for treating cancers lacking p53. PMID:27385096

  2. Experiments on the efficacy and toxicity of locoregional chemotherapy of liver tumors with 5-fluoro-2'-deoxyuridine (FUDR) and 5-fluorouracil (5-FU) in an animal model.

    PubMed

    Bartkowski, R; Berger, M R; Aguiar, J L; Henne, T H; Dörsam, J; Geelhaar, G H; Schlag, P; Herfarth, C

    1986-01-01

    For the investigation of locoregional chemotherapy of liver neoplasms we developed a standardized animal model in the rat. Continuous infusion therapy or repeated bolus injections of FUDR or 5-FU were given via the hepatic artery, the portal vein or the vena cava in tumor-bearing animals. The efficacy of the treatment was determined by measuring the tumor volume 3 weeks after tumor cell implantation. For the evaluation of the local and systemic toxicity serum GOT, GPT, and total bilirubin were determined. DNA single strand breaks were assessed in isolated liver and bone marrow cells. Inhibition of colony formation of bone marrow stem cells was determined by CFU-C and CFU-S bioassay. A significant reduction of tumor growth was observed only after continuous infusion of FUDR via the hepatic artery. Systemic toxicity was lowest in this group for both compounds while the local liver toxicity was only slightly elevated.

  3. 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...

  4. 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

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

    PubMed Central

    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. PMID:24232303

  6. A novel 5-fluorouracil-resistant human esophageal squamous cell carcinoma cell line Eca-109/5-FU with significant drug resistance-related characteristics.

    PubMed

    Zhang, Chi; Ma, Qunfeng; Shi, Yinan; Li, Xue; Wang, Ming; Wang, Junfeng; Ge, Jianlin; Chen, Zhinan; Wang, Ziling; Jiang, Hong

    2017-05-01

    5-Fluorouracil (5-FU) is used for the clinical treatment of esophageal squamous cell carcinomas (ESCCs), yet it also induces chemoresistant cancer cells during treatment, which leads to the failure of the therapy. To further explore the resistance mechanism of 5-FU in ESCC, we established the 5-FU-resistant ESCC cell line Eca-109/5-FU, which was prepared by the stepwise exposure to increasing 5-FU concentrations. MTT assay and nude mouse xenograft models were used to test the drug resistance and proliferation of Eca-109 and Eca-109/5-FU cells in vitro and in vivo. Apoptosis and cell cycle distribution were determined using flow cytometry. Drug resistance-related proteins were detected by western blotting. Metabolomic profiles were obtained from nuclear magnetic resonance (NMR) tests. In regards to Eca-109/5-FU, the decreased susceptibility to 5-FU was determined in vitro and in vivo with slower rate of proliferation. Drug resistance-related proteins (multidrug resistance-associated protein 1 and ATP-binding cassette superfamily G member 2), epithelial-to-mesenchymal transition (EMT)-related proteins (E-cadherin and vimentin) and cancer stem cell-related proteins (prominin-1 and hyaluronate receptor) exhibited significant differences between the two cell lines. The 5-FU-resistant cell line Eca-109/5-FU achieved the ability to tolerate 5-FU, which may depend on significant drug resistance-related characteristics, such as EMT and cancer stem cell-like properties. The metabolism of Eca-109/5-FU was altered, and more than 15 metabolites was found to contribute to the difference in the metabolite profile, such as lactate, glutamate, taurine, glutamine, proline, aspartate, methanol, cystine, glycine and uracil. Our results identified that the resistant cell line Eca-109/5-FU showed quite different characteristics compared with the parental Eca-109 cells. The Eca-109/5-FU cell line provides an experimental model for further steps to select chemotherapeutic

  7. [Cycloferon in treating duodenal ulcers in rats].

    PubMed

    Bul'on, V V; Khnychenko, L K; Sapronov, N S; Kuznetsova, N N; Anikin, V B; arinenko, R Iu; Kovalenko, A L; Alekseeva, L E

    2001-01-01

    The possibility of using cycloferon (interferon inductor) for a complex treatment (in combination with the main drug solcoseryl possessing pronounced therapeutic properties) of duodenum ulcers was experimentally studied in male rats. The experiments showed a considerable difference in the interferon status of animals with model duodenum ulcers treated with cycloferon, solcoseryl, their combination, and placebo (control). The healing effect of solcoseryl administered in combination with cycloferon exceeded that of each component administered separately.

  8. Enhancement of 5-FU sensitivity by the proapoptotic rpL3 gene in p53 null colon cancer cells through combined polymer nanoparticles

    PubMed Central

    Russo, Annapina; Maiolino, Sara; Pagliara, Valentina; Ungaro, Francesca; Tatangelo, Fabiana; Leone, Alessandra; Scalia, Giulia; Budillon, Alfredo

    2016-01-01

    Colon cancer is one of the leading causes of cancer-related death worldwide and the therapy with 5-fluorouracil (5-FU) is mainly limited due to resistance. Recently, we have demonstrated that nucleolar stress upon 5-FU treatment leads to the activation of ribosome-free rpL3 (L3) as proapoptotic factor. In this study, we analyzed L3 expression profile in colon cancer tissues and demonstrated that L3 mRNA amount decreased with malignant progression and the intensity of its expression was inversely related to tumor grade and Bcl-2/Bax ratio. With the aim to develop a combined therapy of 5-FU plus plasmid encoding L3 (pL3), we firstly assessed the potentiation of the cytotoxic effect of 5-FU on colon cancer cells by L3. Next, 10 μM 5-FU and 2 μg of pL3 were encapsulated in biocompatible nanoparticles (NPs) chemically conjugated with HA to achieve active tumor-targeting ability in CD44 overexpressing cancer cells. We showed the specific intracellular accumulation of NPs in cells and a sustained release for 5-FU and L3. Analysis of cytotoxicity and apoptotic induction potential of combined NPs clearly showed that the 5-FU plus L3 were more effective in inducing apoptosis than 5-FU or L3 alone. Furthermore, we show that the cancer-specific chemosensitizer effect of combined NPs may be dependent on L3 ability to affect 5-FU efflux by controlling P-gp (P-glycoprotein) expression. These results led us to propose a novel combined therapy with the use of 5-FU plus L3 in order to establish individualized therapy by examining L3 profiles in tumors to yield a better clinical outcomes. PMID:27835895

  9. Overexpression of fibronectin confers cell adhesion-mediated drug resistance (CAM-DR) against 5-FU in oral squamous cell carcinoma cells.

    PubMed

    Nakagawa, Yoshihiro; Nakayama, Hideki; Nagata, Masashi; Yoshida, Ryoji; Kawahara, Kenta; Hirosue, Akiyuki; Tanaka, Takuya; Yuno, Akira; Matsuoka, Yuichiro; Kojima, Taku; Yoshitake, Yoshihiro; Hiraki, Akimitsu; Shinohara, Masanori

    2014-04-01

    The tumor-associated microenvironment has been shown to protect tumor cells from treatment, and the extracellular matrix (ECM) is known to affect drug resistance as a key regulator of the tumor microenvironment. However, little is known about cell adhesion-mediated drug resistance (CAM-DR) due to cell-ECM contact in patients with oral squamous cell carcinoma (OSCC). In the present study, we evaluated the ECM molecule fibronectin (FN) using DNA microarray data obtained from parental and 5-FU-resistant OSCC cell lines. We investigated the effects of cell adhesion to FN on 5-FU resistance in OSCC cells and examined the activation of FN receptor β1 integrin-mediated survival regulators such as ILK, Akt and NF-κB. In addition, we investigated whether FNIII14, a 22-mer peptide derived from FN that potently prevents β1 integrin-mediated adhesion to FN, could overcome CAM-DR against 5-FU in OSCC cells and examined the activation of survival regulators and apoptosis-related molecules. Consequently, we obtained the following results. FN was extracellularly overexpressed in the 5-FU-resistant cells compared with that observed in the 5-FU-sensitive cells. Cell adhesion to FN enhanced 5-FU resistance and activated integrin-mediated ILK/Akt/NF-κB survival signaling in the 5-FU-resistant OSCC cells. Furthermore, the inhibition of cell adhesion to FN by FNIII14 enhanced chemosensitivity to 5-FU and apoptosis by suppressing ILK/Akt/NF-κB signaling in the 5-FU-resistant cells. These novel findings demonstrate that FN is a potentially useful biomarker and therapeutic target for improving the treatment of OSCC, particularly in the setting of 5-FU resistance.

  10. Inhibition of p53 increases chemosensitivity to 5-FU in nutrient-deprived hepatocarcinoma cells by suppressing autophagy.

    PubMed

    Guo, Xian-ling; Hu, Fei; Zhang, Shan-shan; Zhao, Qiu-dong; Zong, Chen; Ye, Fei; Guo, Shi-wei; Zhang, Jian-wei; Li, Rong; Wu, Meng-chao; Wei, Li-xin

    2014-05-01

    Activation of p53 can induce apoptosis, cell cycle arrest, and cell senescence, although some evidence has suggested that p53 could promote cell survival. However, whether p53 plays a positive role in cancer cell survival to chemotherapy remains unknown. In this study, we show that inhibition of p53 enhanced apoptosis and increased chemosensitivity to 5-fluorouracil (5-FU) in nutrient-deprived hepatocarcinoma cells (HCC). Meanwhile, nutrient-deprivation-induced autophagy was inhibited by pifithrin-α or small interfering RNA targeting p53. The expression of p53 was not increased when HCC were incubated under nutrient-deprived conditions. This indicates that the basal level of p53 is important to autophagy activation in nutrient-deprived HCC cells. Furthermore, combining p53 inhibition and nutrient deprivation or 5-FU treatment resulted in a marked increase in reactive oxygen species generation and mitochondrial damage. Antioxidants reduced nutrient deprivation or 5-FU-induced cell death of HCC after p53 inhibition. Our results suggest that p53 contributes to cell survival and chemoresistance in HCC under nutrient-deprived conditions by modulating autophagy activation.

  11. A morphometric study of the protective effect of cryotherapy on oral mucositis in cancer patients treated with 5-fluorouracil.

    PubMed

    Turkeli, M; Aldemir, M N; Bingol, F; Dogan, C; Kara, A

    2016-10-01

    We investigated cytological changes in oral mucosa smears from patients treated with cryotherapy to determine whether cryotherapy prevented mucositis caused by 5-fluorouracil (5-FU) therapy. Patients with gastrointestinal malignancies were divided into four groups; control patients before 5-FU therapy, patients after 5-FU therapy without cryotherapy, patients with cryotherapy before 5-FU therapy and patients with cryotherapy after 5-FU therapy. Oral mucosa samples from all patients were assessed at the beginning and on day 14 of chemotherapy. We used exfoliative cytology to evaluate cellular changes in the oral mucosa that were caused by 5-FU. Smears from each patient were stained using the Papanicolaou method and analyzed using stereology. Smears were taken from each group before and after 5-FU infusion. We found that nuclear volume was decreased significantly in cells of the 5-FU therapy after cryotherapy patients compared to the 5-FU therapy before cryotherapy patients. We also found significantly decreased cytoplasmic volumes in the 5-FU therapy after cryotherapy patients compared to the 5-FU therapy before cryotherapy patients. The results of cytomorphometric estimations revealed that cryotherapy may be used to prevent damage to oral tissue and may decrease the frequency and duration of oral mucositis caused by 5-FU.

  12. Effect of 5-FU substitution and mutation on Sm protein binding to human U4 snRNA.

    PubMed

    Cui, Wei; Gmeiner, William H

    2002-01-01

    The effects of native and non-native nucleotide substitution on the binding of Sm proteins to human U4 snRNA were investigated to determine if the Sm site was a likely target for the RNA-mediated effects of the anticancer drug 5-FU, and other nucleoside analogues. The Sm binding site of human U4 snRNA was prepared by in vitro transcription, and Sm protein binding was assessed using gel mobility shift assays. The U4:Sm RNA:protein complex was identified by immunoprecipitation with the Sm-specific Y12 antibody. The effects of 5-FU substitution were assessed by including FUTP in the in vitro transcription reactions. The effects of native nucleotide substitution were assessed by mutagenesis. Deletion mutants were used to assess the relative importance of the two stem-loops that flank the Sm binding site for protein binding. Point mutation (U-->G) to the 5'-Urd in the Sm site reduced Sm protein binding while similar point mutation to the 3'-Urd had a lesser effect. Mutation (U-->G) of all Urd in the Sm site completely inhibited Sm protein binding. The central stem-loop contributed significantly to Sm protein complex formation but the 3' stem-loop had little effect. Substitution of Urd by 5-fluorourdine (FUrd) did not inhibit Sm protein binding, but reduced the stability of the resulting complex. The results indicate that 5-FU, or other Uracil analogues, are unlikely to exert RNA-mediated effects through inhibition of Sm protein binding.

  13. Pharmacoeconomic analysis of adjuvant oral capecitabine vs intravenous 5-FU/LV in Dukes' C colon cancer: the X-ACT trial.

    PubMed

    Cassidy, J; Douillard, J-Y; Twelves, C; McKendrick, J J; Scheithauer, W; Bustová, I; Johnston, P G; Lesniewski-Kmak, K; Jelic, S; Fountzilas, G; Coxon, F; Díaz-Rubio, E; Maughan, T S; Malzyner, A; Bertetto, O; Beham, A; Figer, A; Dufour, P; Patel, K K; Cowell, W; Garrison, L P

    2006-04-24

    Oral capecitabine (Xeloda) is an effective drug with favourable safety in adjuvant and metastatic colorectal cancer. Oxaliplatin-based therapy is becoming standard for Dukes' C colon cancer in patients suitable for combination therapy, but is not yet approved by the UK National Institute for Health and Clinical Excellence (NICE) in the adjuvant setting. Adjuvant capecitabine is at least as effective as 5-fluorouracil/leucovorin (5-FU/LV), with significant superiority in relapse-free survival and a trend towards improved disease-free and overall survival. We assessed the cost-effectiveness of adjuvant capecitabine from payer (UK National Health Service (NHS)) and societal perspectives. We used clinical trial data and published sources to estimate incremental direct and societal costs and gains in quality-adjusted life months (QALMs). Acquisition costs were higher for capecitabine than 5-FU/LV, but higher 5-FU/LV administration costs resulted in 57% lower chemotherapy costs for capecitabine. Capecitabine vs 5-FU/LV-associated adverse events required fewer medications and hospitalisations (cost savings pound3653). Societal costs, including patient travel/time costs, were reduced by >75% with capecitabine vs 5-FU/LV (cost savings pound1318), with lifetime gain in QALMs of 9 months. Medical resource utilisation is significantly decreased with capecitabine vs 5-FU/LV, with cost savings to the NHS and society. Capecitabine is also projected to increase life expectancy vs 5-FU/LV. Cost savings and better outcomes make capecitabine a preferred adjuvant therapy for Dukes' C colon cancer. This pharmacoeconomic analysis strongly supports replacing 5-FU/LV with capecitabine in the adjuvant treatment of colon cancer in the UK.

  14. Wheat germ agglutinin-functionalised crosslinked polyelectrolyte microparticles for local colon delivery of 5-FU: in vitro efficacy and in vivo gastrointestinal distribution.

    PubMed

    Glavas-Dodov, Marija; Steffansen, Bente; Crcarevska, Maja S; Geskovski, Nikola; Dimchevska, Simona; Kuzmanovska, Sonja; Goracinova, Katerina

    2013-01-01

    We have previously reported the development and characterisation of wheat germ agglutinin (WGA)-functionalised chitosan-Ca-alginate (CTS-Ca-ALG) microparticles (MPs) loaded with acid-resistant particles of 5-fluorouracil (5-FU). In the present work, our goal was to evaluate the potential of these carriers for efficient treatment of colon cancer by studying in vitro permeability and cell association of 5-FU and [methyl-³H]thymidine uptake in Caco-2 cells, as well as in vivo gastrointestinal distribution. The amount of 5-FU permeated through Caco-2 cells was 15.1, 7.7 and 6.5% for 5-FU solution, CTS-Ca-ALG MPs and WGA conjugates. The concentration of 5-FU associated with Caco-2 cells was significantly greater when delivered from MPs. By incorporation of 5-FU into MPs and further decoration with WGA, an increased [methyl-³H]thymidine uptake was observed few hours after continuous drug treatment followed by significantly reduced uptake after 6 h. Gastrointestinal distribution was in favour of increased localisation and concentration of the particles in colon region.

  15. DKK4 enhances resistance to chemotherapeutics 5-Fu and YN968D1 in colorectal cancer cells

    PubMed Central

    He, Shengli; Shen, Jie; Hu, Nanhua; Xu, Xuanfu; Li, Jin

    2017-01-01

    Dickkopf-related protein 4 (DKK4) is a target of the β-catenin/transcription factor 4 complex in colorectal cancer. Previous research has demonstrated that its expression level may vary and has indicated that it may have a role in the development of resistance to chemotherapy in colorectal cancer cells. In the present study, DKK4 was over expressed in several colorectal cancer cell lines. The DKK4 over-expressing cell lines were screened using reverse transcription quantitative polymerase chain reaction analysis and western blotting. Analysis of cell viability in the control and DKK4 over-expressing cell lines, following treatment with 5-fluorouracil (5-Fu), YN968D1 or both, indicated that DKK4 over-expressing cells exhibit increased drug resistance. The results of Transwell chamber assays suggested that DKK4 had an effect on cell migration. Furthermore, the results from flow cytometric analysis showed that the percentage of apoptotic cells was reduced in the DKK4 over-expressing cell lines, following drug treatment, compared with the control. The present data suggested that DKK4 may enhance the resistance of colorectal cancer cells to 5-Fu and YN968D1 treatment, when used alone or in combination. PMID:28356933

  16. 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

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

    PubMed

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

    2015-12-01

    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.

  18. Prognostic factors for tumour response, progression-free survival and toxicity in metastatic colorectal cancer patients given irinotecan (CPT-11) as second-line chemotherapy after 5FU failure

    PubMed Central

    Freyer, G; Rougier, P; Bugat, R; Droz, J-P; Marty, M; Bleiberg, H; Mignard, D; Awad, L; Herait, P; Culine, S; Trillet-Lenoir, V

    2000-01-01

    Our purpose was to determine, in patients with metastatic colorectal carcinoma treated with irinotecan single-agent after 5-FU failure, the most significant predictive parameters for tumour response, progression-free survival and toxicity. Between October 1992 and April 1995, 455 patients with 5-FU resistant metastatic colorectal carcinoma entered four consecutive phase II trials. The first two studies assessed tumour response, the other two were randomized studies which assessed the efficacy of racecadotril to prevent irinotecan-induced diarrhoea. Due to homogeneous main eligibility criterias, data from those studies could be pooled for statistical analysis. Potential clinical and biological predictive factors (PF) for toxicity, tumour growth control, e.g. response or stabilization and progression-free survival (PFS), were studied in multivariate analysis. 363 patients were evaluable for response, 432 were evaluable for PFS, 368 for neutropenia and 416 for delayed diarrhoea, respectively. Normal baseline haemoglobin level (Hb), time since diagnosis of colorectal carcinoma, grade 3 or 4 neutropenia or diarrhoea at first cycle and a low number of organs involved were the most PF for tumour growth control (P< 0.05). Significant prognostic variables for PFS were WHO Performance Status, liver and lymph-node involvement, time since diagnosis, age and CEA value (P≤ 0.02). Six groups of patients based on the number of unfavourable prognostic factors are presented. Baseline bilirubin, haemoglobin level, number of organs involved and time from diagnosis were PF for neutropenia; PS, serum creatinine, leukocyte count, time from 5-FU progression and prior abdominopelvic irradiation were PF for delayed diarrhoea (P≤ 0.05). These PF should help clinicians to anticipate for a given patient the probability to observe a response/stabilization or a toxicity. These results should also be prospectively confirmed in ongoing or future trials using irinotecan, both as a single agent

  19. Fetal growth in rats treated with lapachol.

    PubMed

    Felício, André Carvalho; Chang, Cláudia Veiga; Brandão, Marcos Antônio; Peters, Vera Maria; Guerra, Martha de Oliveira

    2002-10-01

    Lapachol is a naphthoquinone well known for its therapeutic potential. Previous studies have shown that lapachol does not interfere with embryonic development during the pre-implantation period. However, when administered during the organogenic period at the same dose level, it induces a high fetal death incidence. To evaluate the effect of lapachol during fetogenesis, 20 pregnant Wistar rats were randomly divided into two groups: vehicle (10 mL of a 50% aqueous ethanol solution/kg body weight) and treated (100 mg of lapachol/kg body weight). Lapachol was administered from the 17th to 20th day of pregnancy. The following variables were analyzed: maternal body weight from 16th to 21st day of pregnancy, food intake from 17th to 21st day of pregnancy, clinical signs of physical discomfort, ovarian weights, implantations, resorptions and mortality indices, fetal and placenta weights, external malformations, and fetal organ weights. Results indicated that lapachol was not toxic to mothers, although it was fetotoxic leading to fetal growth retardation.

  20. Venous thromboembolism in colorectal cancer patients with central venous catheters for 5-FU infusion-based pharmacokinetic modulating chemotherapy.

    PubMed

    Yoshikawa, Reigetsu; Yanagi, Hidenori; Noda, Masafumi; Ikeuchi, Hiroki; Nakano, Hiroki; Gega, Makoto; Tsukamoto, Kiyoshi; Oshima, Tsutomu; Inoue, Takashi; Fujiwara, Yoshinori; Shoji, Yasutsugu; Sakaki, Takatoshi; Higasa, Satoshi; Hashimoto-Tamaoki, Tomoko; Yamamura, Takehira

    2005-04-01

    Colorectal cancer patients with central venous catheters (CVC) for pharmacokinetic modulating chemotherapy (PMC) have a substantial risk of venous thromboembolism (VTE). PMC, designed as a hybrid of lower metronomic and higher shorter plasma 5-FU concentrations, has been clinically successful. To determine the effectiveness and safety of D-dimer tests and multidetector-row CT (MDCT) for diagnosis in cancer patients with suspected VTE, we carried out a clinical outcome study on PMC outpatients. Patients received a D-dimer test before and after commencing the PMC regimen. MDCT was performed additionally if the D-dimer test appeared positive or showed signs of VTE. When CT results were positive for thromboembolism, anticoagulation was started. The overall prevalence of VTE in PMC patients was 2.0% (7 of 350 patients). In this study, 34 out of 102 colorectal cancer patients gave a positive D-dimer test (33.3%). CT identified venous thrombi in 2 of the 102 patients (2.0%), mural thrombosis on catheterized veins in another 3 patients (2.9%), and endothelial hyperplasia on catheterized veins in 8 patients (7.8%). The catheters of these patients did not show any significant abnormalities. Patients with negative D-dimer tests showed no signs or symptoms of VTE. In colorectal cancer patients receiving continuous 5-FU infusion via CVC, a D-dimer test can be safely used as the primary diagnostic test for ruling out VTE. We suggest 7.0 microg/ml as the D-dimer cut-off value. Thromboprophylaxis should be considered in the patients showing values >7.0 microg/ml.

  1. Corrupted colonic crypt fission in carcinogen-treated rats

    PubMed Central

    2017-01-01

    Background The colonic crypts in rats reproduce themselves by symmetric fission at the base of the crypts, and proceeding upwards, generate two separate identical crypts. Recently we reported corrupted colonic crypt fission (CCCF) in rats with colonic carcinoma. Here we investigated whether CCCF also occurred in the colonic mucosa without carcinoma in carcinogen-treated rats. Methods Filed Swiss-roll sections from 35 male rats (25 treated with 1,2-dimethyhydrazine (DMH) suspended in EDTA solution, and 10 EDTA-treated) were reviewed. CCCF were regarded those with either asymmetric basal fission, asymmetric lateral sprouting/lateral fission, basal dilatations, or spatial aberrations of the normal (vertical) axis. Results 202 CCCF (38%) were recorded amongst 533 crypts with fission in DMH-treated rats, and only one CCCF (0.1%) was found amongst 571 crypts with fission in EDTA-treated rats (p<0.05). The basal aspect of four adenomas included in Swiss roll sections exhibited CCCF lined either with indigenous (non-dysplastic) epithelium or with dysplastic epithelium. Conclusion It was demonstrated that CCCF without dysplasia develop in carcinogen-treated SD rats. As judged by the figures presented, the possibility that the epithelium in those corrupted crypts was successively replaced by top-down growing dysplastic cells, could not be totally rejected. This is the first report showing that non-dysplastic CCCF may antedate the very early stages of colonic carcinogenesis in SD rats. PMID:28273142

  2. Slug-Dependent Upregulation of L1CAM Is Responsible for the Increased Invasion Potential of Pancreatic Cancer Cells following Long-Term 5-FU Treatment

    PubMed Central

    Lund, Kaja; Dembinski, Jennifer L.; Solberg, Nina; Urbanucci, Alfonso; Mills, Ian G.; Krauss, Stefan

    2015-01-01

    Background Pancreatic adenocarcinoma is a lethal disease with 5-year survival of less than 5%. 5-fluorouracil (5-FU) is a principal first-line therapy, but treatment only extends survival modestly and is seldom curative. Drug resistance and disease recurrence is typical and there is a pressing need to overcome this. To investigate acquired 5-FU resistance in pancreatic adenocarcinoma, we established chemoresistant monoclonal cell lines from the Panc 03.27 cell line by long-term exposure to increasing doses of 5-FU. Results 5-FU-resistant cell lines exhibited increased expression of markers associated with multidrug resistance explaining their reduced sensitivity to 5-FU. In addition, 5-FU-resistant cell lines showed alterations typical for an epithelial-to-mesenchymal transition (EMT), including upregulation of mesenchymal markers and increased invasiveness. Microarray analysis revealed the L1CAM pathway as one of the most upregulated pathways in the chemoresistant clones, and a significant upregulation of L1CAM was seen on the RNA and protein level. In pancreatic cancer, expression of L1CAM is associated with a chemoresistant and migratory phenotype. Using esiRNA targeting L1CAM, or by blocking the extracellular part of L1CAM with antibodies, we show that the increased invasiveness observed in the chemoresistant cells functionally depends on L1CAM. Using esiRNA targeting β-catenin and/or Slug, we demonstrate that in the chemoresistant cell lines, L1CAM expression depends on Slug rather than β-catenin. Conclusion Our findings establish Slug-induced L1CAM expression as a mediator of a chemoresistant and migratory phenotype in pancreatic adenocarcinoma cells. PMID:25860483

  3. 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

    2016-06-28

    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.

  4. Expression of p21WAF1 in Astler-Coller stage B2 colorectal cancer is associated with survival benefit from 5FU-based adjuvant chemotherapy.

    PubMed

    Sulzyc-Bielicka, Violetta; Domagala, Pawel; Urasinska, Elzbieta; Bielicki, Dariusz; Safranow, Krzysztof; Domagala, Wenancjusz

    2011-04-01

    In several, but not all, previous studies, positive p21(WAF1) expression has been suggested as an indicator of a good prognosis in patients with stage III/IV colorectal cancer. However, it is not known whether the same is true for stage B2 patients. The purpose of this study is to assess the influence of p21(WAF1) expression in tumor cells on disease-free survival (DFS) and overall survival (OS) of Astler-Coller stage B2 and C patients with colorectal cancer who underwent 5-fluorouracil-based adjuvant chemotherapy. Nuclear p21(WAF1) was detected by immunohistochemistry in tissue microarrays from 275 colorectal cancers. The expression of p21(WAF1) was associated with DFS (p = 0.025) and OS (p = 0.008) in the subgroup of stage B2 patients that was treated with adjuvant chemotherapy. In multivariate analysis, it remained the only independent prognostic parameter in relation to DFS and OS (p = 0.035 and p = 0.02, respectively). In the subgroup of 72 stage B2 patients with positive p21(WAF1) expression but not in the subgroup of 61 stage B2 patients with negative p21(WAF1) expression, adjuvant chemotherapy was associated with better DFS (85% 5-year survival versus 65% without chemotherapy, p = 0.03) and OS (96% versus 82%, p = 0.014). In the combined stage B2 and C group of patients treated with adjuvant chemotherapy, positive p21(WAF1) expression was also associated with better DFS and OS (p = 0.03, p = 0.002, respectively). Expression of p21(WAF1) in colorectal tumor cells identifies a subgroup of Astler-Coller stage B2 patients who could benefit significantly from 5FU-based chemotherapy and may improve the selection of patients for adjuvant chemotherapy.

  5. Human papillomavirus oncoproteins differentially modulate epithelial-mesenchymal transition in 5-FU-resistant cervical cancer cells.

    PubMed

    Vishnoi, Kanchan; Mahata, Sutapa; Tyagi, Abhishek; Pandey, Arvind; Verma, Gaurav; Jadli, Mohit; Singh, Tejveer; Singh, Sukh Mahendra; Bharti, Alok C

    2016-10-01

    Etiological role of viral proteins E6 and E7 of high-risk HPV in cervical carcinogenesis is well established. However, their contribution in chemoresistance and epithelial-mesenchymal transition (EMT) that leads to advanced metastatic lesions and chemoresistance is poorly defined. In the present study, contribution of viral oncoproteins in acquisition of EMT character during onset of chemoresistance was assessed. A chemoresistant cell line (SiHaCR) was developed from an established HPV16-positive cervical cancer cell line, SiHa, by escalating selection pressure of 5-fluorouracil (5-FU). Expression of Survivin, ABCG2, Snail, Slug, Twist, and Vimentin was examined in SiHa and SiHaCR cells by reverse transcriptase-PCR (RT-PCR) and immunoblotting assays. Mesenchymal phenotype in SiHaCR cells was confirmed by assessment of migration and invasion potentials. SiHaCR cells displayed elevated level of functional and molecular markers associated with chemoresistance (Survivin, ABCG2) and EMT (Snail, Slug, Twist, Vimentin) and reduced E-cadherin. SiHaCR also showed increased levels of HPV16 E6 and E7 transcripts. Specific silencing of HPV16 E6, but not E7 using corresponding siRNA, demonstrated a differential involvement of HPV oncogenes in manifestation of EMT. HPV16 E6 silencing resulted in reduction of Slug and Twist expression. However, the expression of Snail and Vimentin was only marginally affected. In contrast, there was an increase in the expression of E-cadherin. A reduced migration and invasion capabilities were observed only in E6-silenced SiHaCR cells, which further confirmed functional contribution of HPV16 E6 in manifestation of EMT. Taken together, our study demonstrated an active involvement of HPV16 E6 in regulation of EMT, which promotes chemoresistance in cervical cancer.

  6. Behavioral effects of amphetamine in streptozotocin-treated rats

    PubMed Central

    Sevak, Rajkumar J.; Koek, Wouter; Daws, Lynette C.; Owens, William Anthony; Galli, Aurelio; France, Charles P.

    2009-01-01

    Experimentally-induced diabetes can modify the behavioral and neurochemical effects of drugs acting on dopamine systems, possibly through insulin-related regulation of dopamine transporter activity. In this study, several behavioral procedures were used to examine possible changes in sensitivity to amphetamine and other drugs in rats rendered diabetic by a single injection of streptozotocin. Conditioned place preference developed to food (Froot Loops®) in both control and diabetic rats, demonstrating that conditioned place preference with tactile stimuli can occur in streptozotocin-treated rats. Baseline locomotion was lower in streptozotocin-treated as compared to control rats, although amphetamine significantly increased locomotion in all rats. Conditioned place preference developed to amphetamine regardless of whether rats had received streptozotocin or saline. A second study compared the potency of drugs to decrease lever pressing maintained by food, before and after streptozotocin treatment. Gamma-hydroxybutyrate and amphetamine were less potent after streptozotocin while the potency of raclopride, quinpirole, ketamine, haloperidol and cocaine was not significantly changed by streptozotocin. While markedly affecting locomotion, body weight and blood glucose, streptozotocin only modestly affected sensitivity to the behavioral effects of amphetamine and other drugs; these results fail to confirm previous reports of decreased behavioral actions of stimulants in diabetic rats. PMID:18155695

  7. Behavioral effects of amphetamine in streptozotocin-treated rats.

    PubMed

    Sevak, Rajkumar J; Koek, Wouter; Daws, Lynette C; Owens, William Anthony; Galli, Aurelio; France, Charles P

    2008-02-26

    Experimentally-induced diabetes can modify the behavioral and neurochemical effects of drugs acting on dopamine systems, possibly through insulin-related regulation of dopamine transporter activity. In this study, several behavioral procedures were used to examine possible changes in sensitivity to amphetamine and other drugs in rats rendered diabetic by a single injection of streptozotocin. Conditioned place preference developed to food (Froot Loops) in both control and diabetic rats, demonstrating that conditioned place preference with tactile stimuli can occur in streptozotocin-treated rats. Baseline locomotion was lower in streptozotocin-treated as compared to control rats, although amphetamine significantly increased locomotion in all rats. Conditioned place preference developed to amphetamine regardless of whether rats had received streptozotocin or saline. A second study compared the potency of drugs to decrease lever pressing maintained by food, before and after streptozotocin treatment. Gamma-hydroxybutyrate and amphetamine were less potent after streptozotocin while the potency of raclopride, quinpirole, ketamine, haloperidol and cocaine was not significantly changed by streptozotocin. While markedly affecting locomotion, body weight and blood glucose, streptozotocin only modestly affected sensitivity to the behavioral effects of amphetamine and other drugs; these results fail to confirm previous reports of decreased behavioral actions of stimulants in diabetic rats.

  8. c-Myc is regulated by HIF-2α in chronic hypoxia and influences sensitivity to 5-FU in colon cancer

    PubMed Central

    Chung, Daniel C.

    2016-01-01

    Colorectal cancers (CRCs) invariably become hypoxic as they enlarge, and this places unique metabolic demands upon the tumor cells. Hypoxic stress can enhance the invasiveness of cancer cells and induce chemoresistance. c-Myc, an oncogene regulated by hypoxia inducible factors (HIFs), plays a critical role in cell proliferation and metabolism. However, the interplay between c-Myc and HIFs and its clinical significance in hypoxic adaptation in CRCs are unknown. We demonstrate that c-Myc mRNA and protein levels in colon cancer cells are induced within 2 h of hypoxic stress (1% O2) but are then significantly downregulated when exposed to prolonged hypoxia. In chronic hypoxia (over 8 h at 1% O2), HIF-2α but not HIF-1α gradually accumulated in colon cancer cells. Knockdown of HIF-2α increased levels of c-Myc and its downstream target cyclinD1 in chronic hypoxia, indicating that HIF-2α may function to downregulate c-Myc. Chronic hypoxia suppressed the expression of cyclinD1, CDK4, and CDK6, inducing G1 phase block and 5-flurouracil (5-FU) chemoresistance. Overexpression of c-Myc reversed the inhibition of cyclinD1, CDK4, and CDK6, which accelerated the G1/S phase transition under hypoxia and enhanced sensitivity to 5-FU. In contrast, knockdown of c-Myc impaired 5-FU chemosensitivity in colon cancer cells. In summary, HIF-2α plays an important role in regulating the expression of c-Myc in chronic hypoxia, and consequently controls the sensitivity of colon cancer cells to 5-FU treatment in this environment. PMID:27793037

  9. IDH1 R132H Mutation Enhances Cell Migration by Activating AKT-mTOR Signaling Pathway, but Sensitizes Cells to 5-FU Treatment as NADPH and GSH Are Reduced

    PubMed Central

    Qiu, Jiangdong; Huang, Keting; Wu, Mindan; Xia, Chunlin

    2017-01-01

    Aim of study Mutations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene were recently discovered in vast majority of World Health Organization (WHO) grade II/III gliomas. This study is to understand the effects of IDH1 R132H mutation in gliomagenesis and to develop new strategies to treat glioma with IDH1 R132H mutation. Materials and methods Over expression of IDH1 R132H in U87MG cells was done by transfecting cells with IDH1 R132H plasmid. MTT assay, scratch repair assay and western blot were performed to study effects of IDH1 R132H mutation on cell proliferation, migration, regulating AKT-mTOR signaling pathway and cell death respectively. NADP+/NADPH and GSH quantification assays were performed to evaluate effects of IDH1 R132H mutation on the production of antioxidant NADPH and GSH. Results We found that over expression of IDH1 R132H mutation decreased cell proliferation consistent with previous reports; however, it increased cell migration and enhanced AKT-mTOR signaling pathway activation. Mutations in isocitrate dehydrogenase (IDH) 1 also change the function of the enzymes and cause them to produce 2-hydroxyglutarate and not produce NADPH. We tested the level of NADPH and GSH and demonstrated that IDH1 R132H mutant stable cells had significantly low NADPH and GSH level compared to control or IDH1 wild type stable cells. The reduced antioxidants (NADPH and GSH) sensitized U87MG cells with IDH R132H mutant to 5-FU treatment. Conclusion Our study highlights the important role of IHD1 R132H mutant in up- regulating AKT-mTOR signaling pathway and enhancing cell migration. Furthermore, we demonstrate that IDH1 R132H mutation affects cellular redox status and sensitizes gliomas cells with IDH1 R132H mutation to 5FU treatment. PMID:28052098

  10. 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.

  11. 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.

  12. [Analysis of sensitivity of stromal stem cells (CFU-f) from rat bone marrow and fetal liver to 5-fluorouracil].

    PubMed

    Paiushina, O V; Damaratskaia, E I; Bueverova, E I; Nikonova, T M; Butorina, N N; Molchanova, E A; Starostin, V I

    2006-01-01

    The sensitivity of stromal stem cells (CFU-f) from rat bone marrow and fetal liver to the cytotoxic effect of 5-fluorouracil (5-FU) was compared in vivo and in vitro. Cells from both tissues demonstrated a similar resistance to 5-FU in vitro; however, stromal stem cells from fetal liver proved notably more sensitive to 5-FU compared to marrow CFU-f in vivo. Cells forming colonies of different size were identified in stem cell populations from both tissues. Cells giving rise to small colonies had a higher resistance to 5-FU both in vivo and in vitro.

  13. Norepinephrine-induced diuresis in chronically ethanol-treated rats

    SciTech Connect

    Pohorecky, L.A. )

    1989-01-01

    Previous research from this laboratory indicated that noradrenergic mechanisms might mediate ethanol diuresis. Experiments described here examined changes in sensitivity of noradrenergic mechanisms in animals chronically treated with ethanol. Norepinephrine hydrochloride (0-12 ug intracerebroventricularly) produced dose-dependent diuresis in control and ethanol treated rats on the first day of treatment. Tolerance to ethanol diuresis was present after 10 day of ethanol treatment. Lack of responsiveness to norepinephrine-induced diuresis was evident only on the 20th day of treatment in both the ethanol and dextrin-maltose groups of rats. These results indicate a temporal dissociation between the tolerance to ethanol-induced and norepinephrine-induced diuresis and suggest that norepinephrine may not play a primary role in the development of tolerance to the diuretic action of ethanol.

  14. 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.

  15. Neoadjuvant 5-FU or Capecitabine Plus Radiation With or Without Oxaliplatin in Rectal Cancer Patients: A Phase III Randomized Clinical Trial

    PubMed Central

    Yothers, Greg; O’Connell, Michael J.; Beart, Robert W.; Wozniak, Timothy F.; Pitot, Henry C.; Shields, Anthony F.; Landry, Jerome C.; Ryan, David P.; Arora, Amit; Evans, Lisa S.; Bahary, Nathan; Soori, Gamini; Eakle, Janice F.; Robertson, John M.; Moore, Dennis F.; Mullane, Michael R.; Marchello, Benjamin T.; Ward, Patrick J.; Sharif, Saima; Roh, Mark S.; Wolmark, Norman

    2015-01-01

    Background: National Surgical Adjuvant Breast and Bowel Project R-04 was designed to determine whether the oral fluoropyrimidine capecitabine could be substituted for continuous infusion 5-FU in the curative setting of stage II/III rectal cancer during neoadjuvant radiation therapy and whether the addition of oxaliplatin could further enhance the activity of fluoropyrimidine-sensitized radiation. Methods: Patients with clinical stage II or III rectal cancer undergoing preoperative radiation were randomly assigned to one of four chemotherapy regimens in a 2x2 design: CVI 5-FU or oral capecitabine with or without oxaliplatin. The primary endpoint was local-regional tumor control. Time-to-event endpoint distributions were estimated using the Kaplan-Meier method. Hazard ratios were estimated from Cox proportional hazard models. All statistical tests were two-sided. Results: Among 1608 randomized patients there were no statistically significant differences between regimens using 5-FU vs capecitabine in three-year local-regional tumor event rates (11.2% vs 11.8%), 5-year DFS (66.4% vs 67.7%), or 5-year OS (79.9% vs 80.8%); or for oxaliplatin vs no oxaliplatin for the three endpoints of local-regional events, DFS, and OS (11.2% vs 12.1%, 69.2% vs 64.2%, and 81.3% vs 79.0%). The addition of oxaliplatin was associated with statistically significantly more overall and grade 3–4 diarrhea (P < .0001). Three-year rates of local-regional recurrence among patients who underwent R0 resection ranged from 3.1 to 5.1% depending on the study arm. Conclusions: Continuous infusion 5-FU produced outcomes for local-regional control, DFS, and OS similar to those obtained with oral capecitabine combined with radiation. This study establishes capecitabine as a standard of care in the pre-operative rectal setting. Oxaliplatin did not improve the local-regional failure rate, DFS, or OS for any patient risk group but did add considerable toxicity. PMID:26374429

  16. Effect of caffeine on rat offspring from treated dams.

    PubMed

    Aeschbacher, H U; Milon, H; Poot, A; Würzner, H P

    1980-11-01

    Pregnant Sprague-Dawley rats were given caffeine at 1.0, 0.5 and 0.25 g/kg diet during gestation and lactation. At birth, half of the pups from control and treated rats at each dose level were exchanged and cross fostered. Two litters were produced by each animal from each of the experimental groups. Caffeine at dietary concentrations of 0.5 and 0.25 g/kg throughout gestation and lactation had no significant effect on birth weight, litter size or development. There was also no effect at these doses following treatment during either gestation alone, or lactation alone. At 1.0 g/kg there was a slight reduction of birth weight, as well as a trend towards lower weight gain in litters from dams fed the test diet throughout gestation and lactation.

  17. 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

  18. Evaluation of Chromosomal Instability in Diabetic Rats Treated with Naringin

    PubMed Central

    A. Bakheet, Saleh; M. Attia, Sabry

    2011-01-01

    We used the bone marrow DNA strand breaks, micronucleus formations, spermatocyte chromosomal aberrations, and sperm characteristic assays to investigate the chromosomal instability in somatic and germinal cells of diabetic rats treated with multiple doses of naringin. The obtained results revealed that naringin was neither cytotoxic nor genotoxic for the rats at all tested doses. Moreover, naringin significantly reduced the diabetes-induced chromosomal instability in somatic and germinal cells in a dose-dependent manner. In addition, diabetes induced marked biochemical alterations characteristic of oxidative stress including enhanced lipid peroxidation, accumulation of oxidized glutathione, reduction in reduced glutathione, and accumulation of intracellular reactive oxygen species. Treatment with naringin ameliorated these biochemical markers dose-dependently. In conclusion, naringin confers an appealing protective effect against diabetes-induced chromosomal instability towards rat somatic and germinal cells which might be explained partially via diminishing the de novo free radical generation induced by hyperglycemia. Thus, naringin might be a good candidate to reduce genotoxic risk associated with hyperglycemia and may provide decreases in the development of secondary malignancy and abnormal reproductive outcomes risks, which seems especially important for diabetic patients. PMID:21941606

  19. Oral Nucleotides Only Minimally Improve 5-Fluorouracil-Induced Mucositis in Rats.

    PubMed

    Mashtoub, Suzanne; Feo, Benjamin; Whittaker, Alexandra L; Lymn, Kerry A; Martinez-Puig, Daniel; Howarth, Gordon S

    2015-01-01

    Chemotherapy-induced mucositis is characterized by inflammation and ulceration of the intestinal mucosa, compromising intestinal function. Exogenous nucleotides have been reported to repair the mucosa. The nucleotide preparation, Nucleoforce F0328 (Nucleoforce), was investigated for its potential to ameliorate intestinal mucositis in rats. Female Dark Agouti rats (n = 8/group) were gavaged once daily with Nucleoforce (175 mg/kg) or water from Days 0 to 8 and injected (i.p.) with 5-fluorouracil (5-FU; 150 mg/kg) or saline on Day 5. Histological parameters (disease severity, crypt depth, and villus height measurements) and myeloperoxidase activity were quantified. P < 0.05 was considered significant. Jejunal and ileal histological disease severity scores were significantly increased by 5-FU, compared to normal controls (P < 0.05). Nucleoforce treatment in 5-FU-injected rats significantly reduced jejunal and ileal disease severity compared to 5-FU controls (P < 0.05). In 5-FU-injected rats, jejunal and ileal villus heights and crypt depths were significantly decreased compared to 5-FU controls, with no additional Nucleoforce effect (P > 0.05). Intestinal myeloperoxidase activity was significantly elevated by 5-FU (8.8-fold), compared to normal controls (P < 0.05), which was not normalized by Nucleoforce treatment (P > 0.05). Nucleoforce only partially improved parameters associated with experimentally-induced mucositis. Future studies could investigate increased concentrations, more frequent administration, or protective microencapsulation delivery methods, to increase bioavailability.

