Home About us Contact
|
Home About us Contact | ||
|
|
||
Significant Elevation (significant + elevation)
Selected AbstractsTumour Necrosis Factor Receptor 1 and Hepatocyte Regeneration in Acetaminophen Toxicity: A Kinetic Study of Proliferating Cell Nuclear Antigen and Cytokine ExpressionBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 1 2005Laura P. James To examine the effects of tumour necrosis factor receptor 1 on hepatocyte regeneration, immunohistochemical staining with proliferating cell nuclear antigen was performed. Immunohistochemical staining for proliferating cell nuclear antigen was significantly reduced at multiple time points in the knock-out mice and did not normalize until 96 hr. To evaluate the effect of tumour necrosis factor receptor 1 depletion on cytokines known to be involved in regeneration, levels of macrophage inhibitory protein 2, interferon-,-inducible protein-10 and monocyte chemoattractant protein 1 were compared in the two groups of mice. Significant elevation of all cytokines was observed in both groups of mice; however, higher levels were present in the knock-out mice. Depletion of tumour necrosis factor receptor 1 has long-lasting effects on hepatocyte regeneration in acetaminophen toxicity but multiple other factors appear to orchestrate eventual recovery in these mice. [source] Absence of tissue inhibitor of metalloproteinases 3 disrupts alveologenesis in the mouseDEVELOPMENT GROWTH & DIFFERENTIATION, Issue 1 2009Sean E. Gill Tissue inhibitors of metalloproteinases (TIMPs) regulate extracellular matrix (ECM) degradation by matrix metalloproteinases (MMPs) throughout lung development. We examined lungs from TIMP3 null mice and found significant air space enlargement compared with wild type (WT) animals during a time course spanning early alveologenesis (post-partum days 1, 5, 9 and 14). Trichrome staining revealed a similar pattern of collagen distribution in the walls of nascent alveoli; however, the alveolar walls of TIMP3 mutant mice appeared to be thinner than controls. Assessment of MMP2 and MMP9 activities by gelatin zymography demonstrated a significant elevation in the active form of MMP2 at post-partum days 1 and 5. Treatment of null pregnant dams with a broad spectrum synthetic metalloproteinase inhibitor, GM6001, on embryonic day 16.5 enhanced the formation of primitive alveoli during the saccular stage of lung development as evidenced by a partial, but significant, rescue of alveolar size in post-partum day 1 animals. We propose that increased MMP activity in the absence of TIMP3 enhances ECM proteolysis, upsetting proper formation of primitive alveolar septa during the saccular stage of alveologenesis. Therefore, TIMP3 indirectly regulates alveolar formation in the mouse. To our knowledge, ours is the first study to demonstrate that in utero manipulation of the TIMP/MMP proteolytic axis, to specifically inhibit proteolysis, significantly affects lung development. [source] Nickel potentiates the genotoxic effect of benzo[a]pyrene in Chinese hamster lung V79 cellsENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 3 2006Cheng Z. Deng Abstract The modulating effect of acute exposure to NiCl2 on the induction of chromosome aberrations by a model carcinogen, benzo[a]pyrene (B[a]P), was examined in Chinese hamster V79 lung cells. At concentrations up to 20 ,g/ml (84.2 ,M), NiCl2 did not significantly increase the frequency of chromosome aberrations in V79 cells when the cells were exposed concomitantly to 0.5 ,g/ml B[a]P. Addition of the S15 liver microsomal fraction together with the B[a]P did not alter the results. Addition of NiCl2 2 hr before treatment of cells with 0.5 ,g/ml B[a]P also did not result in a significant elevation of the frequency of chromosome aberrations, even at NiCl2 concentrations as high as 20 ,g/ml. Contrasting sharply with these findings, when V79 cells were treated with NiCl2 immediately after B[a]P exposure, a significant increase in the frequency of chromosome damage was observed at NiCl2 concentrations as low as 5 ,g/ml (21.1 ,M). NiCl2 -mediated enhancement of chromosome damage was also observed when V79 cells were exposed to the reactive B[a]P intermediate, benzo[a]pyrene,r,7,t,8-dihydrodiol- t,9,10-epoxide (BPDE). In the BPDE-treated cells, the level of NiCl2 -mediated enhancement was similar to that observed with the tumor promoter 12- o -tetradecanoylphorbol-13-acetate (TPA, 100 ng/ml). These results are consistent with the view that the effect of nickel (II) on B[a]P-induced genetic damage is dependent on the relative times of exposure to Ni2+ and B[a]P. NiCl2 did not enhance the frequency of chromosome aberrations induced by Chromium (VI), regardless of the order of addition of the chemicals to the V79 cells. These results suggest that nickel may act as a promoter of chemically-induced genetic damage through induction of error-prone repair. Environ. Mol. Mutagen., 2006. © 2005 Wiley-Liss, Inc. [source] Ecdysteroid synthesis and imaginal disc development in the midge Chironomus riparius as biomarkers for endocrine effects of tributyltinENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 5 2002Torsten Hahn Abstract Acute effects of the endocrine disruptor bis (tri- n -butyltin) oxide (TBTO) on molting-hormone biosynthesis and imaginaldisc development were investigated in larvae of the midge Chironomus riparius (Meigen). Ecdysteroid synthesis was measured by 24-h incubation of molting-hormone-synthesizing tissues (prothoracic glands) in vitro with or without the addition of TBTO. The amount of ecdysteroids produced was analyzed by radioimmunoassay. Developmental effects in vivo were investigated by determining the developmental phase of the genital imaginal discs before and after a 48-h exposure to TBTO in water. Sex-specific effects were found with both endpoints. Ecdysteroid synthesis was significantly reduced (analysis of variance [ANOVA], p , 0.005) in female larvae at all concentrations (TBTO-Sn at 50, 500, and 5,000 ng/L), whereas a significant elevation of the biosynthesis rate occurred in male larvae in the 500-ng/L treatment (ANOVA, p , 0.05). In vivo experiments with development of the genital imaginal disc within a 48-h exposure period revealed a significantly slower development in female larvae and a significantly faster development in male larvae (contingency tables, p , 0.001) at all concentrations tested (TBTO-Sn at 10, 50, 200, and 1,000 ng/L). These results partly coincided with the in vitro effects on molting-hormone synthesis. The 48-h median lethal concentration (LC50) was 25 ,g/L (20,30 ,g/L 95% confidence intervals). The combination of in vitro and in vivo methods has proven to be a useful approach for the detection of endocrine effects of TBTO in C. riparius at levels 2,000-fold below the LC50 value. High sensitivity and short test duration suggest that chironomids may have potential as freshwater sentinel organisms for endocrine-disrupting chemicals. [source] Parabolic flight primes cytotoxic capabilities of polymorphonuclear leucocytes in humansEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 8 2009I. Kaufmann Abstract Background, Previously performed in vitro studies suggested that gravitational stress may alter functions of immune cells. This study investigated the in vivo effects of parabolic flight manoeuvres as a short-term model of micro- and hypergravity on the cytotoxic and microbicidal polymorphonuclear leucocyte (PMN) functions as the key element of innate immunity. Material and methods, Twenty-one healthy male volunteers underwent 30 subsequent parabolic flight manoeuvres. Each manoeuvre produced 22-s periods of nearly weightlessness close to «0g», with each parabola starting with a pull-up and ending with a pull-out (hypergravity) at 1·8 g for about 20 s each. Blood samples were drawn 24 h prior to take off (T0), after 25,30 parabolas (T1), and 24 h (T2) and 48 h (T3) after flight for determination of (i) leucocyte number and subpopulations, (ii) PMNs' capabilities to produce hydrogen peroxide (H2O2) and to adhere and phagocytose particles and (iii) plasma cytokines known to prime PMN functions [interleukin-8 (IL-8), tumour necrosis factor-, (TNF-,), granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF)]. Results, Parabolic flight induced an increase in leucocyte number with a significant elevation of the PMN fraction. The spontaneous H2O2 production by PMNs did not change; however, the capability of PMNs to produce H2O2 in response to soluble stimuli [N -formyl-methionyl-leucyl-phenylalanine (fMLP), fMLP and TNF-,, calcium ionophore (A23187), phorbol myristate acetate (PMA)] was increased. Adhesive and phagocytic properties of PMNs were not altered. Regarding priming cytokines, IL-8 and G-CSF were significantly elevated. Conclusions, Our data indicate that parabolic flight induces priming of the cytotoxic capabilities of PMNs without affecting microbicidal functions. [source] Increased neurogenesis and brain-derived neurotrophic factor in neurokinin-1 receptor gene knockout miceEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2003Sara Morcuende Abstract It has previously been shown that chronic treatment with antidepressant drugs increases neurogenesis and levels of brain-derived neurotrophic factor in the hippocampus. These changes have been correlated with changes in learning and long-term