Home About us Contact
|
Home About us Contact | ||
|
|
||
Splenic Lymphocytes (splenic + lymphocyte)
Selected AbstractsPharmacokinetics, dose-range, and mutagenicity studies of methylphenidate hydrochloride in B6C3F1 mice,,ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 8 2008Mugimane G. Manjanatha Abstract Methylphenidate hydrochloride (MPH) is one of the most frequently prescribed pediatric drugs for the treatment of attention deficit hyperactivity disorder. In a recent study, increased hepatic adenomas were observed in B6C3F1 mice treated with MPH in their diet. To evaluate the reactive metabolite, ritalinic acid (RA) of MPH and its mode of action in mice, we conducted extensive investigations on the pharmacokinetics (PK) and genotoxicity of the drug in B6C3F1 mice. For the PK study, male B6C3F1 mice were gavaged once with 3 mg/kg body weight (BW) of MPH and groups of mice were sacrificed at various time points (0.25,24 hr) for serum analysis of MPH and RA concentrations. Groups of male B6C3F1 mice were fed diets containing 0, 250, 500, 1,000, 2,000, or 4,000 ppm of MPH for 28 days to determine the appropriate doses for 24-week transgenic mutation studies. Also, the micronucleus frequencies (MN-RETs and MN-NCEs), and the lymphocyte Hprt mutants were determined in peripheral blood and splenic lymphocytes, respectively. Mice fed 4,000 ppm of MPH lost significant BW compared to control mice (P < 0.01). There was a significant increase in the average liver weights whereas kidneys, seminal vesicle, testes, thymus, and urinary bladder weights of mice fed higher doses of MPH were significantly lower than the control group (P , 0.05). There was no significant increase in either the Hprt mutant frequency or the micronucleus frequency in the treated animals. These results indicated that although MPH induced liver hypertrophy in mice, no genotoxicity was observed. Environ. Mol. Mutagen., 2008. Published 2008 Wiley-Liss, Inc. [source] Mutagenicity of zidovudine, lamivudine, and abacavir following in vitro exposure of human lymphoblastoid cells or in utero exposure of CD-1 mice to single agents or drug combinations,,ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 3-4 2007Salina M. Torres Abstract Experiments were performed to investigate the impact of zidovudine (AZT), lamivudine (3TC), and abacavir (ABC) on cell survival and mutagenicity in two reporter genes, hypoxanthine-guanine phosphoribosyltransferase (HPRT) and thymidine kinase (TK), using cell cloning assays for assessing the effects of individual drugs/drug combinations in (1) TK6 human lymphoblastoid cells exposed in vitro and (2) splenic lymphocytes from male CD-1 mice exposed transplacentally on days 12,18 of gestation. In TK6 cells, dose-related increases in HPRT and TK mutant frequencies were found following 3 days of exposure to AZT or 3TC alone (33, 100, or 300 ,M), or to equimolar amounts of AZT-3TC. Compared with single drug exposures, AZT-3TC coexposures generally yielded enhanced elevations in HPRT and TK mutant frequencies. Mutagenicity experiments with ABC alone, or in combination with AZT-3TC, were complicated by the extreme cytotoxicity of ABC. Exposure of cells either to relatively high levels of AZT-3TC short-term (100 ,M, 3 days), or to peak plasma-equivalent levels of AZT-3TC for an extended period (10 ,M, 30 days), resulted in similar drug-induced mutagenic responses. Among sets of mice necropsied on days 13, 15, or 21 postpartum, Hprt mutant frequencies in T-cells were significantly elevated in the AZT-only (200 mg/kg bw/day) and AZT-3TC (200 mg AZT + 100 mg 3TC/kg bw/day) groups at 13 days of age. These results suggest that the mutagenicity by these nucleoside analogs is driven by cumulative dose, and raises the question of whether AZT-3TC has greater mutagenic effects than AZT alone in perinatally exposed children. Environ. Mol. Mutagen. © 2007 Wiley-Liss, Inc. [source] Retinoid- and carotenoid-enriched diets influence the ontogenesis of the immune system in miceIMMUNOLOGY, Issue 2 2003Ada L. Garcia Summary Vitamin A (VA) has been identified as an important factor for the development of the immune system, especially during ontogenesis. It has been shown that antibody secretion and proliferation of lymphocyte