  20. 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

  1. Hypolipidemic effect of β-caryophyllene to treat hyperlipidemic rats.

    PubMed

    Baldissera, Matheus D; Souza, Carine F; Grando, Thirssa H; Doleski, Pedro H; Boligon, Aline A; Stefani, Lenita M; Monteiro, Silvia G

    2017-02-01

    The aim of this study was to evaluate the effect of β-caryophyllene on hypercholesterolemia using a model of hyperlipidemia induced by Triton WR-1339 in rats, as well as its possible effect on hepatic antioxidant enzymes. Thus, total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol were measured in serum, while reactive oxygen species (ROS), thiobarbituric acid reactive substances (TBARS), hepatic 3-hydroxy-3-methylglutayl coenzyme A (HMG-CoA) reductase, superoxide dismutase (SOD), and catalase (CAT) activities were measured in the hepatic tissue. In addition, seric concentrations of β-caryophyllene were measured to perform correlation studies. Serum samples from hypercholesterolemic rats show higher (p < 0.05) levels of total cholesterol, triglycerides, and LDL cholesterol, and lower (p < 0.05) levels of HDL cholesterol compared to non-hypercholesterolemic rats. β-Caryophyllene treatment reduced (p < 0.05) the levels of total cholesterol, triglycerides and LDL cholesterol, similar to the reference drug simvastatin. However, HDL cholesterol levels did not increase with the treatment. β-Caryophyllene treatment was able to inhibit the HMG-CoA reductase activity, as well as to prevent the increase on ROS and TBARS levels, and ameliorate the antioxidant system. In summary, our findings demonstrated that β-caryophyllene has hypolipidemic effect via inhibition of the hepatic HMG-CoA reductase, like the standard drug simvastatin, and this inhibition suggests a possible mechanism of hypolipidemic action. Thus, our results indicate that β-caryophyllene can be used to treat dyslipidemic diseases because it exerts a similar effect as the reference drug, protecting the liver against lipid damage and improving the hepatic antioxidant defense system.

  2. 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.

  3. 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.

  4. Effects of vasopressin on electrolyte transport across isolated colon from normal and dexamethasone-treated rats.

    PubMed Central

    Bridges, R J; Rummel, W; Wollenberg, P

    1984-01-01

    Vasopressin enhanced the absorption of Na+ and Cl- across the short-circuited colon descendens from normal rats. This effect of vasopressin results from an increase in the mucosal to serosal movement of Na+ and Cl- and a decrease in the serosal to mucosal movement of Cl- and was accompanied with a decrease in the short-circuit current (ISC). Neither the base-line absorption of Na+ and Cl-, the vasopressin-induced increase in Na+ and Cl- absorption nor the decrease in ISC were inhibited by amiloride in the colon from normal rats. Colon descendens from rats treated for 3 days with dexamethasone had remarkably higher transmural potential difference (p.d.), tissue conductance (Gt) and ISC. The absorption of Na+ across the short-circuited colon descendens from dexamethasone-treated rats was increased 3-fold when compared to colon from normal rats. The absorption of Cl- in normal rats was reversed to Cl- secretion in treated rats. Amiloride rapidly and reversibly decreased the p.d., Gt and ISC in colon from dexamethasone-treated rats. The transport of Na+ was nearly completely inhibited by amiloride in treated rats. In contrast to its enhancing effects on Na+ absorption in colon from normal rats vasopressin did not enhance Na+ absorption in colon from dexamethasone-treated rats. This enhancement of Cl- absorption by vasopressin was retained in colon from treated rats. This enhancement of Cl- transport was due solely to a decrease in the serosal to mucosal movement of Cl- and was accompanied with a decrease in ISC and Gt. The results support the hypothesis that vasopressin causes inhibition of the electrogenic secretion of Cl- in colon from dexamethasone-treated rats. Furthermore, the results suggest that the increase in the mucosal to serosal movement of Na+ and Cl- and the decrease in the serosal to mucosal movement of Cl- in colon from normal rats are caused by independent effects of vasopressin. PMID:6491990

  5. Bifidobacterium infantis has a beneficial effect on 5-fluorouracil-induced intestinal mucositis in rats.

    PubMed

    Yuan, K-T; Yu, H-L; Feng, W-D; Chong, P; Yang, T; Xue, C-L; Yu, M; Shi, H-P

    2015-03-01

    Intestinal mucositis is a common toxic side effect in cancer patients receiving high-dose chemotherapy. This study aimed to evaluate the beneficial effects of Bifidobacterium infantis in a rat model of intestinal mucositis induced by 5-fluorouracil (5-FU). Thirty male Sprague-Dawley rats were divided into three groups: control, 5-FU, and 5-FU + B. infantis. A single intraperitoneal injection of 5-FU (150 mg/kg) was used to induce intestinal mucositis. B. infantis (1×109 cfu) was administered for 11 days, starting from 7 days before 5-FU injection. Intestinal mucositis was evaluated based on body weight, villus height, immunohistological expression of proliferating cell nuclear antigen (PCNA) and nuclear factor kappa beta (NF-κB), levels of the pro-inflammatory factors interleukin 1 beta and tumour necrosis factor alpha, and myeloperoxidase (MPO) concentration. The results showed that the 5-FU + B. infantis group demonstrated a higher body weight and villus height, increased expression of PCNA, reduced expression of NF-κB and pro-inflammatory factors, and lower MPO concentration compared to the 5-FU group. These data suggest that probiotic B. infantis is effective in reducing chemotherapy-induced intestinal mucositis in rats.

  6. 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.

  7. [Serum and tissue concentration of tegafur and 5-FU after administration of tegafur suppository in patients with lung cancer--correcting the influence of residual blood in the tissue].

    PubMed

    Ohno, K; Nakahara, K; Hashimoto, J; Matsumura, A; Mizuta, T; Akashi, A; Nakagawa, K; Takeda, S; Minami, M; Kawashima, Y

    1989-11-01

    Tissue concentration of tegafur and 5-FU was studied in 25 patients with of primary lung cancer, given 2 x 750 mg of tegafur suppository daily preoperatively (total doses 3.75-9.75 g, mean 5.16 g). Furthermore, the influence of blood remaining in the tissue was corrected in the determination of tegafur and 5-FU concentration. The tegafur level in tumor tissue (9.614 +/- 5.739 micrograms/g) was significantly (p less than 0.01) low compared with those in serum and normal lung tissue (13.185 +/- 8.198 micrograms/ml, 12.954 +/- 10.048 micrograms/g). On the other hand, the 5-FU level in tumor tissue (0.124 +/- 0.208) was significantly (p less than 0.01, p less than 0.05) high compared with those in serum and normal lung tissue (0.019 +/- 0.013 micrograms/ml, 0.035 +/- 0.031 micrograms/g) and showed approximately 2.5 times more minimum effective concentration against tumor cells (0.05 micrograms/g). The results show that preoperative administration of 2 x 750 mg of tegafur suppository daily is effective for the transfer of tegafur and 5-FU to lung cancer tissue.

  8. 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.

  9. Diamine oxidase as a marker of intestinal mucosal injury and the effect of soluble dietary fiber on gastrointestinal tract toxicity after intravenous 5-fluorouracil treatment in rats.

    PubMed

    Fukudome, Ian; Kobayashi, Michiya; Dabanaka, Ken; Maeda, Hiromichi; Okamoto, Ken; Okabayashi, Takehiro; Baba, Ryoko; Kumagai, Nana; Oba, Koji; Fujita, Mamoru; Hanazaki, Kazuhiro

    2014-06-01

    The level of plasma diamine oxidase (DAO) activity is associated with the maturation and integrity of small intestinal mucosa. This study in rats investigated whether a decreased level of plasma DAO could reflect the severity of mucosal injury due to intravenous 5-fluorouracil (5-FU) treatment. The beneficial effect of soluble dietary fiber (SDF) on preventing diarrhea after 5-FU treatment was also examined. To induce diarrhea, 5-FU (50 mg/kg/day for four days) was administered via the tail vein with or without SDF supplementation. After 5-FU treatment, the majority of rats developed moderate to severe diarrhea, and levels of plasma DAO activity significantly decreased compared to those of control group (P < 0.05). Scanning electron microscopy revealed disarrangement of the small intestinal villi. Contrarily, the rats supplemented with SDF had diarrhea less frequently (50.0 vs. 91.7 %, P = 0.025) on day five, and DAO activity levels were significantly higher than in those rats administered 5-FU alone (8.25 ± 5.34 vs. 5.50 ± 4.32, P = 0.023). In conclusion, plasma DAO activity decreases in response to severe intestinal mucosal injury after 5-FU treatment, and SDF supplementation might be a practical and useful treatment for reducing the intestinal toxicity of 5-FU.

  10. Hedyotis diffusa Willd overcomes 5-fluorouracil resistance in human colorectal cancer HCT-8/5-FU cells by downregulating the expression of P-glycoprotein and ATP-binding casette subfamily G member 2

    PubMed Central

    LI, QIONGYU; WANG, XIANGFENG; SHEN, ALING; ZHANG, YUCHEN; CHEN, YOUQIN; SFERRA, THOMAS J.; LIN, JIUMAO; PENG, JUN

    2015-01-01

    Previous studies have demonstrated that Hedyotis diffusa Willd (HDW), a traditional Chinese herbal medicine, exhibits potent anticancer activity in models of colorectal cancer (CRC). Aggressive forms of CRC exhibit resistance to widely used chemotherapeutic drugs, including the antimetabolite, 5-fluorouracil (5-FU); however, less is known with regard to the activity of HDW against 5-FU-resistant cancer. In the present study, the mechanism of action and the potency of ethanol extracts of HDW (EEHDW) were investigated on a multidrug-resistant CRC HCT-8/5-FU cell line. Using an MTT cell proliferation assay, EEHDW treatment was shown to significantly reduce the cell viability of HCT-8/5-FU cells in a dose- and time-dependent manner. Furthermore, EEHDW significantly increased the retention of the ATP-binding cassette (ABC) transporter substrate, rhodamine-123, as compared with the untreated controls. To further investigate the molecular mechanisms targeted by EEHDW in the resistant cells, the expression levels of the ABC drug transporter protein, P-glycoprotein (P-gp), and ABC subfamily G member 2 (ABCG2), were analyzed using reverse-transcription polymerase chain reaction and western blot analysis. The mRNA and protein expression levels of P-gp and ABCG2 were reduced in the HCT-8/5-FU cells following EEHDW treatment, indicating that EEHDW inhibits ABCG2-mediated drug resistance by downregulating the expression of ABCG2 and P-gp. Therefore, the potential application of EEHDW as a chemotherapeutic adjuvant represents a promising alternative approach to the treatment of drug-resistant CRC. PMID:26640560

  11. Hedyotis diffusa Willd overcomes 5-fluorouracil resistance in human colorectal cancer HCT-8/5-FU cells by downregulating the expression of P-glycoprotein and ATP-binding casette subfamily G member 2.

    PubMed

    Li, Qiongyu; Wang, Xiangfeng; Shen, Aling; Zhang, Yuchen; Chen, Youqin; Sferra, Thomas J; Lin, Jiumao; Peng, Jun

    2015-11-01

    Previous studies have demonstrated that Hedyotis diffusa Willd (HDW), a traditional Chinese herbal medicine, exhibits potent anticancer activity in models of colorectal cancer (CRC). Aggressive forms of CRC exhibit resistance to widely used chemotherapeutic drugs, including the antimetabolite, 5-fluorouracil (5-FU); however, less is known with regard to the activity of HDW against 5-FU-resistant cancer. In the present study, the mechanism of action and the potency of ethanol extracts of HDW (EEHDW) were investigated on a multidrug-resistant CRC HCT-8/5-FU cell line. Using an MTT cell proliferation assay, EEHDW treatment was shown to significantly reduce the cell viability of HCT-8/5-FU cells in a dose- and time-dependent manner. Furthermore, EEHDW significantly increased the retention of the ATP-binding cassette (ABC) transporter substrate, rhodamine-123, as compared with the untreated controls. To further investigate the molecular mechanisms targeted by EEHDW in the resistant cells, the expression levels of the ABC drug transporter protein, P-glycoprotein (P-gp), and ABC subfamily G member 2 (ABCG2), were analyzed using reverse-transcription polymerase chain reaction and western blot analysis. The mRNA and protein expression levels of P-gp and ABCG2 were reduced in the HCT-8/5-FU cells following EEHDW treatment, indicating that EEHDW inhibits ABCG2-mediated drug resistance by downregulating the expression of ABCG2 and P-gp. Therefore, the potential application of EEHDW as a chemotherapeutic adjuvant represents a promising alternative approach to the treatment of drug-resistant CRC.

  12. Antihyperglycemic Effect of Quercetin in Ovariectomized Rats Treated with Tamoxifen.

    PubMed

    Silva, Fernanda Coleraus; Bramatti, Isabella Calvo; Toledo, Adrieli Gorlin; Salles, Fernando Marques; Itinose, Ana Maria; Marek, Carla Brugin

    2017-03-01

    Tamoxifen is effective in breast cancer therapy in postmenopausal women; however, it causes adverse effects that alter the glycolytic pathway and induce hyperglycemia. Quercetin, a flavonoid with antioxidant potential, inhibits butyrylcholinesterase (BuChE), which is positively associated with hyperglycemia. Therefore, this study investigated the effect of quercetin on tamoxifen-induced hyperglycemia, using BuChE activity as a bioindicator in adult ovariectomized Wistar rats. The ovariectomized rats were treated orally for 14 days with different concentrations of quercetin (2.5, 7.5, 22.5, and 67.5 mg.kg(-1) b.w.) and tamoxifen (5 mg.kg(-1) b.w.). Subsequently, they were euthanized; blood and tissue samples were collected. The following biochemical parameters were analyzed: plasma glucose levels and BuChE activity in the plasma, liver, intestine, and adipose tissue. The most effective dose of quercetin in reducing hyperglycemia was 22.5 mg.kg(-1) b.w. (Que/TAM 4.5/1, P < .00000), although the doses of 2.5 (Que/TAM 0.5/1, P < .05) and 7.5 mg.kg(-1) b.w. (Que/TAM 1.5/1, P < .05) were also effective. The BuChE activity decreased in the intestine at all tested doses of quercetin coadministered with tamoxifen (P < .01); however, in adipose tissue, there was a biphasic activity with a decrease (P < .05) and increase (P < .05) in activity at doses of 7.5 and 22.5 mg.kg(-1) b.w. of quercetin, respectively. However, the correlation between BuChE and glucose levels was not significant (P > .05). In summary, the findings of the present study suggest that quercetin when associated with tamoxifen decreases in plasma glucose levels. Furthermore, in these cases, BuChE should not be used as an indicator of hyperglycemia.

  13. Obestatin and insulin in pancreas of newborn diabetic rats treated with exogenous ghrelin.

    PubMed

    Turk, Neslihan; Dağistanli, Fatma Kaya; Sacan, Ozlem; Yanardag, Refiye; Bolkent, Sema

    2012-07-01

    The aim of the study was to evaluate the effect of ghrelin treatment on obestatin, insulin gene expression and biochemical parameters in the pancreas of newborn-streptozocin (STZ) diabetic rats. Rats were divided into 4 groups. Group I: control rats treated with physiological saline; group II: control rats treated with 100 μg/kg/day ghrelin; group III: two days after birth rats that received 100mg/kg STZ injected as a single dose to induce neonatal diabetes; group IV: neonatal-STZ-diabetic rats treated with ghrelin for four weeks. Sections of the pancreas were examined with immunohistochemistry for the expression of obestatin and insulin and in situ hybridization for the expression of insulin mRNA. The blood glucose levels were measured. Tissue homogenates were used for protein, glutathione, lipid peroxidation and non-enzymatic glycosylation levels and antioxidant enzyme analysis. There was a significant difference in blood glucose levels in newborn-STZ-diabetic rats compared to ghrelin treated diabetic rats at weeks 1, 2 and 4. In group IV, pancreatic non-enzymatic glycosylation and lipid peroxidation levels were decreased, however, glutathione levels and enzymatic activities were increased. Insulin peptide and mRNA (+) signals in islets of Langerhans and obestatin immunopositive cell numbers showed an increase in group IV compared to group III. These results suggest that administration of ghrelin to newborn rats may prevent effects of diabetes.

  14. 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.

  15. Chinese medicinal herbs in treating model rats with hepatic fibrosis.

    PubMed

    Zhou, Yun-Xiao; Chen, Jiu; Li, Jian-Ping; Wang, Yan-Li; Jin, Xiao-Dong

    2009-12-30

    The objective of this study was to examine the effects of Chinese medicine formula-Yu Zhang Dan (YZD, composed of Herba Lysimachiae, Rhizoma Polygoni Cuspidati, Radix Curcumae) on the model rats with hepatic fibrosis. Forty male Sprague-Dawley (SD) rats were used in the present study, and they were separated randomly into 4 groups: a normal control group (Group A, n=5), a model control (Group B, n=15), a high dose of YZD (Group C, n=10), and a low dose of YZD (Group D, n=10). Hepatic fibrosis in rats was induced by carbon tetrachloride (CCl(4)). The variation of the serum alanine transaminase (ALT), aspartate aminotransferase (AST), hyaluronate acid (HA), laminin (LN), type • • procollagen peptide (P• •NP), L-Glutathione (GSH) was respectively measured with radioimmunoassay (RIA) and detection of transforming growth factor-beta 1 (TGF-β1) and smooth muscle alpha actin (α-SMA) was conducted with immunohistochemistry. The ALT, AST HA, LN and PIII NP levels in the serum of the model control group were significantly higher than those of the normal control group (P<0.05), and both of the high dose of YZD and low dose of YZD significantly decreased the ALT, AST HA, LN and PIII NP levels of the model rats (P<0.05). The TGF-β1 and α-SMA levels of the model control group were significantly higher than those of the normal control group (P<0.05), and both of the high dose of YZD and low dose of YZD significantly decreased the TGF-β1 levels of the model rats (P<0.05) , and only the high dose of YZD significantly decreased the α-SMA levels of the model rats (P<0.05). The expression of TGF-β1 and α-SMA in the liver tissues of the rats were in the cytoplasm of the cells. It may be through decreasing the ALT, AST, HA, LN and PIII NP levels in the serum of the model rats and decreasing the expression of TGF-β1 and α-SMA in the liver tissues of the model rats that YZD significantly relieved the hepatic fibrosis.

  16. 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.

  17. Effect of prostaglandin E/sub 2/ on the small intestine of indomethacin-treated rats

    SciTech Connect

    Romain, N.; Dandrifosse, G.; Forget, P.; Lepoint, A.

    1987-09-07

    In the present study, the protective effect of PGE/sub 2/ on intestinal damage in indomethacin-treated adult rats was investigated. Ileal integrity was evaluated making use of different biochemical and histological parameters : activities of sucrase, maltase and diamine oxidase; concentrations of DNA, putrescine, spermidine and spermine; incorporation of /sup 3/H-thymidine into DNA; mitotic index and mucosal thickness. Results expressed per g of mucosal weight, showed that : - maltase and diamine oxidase activities as well as DNA, spermidine and spermine concentrations decreased markedly in indomethacin-treated rats when compared to control rats; - the decrease of maltase activity as well as DNA, spermidine and spermine concentration was less pronounced in PGE/sub 2/-treated rats when compared to indomethacin-treated rats; - /sup 3/H-thymidine incorporation into DNA and mitotic index values showed no significant variation in the course of different treatments; - mucosal thickness increased strongly, the PGE/sub 2/-protected rats. The authors suggest that PGE/sub 2/ could protect the rat's intestinal mucosa against the effects of indomethacin through a trophic action on intestinal villi. 15 references, 3 tables.

  18. 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.

  19. Zinc content of maturing spermatozoa in oestrogen treated rats.

    PubMed

    Srivastava, A; Chowdhury, A R; Setty, B S

    1983-02-01

    Zinc content of spermatozoa collected from the caput and cauda portions of the rat epididymis was determined by atomic absorption spectroscopy. The results showed about 60% reduction in the spermatozoal zinc content by the time they reach the cauda epididymis. This reduction was inhibited in rats receiving micro dose oestrogen which induced 'functional' sterility. It appears that the fall in zinc content of spermatozoa during their transport in the epididymis is related to sperm maturation and that oestrogen treatment interferes with this reduction in sperm zinc content.

  20. Zinc content in epididymal spermatozoa of metoclopramide-treated rats.

    PubMed

    Kaminska, B; Rozewicka, L; Dominiak, B; Mielnicka, M; Mikulska, D

    1987-01-01

    Zinc content was determined separately in spermatozoa taken from epididymal caput and cauda in rats. It was revealed that spermatozoa transported from the epididymal caput to the cauda reduce about 54% of zinc. This reduction is significantly inhibited in spermatozoa of rats receiving metoclopramide. That is also accompanied by a fall of testosterone level in blood serum and of delta 5, 3 beta-HSD activity in Leydig cells. It was found out that the reduction of zinc in spermatozoa at the time of their passage through the epididymis is the process that depends on androgens.

  1. 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

  2. Growth is compromised in rats fed ozone-treated casein

    SciTech Connect

    Kasai, T.; Iwashita, A.; Kiriyama, S. )

    1993-05-01

    Modified casein containing few phenylalanine residues and no other aromatic amino acid residues was obtained by ozonolysis of casein. Although 68% of phenylalanine was decomposed by ozonolysis of casein, ozonolysis caused alterations beyond the destruction of aromatic amino acid residues. Nearly the same degree of decomposition of amino acid residues was observed in casein ozonated after predigestion by pepsin. Rats were fed diets containing 8% casein supplemented with methionine and aspartic acid (8C-AA), 8% ozonated casein supplemented with methionine and free amino acids lost by ozonolysis (8OC-AA), 8% casein ozonated after predigestion by pepsin supplemented with methionine and free amino acids lost during preparation (8POC-AA) or 7.6% amino acid mixture. The growth of rats fed the 8OC-AA diet was significantly lower than that of those fed 8C-AA or 7.6AA diets. The growth of rats fed the 8POC-AA diet was comparable to growth of those fed 8OC-AA. The biological values of the 8OC-AA and 8POC-AA were comparable to that of 8C-AA, but true digestibility of 8OC-AA was significantly lower than that of 8C-AA. True digestibility 8POC-AA was significantly improved relative to 8OC-AA, but the growth of rats fed 8POC-AA was not improved relative to that of those fed 8OC-AA. Kidney and cecum weights of rats fed 8OC-AA and 8POC-AA were significantly heavier than those of the 8C-AA-fed group, although histopathological examination of kidneys showed no deterioration compared to that of the 8C-AA-fed group.

  3. Rat Plasma Oxidation Status After Nigella Sativa L. Botanical Treatment in CCL(4)-Treated Rats.

    PubMed

    Soleimani, Hengameh; Ranjbar, Akram; Baeeri, Maryam; Mohammadirad, Azadeh; Khorasani, Reza; Yasa, Narguess; Abdollahi, Mohammad

    2008-01-01

    ABSTRACT Nigella sativa Linn. (family Ranunculaceae), commonly known as black cumin, is native to the Mediterranean area and has been used for thousands of years as a health and beauty aid. The present study investigated the protective effects of Nigella sativa (NS) extract (NSE) and oil (NSO) on CCl(4)-induced nitrosative stress and protein oxidation in rat. CCl(4) (0.8 mg/kg) was used as an aid for induction of nitrosative stress. In vitro antioxidant potential was tested in the presence of 2,4-dinitrophenylhyrdazine (DPPH) as an organic nitrogen radical. Doses of 0.2, 0.3, and 1 mg/kg of the NS extract and oil were administered to CCL(4)-treated rats for 10 days. At the end of treatment, blood was taken from rats under anesthesia and plasma was separated. The concentration of nitric oxide (NO), total antioxidant power (TAP), carbonyl molecules (CM) as measure of protein oxidation (PO), tumor necrosis factor-alpha (TNF-alpha), and total thiol molecules (TTM) were measured in plasma. In vitro evaluation of antioxidant effects of NSE and NSO showed that the highest antioxidant activity (80%) was observed with the concentration of 10 and 20 mg/ml, respectively, that were equal to vitamin E (200 mg/ml). Administration of CCL(4) increased plasma PO, NO, TNF-alpha and decreased TAP and TTM. Both NSE and NSO showed significant protection against CCl(4)-induced changes in biochemical parameters, but not dose-dependently. Doses of 0.3 and 1 mg/kg were more effective than doses of 0.2 mg/kg for both NSE and NSO, but dose of 1 mg/kg was the most effective one. The results indicate the potential of NS in preventing CCL(4)-induced toxic nitrosative stress. It is concluded that NS has marked antioxidant potentials that may be beneficial in alleviating complications of many illnesses related to oxidative/nitrosative stress in humans, but preclinical safety measures should be completed before clinical trials.

  4. Delay in growth and the development of nephritis in rats treated with interferon preparations in the neonatal period.

    PubMed Central

    Gresser, I.; Morel-Maroger, L.; Châtelet, F.; Maury, C.; Tovey, M.; Bandu, M. T.; Buywid, J.; Delauche, M.

    1979-01-01

    Suckling rats were injected for 14 to 17 days with potent rat-cell-culture interferon preparations or various heterologous interferon or control preparations. Only treatment with rat interferon resulted in a delay in growth and maturation of different organs and the subsequent development of an "immune complex" type nephritis. Thus, 38 of 43 rats treated with rat interferon developed a severe glomerulonephritis. Thus, 38 of 43 rats treated with rat interferon developed a severe glomerulonephritis, whereas only 3 of 99 rats in the various control groups had minimal renal lesions. Deposits of IgG and C3 along the glomerular basement membrane were only seen in interferon-treated rats. Images Figure 6 Figure 3 Figure 2 Figure 5 Figure 4 Figure 1 PMID:156503

  5. 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.

  6. Antiamnesic effect of stevioside in scopolamine-treated rats

    PubMed Central

    Sharma, Deepika; Puri, Munish; Tiwary, Ashok K.; Singh, Nirmal; Jaggi, Amteshwar Singh

    2010-01-01

    The present study was undertaken to explore the potential of stevioside in memory dysfunction of rats. Memory impairment was produced by scopolamine (0.5 mg/kg, i.p.) in animals. Morris water maze (MWM) test was employed to assess learning and memory. Brain acetylcholinestrase enzyme (AChE) activity was measured to assess the central cholinergic activity. The levels of brain thiobarbituric acid-reactive species (TBARS) and reduced glutathione (GSH) were estimated to assess the degree of oxidative stress. Scopolamine administration induced significant impairment of learning and memory in rats, as indicated by a marked decrease in MWM performance. Scopolamine administration also produced a significant enhancement of brain AChE activity and brain oxidative stress (increase in TBARS and decrease in GSH) levels. Pretreatment of stevioside (250 mg/kg dose orally) significantly reversed scopolamine-induced learning and memory deficits along with attenuation of scopolamine-induced rise in brain AChE activity and brain oxidative stress levels. It may be concluded that stevioside exerts a memory-preservative effect in cognitive deficits of rats possibly through its multiple actions. PMID:20871768

  7. Immunohistochemical distribution of leptin in kidney tissues of melatonin treated diabetic rats.

    PubMed

    Elis Yildiz, S; Deprem, T; Karadag Sari, E; Bingol, S A; Koral Tasci, S; Aslan, S; Nur, G; Sozmen, M

    2015-05-01

    We examined using immunohistochemistry the distribution of leptin in kidney tissues of melatonin treated, streptozotocin (STZ) diabetic rats. The animals were divided into five groups: control, sham, melatonin-treated, diabetic and melatonin-treated diabetic. Kidney sections were prepared and stained with hematoxylin and eosin, and Crossman's triple staining for histological examination. The immunohistochemical localization of leptin in the kidney tissue was determined using the streptavidin-biotin-peroxidase method. We determined that on days 7 and 14, the leptin immunoreactivity of the diabetic and melatonin-treated diabetic groups was weaker than for the other groups. Weak immunoreactivity was found in the proximal and distal tubules of the kidney in the diabetic and melatonin-treated diabetic groups on days 7 and 14, and strong immunoreactivity was found in the control, sham and melatonin groups. Melatonin application had no significant effect on leptin production in the kidney tissues of diabetic rats.

  8. Depressive-like behavior in adrenocorticotropic hormone-treated rats blocked by memantine.

    PubMed

    Tokita, Kenichi; Fujita, Yuko; Yamaji, Takayuki; Hashimoto, Kenji

    2012-08-01

    Hyperactivity of the hypothalamic pituitary-adrenal (HPA) axis plays a role in the pathophysiology of major depressive disorder (MDD). Recent studies suggest the role of the glutamatergic system in the pathophysiology of MDD, and N-methyl-D-aspartate (NMDA) receptor antagonists have shown antidepressant effects in both preclinical and clinical studies. However, little is known about the role of adrenocorticotropic hormone (ACTH) specifically in the glutamatergic response to HPA axis activation. Glutamate is an NMDA receptor agonist, and glycine and D-serine act as co-agonists. Here, we measured brain concentrations of these amino acids in rats given repeated administration of ACTH (100 μg/rat/day, sc, for 14 days). Further, we also evaluated behavioral effects of memantine, a non-competitive NMDA antagonist, on immobility time in the forced swimming test and on locomotor activity in ACTH-treated rats. Compared with control rats, glutamine, glycine, L-serine, and D-serine levels were increased in the hippocampus of ACTH-treated rats; glutamate, glutamine, glycine, L-serine, and D-serine were increased in the cerebellum; and glutamine and glycine were increased in the frontal cortex and striatum, all with statistical significance. Remarkably, these increases in agonists and co-agonists might have led to the augmentation of NMDA receptor activity. ACTH treatment increased immobility time in the forced swimming test and decreased locomotor activity in rats. On the contrary, memantine (10 mg/kg, ip) significantly decreased immobility time in the forced swimming test and increased locomotor activity in ACTH-treated rats. Furthermore, imipramine (15 mg/kg, ip) did not alter immobility time in the forced swimming test whereas this drug significantly decreased locomotor activity in ACTH-treated rats. These results suggest that depressive-like behaviors by chronic ACTH treatment could be blocked by memantine.

  9. 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

  10. Dietary chloride does not correlate with urinary thromboxane in deoxycorticosterone acetate-treated rats.

    PubMed

    Theriot, J A; Passmore, J C; Jimenez, A E; Fleming, J T

    2000-06-01

    Renal vascular resistance in deoxycorticosterone acetate (DOCA) salt-treated uninephrectomized rats is increased by high dietary chloride. Because DOCA salt-hypertensive rats exhibit an increased urinary excretion of thromboxane B2 (TXB2), a metabolite of thromboxane A2 (TXA2), the increased TXB2 excretion by DOCA salt-treated rats could relate to elevated dietary chloride, increased blood pressure, and/or the presence of intact renal tubules. We hypothesized that high NaCl intake, resulting in an elevated tubular chloride excretion, stimulates TXA2 production. A result of that production could be renal vasoconstriction. Baseline blood pressures were measured for 10 days, and then the rats were treated with DOCA (30 mg/kg) and fed (1) normal NaCl, (2) normal sodium with high chloride, or (3) high sodium chloride (NaCl) for 4.5 weeks. Next, the rats were uninephrectomized (1K) or unihydronephrectomized (1KHK) to yield one kidney without an intact tubular system and therefore no macula densa. Two and a half weeks later, urinary excretion of TXB2 was determined. DOCA-high NaCl-fed 1KHK or 1K rats had significant increases in systemic blood pressure to 172 +/- 12 and 190 +/- 5 mm Hg, respectively, compared with no significant increase in blood pressure among the other groups. Urinary TXB2 excretion was increased to 29 +/- 4 pg per 24 hours per gram of body weight in all DOCA-treated 1KHK and 1K animals regardless of diet compared with DOCA-treated animals with two intact kidneys (13 +/- 2 pg per 24 hours per gram of body weight). DOCA treatment in rats with one functional kidney results in the excretion of high levels of urinary TXB2 unrelated to dietary chloride load, blood pressure, or intact renal tubules.

  11. Somatostatin, insulin and glucagon secretion by the perfused pancreas from the cysteamine-treated rat

    SciTech Connect

    Silvestre, R.A.; Miralles, P.; Moreno, P.; Villanueva, M.L.; Marco, J.

    1986-02-13

    In rats, administration of a single dose of cysteamine (300 mg/kg, intragastrically) induces a depletion of pancreatic somatostatin content (approximately 60%) without modifying pancreatic insulin or glucagon content. In perfused pancreases from cysteamine-treated rats, there was a lack of somatostatin response to glucose, arginine or tolbutamide. In the absence of stimulated somatostatin release, the secretory responses of insulin and glucagon to glucose, to arginine, and to tolbutamide were not significantly different from those observed in pancreases from control rats. Our data do not support the concept that pancreatic somatostatin plays a major role in the control of insulin and glucagon release.

  12. 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.

  13. 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.

  14. Electrophysiological observations in hippocampal slices from rats treated with the ketogenic diet.

    PubMed

    Stafstrom, C E; Wang, C; Jensen, F E

    1999-11-01

    The electrophysiological effects of the high-fat, low-carbohydrate ketogenic diet (KD) were assessed in normal and epileptic [kainic-acid(KA)-treated] adult rats using hippocampal slices. In the first set of experiments, normal rats were fed the KD or a standard control diet for 6-8 weeks (beginning on postnatal day 56, P56), after which they were sacrificed for hippocampal slices. All rats on the KD became ketotic. The baseline effects of the KD were determined by comparing extracellular measures of synaptic transmission and responses to evoked stimulation, and hippocampal excitability was tested in Mg(2+)-free medium. There were no differences in EPSP slope, input/output relationship, responses to evoked stimulation or Mg(2+)-free burst frequency between slices from control and KD-fed rats. In another set of experiments, rats were made epileptic by intraperitoneal injection of kainic acid (KA) on P54, which caused status epilepticus followed by the development of spontaneous recurrent seizures (SRS) over the next few weeks. Two days after KA-induced status, rats were divided into a control-fed group and a KD-fed group. Animals on the KD had significantly fewer SRS over the ensuing 8 weeks. In hippocampal slices from KA-treated, KD-fed rats, there were fewer evoked CA1 population spikes than from slices of control-fed rats. These results suggest that the KD does not alter baseline electrophysiological parameters in normal rats. In rats made chronically epileptic by administration of KA, KD treatment was associated with fewer spontaneous seizures and reduced CA1 excitability in vitro. Therefore, at least part of the KD mechanism of action may involve long-term changes in network excitability.

  15. Binding and action of glucagon in isolated adipocytes from cortisol-treated rats.

    PubMed

    Calle, C; Sanchez-Casas, P; Simón, M A; Mayor, P

    1987-05-29

    Evidence for pre-receptor, receptor and post-receptor glucagon defects was investigated in adipocytes from cortisol-treated rats. A decrease in glucagon binding due to a decreased number of receptors was observed. No changes in receptor affinity were detected. Both, the lipolytic response of glucagon and the ability of glucagon to increase basal and theophylline-stimulated cAMP accumulation remained unaltered. Moreover, a hyperglucagonemia accompanied by an increase in glucagon degradation in the serum of cortisol-treated rats was observed. Such alterations could represent a new mechanism by which glucocorticoids exert their biological actions.

  16. 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.

  17. 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

  18. Recovery of presynaptic dopaminergic functioning in rats treated with neurotoxic doses of methamphetamine.

    PubMed

    Cass, W A; Manning, M W

    1999-09-01

    Repeated administration of methamphetamine (METH) to animals can result in long-lasting decreases in striatal dopamine (DA) content. In addition, the evoked overflow of striatal DA is reduced in rats 1 week after neurotoxic doses of METH. However, whether these functional changes in DA release are permanent or tend to recover over time has not been established. In the present study we used in vivo electrochemistry and microdialysis to examine evoked overflow of DA in the striatum of METH-treated rats at several time points after treatment to determine if DA overflow would spontaneously recover. Male Fischer-344 rats were administered METH (5 mg/kg, s.c. ) or saline four times in one day at 2 hr intervals. In vivo electrochemistry experiments in anesthetized rats, and in vivo microdialysis studies in awake rats, were carried out 1 week, 1 month, 6 months, and 12 months after treatment. At 1 week after treatment there were significant decreases in potassium- and amphetamine-evoked overflow of DA, and in clearance of DA, in the striatum of the METH-treated animals. Basal extracellular levels of DA and its metabolites were also decreased. Evoked overflow had partially recovered by 1 month. By 6 months evoked overflow of DA appeared to be normal in the METH-treated rats. However, whole tissue levels of striatal DA were still significantly decreased. All parameters were back to control values by 12 months. These results suggest that presynaptic dopaminergic functioning can recover to normal levels in the striatum of METH-treated rats by 12 months after treatment.

  19. Knockdown of Merm1/Wbscr22 attenuates sensitivity of H460 non-small cell lung cancer cells to SN-38 and 5-FU without alteration to p53 expression levels.

    PubMed

    Yan, Dongmei; Zheng, Xiaoliang; Tu, Linglan; Jia, Jing; Li, Qin; Cheng, Liyan; Wang, Xiaoju

    2015-01-01

    Merm1/Wbscr22 is a novel metastasis promoter that has been shown to be involved in tumor metastasis, viability and apoptosis. To the best of our knowledge, there are currently no studies suggesting the possible correlation between the expression of Merm1/Wbscr22 in tumor cells and chemosensitivity to antitumor agents. In the present study, two human non-small cell lung cancer cell lines, H1299 and H460, were used to investigate whether Merm1/Wbscr22 affects chemosensitivity to antitumor agents, including cisplatin (CDDP), doxorubicin (ADM), paclitaxel (PTX), mitomycin (MMC), 7-Ethyl-10-hydroxycamptothecin (SN-38; the active metabolite of camptothecin) and 5-fluorouracil (5-FU). Merm1/Wbscr22 knockdown cell lines (H1299-shRNA and H460-shRNA) and negative control cell lines (H1299-NC and H460-NC) were established by stable transfection, and the efficiency of Merm1/Wbscr22 knockdown was confirmed by western blotting, immunofluorescence microscopy and quantitative polymerase chain reaction. The results demonstrated that shRNA-mediated knockdown of Merm1/Wbscr22 did not affect cell proliferation in vitro and in vivo. The H460 cells harboring wild type p53 were markedly more sensitive to all six antitumor agents as compared with the p53-null H1299 cells. Downregulation of Merm1/Wbscr22 did not affect H1299 sensitivity to any of the six antitumor agents, whereas attenuated H460 sensitivity to SN-38 and 5-FU, without significant alteration in p53 at both mRNA and protein levels, was identified. The reduced H460 sensitivity to SN-38 was further confirmed in vivo. SN-38 demonstrated significant tumor growth inhibitory activity in both H460 and H460‑NC tumor xenograft models, but only marginally suppressed the H460-shRNA xenograft tumor growth. Furthermore, CDDP (4, 10, 15 µg/ml)-resistant human non-small lung cancer cells A549 (A549-CDDPr-4, 10, 15) expressed significant amounts of Merm1/Wbscr22 protein, as compared with the parental A549 cells. In conclusion, sh

  20. Nicotine ameliorates impairment of working memory in methamphetamine-treated rats.

    PubMed

    Mizoguchi, Hiroyuki; Ibi, Daisuke; Takase, Fumiaki; Nagai, Taku; Kamei, Hiroyuki; Toth, Erika; Sato, Jun; Takuma, Kazuhiro; Yamada, Kiyofumi

    2011-06-20

    Nicotine is hypothesized to have therapeutic effects on attentional and cognitive abnormalities in psychosis. In this study, we investigated the effect of nicotine on impaired spatial working memory in repeated methamphetamine (METH)-treated rats. Rats were administered METH (4 mg/kg, s.c.) once a day for 7 days, and their working memory was assessed with a delayed spatial win-shift task in a radial arm maze. The task consisted of two phases, a training phase and a test phase, separated by a delay. Control animals showed impaired performance in the test phase when the delay time was increased to 120 min or longer, while METH-treated rats showed impaired performance with a shorter delay time of 90 min. Memory impairment in METH-treated rats persisted for at least 14 days after drug withdrawal. METH-induced impairment of working memory was reversed by nicotine (0.3mg/kg, p.o., for 7 days), but the effect was diminished 7 days after the withdrawal. In control rats, nicotine decreased the number of working memory errors in the test with delay time of 120 min when administered before the training phase. Neither post-training nor pre-test administration of nicotine had any effect on working memory. These findings suggest that nicotine may have some protective effect against the impairment of working memory.

  1. Antioxidant effect of Cytisus scoparius against carbon tetrachloride treated liver injury in rats.

    PubMed

    Raja, S; Ahamed, K F H Nazeer; Kumar, V; Mukherjee, Kakali; Bandyopadhyay, A; Mukherjee, Pulok K

    2007-01-03

    The study was aimed to investigate the antioxidant activity of Cytisus scoparius L. (Family: Leguminosae) on CCl(4) (carbon tetrachloride) treated oxidative stress in Wistar albino rats. CCl(4) injection induced oxidative stress by a significant rise in serum glutamate oxaloacetate transaminases (SGOT), serum glutamate pyruvate transaminases (SGPT), lactate dehydrogenase (LDH) and thiobarbituric acid reactive substances (TBARS) along with reduction of superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione-s-transferase (GST) and glutathione reductase (GRD). Pretreatment of rats with different doses of plant extract (250 and 500mg/kg) significantly lowered SGOT, SGPT, LDH and TBARS levels against CCl(4) treated rats. GSH and hepatic enzymes like SOD, CAT, GPx, GRD, and GST were significantly increased by treatment with the plant extract, against CCl(4) treated rats. The activity of extract at the dose of 500mg/kg was comparable to the standard drug, silymarin (25mg/kg). Based on these results, it was observed that Cytisus scoparius extract protects liver from oxidative stress induced by CCl(4) in rats and thus helps in evaluation of the traditional claim on this plant.

  2. Biochemical and immunohistochemical changes in delta-9-tetrahydrocannabinol-treated type 2 diabetic rats.

    PubMed

    Coskun, Zeynep Mine; Bolkent, Sema

    2014-01-01

    The regulation of glucose, lipid metabolism and immunoreactivities of insulin and glucagon peptides by delta-9-tetrahydrocannabinol (Δ(9)-THC) in diabetes were examined in an experimental rat model. Male Sprague-Dawley rats were divided into four groups: (1) control, (2) Δ(9)-THC treated, (3) diabetic, and (4) diabetic+Δ(9)-THC. The type 2 diabetic rat model was established by intraperitoneal (i.p.) injection of nicotinamide (85 mg/kg body weight) followed after 15 min by i.p. injection of streptozotocin (STZ) at 65 mg/kg of body weight. Δ(9)-THC and Δ(9)-THC treated diabetic groups received 3mg/kg/day of Δ(9)-THC for 7 days. The immunolocalization of insulin and glucagon peptides was investigated in the pancreas using a streptavidin-biotin-peroxidase technique. High density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL), very low density lipoprotein cholesterol (VLDL), triglycerides (TG), total cholesterol (TC) and total protein (TP) levels were measured in serum. Total islet area percent of insulin immunoreactive cells slightly changed in diabetic+Δ(9)-THC rats compared to diabetic animals. However, the area percent of glucagon immunoreactive cells showed a decrease in diabetic+Δ(9)-THC rats compared to that of diabetic animals alone. Serum TC, HDL and LDL levels of diabetes+Δ(9)-THC group showed a decrease compared to the diabetic group. These results indicate that Δ(9)-THC may serve a protective role against hyperlipidemia and hyperglycemia in diabetic rats.

  3. 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.

  4. 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.

  5. Anthriscus nemorosa essential oil inhalation prevents memory impairment, anxiety and depression in scopolamine-treated rats.

    PubMed

    Bagci, Eyup; Aydin, Emel; Ungureanu, Eugen; Hritcu, Lucian

    2016-12-01

    Anthriscus nemorosa (Bieb.) Sprengel is used for medicinal purposes in traditional medicine around the world, including Turkey. Ethnobotanical studies suggest that Anthriscus essential oil could improve memory in Alzheimer's disease. The current study was hypothesized to investigate the beneficial effects of inhaled Anthriscus nemorosa essential oil on memory, anxiety and depression in scopolamine-treated rats. Anthriscus nemorosa essential oil was administered by inhalation in the doses of 1% and 3% for 21 continuous days and scopolamine (0.7mg/kg) was injected intraperitoneally 30min before the behavioral testing. Y-maze and radial arm-maze tests were used for assessing memory processes. Also, the anxiety and depressive responses were studied by elevated plus-maze and forced swimming tests. As expected, the scopolamine alone-treated rats exhibited the following: decrease the percentage of the spontaneous alternation in Y-maze test, increase the number of working and reference memory errors in radial arm-maze test, decrease of the exploratory activity, the percentage of the time spent and the number of entries in the open arm within elevated plus-maze test and decrease of swimming time and increase of immobility time within forced swimming test. However, dual scopolamine and Anthriscus nemorosa essential oil-treated rats showed significant improvement of memory formation and exhibited anxiolytic- and antidepressant-like effects in scopolamine-treated rats. These results suggest that Anthriscus nemorosa essential oil inhalation can prevent scopolamine-induced memory impairment, anxiety and depression.