potentiation and may contribute to the therapeutic efficacy of antidepressant drug treatment. Recently, antagonists at the neurokinin-1 receptor, the preferred receptor for the neuropeptide substance P, have been shown to have antidepressant activity. Mice with disruption of the neurokinin-1 receptor gene are remarkably similar both behaviourally and neurochemically to mice maintained chronically on antidepressant drugs. We demonstrate here that there is a significant elevation of neurogenesis but not cell survival in the hippocampus of neurokinin-1 receptor knockout mice. Neurogenesis can be increased in wild-type but not neurokinin-1 receptor knockout mice by chronic treatment with antidepressant drugs which preferentially target noradrenergic and serotonergic pathways. Hippocampal levels of brain-derived neurotrophic factor are also two-fold higher in neurokinin-1 receptor knockout mice, whereas cortical levels are similar. Finally, we examined hippocampus-dependent learning and memory but found no clear enhancement in neurokinin-1 receptor knockout mice. These data argue against a simple correlation between increased levels of neurogenesis or brain-derived neurotrophic factor and mnemonic processes in the absence of increased cell survival. They support the hypothesis that increased neurogenesis, perhaps accompanied by higher levels of brain-derived neurotrophic factor, may contribute to the efficacy of antidepressant drug therapy. [source] Synaptic localization of GABAA receptor subunits in the substantia nigra of the rat: effects of quinolinic acid lesions of the striatumEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2002Fumino Fujiyama Abstract The inhibitory amino acid, ,-aminobutyric acid (GABA), plays a critical role in the substantia nigra (SN) in health and disease. GABA transmission is controlled in part by the type(s) of GABA receptor expressed, their subunit composition and their location in relation to GABA release sites. In order to define the subcellular localization of GABAA receptors in the SN in normal and pathological conditions, sections of SN from control rats and rats that had received quinolinic acid lesions of the striatum were immunolabelled using the postembedding immunogold technique with antibodies against subunits of the GABAA receptor. Immunolabelling for ,1, ,2/3 and ,2 subunits was primarily located at symmetrical synapses. Double-labelling revealed that ,2/3 subunit-positive synapses were formed by terminals that were enriched in GABA. Colocalization of ,1, ,2/3 and ,2 subunits occurred at individual symmetrical synapses, some of which were identified as degenerating terminals derived from the striatum. In the SN ipsilateral to the striatal lesion there was a significant elevation of immunolabelling for ,2/3 subunits of the GABAA receptor at symmetrical synapses, but not of GluR2/3 subunits of the AMPA receptor at asymmetrical synapses. It was concluded that fast GABAA -mediated transmission occurs primarily at symmetrical synapses within the SN, that different receptor subunits coexist at individual synapses and that the upregulation of GABAA receptors following striatal lesions is expressed as increased receptor density at synapses. The upregulation of GABAA receptors in Huntington's disease and its models is thus likely to lead to an increased efficiency of transmission at intact GABAergic synapses in the SN and may partly underlie the motor abnormalities of this disorder. [source] Immunoreactivity of corticotropin-releasing hormone, adrenocorticotropic hormone and , -melanocyte-stimulating hormone in alopecia areataEXPERIMENTAL DERMATOLOGY, Issue 7 2006Hei Sung Kim Abstract:, Psychological factors are believed to play a role in the pathogenesis of alopecia areata (AA), a frequently encountered hair disorder. In our study, statistically significant elevation of psychological stress was felt by AA patients prior hair loss compared with control, which was strongly believed contributory to hair loss (t -test, P < 0.01). The corticotropin-releasing hormone (CRH) and proopiomelanocortin (POMC) mRNA have been identified in the basal layer of the epidermis and pilosebaceous units of the normal scalp. And with the recent discovery of melanocytes and dermal fibroblasts capable of corticosterone production, the presence of a local stress response system resembling the hypothalamic,pituitary,adrenal (HPA) axis has been suggested. The local stress response system is involved in regulation of the normal hair cycle, but its precise role in AA is unknown. The influence of a local HPA axis or rather, CRH,POMC axis in AA was investigated by analysing immunohistochemically the expression