populations depend on retinoids. In the present study we investigated the influence of a base VA diet and diets enriched with VA, ,-carotene and lycopene, on the ontogenesis of the immune system in mice. We examined the absolute and relative concentrations of splenic B lymphocytes (CD45R/B220), T lymphocytes (CD3+) and their subpopulations (CD4+ and CD8+), and measured serum immunoglobulin G (IgG) concentrations in the offspring of supplemented dams at different ages (1, 3, 5, 7, 14, 21 and 65 days). The experimental diets resulted in higher numbers of T and B lymphocytes after VA and carotenoid enrichment, when compared, at various time-points, with the base diet. Higher values of total serum IgG were found in the ,-carotene-enriched diet group on day 7. On days 7 and 14, the enriched diets induced significant alterations in the percentages and total numbers of splenic lymphocytes in comparison to the base diet. Our results confirm that supplementation with VA and carotenoids affect the immune-cell function during ontogenesis and suggest a possible role of these nutritional factors on the development of the immune system. [source] Inverse Association between T-Cell Immunoglobulin and Mucin Domain-1 and T-bet in a Mouse Model of Allergic Rhinitis,THE LARYNGOSCOPE, Issue 6 2007Geng Xu MD Abstract Background: It has been suggested that human hepatitis A virus cellular receptor, also known as T-cell immunoglobulin and mucin domain-1 (TIM-1), plays an important role in the development of allergic diseases on the basis of epidemiologic data, but the molecular mechanism has been unclear. In a murine model of ovalbumin (OVA)-sensitized allergic rhinitis (AR), we examined the expression of TIM-1 and its correlation with T helper1-associated transcription factor, T-bet, as a potential mediator of T-cell immunoglobulin expression. Methods: Mice were challenged intranasally with OVA to elicit AR. The expression of TIM-1 in nasal tissues was examined by real-time reverse-transcription polymerase chain reaction (RT-PCR), and the surface expression of TIM-1 in peripheral blood mononuclear cells was evaluated by means of flow cytometry. In addition, the expression of TIM-1 as well as T-bet in splenic lymphocytes was examined by Western blotting. Results: TIM-1 mRNA was increased significantly in nasal tissues (P < .05) as seen by real-time RT-PCR. Flow cytometry indicated a differential TIM-1 expression of 135.5 ± 34.2 in the AR group versus 51.1 ± 10.9 in the control group (P < .05). The mean values of normalized TIM-1 were 0.43 ± 0.18 and 0.21 ± 0.10 in AR and control groups, respectively, whereas the mean values of normalized T-bet were 0.22 ± 0.13 and 0.67 ± 0.17 in the AR and control groups, respectively. There was a significant difference in the production of TIM-1 as well as T-bet in AR mice versus control mice (P < .05). The increased production of TIM-1 correlated significantly with the decreased T-bet in spleen tissue of AR mice (r = ,0.52, P < .05). Conclusion: Our experimental model recapitulates an increase in lymphocyte TIM-1 expression seen in AR both locally and systemically. Our results also demonstrate an inverse relationship between lymphocyte TIM-1 and T-bet expression, suggesting a possible mechanism that TIM-1 influences the development of AR. [source] CTLA-4Ig blocks the development and progression of citrullinated fibrinogen,induced arthritis in DR4-transgenic miceARTHRITIS & RHEUMATISM, Issue 10 2010David Yue Objective To assess the role of T cells in the mouse model of citrullinated human fibrinogen,induced rheumatoid arthritis (RA) using CTLA-4Ig, an agent that blocks T cell costimulation, which is required for T cell activation. Methods Humanized HLA,DR,1*0401,transgenic (DR4-Tg) mice were immunized with Cit,human fibrinogen to induce arthritis. Prior to, and at the onset or peak of, arthritis, the DR4-Tg mice were treated with CTLA-4Ig or control human IgG1 or were left untreated. Arthritis development and progression were monitored by measuring ankle swelling with calipers and by assessing histopathologic changes. The immune responses to the citrullinated antigens and the corresponding unmodified antigens, as well as the arthritogenicity of lymphocytes from these mice, were