  6. Effect of O-ethylrutoside on serum and hepatic lipids in acute ethanal-treated rats.

    PubMed

    Wójcicki, J

    1977-01-01

    The serum total lipids, triglycerides, total cholesterol and free fatty acid concentrations, as well as hepatic triglyceride and cholesterol levels, were increased in acutely ethanol-treated rats. Treatment of ethanol-given animals with o-ethylrutoside resulted in a significant reduction in all examined fractions of serum lipids and in the hepatic total cholesterol level.

  7. Pixe analysis of trace elements in tissues of rats treated with anticonvulsants

    NASA Astrophysics Data System (ADS)

    Hurd, R. W.; Van Rinsvelt, H. A.; Kinyua, A. M.; O'Neill, M. P.; Wilder, B. J.; Houdayer, A.; Hinrichsen, P. F.

    1987-04-01

    Several lines of evidence implicate metals in epilepsy. Anticonvulsant drugs are noted to alter levels of metals in humans and animals. PIXE analysis was used to investigate effects of three anticonvulsant drugs on tissue and brain cortex trace elements. The content of zinc and copper was increased in liver and spleen of rats treated with anticonvulsants while selenium was decreased in cortex.

  8. Pineal gland: influence on gonads of male rats treated with androgen 3 days after birth.

    PubMed

    Reiter, R J; Hoffman, J C; Rubin, P H

    1968-04-26

    Either blinding or the injection of 1 milligram of testosterone propionate into male Sprague-Dawley rats, 3 days old, results in testes and accessory organs (seminal vesicles and coagulating glands) that are smaller than normal when the rats are 72 days old. The response to blinding is prevented by removal of the pineal gland, whereas the response to treatment with testosterone is unaffected by pinealectomy. Combination of the two treatments in 3-day- old rats causes testes to be less than one-third their normal size at 72 days of age; pinealectomy in these rats permits the reproductive organs to grow to the same size as those in the androgen-treated animals.

  9. Further evidence of benzene carcinogenicity. Results on Wistar rats and Swiss mice treated by ingestion.

    PubMed

    Maltoni, C; Conti, B; Perino, G; Di Maio, V

    1988-01-01

    Wistar rats and Swiss mice were treated by ingestion (stomach tube) with benzene in olive oil at a dose of 500 and 0 mg/kg b.w. once daily, 4-5 days weekly, for 104 weeks (rats) or for 78 weeks (mice). In Wistar rats, benzene caused Zymbal gland carcinomas, carcinomas of the oral cavity, and carcinomas of the nasal cavities, and an increase in the incidence of total malignant tumors. In Swiss mice, benzene produced Zymbal gland carcinomas and dysplasias and an increase in the incidence of mammary carcinomas (in females), lung tumors, and total malignant tumors. These experiments further confirm that benzene is a multipotential carcinogen as was shown before by long-term bioassays performed on Sprague-Dawley rats in the same Experimental Unit.

  10. 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

  11. 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

  12. 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.

  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. Sustained Fos expression is observed in the developing brainstem auditory circuits of kanamycin-treated rats.

    PubMed

    Lee, Jae Ho; Kim, Hee Jung; Suh, Myung-Whan; Ahn, Seung Cheol

    2011-11-14

    It has been demonstrated that kanamycin treatment during early developmental period induces partial cochlear destruction and enhanced glutamatergic transmission at the medial nucleus of the trapezoid body (MNTB) - the lateral superior olive (LSO) synapses in the superior olivary complex (SOC). As c-fos was expected to be expressed in the SOC by kanamycin-induced cochlear damage, the expression of c-fos protein (Fos) was investigated using immunohistochemistry in kanamycin-treated rat pups. In the control rat pups less than postnatal (P) day 9 in age, Fos-like immunoreactivity (Fos-IR) was transiently observed in the MNTB and LSO on P6, but disappeared on P9, which reflects a physiologic process. In contrast, in kanamycin-treated rats, Fos-IR was consistently observed through P9. Because a significant increase in terminal uridine deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick-end labeling (TUNEL) and glial fibrillary acidic protein (GFAP) IR was not demonstrated in the MNTB and LSO of kanamycin-treated rats, the increased Fos-IR does not appear to indicate an ongoing pathologic process, but may be related to the increased activity caused by the disturbance in excitatory and inhibitory balance between brainstem auditory circuits.

  15. Spontaneous appearance of uterine tumors in vehicle and 3-methylcholanthrene-treated Wistar rats.

    PubMed

    Anger, Dana L; Crankshaw, Denis J; Foster, Warren G

    2006-11-01

    During the conduct of a study designed to determine the effect of 3-methylcholanthrene (3-MC), a synthetic polycyclic aromatic hydrocarbon (PAH) that acts through the aryl hydrocarbon receptor (AhR), on uterine contractility in Wistar rats, uterine tumors were identified in both vehicle and 3-MC-treated animals. The objective of the current study was to describe the histological characteristics of these tumors. Sexually mature female rats (110 days old) were treated with 70 micro mol/kg 3-MC or vehicle (olive oil) for 4 days and euthanized by exsanguination. At necropsy uterine tumors were unexpected findings in two vehicle and four 3-MC-treated rats. The tumors appeared as multiple unilateral or bilateral subserosal nodes. No tumors were found in other tissues on gross inspection. Prior to necropsy, tumor-presenting animals were acyclic and arrested in a state of persistent proestrus. Haematoxylin and eosin staining of tumor sections revealed nests of acidophilic granule-containing cells within a highly vascular stroma of the uterine wall below the muscularis. Positive periodic acid Schiff (PAS) staining suggested the presence of glycogen or glycophospholipids within these granules, however, negative PAS diastase staining indicated that the acidophilic bodies were not composed of glycogen. The tumors are histologically similar to human dysgerminomas. We conclude that these tumors are unrelated to treatment and are of a granular type not previously documented in Wistar rats.

  16. 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.

  17. Zinc improves the immune function and the proliferation of lymphocytes in Cadmium-treated rats

    PubMed Central

    Hassan, Iftekhar; Bashandy, Samir; Taha, Nael Abu; Mahmood, Amer; Alomar, Suliman; Alhazza, Iibrahim; Mashaly, Ashraf; Rady, Ahmed

    2014-01-01

    The effects of Cadmium (Cd) exposure and the treatment with Zinc (Zn) on immune functions of splenocytes and cultured lymphocytes of rats were studied. The exposure of rats to Cd was at a dose of 2.2 mg/kg CdCl2, injected subcutaneously four times weekly for 2 months. Rats were supplemented with Zn (2.2 mg/kg ZnCl2, injected subcutaneously four times weekly for 2 months) one hour prior to Cd exposure. Spleens were removed and splenocytes were isolated and cultured. The proliferation capacity of lymphocytes and their homing to the spleen were studied. Ribonucleic acid (RNA) was extracted from stimulated lymphocytes in order to analyse gene expressions using RT-PCR. Accordingly, proliferation of lymphocytes was found to be suppressed in Cd-treated rats, both in vivo and in vitro. Zinc served to activate the proliferation of B and T lymphocytes in Cd-treated rats both in vivo and in vitro. Antigen-activated lymphocytes showed that Cd impaired the mRNA expression of CD68, Ccl22 and CXCL10. Zinc was not found to restore mRNA expression of these genes to the normal levels. Zinc was found to decrease the MDA level with replenishment of activity of key antioxidant enzymes and proteins in Cd-pre-treated animals significantly. Moreover, the histopathological examination of spleen samples also agreed with the molecular, immunological and redox findings. Hence, Zn is able to restore the normal structure, redox status and immunity in Cd-induced damage in the rat model system. PMID:26155160

  18. Voluntary Exercise Impairs Initial Delayed Spatial Alternation Performance in Estradiol Treated Ovariectomized Middle-Aged Rats

    PubMed Central

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

    2013-01-01

    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. PMID:24013039

  19. 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.

  20. 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

  1. Emu oil expedites small intestinal repair following 5-fluorouracil-induced mucositis in rats.

    PubMed

    Mashtoub, Suzanne; Tran, Cuong D; Howarth, Gordon S

    2013-11-01

    Mucositis resulting from cancer chemotherapy is characterized by intestinal inflammation and ulceration. Previously, emu oil (EO) improved intestinal architecture (Br J Nutr, 2010) in a rat model of chemotherapy-induced mucositis. We investigated EO for its further potential to promote intestinal repair in this mucositis model. Female Dark Agouti rats (n = 8/group) were gavaged with water, olive oil (OO) or EO once daily (1 mL), injected with 5-fluorouracil (5-FU) or saline on day 5 and euthanized on day 8, 9, 10 or 11. Intestinal villus height (VH) and crypt depth (CD), neutral mucin-secreting goblet cell (GC) count, myeloperoxidase (MPO) activity and selected cytokines were quantified; P < 0.05 was considered significant. In 5-FU-injected rats, only EO administration significantly increased VH in the ileum (day 8), jejunum and jejunum-ileum junction (days 8 and 9) compared to 5-FU controls (P < 0.05). GC count was significantly reduced by 5-FU (jejunum: days 8 and 9; ileum: day 8; P < 0.05) and EO increased ileal GC on days 10 and 11 compared to 5-FU controls. MPO activity was significantly increased in jejunum (days 8 and 9) and ileum (day 8) following 5-FU injection, compared to normal controls (P < 0.05). Both EO and OO significantly reduced jejunal MPO on days 8 and 9; however, only EO decreased ileal MPO on day 8. Cytokine levels were not significantly affected by either oil or 5-FU administration at the day 8 time point. Promotion of repair from injury could represent a new mechanism of action for EO, suggesting potential as an adjunct to conventional treatment approaches for cancer management.

  2. An evaluation of aversive memory and hippocampal oxidative status in streptozotocin-induced diabetic rats treated with resveratrol.

    PubMed

    Bagatini, Pamela Brambilla; Xavier, Léder Leal; Bertoldi, Karine; Moysés, Felipe; Lovatel, Gisele; Neves, Laura Tartari; Barbosa, Sílvia; Saur, Lisiani; de Senna, Priscylla Nunes; Souto, André Arigony; Siqueira, Ionara Rodrigues; Achaval, Matilde

    2017-01-01

    The present study evaluated the effects of streptozotocin (STZ)-induced diabetes on aversive memory, free radical content and enzymatic antioxidant activity in the hippocampus of adult Wistar rats submitted to oral treatment with resveratrol. Animals were divided into eight groups: non-diabetic rats treated with saline (ND SAL), non-diabetic rats treated with resveratrol at a dose 5mg/kg (ND RSV 5), non-diabetic rats treated with resveratrol at a dose 10mg/kg (ND RSV 10), non-diabetic rats treated with resveratrol at a dose 20mg/kg (ND RSV 20), diabetic rats treated with saline (D SAL), diabetic rats treated with resveratrol at a dose 5mg/kg (D RSV 5), diabetic rats treated with resveratrol at a dose 10mg/kg (D RSV 10) and diabetic rats treated with resveratrol at a dose 20mg/kg (D RSV 20). The animals received oral gavage for 35days. The contextual fear conditioning task was performed to evaluate aversive-based learning and memory. The oxidative status was evaluated in the hippocampus, by measuring the free radical content - using a 2',7'-dichlorofluorescein diacetate probe - and enzymatic antioxidant activities, such as superoxide dismutase and glutathione peroxidase. Our main behavioral results demonstrated that rats from the D RSV 10 and D RSV 20 groups showed an increase in freezing behavior when compared, respectively, to the ND RSV 10 (p<0.01) and ND RSV 20 (p<0.05). Oxidative stress parameters remained unchanged in the hippocampus of all the experimental groups. In contrast to previous experimental findings, our study was unable to detect either cognitive impairments or oxidative stress in the hippocampus of the diabetic rats. We suggest additional long-term investigations be conducted into the temporal pattern of STZ-induced diabetic disruption in memory and hippocampal oxidative status, as well as the effects of resveratrol on these parameters, in a time and dose-dependent manner.

  3. Prostanoid production in the presence of platelet activation in hypoxic cocaine-treated rats.

    PubMed

    Togna, G; Graziani, M; Sorrentino, C; Caprino, L

    1996-01-01

    To extend our previous in vitro data, we investigated the effects of cocaine on thromboxane A2 (TXA2) and prostacyclin (PGI2) production in vivo in the rat. To obtain the slight platelet activation that our in vitro experiments showed useful to highlight the effect of cocaine, we infused cocaine in rats in the presence of platelet-activating factors (circulation of blood through a perspex vascular device or by infusion of sodium arachidonate) and in various respiratory conditions. Experiments were conducted in rats breathing atmospheric air (normoxic conditions) and in rats breathing an oxygen-poor mixture (hypoxic conditions). In rats under hypoxic conditions cocaine invariably increased TXA2 plasma levels, whereas in normoxic conditions it increased TXA2 only in the presence of platelet-activating factors. Cocaine significantly increased PGI2 plasma levels in arachidonate-treated rats in hypoxic respiratory conditions; in normoxic conditions cocaine left PGI2 levels unchanged. These results support the hypothesis that in cocaine users who have concomitant pathological conditions able to activate platelets, such as atherosclerosis, coronary vasospasm or ischaemia, or both, cocaine may contribute to the onset of thrombotic phenomena by interfering with the prostaglandin system.

  4. Altered tolbutamide pharmacokinetics by a decrease in hepatic expression of CYP2C6/11 in rats pretreated with 5-fluorouracil.

    PubMed

    Fukuno, Shuhei; Nagai, Katsuhito; Kasahara, Keita; Mizobata, Yuki; Omotani, Sachiko; Hatsuda, Yasutoshi; Myotoku, Michiaki; Konishi, Hiroki

    2017-01-31

    1. We investigated the change in the pharmacokinetic profile of tolbutamide (TB), a substrate for CYP2C6/11, 4 days after single administration of 5-fluorouracil (5-FU), and the hepatic gene expression and activity of CYP2C6/11 were also examined in 5-FU-pretreated rats. 2. Regarding the pharmacokinetic parameters of the 5-FU group, the area under the curve (AUC) was significantly increased, and correspondingly, the elimination rate constant at the terminal phase (ke) was significantly decreased without significant change in the volume of distribution at the steady state (Vdss). 3. The metabolic production of 4-hydroxylated TB in hepatic microsomes was significantly reduced by the administration of 5-FU. 4. The expression level of mRNAs for hepatic CYP2C6 and CYP2C11 was significantly lower than in the control group when the rats were pretreated with 5-FU. 5. These results demonstrated that the pharmacokinetic profile of TB was altered by the treatment with 5-FU through a metabolic process, which may be responsible for the decreased CYP2C6/11 expression at mRNA levels.

  5. Changes in antioxidant defense status in hypercholesterolemic rats treated with Ajuga iva.

    PubMed

    Bouderbala, S; Lamri-Senhadji, M; Prost, J; Lacaille-Dubois, M A; Bouchenak, M

    2008-06-01

    The aim of the study was to investigate the effect of aqueous extract of Ajuga iva (Ai) on serum and tissues lipid peroxidation as well as antioxidant enzymes activities in red blood cells (RBC) and tissues, in high hypercholesterolemic rats (HC). Male Wistar rats (n=12) were fed on 1% cholesterol-enriched diet for 15d. After this adaptation phase, hypercholesterolemic rats (total cholesterol=6.5+/-0.6mol/l) were divided into two groups fed the same diet and treated or not with Ai for 15d. Thiobarbituric acid reactive substances (TBARS) concentrations in serum, LDL-HDL(1), HDL(2) and HDL(3) were respectively, 5-, 7.8-, 2.3- and 5-fold lower in Ai treated than untreated hypercholesterolemic groups. TBARS concentrations were 1.4-fold lower in heart and 2.8-fold higher in kidney in Ai-HC treated than untreated HC group. Superoxide dismutase activity was respectively, 1.2- and 1.4-fold higher in RBC and muscle in Ai treated than untreated group. In RBC, Ajuga iva treatment enhanced glutathione peroxidase (GSH-Px) (+9%) and glutathione reductase (GSSH-Red) (+12%) in Ai-HC treated than untreated HC group. GSSH-Red activity was 1.4- and 1.5-fold higher in adipose tissue and heart, respectively and 3.7-fold lower in kidney in Ai treated than untreated group. Liver catalase activity was 1.6-fold higher in Ai treated than untreated group. Adipose tissue and muscle total glutathione content represented in Ai treated group 35% and 36% of the value noted in untreated group. Nitric oxide values of liver, adipose tissue and heart were 3.3-, 2.5- and 3.4-fold higher in Ai-HC than HC group. Ajuga iva treatment enhanced alpha-tocopherol contents (+25%) in Ai treated than untreated group. In conclusion, Ajuga iva treatment is more effective to improve the antioxidant capacity of RBC than that of tissues. Indeed, Ai is able to reduce the oxidative stress in hypercholesterolemic rats by increasing the antioxidant enzymes activity.

  6. 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.

  7. [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.

  8. Growth response of weanling rats to heated, aged, fractionated, and chemically treated yogurts.

    PubMed

    Hargrove, R E; Alford, J A

    1980-07-01

    Significance of viable cultures in yogurt at time of ingestion on rate of growth of weaning rats was determined. Fresh yogurts were compared with those in which cultures were treated with heat, hydrogen peroxide, and ethylene oxide. They also were aged and freeze-dried. Fractions of yogurt prepared by ultrafiltration were recombined to determine which fraction gave the highest rate of gain in weight. Cultures were inactivated and growth in rats was depressed when yogurt was heated at 60 C and above for 2 min. Hydrogen peroxide reduced the viable yogurt count and rate of gain but not feed consumption. Yogurts treated with ethylene oxide were toxic. Aging did not effect culture viability or feed efficiency, but growth response was reduced. Fractionation of yogurt into components of high and low molecular weight and recombinations with control milk fractions indicated that the growth stimulant remained in the component of high molecular weight.

  9. 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

  10. Locomotion and physical development in rats treated with ionizing radiation in utero

    SciTech Connect

    Zaman, M.S.; Hupp, E.W. Texas Woman's Univ., Houston, TX ); Lancaster, F.E. )

    1993-01-01

    Effects of ionizing radiation on the emergence of locomotor skill, and physical development were studied in laboratory rats (Fisher F-344 inbred strain). Rats were treated with 3 different doses of radiation (150 rad, 15 rad, and 6.8 rad) delivered on the 20th day of prenatal life. Results indicated that relatively moderate (15 rad) to high (150 rad) doses of radiation had effects on certain locomotion and physical development parameters. Exposure to 150 rad delayed pivoting, cliff-avoidance, upper jaw tooth eruption, and decreased body weights. Other parameters, such as negative geotaxis, eye opening, and lower jaw tooth eruption were marginally delayed in the 150 rad treated animals. Exposure to 15 rad delayed pivoting and cliff-avoidance.

  11. Increase in lactate dehydrogenase isoenzyme-4 and splenocyte toxicity in methomyl-treated rats.

    PubMed

    Lohitnavy, O; Sinhaseni, P

    1998-09-01

    The toxic effect of methomyl was studied in rats after a single or repeated oral administration. Rats treated with a single dose of methomyl (3, 5, or 7 mg/kg) showed significant increase (P < 0.05) in total lactate dehydrogenase (LDH) activity on day 1. The highest level of LDH activity was observed on day 3 in rats receiving 7 mg/kg of methomyl. The total LDH activity returned to normal on day 7 after dosing. Specific increases in LDH-3 and LDH-4 isoenzyme activities were observed. In rats treated with a single dose of 6 and 8 mg/kg of methomyl, spleen weight and splenocyte viability significantly dropped (P < 0.05) on days 1 and 3, respectively. Splenotoxicity was prevented by pretreatment with 60 mg/kg of N-acetylcysteine. The results suggest that the splenotoxic effect of methomyl is more likely directly related to oxidative cell injury than to cholinesterase inhibition. The significance of cytotoxic effects and the nature of cytotoxicity in relation to reactive oxidative damage deserve further investigation.

  12. 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

  13. The antioxidant and antigenotoxic effects of pycnogenol(®) on rats treated with cisplatin.

    PubMed

    Aydin, Birsen; Unsal, Meftun; Sekeroglu, Zulal A; Gülbahar, Yavuz

    2011-09-01

    Oxidative stress and inflammation are implicated in the pathogenesis of cisplatin-induced toxicity. Pycnogenol® is known for its strong antioxidant and anti-inflammatory effects. In this study, the possible protective effects of pycnogenol on kidney, bone marrow, and red blood cells in rats treated with cisplatin were investigated. The rats were divided into four groups. Group 1 was the control and groups 2, 3, and 4 were orally treated with pycnogenol (200 mg/kg bw, o.p) for 5 days, treated with cisplatin (7 mg/kg bw, i.p.) on the fifth day and treated with cisplatin plus pycnogenol, respectively. Antioxidative parameters in kidney and red blood cells were measured. Chromosome anomalies in bone marrow and renal histopathology were also investigated. Activities of pro-oxidant enzymes (myeloperoxidase and xanthine oxidase), malondialdehyde, and nitric oxide levels significantly increased but antioxidant enzymes activities decreased in the kidneys and red blood cells after cisplatin treatment. Pycnogenol treatment prior to the administration of cisplatin significantly decreased cisplatin-induced injury, as evidenced by its normalizing these parameters. Chromosomal aberrations decreased and mitotic index frequencies increased in bone marrow treated with cisplatin plus pycnogenol. These findings suggest that pycnogenol may be a useful protective agent against the toxicity associated with cisplatin therapy.

  14. Modulation of oxidative stress by enalapril and valsartan in adrenaline treated rats: a comparative study.

    PubMed

    Huda, S; Akhter, N

    2014-04-01

    Angiotensin (Ang II) II is known to promote oxidative stress in acute myocardial infarction (AMI). Inhibition of renin angiotensin system (RAS) or blockade of Ang II receptors may therefore be effective in reducing oxidative stress during AMI. The study evaluates and compares the protective effect of Angiotensin Converting Enzyme (ACE) inhibitor and AT1 receptor blocker in adrenaline induced oxidative stress in rats. Rats were treated with two successive injections of adrenaline subcutaneously at a dose of 2 mg/kg administered 24 hours apart. In other two groups of rats enalapril (30 mg/kg) or valsartan (30 mg/kg) were given orally once daily through intragastric tube for 2 weeks and then two injections of adrenaline were administered 24 hours apart. Serum Aspertate Transaminase (AST), plasma Malonde Aldehyde (MDA), erythrocyte GSH and serum vitamin E levels were measured 24 hours after the 2nd injection of adrenaline in all the groups. Administration of adrenaline caused significant increase (p < 0.001) in serum AST and plasma MDA levels and decrease (p < 0.001) in erythrocyte GSH and serum vitamin E levels. Pre-treatment of enalapril or valsartan for 14 days reduced (p < 0.001) serum AST and plasma MDA levels and increased the concentration of erythrocyte GSH in enalapril pre-treated group (p < 0.01) and in valsartan pre-treated group (p < 0.05). Pre-treatment of enalapril or valsartan also increased (p < 0.01) serum vitamin E levels in adrenaline treated rats. However, no significant difference was noted between the effect of enalapril and valsartan on serum AST, plasma MDA, erythrocyte GSH and serum vitamin E levels. It may be concluded that both enalapril and valsartan offered cardioprotection in adrenaline induced oxidative stress, but the protection afforded by valsartan was not superior to enalapril.

  15. Blood-brain barrier disruption in the striatum of rats treated with 3-nitropropionic acid.

    PubMed

    Duran-Vilaregut, Joaquim; del Valle, Jaume; Camins, Antoni; Pallàs, Mercè; Pelegrí, Carme; Vilaplana, Jordi

    2009-01-01

    3-nitropropionic acid (3-NPA) is a natural toxin that is used to induce models of Huntington's disease (HD) in experimental animals. Here we injected 3-NPA into Sprague-Dawley rats in order to evaluate its effects on the blood-brain barrier (BBB). Evans blue (EB) extravasation was used to identify injured areas in the brains of the treated animals and immunostainings of endothelial brain barrier antigen (EBA), zona occludens-1 (ZO-1) and laminin were used as markers to characterize the effects of the neurotoxin on the BBB. Treated rats had a significant loss of body weight compared to controls, and a correlation between motor affectation and body weight loss was observed in the former. The lateral part of the striatum was specifically injured in treated animals and the BBB almost disappeared in the core of the injured areas, as evidenced by a high EB extravasation and severe alterations of the immunostainings of the three BBB integrity markers compared to those of control animals. We conclude that the BBB is severely affected in the 3-NPA rat model of HD and that disruption of this barrier is a crucial event during the development of this disease.

  16. 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.

  17. Insulin-exacerbated hypertension in captopril-treated spontaneously hypertensive rats: role of sympathoexcitation.

    PubMed

    Roysommuti, Sanya; Mozaffari, Mahmood S; Wyss, J Michael

    2003-11-01

    Insulin excess exacerbates hypertension in spontaneously hypertensive rats (SHR). This study examined the relative contribution of the renin-angiotensin system and the sympathetic nervous system in this phenomenon. In SHR, daily subcutaneous injections of insulin were initiated either before short-term angiotensin-converting enzyme inhibition with captopril or after lifetime captopril treatment. Insulin treatment resulted in significant increases in mean arterial pressure and heart rate and captopril treatment lowered arterial pressure, but captopril did not lower arterial pressure more in the insulin-treated compared with control rats. To test the contribution of the sympathetic nervous system to this form of hypertension, each rat was intravenously infused with either a ganglionic blocker (i.e., hexamethonium) or a centrally acting alpha2-adrenergic receptor agonist (i.e., clonidine). Administration of either agent largely eliminated the differences in mean arterial pressure and heart rate between the insulin-treated and saline-treated SHR, irrespective of captopril treatment. These data indicate that in SHR, the ability of insulin to increase blood pressure is closely related to sympathoexcitation, which is unresponsive to blockade of angiotensin-converting enzyme.

  18. Biochemical effects in normal and stone forming rats treated with the ripe kernel juice of plantain (musa paradisiaca).

    PubMed

    Devi, V K; 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.

  19. 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.

  20. Accumbal FosB/DeltaFosB immunoreactivity and conditioned place preference in alcohol-preferring AA rats and alcohol-avoiding ANA rats treated repeatedly with cocaine.

    PubMed

    Marttila, Kristiina; Petteri Piepponen, T; Kiianmaa, Kalervo; Ahtee, Liisa

    2007-07-30

    Transcription factor DeltaFosB has been implicated in the psychomotor responses and rewarding effects of drugs of abuse. In the present study, we compared the effects of cocaine on the expression of DeltaFosB-like proteins by immunohistochemistry in striatal brain areas of alcohol-preferring (AA) and alcohol-avoiding (ANA) rats. Cocaine was administered using a previously verified treatment paradigm that sensitized the locomotor response to cocaine in AA but not in ANA rats. We also studied the rewarding effects of cocaine with a conditioned place preference (CPP) paradigm in both lines of rats. Cocaine treatment increased the FosB/DeltaFosB immunoreactivity (IR) in the nucleus accumbens of AA rats but not in ANA rats. In addition, after repeated saline injections the accumbal FosB/DeltaFosB IR was significantly greater in saline-injected AA rats than in ANA rats. In the caudate-putamen cocaine significantly increased FosB/DeltaFosB IR, but no differences were found between the rats of two lines. In the CPP experiment, AA rats treated with cocaine 2.5 mg/kg preferred the cocaine-associated compartment, in contrast to ANA rats, which did not show such a preference. In conclusion, our findings show that AA rats are more sensitive to cocaine than ANA rats, and suggest that one possible mediator for this increased sensitivity could be the increased expression of fosB-derived proteins in the nucleus accumbens of AA rats.

  1. Differential expression of parvalbumin in neonatal phencyclidine-treated rats and socially isolated rats.

    PubMed

    Kaalund, Sanne S; Riise, Jesper; Broberg, Brian V; Fabricius, Katrine; Karlsen, Anna S; Secher, Thomas; Plath, Niels; Pakkenberg, Bente

    2013-02-01

    Decreased parvalbumin expression is a hallmark of the pathophysiology of schizophrenia and has been associated with abnormal cognitive processing and decreased network specificity. It is not known whether this decrease is due to reduced expression of the parvalbumin protein or degeneration of parvalbumin-positive interneurons (PV(+) interneurons). In this study, we examined PV(+) expression in two rat models of cognitive dysfunction in schizophrenia: the environmental social isolation (SI) and pharmacological neonatal phencyclidine (neoPCP) models. Using a stereological method, the optical fractionator, we counted neurons, PV(+) interneurons, and glial cells in the medial prefrontal cortex (mPFC) and hippocampus (HPC). In addition, we quantified the mRNA level of parvalbumin in the mPFC. There was a statistically significant reduction in the number of PV(+) interneurons (p = 0.021) and glial cells (p = 0.024) in the mPFC of neonatal phencyclidine rats, but not in SI rats. We observed no alterations in the total number of neurons, hippocampal PV(+) interneurons, parvalbumin mRNA expression or volume of the mPFC or HPC in the two models. Thus, as the total number of neurons remains unchanged following phencyclidine (PCP) treatment, we suggest that the decreased number of counted PV(+) interneurons represents a reduced parvalbumin protein expression below immunohistochemical detection limit rather than a true cell loss. Furthermore, these results indicate that the effect of neonatal PCP treatment is not limited to neuronal populations.

  2. Restorative effects of GDNF on striatal dopamine release in rats treated with neurotoxic doses of methamphetamine.

    PubMed

    Cass, W A; Manning, M W; Bailey, S L

    2000-09-01

    Repeated methamphetamine (METH) administration to animals can result in long-lasting decreases in striatal dopamine (DA) release and content. Glial cell line-derived neurotrophic factor (GDNF) has pronounced effects on dopaminergic systems in vivo, including neuroprotective effects against METH. The present experiments were designed to examine the ability of GDNF to reverse, or accelerate recovery from, METH-induced alterations in striatal DA release. Male Fischer-344 rats were administered METH (5 mg/kg, s.c.) or saline 4 times in one day at 2-hour intervals. Seven days later the animals were anesthetized and given a single injection of 10 microg GDNF, or vehicle, into the right striatum. Three weeks later microdialysis experiments were carried out in both the right and left striata to examine basal and evoked levels of DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). In animals treated with METH followed by vehicle 7 days later, there were significant reductions in potassium- and amphetamine-evoked overflow of DA, and in basal levels of DOPAC and HVA, compared to control animals. In rats treated with METH followed 7 days later with GDNF, there were significant increases in potassium- and amphetamine-evoked overflow of DA on the right, GDNF-treated, side of the brain compared to the left side. Basal levels of DOPAC and HVA were also elevated on the GDNF-treated side of the brain. These results suggest that GDNF can accelerate recovery of dopaminergic release processes in the striatum of rats treated with neurotoxic doses of METH.

  3. Multicenter phase II study of infusional 5-fluorouracil (5-FU), leucovorin, and oxaliplatin, plus biweekly cetuximab as first-line treatment in patients with metastatic colorectal cancer (CELINE trial)

    PubMed Central

    Kotake, Masanori; Aoyama, Toru; Munemoto, Yoshinori; Doden, Kenji; Kataoka, Masato; Kobayashi, Kenji; Nishimura, Genichi; Fujita, Hidehito; Nakamura, Keishi; Takehara, Akira; Tanaka, Chihiro; Sakamoto, Junichi; Nagata, Naoki; Oba, Koji; Kondo, Ken

    2017-01-01

    The current phase II study investigated the efficacy and safety of biweekly cetuximab combined with standard oxaliplatin-based chemotherapy [infusional 5-fluorouracil (5-FU), leucovorin, and oxaliplatin (FOLFOX-6)] in the first-line treatment of KRAS wild-type metastatic colorectal cancer (mCRC). Sixty patients with a median age of 64 years (range, 38–82 syears) received a biweekly intravenous infusion of cetuximab (500 mg/m2 on day 1) followed by FOLFOX-6 (2-hour oxaliplatin 85 mg/m2 infusion on day 1 in tandem with a 2-h leucovorin 200 mg/m2 infusion on days 1 and 2, and 5-FU as a 400 mg/m2 bolus followed by a 46-hour 2,400 mg/m2 infusion on days 1–3). Patient response rate was 70%, with 95% disease control rates. The median progression-free survival was 13.8 months. Thirteen patients (21.7%) were able to undergo resection of previously unresectable metastases, with the aim of curing them. The median follow-up was 22.7 months, and median overall survival was 31.0 months. Cetuximab did not increase FOLFOX-6 toxicity and was generally well tolerated. The results of the current study demonstrate that the combination of biweekly cetuximab with FOLFOX-6 was well tolerated and had a manageable safety profile for the first-line treatment of KRAS wild-type metastatic colorectal cancer. Efficacy was comparable to other treatment regimens. The results support the administration of biweekly cetuximab in combination with FOLFOX-6, which may be more convenient and provide treatment flexibility in this setting for patients with metastatic colorectal cancers.

  4. Exercise training enhances insulin-stimulated nerve arterial vasodilation in rats with insulin-treated experimental diabetes.

    PubMed

    Olver, T Dylan; McDonald, Matthew W; Grisé, Kenneth N; Dey, Adwitia; Allen, Matti D; Medeiros, Philip J; Lacefield, James C; Jackson, Dwayne N; Rice, Charles L; Melling, C W James; Noble, Earl G; Shoemaker, J Kevin

    2014-06-15

    Insulin stimulates nerve arterial vasodilation through a nitric oxide (NO) synthase (NOS) mechanism. Experimental diabetes reduces vasa nervorum NO reactivity. Studies investigating hyperglycemia and nerve arterial vasodilation typically omit insulin treatment and use sedentary rats resulting in severe hyperglycemia. We tested the hypotheses that 1) insulin-treated experimental diabetes and inactivity (DS rats) will attenuate insulin-mediated nerve arterial vasodilation, and 2) deficits in vasodilation in DS rats will be overcome by concurrent exercise training (DX rats; 75-85% VO2 max, 1 h/day, 5 days/wk, for 10 wk). The baseline index of vascular conductance values (VCi = nerve blood flow velocity/mean arterial blood pressure) were similar (P ≥ 0.68), but peak VCi and the area under the curve (AUCi) for the VCi during a euglycemic hyperinsulinemic clamp (EHC; 10 mU·kg(-1)·min(-1)) were lower in DS rats versus control sedentary (CS) rats and DX rats (P ≤ 0.01). Motor nerve conduction velocity (MNCV) was lower in DS rats versus CS rats and DX rats (P ≤ 0.01). When compared with DS rats, DX rats expressed greater nerve endothelial NOS (eNOS) protein content (P = 0.04). In a separate analysis, we examined the impact of diabetes in exercise-trained rats alone. When compared with exercise-trained control rats (CX), DX rats had a lower AUCi during the EHC, lower MNCV values, and lower sciatic nerve eNOS protein content (P ≤ 0.03). Therefore, vasa nervorum and motor nerve function are impaired in DS rats. Such deficits in rats with diabetes can be overcome by concurrent exercise training. However, in exercise-trained rats (CX and DX groups), moderate hyperglycemia lowers vasa nervorum and nerve function.

  5. Antidiabetic-drug combination treatment for glucose intolerance in adult female rats treated acutely with olanzapine.

    PubMed

    Boyda, Heidi N; Procyshyn, Ric M; Asiri, Yahya; Wu, Claire; Wang, Cathy K; Lo, Ryan; Pang, Catherine C Y; Honer, William G; Barr, Alasdair M

    2014-01-03

    Second generation antipsychotic drugs are routinely used as treatment for psychotic disorders. Many of these compounds, including olanzapine, cause metabolic side-effects such as impaired glucose tolerance and insulin resistance. Individual antidiabetic drugs can help control elevated glucose levels in patients treated with antipsychotics, but the effects of combining antidiabetics, which routinely occurs with Type 2 diabetes mellitus patients, have never been studied. Presently, we compared the effects of the three different antidiabetics metformin (500mg/kg, p.o.), rosiglitazone (30mg/kg, p.o.) and glyburide (10mg/kg, p.o.) on metabolic dysregulation in adult female rats treated acutely with olanzapine. In addition, dual combinations of each of these antidiabetics were compared head-to-head against each other and the individual drugs. The animals received two daily treatments with antidiabetics and were then treated acutely with olanzapine (10mg/kg, i.p.). Fasting glucose and insulin levels were measured, followed by a 2h glucose tolerance test. Olanzapine caused a large and highly significant glucose intolerance compared to vehicle treated rats. Rosiglitazone decreased glucose levels non-significantly, while both metformin and glyburide significantly decreased glucose levels compared to olanzapine-only treated animals. For antidiabetic dual-drug combinations, the rosiglitazone-metformin group showed an unexpected increase in glucose levels compared to all of the single antidiabetic drugs. However, both the metformin-glyburide and rosiglitazone-glyburide groups showed significantly greater reductions in glucose levels following olanzapine than with single drug treatment alone for metformin or rosiglitazone, bringing glucose levels down to values equivalent to vehicle-only treated animals. These findings indicate that further study of antidiabetic dual-drug combinations in patients treated with antipsychotic drugs is warranted.

  6. Growth inhibition, tumor maturation, and extended survival in experimental brain tumors in rats treated with phenylacetate.

    PubMed

    Ram, Z; Samid, D; Walbridge, S; Oshiro, E M; Viola, J J; Tao-Cheng, J H; Shack, S; Thibault, A; Myers, C E; Oldfield, E H

    1994-06-01

    Phenylacetate is a naturally occurring plasma component that suppresses the growth of tumor cells and induces differentiation in vitro. To evaluate the in vivo potential and preventive and therapeutic antitumor efficacy of sodium phenylacetate against malignant brain tumors, Fischer 344 rats (n = 50) bearing cerebral 9L gliosarcomas received phenylacetate by continuous s.c. release starting on the day of tumor inoculation (n = 10) using s.c. osmotic minipumps (550 mg/kg/day for 28 days). Rats with established brain tumors (n = 12) received continuous s.c. phenylacetate supplemented with additional daily i.p. dose (300 mg/kg). Control rats (n = 25) were treated in a similar way with saline. Rats were sacrificed during treatment for electron microscopic studies of their tumors, in vivo proliferation assays, and measurement of phenylacetate levels in the serum and cerebrospinal fluid. Treatment with phenylacetate extended survival when started on the day of tumor inoculation (P < 0.01) or 7 days after inoculation (P < 0.03) without any associated adverse effects. In the latter group, phenylacetate levels in pooled serum and cerebrospinal fluid samples after 7 days of treatment were in the therapeutic range as determined in vitro (2.45 mM in serum and 3.1 mM in cerebrospinal fluid). Electron microscopy of treated tumors demonstrated marked hypertrophy and organization of the rough endoplasmic reticulum, indicating cell differentiation, in contrast to the scant and randomly distributed endoplasmic reticulum in tumors from untreated animals. In addition, in vitro studies demonstrated dose-dependent inhibition of the rate of tumor proliferation and restoration of anchorage dependency, a marker of phenotypic reversion. Phenylacetate, used at clinically achievable concentrations, prolongs survival of rats with malignant brain tumors through induction of tumor differentiation. Its role in the treatment of brain tumors and other cancers should be explored further.

  7. Determination of DNA damage and telomerase activity in stanozolol-treated rats

    PubMed Central

    Kara, Mehtap; Ozcagli, Eren; Fragkiadaki, Persefoni; Kotil, Tugba; Stivaktakis, Polychronis D.; Spandidos, Demetrios A.; Tsatsakis, Aristides M.; Alpertunga, Buket

    2017-01-01

    Anabolic androgenic steroids (AAS) are performance-enhancing drugs commonly abused by atheletes. Stanozolol is a synthetic testosterone-derived anabolic steroid. Although it is well known that AAS have several side-effects, there are only few toxicological studies available on the toxic effects and mechanisms of action of stanozolol. The aim of this study was to investigate the genotoxic effects of stanozolol and to determine its effects on telomerase activity in Sprague-Dawley male rats. For this purpose, 34 male rats were divided into 5 groups as follows: i) the control group (n=5); ii) the propylene glycol (PG)-treated group (n=5); iii) the stanozolol-treated group (n=8); iv) the PG-treated group subjected to exercise (n=8); and v) the stanozolol-treated group subjected to exercise (n=8). PG is used as a solvent control in our study. Stanozolol (5 mg/kg) and PG (1 ml/kg) were injected subcutaneously 5 days/week for 28 days. After 28 days, the animals were sacrificed, and DNA damage evaluation (comet assay) and telomerase activity assays were then performed using peripheral blood mononuclear cells (PBMCs). Telomerase activity was measured by using the TeloTAGGG Telomerase PCR ELISA PLUS kit. The results of this study revealed that stanozolol treatment induced DNA damage, while exercise exerted a protective effect. Stanozolol treatment without exercise stimulation was associated with a significant increase in telomerase activity in the PBMCs. PMID:28352339

  8. 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.

  9. 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

  10. Withdrawal and bidirectional cross-withdrawal responses in rats treated with adenosine agonists and morphine.

    PubMed

    Coupar, I M; Tran, B L

    2001-07-06

    The aim of this study was to investigate whether the A1/A2 receptor agonist, 5'-N-ethylcarboxamidoadenosine (NECA), and the selective A1 agonist, N6-cyclopentyladenosine (CPA), induced physical dependence by quantifying specific antagonist-precipitated withdrawal syndromes in conscious rats. In addition, the presence of bidirectional cross-withdrawal was also investigated. The agonists were administered s.c. to groups of rats at 12 h intervals. Antagonists were administered s.c., 12 hours after the last dose, followed by observation and measurement of faecal output for 20 min. NECA (4 x 0.03 mg kg(-1), s.c) and CPA (4 x 0.03, 0.1 and 0.3 mg kg(-1), s.c.) induced physical dependence, as shown by the expression of a significant withdrawal syndrome when challenged with the adenosine A1/A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX, 0.1 mg kg(-1), s.c.) and the A1 antagonist, 8-cyclopentyl-1,3-dipropylxanthine (CPDPX, 0.1 mg kg(-1), s.c.) respectively. The syndromes consisted of teeth chattering and shaking behaviours shown to occur in morphine-dependent animals withdrawn with naloxone viz, paw, body and 'wet-dog' shakes, but with the additional behaviours of head shaking and yawning. In further contrast to the opiate withdrawal syndrome, no diarrhoea occurred in the groups of animals treated with adenosine agonists and withdrawn with their respective antagonists. Bidirectional cross-withdrawal syndromes were also revealed when naloxone (3 mg kg(-1), s.c.) was administered to adenosine agonist pre-treated rats and adenosine antagonists were given to morphine pre-treated rats. This study provides further information illustrating that close links exist between the adenosine and opiate systems.

  11. 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.

  12. Pulmonary oxygen toxicity in rats treated with cytochrome P-450 inducers

    SciTech Connect

    Ebel, R.E.; Barlow, R.L.; Gregory, E.M.

    1987-05-01

    Pulmonary oxygen toxicity is assumed to result from damage caused by superoxide (O/sub 2//sup -/) hydrogen peroxide (H/sub 2/O/sub 2/) and/or hydroxyl radical (OH) produced by the partial reduction of molecular oxygen (O/sub 2/). The microsomal cytochrome P-450 (P-450) monooxygenase system is known to produce O/sub 2//sup -/ and H/sub 2/O/sub 2/. They have studied the influence of monooxygenase induction using phenobarbital (PB) and ..beta..-naphthoflavone (..beta..-NF) on O/sub 2/ toxicity in the rat. PB- or ..beta..-NF induce hepatic P-450 but only ..beta..-NF induces pulmonary P-450. Pulmonary microsomes produced O/sub 2//sup -/ and H/sub 2/O/sub 2/ at rates (expressed per mg microsomal protein) which did not vary as a function of pretreatment. Rats were exposed to 100% O/sub 2/ for up to 3 days. After 3 days of O/sub 2/, lung weights were about 50% above controls regardless of pretreatment. The microsomal monooxygenase enzymes (P-450, b/sub 5/ and NADPH P-450 reductase) were quantified in liver and lung. Lung microsomal P-450 was reduced after 3 days of O/sub 2/ exposure regardless of pretreatment. The protective enzymes (catalase, superoxide dismutase (SOD) and glutathione (GSH) peroxidase) and non-protein sulfhydryl groups (NPSH) were also quantified in lung and liver samples. Lung NPSH and GSH peroxidase were increased after 3 days of O/sub 2/ exposure regardless of pretreatment while SOD was increased in controls and PB- but not ..beta..-NF-treated rats. Three of 14 ..beta..-NF-treated rats died during O/sub 2/ exposure while no animals in the control or PB-treated groups died.

  13. 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.

  14. 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

  15. 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

  16. Mediation of oxidative stress in hypothalamic ghrelin-associated appetite control in rats treated with phenylpropanolamine.