levels of CRH and POMC peptides, including the adrenocorticotropic hormone (ACTH) and , -melanocyte-stimulating hormone (, -MSH), in a number of AA lesions and normal scalp (as control). The epidermis and pilosebaceous units of normal scalp stained weakly with CRH, ACTH and , -MSH, whereas those from the affected sites of the AA group showed intense expression of the peptides (chi-square test, P < 0.01). The meaning of this enhanced expression and their role in the pathogenesis of AA should be further evaluated in future. [source] Blood pressure and vascular reactivity to endothelin-1, phenylephrine, serotonin, KCl and acetylcholine following chronic alcohol consumption in vitroFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 3 2001Tijen Utkan Ethanol has been reported to cause hypertension, the mechanism of which is unknown. Therefore, the effect of chronic ethanol consumption on vascular responsiveness and blood pressure was investigated. Systolic blood pressure was recorded weekly by tail-cuff method. Aortic rings from rats fed chow ad libitum or pair-fed liquid diets containing either ethanol (7.2% v/v) or isocaloric carbohydrate for 4 weeks were placed in organ chambers for isometric tension measurement. There was a mild but significant elevation of the systolic blood pressure in the alcohol-fed rats by week 1 compared to baseline measurements and this remained higher. No significant changes in reactivity of rat isolated aortas to phenylephrine, serotonin, endothelin-1 (ET-1) and KCl were seen in chronic ethanol consumption. In addition, the sensitivity (i.e. pD2) of alcohol-fed aortic rings to the vasoconstrictors was also unchanged compared to controls. Chronic ethanol consumption, however, increased relaxation to acetylcholine with increased pD2 values, but did not alter relaxation to sodium nitroprusside, a cyclic guanosine monophosphate (cGMP)-dependent direct smooth muscle dilator. The results indicate that chronic ethanol consumption significantly potentiates endothelium-dependent relaxations in aortic rings, probably through interference with the production and/or the release of nitric oxide (NO) or adaptive alterations in muscarinic receptors on the endothelial cells, and that increased vascular responsiveness to several vasoconstrictors is not a mechanism responsible for the blood pressure elevation in the chronic alcohol consumption in rats. [source] Heritability of plasma amyloid , in typical late-onset Alzheimer's disease pedigreesGENETIC EPIDEMIOLOGY, Issue 1 2001Nilufer Ertekin-Taner Abstract Plasma amyloid ,42 peptide (A,42) levels are significantly elevated in all genetic forms of early-onset Alzheimer's disease caused by familial Alzheimer's disease mutations or Down's syndrome. Moreover, recent studies have determined that both plasma A,42 and A,40 levels are significantly elevated in late-onset Alzheimer's disease (LOAD) patients, their cognitively normal first-degree relatives, and members of typical LOAD families when compared to appropriate controls. To determine the magnitude of the genetic component affecting plasma A, levels, we estimated the heritability of plasma A,42 and A,40 in 15 extended, multigenerational LOAD pedigrees, using a variance components method. Heritability estimates as high as 73 and 54% were found for plasma A,42 and A,40 levels, respectively. Inclusion of the ApoE ,4 dosage as a covariate was not found to have a significant effect on the heritability of these traits. These results suggest that genetic determinants other than ApoE account for a very substantial percentage of the phenotypic variance in plasma A, levels. The high heritability and the significant elevation of these traits in LOAD pedigrees suggest that at least some of the genetic determinants of plasma A, levels may lead to elevated A, and LOAD in these families. Thus, we suggest that plasma A, levels are quantitative traits that may be excellent surrogate markers for use in linkage analysis to identify loci that are important in typical LOAD. Genet. Epidemiol. 