examined. The latter was performed using lymphocyte transfers from CTLA-4Ig,treated or control mice via intraperitoneal injection into naive DR4-Tg mice. Recipient mice also received an intraarticular injection of Cit,human fibrinogen, unmodified human fibrinogen, or vehicle. Results CTLA-4Ig,treated, but not human IgG1-treated, arthritic mice had significantly reduced ankle swelling and pathologic joint damage. Treatment with CTLA-4Ig, but not human IgG1, suppressed Cit,human fibrinogen,induced T cell activation, including citrulline-specific T cell activation, when given prior to disease onset. Transfer of splenic lymphocytes from untreated or human IgG1,treated arthritic mice caused arthritis in recipients, and this occurred when Cit,human fibrinogen, but not unmodified fibrinogen, was deposited into the joint. Splenocytes from CTLA-4Ig,treated mice were unable to transfer arthritis. Conclusion Activated citrulline-specific T cells play a direct role in the development and progression of arthritis in this model of Cit,human fibrinogen,induced RA. [source] The Role of the Bcl-3 Proto-Oncogene in Thyroid Hormone-Induced Liver Cell ProliferationARTIFICIAL ORGANS, Issue 6 2009Raza Malik Abstract The aim of the study was to determine if thyroid hormone-induced liver cell proliferation occurs through the Bcl-3 proto-oncogene. Rodents (including Bcl-3 knockout mice and the wild-type strain) were injected with a single dose of tri-iodothyronine (T3) and sacrificed at various time points. Hepatic mRNA (real-time polymerase chain reaction ) and protein expression (Western analysis) of Bcl-3 was quantified in rats stimulated with T3. Cell proliferation was induced in a variety of cell types after T3 injection at 24 h including hepatocytes (7 ± 1.1% vs. 0.45 ± 0.025%; P < 0.01), hepatic nonparenchymal cells (3.8 ± 1.2% vs. 0.3 ± 0.01%; P < 0.01), renal tubular cells (8.1 ± 1.6% vs. 0.2 ± 0.035%; P < 0.01), and splenic lymphocytes (4.8 ± 1.2% vs. 0.35 ± 0.02%; P < 0.01). We showed a twofold increase in hepatic Bcl-3 mRNA (P < 0.01) and protein expression (P < 0.01) at 24 h in rats stimulated with T3. However, there were no differences in the rate of liver cell proliferation between Bcl-3 knockout mice and the wild-type strain (0.4 ± 0.15% vs. 0.3 ± 0.1%), indicating that Bcl-3 was not functionally involved in thyroid hormone-induced liver cell proliferation. A single gene is unlikely to initiate the process of thyroid hormone-induced cell proliferation. A complex interaction between the genomic and nongenomic effects of thyroid hormone is likely to regulate the mitogenic effects. [source] Isolation of an anti-angiogenic substance from Agaricus blazei Murill: Its antitumor and antimetastatic actionsCANCER SCIENCE, Issue 9 2004Yoshiyuki Kimura We previously found that ergosterol isolated from Agaricus blazei inhibited tumor growth through the inhibition of tumor-induced neovascularization. In the present study, we isolated further anti-angiogenic substances (A-1 and A-2) from this fungus using an assay system of angiogenesis induced by Matrigel supplemented with vascular endothelial growth factor, and A-1 was identified as sodium pyroglutamate. Next, we examined the antitumor and antimetastatic actions of A-1 using Lewis lung carcinoma (LLC)-bearing mice. A-1 (30, 100 and 300 mg/kg) inhibited tumor growth and metastasis to the lung. The reduction of the numbers of splenic lymphocytes, CD4+ and CD8+ T cells in LLC-bearing mice was inhibited by the oral administration of A-1 (30, 100 and 300 mg/kg). Further, A-1 increased the number of apoptotic cells of tumors and the numbers of CD8+ T and natural killer cells invading the tumors, and inhibited the increase of von Willebrand factor expression (a measure of angiogenesis) in the tumors. These results suggest that the antitumor and antimetastatic actions of A-1 (sodium pyroglutamate) may be associated with inhibition of the reduction of immune response caused by the tumor growth and tumor-induced neovascularization. This is the first report showing that sodium pyroglutamate isolated from A. blazei as an anti-angiogenic substance has potent antitumor and antimetastatic actions, as well as immune-modulatory activity, in tumor-bearing mice. [source] | ||||||||||