    PubMed

    Yu, C-H; Chu, S-C; Chen, P-N; Hsieh, Y-S; Kuo, D-Y

    2017-04-01

    Phenylpropanolamine (PPA)-induced appetite control is associated with oxidative stress in the hypothalamus. This study explored whether hypothalamic antioxidants participated in hypothalamic ghrelin system-associated appetite control in PPA-treated rats. Rats were given PPA daily for 4 days, and changes in food intake and the expression of neuropeptide Y (NPY), the cocaine- and amphetamine-regulated transcript (CART), superoxide dismutase, catalase, ghrelin, acyl ghrelin (AG), ghrelin O-acyltransferase (GOAT) and the ghrelin receptor (GHSR1a) were examined and compared. Results showed that both food intake and the expression of NPY and ghrelin/AG/GOAT/GHSR1a decreased in response to PPA treatment with maximum decrease on Day 2 of the treatment. In contrast, the expression of antioxidants and CART increased, with the maximum increase on Day 2, with the expression opposite to that of NPY and ghrelin. A cerebral infusion of either a GHSR1a antagonist or reactive oxygen species scavenger modulated feeding behavior and NPY, CART, antioxidants and ghrelin system expression, showing the involvement of ghrelin signaling and oxidative stress in regulating PPA-mediated appetite control. We suggest that hypothalamic ghrelin signaling system, with the help of antioxidants, may participate in NPY/CART-mediated appetite control in PPA-treated rats.

  17. 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

  18. Functional changes in piriform cortex pyramidal neurons in the chronic methamphetamine-treated rat.

    PubMed

    Hori, Nobuaki; Kadota, Tomoko; Akaike, Norio

    2015-01-01

    Chronic treatment of rats with methamphetamine (MAP) causes a range of functional changes to the central nervous system (CNS), including a toxicity that is widespread throughout the brain (Frost and Cadet 2000; Fasihpour et al. 2013). In this report, we examined the effect of chronic MAP treatment on pyramidal neurons of the rat piriform cortex, an area involved in sensory processing, associative learning and a model system for studies on synaptic plasticity. MAP treatment significantly depolarized the membrane potential and decreased neuronal input resistance. Furthermore, the voltage-dependence of both AMPA and NMDA responses was disturbed by chronic MAP treatment, and the extent of long-term potentiation (LTP) was decreased. Morphological changes of MAP-treated rat pyramidal neurons were observed as blebbing of the dendrite trees. The changes we observed represent detrimental effects on the function of piriform cortical neurons further illustrating deficits in synaptic plasticity extend beyond the hippocampus. These changes may contribute to behavioural deficits in chronic MAP-treated animals.

  19. Concerning the mechanism of increased thermogenesis in rats treated with dehydroepiandrosterone.

    PubMed

    Bobyleva, V; Kneer, N; Bellei, M; Battelli, D; Lardy, H A

    1993-06-01

    Dehydroepiandrosterone (DHEA) treatment of rats decreases gain of body weight without affecting food intake; simultaneously, the activities of liver malic enzyme and cytosolic glycerol-3-P dehydrogenase are increased. In the present study experiments were conducted to test the possibility that DHEA enhances thermogenesis and decreases metabolic efficiency via transhydrogenation of cytosolic NADPH into mitochondrial FADH2 with a consequent loss of energy as heat. The following results provide evidence which supports the proposed hypothesis: (a) the activities of cytosolic enzymes involved in NADPH production (malic enzyme, cytosolic isocitrate dehydrogenase, and aconitase) are increased after DHEA treatment; (b) cytosolic glycerol-3-P dehydrogenase may use both NAD+ and NADP+ as coenzymes; (c) activities of both cytosolic and mitochondrial forms of glycerol-3-P dehydrogenase are increased by DHEA treatment; (d) cytosol obtained from DHEA-treated rats synthesizes more glycerol-3-P during incubation with fructose-1,6-P2 (used as source of dihydroxyacetone phosphate) and NADP+; the addition of citrate in vitro further increases this difference; (e) mitochondria prepared from DHEA-treated rats more rapidly consume glycerol-3-P added exogenously or formed endogenously in the cytosol in the presence of fructose-1,6-P2 and NADP+.

  20. 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.

  1. Agmatine Prevents Adaptation of the Hippocampal Glutamate System in Chronic Morphine-Treated Rats.

    PubMed

    Wang, Xiao-Fei; Zhao, Tai-Yun; Su, Rui-Bin; Wu, Ning; Li, Jin

    2016-12-01

    Chronic exposure to opioids induces adaptation of glutamate neurotransmission, which plays a crucial role in addiction. Our previous studies revealed that agmatine attenuates opioid addiction and prevents the adaptation of glutamate neurotransmission in the nucleus accumbens of chronic morphine-treated rats. The hippocampus is important for drug addiction; however, whether adaptation of glutamate neurotransmission is modulated by agmatine in the hippocampus remains unknown. Here, we found that continuous pretreatment of rats with ascending doses of morphine for 5 days resulted in an increase in the hippocampal extracellular glutamate level induced by naloxone (2 mg/kg, i.p.) precipitation. Agmatine (20 mg/kg, s.c.) administered concurrently with morphine for 5 days attenuated the elevation of extracellular glutamate levels induced by naloxone precipitation. Furthermore, in the hippocampal synaptosome model, agmatine decreased the release and increased the uptake of glutamate in synaptosomes from chronic morphine-treated rats, which might contribute to the reduced elevation of glutamate levels induced by agmatine. We also found that expression of the hippocampal NR2B subunit, rather than the NR1 subunit, of N-methyl-D-aspartate receptors (NMDARs) was down-regulated after chronic morphine treatment, and agmatine inhibited this reduction. Taken together, agmatine prevented the adaptation of the hippocampal glutamate system caused by chronic exposure to morphine, including modulating extracellular glutamate concentration and NMDAR expression, which might be one of the mechanisms underlying the attenuation of opioid addiction by agmatine.

  2. Neurotransmitter agonists inhibit inositol phosphate formation in the brain of bupropione-treated rats

    SciTech Connect

    Butler, P.D.; Hungund, B.; Suckow, R.; Barkai, A.I.

    1986-03-05

    Bupropione is a chemically unique antidepressant whose mechanism of action is not known. In this study they have evaluated the effect of chronic treatment with bupropione on the receptor-mediated release of inositol phosphates (IP) from brain slices in rats. Animals were implanted with Alzet osmotic pumps that delivered bupropione at a constant rate (40mg/kg/day) for 2 weeks. Cross-chopped slices of cerebral cortex from control and drug-treated rats were prelabelled with myo-/sup 3/H-inositol in HEPES buffer containing 11 mM LiCl. Accumulation of IP was measured in the presence and absence of the following agonists: Carbamylcholine (100..mu..m); norepinephrine (5..mu..M) and serotonin (10..mu..M). All agonists stimulated release of IP from slices of control animals but appeared to inhibit IP release in bupropione-treated rats. These results indicate that a phospholipase C inhibitor may appear following the activation of this enzyme by the agonist, and that the agonist-induced formation of the apparent inhibitor may be markedly enhanced after treatment with bupropione.

  3. Honey Attenuates the Detrimental Effects of Nicotine on Testicular Functions in Nicotine Treated Wistar Rats.

    PubMed

    Kolawole, T A; Oyeyemi, W A; Adigwe, C; Leko, B; Udeh, C; Dapper, D V

    2015-12-20

    Effect of honey on reproductive functions of male rats exposed to nicotine was examined in this study. Thirty-two adult male wistar rats (n=8/Group) were grouped as Control (distilled water), Nicotine (1.0mg/kg bwt), Honey (100mg/kg bwt) and Nicotine with Honey. The animals were orally treated for 35 days consecutively. Epididymis sperm motility, viability, morphology and counts were estimated, serum Follicle Stimulating Hormone (FSH), Leutinizing Hormone (LH) and Testosterone were assayed using ELISA method and testicular histology were also assessed. Significant reduction in percentage sperm motility, viability, morphology and counts were observed in nicotine group compared to control. Serum FSH, LH and testosterone levels were significantly reduced in nicotine group when compared with the control. There was significant improvement in sperm motility, viability, morphology, counts, FSH, LH and Testosterone in group co-treated with nicotine and honey  relative to nicotine group. Also, the degenerative seminiferous tubule architecture due to nicotine was improved by honey. In conclusion, honey may suppress nicotine toxic effect on reproductive functions in male Wistar rats.

  4. Morphometric and neurochemical alterations found in l-BMAA treated rats.

    PubMed

    de Munck, Estefanía; Muñoz-Sáez, Emma; Miguel, Begoña G; Solas, M Teresa; Martínez, Ana; Arahuetes, Rosa M

    2015-05-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscle paralysis that reflects the motoneurons' degeneration. Several studies support the relationship between β-N-methylamino-l-alanine (l-BMAA), a neurotoxic amino acid produced by cyanobacteria and diatoms, and the sporadic occurrence of ALS and other neurodegenerative diseases. Therefore, the study of its neurotoxicity mechanisms has assumed great relevance in recent years. Recently, our research team has proposed a sporadic ALS animal model by l-BMAA administration in rats, which displays many pathophysiological features of human ALS. In this paper, we deepen the characterization of this model corroborating the occurrence of alterations present in ALS patients such as decreased muscle volume, thinning of the motor cortex, enlarged brain's lateral ventricles, and alteration of both bulbar nuclei and neurotransmitters' levels. Therefore, we conclude that l-BMAA treated rats could be a good model which mimics degenerative features that ALS causes in humans.

  5. Enzymatic activities in brains of diabetic rats treated with vanadyl sulphate and sodium tungstate.

    PubMed

    Lemberg, A; Fernández, M A; Ouviña, G; Rodríguez, R R; Peredo, H A; Susemihl, C; Villarreal, I; Filinger, E J

    2007-12-01

    The hypothesis of the present study was that diabetes mellitus might affect brain metabolism. Streptozotocin (STZ)-induced diabetic rats, treated with vanadyl sulphate (V) and sodium tungstate (T) were employed to observe the aspartate aminotransferase (AST), alanine aminotransferase (ALT) and creatine kinase (CK) activities in brain homogenates. Significant increases in AST, ALT and CK activities were found in diabetic brain homogenates against controls, suggesting increments of transamination in brain and/or increases in cell membrane permeability to these enzymes. The increase in brain CK possibly expresses alterations in energy production. The decrease in CK activity caused by V and T treatment in diabetic rats suggests that both agents tend to normalize energy consumption. It is also possible that V and T-induced hypoglycemic effects cause metabolic alterations in brain.

  6. Effect of aluminium on duodenal calcium transport in pregnant and lactating rats treated with bromocriptine.

    PubMed

    Orihuela, Daniel

    2007-09-01

    The aim of present work was to study the effect of oral aluminium (Al) overload on intestinal calcium (Ca) absorption in the critical stages of pregnancy and lactation of rats and to find out possible relationships with prolactin (PRL) and 17beta-estradiol (E2) circulating levels. Adult female Wistar rats were orally treated from day 1 of pregnancy with 0 (control), or 50 mg elemental Al (as chloride)/kg body weight per day. Ca transport was determined by everted duodenal sacs technique using 2 microCi of (45)CaCl(2) as flux marker (JCa(ms)). Al treatment reduced JCa(ms) either in late pregnancy (day 19) or in middle lactation (day 9 postpartum). Oral administration of bromocriptine (BrC), an inhibitor of PRL secretion, at dose of 10 mg/kg body weight given 18 h before JCa(ms) measurements were done, produced a significant decrease in the inhibitory effect of Al on JCa(ms), expressed as percent of control, at day 9 of nursing (vehicle: 51+/-7%, BrC: 28+/-4%, P <0.05). A positive correlation between Al effects on JCa(ms) and the physiological variations of E2 serum levels along pregnancy and lactation in BrC-treated rats was also found (r(2)=0.277, P =0.001). We conclude Al could reduce transcellular Ca absorption in the duodenum by interfering with physiological mechanisms of Ca transport partially mediated by serum level increments of E2 and PRL, observed in late pregnancy and mainly during middle lactation of rats.

  7. Hippocampal somatostatin receptors and modulation of adenylyl cyclase activity in histamine-treated rats.

    PubMed

    Puebla, L; Rodríguez-Martín, E; Arilla, E

    1996-01-01

    In the present study, the effects of an intracerebroventricular (i.c.v.) dose of histamine (0.1, 1.0 or 10.0 micrograms) on the hippocampal somatostatin (SS) receptor/effector system in Wistar rats were investigated. In view of the rapid onset of histamine action, the effects of histamine on the somatostatinergic system were studied 2 h after its administration. Hippocampal SS-like immunoreactivity (SSLI) levels were not modified by any of the histamine doses studied. SS-mediated inhibition of basal and forskolin (FK)-stimulated adenylyl cyclase (AC) activity was markedly increased in hippocampal membranes from rats treated with 10 micrograms of histamine (23% +/- 1% vs. 17% +/- 1% and 37% +/- 2% vs. 23% +/- 1%, respectively). In contrast, neither the basal nor the FK-stimulated enzyme activities were affected by histamine administration. The functional activity of the hippocampal guanine-nucleotide binding inhibitory protein (Gi protein), as assessed by the capacity of the stable GTP analogue 5'-guanylylimidodiphosphate (Gpp[NH]p) to inhibit FK-stimulated AC activity, was not modified by histamine administration. These data suggest that the increased response of the enzyme to SS was not related to an increased functional activity of Gi proteins. In fact, the increased AC response to SS in hippocampal membranes from histamine (10 micrograms)-treated rats was associated with quantitative changes in the SS receptors. Equilibrium binding data obtained with [125I]Tyr11-SS indicate an increase in the number with specific SS receptors (541 +/- 24 vs. 365 +/- 16 fmol/mg protein, P < 0.001) together with a decrease in their apparent affinity (0.57 +/- 0.04 vs. 0.41 +/- 0.03 nM, P < 0.05) in rat hippocampal membranes from histamine (10 micrograms)-treated rats as compared to control animals. With the aim of determining if these changes were related to histamine binding to its specific receptor sites, the histaminergic H1 and H2 receptor antagonists mepyramine and cimetidine

  8. 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.

  9. Non-specific recognition in phagocytosis: ingestion of aldehyde-treated erythrocytes by rat peritoneal macrophages.

    PubMed Central

    Capo, C; Bongrand, P; Benoliel, A M; Depieds, R

    1979-01-01

    Particles were chemically modified with aldehydes and incubated with rat peritoneal cells for phagocytosis. All dialdehydes and lower monaldehydes tested (methanal, ethanal and propanal) made sheep erythrocytes phagocytosable. Failure of higher monaldehydes to induce phagocytosis of treated erythrocytes was not due to lack of reactivity with red cell membranes. All erythrocytes tested (bird and mammal red cells were used) and rat thymocytes were phagocytosed by rat macrophages after incubation with aldehyde. Treatment of Candida albicans did not induce phagocytosis: this failure was not due to lack of aldehyde binding (as demonstrated with [14C]-methanal) nor to anti-phagocytic properties of the parasite membrane. Sheep erythrocytes were submitted to enzymatic treatment (pronase, trypsin, neuraminidase) or incubated with succinic anhydride (to block free NH2 groups) or iodacetamide (to block free SH groups) before aldehyde treatment: phagocytosis was not decreased, which suggested that aldehydes did not act by altering some definite surface structure of the treated particles. Treatment of erythrocytes with cross-linking compounds such as tetraazotized o-dianisidine (coupling occurs mainly on tyrosine and histidine residues) or l-ethyl(3-dimethyl aminopropyl) carbodiimide (a bivalent reagent binding free COOH groups) did not induce any substantial phagocytosis of erythrocytes. Phagocytosis of aldehyde treated erythrocytes was partly correlated with hydrophobicity of these cells, as measured with a two-phase partition system. It is concluded that aldehyde-mediated phagocytosis of erythrocytes is mainly due to cross-linking of red cell membrane structures, probably involving free OH groups, which must increase local rigidity and thereby modify hydrophobicity of the red cell surface. Images Figure 1 PMID:437841

  10. Non-specific recognition in phagocytosis: ingestion of aldehyde-treated erythrocytes by rat peritoneal macrophages.

    PubMed

    Capo, C; Bongrand, P; Benoliel, A M; Depieds, R

    1979-03-01

    Particles were chemically modified with aldehydes and incubated with rat peritoneal cells for phagocytosis. All dialdehydes and lower monaldehydes tested (methanal, ethanal and propanal) made sheep erythrocytes phagocytosable. Failure of higher monaldehydes to induce phagocytosis of treated erythrocytes was not due to lack of reactivity with red cell membranes. All erythrocytes tested (bird and mammal red cells were used) and rat thymocytes were phagocytosed by rat macrophages after incubation with aldehyde. Treatment of Candida albicans did not induce phagocytosis: this failure was not due to lack of aldehyde binding (as demonstrated with [14C]-methanal) nor to anti-phagocytic properties of the parasite membrane. Sheep erythrocytes were submitted to enzymatic treatment (pronase, trypsin, neuraminidase) or incubated with succinic anhydride (to block free NH2 groups) or iodacetamide (to block free SH groups) before aldehyde treatment: phagocytosis was not decreased, which suggested that aldehydes did not act by altering some definite surface structure of the treated particles. Treatment of erythrocytes with cross-linking compounds such as tetraazotized o-dianisidine (coupling occurs mainly on tyrosine and histidine residues) or l-ethyl(3-dimethyl aminopropyl) carbodiimide (a bivalent reagent binding free COOH groups) did not induce any substantial phagocytosis of erythrocytes. Phagocytosis of aldehyde treated erythrocytes was partly correlated with hydrophobicity of these cells, as measured with a two-phase partition system. It is concluded that aldehyde-mediated phagocytosis of erythrocytes is mainly due to cross-linking of red cell membrane structures, probably involving free OH groups, which must increase local rigidity and thereby modify hydrophobicity of the red cell surface.

  11. Grape seed extract protects IEC-6 cells from chemotherapy-induced cytotoxicity and improves parameters of small intestinal mucositis in rats with experimentally-induced mucositis.

    PubMed

    Cheah, Ker Y; Howarth, Gordon S; Yazbeck, Roger; Wright, Tessa H; Whitford, Eleanor J; Payne, Caroline; Butler, Ross N; Bastian, Susan E P

    2009-02-01

    Mucositis is a common side-effect of high-dose chemotherapy regimens. Grape seed extract (GSE) represents a rich source of proanthocyanidins with the potential to decrease oxidative damage and inflammation within the gastrointestinal tract. We evaluated GSE for its capacity to decrease the severity of chemotherapy-induced mucositis in vitro and in vivo. In vitro: GSE was administered to IEC-6 intestinal epithelial cells prior to damage induced by 5-Fluorouracil (5-FU). Cell viability was determined by neutral red assay. In vivo: Female Dark Agouti rats (130-180 g) were gavaged with 1 ml GSE (400 mg/kg) daily (day 3-11) and received 5-FU (150 mg/kg) by intraperitoneal (i.p.) injection on day nine to induce mucositis. Rats were sacrificed at day 12 and intestinal tissues collected for myeloperoxidase and sucrase activity assays and histological analyses. Statistical analysis was performed by one-way ANOVA. GSE prevented the decrease in IEC-6 cell viability induced by 5-FU (p < 0.01). Compared with 5-FU controls, GSE significantly reduced myeloperoxidase activity by 86% and 27% in the proximal jejunum (p < 0.001) and distal ileum (p < 0.05) respectively; decreased qualitative histological scores of damage (p < 0.05) in the proximal jejunum; increased villus height in the proximal jejunum (17%; p < 0.05) and distal ileum (50%; p < 0.01), and attenuated the 5-FU-induced reduction of mucosal thickness by 16% in the jejunum (p < 0.05) and 45% in the ileum (p < 0.01). GSE partially protected IEC-6 cells from 5-FU-induced cytotoxicity and ameliorated intestinal damage induced by 5-FU in rats. GSE may represent a promising prophylactic adjunct to conventional chemotherapy for preventing intestinal mucositis.

  12. Hypertension and impairment of endothelium-dependent relaxation of arteries from spontaneously hypertensive and L-NAME-treated Wistar rats.

    PubMed

    Sekiguchi, F; Miyake, Y; Hirakawa, A; Nakahira, T; Yamaoka, M; Shimamura, K; Yamamoto, K; Sunano, S

    2001-04-01

    Effects of chronic treatment of normotensive Wistar rats with N(omega)-nitro-L-arginine methyl ester (L-NAME) on blood pressure and on endothelium-dependent relaxation of the aorta, carotid and iliac arteries were studied. The endothelium-dependent relaxation was compared in arteries from normotensive Wistar Kyoto rats (WKY) and genetically hypertensive rats (stroke-prone spontaneously hypertensive rats, SHRSP). Chronic treatment of normotensive Wistar rats with L-NAME caused an elevation of blood pressure. The elevated blood pressure at 15 weeks of age was significantly higher in these animals than that of untreated Wistar rats, but lower than that of SHRSP. Endothelium-dependent relaxation of the arteries induced by acetylcholine (ACh) was almost abolished by chronic treatment with L-NAME. The remaining small relaxation in arteries from L-NAME-treated rats was completely inhibited by application of L-NAME (10(-4) M). In such preparations, higher concentrations of ACh induced a contraction, which was abolished by removal of the endothelium or by an application of indomethacin (10(-5) M). Endothelium-independent relaxation induced by sodium nitroprusside was similar between preparations from untreated and L-NAME-treated Wistar rats. Endothelium-dependent relaxation was significantly impaired in preparations from SHRSP, when compared with that in those from WKY. However, the impairment was less prominent in preparations from SHRSP than in those from L-NAME-treated rats. These results suggest that the impairment of endothelium-dependent relaxation in the arteries from L-NAME-treated rats is not due to the elevated blood pressure resulting from the chronic treatment, and that impairment of NO synthesis by the endothelium does not play a major role in the initiation of hypertension in SHRSP.

  13. Reissner's membrane and the spiral ligament in normal rats and those treated with ethacrynic acid

    NASA Technical Reports Server (NTRS)

    Ross, M. D.

    1981-01-01

    A description is presented of recent ultrastructural findings in Reissner's membrane and the spiral ligament in rats treated daily with ethacrynic acid during the 2nd and 3rd weeks of postnatal life, a period of final maturation of the inner ear and its fluids. A distension of Reissner's membrane in every cochlear turn, indicative of mild endolymphatic hydrops, was found to occur in animals that received a higher dose of ethacrynic acid. Ultrastructurally, the cytoplasm of the epithelial cells of Reissner's membrane showed increased electron density after treatment with ethacrynic acid. This increase was most pronounced in animals treated with a greater quantity of the drug. The epithelial cells had similar ultracellular features throughout except that the cells were much thinner in the region of maximal distension.

  14. Strontium is incorporated in different levels into bones and teeth of rats treated with strontium ranelate.

    PubMed

    Oliveira, Josianne P; Querido, William; Caldas, Rogério J; Campos, Andrea P C; Abraçado, Leida G; Farina, Marcos

    2012-09-01

    The aim of this study was to evaluate the strontium incorporation into specific bones and teeth of rats treated with strontium ranelate. The relative strontium levels [Sr/(Ca + Sr) ratio] were obtained by synchrotron radiation micro X-ray fluorescence. The incisor teeth were further examined by energy dispersive X-ray spectroscopy (EDS) in a scanning electron microscope. The isolated mineral phase was investigated by EDS in a transmission electron microscope and X-ray diffraction. The strontium content was markedly increased in animals treated with strontium ranelate, with different incorporation levels found among specific bones, regions within the same bone and teeth. The highest strontium levels were observed in the iliac crest, mandible and calvaria, while the lowest were observed in the femoral diaphysis, lumbar vertebrae, rib and alveolar bone. The strontium content was higher in the femoral neck than in the diaphysis. The strontium levels also varied within the alveolar bone. High levels of strontium were found in the incisor tooth, with values similar to those in the iliac crest. Strontium was observed in both enamel and dentin. The strontium content of the molar tooth was negligible. Strontium was incorporated into the mineral substance, with up to one strontium replacing one out of 10 calcium ions within the apatite crystal lattice. The mineral from treated animals presented increased lattice parameters, which might be associated to their bone strontium contents. In conclusion, the incorporation of strontium occurred in different levels into distinct bones, regions within the same bone and teeth of rats treated with strontium ranelate.

  15. Reproductive parameters of female Wistar rats treated with methylphenidate during development.

    PubMed

    Montagnini, Bruno Garcia; Silveira, Kennia Moura; Pierone, Bruna Caroline; de Azevedo Camim, Nathália; Anselmo-Franci, Janete Aparecida; de Fátima Paccola Mesquita, Suzana; Kiss, Ana Carolina Inhasz; Gerardin, Daniela Cristina Ceccatto

    2016-12-01

    Methylphenidate (MPH), a psychoactive agent that acts mainly by blocking the uptake of dopamine, is the main drug used to treat Attention Deficit Hyperactivity Disorder in children and adolescents. During development, important changes in brain architecture and plasticity occur, these changes, sensitive to exposure to stimulant drugs, are important in the control of GnRH secretion, influencing the release of sex hormones throughout the ovarian cycle. This study investigated the effects of repeated treatment with MPH during development on reproductive parameters of adult female rats. Wistar rats received MPH 2.5mg/kg, MPH 5.0mg/kg, or tap water (gavage) from postnatal day (PND) 21 to PND 60. From PND 75, one subgroup of females was selected for evaluation of estrous cycle, estradiol levels, weight of sexual organs, and histomorphological analysis of ovary follicles and uterus. In another subgroup, the sexual and maternal behaviors were evaluated at PND 90 and on lactational day 5, respectively. No significant alterations were observed in the MPH groups. This study demonstrated that repeated administration of MPH during the period corresponding to childhood to early adulthood does not interfere in the reproductive function of female rats in adulthood.

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

    PubMed

    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 (E max) and the theoretical maximum flow (Q max), using the elastance-resistance model. Physically, E max reflects the contractility of the myocardium as an intact heart, whereas Q max has an inverse relationship with the LV internal resistance. Compared with the sham rats, the cardiodynamic condition was characterized by a decline in E max associated with the increased Q max in the lipopolysaccharide-treated rats. Methylprednisolone therapy increased E max, which suggests that the drug may have protected the contractile status from deteriorating in the inflamed heart. By contrast, methylprednisolone therapy considerably reduced Q max, 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

  17. 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.

  18. 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.

  19. 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

  20. In Vivo Evaluation of Transdermal Iodide Microemulsion for Treating Iodine Deficiency Using Sprague Dawley Rats.

    PubMed

    Alayoubi, Alaadin; Sullivan, Ryan D; Lou, Hao; Patel, Hemlata; Mandrell, Timothy; Helms, Richard; Almoazen, Hassan

    2016-06-01

    The objective of this study was to evaluate the transdermal efficiency of iodide microemulsion in treating iodine deficiency using rats as an animal model. Animals were fed either iodine-deficient diet (20 μg/kg iodide) or control diet (200 μg/kg iodide) over a 17-month period. At month 14, iodide microemulsion was applied topically in iodine-deficient group and physiological evaluations of thyroid gland functions were characterized by monitoring the thyroid hormones (T3, T4), thyroid-stimulating hormone (TSH), iodide ion excretion in urine, and the overall rat body weights in both groups. Moreover, morphological evaluations of thyroid gland before and after treatment were performed by ultrasound imaging and through histological assessment. Prior to microemulsion treatment, the levels of T3, T4, and TSH in iodine-deficient group were statistically significant as compared to that in the control group. The levels of T3 and T4 increased while TSH level decreased significantly in iodine-deficient group within the first 4 weeks of treatment. After treatment, iodide concentration in urine increased significantly. There was no statistical difference in weight between the two groups. Ultrasound imaging and histological evaluations showed evidence of hyperplasia in iodine-deficient group. Topical iodide microemulsion has shown a promising potential as a novel delivery system to treat iodine deficiency.

  1. Influence of capsaicin on fluctuation of digoxin pharmacokinetics in lipopolysaccharide-treated rats.

    PubMed

    Kato, Ryuji; Higashitani, Akina; Irie, Takako; Kusukawa, Yugo; Yamamoto, Yu; Nakagawa, Machiko; Urashima, Yoko; Nagata, Makoto; Hayashi, Tetsuya; Ijiri, Yoshio; Tanaka, Kazuhiko

    2012-08-01

    In the present study, we investigated the influence of Cap on digoxin pharmacokinetics in lipopolysaccharide (LPS)-treated rats. After the oral administration of digoxin (0.1 mg/kg), the area under the plasma concentration-time curve (AUC) of digoxin increased significantly until day 3 after LPS treatment. In the LPS + Cap group, the recovery period of AUC was shortened to 3 days. On days 5 and 7, the maximum plasma concentrations decreased significantly as compared to the control group. The bioavailability of digoxin in LPS group was higher than that in the LPS + Cap group. The hepatic cytochrome P450 (CYP) 3A2 content decreased significantly until day 5 after LPS administration, but it returned to the control level until 5 days in the LPS + Cap group. Hepatic CYP3A2 mRNA expression of LPS group decreased significantly until day 3, but it returned to the control level on day 3 and increased significantly until day 7 in the LPS + Cap group. The DNA-binding activity of pregnane X receptor (PXR) was increased on days 3-7 in the Cap and LPS + Cap group. Cap decreased the absorption of digoxin by inducing CYP3A2 mRNA expression via indirect activation of PXR in LPS-treated rats.

  2. The fractionation of isolated liver cells from normal and carcinogen treated rats.

    PubMed Central

    Horsfall, A. C.; Ketterer, B.

    1976-01-01

    Suspensions of isolated cells were obtained from livers of normal rats and rats treated with the hepatocarcinogen N,N-dimethyl-4-aminoazobenzene. Differential centrifugation of dispersed cells yielded a large parenchymal cell fraction and a small non-parencymal cell fraction. By means of rate sedimentation through different concnetrations of Ficoll, parenchymal cells were separated into cells with fast, intermediate and slow rates of sedimentation. Periods of sedimentation were brief and centrifugal forces low in order to retain the best possible state of preservation of cells. DNA, RNA and protein contents, acid phosphatase activity, cell size and nucleocytoplasmic ratios of parenchymal cells sedimenting at fast, intermediate and slow rates were measured. Cell fractions from normal livers had properties suggesting that faster sedimenting cells were derived from the centre and middle of the lobule whereas slowly sedimenting cells were periportal; however, much of the periportal cell population remained in a residue of undissociated tissue. Compared with normal cells, carcinogen treated cells appeared to fractionate according to different physical and chemical criteria and could not be related to their origin within the liver lobule. They were smaller, slower sedimenting, lower in protein and RNA content and acid phosphatase activity. The tissue residue contained abnromal histological structures. PMID:814912

  3. Enhanced feminine sexual behavior and infertility in female rats prenatally treated with an antiestrogen.

    PubMed

    Vega Matuszczyk, Josefa

    2003-07-01

    An attempt to elucidate the possible role of prenatal estrogen on the development of feminine sexual behavior and reproductive function was made by treating females with the antiestrogen CI628 prenatally on days 13-19. Control females were prenatally treated with saline or remained untreated. The animals were delivered by caesarian section on day 22 of pregnancy and placed with foster mothers whose newborn pups had been previously removed. Intact peripubertal females in each treatment group were observed for several reproductive measures, including the capacity to become pregnant. Other females were ovariectomized in adulthood and treated with estradiol benzoate (EB) (1, 1.5, 2 or 4 micro g/rat) and 0.5 mg progesterone and tested for receptivity, proceptivity and sexual partner preference. Two weeks after the completion of these tests, the females were injected daily for 7 days with 0.25 mg testosterone and tested for sexual partner preference and mounting behavior. The results obtained showed accelerated vaginal opening, and infertility in the antiestrogen-treated intact females and enhanced receptivity and proceptivity in response to 1 micro g EB in the antiestrogen ovariectomized females. Sexual partner preference and mounting behavior did not differ between groups. These results suggest an involvement of prenatal estrogen on the development of female reproductive function, but not on behavioral differentiation.

  4. Mitigation of 5-Fluorouracil induced renal toxicity by chrysin via targeting oxidative stress and apoptosis in wistar rats.

    PubMed

    Rashid, Summya; Ali, Nemat; Nafees, Sana; Hasan, Syed Kazim; Sultana, Sarwat

    2014-04-01

    5-Fluorouracil (5-FU) is a potent antineoplastic agent commonly used for the treatment of various malignancies. It has diverse adverse effects such as cardiotoxicity, nephrotoxicity and hepatotoxicity which restrict its wide and extensive clinical usage. It causes marked organ toxicity coupled with increased oxidative stress and apoptosis. Chrysin (CH), a natural flavonoid found in many plant extracts, propolis, blue passion flower. It has antioxidative and anti-cancerous properties. The present study was designed to investigate the protective effects of CH against 5-FU induced renal toxicity in wistar rats using biochemical, histopathological and immunohistochemical approaches. Rats were subjected to prophylactic oral treatment of CH (50 and 100mg/kg b.wt.) for 21 days against renal toxicity induced by single intraperitoneal administration of 5-FU (150 mg/kg b.wt.). The possible mechanism of 5-FU induced renal toxicity is the induction of oxidative stress; activation of apoptotic pathway by upregulation of p53, bax, caspase-3 and down regulating Bcl-2. However prophylactic treatment of CH decreased serum toxicity markers, increased anti-oxidant armory as well as regulated apoptosis in kidney. Histopathological changes further confirmed the biochemical and immunohistochemical results. Therefore, results of the present finding suggest that CH may be a useful modulator in mitigating 5-FU induced renal toxicity.

  5. [Diamine oxidase as blood biomarker in rats and humans to GI tract toxicity of fluorouracil anti-cancer drugs].

    PubMed

    Goto, Tetsuhiro; Matsubara, Taketo; Yoshizawa, Yasuo; Sasaya, Shouji; Nemoto, Hiroshi; Sanada, Yutaka; Moriyama, Kenji; Kouchi, Yasuhide

    2011-05-01

    Diarrhea is a side effect of a 5-fluorouracil (5-FU) anti-cancer drug-induced intestinal mucosal disorder, which sometimes becomes more severe. Blood diamine oxidase (DAO; EC1. 4. 3. 6) activity is reported to be significantly correlated with activity in the small intestinal mucosal tissue, and to be a reliable indicator of small intestinal mucosal integrity and maturity. Here, we investigated whether blood DAO activity can be a biomarker for the gastrointestinal (GI) mucosal disorder caused by 5-FU anti-cancer drugs, both in rats and humans. From results of the rat study, the degree of jejunal mucosal disorder caused by the 5-FU anti-cancer drug was well correlated with a decrease in blood DAO activity. Clinically, 12 out of 28 patients (43%) administered 5-FU anti-cancer drug suffered from diarrhea. The plasma DAO activity within one week of the onset of diarrhea significantly decreased compared with that before the administration. Furthermore, before drug administration, plasma DAO activity in patients suffering from diarrhea was higher than those in patients without diarrhea. Although DAO activity differs by the individual, it is a useful biomarker for estimating the degree of intestinal mucosal disorder, and possibly for estimating manifestations of diarrhea induced by 5-FU anti-cancer drug administration.

  6. Supplementation of Citrus maxima Peel Powder Prevented Oxidative Stress, Fibrosis, and Hepatic Damage in Carbon Tetrachloride (CCl4) Treated Rats.

    PubMed

    Chowdhury, Mohammed Riaz Hasan; Sagor, Md Abu Taher; Tabassum, Nabila; Potol, Md Abdullah; Hossain, Hemayet; Alam, Md Ashraful

    2015-01-01

    Citrus maxima peel is rich in natural phenolic compounds and has a long use in the traditional medicine. HPLC-DAD analysis on Citrus maxima peel powder exhibited the presence of various phenolic compounds such as caffeic acid and (-)-epicatechin. To determine the plausible hepatoprotective activity of Citrus maxima peel powder, we used carbon tetrachloride (CCl4) treated rat model. Liver damage in rats was confirmed by measuring the AST, ALT, and ALP enzyme activities. In addition, lipid peroxidation products (MDA), nitric oxide, advanced protein oxidation products level (APOP), and catalase activities were also analyzed along with the histological profiling for the inflammatory cell infiltration, collagen, and iron deposition in liver. Dietary supplementation of Citrus maxima peel powder exhibited significant reduction of serum AST, ALT, and ALP activities in carbon tetrachloride treated rats. Moreover, Citrus maxima peel powder also showed a significant reduction of the oxidative stress markers (MDA, NO, and APOP level) and restored the catalase activity in CCl4 treated rats. Histological examination of the liver section revealed reduced inflammatory cells infiltration, collagen, and iron deposition in CCl4 treated rats. The results from this study demonstrated that Citrus maxima peel powder produced significant hepatoprotective action in CCl4 administered rats.

  7. 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

  8. Structural alterations in the seminiferous tubules of rats treated with immunosuppressor tacrolimus

    PubMed Central

    Caneguim, Breno H; Cerri, Paulo S; Spolidório, Luís C; Miraglia, Sandra M; Sasso-Cerri, Estela

    2009-01-01

    Background Tacrolimus (FK-506) is an immunosuppressant that binds to a specific immunophilin, resulting in the suppression of the cellular immune response during transplant rejection. Except for some alterations in the spermatozoa, testicular morphological alterations have not been described in rats treated with tacrolimus. In the present study, we purpose to evaluate if the treatment with tacrolimus at long term of follow-up interferes in the integrity of the seminiferous tubules. Methods Rats aging 42-day-old received daily subcutaneous injections of 1 mg/kg/day of tacrolimus during 30 (T-30) and 60 (T-60) days; the rats from control groups (C-30 and C-60) received saline solution. The left testes were fixed in 4% formaldehyde and embedded in glycol methacrylate for morphological and morphometric analyses while right testes were fixed in Bouin's liquid and embedded in paraffin for detection of cell death by the TUNEL method. The epithelial and total tubular areas as well as the stages of the seminiferous epithelium and the number of spermatocytes, spermatids and Sertoli cells (SC) per tubule were obtained. Results In the treated groups, seminiferous tubules irregularly outlined showed disarranged cellular layers and loss of germ cells probably due to cell death, which was revealed by TUNEL method. In addition to germ cells, structural alterations in the SC and folding of the peritubular tissue were usually observed. The morphometric results revealed significant decrease in the number of SC, spermatocytes, spermatids and significant reduction in the epithelial and total tubular areas. Conclusion Tacrolimus induces significant histopathological disorders in the seminiferous tubules, resulting in spermatogenic damage and reduction in the number of Sertoli cells. A careful evaluation of the peritubular components will be necessary to clarify if these alterations are related to the effect of FK-506 on the peritubular tissue. PMID:19243597

  9. Modifications in Bone Matrix of Estrogen-Deficient Rats Treated with Intermittent PTH

    PubMed Central

    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

  10. Ultrastructural features of sprouted mossy fiber synapses in kindled and kainic acid-treated rats.

    PubMed

    Cavazos, José E; Zhang, Peisu; Qazi, Romena; Sutula, Thomas P

    2003-04-07

    The mossy fiber pathway in the dentate gyrus undergoes sprouting and synaptic reorganization in response to seizures. The types of new synapses, their location and number, and the identity of their postsynaptic targets determine the functional properties of the reorganized circuitry. The goal of this study was to characterize the types and proportions of sprouted mossy fiber synapses in kindled and kainic acid-treated rats. In normal rats, synapses labeled by Timm histochemistry or dynorphin immunohistochemistry were rarely observed in the supragranular region of the inner molecular layer when examined by electron microscopy. In epileptic rats, sprouted mossy fiber synaptic terminals were frequently observed. The ultrastructural analysis of the types of sprouted synapses revealed that 1) in the supragranular region, labeled synaptic profiles were more frequently axospinous than axodendritic, and many axospinous synapses were perforated; 2) sprouted mossy fiber synaptic terminals formed exclusively asymmetric, putatively excitatory synapses with dendritic spines and shafts in the supragranular region and with the soma of granule cells in the granule cell layer; 3) in contrast to the large sprouted mossy fiber synapses in resected human epileptic hippocampus, the synapses formed by sprouted mossy fibers in rats were smaller; and 4) in several cases, the postsynaptic targets of sprouted synapses were identified as granule cells, but, in one case, a sprouted synaptic terminal formed a synapse with an inhibitory interneuron. The results demonstrate that axospinous asymmetric synapses are the most common type of synapse formed by sprouted mossy fiber terminals, supporting the viewpoint that most sprouted mossy fibers contribute to recurrent excitation in epilepsy.

  11. 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

  12. 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

  13. Imipramine-induced c-Fos expression in the medial prefrontal cortex is decreased in the ACTH-treated rats.

    PubMed

    Li, Bingjin; Suemaru, Katsuya; Kitamura, Yoshihisa; Gomita, Yutaka; Araki, Hiroaki; Cui, Ranji

    2013-11-01

    Previous studies have shown that the antidepressive-like effect of tricyclic antidepressants is blocked by repeated treatments with adrenocorticotropic hormone (ACTH). However, little is known about the neuroanatomy underlying the mechanism of the imipramine treatment-resistant depression model. In the present study, first experimental evidence showed no significant difference of the serum imipramine concentrations between the saline and ACTH-treated rats. In further study, imipramine produced significant increases in the c-Fos expression in the medial prefrontal cortex (mPFC), the dentate gyrus of the hippocampus (DGH), and the central nucleus of the amygdala (CeA), in rats repeatedly treated with saline. The imipramine-increased c-Fos immunoreactivity was suppressed in the mPFC of rats repeatedly treated with ACTH. However, there was no significant difference in c-Fos expression in the DGH and CeA between ACTH- and saline-treated rats. These results suggest that the mPFC is maybe involved in effects of the imipramine in the ACTH-treated rats.

  14. 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.

  15. 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.

  16. Strain differences in urinary factors that promote calcium oxalate crystal formation in the kidneys of ethylene glycol-treated rats.

    PubMed

    Li, Yan; McMartin, Kenneth E

    2009-05-01

    Ethylene glycol (EG)-induced hyperoxaluria is the most commonly employed experimental regimen as an animal model of calcium oxalate (CaOx) stone formation. The variant sensitivity to CaOx among different rat strains has not been fully explored, although the Wistar rat is known to accumulate more CaOx in kidney tissue after low-dose EG exposure than in the Fischer 344 (F344) rats. Supersaturation of CaOx in tubular fluid contributes to the amount of CaOx crystal formation in the kidney. We hypothesized that the urinary supersaturation of CaOx in Wistar rats is higher than that of F344 rats, thereby allowing for greater CaOx crystal deposition in the Wistar rat. Age-matched male Wistar and F344 rats were treated with 0.75% EG or drinking water for 8 wk. Twenty-four-hour urine was collected at 0, 2, 4, 6, and 8 wk for analysis of key electrolytes to calculate the CaOx supersaturation. Plasma oxalate level was also measured. Our data confirmed the different sensitivity to renal toxicity from EG between the two rat strains (Wistar > F344). After EG treatment, the plasma oxalate level and urine oxalate excretion were markedly greater in the Wistar rats than in the F344 rats, while urine calcium was slightly decreased in Wistars. Thus, the CaOx supersaturation in urine of Wistar rats was higher, which led to a greater crystal deposition in kidney in Wistar rats. These studies suggest that during EG treatment, changes in urine electrolytes and in CaOx supersaturation occur to a greater extent in the Wistar rat, in agreement with its greater sensitivity to EG toxicity.

  17. 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

  18. 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.

  19. 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.

  20. Histomorphologic and ultrastructural recovery of myopathy in rats treated with low-level laser therapy.

    PubMed

    Servetto, Natalia; Cremonezzi, David; Simes, Juan Carlos; Di Pietro, Antonio; Campana, Vilma R

    2017-03-09

    The purpose of the present work was to study the effect of low-level laser therapy (LLLT): helium-neon (He-Ne) and gallium arsenide (Ga-As) laser on the histomorphology of muscle and mitochondria in experimental myopathy in rats. Thirty Suquía strain female rats were distributed in groups: (A) control (intact), (B) injured, (C) injured and treated with He-Ne laser, (D) injured and treated with Ga-As laser, (E) irradiated with He-Ne laser on the non-injured muscle, and (F) irradiated with Ga-As laser on the non-injured muscle. Myopathy was induced by injecting 0.05 mg/rat/day of adrenaline in the left gastrocnemius muscle at the same point on five consecutive days, in groups B, C, and D. LLLT was applied with 9.5 J cm(-2) daily for seven consecutive days in groups C, D, E, and F. The muscles were examined with optic and electronic microscopy. The inflammation was classified as absent, mild, and intense and the degree of mitochondrial alteration was graded I, II, III, and IV. Categorical data were statistically analyzed by Chi-square and the Fisher-Irwin Bilateral test, setting significant difference at p < 0.05. The damage found in muscle and mitochondria histomorphology in animals with induced myopathy (B) was intense or severe inflammation with grade III or IV of mitochondrial alteration. They underwent significant regression (p < 0.001) compared with the groups treated with He-Ne (C) and Ga-As (D) laser, in which mild or moderate inflammation was seen and mitochondrial alteration grades I and II, recovering normal myofibrillar architecture. No differences were found between the effects caused by the two lasers, or between groups A, E, and F. Group A was found to be different from B, C, and D (p < 0.001). LLLT in experimental myopathy caused significant muscular and mitochondrial morphologic recovery.