21:19,30, 2001. © 2001 Wiley-Liss, Inc. [source] Neutrophil depletion protects against murine acetaminophen hepatotoxicity,,HEPATOLOGY, Issue 6 2006Zhang-Xu Liu We previously reported that liver natural killer (NK) and NKT cells play a critical role in mouse model of acetaminophen (APAP)-induced liver injury by producing interferon gamma (IFN-,) and modulating chemokine production and subsequent recruitment of neutrophils into the liver. In this report, we examined the role of neutrophils in the progression of APAP hepatotoxicity. C57BL/6 mice were given an intraperitoneal toxic dose of APAP (500 mg/kg), which caused severe acute liver injury characterized by significant elevation of serum ALT, centrilobular hepatic necrosis, and increased hepatic inflammatory cell accumulation. Flow cytometric analysis of isolated hepatic leukocytes demonstrated that the major fraction of increased hepatic leukocytes at 6 and 24 hours after APAP was neutrophils (Mac-1+Gr-1+). Depletion of neutrophils by in vivo treatment with anti-Gr-1 antibody (RB6-8C5) significantly protected mice against APAP-induced liver injury, as evidenced by markedly reduced serum ALT levels, centrilobular hepatic necrosis, and improved mouse survival. The protection was associated with decreased FasL-expressing cells, cytotoxicity against hepatocytes, and respiratory burst in hepatic leukocytes. In intracellular adhesion molecule (ICAM)-1,deficient mice, APAP caused markedly reduced liver injury when compared with wild-type mice. The marked protection in ICAM-1,deficient mice was associated with decreased accumulation of neutrophils in the liver. Hepatic GSH depletion and APAP-adducts showed no differences among the antibody-treated, ICAM-1,deficient, and normal mice. In conclusion, accumulated neutrophils in the liver contribute to the progression and severity of APAP-induced liver injury. (HEPATOLOGY 2006;43:1220,1230.) [source] Interleukin-17 as a new marker of severity of acute hepatic injuryHEPATOLOGY RESEARCH, Issue 4 2007Yuki Yasumi Aim:, To determine cytokines associated with the progression of acute hepatic injury (AHI), we comprehensively evaluated the serum levels of 17 cytokines. Methods:, We simultaneously measured serum levels of 17 cytokines on admission using a newly developed suspension array protein assay system in 51 patients with AHI, including 15 conventional AHI (CAHI), 15 severe AHI (SAHI) and 21 fulminant hepatic failure (FHF). Results:, Interleukin (IL)-6, IL-8 and IL-17 levels were significantly different among the three disease types as determined by one-way analysis of variance, and only the IL-17 level showed a significant elevation in SAHI and FHF than in CAHI. Namely, the IL-17 levels in SAHI and FHF patients were 4.4 (2.0,11.0) (mean [1 .s.d. range]) and 5.6 (2.0,18.5) pg/mL, respectively, whereas all CAHI patients showed levels lower than the lower limit of detection (2.0 pg/mL). In multiple regression analysis for each factor of model for end-stage liver disease (MELD) score, only IL-10 level was selected as the significant independent variable for total bilirubin level, only IL-17 level for prothrombin time, and TNF-, and IL-1, levels for creatinine level. Conclusion:, These data suggest the usefulness of serum IL-17 level in evaluating the severity of AHI, thus emphasizing the necessity for the basic investigation of the pathological role of IL-17 in acute hepatitis. [source] Transcription factor NF-,B activation after in vivo perforant path LTP in mouse hippocampusHIPPOCAMPUS, Issue 6 2004Ramiro Freudenthal Abstract There is increasing evidence that transcription factors (TFs) play a critical role in maintaining later phases of hippocampal long-term potentiation (LTP). We have been led to study the role in synaptic plasticity of the powerful, yet generally unheralded, NF-,B TF because it may serve as both a signaling molecule after its activation at the synapse and then a transcription initiator upon reaching the nucleus. In the present study, we show that LTP activates NF-,B in the intact mouse hippocampus. Mice were sacrificed 15 min after one of three treatments: tetanization (high-frequency stimulation [HFS]), low-frequency stimulation (LFS), or no stimulated control animals (CT). In a first study, nuclear NF-,B activity from hippocampus was estimated by electrophoretic mobility shift assays (EMSAs). A higher level of hippocampal TF binding to the NF-,B recognition element was found in the HFS group compared with LFS or CT. In a second study, NF-,B activity was evaluated by immunohistochemistry with a specific antibody that recognizes the activated form of NF-,B. This antibody binds to the exposed nuclear location sequence on the p65 subunit of NF-,B consequent to its dissociation from the inhibitory I,B molecule. In the four subfields of hippocampus examined,granule cell layer, hilus of the dentate gyrus, CA3 and CA1 pyramidal fields of the hippocampal gyrus,the highest levels of activated NF-,B, statistically significant in all cases were found after HFS. In certain comparisons, LFS animals also showed significant elevation with respect to CT. These results support the role of NF-,B as part of the synaptic signaling and transcriptional regulation mechanism required in long-term plasticity, emphasizing the combinatorial nature of TF function. © 2004 