  1. 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.

  2. 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

  3. [Multiple hepatic cysts in rat rendered diabetic by streptozotocin and treated by islets of Langerhans grafts: the role of streptozotocin].

    PubMed

    Viatettes, B; Barrat, E; Lassmann, V; Guidon, J; Altomare, E; Simon, C; Vague, P

    1978-01-01

    This study is based on the investigation by light and electron microscopy of hepatic biopsies from 14 rats rendered diabetic by streptozotocin and treated by portal embolization of islets of Langerhans. Macroscopically, voluminous projecting cysts were observed, sometimes occupying a whole lobe. By light microscopy, the cysts were lined with canalicular-type epithelium. Ultrastructural studies confirmed the canalicular nature of these cells and cilia were frequently observed. The presence of identical cysts in rats rendered diabetic by streptozotocin but not treated by embolization proves that this product is the agent responsible for the induction of this adenomatosis.

  4. 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

  5. Kidney injury biomarkers in hypertensive, diabetic, and nephropathy rat models treated with contrast media.

    PubMed

    Rouse, Rodney L; Stewart, Sharron R; Thompson, Karol L; Zhang, Jun

    2013-01-01

    Contrast-induced nephropathy (CIN) refers to a decline in renal function following exposure to iodinated contrast media (CM). The present study was initiated to explore the role of known human risk factors (spontaneous hypertension, diabetes, protein-losing nephropathy) on CIN development in rodent models and to determine the effect of CM administration on kidney injury biomarkers in the face of preexisting kidney injury. Spontaneously hypertensive rats (hypertension), streptozotocin-treated Sprague Dawley rats (diabetes), and Dahl salt-sensitive rats (protein-losing nephropathy) were given single intravenous injections of the nonionic, low osmolar contrast medium, iohexol. Blood urea nitrogen (BUN), serum creatinine (sCr), and urinary biomarkers; albumin, lipocalin 2 (Lcn-2), osteopontin (Opn), kidney injury molecule 1 (Kim-1), renal papillary antigen 1 (Rpa-1), α-glutathione S-transferase (α-Gst), µ-glutathione S-transferase (µ-Gst), and beta-2 microglobulin (β2m) were measured in disease models and appropriate controls to determine the response of these biomarkers to CM administration. Each disease model produced elevated biomarkers of kidney injury without CM. Preexisting histopathology was exacerbated by CM but little or no significant increases in biomarkers were observed. When 1.5-fold or greater sCr increases from pre-CM were used to define true positives, receiver-operating characteristic curve analysis of biomarker performance showed sCr was the best predictor of CIN across disease models. β2m, Lcn-2, and BUN were the best predictors of histopathology defined kidney injury.

  6. Effect of dual-type oligosaccharides on constipation in loperamide-treated rats

    PubMed Central

    Han, Sung Hee; Hong, Ki Bae; Kim, Eun Young; Ahn, So Hyun

    2016-01-01

    BACKGROUND/OBJECTIVES Constipation is a condition that can result from intestinal deformation. Because humans have an upright posture, the effects of gravity can cause this shape deformation. Oligosaccharides are common prebiotics and their effects on bowel health are well known. However, studies of the physiological functionality of a product that contains both lactulose and galactooligosaccharides are insufficient. We investigated the constipation reduction effect of a dual-type oligosaccharide, Dual-Oligo, in loperamide-treated rats. MATERIALS/METHODS Dual-Oligo consists of galactooligosaccharides (15.80%) and lactulose (51.67%). Animals were randomly divided into four groups, the normal group (normal), control group (control), low concentration of Dual-Oligo (LDO) group, and high concentration of Dual-Oligo (HDO) group. After 7 days of oral administration, fecal pellet amount, fecal weight, water content of fecal were measured. Blood chemistry, short-chain fatty acid (SCFA), gastrointestinal transit ratio and length and intestinal mucosa were analyzed. RESULTS Dual-Oligo increased the fecal weight, and water content of feces in rats with loperamide-induced constipation. Gastrointestinal transit ratio and length and area of intestinal mucosa significantly increased after treatment with Dual-Oligo in loperamide-induced rats. A high concentration of Dual-Oligo tended to produce more acetic acid than that observed for the control group, and Dual-Oligo affected the production of total SCFA. Bifidobacteria concentration of cecal contents in the high-concentration oligosaccharide (HDO) and low-concentration oligosaccharide (LDO) groups was similar to the result of the normal group. CONCLUSIONS These results showed that Dual-Oligo is a functional material that is derived from a natural food product and is effective in ameliorating constipation. PMID:27909555

  7. 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.

  8. Kinetics of changes in the crypts of the jejunal mucosa of dimethylhydrazine-treated rats.

    PubMed Central

    Sunter, J. P.; Appleton, D. R.; Wright, N. A.; Watson, A. J.

    1978-01-01

    When symmetrical 1,2 dimethylhydrazine was administered to rats by weekly s.c. injection, 37% of the animals had developed small intestinal carcinomas after 21-27 weeks. These lesions were largely localized to duodenum and upper jejunum. At the same time there was a diffuse crypt hyperplasia in the jejunum which affected all the treated animals, not just those with neoplasms. This marked hyperplasia was preceded by a modest sustained crypt elongation which was seen soon after DMH injections began. In these hyperplastic jejunal crypts the absolute size of the proliferative compartment was increased, but the growth fraction calculated from labelling studies appeared to fall, probably by reduction in relative size of the proliferating population within the proliferative compartment. No convincing alteration in actual cell-cycle time was observed in the abnormal crypts. There was a slight (25%) increase in cell-production rate in the abnormal crypts. Images Fig. 1 PMID:656298

  9. Demonstration of direct lineage between hepatocytes and hepatocellular carcinoma in diethylnitrosamine-treated rats.

    PubMed

    Bralet, Marie-Pierre; Pichard, Virginie; Ferry, Nicolas

    2002-09-01

    The question whether hepatocellular carcinoma (HCC) arises from dedifferentiation of mature hepatocytes or from proliferation of liver stem cells is still debated. In the present study, we used retroviral-mediated genetic labeling to investigate the fate of mature hepatocytes in rats after administration of diethylnitrosamine (DEN). Mature hepatocytes were genetically labeled by intravenous injection of retroviral vectors containing the Escherichia coli beta-galactosidase gene coupled to a nuclear localization signal (nls-LacZ) 1 day after partial hepatectomy. Liver biopsies performed after completion of hepatic regeneration showed that 18.3% of hepatocytes expressed the nls-LacZ transgene. Rats were then treated with DEN in drinking water for 12 weeks and sacrificed between 98 and 151 days after the onset of DEN administration. Clones of beta-galactosidase positive cells were observed, half of which (53%) also expressed the placental form of glutathione-S-transferase (GSTp), a marker of preneoplastic cells. HCCs of various sizes expressing GSTp were present in all animals. Careful examination of 90 HCCs revealed that 16 (17.7%) also expressed nls-LacZ. This figure precisely matched the proportion of labeled hepatocytes before DEN treatment (18.3%). In conclusion, a random clonal origin of HCC from mature hepatocytes is seen in the DEN model of hepatocarcinogenesis.

  10. 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.

  11. 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

  12. Lipid peroxidation and antioxidant system in rats acutely treated with acetone.

    PubMed

    Mathias, M G; Almeida, B B de; Bueno, J E; Portari, G V; Jordao, A A

    2010-06-01

    Cascades of metabolic changes leading to acetone production are induced in states of energy catabolism such as starvation or the use of a ketogenic diet. The reduced capacity for cell detoxification or the increased generation of free radicals is responsible for the toxic effect of acetone. The objective of the present study was to determine the effects of acute treatment (AT) with acetone on the oxidative and metabolic status of rats. The AT group (n=16) was treated by gavage with a single administration of 7.0 g acetone/kg body weight at a concentration of 25% (m/v). Eight rats were euthanized 6 h later (AT6) and eight 24 h later (AT24). Acetone levels were determined in blood and urine and oxidative parameters were analyzed by determining thiobarbituric acid reactive species (TBARS, indicators of lipid peroxidation) and reduced glutathione (GSH) and vitamin E as antioxidant parameters. Serum glucose, blood cholesterol and triglycerieds and hepatic fat were also determined. The results indicated a significant difference in the hepatic oxidative parameters, serum glucose and in plasma triglycerides between the groups. Thus, we conclude that the administration of acute acetone doses can promote changes in some biochemical parameters and in the hepatic oxidative profile.

  13. Lycium barbarum polysaccharides prevent memory and neurogenesis impairments in scopolamine-treated rats.

    PubMed

    Chen, Weiwei; Cheng, Xiang; Chen, Jinzhong; Yi, Xin; Nie, Dekang; Sun, Xiaohui; Qin, Jianbing; Tian, Meiling; Jin, Guohua; Zhang, Xinhua

    2014-01-01

    Lycium barbarum is used both as a food additive and as a medicinal herb in many countries, and L. barbarum polysaccharides (LBPs), a major cell component, are reported to have a wide range of beneficial effects including neuroprotection, anti-aging and anticancer properties, and immune modulation. The effects of LBPs on neuronal function, neurogenesis, and drug-induced learning and memory deficits have not been assessed. We report the therapeutic effects of LBPs on learning and memory and neurogenesis in scopolamine (SCO)-treated rats. LBPs were administered via gastric perfusion for 2 weeks before the onset of subcutaneous SCO treatment for a further 4 weeks. As expected, SCO impaired performance in novel object and object location recognition tasks, and Morris water maze. However, dual SCO- and LBP-treated rats spent significantly more time exploring the novel object or location in the recognition tasks and had significant shorter escape latency in the water maze. SCO administration led to a decrease in Ki67- or DCX-immunoreactive cells in the dentate gyrus and damage of dendritic development of the new neurons; LBP prevented these SCO-induced reductions in cell proliferation and neuroblast differentiation. LBP also protected SCO-induced loss of neuronal processes in DCX-immunoreactive neurons. Biochemical investigation indicated that LBP decreased the SCO-induced oxidative stress in hippocampus and reversed the ratio Bax/Bcl-2 that exhibited increase after SCO treatment. However, decrease of BDNF and increase of AChE induced by SCO showed no response to LBP administration. These results suggest that LBPs can prevent SCO-induced cognitive and memory deficits and reductions in cell proliferation and neuroblast differentiation. Suppression of oxidative stress and apoptosis may be involved in the above effects of LBPs that may be a promising candidate to restore memory functions and neurogenesis.

  14. Lycium barbarum Polysaccharides Prevent Memory and Neurogenesis Impairments in Scopolamine-Treated Rats

    PubMed Central

    Chen, Jinzhong; Yi, Xin; Nie, Dekang; Sun, Xiaohui; Qin, Jianbing; Tian, Meiling; Jin, Guohua; Zhang, Xinhua

    2014-01-01

    Lycium barbarum is used both as a food additive and as a medicinal herb in many countries, and L. barbarum polysaccharides (LBPs), a major cell component, are reported to have a wide range of beneficial effects including neuroprotection, anti-aging and anticancer properties, and immune modulation. The effects of LBPs on neuronal function, neurogenesis, and drug-induced learning and memory deficits have not been assessed. We report the therapeutic effects of LBPs on learning and memory and neurogenesis in scopolamine (SCO)-treated rats. LBPs were administered via gastric perfusion for 2 weeks before the onset of subcutaneous SCO treatment for a further 4 weeks. As expected, SCO impaired performance in novel object and object location recognition tasks, and Morris water maze. However, dual SCO- and LBP-treated rats spent significantly more time exploring the novel object or location in the recognition tasks and had significant shorter escape latency in the water maze. SCO administration led to a decrease in Ki67- or DCX-immunoreactive cells in the dentate gyrus and damage of dendritic development of the new neurons; LBP prevented these SCO-induced reductions in cell proliferation and neuroblast differentiation. LBP also protected SCO-induced loss of neuronal processes in DCX-immunoreactive neurons. Biochemical investigation indicated that LBP decreased the SCO-induced oxidative stress in hippocampus and reversed the ratio Bax/Bcl-2 that exhibited increase after SCO treatment. However, decrease of BDNF and increase of AChE induced by SCO showed no response to LBP administration. These results suggest that LBPs can prevent SCO-induced cognitive and memory deficits and reductions in cell proliferation and neuroblast differentiation. Suppression of oxidative stress and apoptosis may be involved in the above effects of LBPs that may be a promising candidate to restore memory functions and neurogenesis. PMID:24505383

  15. Reduced RANKL expression impedes osteoclast activation and tooth eruption in alendronate-treated rats.

    PubMed

    Bradaschia-Correa, Vivian; Moreira, Mariana M; Arana-Chavez, Victor E

    2013-07-01

    The creation of the eruption pathway requires the resorption of the occlusal alveolar bone by osteoclasts and signaling events between bone and dental follicle are necessary. The aim of the present study has been to evaluate the effect of alendronate on osteoclastogenesis and the expression of the regulator proteins of osteoclast activation, namely RANK, RANKL and OPG, in the bone that covers the first molar germ. Newborn Wistar rats were treated daily with 2.5 mg/kg alendronate for 4, 8, 14, 21 and 28 days, whereas controls received sterile saline solution. At the time points cited, maxillae were fixed, decalcified and processed for light and electron microscopic analysis. TRAP histochemistry was performed on semi-serial sections and the osteoclasts in the occlusal half of the bony crypt surface were counted. TUNEL analysis was carried out on paraffin sections. The occlusal bone that covers the upper first molar was removed in additional 4- and 8-day-old alendronate-treated and control rats in which the expression of RANK, RANKL and OPG was analyzed by SDS-polyacrylamide gel electrophoresis and Western blotting. TRAP-positive osteoclasts were more numerous in the alendronate group at all time points, despite their unactivated phenotype and the presence of apoptotic cells. RANKL expression in the alendronate specimens was inhibited at all time points, unlike in controls. Our findings indicate that the expression of RANKL in the occlusal portion of the bony crypt is unrelated to osteoclast recruitment and differentiation but is crucial to their activation during the creation of the eruption pathway.

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

    PubMed

    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

    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.

  17. [A case of recurrent gastroesophageal junction adenocarcinoma successfully treated with radiation plus chemotherapy (5-FU+CDDP, S-1, Paclitaxel, CPT-11) for long-term survival with good QOL].

    PubMed

    Kojima, Taiki; Matsui, Takanori; Uemura, Takanori; Fujimitsu, Yasunobu; Kure, Narihiro; Mochizuki, Yoshinari; Kojima, Hiroshi

    2008-11-01

    We report a 63-year-old man with recurrent gastroesophageal junction adenocarcinoma. He underwent esophagogastrectomy in August 2004. After curative operation with Stage III (pT3N1M0), a recurrence was found at the anastomosis site in November 2004. Chemoradiotherapy with S-1 followed by chemotherapy (S-1) was performed from January 2005 to April 2006. Lymphnode metastasis to the left side of the main bronchus appeared in May 2006, and paclitaxel was used until December 2007 when PR was indicated by CT scan and GIF. Now he is receiving CPT-11. During these 3 years and 3 months, his performance status was maintained from 0 to 1.

  18. Endothelium-dependent relaxation in pulmonary arteries of L-NAME-treated Wistar and stroke-prone spontaneously hypertensive rats.

    PubMed

    Sekiguchi, Fumiko; Yamamoto, Kazuo; Matsuda, Kyoko; Kawata, Kyoko; Negishi, Maki; Shinomiya, Kazuaki; Shimamur, Keiichi; Sunano, Satoru

    2002-10-01

    To evaluate whether the elevated blood pressure induced by chronic treatment with N(omega)-nitro-L-arginine methyl ester (L-NAME) contributes to an impairment of endothelium-dependent relaxation (EDR), the effects of chronic treatment of Wistar rats with L-NAME on systolic blood pressure, pulmonary arterial blood pressure and EDR of the pulmonary arteries were studied and compared with those of stroke-prone spontaneously hypertensive rats (SHRSP). While the systolic blood pressure (SBP) of Wistar rats was increased above that of controls by chronic treatment with L-NAME, it was still significantly lower than that of SHRSP. Chronic treatment with L-NAME did not affect pulmonary arterial blood pressure. On the other hand, the pulmonary arterial blood pressure of SHRSP was slightly but significantly higher than that of the control normotensive Wistar Kyoto rats (WKY). EDR in response to acetylcholine in the pulmonary artery of L-NAME-treated rats was significantly smaller than that in control Wistar rats. The EDR markedly increased in the presence of L-arginine and completely disappeared in the presence of N(omega)-nitro-L-arginine. Indomethacin hardly affected EDR. In preparations from SHRSP, the EDR was not different from that in those from WKY. Relaxation induced by sodium nitroprusside was identical in all preparations. Elevation of SBP and the impairment of EDR observed in L-NAME-treated rats recovered two weeks following cessation of treatment. These results suggest that the impaired EDR in the pulmonary artery of L-NAME-treated rats is not due to an L-NAME-induced increase in blood pressure but due to the inhibition of nitric oxide synthase by the drug remaining in the endothelium.

  19. Hepato- and nephroprotective effects of bradykinin potentiating factor from scorpion (Buthus occitanus) venom on mercuric chloride-treated rats

    PubMed Central

    Salman, Muhammad M. A.; Kotb, Ahmed M.; Haridy, Mohie A. M.; Hammad, Seddik

    2016-01-01

    Bioactive peptides such as bradykinin potentiating factor (BPF), have, anti-oxidative, anti-inflammatory, immunomodulatory and ameliorative effects in chronic diseases and play a potential role in cancer prevention. It is known that the liver and kidney accumulate inorganic mercury upon exposure, which often leads to mercury intoxication in these organs. In this study, we investigated the effect of bradykinin potentiating factor (BPF), a scorpion venom peptide, on mercuric chloride-induced hepatic and renal toxicity in rats. We used 20 adult male Albino rats divided into four equal groups: the first group was injected with saline (control); the second group was administered daily with mercuric chloride (HgCl2) for 2 weeks; the third group was administered with BPF twice weekly for 2 successive weeks, while the fourth group was exposed to BPF followed by HgCl2. We observed that HgCl2 treated rats had a significant increase in serum ALT, AST, ALP, creatinine and urea levels compared to control. Furthermore, HgCl2 treated rats showed a marked decrease in total proteins, albumin and uric acids compared to control. The previously studied parameters were not significantly changed in BPF pretreated rats compared to control. Moreover, a significant decrease in the activities of glutathione perioxidase (GSH), superoxide dismutase (SOD), and catalase (CAT), in addition to a significant increase in the level of malondialdehyde (MDA) were observed in hepatic and renal tissues of rats after HgCl2 treatment. In contrast, the HgCl2/BPF treated rats showed a significant elevation in the activity of GSH, SOD, and CAT accompanied with a significant regression in the level of MDA compared to the HgCl2 exposed rats. We conclude that treatment with BPF is a promising prophylactic approach for the management of mercuric chloride-induced hepato- and nephro-toxicities. PMID:28337111

  20. Sodium-, potassium-, chloride-, and bicarbonate-related effects on blood pressure and electrolyte homeostasis in deoxycorticosterone acetate-treated rats.

    PubMed

    Ziomber, Agata; Machnik, Agnes; Dahlmann, Anke; Dietsch, Peter; Beck, Franz-Xaver; Wagner, Hubertus; Hilgers, Karl F; Luft, Friedrich C; Eckardt, Kai-Uwe; Titze, Jens

    2008-12-01

    Na(+) loading without Cl(-) fails to increase blood pressure in the DOCA model. We compared the changes in the total body (TB) effective Na(+), K(+), Cl(-), and water (TBW) content as well as in intracellular (ICV) or extracellular (ECV) volume in rats receiving DOCA-NaCl, DOCA-NaHCO(3), or DOCA-KHCO(3). We divided 42 male rats into 5 groups. Group 1 was untreated, group 2 received 1% NaCl, and groups 3, 4, and 5 were treated with DOCA and received 1% NaCl, 1.44% NaHCO(3), or 1.7% KHCO(3) to drink. We measured mean arterial blood pressure (MAP) directly after 3 wk. Tissue electrolyte and water content was measured by chemical analysis. Compared with control rats, DOCA-NaCl increased MAP while DOCA-NaHCO(3) and DOCA-KHCO(3) did not. DOCA-NaCl increased TBNa(+) 26% but only moderately increased TBW. DOCA-NaHCO(3) led to similar TBNa(+) excess, while TBW and ICV, but not ECV, were increased more than in DOCA-NaCl rats. DOCA-KHCO(3) did not affect TBNa(+) or volume. At a given TB(Na(+)+K(+)) and TBW, MAP in DOCA-NaCl rats was higher than in control, DOCA-NaHCO(3), and DOCA-KHCO(3) rats, indicating that hypertension in DOCA-NaCl rats was not dependent on TB(Na(+)+K(+)) and water mass balance. Skin volume retention was hypertonic compared with serum and paralleled hypertension in DOCA-NaCl rats. These rats had higher TB(Na(+)+K(+))-to-TBW ratio in accumulated fluid than DOCA-NaHCO(3) rats. DOCA-NaCl rats also had increased intracellular Cl(-) concentrations in skeletal muscle. We conclude that excessive cellular electrolyte redistribution and/or intracellular Na(+) or Cl(-) accumulation may play an important role in the pathogenesis of salt-sensitive hypertension.

  1. Evaluation of hyperdiploidy in the bladder epithelial cells of male F344 rats treated with ortho-phenylphenol.

    PubMed

    Balakrishnan, S; Eastmond, D A

    2003-05-09

    Ortho-phenylphenol (OPP) is a broad-spectrum fungicide and anti-bacterial agent that has been shown to cause bladder cancer in male F344 rats. An earlier study to investigate the potential role of aneuploidy in OPP-induced bladder carcinogenicity, failed to detect increases in frequencies of hyperdiploidy/polyploidy in treated animals, presumably due to the presence of polyploid cells in the bladder. To overcome this problem, we utilized a novel approach to determine increases in numerical alterations in the slowly dividing replicating cells of the rat bladder following treatment with OPP. Collagenase digestion of the bladder was used to enrich for actively-dividing cells and FISH in conjunction with BrdU was employed to detect hyperdiploidy in the replicating interphase cells. Initial studies were performed using FISH with a chromosome 4 probe. Follow-up studies were conducted with OPP and a positive control, vinblastine sulfate using probes for chromosomes 4 and 19. No significant increases in hyperdiploidy/polyploidy were seen in the replicating bladder cells of the OPP-treated rats using FISH with either the chromosome 4 or 19 probes. As expected, no significant increases in hyperdiploidy were seen in the non-replicating cells. In contrast, highly significant increases in hyperdiploidy/polyploidy, as detected using FISH with probes for either chromosome 4 or 19, were seen in the replicating cells from rats treated with a combination of OPP and vinblastine. The inability to detect increases in hyperdiploidy/polyploidy in the bladder of OPP-treated rats indicates that chromosome gain is unlikely to play a major role in the early genotoxic effects of OPP. However, the increase in hyperdiploidy/polyploidy induced by vinblastine sulfate in OPP-treated rats, clearly demonstrates that this approach using FISH in combination with BrdU is capable of detecting changes in chromosome number even in slowly-dividing tissues, such as the urinary bladder.

  2. Mechanism of antifertility in male rats treated with 3-monochloro-1,2-propanediol (3-MCPD).

    PubMed

    Kwack, Seung Jun; Kim, Soon Sun; Choi, Yo Woo; Rhee, Gyu Seek; Da Lee, Rhee; Seok, Ji Hyun; Chae, Soo Yeong; Won, Yong Hyuck; Lim, Kwon Jo; Choi, Kwang Sik; Park, Kui Lea; Lee, Byung Mu

    2004-12-01

    3-Monochloro-1,2-propanediol (3-MCPD) is a food contaminant that is often found in foods containing acid-hydrolyzed (AH) protein, like seasonings and savory food products. The purpose of the present study was to investigate the effects of 3-MCPD on male fertility, sperm, and hormonal levels and its antifertility mechanism. In vivo male fertility testing was performed to observe the adverse effects of 3-MCPD on the functioning of the male reproductive system and pregnancy outcome. 3-MCPD (0.01-5 mg/kg) was administered daily by gavage to Sprague-Dawley (SD) male rats for 4 wk. At the end of the pretreatment period, male rats were mated overnight with untreated females. Males successfully inducing pregnancy were sacrificed to assess sperm parameters, reproductive organ histopathology, and spermatogenesis. The resulting pregnant females were sacrificed on 20 of gestation to evaluate pregnancy outcome. The paternal administration of 3-MCPD (5 mg/kg) was found to result in adverse effects on male fertility and pregnancy outcome without inducing remarkable histopathological changes in testes and epididymides. Additionally, 3-MCPD (5 mg/kg) significantly reduced sperm motility, copulation, fertility indices, and the number of live fetuses showed steep dose-response curves. 3-MCPD did not affect spermatogenesis or induce hormonal changes in the blood and testes of male rats. An in vitro hormone assay using primary isolated Leydig cells showed no significant changes in related hormone levels after 3-MCPD treatment. To evaluate the effects of 3-MCPD on apoptotic induction and H+-ATPase levels in the testis and epididymis, 10 or 100 mg/kg of 3-MCPD was administered by gavage to male rats and testes and epididymides were examined at 3, 6, 12, and 24 h later. Apoptosis was not detected in the testes of animals treated with 100 mg/kg 3-MCPD. However, the level of H+-ATPase in the cauda epididymis was reduced by 3-MCPD treatment. These results indicate that 3-MCPD induced a

  3. Thyroid and pituitary thyroxine-5'-deiodinase activity and thyrotrophin secretion in lithium-treated rats.

    PubMed

    Frankenfeld, T G P; Corrêa Da Costa, V M; Nascimento-Saba, C C A; Ortiga-Carvalho, T M; Santos, R M M; Lisboa, P C; Carvalho, D P; Rosenthal, D

    2002-08-01

    Some authors have reported increased serum thyrotrophin (TSH) in animals chronically treated with lithium, suggesting that lithium might decrease pituitary thyroxine (T(4))-5'-deiodinase activity. On the other hand, the effect of lithium treatment on thyroidal T(4)-5'-deiodinase activity is also unknown. The present study was undertaken to evaluate the effects of lithium treatment on pituitary and thyroid T(4)-5'-deiodinase activity. Serum and pituitary TSH levels and thyroidal and pituitary T(4)-5'-deiodinase activities were determined in 3-month-old isogenic male Dutch-Miranda rats treated with lithium for 8 weeks. Chronic lithium treatment produced a slight increase in pituitary TSH content, but no change in serum TSH, and a significant increase in the thyroidal T(4)-5'-deiodinase activity. However, the pituitary T(4)-5'-deiodinase activity was unaffected by lithium administration. As far as we know, the present data show for the first time that chronic lithium treatment can increase the thyroxine to tri-iodothyronine conversion in the murine thyroid gland, be it directly or indirectly.

  4. Antimutagenic Effect of Hibiscus sabdariffa L. Aqueous Extract on Rats Treated with Monosodium Glutamate

    PubMed Central

    Kerkhoff, Jacqueline; Vieira Júnior, Gerardo Magela; de Campos, Kleber Eduardo; Sugui, Marina Mariko

    2017-01-01

    Hibiscus sabdariffa L. is a plant of the Malvaceae family, commonly known as roselle. H. sabdariffa is known to contain antioxidant, cholesterol-lowering, antiobesity, insulin resistance reduction, antihypertensive, and skin cancer chemopreventive properties. This study evaluated the effects of H. sabdariffa aqueous extract against cyclophosphamide (CPA, 25 mg/Kg) induced damage to DNA in male Wistar rats by micronucleus test. Samples of H. sabdariffa calyx were obtained in the municipality of Barra do Garças, Mato Grosso, Brazil. The aqueous extract was prepared by infusion and each animal received a daily dose of 400 mg/Kg by gavage for 15 consecutive days of treatment. The presence of anthocyanins was confirmed by ferric chloride test and phenolic compounds using high-performance liquid chromatography, with emphasis on the identification of rutin. The animals were sacrificed by deepening of anaesthesia to obtain bone marrow and determination of the frequency of micronucleated polychromatic erythrocytes. The group treated with the aqueous extract of H. sabdariffa revealed a 91% reduction in micronucleus frequency when compared with the positive control group. Under the conditions tested, H. sabdariffa L. presented a protective effect to CPA-induced damage to DNA of the treated animals, and it is a potential candidate as a chemopreventive agent against carcinogenesis. PMID:28197528

  5. Antimutagenic Effect of Hibiscus sabdariffa L. Aqueous Extract on Rats Treated with Monosodium Glutamate.

    PubMed

    Gheller, Ana Carla Guidini Valentini; Kerkhoff, Jacqueline; Vieira Júnior, Gerardo Magela; de Campos, Kleber Eduardo; Sugui, Marina Mariko

    2017-01-01

    Hibiscus sabdariffa L. is a plant of the Malvaceae family, commonly known as roselle. H. sabdariffa is known to contain antioxidant, cholesterol-lowering, antiobesity, insulin resistance reduction, antihypertensive, and skin cancer chemopreventive properties. This study evaluated the effects of H. sabdariffa aqueous extract against cyclophosphamide (CPA, 25 mg/Kg) induced damage to DNA in male Wistar rats by micronucleus test. Samples of H. sabdariffa calyx were obtained in the municipality of Barra do Garças, Mato Grosso, Brazil. The aqueous extract was prepared by infusion and each animal received a daily dose of 400 mg/Kg by gavage for 15 consecutive days of treatment. The presence of anthocyanins was confirmed by ferric chloride test and phenolic compounds using high-performance liquid chromatography, with emphasis on the identification of rutin. The animals were sacrificed by deepening of anaesthesia to obtain bone marrow and determination of the frequency of micronucleated polychromatic erythrocytes. The group treated with the aqueous extract of H. sabdariffa revealed a 91% reduction in micronucleus frequency when compared with the positive control group. Under the conditions tested, H. sabdariffa L. presented a protective effect to CPA-induced damage to DNA of the treated animals, and it is a potential candidate as a chemopreventive agent against carcinogenesis.

  6. Quercetin Improves Neurobehavioral Performance Through Restoration of Brain Antioxidant Status and Acetylcholinesterase Activity in Manganese-Treated Rats.

    PubMed

    Adedara, Isaac A; Ego, Valerie C; Subair, Temitayo I; Oyediran, Oluwasetemi; Farombi, Ebenezer O

    2017-04-01

    The present study investigated the neuroprotective mechanism of quercetin by assessing the biochemical and behavioral characteristics in rats sub-chronically treated with manganese alone at 15 mg/kg body weight or orally co-treated with quercetin at 10 and 20 mg/kg body weight for 45 consecutive days. Locomotor behavior was monitored using video-tracking software during a 10-min trial in a novel environment whereas the brain regions namely the hypothalamus, cerebrum and cerebellum of the rats were processed for biochemical analyses. Results indicated that co-treatment with quercetin significantly (p < 0.05) prevented manganese-induced locomotor and motor deficits specifically the decrease in total distance travelled, total body rotation, maximum speed, absolute turn angle as well as the increase in time of immobility and grooming. The improvement in the neurobehavioral performance of manganese-treated rats following quercetin co-treatment was confirmed by track and occupancy plot analyses. Moreover, quercetin assuaged manganese-induced decrease in antioxidant enzymes activities and the increase in acetylcholinesterase activity, hydrogen peroxide generation and lipid peroxidation levels in the hypothalamus, cerebrum and cerebellum of the rats. Taken together, quercetin mechanisms of ameliorating manganese-induced neurotoxicity is associated with restoration of acetylcholinesterase activity, augmentation of redox status and inhibition of lipid peroxidation in brain of rats.

  7. 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.

  8. Unscheduled DNA synthesis in rat pleural mesothelial cells treated with mineral fibres.

    PubMed

    Renier, A; Lévy, F; Pillière, F; Jaurand, M C

    1990-08-01

    Unscheduled DNA synthesis (UDS) was studied in confluent rat pleural mesothelial cells (RPMCs) arrested in G0/G1 with hydroxyurea (HU) and treated with various fibre types, i.e., chrysotile, crocidolite or attapulgite. In addition, the effects of UV light and of benzo[a]pyrene were determined as references. Using autoradiography after [3H]thymidine incorporation ([3H]dThd), RPMCs treated with 4 micrograms/cm2 of chrysotile fibres exhibited a low but significant enhancement of net grains compared to untreated cells. Treatment with higher doses of chrysotile was not possible because of the impairment of microscopic observation due to the presence of the fibres. Using liquid scintillation counting, RPMCs treated with chrysotile or crocidolite showed a significant dose-dependent increase in [3H]dThd incorporation compared to untreated cells. In contrast, attapulgite did not enhance [3H]dThd incorporation compared to untreated cells. Treatment of RPMCs with 1, 2 or 4 micrograms/ml of benzo[a]pyrene resulted in a significant increase in [3H]dThd incorporation. In order to discount a possible role of S cells in the augmentation of [3H]dThd incorporation, despite the presence of 5 mM HU, S cells were counted by autoradiography. Results indicated that the percentage of S cells was similar in asbestos-treated and untreated cultures. Stimulation of the S phase also seems unlikely because treatment of RPMCs with asbestos fibres in the absence of HU resulted in a reduction of [3H]dThd incorporation attributed to an impairment of the S phase by the fibres. 1-4 micrograms/ml benzo[a]pyrene or 10-50 J/m2 UV light resulted in an approximate doubling of [3H]dThd incorporation. The effects of inhibitors of DNA repair were determined in chrysotile-treated RPMCs. [3H]dThd incorporation was inhibited by cytosine arabinoside and nalidixic acid. These results show that asbestos produces UDS in RPMCs.

  9. Treating congenital megacolon by transplanting GDNF and GFRα-1 double genetically modified rat bone marrow mesenchymal stem cells.

    PubMed

    Zhou, C B; Peng, C H; Pang, W B; Zhang, D; Chen, Y J

    2015-08-14

    We studied the survival and gene expression of glial cell line-derived neurotrophic factor (GDNF) and GDNF receptor α-1 (GFRα-1) double-genetically modified rat bone marrow mesenchymal stem cells (BMSCs) transplanted into the intestinal walls of the rat models with congenital megacolon and determine the feasibility of treatment by transplantation of double-genetically modified rat BMSCs. The rat colorectal intestinal wall nerve plexus was treated with the cationic surface active agent benzalkonium chloride to establish an experimental megacolon model. The rat target genes GDNF and GFRα-1 were extracted and ligated into pEGFP-N1. Eukaryotic fluorescent expression vectors carrying the GDNF and GFRα-1 genes were transfected into BMSCs by in vitro culture. We treated congenital megacolon by transplanting double-genetically modified rat bone marrow mesenchymal stem cells. The pEGFP-EGFP-GDNF-GFRα-1 double-gene co-expressing the eukaryotic expression plasmid vector was successfully established. Protein gene protein 9.5 and vasoactive intestinal peptide-positive ganglion cells showed no positive expression in the phosphate-buffered saline transplantation group based on an immunofluorescence test at 1, 2, and 4 weeks after transplantation of BMSCs. Additionally, compared with the phosphate-buffered saline transplantation group, the expression of rearranged during transfection, GDNF, and GFRα-1 mRNA in the stem cell transplantation group increased gradually. The double-genetically modified BMSCs colonized and survived in the intestinal wall of the experimental megacolon rat model and expressed related genes, partially recovering the colonic neuromuscular regulatory functions and thus providing an experimental basis for treating congenital megacolon by cellular transplantation.

  10. [THE EFFECT OF PERINATAL HYPOXIA ON THE STRUCTURE OF BLOOD-BRAIN BARRIER IN RATS TREATED WITH SALIFEN].

    PubMed

    Otellin, V A; Khozhai, L I; Tyurenkov, I N

    2015-01-01

    The work was performed on Wistar rats, which were dividedinto 3 groups: 1st group--experimental rats subjected to hypoxia and treated with salifen (15 mg/kg for 14 days), 2nd group--control rats exposed to hypoxia only without treatment, and 3rdgroup--intact animals (8-10 animals in each group). Using themethods of light and electron microscopy, the effect of salifen onthe structural characteristics of the elements of the blood-brainbarrier (BBB) in the neocortex was studied in rats after exposureto hypoxia in the early postnatal period--on postnatal Day 2(model of human preterm pregnancy). The results showed thatsalifen had a positive effect on the state of the microvasculatureafter perinatal hypoxia, in particular, on the state of endothelialcells. Its active participation in the compensatory-adaptive reactions of the BBB in response to hypoxia exposure was detected,and the prospects of further studies of the protective properties ofsalifen are emphasized.

  11. Mucin-depleted foci (MDF) in the colon of rats treated with azoxymethane (AOM) are useful biomarkers for colon carcinogenesis.

    PubMed

    Femia, Angelo Pietro; Dolara, Piero; Caderni, Giovanna

    2004-02-01

    Crypt foci with absent or scant mucous production (mucin-depleted foci, MDF) were recently described by our group in the colon of azoxymethane (AOM)-treated rats. Since MDF are dysplastic and easy to quantify, we think that MDF are pre-neoplastic lesions that could be used as biomarkers for carcinogenesis. To test this hypothesis, we studied MDF in azoxymethane (AOM)-initiated rats treated with cholic acid (CHA), a promoter of colon carcinogenesis or with piroxicam (PXC), a colon cancer-inhibiting drug. Aberrant crypt foci (ACF) were determined as well. F344 male rats were treated with AOM (15 mg/kg x 2, s.c.) and then divided into: controls, which were fed AIN76 diet; CHA group, which was fed AIN76 diet containing CHA 0.5% w/w; PXC group, which was fed AIN76 diet containing PXC 0.02% w/w. Ten weeks after the first dose of AOM, the total number of MDF was significantly increased in rats treated with CHA (P<0.05) and drastically reduced (P<0.01) in rats treated with PXC (MDF/colon were 6.10 +/- 1.26, 10.59 +/- 1.96 and 1.31 +/- 0.21 in controls, CHA and PXC groups, respectively, means +/- SE). The multiplicity of MDF was also increased in CHA-treated rats. On the contrary, ACF multiplicity was significantly decreased by CHA. In PXC-treated rats there were fewer ACF with lower multiplicity. The effect of PXC was also investigated 15 weeks after the first AOM dose and the results showed that the total number of MDF in the PXC group was significantly lower than in controls. The number of 'large' MDF, formed by 12 or more crypts, was also reduced (P<0.01) by PXC ('large' MDF were 1.7 +/- 0.5 and 0.4 +/- 0.2 in control and PXC groups, respectively). Since CHA promotes and PXC reduces colon cancer, MDF are correlated with carcinogenesis and can be proposed as endpoints to study the modulation of colon carcinogenesis in short-term experiments.

  12. Effects of monascin on anti-inflammation mediated by Nrf2 activation in advanced glycation end product-treated THP-1 monocytes and methylglyoxal-treated wistar rats.

    PubMed

    Lee, Bao-Hong; Hsu, Wei-Hsuan; Huang, Tao; Chang, Yu-Ying; Hsu, Ya-Wen; Pan, Tzu-Ming

    2013-02-13

    Hyperglycemia is associated with advanced glycation end products (AGEs). This study was designed to evaluate the inhibitory effects of monascin on receptor for advanced glycation end product (RAGE) signal and THP-1 monocyte inflammation after treatment with S100b, a specific ligand of RAGE. Monascin inhibited cytokine production by S100b-treated THP-1 monocytes via up-regulation of nuclear factor-erythroid 2-related factor-2 (Nrf2) and alleviated p47phox translocation to the membrane. Methylglyoxal (MG, 600 mg/kg bw) was used to induce diabetes in Wistar rats. Inhibitions of RAGE and p47phox by monascin were confirmed by peripheral blood mononuclear cells (PBMCs) of MG-induced rats. Silymarin (SM) was used as a positive control group. It was found that monascin promoted heme oxygenase-1 (HO-1) expression mediated by Nrf2. Suppressions of AGEs, tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-β) in serum of MG-induced rats were attenuated in the monascin administration group treated with retinoic acid (RA). RA treatment resulted in Nrf2 inactivation by increasing RA receptor-α (RARα) activity, suggesting that RA acts as an inhibitor of Nrf2. The results showed that monascin exerted anti-inflammatory and antioxidative effects mediated by Nrf2 to prevent the development of diseases such as type 2 diabetes caused by inflammation.

  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

    2007-01-05

    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. Downregulation of CREB expression in Alzheimer's brain and in Aβ-treated rat hippocampal neurons

    PubMed Central

    2011-01-01

    Background Oxidative stress plays an important role in neuronal dysfunction and neuron loss in Alzheimer's brain. Previous studies have reported downregulation of CREB-mediated transcription by oxidative stress and Aβ. The promoter for CREB itself contains cyclic AMP response elements. Therefore, we examined the expression of CREB in the hippocampal neurons of Tg2576 mice, AD post-mortem brain and in cultured rat hippocampal neurons exposed to Aβ aggregates. Results Laser Capture Microdissection of hippocampal neurons from Tg2576 mouse brain revealed decreases in the mRNA levels of CREB and its target, BDNF. Immunohistochemical analysis of Tg2576 mouse brain showed decreases in CREB levels in hippocampus and cortex. Markers of oxidative stress were detected in transgenic mouse brain and decreased CREB staining was observed in regions showing abundance of astrocytes. There was also an inverse correlation between SDS-extracted Aβ and CREB protein levels in Alzheimer's post-mortem hippocampal samples. The levels of CREB-regulated BDNF and BIRC3, a caspase inhibitor, decreased and the active cleaved form of caspase-9, a marker for the intrinsic pathway of apoptosis, was elevated in these samples. Exposure of rat primary hippocampal neurons to Aβ fibrils decreased CREB promoter activity. Decrease in CREB mRNA levels in Aβ-treated neurons was reversed by the antioxidant, N-acetyl cysteine. Overexpression of CREB by adenoviral transduction led to significant protection against Aβ-induced neuronal apoptosis. Conclusions Our findings suggest that chronic downregulation of CREB-mediated transcription results in decrease of CREB content in the hippocampal neurons of AD brain which may contribute to exacerbation of disease progression. PMID:21854604

  15. 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

  16. Molecular, Anatomical, Physiological, and Behavioral Studies of Rats Treated with Buprenorphine after Spinal Cord Injury

    PubMed Central

    Santiago, José M.; Rosas, Odrick; Torrado, Aranza I.; González, María M.; Kalyan-Masih, Priya O.

    2009-01-01

    Abstract Acute pain is a common symptom experienced after spinal cord injury (SCI). The presence of this pain calls for treatment with analgesics, such as buprenorphine. However, there are concerns that the drug may exert other effects besides alleviation of pain. Among those reported are in vitro changes in gene expression, apoptosis, and necrosis. In this investigation, the effect of buprenorphine was assessed at the molecular, behavioral, electrophysiological, and histological levels after SCI. Rats were injured at the T10 thoracic level using the NYU impactor device. Half of the animals received buprenorphine (0.05 mg/kg) for 3 consecutive days immediately after SCI, and the other half were untreated. Microarray analysis (n = 5) was performed and analyzed using the Array Assist software. The genes under study were grouped in four categories according to function: regeneration, apoptosis, second messengers, and nociceptive related genes. Microarray analysis demonstrated no significant difference in gene expression between rats treated with buprenorphine and the control group at 2 and 4 days post-injury (DPI). Experiments performed to determine the effect of buprenorphine at the electrophysiological (tcMMEP), behavioral (BBB, grid walking and beam crossing), and histological (luxol staining) levels revealed no significant difference at 7 and 14 DPI in the return of nerve conduction, functional recovery, or white matter sparing between control and experimental groups (p > 0.05, n = 6). These results show that buprenorphine (0.05 mg/kg) can be used as part of the postoperative care to reduce pain after SCI without affecting behavioral, physiological, or anatomical parameters. PMID:19653810

  17. Alteration of serum and cardiac tissue adropin, copeptin, irisin and TRPM2 expressions in DOX treated male rats.

    PubMed

    Aydin, S; Eren, M N; Kuloglu, T; Aydin, S; Yilmaz, M; Gul, E; Kalayci, M; Yel, Y; Cakmak, T; Bico, S

    2015-04-01

    Doxorubicin (DOX) cardiotoxicity is a significant side effect in cancer survivors. DOX and its metabolites alter cardiac gene expression and affect metabolic energy-related peptides. Adropin, copeptin, irisin and TRPM2 are produced locally in the heart and play a role in energy homeostasis. We investigated the fates of adropin, copeptin, irisin and TRPM2 in serum and cardiac tissues of DOX treated rats. Animals were divided into three groups of six: 1) untreated controls, 2) DOX treated and 3) saline treated. The rats were fed a standard diet ad libitum for 14 days then were sacrificed and heart and serum samples were taken. Adropin, copeptin, irisin levels in tissue homogenates and serum were measured using ELISA. Immunoreactivity of heart tissue adropin, copeptin, irisin and TRPM2 also were investigated. The peptides increased in both serum and cardiac tissue homogenates in animals treated with DOX compared to the other groups. DOX increased adropin in endocardial and myocardial cells, but it decreased expression of copeptin. DOX did not affect endocardial irisin and TRPM2 expressions, but myocardial irisin and TRPM2 expressions were increased. Serum adropin, irisin and copeptin were increased in DOX treated rats. Cardiac adropin, copeptin, irisin and TRPM2 are affected by DOX and may play a role in DOX cardiotoxicity.

  18. Long-term Morphine-treated Rats are more Sensitive to Antinociceptive Effect of Diclofenac than the Morphine-naive rats

    PubMed Central

    Akbari, Esmaeil; Mirzaei, Ebrahim; Shahabi Majd, Naghi

    2013-01-01

    This study investigates the effectiveness of the antinociceptive effects of diclofenac, an NSAID, on the nociceptive behavior of morphine-treated rats on formalin test. Rats were treated with morphine-containing drinking water for twenty one days, which induced morphine dependence. The antinociceptive effects of 8, 16, and 32 mg/kg doses of diclofenac were then evaluated and compared with distilled water in a formalin-based model of pain. Diclofenac potentiated pain suppression in morphine-dependent rats during the interphase of the formalin test and reduced the pain score during phase II. The post-test analysis revealed that both 16 mg/kg (p < 0.0001) and 32 mg/kg (p < 0.0001) doses of diclofenac had a significant effect on the interphase, while 8 mg/kg (p < 0.05), 16 mg/kg (p < 0.05), and 32 mg/kg (p < 0.01) doses of diclofenac significantly affected phase II. In contrast, the antinociceptive effects of diclofenac on morphine-naïve rats were observed during phase II only with the a 32 mg/kg dose (p < 0.05). In general, these results suggest that the long-term use of morphine in rats increases their sensitivity to the antinociceptive effects of diclofenac. Furthermore, the results support the existence of a non-opioid-dependent mechanism of pain suppression during the interphase of formalin test. PMID:24250586

  19. 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.

  20. Influence of Piper betle on hepatic marker enzymes and tissue antioxidant status in ethanol-treated Wistar rats.

    PubMed

    Saravanan, R; Prakasam, A; Ramesh, B; Pugalendi, K V

    2002-01-01

    Piper betle L. is a commonly used masticatory in Asia. This study was carried out to investigate the hepatoprotective and antioxidant properties of P. betle, using ethanol intoxication as a model of hepatotoxic and oxidative damage. Ethanol-treated rats exhibited elevation of hepatic marker enzymes and disturbances in antioxidant defense when compared with normal rats. Oral administration of P. betle extract (100, 200, or 300 mg/kg body weight) for 30 days significantly (P <.05) decreased aspartate aminotransferase (AST), alanine aminotransferase (ALT), thiobarbituric acid reactive substances (TBARS), and lipid hydroperoxides in ethanol treated rats. The extract also improved the tissue antioxidant status by increasing the levels of nonenzymatic antioxidants (reduced glutathione, vitamin C, and vitamin E) and the activities of free radical-detoxifying enzymes such as superoxide dismutase, catalase, and glutathione peroxidase in liver and kidney of ethanol-treated rats. The highest dose of P. betle extract (300 mg/kg body weight) was most effective. The results were comparable with the known hepatoprotective drug, silymarin. These results indicate that P. betle could afford a significant hepatoprotective and antioxidant effect.

  1. 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.

  2. 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

  3. Superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase in the heart of hypergravity-treated and aging rats

    NASA Astrophysics Data System (ADS)

    Utko, Natalie

    2005-08-01

    Activities of superoxide dismutase (SOD), catalase, glutathione peroxidase (GP), and glutathione reductase (GR) were determined in the heart of young and old control and hypergravity (HG) treated male Wistar rats. Relatively small and insignificant changes were observed when comparing enzyme activities in the heart of young and old control rats, whereas HG induced significant decline of SOD and GP in the group of old rats and GR in young animals. Statistically highly significant positive correlation found for SOD and downstream acting catalase in young (r=0.72; P<0.00001) and old rats (r=0,86; P<0.00001) was preserved in HG- treated young animals as well (r=0.66; P<0.02), assuming that SOD-catalase pair could remain functionally related in both aging and HG. However, three-dimensional (3D) non- linear plotting and cluster analysis revealed significant alterations in enzyme relations in the heart of both aging and HG-treated animals.

  4. Diet-dependent modulation of hippocampal expression of endocannabinoid signaling-related proteins in cannabinoid antagonist-treated obese rats.

    PubMed

    Rivera, Patricia; Luque-Rojas, María Jesús; Pastor, Antoni; Blanco, Eduardo; Pavón, Francisco J; Serrano, Antonia; Crespillo, Ana; Vida, Margarita; Grondona, Jesús M; Cifuentes, Manuel; Bermúdez-Silva, Francisco J; de la Torre, Rafael; de Fonseca, Fernando Rodríguez; Suárez, Juan

    2013-01-01

    Diet-induced obesity produces changes in endocannabinoid signaling (ECS), influencing the regulation of energy homeostasis. Recently, we demonstrated that, in high-fat-diet-fed rats, blockade of CB1 receptor by AM251 not only reduced body weight but also increased adult neurogenesis in the hippocampus, suggesting an influence of diet on hippocampal cannabinoid function. To further explore the role of hippocampal ECS in high-fat-diet-induced obesity, we investigated whether the immunohistochemical expression of the enzymes that produce (diacylglycerol lipase alpha and N-acyl phosphatidylethanolamine phospholipase D) and degrade (monoacylglycerol lipase and fatty acid amino hydrolase) endocannabinoids may be altered in the hippocampus of AM251 (3 mg/kg)-treated rats fed three different diets: standard diet (normal chow), high-carbohydrate diet (70% carbohydrate) and high-fat diet (60% fat). Results indicated that AM251 reduced caloric intake and body weight gain, and induced a modulation of the expression of ECS-related proteins in the hippocampus of animals exposed to hypercaloric diets. These effects were differentially restricted to either the 2-arachinodoyl glycerol or anandamide signaling pathways, in a diet-dependent manner. AM251-treated rats fed the high-carbohydrate diet showed a reduction of the diacylglycerol lipase alpha : monoacylglycerol lipase ratio, whereas AM251-treated rats fed the high-fat diet showed a decrease of the N-acyl phosphatidylethanolamine phospholipase D : fatty acid amino hydrolase ratio. These results are consistent with the reduced levels of hippocampal endocannabinoids found after food restriction. Regarding the CB1 expression, AM251 induced specific changes focused in the CA1 stratum pyramidale of high-fat-diet-fed rats. These findings indicated that the cannabinoid antagonist AM251 modulates ECS-related proteins in the rat hippocampus in a diet-specific manner. Overall, these results suggest that the hippocampal ECS participates

  5. Calcitriol promotes augmented dopamine release in the lesioned striatum of 6-hydroxydopamine treated rats

    PubMed Central

    Cass, Wayne A.; Peters, Laura E.; Fletcher, Anita M.; Yurek, David M.

    2014-01-01

    Current therapies for Parkinson's disease (PD) offer symptomatic relief but do not provide a cure or slow the disease process. Treatments that could halt progression of the disease or help restore function to damaged neurons would be of substantial benefit. Calcitriol, the active metabolite of vitamin D, has been shown to have significant effects on the brain. These effects include upregulating trophic factor levels, and reducing the severity of some central nervous system lesions. While previous studies have shown that calcitriol can be neuroprotective in 6-hydroxydopamine (6-OHDA) rodent models of PD, the present experiments were designed to examine the ability of calcitriol to promote restoration of extracellular DA levels and tissue content of DA in animals previously lesioned with 6-OHDA. Male Fischer-344 rats were given a single injection of 12 µg 6-OHDA into the right striatum. Four weeks later the animals were administered vehicle or calcitriol (0.3 or 1.0 µg/kg, s.c.) once a day for eight consecutive days. Three weeks after the calcitriol treatments in vivo microdialysis experiments were conducted to measure potassium and amphetamine evoked overflow of DA from both the left and right striata. In control animals treated with 6-OHDA and vehicle there were significant reductions in both potassium and amphetamine evoked overflow of DA on the lesioned side of the brain compared to the contralateral side. In animals treated with 6-OHDA followed by calcitriol there was significantly greater potassium and amphetamine evoked overflow of DA from the lesioned striatum compared to that from the control animals. The calcitriol treatments also led to increases in postmortem tissue levels of DA in the striatum and substantia nigra. These results suggest that calcitriol may help promote recovery of dopaminergic functioning in injured nigrostriatal neurons. PMID:24858239

  6. 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.

  7. Peripheral 5-HT₁D and 5-HT₇ serotonergic receptors modulate sympathetic neurotransmission in chronic sarpogrelate treated rats.

    PubMed

    García-Pedraza, José Ángel; García, Mónica; Martín, María Luisa; Gómez-Escudero, Jesús; Rodríguez-Barbero, Alicia; Román, Luis San; Morán, Asunción

    2013-08-15

    5-HT₂ receptor activation induces vasoconstriction, hypertension and platelet aggregation; therefore, its blocking may be useful in cardiovascular diseases, probably due to alterations in the modulation of serotonergic system. The aim of this study was to evaluate whether 5-HT₂ receptor blockade changes serotonergic modulation of sympathetic neurotransmission in pithed rats. Serotonergic modulation of sympathetic neurotransmission was investigated in Wistar rats treated with sarpogrelate, a 5-HT₂ receptor antagonist, during 14 days (30 mg/kg/day). After central nervous system destruction, we conducted electrical stimulation throughout the spinal cord flow to study the 5-HT-related products action on adrenergic system. 5-Hydroxytryptamine exerted inhibition of sympathetic outflow in sarpogrelate-treated pithed rats. This effect was mimicked and enhanced by 5-CT (5-HT₁/₇ receptor agonist). L-694,247 and AS-19, 5-HT₁D and 5-HT₇ receptor agonists respectively, reproduced this action. Pretreatment with LY310762+SB258719 (5-HT₁D and 5-HT₇ receptor antagonists, respectively) completely abolished 5-CT inhibitory action. The nature of this action was prejunctional since these agonists did not modify the pressor responses induced by exogenous noradrenaline. Western Blot analysis confirmed a higher expression of 5-HT₁D receptors in sarpogrelate-treated rats. Experimental 5-HT₂ receptor blockade induces changes in the 5-HT receptors involved in the serotonergic inhibition of sympathetic-induced pressor responses. Prejunctional activation of 5-HT₁D and 5-HT₇ receptors induces a significantly higher serotonergic inhibition on adrenergic neurotransmission in sarpogrelate-treated pithed rats. The antagonism of 5-HT₂ receptors produces an enhancement of serotonergic sympathoinhibitory effect, which may explain the beneficial effects of this blockade in cardiovascular disorders where 5-hydroxytryptamine plays a crucial role.

  8. 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.

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

    PubMed

    Liu, Shu-Ting; Huang, Shih-Ming; Ho, Ching-Liang; Yen, Li-Chen; Huang, Chi-Jung; Lin, Wei-Shiang; Chan, James Yi-Hsin

    2015-11-10

    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.

  11. Protective effect of sodium ferulate on acetaldehyde-treated precision-cut rat liver slices.

    PubMed

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

    2012-06-01

    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-β(1), 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.

  12. Analysis of gene expression profiles in healing rat fractures treated with nail and plate fixation.

    PubMed

    Wang, S D; Li, X L; Liu, H P

    2014-10-20

    To compare fracture healing therapies, the gene expression profiles of rat fracture samples treated with nail and plate fixation were analyzed at 1 day, 3 days, 1 week, 2 weeks, 4 weeks, and 6 weeks after surgery. The gene expression profiles GSE1685, which include 19 samples, were downloaded from the Gene Expression Omnibus database. After preprocessing, the gene expression profiles were subjected to time series analysis using the Short Time-series Expression Miner software, and the significantly differentially expressed gene (DEG) sets were selected. Further, the distributions of those DEG sets on the corresponding chromosomes were identified using the functional classification tool. Finally, the DEGs were subjected to function and pathway enrichment analysis. DEG analysis indicated that the number of DEGs (854 genes) from nail fixation was significantly lower than that of DEGs (1029 genes) from plate fixation. The DEGs were mainly enriched in cell proliferation, cellular localization, and response to wounding functions. Several critical DEGs expressed during the fracture healing process were screened, and 2 common pathways were enriched for the DEGs in the nail fixation and plate fixation. These DEGs and pathways may be potential targets or predictive markers during fracture healing.

  13. 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.

  14. 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

  15. Detection of micronuclei, cell proliferation and hyperdiploidy in bladder epithelial cells of rats treated with o-phenylphenol.

    PubMed

    Balakrishnan, S; Uppala, P T; Rupa, D S; Hasegawa, L; Eastmond, D A

    2002-01-01

    o-Phenylphenol (OPP), a widely used fungicide and antibacterial agent, has been considered to be among the top 10 home and garden pesticides used in the USA. Earlier studies have consistently shown that the sodium salt of OPP (SOPP) causes bladder cancer in male Fischer 344 (F344) rats, whereas OPP has produced variable results. This difference has been attributed to the presence of the sodium salt. To determine cellular and genetic alterations in the rat bladder and the influence of the sodium salt, F344 rats were administered 2% OPP, 2% NaCl and 2% NaCl + 2% OPP in their diet for 14 days. Twenty-four hours before being killed the animals were administered 5-bromo-2'-deoxyuridine (BrdU) by i.p. injection. Bladder cells were isolated, stained with DAPI and scored for the presence of micronuclei and incorporation of BrdU into replicating cells. To determine changes in chromosome number, we used fluorescence in situ hybridization (FISH) with a DNA probe for rat chromosome 4. Significant increases in the frequency of micronuclei and BrdU incorporation were seen in bladder cells of rats from all treatment groups. In contrast, the frequency of hyperdiploidy/polyploidy in treated animals was not increased over that seen in controls. A high control frequency of cells with three or more hybridization signals was seen, probably due to the presence of polyploid cells in the bladder. The presence of polyploid cells combined with cytotoxicity and compensatory cell proliferation makes it difficult to determine whether OPP is capable of inducing aneuploidy in the rat urothelium. In summary, these studies show that OPP can cause cellular and chromosomal alterations in rat bladder cells in the absence of the sodium salt. These results also indicate that at high concentrations the sodium salt can enhance chromosomal damage in the rat urothelium.

  16. 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

    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.

  17. Exercise aggravates cardiovascular risks and mortality in rats with disrupted nitric oxide pathway and treated with recombinant human erythropoietin.

    PubMed

    Meziri, Fayçal; Binda, Delphine; Touati, Sabeur; Pellegrin, Maxime; Berthelot, Alain; Touyz, Rhian M; Laurant, Pascal

    2011-08-01

    Chronic administration of recombinant human erythropoietin (rHuEPO) can generate serious cardiovascular side effects such as arterial hypertension (HTA) in clinical and sport fields. It is hypothesized that nitric oxide (NO) can protect from noxious cardiovascular effects induced by chronic administration of rHuEPO. On this base, we studied the cardiovascular effects of chronic administration of rHuEPO in exercise-trained rats treated with an inhibitor of NO synthesis (L-NAME). Rats were treated or not with rHuEPO and/or L-NAME during 6 weeks. During the same period, rats were subjected to treadmill exercise. The blood pressure was measured weekly. Endothelial function of isolated aorta and small mesenteric arteries were studied and the morphology of the latter was investigated. L-NAME induced hypertension (197 ± 6 mmHg, at the end of the protocol). Exercise prevented the rise in blood pressure induced by L-NAME (170 ± 5 mmHg). However, exercise-trained rats treated with both rHuEPO and L-NAME developed severe hypertension (228 ± 9 mmHg). Furthermore, in these exercise-trained rats treated with rHuEPO/L-NAME, the acetylcholine-induced relaxation was markedly impaired in isolated aorta (60% of maximal relaxation) and small mesenteric arteries (53%). L-NAME hypertension induced an internal remodeling of small mesenteric arteries that was not modified by exercise, rHuEPO or both. Vascular ET-1 production was not increased in rHuEPO/L-NAME/training hypertensive rats. Furthermore, we observed that rHuEPO/L-NAME/training hypertensive rats died during the exercise or the recovery period (mortality 51%). Our findings suggest that the use of rHuEPO in sport, in order to improve physical performance, represents a high and fatal risk factor, especially with pre-existing cardiovascular risk.

  18. Metabolism of symmetrical N-nitroso-di-n-alkylamines in isolated hepatocytes from control and EtOH treated rats

    SciTech Connect

    Gorsky, L.D.; Hollenberg, P.F.

    1986-05-01

    N-nitrosodialkylamines are known to be carcinogenic in laboratory animals giving rise to hepatocellular carcinomas and a variety of other neoplasms in different organs of the body. The liver is the main target organ for tumor production in the rat; however, the biological effects of the C/sub 1/ (N-nitrosodimethylamine) through C/sub 4/ (N-nitrosodi-n-butylamine) series of symmetrical N-nitrosodialkylamines are dependent on the route of administration, the absolute dose, and the dosing regimen. For those reasons the authors have chosen to study the metabolism of N-nitrosodialkylamines in isolated rat hepatocytes. These studies were designed to compare the metabolism of the N-nitrosodialkylamines in hepatocytes isolated from control and EtOH-treated rates. For instance, after incubation of /sup 14/C-diethylnitrosamine (15 ..mu..M) with hepatocytes from control animals for 3 hours, 9% of the dose was metabolized to CO/sub 2/, 2% was found associated with the acid precipitable fraction and no radioactivity was associated with the DNA. In contrast to these results, however, in similar studies using hepatocytes isolated from EtOH-treated rats, 25% of the dose was metabolized to CO/sub 2/, 2.9% was incorporated into the acid precipitable fraction and 0.8% was associated with the DNA. These data demonstrate that EtOH treatment of rats results in increased hepatocellular metabolism of diethyl nitrosamine including the generation of DNA alkylating intermediates.

  19. Sensitization of capsaicin and icilin responses in oxaliplatin treated adult rat DRG neurons

    PubMed Central

    2010-01-01

    Background Oxaliplatin chemotherapy induced neuropathy is a dose related cumulative toxicity that manifests as tingling, numbness, and chronic pain, compromising the quality of life and leading to discontinued chemotherapy. Patients report marked hypersensitivity to cold stimuli at early stages of treatment, when sensory testing reveals cold and heat hyperalgesia. This study examined the morphological and functional effects of oxaliplatin treatment in cultured adult rat DRG neurons. Results 48 hour exposure to oxaliplatin resulted in dose related reduction in neurite length, density, and number of neurons compared to vehicle treated controls, using Gap43 immunostaining. Neurons treated acutely with 20 μg/ml oxaliplatin showed significantly higher signal intensity for cyclic AMP immunofluorescence (160.5 ± 13 a.u., n = 3, P < 0.05), compared to controls (120.3 ± 4 a.u.). Calcium imaging showed significantly enhanced capsaicin (TRPV1 agonist), responses after acute 20 μg/ml oxaliplatin treatment where the second of paired capsaicin responses increased from 80.7 ± 0.6% without oxaliplatin, to 171.26 ± 29% with oxaliplatin, (n = 6 paired t test, P < 0.05); this was reduced to 81.42 ± 8.1% (P < 0.05), by pretretreatment with the cannabinoid CB2 receptor agonist GW 833972. Chronic oxaliplatin treatment also resulted in dose related increases in capsaicin responses. Similarly, second responses to icilin (TRPA1/TRPM8 agonist), were enhanced after acute (143.85 ± 7%, P = 0.004, unpaired t test, n = 3), and chronic (119.7 ± 11.8%, P < 0.05, n = 3) oxaliplatin treatment, compared to control (85.3 ± 1.7%). Responses to the selective TRPM8 agonist WS-12 were not affected. Conclusions Oxaliplatin treatment induces TRP sensitization mediated by increased intracellular cAMP, which may cause neuronal damage. These effects may be mitigated by co-treatment with adenylyl cyclase inhibitors, like CB2 agonists, to alleviate the neurotoxic effects of oxaliplatin. PMID:21106058

  20. Increased apoptosis in osteoclasts and decreased RANKL immunoexpression in periodontium of cimetidine-treated rats.

    PubMed

    Longhini, Renata; de Oliveira, Priscila Aparecida; de Souza Faloni, Ana Paula; Sasso-Cerri, Estela; Cerri, Paulo Sérgio

    2013-02-01

    It has been demonstrated that histamine interferes with the recruitment, formation and activity of osteoclasts via H(1)- and H(2)-receptors. Cimetidine is a H(2)-receptor antagonist used for treatment of gastric ulcers that seems to prevent bone resorption. In this study, a possible cimetidine interference was investigated in the number of alveolar bone osteoclasts. The incidence of osteoclast apoptosis and immunoexpression of RANKL (receptor activator of nuclear factor κB ligand) was also evaluated. Adult male rats were treated with 100 mg kg(-1) of cimetidine for 50 days (CimG); the sham group (SG) received saline. Maxillary fragments containing the first molars and alveolar bone were fixed, decalcified and embedded in paraffin. The sections were stained by H&E or submitted to tartrate-resistant acid phosphatase (TRAP) method. TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling) method and immunohistochemical reactions for detecting caspase-3 and RANKL were performed. The number of TRAP-positive osteoclasts, the frequency of apoptotic osteoclasts and the numerical density of RANKL-positive cells were obtained. Osteoclast death by apoptosis was confirmed by transmission electron microscopy (TEM). In CimG, TRAP-positive osteoclasts with TUNEL-positive nuclei and caspase-3-immunolabeled osteoclasts were found. A significant reduction in the number of TRAP-positive osteoclasts and a high frequency of apoptotic osteoclasts were observed in CimG. Under TEM, detached osteoclasts from the bone surface showed typical features of apoptosis. Moreover, a significant reduction in the numerical density of RANKL-positive cells was observed in CimG. The significant reduction in the number of osteoclasts may be due to cimetidine-induced osteoclast apoptosis. However, RANKL immunoexpression reduction also suggests a possible interference of cimetidine treatment in the osteoclastogenesis.

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

    PubMed

    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.

  2. 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

  3. 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.

  4. 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.

  5. Phase II antioxidant enzyme activities in brain of male and female ACI rats treated chronically with estradiol.

    PubMed

    Stakhiv, Timothy M; Mesia-Vela, Sonia; Kauffman, Frederick C

    2006-08-09

    Activities of Phase II antioxidant enzymes, including NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione S-transferase (GST), UDP-glucuronosyltransferase (UGT), and phenol sulfotransferase 1A1 (SULT1A1) were measured in brain of August-Copenhagen Irish (ACI) rats exposed chronically to low doses of estradiol (E(2)). ACI rats were selected for study because this strain is highly responsive to treatment with low doses of E(2) as indexed by a high incidence of E(2)-induced mammary tumors compared to other strains. Rats were exposed chronically to 3 mg E(2) contained in cholesterol pellets implanted subcutaneously for 6 weeks. This treatment increased activities of all four enzymes in the striatum of male but not female ACI rats. Blood E(2) levels at time of sacrifice correlated closely with activities of striatal NQO1, GST, and SULT1A1, but not with striatal UGT. NQO1, GST, and SULT1A1 activities in other brain regions including the cortex, cerebellum, and hippocampus were less sensitive to chronic E(2) treatment. NQO1 was primarily localized in vascular elements and neurons and SULT1A1 primarily in neurons and neuropil of control and E(2)-treated rats. Collectively, these results suggest that enhanced expression of NQO1, GST, and SULT1A1 may contribute to the antioxidant effects of E(2) in the striatum, an area of the brain that may be particularly prone to oxidative stress because of its high content of catecholamines.

  6. 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

  7. 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

    2015-12-03

    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

  8. Functional and structural recovery of the injured spinal cord in rats treated with gonadotropin-releasing hormone.

    PubMed

    Calderón-Vallejo, Denisse; Quintanar-Stephano, Andrés; Hernández-Jasso, Irma; Jiménez-Hernández, Violeta; Ruiz-Ornelas, Jannet; Jiménez, Ismael; Quintanar, J Luis

    2015-03-01

    Several studies have shown that gonadotropin-releasing hormone (GnRH) have extra-pituitary roles, including neurotrophic effects. This study was to evaluate the effects of GnRH treatment on the spinal cord injury (SCI) of rats. Ovariectomized rats were divided into: sham SCI surgery (Sham), SCI treated with saline solution (SCI + SS), and SCI treated with GnRH (SCI + GnRH). The SCI was induced by compression. One day after the lesion, SCI + GnRH group was injected with GnRH (60 µg/kg/twice/day; i.m.) for 15 days and the other groups with saline solution. To kinematic gait analysis, length and velocity of the stride were measured. In spinal cord, axonal morphometry and spared white and gray matter were analyzed by histochemistry. Protein expression of spinophilin was evaluated by western blot. The results showed that, 5 weeks after the injury, the group of animals treated with GnRH, significantly increased the length and velocity of the stride compared to SCI + SS group and they were similar to Sham group. In spinal cord, GnRH treatment increased the number and caliber of nerve axons and in the case of white matter, spared tissue was significantly higher than those animals treated with saline solution. The expression of spinophilin in spinal cord of SCI + GnRH group was slightly increased with respect to those not treated. In conclusion, GnRH treatment improves recovery of gait and decreases histopathological damage in the injured spinal cord of rat. These findings suggest that GnRH acts as a neurotrophic factor and can be used as a potential therapeutic agent for treatment of SCI.

  9. Effect of chromium on carbohydrate and lipid metabolism in a rat model of type 2 diabetes mellitus: the fat-fed, streptozotocin-treated rat.

    PubMed

    Sahin, Kazim; Onderci, Muhittin; Tuzcu, Mehmet; Ustundag, Bilal; Cikim, Gurkan; Ozercan, Ibrahim H; Sriramoju, Vidyasagar; Juturu, Vijaya; Komorowski, James R

    2007-09-01

    Chromium supplements are widely used as an alternative remedy for type 2 diabetes mellitus (T2DM). In vitro study findings show that chromium picolinate (CrPic) may improve insulin sensitivity by enhancing intracellular insulin receptor. In this study, we evaluated the metabolic effects of CrPic in a rat model of T2DM. Male Sprague-Dawley rats (n = 45, 8 weeks old) were divided into 3 groups. The controls (group I) received a standard diet (12% of calories as fat); group II received a high-fat diet (HFD; 40% of calories as fat) for 2 weeks and then were intraperitoneally injected with streptozotocin (STZ, 40 mg/kg; HFD/STZ) on day 14; group III rats were given group II diets with the addition of 80 microg CrPic per kilogram body weight per day. The addition of CrPic in the group III treatment lowered glucose by an average of 63% (P < .001), total cholesterol by 9.7% (P < .001), and triglycerides by 6.6% (P < .001) compared with group II treatment. Compared with group II, CrPic treatment also lowered free fatty acid levels by 24% (P < .001), blood urea by 33% (P < .05), and creatinine level by 25% (P < .01), and reduced the severity of glomerular sclerosis (P < .0001). Histopathologic findings suggest that the CrPic-treated group had normal renal tubular appearance compared with the HFD/STZ-treated group. Normal appearance of hepatocytes was observed in the CrPic-treated group. These results showed that CrPic has marked beneficial effects against microvascular complications. In conclusion, HFD/STZ rats provide a novel animal model for T2DM. Further treatment with CrPic for 10 weeks significantly ameliorated changes in metabolic risk factors including favorable changes in histopathology of the liver, kidney, and pancreas, suggesting its potential role in the management of diabetes.

  10. 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

  11. Azithromycin, rifabutin, and rifapentine for treatment and prophylaxis of Mycobacterium avium complex in rats treated with cyclosporine.

    PubMed Central

    Brown, S T; Edwards, F F; Bernard, E M; Tong, W; Armstrong, D

    1993-01-01

    Azithromycin, rifabutin, and rifapentine were used to treat or prevent disseminated Mycobacterium avium complex (MAC) infections produced in rats immunosuppressed with cyclosporine. Animals with bacteremic infections were treated 1 week after intravenous inoculation with 10(7) CFU of MAC with azithromycin, 100 mg/kg of body weight administered subcutaneously for 5 days and then 75 mg/kg on Monday, Wednesday, and Friday, or with rifabutin or rifapentine, 20 mg/kg administered intraperitoneally on Monday through Friday. All three drugs showed efficacy after 1 and 2 months. Rifabutin cleared the organisms from tissues more rapidly than azithromycin or rifapentine. To approximate prophylaxis, treatment was started 2 weeks before intravenous inoculation with 10(4) organisms. MAC infections were undetectable in treated animals after 4 months, while control animals had disseminated infections. These findings support the rationale for clinical trials of treatment and prophylaxis with these agents. The cyclosporine-treated rat appears to be a useful model in which to evaluate compounds for the treatment and prophylaxis of disseminated MAC infections. PMID:8384809

  12. Hydrophilic interaction chromatography-mass spectrometry for anionic metabolic profiling of urine from antibiotic-treated rats.

    PubMed

    Kok, Miranda G M; Swann, Jonathan R; Wilson, Ian D; Somsen, Govert W; de Jong, Gerhardus J

    2014-04-01

    Hydrophilic interaction chromatography-mass spectrometry (HILIC-MS) was used for anionic metabolic profiling of urine from antibiotic-treated rats to study microbial-host co-metabolism. Rats were treated with the antibiotics penicillin G and streptomycin sulfate for four or eight days and compared to a control group. Urine samples were collected at day zero, four and eight, and analyzed by HILIC-MS. Multivariate data analysis was applied to the urinary metabolic profiles to identify biochemical variation between the treatment groups. Principal component analysis found a clear distinction between those animals receiving antibiotics and the control animals, with twenty-nine discriminatory compounds of which twenty were down-regulated and nine up-regulated upon treatment. In the treatment group receiving antibiotics for four days, a recovery effect was observed for seven compounds after cessation of antibiotic administration. Thirteen discriminatory compounds could be putatively identified based on their accurate mass, including aconitic acid, benzenediol sulfate, ferulic acid sulfate, hippuric acid, indoxyl sulfate, penicillin G, phenol and vanillin 4-sulfate. The rat urine samples had previously been analyzed by capillary electrophoresis (CE) with MS detection and proton nuclear magnetic resonance ((1)H NMR) spectroscopy. Using CE-MS and (1)H NMR spectroscopy seventeen and twenty-five discriminatory compounds were found, respectively. Both hippuric acid and indoxyl sulfate were detected across all three platforms. Additionally, eight compounds were observed with both HILIC-MS and CE-MS. Overall, HILIC-MS appears to be highly complementary to CE-MS and (1)H NMR spectroscopy, identifying additional compounds that discriminate the urine samples from antibiotic-treated and control rats.

  13. Inhibition of in vitro human chorionic gonadotropin-stimulated testosterone production in testis and of ovulation in the rat by charcoal-treated rat testicular extract

    SciTech Connect

    de Bellabarba, G.A.; Bishop, W.; Rojas, F.J.

    1984-01-16

    Previously, the authors described the presence of a factor obtained from rat testis that was found to inhibit human chorionic gonadotropin (hCG) binding to gonadal receptors. In the present study, similarly prepared testicular extract was tested for its effects on in vitro hCG-stimulated testosterone production by isolated testis interstitial cells and for its effect on spontaneous ovulation in the rat. Incubation of interstitial cells with charcoal-treated extract significantly inhibited the steroidogenic response to hCG in a dose-related manner. This inhibition was also apparent after heating the extract for 10 min at 100/sup 0/C. A single i.p. injection of testicular extract inhibited spontaneous ovulation in the rat. This effect was also observed after heating the extract for 10 min at 100/sup 0/C. It is concluded that the aqueous testicular extract contains a factor able to antagonize the physiological events mediated by luteinizing hormone (LH)/hCG, and that this factor is consistent with the presence of an LH/hCG-binding inhibitory activity in rat testis.

  14. Limitation of adipose tissue enlargement in rats chronically treated with semicarbazide-sensitive amine oxidase and monoamine oxidase inhibitors.

    PubMed

    Carpéné, C; Abello, V; Iffiú-Soltész, Z; Mercier, N; Fève, Bruno; Valet, P

    2008-06-01

    Inhibition of semicarbazide-sensitive amine oxidases (SSAO) and monoamine oxidases (MAO) reduces fat deposition in obese rodents: chronic administration of the SSAO-inhibitor semicarbazide (S) in combination with pargyline (MAO-inhibitor) has been shown to reduce body weight gain in obese Zucker rats, while (E)-2-(4-fluorophenethyl)-3-fluoroallylamine, an SSAO- and MAO-B inhibitor, has been reported to limit weight gain in obese and diabetic mice. Our aim was to state whether such weight gain limitation could occur in non-obese, non-diabetic rats and to extend these observations to other amine oxidase inhibitors. Prolonged treatment of non-obese rats with a high dose of S (900 micromol kg(-1) day(-1)) reduced body weight gain and limited white adipose tissue enlargement. When chronically administered at a threefold lower dose, S also inhibited SSAO activity but not fat depot enlargement, suggesting that effects other than SSAO inhibition were involved in adipose tissue growth retardation. However, combined treatment of this lower dose of S with pargyline inhibited SSAO, MAO, energy intake, weight gain and fat deposition. Adipocytes from treated rats exhibited unchanged insulin responsiveness but impaired antilipolytic responses to amine oxidase substrates. Phenelzine clearly inhibited both MAO and SSAO when tested on adipocytes. Obese rats receiving phenelzine i.p. at 17 micromol kg(-1) day(-1) for 3 weeks, exhibited blunted MAO and SSAO activities in any tested tissue, diminished body weight gain and reduced intra-abdominal adipose tissue. Their adipocytes were less responsive to lipogenesis activation by tyramine or benzylamine. These observations suggest that SSAO inhibition is not sufficient to impair fat deposition. However, combined MAO and SSAO inhibition limits adiposity in non-obese as well as in obese rats.

  15. 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.

  16. Fixed-ratio discrimination training as replacement therapy in Parkinson's disease: studies in a 6-hydroxydopamine-treated rat model.

    PubMed

    Van Keuren, K R; Stodgell, C J; Schroeder, S R; Tessel, R E

    1998-01-05

    Severe 6-hydroxydopamine (6-OHDA)-induced neostriatal dopamine (DA) depletion is generally held to be irreversible. Adult rats administered 6-OHDA soon after weaning, or neonatally, respectively model Parkinson's disease (PD) and Lesch-Nyhan syndrome (LNS). Prior studies in our laboratory indicate that prolonged training on incrementally more difficult fixed-ratio (FR) discriminations can reverse 'irreversible' 6-OHDA-induced neostriatal DA depletion in adult LNS rats. The present study evaluated the effects of such training on neostriatal DA depletion and its functional consequences in adult PD and control (vehicle-injected) rats. After recovery from 6-OHDA-induced hypophagia, rats were sacrificed to assess neostriatal DA depletion magnitude, or were food-deprived and either subjected to food-maintained operant FR discrimination training or allowed to remain in their home cages. 6-OHDA treatment antagonized amphetamine (AMP)-induced increases in brief rearing behavior and locomotor activity in 3-month-old PD rats prior to training, and reduced operant response rates throughout training without affecting learning rates. One week after training, AMP-increased locomotor and brief-rearing frequencies were augmented in all groups except trained controls, and the prior inhibitory effect of 6-OHDA treatment on AMP-increased behavioral frequencies was essentially eliminated. Cumulative apomorphine (APO) dose-effect curve (0.1-3.2 mg/kg) construction 3 weeks post-training revealed that 6-OHDA treatment abolished APO-induced intense licking behavior. However, training eliminated the hyperresponsiveness of 6-OHDA-treated rats to the locomotor- and brief-rearing stimulant effects of APO but did not affect the depletion of neostriatal DA. Nevertheless, 6-OHDA-induced increases in neostriatal DOPAC/DA and HVA/DA ratios were normalized by age/food-deprivation while that of 3MT/DA was not. These findings suggest that training reduces the functional responsiveness of at least some

  17. NMR-based plasma metabolomic discrimination for male fertility assessment of rats treated with Eurycoma longifolia extracts.

    PubMed

    Ebrahimi, Forough; Ibrahim, Baharudin; Teh, Chin-Hoe; Murugaiyah, Vikneswaran; Chan, Kit-Lam

    2017-03-17

    Male infertility is one of the leading causes of infertility which affects many couples worldwide. Semen analysis is a routine examination of male fertility status which is usually performed on semen samples obtained through masturbation that may be inconvenient to patients. Eurycoma longifolia (Tongkat Ali, TA), native to Malaysia, has been traditionally used as a remedy to boost male fertility. In our recent studies in rats, upon the administration of high-quassinoid content extracts of TA including TA water (TAW), quassinoid-rich TA (TAQR) extracts, and a low-quassinoid content extract including quassinoid-poor TA (TAQP) extract, sperm count (SC) increased in TAW- and TAQR-treated rats when compared to the TAQP-treated and control groups. Consequently, the rats were divided into normal- (control and TAQP-treated) and high- (TAW- and TAQR-treated) SC groups [Ebrahimi et al. 2016]. Post-treatment rat plasma was collected. An optimized plasma sample preparation method was developed with respect to the internal standards sodium 3- (trimethylsilyl) propionate- 2,2,3,3- d4 (TSP) and deuterated 4-dimethyl-4-silapentane-1-ammonium trifluoroacetate (DSA). Carr-Purcell-Meibum-Gill (CPMG) experiments combined with orthogonal partial least squares discriminant analysis (OPLS-DA) was employed to evaluate plasma metabolomic changes in normal- and high-SC rats. The potential biomarkers associated with SC increase were investigated to assess fertility by capturing the metabolomic profile of plasma. DSA was selected as the optimized internal standard for plasma analysis due to its significantly smaller half-height line width (W h/2) compared to that of TSP. The validated OPLS-DA model clearly discriminated the CPMG profiles in regard to the SC level. Plasma profiles of the high-SC group contained higher levels of alanine, lactate, and histidine, while ethanol concentration was significantly higher in the normal-SC group. This approach might be a new alternative applicable to the

  18. Fermented milk containing Lactobacillus paracasei subsp. paracasei CNCM I-1518 reduces bacterial translocation in rats treated with carbon tetrachloride.

    PubMed

    Sánchez, Elisabet; Nieto, Juan C; Vidal, Silvia; Santiago, Alba; Martinez, Xavier; Sancho, Francesc J; Sancho-Bru, Pau; Mirelis, Beatriz; Corominola, Helena; Juárez, Candido; Manichanh, Chaysavanh; Guarner, Carlos; Soriano, German

    2017-04-03

    Probiotics can prevent pathological bacterial translocation by modulating intestinal microbiota and improving the gut barrier. The aim was to evaluate the effect of a fermented milk containing Lactobacillus paracasei subsp. paracasei CNCM I-1518 on bacterial translocation in rats with carbon tetrachloride (CCl4)-induced cirrhosis. Sprague-Dawley rats treated with CCl4 were randomized into a probiotic group that received fermented milk containing Lactobacillus paracasei subsp. paracasei CNCM I-1518 in drinking water or a water group that received water only. Laparotomy was performed one week after ascites development. We evaluated bacterial translocation, intestinal microbiota, the intestinal barrier and cytokines in mesenteric lymph nodes and serum. Bacterial translocation decreased and gut dysbiosis improved in the probiotic group compared to the water group. The ileal β-defensin-1 concentration was higher and ileal malondialdehyde levels were lower in the probiotic group than in water group. There were no differences between groups in serum cytokines but TNF-α levels in mesenteric lymph nodes were lower in the probiotic group than in the water group. Fermented milk containing Lactobacillus paracasei subsp. paracasei CNCM I-1518 decreases bacterial translocation, gut dysbiosis and ileal oxidative damage and increases ileal β-defensin-1 expression in rats treated with CCl4, suggesting an improvement in the intestinal barrier integrity.

  19. 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.

  20. 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.

  1. Fermented milk containing Lactobacillus paracasei subsp. paracasei CNCM I-1518 reduces bacterial translocation in rats treated with carbon tetrachloride

    PubMed Central

    Sánchez, Elisabet; Nieto, Juan C.; Vidal, Silvia; Santiago, Alba; Martinez, Xavier; Sancho, Francesc J.; Sancho-Bru, Pau; Mirelis, Beatriz; Corominola, Helena; Juárez, Candido; Manichanh, Chaysavanh; Guarner, Carlos; Soriano, German

    2017-01-01

    Probiotics can prevent pathological bacterial translocation by modulating intestinal microbiota and improving the gut barrier. The aim was to evaluate the effect of a fermented milk containing Lactobacillus paracasei subsp. paracasei CNCM I-1518 on bacterial translocation in rats with carbon tetrachloride (CCl4)-induced cirrhosis. Sprague-Dawley rats treated with CCl4 were randomized into a probiotic group that received fermented milk containing Lactobacillus paracasei subsp. paracasei CNCM I-1518 in drinking water or a water group that received water only. Laparotomy was performed one week after ascites development. We evaluated bacterial translocation, intestinal microbiota, the intestinal barrier and cytokines in mesenteric lymph nodes and serum. Bacterial translocation decreased and gut dysbiosis improved in the probiotic group compared to the water group. The ileal β-defensin-1 concentration was higher and ileal malondialdehyde levels were lower in the probiotic group than in water group. There were no differences between groups in serum cytokines but TNF-α levels in mesenteric lymph nodes were lower in the probiotic group than in the water group. Fermented milk containing Lactobacillus paracasei subsp. paracasei CNCM I-1518 decreases bacterial translocation, gut dysbiosis and ileal oxidative damage and increases ileal β-defensin-1 expression in rats treated with CCl4, suggesting an improvement in the intestinal barrier integrity. PMID:28368023

  2. 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.

  3. 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

  4. 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.

  5. High dose of green tea infusion normalized spiral artery density in rats treated with the depot-medroxyprogesterone acetate

    PubMed Central

    Emilda, A S; Veri, Nora; Alchalidi, Alchalidi

    2017-01-01

    Aim: The purpose of this study was to investigate the effects of green tea (GT) on the spiral artery density and endometrial thickness in female rats treated with the depot-medroxyprogesterone acetate (DMPA). Material and Methods: A total of 24 female rats were randomly divided into four groups (n = 6 each): The control group (no treatment), the DMPA-treated group, treated with DMPA and GT doses of 165 mg/kg of body weight/day, and treated with DMPA and GT doses of 330 mg/kg of body weight/day. Spiral artery density and endometrial thickness were subjected to histopathological analysis. Results: Spiral artery density decreased in the DMPA-treated group, despite the insignificant difference (P > 0.05). With regard to the administration of GT at doses of 165 and 330 mg/g of body weight/day, only GT at the high dose was capable of significantly preventing a decrease in spiral artery density (P < 0.05). At this dose, the spiral arteries achieved a density comparable to that of the control group (P > 0.05). Meanwhile, the administration of DMPA and/or DMPA with GT did not cause significant changes in endometrial thickness relative to the control group (P > 0.05). Conclusions: DMPA induced a decrease in spiral artery density, despite the insignificant differences, and these changes could be normalized by the administration of high doses of GT. Therefore, GT could be a candidate herb to prevent the adverse effects of the contraceptive DMPA. PMID:28163962

  6. Inflammation and hyperalgesia in rats neonatally treated with capsaicin: effects on two classes of nociceptive neurons in the superficial dorsal horn.

    PubMed

    Ren, K; Williams, G M; Ruda, M A; Dubner, R

    1994-11-01

    To address the mechanisms of hyperalgesia and dorsal horn plasticity following peripheral tissue inflammation, the effects of adjuvant-induced inflammation of the rat hindpaw on behavioral nociception and nociceptive neuronal activity in the superficial dorsal horn were examined in neonatally capsaicin-treated rats 6-8 weeks of age. Capsaicin treatment resulted in an 82% loss of unmyelinated fibers in L5 dorsal roots, a dramatic reduction of substance P-like immunoreactivity in the spinal cord, and a significant decrease in the percentage of dorsal horn nociceptive neurons that responded to C-fiber stimulation and noxious heating of the skin. The thermal nociceptive threshold was significantly increased in capsaicin-treated rats, but behavioral hyperalgesia to thermal stimuli still developed in response to inflammation. Following inflammation, there was a significant decrease in mechanical threshold and an increase in response duration to mechanical stimuli in both vehicle- and capsaicin-treated rats, suggesting that a state of mechanical hyperalgesia was also induced. The capsaicin treatment appears to have differential effects on nociceptive specific (NS) and wide-dynamic-range (WDR) neurons in inflamed rats. Expansion of the receptive fields of nociceptive neurons, a measure of the effect of inflammation-induced CNS plasticity, was less extensive for NS than for WDR neurons in capsaicin-treated rats. Compared to vehicle-treated rats, a smaller population of NS neurons, but a similar percentage of WDR neurons, had background activity in inflamed capsaicin-treated rats. C-fiber strength electrical stimulation of the sciatic nerve produced expansion of the receptive fields in a greater portion of NS neurons (53%, P < 0.05) in capsaicin- than in vehicle-treated rats (32%). There was no difference in stimulation-induced expansion of the receptive fields for WDR neurons between vehicle- or capsaicin-treated rats. An N-methyl-D-aspartate receptor antagonist, MK-801

  7. Prolongation of rat heart allografts by donor-specific blood transfusion treated with ultraviolet irradiation

    SciTech Connect

    Oluwole, S.F.; Iga, C.; Lau, H.; Hardy, M.A.