Wiley-Liss, Inc. [source] The protective effect of N -acetylcysteine against cyclosporine A-induced hepatotoxicity in ratsJOURNAL OF APPLIED TOXICOLOGY, Issue 1 2008Hasan Kaya Abstract The immunosuppressive agent cyclosporine A (CsA) has been reported to exert measurable hepatotoxic effects. One of the causes leading to hepatotoxicity is thought to be reactive oxygen radical formation. The aim of this study was to investigate the effects of N -acetylcysteine (NAC) treatment on CsA-induced hepatic damage by both analysing superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), aspartate aminotransferase (AST) and alanine transaminase (ALT) activities with malondialdehyde (MDA) and nitric oxide (NO) levels, and using an histological approach. CsA administration produced a decrease in hepatic SOD activity, and co-administration of NAC with CsA resulted in an increase in SOD activity. MDA and NO levels increased in the CsA group and NAC treatment prevented those increases. A significant elevation in serum AST and ALT activities was observed in the CsA group, and when NAC and CsA were co-administered, the activities of AST and ALT were close to the control levels. CsA treatment caused evident morphological alterations. Control rats showed no abnormality in the cytoarchitecture of the hepatic parenchyma. The co-administration of NAC with CsA showed no signs of alteration and the morphological pattern was almost similar to the control group. In conclusion, CsA induced liver injury and NAC treatment prevented the toxic side effects induced by CsA administration through the antioxidant and radical scavenging effects of NAC. Copyright © 2007 John Wiley & Sons, Ltd. [source] Effects of long-term administration of N-3 polyunsaturated fatty acids (PUFA) and selective estrogen receptor modulator (SERM) derivatives in ovariectomized (OVX) miceJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2003L. Zeitlin Abstract We studied the beneficial effects of dietary consumption of n-3 polyunsaturated fatty acids (PUFA) and two selective estrogen receptor modulator (SERM) derivatives (SERM-I and SERM-II) and their combined effect on serum lipids, skin dermis and adipose layers, bone marrow adipogenesis, and cytokine secretion in mice. Two different ovariectomized (OVX) models were studied: treatment began immediately post-OVX in one and 3 months post-OVX in the other. Our results showed that n-3 PUFA and both SERMs decreased triglyceride levels in the serum, and that SERMs also decreased serum cholesterol levels while n-3 PUFA had no similar effect. SERMs had no effect on IL-6, IL-1 beta, or IL-10 levels, but they decreased ex vivo tumor necrosis factor (TNF-,). N-3 PUFA decreased secretion of non-induced IL-6 and TNF-, from cultured BMC and IL-1 beta levels in vivo (i.e., in bone marrow plasma), but its main effect was a significant elevation in the secretion of IL-10, a known anti-inflammatory cytokine. OVX-induced B-lymphopoiesis was not affected by LY-139481 (SERM-I) while LY-353381 (SERM-II) exhibited an estrogen-antagonistic effect in sham and OVX mice and elevated the amount of B-cells in bone marrow. Fish oil consumption prevented the elevation in B-lymphopoiesis caused by OVX, but had no curative effect on established augmented B-lymphopoiesis. This activity could be mediated via the elevation of IL-10 which was shown to suppress B-lymphopoiesis. Both SERMs and n-3 PUFA inhibited the increase in adipose tissue thickness caused by OVX in mice. Our results showed that n-3 PUFA, could prevent some of the deleterious outcomes of estrogen deficiency that were not affected by SERMs. We observed no significant beneficial effects of the combined administration of SERM-I, SERM-II, and PUFA on the studied parameters. The exact mechanism by which polyunsaturated fatty acids exert their activities is still not clear, but peroxisome proliferator-activated receptors (PPARs) might be involved in processes which are modulated by n-3 PUFA. J. Cell. Biochem. 90: 347,360, 2003. © 2003 Wiley-Liss, Inc. [source] Suppressive role of endogenous regucalcin in the enhancement of protein kinase activity with proliferation of cloned rat hepatoma cells (H4-II-E)JOURNAL OF CELLULAR BIOCHEMISTRY, Issue S36 2001Shyuichiroh Inagaki Abstract The role of endogenous regucalcin, which is a regulatory protein in calcium signaling, in the regulation of protein kinase activity in the proliferation of the cloned rat hepatoma cells (H4-II-E) was investigated. Hepatoma cells were cultured for 6,72,h in the presence of fetal bovine serum (FBS; 1 or 10%). The number of cells and protein kinase activity in the 5500,g supernatant of cell homogenate was significantly increased 24 and 48,h after the culture with FBS (1 or 10%); the culture with 10% FBS was potent effect as compared with that of 1% FBS. FBS (10%)-increased protein kinase activity preceded a significant elevation of cell number of 6,h after culture. Serum stimulation-induced increase in protein kinase activity was significantly decreased in the presence of trifluoperazine (50,,M), staurosporine (10,6,M) or genistein (10,5,M) in the enzyme reaction mixture. The presence of anti-regucalcin monoclonal antibody (40 or 80,ng/ml) in the reaction mixture caused a significant increase in protein kinase activity in the cells cultured with FBS (1 or 10%). This increase was completely blocked by addition of regucalcin (10,6,M), which can reveal an inhibitory effect on protein kinase activity. Moreover, the effect of antibody in increasing protein kinase activity was significantly inhibited in the presence of trifluoperazine, staurosporine, or genistein, indicating that endogenous regucalcin has an inhibitory effect on Ca2+/calmodulin-dependent protein kinase, protein kinase C, and protein tyrosine kinase. The present study suggests that endogenous regucalcin plays a suppressive role in the enhancement of various protein kinase activities associated with a proliferation of the cloned rat hepatoma cells (H4-II-E). J. Cell. Biochem. 36: 12-18, 2001. © 2001 Wiley-Liss. Inc. [source] Induced hypothyroidism accelerates the regression of liver fibrosis in ratsJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 12 2007Rafael Bruck Abstract Background and Aim:, It has been shown in previous studies that hypothyroidism prevents the development of liver fibrosis in bile duct ligated rats and in rats chronically treated with thioacetamide (TAA). In recent years, regression of liver fibrosis (occurring spontaneously or during treatment) has been demonstrated in rodent models such as bile duct ligation and CCl4 administration. Therefore, in the present study, the potential therapeutic effect of hypothyroidism on liver fibrosis was investigated. Methods:, Liver fibrosis was induced in rats by administration of TAA (200 mg/kg, i.p., twice weekly) for 12 weeks. Hypothyroidism was then induced by either methimazole (0.04%) or propylthiouracil (0.05%) administered in drinking water for 8 weeks. Control euthyroid rats received normal drinking water. Hypothyroidism was confirmed by a significant elevation of serum thyroid-stimulating hormone levels. Results:, Eight weeks after the cessation of TAA administration, spleen weight, histological score of liver fibrosis, and hepatic hydroxyproline content were significantly lower in both groups of hypothyroid rats as compared to euthyroid controls (P < 0.001). In vitro studies using the rat hepatic stellate cell line HSC-T6 using northern blot analysis and zymography, respectively, showed that high concentrations of triiodotyronine (T3) enhanced transforming growth factor (TGF)-,-induced collagen I gene expression, and reduced metalloproteinase (MMP)-2 secretion, implying that reducing the levels of T3 may contribute to resolution of fibrosis. Additionally, low T3 concentration inhibited HSC-T6 proliferation. Conclusion:, Pharmacologically induced hypothyroidism accelerates the resolution of liver fibrosis in rats. This beneficial effect may in part be due to prevention of T3 -induced stimulation of collagen synthesis and reduction of MMP-2 secretion. [source] Elevated endogenous GABA level correlates with decreased fMRI signals in the rat brain during acute inhibition of GABA transaminaseJOURNAL OF NEUROSCIENCE RESEARCH, Issue 3 2005Zhengguang Chen Abstract Vigabatrin and gabaculine, both highly specific inhibitors of GABA (,-aminobutyric acid) transaminase, cause significant elevation of endogenous GABA levels in brain. The time course of GABA concentration after acute GABA transaminase inhibition was measured quantitatively in the ,-chloralose-anesthetized rat brain using in vivo selective homonuclear polarization transfer spectroscopy. The blood oxygenation level-dependent (BOLD) effect in functional magnetic resonance imaging (fMRI) has been considered to be coupled tightly to neuronal activation via the metabolic demand of associated glutamate transport. Correlated with the rise in endogenous GABA level after vigabatrin or gabaculine treatment, the intensity of BOLD-weighted fMRI signals in rat somatosensory cortex during forepaw stimulation was found to be reduced significantly. These results are consistent with previous findings that inhibition of GABA transaminase leads to augmented GABA release and potentiation of GABAergic inhibition. © 2004 Wiley-Liss, Inc. [source] Effect of natural seasonal pollen