    1985-07-01

    The effect of donor-specific blood transfusion was compared to that of UVB-irradiated donor-specific blood transfusion on heart allograft survival in inbred rats with major histocompatibility differences. In one series ACI rats received heterotopic heart grafts from Lewis rats and 1 mL transfusion of donor-type blood at 1, 2, and 3 weeks prior to the transplantation. Fifty percent of the grafts were permanently accepted (survival greater than 200 days). Following UVB-irradiated donor-specific blood transfusion, 55% of the grafts survived indefinitely. In a mixed lymphocyte reaction ACI lymphocytes are weak responders to Lewis lymphocytes. In another series, Lewis rats received ACI hearts. Donor-specific transfusions at 1, 2, and 3 weeks prior to transplantation did not significantly alter the survival of heart allografts. Lewis lymphocytes react strongly to ACI stimulator cells in a mixed lymphocyte reaction. However, when the donor blood was UVB-irradiated prior to transfusion, the ACI allograft survival was significantly prolonged in this ACI-to-Lewis strain combination. When Lewis rats received W/F hearts following either donor-specific or UVB-irradiated donor-specific transfusions, the hearts' survival was similarly and significantly prolonged, but did not become permanent. Mixed lymphocyte reaction reveals that the stimulation index of Lewis lymphocytes against W/F lymphocytes is greater than that of ACI versus Lewis, but is less than that between Lewis responder cells against ACI stimulators.

  8. 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

  9. 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.

  10. Aged garlic extract ameliorates immunotoxicity, hematotoxicity and impaired burn-healing in malathion- and carbaryl-treated male albino rats.

    PubMed

    Ramadan, Gamal; El-Beih, Nadia M; Ahmed, Rehab S A

    2017-03-01

    Malathion and carbaryl are the most widely used organophosphate and carbamate insecticides, respectively, especially in developing countries; they pose a potential health hazard for both humans and animals. Here, we evaluated the protective effects of an odorless (free from allicin) Kyolic aged garlic extract (AGE, containing 0.1% S-allylcysteine; 200 mg/kg body weight) on the toxicity induced by 0.1 LD50 of malathion (89.5 mg/kg body weight) and/or carbaryl (33.9 mg/kg body weight) in male Wistar rats. Doses were orally administered to animals for four consecutive weeks. The present study showed that AGE completely modulated most adverse effects induced by malathion and/or carbaryl in rats including the normocytic normochromic anemia, immunosuppression, and the delay in the skin-burning healing process through normalizing the count of blood cells (erythrocytes, leucocytes and platelets), hemoglobin content, hematocrit value, blood glucose-6-phosphodehydrogenase activity, weights and cellularity of lymphoid organs, serum γ-globulin concentration, and the delayed type of hypersensitivity response to the control values, and accelerating the inflammatory and proliferative phases of burn-healing. In addition, AGE completely modulated the decrease in serum reduced glutathione (GSH) concentration and the increase in clotting time in malathion alone and carbaryl alone treated rats. Moreover, AGE induced a significant increase (P < 0.001) in serum GSH concentration (above the normal value) and accelerating burn-healing process in healthy rats. In conclusion, AGE was effective in modulating most adverse effects induced in rats by malathion and carbaryl, and hence may be useful as a dietary adjunct for alleviating the toxicity in highly vulnerable people to insecticides intoxication. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 789-798, 2017.

  11. Evaluation of Glycemic and Lipid Profile of Offspring of Diabetic Wistar Rats Treated with Malpighia emarginata Juice

    PubMed Central

    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. PMID:21318139

  12. 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.

  13. 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.

  14. Effect of X-radiation on lipid peroxidation and antioxidant systems in rats treated with saponin-containing compounds.

    PubMed

    Yalinkilic, Omer; Enginar, Huseyin

    2008-01-01

    The aim of this study was to investigate the effect of three saponin-containing plant species extracts (Aesculuc hippocastanum L. seed extract [AHE], Medicago sativa L. extract [MSE] and Spinacia oleracea L. extract [SOE]) on lipid peroxidation and on antioxidant systems in rats exposed to X-rays (XR). The rats were divided into three categories. The first category served as controls and received only a standard diet. The second category served as the radiation group and received 5 and 10 Gy XR dose. The third category (XR+extract-treated) received plant extracts (25.0 or 50.0 mg kg(-1) live weight) and 5 or 10 Gy XR dose. Blood samples were analyzed for their content of malondialdehyde (MDA), reduced glutathione (GSH), plasma vitamin C, beta-carotene and retinol. In animals receiving XR, the plasma MDA (P < 0.001) value significantly increased but the level of GSH (P < 0.01), vitamin C (P < 0.001), retinol and beta-carotene (P < 0.001) decreased significantly with increasing XR doses. In the XR+extract-treated groups, the concentrations of MDA increased significantly with increasing radiation but their concentrations decreased significantly with increasing extract concentrations. Plasma concentrations of GSH, beta-carotene, retinol and vitamin C in XR+extract-treated groups decreased significantly with increasing XR dose but their concentrations increased with increasing extract doses. Further, comparison of blood samples of XR+extract-treated groups with those from the control group showed that GSH, beta-carotene, retinol and vitamin C values increased significantly but that MDA values decreased significantly. The results showed that all extracts have enhanced the antioxidant status and decreased the incidence of free radical-induced lipid peroxidation in blood samples of rats exposed to XR. However, the antioxidant effect of AHE-administered animals was more effective than that of MSE- and SOE-administered whole-body XR rats. We conclude that the supplementation

  15. 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

    2016-09-05

    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.

  16. A Rat Model of Sytemic Chemotherapy for Breast Cancer to Evaluate and Treat Chemobrain

    DTIC Science & Technology

    2007-09-01

    and under approval from the USAMRMC Animal Care and Use Review Office (ACURO). Female Sprague-Dawley rats (11-21 weeks old, 200 - 300 g) were...combination CMF or CAF at 65/6.5/65 mg/kg i.p. to Sprague- Dawley females aged 80-150 days and weighing 170-300 grams. These doses were scaled to human...monitor the wellbeing of the animals, weight gain and loss were by far the most informative indicators of overall animal health . As depicted, rats

  17. Effect of increased calcium intake on cardiac and vascular Na(+)-K(+)-ATPase activity in oral contraceptive-treated female Sprague-Dawley rats.

    PubMed

    Olatunji, L A; Soladoye, A O

    2006-11-01

    The present study aimed at investigating the influence of increased dietary calcium on Na(+)-K(+)-ATPase activity in heart and aorta of female Sprague-Dawley rats treated with oral contraceptive (OC) steroids. Rats were grouped as control (CR), OC-treated and OC+calcium-treated. OC-treated and OC+calcium-treated received a combination of OC steriods (ethinyloestradiol and norgestrel; ig). OC+calcium-treated rats were fed with 2.5% calcium diet, while OC-treated and CR groups were fed on 0.9% calcium diet. The activity of Na(+)-K(+)-ATPase in heart and aorta was significantly lower in OC-treated rats than those in the other groups. OC treatment caused significant increase in plasma glucose and significant decrease in plasma K+ as compared to control group. Decrease in Na(+)-K(+)-ATPase activity and plasma K+ was abrogated by increased calcium intake, while increase in plasma glucose was not normalized by calcium supplementation. Plasma levels of Na+, lipid peroxidation index and ascorbic acid were comparable among the three groups. These results showed that OC treatment could lead to impaired activity of cardiac and vascular Na(+)-K(+)-ATPase, possibly due to reduced plasma K+ level and these effects could be abolished by high calcium diet.

  18. 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...

  19. Modulatory effects of Aloe vera leaf gel extract on oxidative stress in rats treated with streptozotocin.

    PubMed

    Rajasekaran, S; Sivagnanam, K; Subramanian, S

    2005-02-01

    Oxidative stress is currently suggested as a mechanism underlying diabetes and diabetic-related complications. Oxidative stress results from an imbalance between radical-generating and radical-scavenging systems. Many secondary plant metabolites have been reported to possess antioxidant activity. This study was designed to evaluate the potential antioxidative activity of the ethanolic extract from Aloe vera leaf gel in the plasma and pancreas of streptozotocin (STZ)-induced diabetic rats. Glibenclamide was used as a standard reference drug. Oral administration of ethanolic extract at a concentration of 300 mg kg(-1) body weight for 21 days resulted in a significant reduction in fasting blood glucose, thiobarbituric acid reactive substances, hydroperoxides and alpha-tocopherol and significant improvement in ascorbic acid, reduced glutathione and insulin in the plasma of diabetic rats. Similarly, the treatment also resulted in a significant reduction in thiobarbituric acid reactive substances, hydroperoxides, superoxide dismutase, catalase and glutathione peroxidase and significant improvement in reduced glutathione in the pancreas of STZ-induced diabetic rats when compared with untreated diabetic rats. The ethanolic extract appeared to be more effective than glibenclamide in controlling oxidative stress. Thus, this study confirms the ethnopharmacological use of Aloe vera in ameliorating the oxidative stress found in diabetes.

  20. Anti-tumor effects of cimetidine on hepatocellular carcinomas in diethylnitrosamine-treated rats.

    PubMed

    Furuta, Koichiro; Sato, Shuichi; Miyake, Tatsuya; Okamoto, Eisuke; Ishine, Junichi; Ishihara, Shunji; Amano, Yuji; Adachi, Kyoichi; Kinoshita, Yoshikazu

    2008-02-01

    Cimetidine is known to have an anti-tumor effect on certain types of malignancies, though on hepatocellular carcinomas (HCCs), its effect remains unclear. We studied the anti-tumor effects of cimetidine on chemically-induced HCCs in rats. Four-week-old male Wistar rats (n=105) were divided into 4 groups. Those in groups A and B were administered diethylnitrosamine (DEN) intraperitoneally at 100 mg/kg body weight every week for 6 weeks, during which rats in group A were given tap water and those in group B received cimetidine (100 mg/kg/day) in their drinking water. Rats in groups C and D were administered saline instead of DEN and given tap water with 100 mg/kg/day of cimetidine, respectively. The animals were sacrificed at 7, 12, 22 and 32 weeks after the first administration of drugs and examined. Liver nodules were observed only in groups A and B, with the number of nodules, maximum diameter of the largest nodule, and liver weight significantly lower in group B. Immunohistochemistry findings showed that glutathione S-transferase placental-positive preneoplastic foci were significantly decreased in group B. Cimetidine treatment decreased the number of proliferating cell nuclear antigen-positive hepatocytes and tended to enhance natural killer (NK) cell activity in splenic lymphocytes. In addition, flow cytometry revealed that the proportion of NK cells among total splenic lymphocytes was not affected by cimetidine treatment. Our results showed that cimetidine has an inhibiting effect on hepatocarcinogenesis.

  1. 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...

  2. Messenger RNA patterns in rat liver nuclei before and after treat-ment with growth hormone.

    PubMed

    Drews, J; Brawerman, G

    1967-06-09

    Like cortisol, growth hormone enhances RNA synthesis in rat liver nuclei. However, DNA-RNA hybridization experiments show that the application of growth hormone does not stimulate the formation of new species of messenger RNA. The latter phenomenon was observed after treatment with cortisol.

  3. Studies of nuclei separated by zonal centrifugation from liver of rats treated with thioacetamide

    PubMed Central

    Gonzalez-Mujica, F.; Mathias, A. P.

    1973-01-01

    1. The effects of the inclusion of thioacetamide in the diet on the properties of rat liver nuclei were studied both in adolescent rats, in which the parenchymal cells contain diploid nuclei, and in young adult rats, with a high proportion of tetraploid nuclei. 2. These investigations included a survey of the sedimentation properties of the nuclei, the nuclear volumes, content of DNA, RNA and protein, the incorporation in vivo of [3H]thymidine into DNA and [14C]orotate into RNA, and measurements of the activity of RNA polymerase and ribonuclease. These studies were conducted on nuclei fractionated by zonal centrifugation. 3. In both groups of animals, exposure to thioacetamide produced large numbers of nuclei that were abnormal in their chemical composition and enzymic activity. The changes were complex as regards both the types of nuclei that were affected and in their variation with time. 4. In adolescent rats two waves of synthesis of DNA and RNA were observed, one at 3 days and the other after 2 weeks of treatment. The first decline in the incorporations into both DNA and RNA coincided with a decrease in the pool sizes of some of the precursors. The activity of RNA polymerase was not substantially altered. A marked increase in the content of protein was observed before the first wave of synthesis. The normal progressive increase in tetraploid nuclei was prevented. 5. In young adult rats two waves of DNA synthesis were detected. Each was preceded by a large increase in the amount of protein per nucleus but was not accompanied by increased RNA synthesis. After 4 weeks of treatment, the diploid stromal nuclei appeared mainly unaffected and large numbers of tetraploid nuclei with a greatly increased quantity of protein were observed. PMID:4353443

  4. 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.

  5. 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.

  6. 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

    2016-05-05

    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.

  7. 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

  8. 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

  9. 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

  10. 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

  11. Conditioned place preference and locomotor sensitization after repeated administration of cocaine or methamphetamine in rats treated with epidermal growth factor during the neonatal period.

    PubMed

    Mizuno, Makoto; Malta, Romulo S; Nagano, Tadasato; Nawa, Hiroyuki

    2004-10-01

    Epidermal growth factor (EGF) and its structurally related proteins are involved in the developmental regulation of various brain neurons, including midbrain dopaminergic neurons. We recently reported EGF and EGF-receptor abnormalities in both the brain tissues and blood of schizophrenic patients. Administration of EGF to neonatal rats transiently increases tyrosine hydroxylase expression and subsequently results in behavioral abnormalities in prepulse inhibition of acoustic startle, locomotor activity, and social interaction after development. The enhanced locomotor and stereotypic responses of the neonatally EGF-treated rats are considered to be an animal model for positive schizophrenia symptoms. In the present study, we investigated psychostimulant sensitivity of neonatally EGF-treated rats. At the adult stage, EGF-treated rats were challenged with cocaine (15 mg/kg) or methamphetamine (1 mg/kg), and conditioned place preference and locomotor activity were examined. The rats that received EGF during the neonatal period had significantly higher conditioned place preference for where cocaine or methamphetamine was administered than controls. The neonatal EGF treatment enhanced behavioral response to methamphetamine and behavioral sensitization to cocaine at the adult stage. Drug-naive controls gradually increased locomotor responses to cocaine during their daily injections, whereas EGF-treated rats exhibited a larger increase in cocaine responses. These results indicate that overactivation of the EGF receptors (ErbB1) during the neonatal period influences future sensitivity to psychostimulants. Our findings indicate a potential link between EGF-receptor activation and drug addiction.

  12. Time course of disassociation of bone formation signals with bone mass and bone strength in sclerostin antibody treated ovariectomized rats.

    PubMed

    Ma, Yanfei L; Hamang, Matthew; Lucchesi, Jonathan; Bivi, Nicoletta; Zeng, Qianqiang; Adrian, Mary D; Raines, Sarah E; Li, Jiliang; Kuhstoss, Stuart A; Obungu, Victor; Bryant, Henry U; Krishnan, Venkatesh

    2017-04-01

    Sclerostin antibodies increase bone mass by stimulating bone formation. However, human and animal studies show that bone formation increases transiently and returns to pre-treatment level despite ongoing antibody treatment. To understand its mechanism of action, we studied the time course of bone formation, correlating the rate and extent of accrual of bone mass and strength after sclerostin antibody treatment. Ovariectomized (OVX) rats were treated with a sclerostin-antibody (Scle-ab) at 20mg/kg sc once weekly and sacrificed at baseline and 2, 3, 4, 6, and 8weeks post-treatment. In Scle-ab treated rats, serum PINP and OCN rapidly increased at week 1, peaked around week 3, and returned to OVX control levels by week 6. Transcript analyses from the distal femur revealed an early increase in bone formation followed by a sustained decrease in bone resorption genes. Lumbar vertebral (LV) osteoblast surface increased 88% by week 2, and bone formation rate (BFR/BS) increased 138% by week 4. Both parameters were below OVX control by week 8. Bone formation was primarily a result of modeling based formation. Endocortical and periosteal BFR/BS peaked around week 4 at 313% and 585% of OVX control, respectively. BFR/BS then declined but remained higher than OVX control on both surfaces through week 8. Histomorphometric analyses showed LV-BV/TV did not further increase after week 4, while BMD continued to increase at LV, mid femur (MF), and femoral neck (FN) through week 8. Biomechanical tests showed a similar improvement in bone strength through 8weeks in MF and FN, but bone strength plateaued between weeks 6 and 8 for LV. Our data suggest that bone formation with Scle-ab treatment is rapid and modeling formation dominated in OVX rats. Although transient, the bone formation response persists longer in cortical than trabecular bone.

  13. 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

  14. 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

  15. Altered regulation of luteinizing hormone secretion in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated male rats

    SciTech Connect

    Bookstaff, R.C.

    1989-01-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) severely decreases plasma androgen concentrations, yet plasma luteinizing hormone (LH) concentrations remain unchanged. The mechanism by which TCDD prevents the expected compensatory increase in plasma LH was investigated. No effect on the plasma disappearance rate of LH or on pituitary capacity to synthesize or secrete LH was detected. Rather, TCDD altered the regulation of LH secretion by substantially increasing the potency of both androgens and estrogens as feedback inhibitors of LH secretion. The mechanism by which TCDD alters androgen-regulated LH secretion was further investigated. Seven days after dosing, TCDD decreased plasma testosterone concentrations but prevented the expected compensatory increases in pituitary gonadotropin-releasing hormone (GnRH) receptor number, pituitary responsiveness to GnRH, and plasma LH concentrations as seen in similarly hypoandrogenic vehicle dosed rats. Furthermore, the TCDD dose-response relationships for preventing the compensatory increases in pituitary GnRH receptor number and plasma LH concentration were similar. However, in the absence of gonadal steroids (7 days after castration) TCDD did not affect the compensatory increases in pituitary GnRH receptor number, pituitary responsiveness to GnRH, or plasma LH concentration. All of these parameters increased substantially relative to intact TCDD treated rats, and to levels virtually identical to those seen in castrated control rats. Treatment of castrated rats with testosterone restored the ability of TCDD to prevent these compensatory increases. Taken together, these results demonstrate that the presence of androgens is required for TCDD to alter the regulation of pituitary GnRH receptors.

  16. 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.

  17. Ergosteroids: induction of thermogenic enzymes in liver of rats treated with steroids derived from dehydroepiandrosterone.

    PubMed

    Lardy, H; Partridge, B; Kneer, N; Wei, Y

    1995-07-03

    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.

  18. Peripheral body temperature and thermogenic drinking in cold-treated rats.

    PubMed

    Nelson, E L; Fregly, M J; Tyler, P E

    1975-12-01

    Transfer of rats abruptly from air at 5 degrees C to air at 26 degrees C was accompanied by a significant increase in water intake (thermogenic drinking) during the first hour after transfer. A possibility existed that the increased water intake observed under these conditions was attributable to the rapid change in skin temperature. Thus, the objective of this study was to determine the effect on thermogenic drinking of a slow, as opposed to an abrupt, change in ambient temperature. The results indicated that warming room air rates of either 0.5 or 1.0 centigrade deg/min had no effect on thermogenic drinking when compared with the water intake of rats removed abruptly from cold. Thermogenic drinking does not appear to be initiated by a specific pattern of changes in peripheral temperature relative to colonic temperature.

  19. 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

  20. 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

  1. 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

  2. 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

  3. Administration of olanzapine as an antiemetic agent changes glucose homeostasis in cisplatin-treated rats.

    PubMed

    Machida, Maiko; Miyamura, Yuki; Machida, Takuji; Koyama, Kinuko; Iizuka, Kenji; Hirafuji, Masahiko

    2015-01-01

    We investigated the effects of olanzapine on cisplatin-induced pica (the consumption of non-nutrient materials such as kaolin) and glucose homeostasis in rats to clarify the effects of olanzapine when used as an anti-emetic drug. Rats were injected intraperitoneally (i.p.) with either 5 mg/kg cisplatin or saline. Additionally, 2 or 10 mg/kg olanzapine were administered i.p. to the rats 10 min before the administration of cisplatin and subsequently administered every 24 h for 3 d. Kaolin and food intake was measured using an automatic monitoring apparatus. Plasma glucose levels were measured by an enzyme electrode method. The plasma levels of insulin and intact proinsulin were measured by enzyme-linked immunosorbent assay (ELISA). The proinsulin-to-insulin (P/I) ratio was calculated. Cisplatin significantly increased kaolin intake, but decreased food intake and body weight up to 72 h. Olanzapine had no effect on these parameters. Neither olanzapine nor cisplatin alone had a significant effect on the plasma levels of glucose, insulin, or proinsulin. However, a combination of olanzapine and cisplatin significantly decreased plasma insulin levels, but increased plasma intact proinsulin levels and the P/I ratio. Our results suggest that an additive deterioration of insulin-secreting beta-cell function and disturbance of glucose homeostasis should be considered during treatment of patients with olanzapine for cisplatin-induced nausea and vomiting.

  4. Histopathology and cytotoxicity as biomarkers in treated rats with cadmium and some therapeutic agents

    PubMed Central

    El-Refaiy, Amal I.; Eissa, Fawzy I.

    2013-01-01

    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

  5. Behavioral changes and brain energy metabolism dysfunction in rats treated with methamphetamine or dextroamphetamine.

    PubMed

    Feier, Gustavo; Valvassori, Samira S; Lopes-Borges, Jéssica; Varela, Roger B; Bavaresco, Daniela V; Scaini, Giselli; Morais, Meline O; Andersen, Monica L; Streck, Emilio L; Quevedo, João

    2012-11-14

    Studies have demonstrated that AMPHs produce long-term damage to the brain dopaminergic, serotoninergic and glutamatergic regions. Prefrontal cortex, amygdala, hippocampus and striatum appear to be involved in the toxicity and behavioral changes induced by AMPHs. A single dose of AMPH causes mitochondrial dysfunction and oxidative stress in rat brain. The goal of the present study was thus to investigate the potency of two amphetamines, dextroamphetamine (d-AMPH) and methamphetamine (m-AMPH), on the behavior and energetic dysfunction in the brain of rats. d-AMPH and m-AMPH increased the crossing and rearing behaviors. The numbers of visits to the center were increased by d-AMPH and m-AMPH only at 2mg/kg. Likewise, at a high dose (2 mg/kg), the injection of m-AMPH increased the amount of sniffing. The AMPHs significantly decreased the activities of Krebs cycle enzymes (citrate synthase and succinate dehydrogenase) and mitochondrial respiratory chain complexes (I-IV); nevertheless, this effect varied depending on the brain region evaluated. In summary, this study demonstrated that at high doses, m-AMPH, increased stereotyped (sniffing) behavior in rats, but d-AMPH did not. However, this study shows that d-AMPH and m-AMPH seem to have similar effects on the brains energetic metabolism.

  6. 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

  7. Mitochondrial and peroxisomal fatty acid oxidation in liver homogenates and isolated hepatocytes from control and clofibrate-treated rats.

    PubMed

    Mannaerts, G P; Debeer, L J; Thomas, J; De Schepper, P J

    1979-06-10

    Mitochondrial and peroxisomal fatty acid oxidation were compared in whole liver homogenates. Oxidation of 0.2 mM palmitoyl-CoA or oleate by mitochondria increased rapidly with increasing molar substrate:albumin ratios and became saturated at ratios below 3, while peroxisomal oxidation increased more slowly and continued to rise to reach maximal activity in the absence of albumin. Under the latter condition mitochondrial oxidation was severely depressed. In homogenates from normal liver peroxisomal oxidation was lower than mitochondrial oxidation at all ratios tested except when albumin was absent. In contrast with mitochondrial oxidation, peroxisomal oxidation did not produce ketones, was cyanide-insensitive, was not dependent on carnitine, and was not inhibited by (+)-octanoylcarnitine, malonyl-CoA and 4-pentenoate. Mitochondrial oxidation was inhibited by CoASH concentrations that were optimal for peroxisomal oxidation. In the presence of albumin, peroxisomal oxidation was stimulated by Triton X-100 but unaffected by freeze-thawing; both treatments suppressed mitochondrial oxidation. Clofibrate treatment increased mitochondrial and peroxisomal oxidation 2- and 6- to 8-fold, respectively. Peroxisomal oxidation remained unchanged in starvation and diabetes. Fatty acid oxidation was severely depressed by cyanide and (+)-octanoylcarnitine in hepatocytes from normal rats. Hepatocytes from clofibrate-treated rats, which displayed a 3- to 4-fold increase in fatty acid oxidation, were less inhibited by (+)-octanoylcarnitine. Hydrogen peroxide production was severalfold higher in hepatocytes from treated animals oxidizing fatty acids than in control hepatocytes. Assuming that all H2O2 produced during fatty acid oxidation was due to peroxisomal oxidation, it was calculated that the contribution of the peroxisomes to fatty acid oxidation was less than 10% both in cells from control and clofibrate-treated animals.

  8. Identification and Verification of Potential Therapeutic Target Genes in Berberine-Treated Zucker Diabetic Fatty Rats through Bioinformatics Analysis

    PubMed Central

    Bao, Yu-Ting; Li, Zhe-Ming; Zhou, Xiao-Jie; He, Jia-Na; Dai, Shi-Jie; Li, Chang yu

    2016-01-01

    Background Berberine is used to treat diabetes and dyslipidemia. However, the effect of berberine on specific diabetes treatment targets is unknown. In the current study, we investigated the effect of berberine on the random plasma glucose, glycated hemoglobin (HbA1C), AST, ALT, BUN and CREA levels of Zucker diabetic fatty (ZDF) rats, and we identified and verified the importance of potential therapeutic target genes to provide molecular information for further investigation of the mechanisms underlying the anti-diabetic effects of berberine. Methods ZDF rats were randomly divided into control (Con), diabetic (DM) and berberine-treated (300 mg⋅kg−1, BBR) groups. After the ZDF rats were treated with BBR for 12 weeks, its effect on the random plasma glucose and HbA1C levels was evaluated. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), CREA and OGTT were measured from blood, respectively. The levels of gene expression in liver samples were analyzed using an Agilent rat gene expression 4x44K microarray. The differentially expressed genes (DEGs) were screened as those with log2 (Con vs DM) ≥ 1 and log2 (BBR vs DM) ≥ 1 expression levels, which were the genes with up-regulated expression, and those with log2 (Con vs DM) ≤ -1 and log2 (BBR vs DM) ≤ -1 expression levels, which were the genes with down-regulated expression; the changes in gene expression were considered significant at P<0.05. The functions of the DEGs were determined using gene ontology (GO) and pathway analysis. Furthermore, a protein-protein interaction (PPI) network was constructed using STRING and Cytoscape software. The expression levels of the key node genes in the livers of the ZDF rats were also analyzed using qRT-PCR. Results We found that 12 weeks of berberine treatment significantly decreased the random plasma glucose, HbA1C levels and improved glucose tolerance. There was a tendency for berberine to reduce AST, ALT, BUN except increase

  9. A multicenter phase II study of irinotecan in patients with advanced colorectal cancer previously treated with 5-fluorouracil.

    PubMed

    Méndez, Miguel; Salut, Antonieta; García-Girón, Carlos; Navalon, Marta; Diz, Pilar; García López, Maria José; España, Pilar; de la Torre, Ascensión; Martínez del Prado, Purificación; Duarte, Isabel; Pujol, Eduardo; Arizcun, Alberto; Cruz, Juan Jesús

    2003-11-01

    This multicenter, open-label, phase II study was performed to assess the efficacy and toxicity of irinotecan 350 mg/m2 intravenously every 3 weeks in patients with advanced colorectal cancer (CRC) previously treated with 5-fluorouracil (5-FU). The study enrolled 115 patients and a total of 558 cycles (median, 6 per patient) were administered. The overall objective response rate on an intent-to-treat basis was 18% (with 1 complete response and 20 partial responses), whereas 42 patients (37%) showed stable disease. Median time to progression was 4.8 months and median survival was 13.6 months. Grade 3/4 toxicities included delayed diarrhea (19.1%), nausea/vomiting (10.4%), and neutropenia (8.7%). There were 2 toxic deaths, 1 from delayed diarrhea and 1 from hemorrhage and grade 4 mucositis. In conclusion, the present study confirms the antitumor efficacy of irinotecan monotherapy in patients with CRC pretreated with 5-FU.

  10. Lipid peroxidation in the liver of rats treated with V and/or Mg in drinking water.

    PubMed

    Scibior, Agnieszka; Zaporowska, Halina; Niedźwiecka, Irmina

    2009-10-01

    The effect of V(5+) and Mg treatment on spontaneous and stimulated lipid peroxidation (LPO) was studied in liver supernatants obtained from outbred 5-month-old, albino male Wistar rats. The 2-month-old animals daily received deionized water to drink (control, group I); group II - water solution of NaVO(3) (SMV) at a concentration of 0.125 mg V ml(-1); group III - water solution of MgSO(4) (MS) at a concentration of 0.06 mg Mg ml(-1), group IV - water solution of SMV-MS at the same concentrations as in groups II and III for V and Mg, respectively, over a 12-week period. Three metal salts were selected as agents that may modify the LPO process (FeSO(4), NaVO(3) and MgSO(4)). V-intoxicated rats and those treated with V and Mg in combination had higher liver spontaneous malondialdehyde (MDA) formation, compared with the control and Mg-supplemented animals. In the same groups of animals the total antioxidant status (TAS) was also significantly lowered, in comparison with the control. In the supernatants obtained from the above-mentioned groups of rats a significant increase in MDA concentration was found in the presence of exogenous 30 microm FeSO(4) as well as 30, 100, 200 and 400 microm NaVO(3), compared with groups I and III. Significantly elevated MDA production was also observed in the supernatants obtained from the rats exposed to V and Mg in combination in the presence of exogenous 100 and 200 microm MgSO(4) in comparison with the control and group III as well as in the presence of exogenous 400 and 600 microm MgSO(4) compared only with group III. In vitro treatment with 1000 microm MgSO(4 )of control liver supernatants and those obtained from group III significantly enhanced MDA level, compared with spontaneous MDA formation. The two-way ANOVA indicated that the changes in the basal MDA level and in TAS in the rats at combined V and Mg application, were not due to V-Mg interaction, but resulted from independent action of V. In addition, the three-way ANOVA

  11. Investigation of drug-drug interaction via mechanism-based inhibition of cytochrome P450 3A by macrolides in dexamethasone-treated female rats.

    PubMed

    Kanazu, Takushi; Sato, Norihito; Kadono, Kyoko; Touchi, Akira; Takeda, Yuri; Yamaguchi, Yoshitaka; Baba, Takahiko

    2012-05-01

    The in vitro and in vivo inhibition of cytochrome P450 (CYP) 3A with mechanism-based inhibition (MBI) by macrolides was investigated using dexamethasone-treated female rats (DEX-female rats). In the in vitro CYP inhibition studies using erythromycin (ERM) and clarithromycin (CAM), similar inhibition responses were observed between human and DEX-female rat liver microsomes, however, there were fewer effects in intact male rats. The ex vivo study showed that midazolam (MDZ) metabolism in liver microsomes of DEX-female rats was reduced by ERM administration and the inhibitory effect was increased with increasing ERM doses, indicating that metabolite intermediate complex formation caused irreversible inhibition of CYP3A activity in DEX-female rats as well as in humans. In the in vivo studies, ERM and CAM significantly increased the area under the plasma concentration-time curve of MDZ and decreased the total clearance in DEX-female rats. It was concluded that the DDIs via MBI of CYP3A following macrolide administration in humans could be reproduced in female rats, suggesting that DEX-female rats can serve as an in vivo model for assessing this DDI in humans.

  12. 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

  13. 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.

  14. 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.

  15. Biospeciation of tungsten in the serum of diabetic and healthy rats treated with the antidiabetic agent sodium tungstate.

    PubMed

    Gómez-Gómez, M Milagros; Rodríguez-Fariñas, Nuria; Cañas-Montalvo, Benito; Domínguez, Jorge; Guinovart, Joan; Cámara-Rica, Carmen

    2011-05-30

    It is known that oral administration of sodium tungstate preserves the pancreatic beta cell function in diabetic rats. Healthy and streptozotocin-induced diabetic rats were treated with sodium tungstate for one, three or six weeks, after which the species of W in serum, were analysed. An increase in serum W with treatment time was observed. After six weeks, the serum W concentration in diabetic rats (70 mg L(-1)) was about 4.6 times higher than in healthy specimens. This different behaviour was also observed for Cu accumulation, while the Zn pattern follows the contrary. The patterns observed in the retention of Cu and Zn may be attributable to a normalization of glycaemia. The speciation analysis of W was performed using 2D separations, including an immunoaffinity packing and a SEC (Size Exclusion Chromatography) column coupled to an ICP-MS (Inductively Coupled Plasma Mass Spectrometry) for elemental detection. Ultrafiltration data together with SEC-ICP-MS results proved that around 80% of serum W was bound to proteins, the diabetic rats registering a higher W content than their healthy counterparts. Most of the protein-bound W was due to a complex with albumin. An unknown protein with a molecular weight higher than 100 kDa was also found to bind a small amount of W (about 2%). MALDI-TOF (Matrix-Assisted Laser Desorption Ionization Time-of-Flight) analysis of the desalted and concentrated chromatographic fractions confirmed albumin as the main protein bound to tungstate in rat serum, while no binding to transferrin (Tf) was detected. The interaction between glutathione and W was also evaluated using standard solutions; however, the formation of complexes was not observed. The stability of the complexes between W and proteins when subjected to more stringent procedures, like those used in proteomic methodologies (denaturing with urea or SDS, boiling, sonication, acid media, reduction with β-mercaptoethanol (BME) or DTT (dithiotreitol) and alkylation with

  16. Hepatoprotective effects of Nigella sativa L and Urtica dioica L on lipid peroxidation, antioxidant enzyme systems and liver enzymes in carbon tetrachloride-treated rats

    PubMed Central

    Kanter, Mehmet; Coskun, Omer; Budancamanak, Mustafa

    2005-01-01

    AIM: To investigate the effects of Nigella sativa L (NS) and Urtica dioica L (UD) on lipid peroxidation, antioxidant enzyme systems and liver enzymes in CCl4-treated rats. METHODS: Fifty-six healthy male Wistar albino rats were used in this study. The rats were randomly allotted into one of the four experimental groups: A (CCl4-only treated), B (CCl4+UD treated), C (CCl4+NS treated) and D (CCl4+UD+NS treated), each containing 14 animals. All groups received CCl4 (0.8 mL/kg of body weight, sc, twice a week for 60 d). In addition, B, C and D groups also received daily i.p. injections of 0.2 mL/kg NS or/and 2 mL/kg UD oils for 60 d. Group A, on the other hand, received only 2 mL/kg normal saline solution for 60 d. Blood samples for the biochemical analysis were taken by cardiac puncture from randomly chosen-seven rats in each treatment group at beginning and on the 60th d of the experiment. RESULTS: The CCl4 treatment for 60 d increased the lipid peroxidation and liver enzymes, and also decreased the antioxidant enzyme levels. NS or UD treatment (alone or combination) for 60 d decreased the elevated lipid peroxidation and liver enzyme levels and also increased the reduced antioxidant enzyme levels. The weight of rats decreased in group A, and increased in groups B, C and D. CONCLUSION: NS and UD decrease the lipid per-oxidation and liver enzymes, and increase the anti-oxidant defense system activity in the CCl4-treated rats. PMID:16425366

  17. 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.

  18. 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

  19. 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.

  20. 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

  1. Sex differences in catalepsy: evidence for hormone-dependent postural mechanisms in haloperidol-treated rats.

    PubMed

    Field, E F; Whishaw, I Q; Pellis, S M

    2000-05-01

    Catalepsy, a symptom of Parkinson's disease and related disorders can be produced in rats and other laboratory animals by the blockade of nigrostriatal dopamine using dopaminergic antagonists such as haloperidol. When haloperidol-induced cataleptic rats are placed facing downward on an inclined plane, they will brace against the resulting downward force by pushing backwards, and if they lose postural stability, or their position on the inclined plane, they will jump forward. Females, however, jump from the inclined plane at a significantly lower angle than do males. Frame-by-frame analysis of the jumping sequences revealed that females and males use a different combination of postural adjustments to maintain their position on the inclined plane prior to jumping. Furthermore, gonadal hormone manipulations at birth and in adulthood reveal that these sex differences in postural adjustments are dependent on the organizational effects of gonadal hormones in the perinatal period. These results provide evidence for sex differences in postural support mechanisms and suggest that the sex of subjects, or their hormonal state, must be considered when studying the behavioral aspects of neurological disorders such as Parkinson's disease which include a postural component.

  2. 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

  3. 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

  4. 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.

  5. 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.

  6. 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

  7. Insights into the mechanisms mediating hyperglycemic and stressogenic outcomes in rats treated with monocrotophos, an organophosphorus insecticide.

    PubMed

    Joshi, Apurva Kumar Ramesh; Nagaraju, Raju; Rajini, Padmanabhan Sharda

    2012-03-29

    The present investigation provides mechanistic insights into the hyperglycemic and stressogenic effects of monocrotophos, an organophosphorus insecticide. Pre-treatment of rats with mifepristone (glucocorticoid receptor antagonist) prevented induction of liver tyrosine aminotransferase activity (TAT), but was ineffective in attenuating hyperglycemia induced by monocrotophos. Pre-treatment with propranolol (β-adrenergic receptor antagonist) and phentolamine (α-adrenergic receptor antagonist) were effective in abrogating monocrotophos-induced hyperglycemia. Interestingly, while propranolol offered partial protection against hyperglycemia, phentolamine completely abolished the same. However, monocrotophos-induced hyperlactacidemia was completely abolished by propranolol. Both the adrenoreceptor antagonists, however, failed to attenuate the stressogenic potential of monocrotophos. Hyperglycemia and hyperlactacidemia induced by monocrotophos were abolished by pre-treatment with atropine. Exogenous epinephrine was associated with hyperglycemia and hyperlactacidemia. The impact of adrenergic antagonists on epinephrine-induced hyperglycemia and hyperlactacidemia were remarkably similar to that of monocrotophos-induced hyperglycemia and hyperlactacidemia. Further, hydrazine sulfate (a gluconeogenesis inhibitor) abolished hyperglycemia in monocrotophos-treated rats. From our data, it can be hypothesized that excessive stimulation of adrenoreceptors, probably elicited by increased plasma epinephrine, mediates hyperglycemic outcomes induced by monocrotophos. Pattern of changes in plasma lactate suggests that β-adrenergic activation mediates monocrotophos-induced hyperlactacidemia, while α-adrenergic receptor mediates lactate utilization, leading to hyperglycemia. Induction of liver TAT activity is attributable to glucocorticoid receptor activation as a result of hypercorticosteronemia.

  8. Pituitary and brain D2 receptor density measured in vitro and in vivo in EEDQ treated male rats

    SciTech Connect

    Ekman, A.; Eriksson, E. )

    1991-01-01

    The effect of the alkylating compound N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) on dopamine D2 receptor density in rat pituitary and brain was measured using in vitro and in vivo radioligand binding techniques. In the in vitro radioligand binding experiments EEDQ was found to reduce the density (B{sub max}) of ({sup 3}H)-spiperone binding sites in the striatum by 86% while in the pituitary the corresponding decrease was only 37%. The affinity (K{sub D}) of the remaining striatal and pituitary D2 receptors was not different in EEDQ treated animals as compared to controls. When D2 receptor density was measured in vivo the effect of EEDQ was less pronounced. Thus, in rats given EEDQ the specific binding of either of the two D2 ligands ({sup 3}H)-raclopride or ({sup 3}H)-spiperone in striatum and in the limbic forebrain was reduced by 45-62%; moreover, no significant decrease in pituitary D2 receptor density was observed. The data are discussed in relation to the finding that the same dose of EEDQ that failed to influence pituitary D2 receptor density as measured in vivo effectively antagonizes the prolactin decreasing effect of the partial D2 agonist (-)-3-(3-hydroxyphenyl)-N-n-propyl-piperidine ((-)-3-PPP).

  9. Expression of metallothioneins I and II related to oxidative stress in the liver of aluminium-treated rats.

    PubMed

    Ghorbel, Imen; Chaabane, Mariem; Elwej, Awatef; Boudawara, Ons; Abdelhedi, Sameh; Jamoussi, Kamel; Boudawara, Tahya; Zeghal, Najiba

    2016-10-01

    Hepatotoxicity, induced by aluminium chloride (AlCl3), has been well studied but there are no reports about liver metallothionein (MT) genes induction. Therefore, it is of interest to establish the mechanism involving the relation between MT gene expression levels and the oxidative stress status in hepatic cells of aluminium-treated rats. Aluminium (Al) was administered to rats in their drinking water at a dose of 50 mg/kg body weight for three weeks. AlCl3 provoked hepatotoxicity objectified by an increase in malondialdehyde (MDA), hydrogen peroxide (H2O2), advanced oxidation protein products (AOPP), protein carbonyls (PCO) and a decrease in reduced glutathione (GSH), non-protein thiols (NPSH) and vitamin C. CAT and Glutathione peroxidase (GPx) activities were decreased while Mn-SOD gene expression, total Metallothionein content and MT I and MT II genes induction were increased. There are changes in plasma of some trace elements, albumin levels, transaminases, LDH and ALP activities. All these changes were supported by histopathological observations.

  10. 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

  11. Changes in surfactant protein A mRNA levels in a rat model of insulin-treated diabetic pregnancy.

    PubMed

    Moglia, B B; Phelps, D S

    1996-02-01

    Maternal diabetes during pregnancy is associated with increased risk of neonatal respiratory distress syndrome (RDS). Previous studies using rat models for the diabetic pregnancy have documented decreased amounts of surfactant protein mRNA in the lungs of fetuses. In this study, we measured fetal lung surfactant-associated protein A (SP-A) mRNA from diabetic rats treated with insulin by daily injection or osmotic pump. Lungs were taken from fetuses on gestational d 20, and RNA was isolated and subjected to Northern blotting and densitometry to quantify SP-A mRNA. Fetal lung SP-A mRNA from untreated diabetic pregnancies was 34 +/- 2.9% of control. Insulin treatment increased levels to 55 +/- 4.2% of control values. Fetal lung SP-A mRNA levels were affected by the timing, length, and effectiveness of insulin treatment. Although levels from all treatment groups were still less than control values, insulin treatment during the last 5 or 10 d of pregnancy resulted in a substantial increase in SP-A mRNA levels over those of from untreated diabetic pregnancies. However, fetuses from the group with insulin treatment for the entire pregnancy showed decreases in fetal SP-A mRNA levels. Although the mechanism(s) responsible for the effects of diabetes and its treatment on fetal SP-A expression remain unclear, it appears unlikely that hyperglycemia is the principal cause.

  12. Induction of hepatic metallothioneins determined at isoprotein and messenger RNA levels in glucocorticoid-treated rats.

    PubMed Central

    Lehman-McKeeman, L D; Andrews, G K; Klaassen, C D

    1988-01-01

    Induction of metallothionein-I (MT-I) and metallothionein-II (MT-II) by glucocorticoids was determined by h.p.l.c. analysis of proteins and Northern-blot analysis of MT mRNAs. Rats were injected with dexamethasone (0.03-10 mumol/kg) and hepatic concentrations of MTs were determined 24 h later. In control rats, only MT-II was detected (9.4 +/- 2.5 micrograms/g of liver), whereas the hepatic concentration of MT-I was below the detection limit (5 micrograms of MT/g). Dexamethasone did not increase MT-I above the detection limit at any dosage tested, but MT-II increased to 2.5 times control values at dosages of 0.30 mumol/kg and higher. Time-course experiments indicated that MT-II reached a maximum at 24 h after a single dosage of dexamethasone and returned to control values by 48 h. To determine whether dexamethasone increased MT-I in liver, samples were saturated with 109Cd, after which the amount of 109Cd in MT-I and MT-II was determined. Results indicated that, by this approach, MT-I and MT-II could be detected in control rats, and there was approx. 1.8 times more 109Cd in MT-II than in MT-I. At 24 h after administration of dexamethasone (1 mumol/kg), there was a small increase in the amount of 109Cd bound to MT-I, whereas the amount of 109Cd bound to MT-II increased to more than 2 times control values. Northern-blot hybridization with mouse cRNA probes indicated that MT-I and MT-II mRNAs increased co-ordinately after administration of dexamethasone. Thus, although glucocorticoids increase both MT-I and MT-II mRNAs, MT-II preferentially accumulates after administration of dexamethasone. Images Fig. 4. PMID:3342021

  13. 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

  14. RNA-Seq profiling reveals novel hepatic gene expression pattern in aflatoxin B1 treated rats.

    PubMed

    Merrick, B Alex; Phadke, Dhiral P; Auerbach, Scott S; Mav, Deepak; Stiegelmeyer, Suzy M; Shah, Ruchir R; Tice, Raymond R

    2013-01-01

    Deep sequencing was used to investigate the subchronic effects of 1 ppm aflatoxin B1 (AFB1), a potent hepatocarcinogen, on the male rat liver transcriptome prior to onset of histopathological lesions or tumors. We hypothesized RNA-Seq would reveal more differentially expressed genes (DEG) than microarray analysis, including low copy and novel transcripts related to AFB1's carcinogenic activity compared to feed controls (CTRL). Paired-end reads were mapped to the rat genome (Rn4) with TopHat and further analyzed by DESeq and Cufflinks-Cuffdiff pipelines to identify differentially expressed transcripts, new exons and unannotated transcripts. PCA and cluster analysis of DEGs showed clear separation between AFB1 and CTRL treatments and concordance among group replicates. qPCR of eight high and medium DEGs and three low DEGs showed good comparability among RNA-Seq and microarray transcripts. DESeq analysis identified 1,026 differentially expressed transcripts at greater than two-fold change (p<0.005) compared to 626 transcripts by microarray due to base pair resolution of transcripts by RNA-Seq, probe placement within transcripts or an absence of probes to detect novel transcripts, splice variants and exons. Pathway analysis among DEGs revealed signaling of Ahr, Nrf2, GSH, xenobiotic, cell cycle, extracellular matrix, and cell differentiation networks consistent with pathways leading to AFB1 carcinogenesis, including almost 200 upregulated transcripts controlled by E2f1-related pathways related to kinetochore structure, mitotic spindle assembly and tissue remodeling. We report 49 novel, differentially-expressed transcripts including confirmation by PCR-cloning of two unique, unannotated, hepatic AFB1-responsive transcripts (HAfT's) on chromosomes 1.q55 and 15.q11, overexpressed by 10 to 25-fold. Several potentially novel exons were found and exon refinements were made including AFB1 exon-specific induction of homologous family members, Ugt1a6 and Ugt1a7c. We find the

  15. Cannabinoid CB2 receptors in the enteric nervous system modulate gastrointestinal contractility in lipopolysaccharide-treated rats.

    PubMed

    Duncan, Marnie; Mouihate, Abdeslam; Mackie, Ken; Keenan, Catherine M; Buckley, Nancy E; Davison, Joseph S; Patel, Kamala D; Pittman, Quentin J; Sharkey, Keith A

    2008-07-01

    Enhanced intestinal transit due to lipopolysaccharide (LPS) is reversed by cannabinoid (CB)2 receptor agonists in vivo, but the site and mechanism of action are unknown. We have tested the hypothesis that CB2 receptors are expressed in the enteric nervous system and are activated in pathophysiological conditions. Tissues from either saline- or LPS-treated (2 h; 65 microg/kg ip) rats were processed for RT-PCR, Western blotting, and immunohistochemistry or were mounted in organ baths where electrical field stimulation was applied in the presence or absence of CB receptor agonists. Whereas the CB2 receptor agonist JWH133 did not affect the electrically evoked twitch response of the ileum under basal conditions, in the LPS-treated tissues JWH133 was able to reduce the enhanced contractile response in a concentration-dependent manner. Rat ileum expressed CB2 receptor mRNA and protein under physiological conditions, and this expression was not affected by LPS treatment. In the myenteric plexus, CB2 receptors were expressed on the majority of neurons, although not on those expressing nitric oxide synthase. LPS did not alter the distribution of CB2 receptor expression in the myenteric plexus. In vivo LPS treatment significantly increased Fos expression in both enteric glia and neurons. This enhanced expression was significantly attenuated by JWH133, whose action was reversed by the CB2 receptor antagonist AM630. Taking these facts together, we conclude that activation of CB2 receptors in the enteric nervous system of the gastrointestinal tract dampens endotoxin-induced enhanced intestinal contractility.

  16. CNTF-Treated Astrocyte Conditioned Medium Enhances Large-Conductance Calcium-Activated Potassium Channel Activity in Rat Cortical Neurons.

    PubMed

    Sun, Meiqun; Liu, Hongli; Xu, Huanbai; Wang, Hongtao; Wang, Xiaojing

    2016-08-01

    Seizure activity is linked to astrocyte activation as well as dysfunctional cortical neuron excitability produced from changes in calcium-activated potassium (KCa) channel function. Ciliary neurotrophic factor-treated astrocyte conditioned medium (CNTF-ACM) can be used to investigate the peripheral effects of activated astrocytes upon cortical neurons. However, CNTF-ACM's effect upon KCa channel activity in cultured cortical neurons has not yet been investigated. Whole-cell patch clamp recordings were performed in rat cortical neurons to evaluate CNTF-ACM's effects upon charybdotoxin-sensitive large-conductance KCa (BK) channel currents and apamin-sensitive small-conductance KCa (SK) channel current. Biotinylation and RT-PCR were applied to assess CNTF-ACM's effects upon the protein and mRNA expression, respectively, of the SK channel subunits SK2 and SK3 and the BK channel subunits BKα1 and BKβ3. An anti-fibroblast growth factor-2 (FGF-2) monoclonal neutralizing antibody was used to assess the effects of the FGF-2 component of CNTF-ACM. CNTF-ACM significantly increased KCa channel current density, which was predominantly attributable to gains in BK channel activity (p < 0.05). CNTF-ACM produced a significant increase in BKα1 and BKβ3 expression (p < 0.05) but had no significant effect upon SK2 or SK3 expression (p > 0.05). Blocking FGF-2 produced significant reductions in KCa channel current density (p > 0.05) as well as BKα1 and BKβ3 expression in CNTF-ACM-treated neurons (p > 0.05). CNTF-ACM significantly enhances BK channel activity in rat cortical neurons and that FGF-2 is partially responsible for these effects. CNTF-induced astrocyte activation results in secretion of neuroactive factors which may affect neuronal excitability and resultant seizure activity in mammalian cortical neurons.

  17. A sodium-glucose co-transporter 2 inhibitor empagliflozin prevents abnormality of circadian rhythm of blood pressure in salt-treated obese rats.

    PubMed

    Takeshige, Yui; Fujisawa, Yoshihide; Rahman, Asadur; Kittikulsuth, Wararat; Nakano, Daisuke; Mori, Hirohito; Masaki, Tsutomu; Ohmori, Koji; Kohno, Masakazu; Ogata, Hiroaki; Nishiyama, Akira

    2016-06-01

    Studies were performed to examine the effects of the selective sodium-glucose co-transporter 2 (SGLT2) inhibitor empagliflozin on urinary sodium excretion and circadian blood pressure in salt-treated obese Otsuka Long Evans Tokushima Fatty (OLETF) rats. Fifteen-week-old obese OLETF rats were treated with 1% NaCl (in drinking water), and vehicle (0.5% carboxymethylcellulose, n=10) or empagliflozin (10 mg kg(-1)per day, p.o., n=11) for 5 weeks. Blood pressure was continuously measured by telemetry system. Glucose metabolism and urinary sodium excretion were evaluated by oral glucose tolerance test and high salt challenge test, respectively. Vehicle-treated OLETF rats developed non-dipper type blood pressure elevation with glucose intolerance and insulin resistance. Compared with vehicle-treated animals, empagliflozin-treated OLETF rats showed an approximately 1000-fold increase in urinary glucose excretion and improved glucose metabolism and insulin resistance. Furthermore, empagliflozin prevented the development of blood pressure elevation with normalization of its circadian rhythm to a dipper profile, which was associated with increased urinary sodium excretion. These data suggest that empagliflozin elicits beneficial effects on both glucose homeostasis and hypertension in salt-replete obese states.

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. Prostacyclin effects on the blood pressure responses to norepinephrine in rats treated with aspirin or indomethacin.

    PubMed

    Carmignani, M; Marchetti, P; Caprino, L

    1980-01-01

    The atherosclerotic condition is associated with a reduction of PGI2 synthesis; moreover, in the presence of elevated serum cholesterol levels, pressor responses to norepinephrine are potentiated. In order to verify if a complete inhibition of PGI2 production affects the vascular reactivity, it was assayed two cycloxygenase inhibitors (lysine acetylsalicylate and indomethacin) in rats. The two drugs significantly potentiated the blood pressure responses to norepinephrine, and completely inhibited PGI2-like substances production by arterial rings. The prostacyclin infusion (15 ng/kg/min, i.v.) completely reversed such potentiation, without any major modification in the basal blood pressure values. These results show that PGI2 production is responsible for vascular tone modulation and may partially explain the altered vascular reactivity in the atherosclerotic condition.

  3. Changed Synaptic Plasticity in Neural Circuits of Depressive-Like and Escitalopram-Treated Rats

    PubMed Central

    Li, Xiao-Li; Yuan, Yong-Gui; Xu, Hua; Wu, Di; Gong, Wei-Gang; Geng, Lei-Yu; Wu, Fang-Fang; Tang, Hao; Xu, Lin

    2015-01-01

    Background: Although progress has been made in the detection and characterization of neural plasticity in depression, it has not been fully understood in individual synaptic changes in the neural circuits under chronic stress and antidepressant treatment. Methods: Using electron microscopy and Western-blot analyses, the present study quantitatively examined the changes in the Gray’s Type I synaptic ultrastructures and the expression of synapse-associated proteins in the key brain regions of rats’ depressive-related neural circuit after chronic unpredicted mild stress and/or escitalopram administration. Meanwhile, their depressive behaviors were also determined by several tests. Results: The Type I synapses underwent considerable remodeling after chronic unpredicted mild stress, which resulted in the changed width of the synaptic cleft, length of the active zone, postsynaptic density thickness, and/or synaptic curvature in the subregions of medial prefrontal cortex and hippocampus, as well as the basolateral amygdaloid nucleus of the amygdala, accompanied by changed expression of several synapse-associated proteins. Chronic escitalopram administration significantly changed the above alternations in the chronic unpredicted mild stress rats but had little effect on normal controls. Also, there was a positive correlation between the locomotor activity and the maximal synaptic postsynaptic density thickness in the stratum radiatum of the Cornu Ammonis 1 region and a negative correlation between the sucrose preference and the length of the active zone in the basolateral amygdaloid nucleus region in chronic unpredicted mild stress rats. Conclusion: These findings strongly indicate that chronic stress and escitalopram can alter synaptic plasticity in the neural circuits, and the remodeled synaptic ultrastructure was correlated with the rats’ depressive behaviors, suggesting a therapeutic target for further exploration. PMID:25899067

  4. Gamma irradiation of isolated rat islets pretransplantation produces indefinite allograft survival in cyclosporine-treated recipients

    SciTech Connect

    James, R.F.; Lake, S.P.; Chamberlain, J.; Thirdborough, S.; Bassett, P.D.; Mistry, N.; Bell, P.R.

    1989-06-01

    In this study we have examined the use of low-dose gamma-irradiation for the reduction of islet immunogenicity in the strong allogeneic combination of WAG rat islets transplanted into diabetic AUG recipients. First, we determined that gamma-irradiation reduced immunogenicity in vitro by use of a modified MLR with WAG islets as stimulators and AUG splenocytes as responders. We then determined the maximum dose of gamma-irradiation that could be used (250 rads) before islet function was affected. As 250 rads islet pretreatment alone was ineffective in prolonging allograft survival, we combined the pretreatment with a short course (days 0, 1, 2; 30 mg/kg) of cyclosporine. We found that CsA was only effective in significantly prolonging allograft survival when given subcutaneously in olive oil. The CsA treatment alone gave a significantly prolonged survival time for the islet allografts (median, 37 days vs. 6 days for controls), but when combined with the 250 rads islet pretreatment a synergistic effect was seen with 100% becoming long-term survivors (greater than 100 days). The long-term surviving AUG rats from both the CsA alone group and the CsA plus 250 rads pretreated islets group were challenged with WAG dendritic cells (DC). The islets from the 250 rads pretreated group were subsequently rejected (day 6) while the CsA alone group were not affected. The role of low dose gamma-irradiation when combined with CsA treatment of islet graft recipients in inducing specific unresponsiveness will be discussed.

  5. 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.

  6. Beneficial effects of L-arginine–nitric oxide-producing pathway in rats treated with alloxan

    PubMed Central

    Vasilijević, Ana; Buzadžić, Biljana; Korać, Aleksandra; Petrović, Vesna; Janković, Aleksandra; Korać, Bato

    2007-01-01

    In an attempt to elucidate molecular mechanisms and factors involved in β cell regeneration, we evaluated a possible role of the l-arginine–nitric oxide (NO)-producing pathway in alloxan-induced diabetes mellitus. Diabetes was induced in male Mill Hill rats with a single alloxan dose (120 mg kg−1). Both non-diabetic and diabetic groups were additionally separated into three subgroups: (i) receiving l-arginine · HCl (2.25%), (ii) receiving l-NAME · HCl (0.01%) for 12 days as drinking liquids, and (iii) control. Treatment of diabetic animals started after diabetes induction (glucose level ≥ 12 mmol l−1). We found that disturbed glucose homeostasis, i.e. blood insulin and glucose levels in diabetic rats was restored after l-arginine treatment. Immunohistochemical findings revealed that l-arginine had a favourable effect on β cell neogenesis, i.e. it increased the area of insulin-immunopositive cells. Moreover, confocal microscopy showed colocalization of insulin and pancreas duodenum homeobox-1 (PDX-1) in both endocrine and exocrine pancreas. This increase in insulin-expressing cells was accompanied by increased cell proliferation (observed by proliferating cell nuclear antigen-PCNA immunopositivity) which occurred in a regulated manner since it was associated with increased apoptosis (detected by the TUNEL method). Furthermore, l-arginine enhanced both nuclear factor-kB (NF-kB) and neuronal nitric oxide synthase (nNOS) immunopositivities. The effect of l-arginine on antioxidative defence was observed especially in restoring to control level the diabetes-induced increase in glutathione peroxidase activity. In contrast to l-arginine, diabetic pancreas was not affected by l-NAME supplementation. In conclusion, the results suggest beneficial l-arginine effects on alloxan-induced diabetes resulting from the stimulation of β cell neogenesis, including complex mechanisms of transcriptional and redox regulation. PMID:17717015

  7. Nitric oxide-releasing flurbiprofen reduces formation of proinflammatory hydrogen sulfide in lipopolysaccharide-treated rat.

    PubMed

    Anuar, Farhana; Whiteman, Matthew; Siau, Jia Ling; Kwong, Shing Erl; Bhatia, Madhav; Moore, Philip K

    2006-04-01

    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-alpha, IL-1beta and nitrate/nitrite (NO(x)) 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-kappaB) activation. Nitroflurbiprofen (3-30 mg kg(-1), i.p.) administration resulted in a dose-dependent inhibition of the LPS-mediated increase in plasma TNF-alpha, IL-1beta and NO(x) 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-kappaB 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.

  8. Brain mitochondria from rats treated with sulforaphane are resistant to redox-regulated permeability transition.

    PubMed

    Greco, Tiffany; Fiskum, Gary

    2010-12-01

    Oxidative stress promotes Ca2+-dependent opening of the mitochondrial inner membrane permeability transition pore (PTP), causing bioenergetic failure and subsequent cell death in many paradigms, including those related to acute brain injury. One approach to pre-conditioning against oxidative stress is pharmacologic activation of the Nrf2/ARE pathway of antioxidant gene expression by agents such as sulforaphane (SFP). This study tested the hypothesis that administration of SFP to normal rats increases resistance of isolated brain mitochondria to redox-sensitive PTP opening. SFP or DMSO vehicle was administered intraperitoneally to adult male rats at 10 mg/kg 40 h prior to isolation of non-synaptic brain mitochondria. Mitochondria were suspended in medium containing a respiratory substrate and were exposed to an addition of Ca2+ below the threshold for PTP opening. Subsequent addition of tert-butyl hydroperoxide (tBOOH) resulted in a cyclosporin A-inhibitable release of accumulated Ca2+ into the medium, as monitored by an increase in fluorescence of Calcium Green 5N within the medium, and was preceded by a decrease in the autofluorescence of mitochondrial NAD(P)H. SFP treatment significantly reduced the rate of tBOOH-induced Ca2+ release but did not affect NAD(P)H oxidation or inhibit PTP opening induced by the addition of phenylarsine oxide, a direct sulfhydryl oxidizing agent. SFP treatment had no effect on respiration by brain mitochondria and had no effect on PTP opening or respiration when added directly to isolated mitochondria. We conclude that SFP confers resistance of brain mitochondria to redox-regulated PTP opening, which could contribute to neuroprotection observed with SFP.

  9. Different effect of handle region peptide on β-cell function in different sexes of rats neonatally treated with sodium L-glutamate.

    PubMed

    Wu, Yi-xi; Sun, Ru-qiong; Yin, Guo-shu; Xu, Dong-chuan; Wang, Ping; Lin, Kun; Lin, Chu-jia; Lin, Shao-da

    2015-03-17

    BACKGROUND The (pro)renin receptor ((P)RR) was reported to be expressed in various tissues including the pancreas, and handle region peptide (HRP) is believed to block the function of (P)RR. This study aimed to investigate the effect of HRP on the glucose tolerance status and β-cell function of female rats, neonatally treated with sodium L-glutamate (MSG) and to compare with the previously reported HRP effect on male rats. MATERIAL AND METHODS Female MSG rats aged 8 weeks were divided into MSG control group and HRP treated group and the normal SD rats served as control. The MSG rats were treated with HRP by osmotic minipumps with dose of 1 mg/kg per day for total 28 days. Glucose tolerance status was evaluated at the end of the study. Islets α-cell and β-cell were marked with insulin antibody and glucagon antibody respectively. The proliferation of islet cells and expression of subunit of NADPH oxidase P22phox were marked by PCNA and P22phox antibody. Picrosirius red staining was performed for evaluating fibrosis of islets. RESULTS HRP improved the glucose status tolerance with decreasing α-cell mass, islets PCNA-positive cells, expression of P22phox and picrosirius red stained areas, and increasing β-cell mass in female MSG rats. The indexes with obviously interacted effect of sexes and HRP for the MSG rats were the AUC of blood glucose concentration (P<0.01), α-cell mass (P<0.05), proliferation of islet cells (P<0.01) and area of picrosirius red staining (P<0.01). CONCLUSIONS HRP improved the glucose tolerance status in the females although it was previously reported to worsen the glucose tolerance in male MSG rats. Different levels of sex hormones may partly account for the disparate effects observed for HRP in different sexes.

  10. Structural changes of gut microbiota in a rat non-alcoholic fatty liver disease model treated with a Chinese herbal formula.

    PubMed

    Yin, Xiaochen; Peng, Jinghua; Zhao, Liping; Yu, Yunpeng; Zhang, Xu; Liu, Ping; Feng, Qin; Hu, Yiyang; Pang, Xiaoyan

    2013-05-01

    Accumulating evidence indicates that disruption of the gut microbiota by a high-fat diet (HFD) may play a pivotal role in the progression of metabolic disorders such as non-alcoholic fatty liver disease (NAFLD). In this study, the structural changes of gut microbiota were analyzed in an HFD-induced NAFLD rat model during treatment with an ancient Chinese herbal formula (CHF) used in clinical practice -Qushi Huayu Fang. CHF treatment significantly reduced body weight, alleviated hepatic steatosis, and decreased the content of triglycerides and free fatty acids in the livers of the rats. Gut microbiota of treated and control rats were profiled with polymerase chain reaction-denaturing gradient gel electrophoresis and bar-coded pyrosequencing of the V3 region of 16S rRNA genes. Both analyses indicated that the CHF-treated group harbored significantly different gut microbiota from that of model rats. Partial least squares discriminant analysis and taxonomy-based analysis were further employed to identify key phylotypes responding to HFD and CHF treatment. Most notably, the genera Escherichia/Shigella, containing opportunistic pathogens, were significantly enriched in HFD-fed rats compared to controls fed normal chow (P<0.05) but they decreased to control levels after CHF treatment. Collinsella, a genus with short chain fatty acid producers, was significantly elevated in CHF-treated rats compared to HFD-fed rats (P<0.05). The results revealed that the bacterial profiles of HFD-induced rats could be modulated by the CHF. Elucidation of these differences in microbiota composition provided a basis for further understanding the pharmacological mechanism of the CHF.

  11. Immuno-neutralization of circulating relaxin does not alter the breast cancer-protective action of parity in MNU-treated rats.

    PubMed

    Steinetz, Bernard G; Sherwood, O David; Lasano, Sally; Horton, Lori; Bosland, Maarten C

    2004-04-01

    Early pregnancy and childbirth protects women against future development of breast cancer by an unknown mechanism. Parity likewise reduces mammary cancer incidence in rats exposed to the carcinogen, N-methyl-N-nitrosourea (MNU), providing a model for the human phenomenon. We hypothesized that relaxin, a 6KD luteal mammotropic hormone of pregnancy, might be the anti-cancer pregnancy factor, and that induced relaxin deficiency during rat gestation would restore carcinogen sensitivity. Forty-one pregnant (age 50 days) and 25 age-matched virgin Sprague-Dawley rats were used. Relaxin deficiency was induced by injecting mouse monoclonal anti-rat relaxin antibody (MCA1) days 12-18 of gestation. Pregnant controls were injected with vehicle or mouse IgG on the same schedule. Because MCA1 disrupts parturition, all rats underwent cesarean section on day 22. At age 100 days, all rats were injected i.v. with MNU (50mg/Kg) and examined daily for tumors until euthanized at age 240 days. Mammary tumor incidence and frequency were significantly (p<0.01) reduced and tumor latency was increased (p<0.001) in primiparous as compared with virgin rats. However, tumor incidence, type, size and latency were similar in MCA1-treated and control primiparous rats. Thus, luteal relaxin does not appear to be the factor responsible for resistance to breast cancer.

  12. Tipepidine, a non-narcotic antitussive, exerts an antidepressant-like effect in the forced swimming test in adrenocorticotropic hormone-treated rats.

    PubMed

    Kawaura, Kazuaki; Ogata, Yukino; Honda, Sokichi; Soeda, Fumio; Shirasaki, Tetsuya; Takahama, Kazuo

    2016-04-01

    We investigated whether tipepidine exerts an antidepressant-like effect in the forced swimming test in adrenocorticotropic hormone (ACTH)-treated rats, which is known as a treatment-resistant depression model, and we studied the pharmacological mechanisms of the effects of tipepidine. Male Wistar rats (5-7 weeks old) were used in this study. Tipepidine (20 and 40 mg/kg, i.p.) decreased the immobility time in the forced swimming test in ACTH-treated rats. The anti-immobility effect of tipepidine was blocked by a catecholamine-depleting agent, alpha-methyl-p-tyrosine (300 mg/kg, s.c.), but not by a serotonin-depleting agent, p-chlorophenylalanine. The anti-immobility effect of tipepidine was also blocked by a dopamine D1 receptor antagonist, SCH23390 (0.02 mg/kg, s.c.) and an adrenaline α2 receptor antagonist, yohimbine (2 mg/kg, i.p.). In microdialysis technique, tipepidine (40 mg/kg, i.p.) increased the extracellular dopamine level of the nucleus accumbens (NAc) in ACTH-treated rats. These results suggest that tipepidine exerts an antidepressant-like effect in the forced swimming test in ACTH-treated rats, and that the effect of tipepidine is mediated by the stimulation of dopamine D1 receptors and adrenaline α2 receptors. The results also suggest that an increase in the extracellular dopamine level in the NAc may be involved in the antidepressant-like effect of tipepidine in ACTH-treated rats.

  13. 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

  14. Salvianolic acid B prevents bone loss in prednisone-treated rats through stimulation of osteogenesis and bone marrow angiogenesis.

    PubMed

    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

  15. Isolation of pseudoperoxidase-positive astrocyte granules from intact rat brain and cysteamine-treated neuroglial cultures.

    PubMed

    Cissé, S; Schipper, H M

    1993-06-25

    A subpopulation of astrocytes in periventricular regions of aging brain and in cysteamine (CSH)-treated glial cultures contain autofluorescent cytoplasmic granules that exhibit an affinity for Gomori's chrome alum hematoxylin (CAH), and non-enzymatic peroxidase activity. Although shown to be histochemically distinct from lipofuscin, the lack of pure preparations of these glial inclusions has hindered the elucidation of their precise chemical constituents. Using sucrose gradient fractionation and density centrifugation on percoll, we obtained enriched preparations of astrocyte cytoplasmic granules from intact rat brain and CSH-treated astrocyte cultures. The presence and relative purity of these inclusions were confirmed by laser scanning confocal microscopy for red autofluorescent granules, diaminobenzidine histochemistry for non-enzymatic peroxidase activity and chrome alum hematoxylin (Gomori) staining. In the enriched fractions, the smaller granules (0.5-4.0 microns) were spherical and weakly autofluorescent, whereas larger inclusions (5.0-10.0 microns) tended to be intensely autofluorescent and pleomorphic. As in situ, the purified material was argyrophilic and did not stain for lipids. Isolation of these astrocytic inclusions should permit a more thorough characterization of their biochemical contents.

  16. Aging and Oxidative Stress Decrease Pineal Elongation Factor 2: In Vivo Protective Effect of Melatonin in Young Rats Treated With Cumene Hydroperoxide.

    PubMed

    Muñoz, Mario F; Argüelles, Sandro; Cano, Mercedes; Marotta, Francesco; Ayala, Antonio

    2017-01-01

    We studied the alterations of Elongation Factor 2 (eEF2) in the pineal gland of aged rats as well as the possible protective role of exogenous melatonin on these changes in young rats treated with cumene hydroperoxide (CH), a compound that promotes lipid peroxidation and inhibits protein synthesis. The study was performed using male Wistar rats of 3 (control), 12, and 24 months and 3-month-old rats treated with CH, melatonin, and CH plus melatonin. We found that pineal eEF-2 is affected by aging and CH, these changes being prevented by exogenous melatonin in the case of CH-treated rats. The proteomic studies show that many other proteins are affected by aging and oxidative stress in the pineal gland. The results suggest that one of the possible mechanisms underlying pineal gland dysfunction during aging is the effect of lipid peroxidation on eEF-2, which is a key component of protein synthesis machinery. J. Cell. Biochem. 118: 182-190, 2017. © 2016 Wiley Periodicals, Inc.

  17. 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.

  18. 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.

  19. 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

  20. In vivo imaging of mitochondrial function in methamphetamine-treated rats.

    PubMed

    Shiba, Takeshi; Yamato, Mayumi; Kudo, Wataru; Watanabe, Toshiaki; Utsumi, Hideo; Yamada, Ken-ichi

    2011-08-01

    Abuse of the powerfully addictive psychostimulant, methamphetamine, occurs worldwide. Recent studies have suggested that methamphetamine-induced dopaminergic neurotoxicity is related to oxidative stress. In response to nerve activation, the mitochondrial respiratory chain is rapidly activated. The enhancement of mitochondrial respiratory chain activation may induce oxidative stress in the brain. However, there is little experimental evidence regarding the mitochondrial function after methamphetamine administration in vivo. Here, we evaluated whether a single administration of methamphetamine induces ATP consumption and overactivation of mitochondria. We measured mitochondrial function in two different ways: by monitoring oxygen partial pressure using an oxygen-selective electrode, and by imaging of redox reactions using a nitroxyl radical (i.e., nitroxide) coupled with Overhauser-enhanced magnetic resonance imaging (OMRI). A single administration of methamphetamine to Wistar rats induced dopaminergic nerve activation, ATP consumption and an increase in mitochondrial respiratory chain function in both the striatum and cortex. Furthermore, antioxidant TEMPOL prevented the increase in mitochondrial oxidative damage and methamphetamine-induced sensitization. These findings suggest that energy-supplying reactions after dopaminergic nerve activation are associated with oxidative stress in both the striatum and cortex, leading to abnormal behavior.

  1. 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.

  2. Comparison between PACAP- and enriched environment-induced retinal protection in MSG-treated newborn rats.

    PubMed

    Kiss, Peter; Atlasz, Tamas; Szabadfi, Krisztina; Horvath, Gabor; Griecs, Monika; Farkas, Jozsef; Matkovits, Attila; Toth, Gabor; Lubics, Andrea; Tamas, Andrea; Gabriel, Robert; Reglodi, Dora

    2011-01-10

    Pituitary adenylate cyclase activating polypeptide (PACAP) and its receptors occur throughout the nervous system, including the retina. PACAP exerts diverse actions in the eye: it influences ocular blood flow, contraction of the ciliary muscle, and has retinoprotective effects. This effect has been proven in different models of retinal degeneration. We have previously shown that PACAP protects against monosodium-glutamate (MSG)-induced damage in neonatal rats. The beneficial effects of enriched environment, another neuroprotective strategy, have long been known. Environmental enrichment has been shown to decrease different neuronal injuries. It also influences the development of the visual system. We have recently demonstrated that significant neuroprotection can be achieved in MSG-induced retinal degeneration in animals kept in an enriched environment. Combination of neuroprotective strategies often results in increased protection. Therefore, the aim of the present study was to compare the two neuroprotective strategies alone and in combination therapy. We found that both PACAP and environmental enrichment led to a similar degree of retinal protection, but the two treatments together did not lead to increased protection: their effects were not additive.

  3. The axon reaction in spinal ganglion neurons of acrylamide-treated rats.

    PubMed

    Jones, H B; Cavanagh, J B

    1986-01-01

    Rats were given acrylamide in doses of either 30 or 50 mg/kg (5 days each week) for up to 3 weeks and killed at weekly intervals. The right sciatic nerve was tied tightly at the level of the major trochanter 4 days before killing the animals by perfusion fixation when ipsilateral and contralateral sensory ganglia (L5 and L6) were removed. The effects on neuronal perikarya of axotomy alone, of acrylamide alone and of these combined were studied by light and electron microscopy. The responses to axotomy and to acrylamide intoxication shared certain features, namely peripheral Nissl substance and to a lesser degree nuclear eccentricity, nucleolemmal crenation and mitochondrial enlargement. Neurofilament loss was present only with acrylamide. In combined axotomy and acrylamide all these five features were prominent. These findings indicate firstly that the individual responses to axotomy and to acrylamide, while sharing several features, are subtly different and secondly that acrylamide appears to impede the vital neuronal responses directed towards repair of the axon.

  4. Evaluation of hepatotoxicity and oxidative stress in rats treated with tert-butyl hydroperoxide.

    PubMed

    Oh, Jung Min; Jung, Young Suk; Jeon, Byung Suk; Yoon, Byung Il; Lee, Kye Sook; Kim, Bong Hee; Oh, Soo Jin; Kim, Sang Kyum

    2012-05-01

    Although tert-butyl hydroperoxide (t-BHP) is commonly used to induce oxidative stress, little is known about the time- or dose-dependence of its oxidative effects. In this study, we examined hepatotoxicity and oxidative stress in male rats at various times (0-24 h) after t-BHP (0, 0.2, 0.5, 1 or 3 mmol/kg, ip) treatment. Serum hepatotoxicity parameters were increased from 2 h following 1 mmol/kg t-BHP and reached their maximum values at 8 h. Plasma malondialdehyde levels were maximally elevated by 62% at 0.5 h and returned to control levels by 4 h. Hepatic glutathione levels were decreased between 0.5 and 2 h, and hepatic glutathione disulfide levels were increased at 2h. Interestingly, hepatic glutathione levels were increased at 24 h, which may be attributed to up-regulation of glutathione synthesis through induction of gamma-glutamylcysteine ligase expression. The elevation of hepatotoxic parameters and plasma MDA was observed from 0.5 to 1 mmol/kg t-BHP, respectively, in a dose-dependent manner. Considering that the maximal dose resulted in 20% lethality, 1 mmol/kg of t-BHP may be suitable for evaluating antioxidant activity of tested compounds. Our results provide essential information to characterize the t-BHP-induced oxidative stress and hepatotoxicity.

  5. Mercury in the dorsal root ganglia of rats treated with inorganic or organic mercury

    SciTech Connect

    Schioenning, J.D.; Moeller-Madsen, B.; Danscher, G. )

    1991-10-01

    Autometallographic silver amplification has been used to demonstrate the localization of mercury deposits in rat dorsal root ganglia after repeated intraperitoneal injections of mercuric chloride or methylmercuric chloride. The silver-enhanced mercury deposits were demonstrated with the light and electron microscope. The degree of intracellular staining of the individual cells depended on the mercury compound and total dosage. Ganglion cells (types A and B) and macrophages were found to accumulate mercury after a total dosage of 400 {mu}g HgCl{sub 2}. After 600 {mu}g HgCl{sub 2}, satellite cells, endothelial cells and fibroblasts were additionally found to contain mercury deposits. Treatment with 6,000 {mu}g CH{sub 3}HgCl caused faint staining of type A and B ganglion cells and fibroblasts. Macrophages, however, were the most heavily stained cells after treatment with CH{sub 3}HgCl. Ultrastructurally, mercury was exclusively located in lysosomes. This was irrespective of the cell type and mercury compound used for treatment.

  6. Metabolism, microflora effects, and genotoxicity in haloacetic acid-treated cultures of rat cecal microbiota.

    PubMed

    Nelson, G M; Swank, A E; Brooks, L R; Bailey, K C; George, S E

    2001-04-01

    Haloacetic acids are by-products of drinking water disinfection. Several compounds in this class are genotoxic and have been identified as rodent hepatocarcinogens. Enzymes produced by the normal intestinal bacteria can transform some promutagens and procarcinogens to their biologically active forms. The present study was designed to investigate the influence of the cecal microbiota on the mutagenicity of haloacetic acids, and to look at changes in the microbiota populations and enzyme activities associated with exposure to haloacetic acids. PYG medium containing 1 mg/ml of monochloroacetic (MCA), monobromoacetic (MBA), dichloroacetic (DCA), dibromoacetic (DBA), trichloroacetic (TCA), tribromoacetic (TBA), or bromochloroacetic (BCA) acid was inoculated with rat cecal homogenate and incubated anaerobically at 37 degrees C. Growth curves were performed with enumeration of the microflora populations on selective media. Mutagenicity in a Salmonella microsuspension bioassay was determined after incubation for various lengths of time, with or without the cecal microbiota. At 15 h of incubation, enzyme assays determined the activities for beta-glucuronidase, beta-galactosidase, beta-glucosidase, azoreductase, nitroreductase, dechlorinase, and dehydrochlorinase. The haloacetic acids, with the exception of BCA, were toxic to the cecal microbiota, and especially to the enterococci. DBA, TBA, and BCA were mutagenic in the microsuspension assay, but the presence of the intestinal flora did not significantly alter the mutagenicity. BCA increased the activities of several enzymes, and therefore has the potential to affect the biotransformation of co-exposed compounds.

  7. 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 ...

  8. 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....

  9. Decreased Immunoreactivities of the Chloride Transporters, KCC2 and NKCC1, in the Lateral Superior Olive Neurons of Kanamycin-treated Rats

    PubMed Central

    Suh, Myung-Whan

    2012-01-01

    Objectives From our previous study about the weak expressions of potassium-chloride (KCC2) and sodium-potassium-2 chloride (NKCC1) co-transporters in the lateral superior olive (LSO) in circling mice, we hypothesized that partially damaged cochlea of circling mice might be a cause of the weak expressions of KCC2 or NKCC1. To test this possibility, we reproduced the altered expressions of KCC2 and NKCC1 in the LSO of rats, whose cochleae were partially destroyed with kanamycin. Methods Rat pups were treated with kanamycin from postnatal (P)3 to P8 (700 mg/kg, subcutaneous injection, twice a day) and sacrificed for immunohistochemical analysis, scanning electron microscope (SEM) and auditory brain stem response. Results The SEM study revealed partially missing hair cells in P9 rats treated with kanamycin, and the hearing threshold was elevated to 63.8±2.5 dB SPL (4 ears) at P16. Both KCC2 and NKCC1 immunoreactivities were more prominent in control rats on P16. On 9 paired slices, the mean densities of NKCC1 immunoreactivities were 118.0±1.0 (control) and 112.2±1.2 (kanamycin treated), whereas those of KCC2 were 115.7±1.5 (control) and 112.0±0.8 (kanamycin treated). Conclusion We concluded that weak expressions of KCC2 and NKCC1 in circling mice were due to partial destruction of cochleae. PMID:22977707

  10. Antioxidative and Neuroprotective Effects of Curcumin in an Alzheimer's Disease Rat Model Co-Treated with Intracerebroventricular Streptozotocin and Subcutaneous D-Galactose.

    PubMed

    Huang, Han-Chang; Zheng, Bo-Wen; Guo, Yu; Zhao, Jian; Zhao, Jiang-Yan; Ma, Xiao-Wei; Jiang, Zhao-Feng

    2016-04-05

    Epidemiological data imply links between the increasing incidences of Alzheimer's disease (AD) and type 2 diabetes mellitus. In this study, an AD rat model was established by combining treatments with intracerebroventricular streptozotocin (icv-STZ) and subcutaneous D-galactose, and the effects of curcumin on depressing AD-like symptoms were investigated. In the AD model group, rats were treated with icv-STZ in each hippocampus with 3.0 mg/kg of bodyweight once and then were subcutaneously injected with D-galactose daily (125 mg/kg of bodyweight) for 7 weeks. In the curcumin-protective group, after icv-STZ treatment, rats were treated with D-galactose (the same as in the AD model group) and intraperitoneally injected with curcumin daily (10 mg/kg of bodyweight) for 7 weeks. Vehicle-treated rats were treated as control. Compared with the vehicle control, the amount of protein carbonylation and glutathione in liver, as well as malondialdehyde in serum, were upregulated but glutathione peroxidase activity in blood was downregulated in the AD model group. The shuttle index and locomotor activity of rats in the AD model group were decreased compared with the vehicle control group. Furthermore, AD model rats showed neuronal damage and neuron loss with formation of amyloid-like substances and neurofibrillary tangles, and the levels of both β-cleavage of AβPP and phosphorylation of tau (Ser396) were significantly increased compared with the vehicle control group. Notably, compared with the AD model group, oxidative stress was decreased and the abilities of active avoidance and locomotor activity were improved, as well as attenuated neurodegeneration, in the curcumin-protective group. These results imply the applications of this animal model for AD research and of curcumin in the treatment of AD.

  11. 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.

  12. Effects of olive oil and its fractions on oxidative stress and the liver's fatty acid composition in 2,4-Dichlorophenoxyacetic acid-treated rats

    PubMed Central

    2010-01-01

    Background Olive oil's beneficial effects are not only related to its high content of oleic acid, but also to the antioxidant potential of its polyphenols. In this study, we assess the effects of virgin olive oil and its fractions on 2,4-D- induced oxidative damage in the liver of rats. Methods Male Wistar rats were randomly divided into eight groups of ten each: (C) a control group, (D) group that received 2,4-D (5 mg/kg b.w.), (D/EVOO) group treated with 2,4-D plus extra virgin olive oil, (D/OOHF) group that received 2,4-D plus hydrophilic fraction, (D/OOLF) group treated with 2,4-D plus lipophilic fraction, (EVOO) group that received only extra virgin olive oil, (OOHF) group given hydrophilic fraction and (OOLF) group treated with lipophilic fraction. These components were daily administered by gavage for 4 weeks. Results A significant liver damage was observed in rats treated with 2,4-D via increased serum levels of transaminases and alkaline phosphatase, hepatic lipid peroxidation and decreased hepatic antioxidant enzyme activities, namely, superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase. The liver's fatty acid composition was also significantly modified with 2,4-D exposure. However, extra virgin olive oil and hydrophilic fraction intake during 2,4-D treatment induced a significant increase in the antioxidant enzyme activities and a decrease in the conjugated dienes (CD) and thiobarbituric acid-reactive substances (TBARs) levels in the liver. The lipophilic fraction supplemented to 2,4-D- treated rats did not show any improvement in the liver oxidative status while a marked improvement was detected in the hepatic fatty acid composition of rats supplemented with olive oil and the two fractions. Conclusion We concluded that the protective effect of olive oil against oxidative damage induced by 2,4-D is mainly related to the antioxidant potential of its hydrophilic fraction. PMID:21034436

  13. Bifractionated CPT-11 with LV5FU2 infusion (FOLFIRI-3) in combination with bevacizumab: clinical outcomes in first-line metastatic colorectal cancers according to plasma angiopoietin-2 levels

    PubMed Central

    2013-01-01

    Background Optimization of chemotherapy effectiveness in metastatic colorectal cancers (mCRC) is a major endpoint to enhance the possibility of curative intent surgery. FOLFIRI3 has shown promising results as second-line chemotherapy for mCRC patients previously exposed to oxaliplatin. The clinical efficacy of FOLFIRI3 was never determined in association with bevacizumab in non-previously treated mCRC patients. Methods We conducted a phase II clinical trial to characterize the response rate and toxicity profile of FOLFIRI3-bevacizumab as initial treatment for mCRC. Sixty-one patients enrolled in 3 investigation centers were treated with FOLFIRI3-bevacizumab (median of 10 cycles) followed by a maintenance therapy combining bevacizumab and capecitabine. Levels of plasma angiopoietin-2 (Ang-2) were measured by enzyme-linked immunosorbent assay at baseline. Results Overall response rate (ORR) was 66.7% (8% of complete and 58% of partial responses). The disease control rate was 91.7%. After a median time of follow-up of 46.7 months, 56 patients (92%) had progressed or died. The median progression free survival (PFS) was 12.7 months (95% confidence interval (CI) 9.7-15.8 months). The median overall survival (OS) was 24.5 months (95% CI: 10.6-38.3 months). Twenty-one patients underwent curative intent-surgery including 4 patients with disease initially classified as unresectable. Most common grade III-IV toxicities were diarrhea (15%), neutropenia (13%), asthenia (10%), and infections (4%). Hypertension-related medications needed to be increased in 3 patients. In multivariate analysis, surgery of metastases and Ang-2 levels were the only independent prognostic factors for PFS and OS. Indeed, baseline level of Ang-2 above 5 ng/mL was confirmed as an independent prognostic factor for progression free survival (HR = 0.357; 95% CI: 0.168-0.76, p = 0.005) and overall survival (HR = 0.226; 95% CI: 0.098-0.53, p = 0.0002). Conclusions As front-line therapy

  14. ABCC2-24C > T polymorphism is associated with the response to platinum/5-Fu-based neoadjuvant chemotherapy and better clinical outcomes in advanced gastric cancer patients

    PubMed Central

    Shan, Fei; Li, Shuangxi; Li, Zhongwu; Xiao, Aitang; Xing, Zhaodong; Xue, Kan; Li, Zhemin; Hu, Ying; Jia, Yongning; Miao, Rulin; Zhang, Lianhai; Bu, Zhaode; Wu, Aiwen; Ji, Jiafu

    2016-01-01

    Several studies have evaluated the efficacy of neoadjuvant treatment using oxaliplatin and fluoropyrimidines in advanced gastric cancer (GC). However, preoperative biomarkers predictive of clinical outcome remain lacking. We examined polymorphisms in the MTHFR, DPYD, UMPS, ABCB1, ABCC2, GSTP1, ERCC1, and XRCC1 genes to evaluate their usefulness as pharmacogenetic markers in a cohort of 103 GC patients treated with preoperative chemotherapy. DNA was extracted from peripheral blood cells, and the genotypes were analyzed using a SNaPShotTM assay, polymerase chain reaction amplification, and sequencing. The ABCC2-24C > T (rs717620) genotype was associated with pathologic response to neoadjuvant chemotherapy. Patients with the TT and TC genotypes responded to neoadjuvant chemotherapy 3.80 times more often than those with the CC genotype (95% CI: 1.27–11.32). Patients with the CC genotype also had poorer outcomes than those with other genotypes. Thus, ABCC2-24C > T polymorphism may help to predict the response to preoperative chemotherapy in GC patients. PMID:27487151

  15. 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.

  16. 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

    2015-09-05

    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.

  17. Low doses of ethanol decrease the activity of the angiotensin-converting enzyme in the aorta of aging rats and rats treated with a nitric oxide synthase inhibitor and dexamethasone.

    PubMed

    Emel'yanov, Maksim O; Korystova, Antonina F; Kublik, Ludmila N; Levitman, Maria Kh; Shaposhnikova, Vera V; Korystov, Yuri N

    2012-01-01

    In the present study, the activity of ACE (angiotensin-converting enzyme) in the aorta of senescent rats and rats treated with the NOS (NO synthase) inhibitor L-NAME (NG-nitro-L-arginine methyl ester) or dexamethasone and the effect of low doses of ethanol (0.2-1.2 g/kg of body weight, daily for 8-12 days) on this activity were studied. We found that ACE activity increased with age and in response to L-NAME and dexamethasone treatment. Ethanol at a dose of 0.4 g/kg of body weight per day decreased ACE activity in the aorta of aged rats and of rats treated with L-NAME or dexamethasone to the level of activity in young control rats. The optimal ethanol dose (the dose inducing a maximum decrease in ACE activity) increased with increasing doses of dexamethasone: 0.4 g/kg of body weight per day at 30 μg of dexamethasone/kg of body weight and 0.8 g/kg of body weight per day at 100 μg of dexamethasone/kg of body weight. It was also found that optimal doses of ethanol increased the number of cells in the thymus of rats treated with dexamethasone. The optimal dose of ethanol of 0.4 g/kg of body weight per day, which induced a maximum decrease in ACE activity in rat aorta, corresponded to a dose of 30 g of ethanol/day, which, according to epidemiological data, produces a maximum decrease in the incidence of cardiovascular disease in humans. In conclusion, the decrease in ACE activi