exposure and repeated nasal allergen provocations on elevation of exhaled nitric oxideALLERGY, Issue 11 2009K. Bergmann-Hug Background:, Exhaled nitric oxide (FENO) is a marker for allergic airway inflammation. We wondered whether in patients with intermittent allergic rhinitis only (i) natural pollen exposure and (ii) artificial pollen exposure by repeated nasal allergen provocations may lead to an elevation of FENO. Methods:, In two prospective studies, we compared the FENO of nonatopic controls with the FENO of nonasthmatic individuals with mild intermittent rhinitis to tree and/or grass pollen. Study I: 13 atopic individuals and seven controls had measurements of FENO, blood eosinophils and eosinophilic cationic protein (ECP) before, during and after pollen season. Study II: 16 atopic individuals and 12 controls had nasal allergen provocations on four following days out of pollen season, with daily measurements of FENO before, 2 and 6 h after provocation, and determination of blood eosinophils, ECP and FEV1 at baseline, on days 5 and 10,12. Results:, Natural pollen exposure (study I) caused a significant elevation of FENO in allergic individuals. Nasal allergen provocations (study II) did not elicit a statistically significant rise neither of FENO nor of blood eosinophils between baseline and day 5. However, a subgroup of four individuals with a rise of blood eosinophils during nasal allergen provocations showed also a rise of FENO. Conclusions:, We suppose that in allergic rhinitis a concomitant reaction of the bronchial system is dependent on a strong local inflammation leading to a generalized immune stimulation. [source] Peripheral blood lymphocytes P-glycoprotein (P-gp, gp-170) expression in allogeneic kidney transplant patientsNEPHROLOGY, Issue 3 2006KATARZYNA KOTRYCH SUMMARY: Aim and Methods: P-glycoprotein (gp-170, P-gp) is a transmembrane transporter involved in drug, for example cyclosporine A, efflux from the cells thus limiting their intracellular concentration. Expression of the transporter on the surface of immune competent cells may be associated with poor prognosis in kidney transplant patients. The aim of the present study was to evaluate P-gp expression on the surface of CD4+, CD8+, CD19+ and CD56+ cells in kidney transplant patients treated with cyclosporine A as a main immunosuppressant, using flow cytometry. Results: It was found that P-gp expression in kidney transplant patients with acute rejection did not differ significantly from transplanted patients without rejection studied in the same period after transplantation, as well as from the healthy controls. Administration of 3-day course of 1000 mg/24 h methylprednisolone did not affect the expression of P-gp in the studied cells, except for significant elevation in CD56+ cells, which disappeared at 2 weeks after cessation of steroid administration. Conclusion: Based on the results from the present study it can be concluded that P-gp expression is not a prognostic factor of acute kidney graft rejection. [source] Pilocarpine treatment in a mixed cohort of xerostomic patientsORAL DISEASES, Issue 1 2007DJ Aframian Objective:, To compare the effect of a single 5-mg dose of pilocarpine hydrochloride on the salivary flow rate in three groups of xerostomic patients. Subjects and methods:, Forty-five patients were divided into three groups according to the etiology of their xerostomia: (i) radiotherapy; (ii) Sjögren's syndrome; and (iii) sialosis and xerogenic medications. Following the oral administration of a 5-mg pilocarpine hydrochloride tablet blood pressure, heart rate, body temperature and saliva secretion rates were monitored hourly for 3 h and adverse events were reported. Results:, The most significant and persistent elevation of salivary flow rate was observed in the sialosis/drug-induced group followed by the Sjögren's syndrome group. The radiotherapy group presented a significant elevation of salivary secretion rate after 1 and 2 h, but returned to baseline at 3 h. No significant changes in vital signs were reported, except for low diastolic pressure measured at 1 h in the radiotherapy group. Several adverse events were recorded throughout the trial; however, only one patient withdrew from the study. Conclusion:, Treatment with pilocarpine hydrochloride tablets may improve saliva secretion in patients taking xerogenic medications and/or suffering from metabolic sialosis expanding the beneficial potential of this sialogogue. [source] Pilocarpine for the treatment of salivary glands' impairment caused by radioiodine therapy for thyroid cancerORAL DISEASES, Issue 3 2006DJ Aframian Objectives:, To study the effect of single-dose pilocarpine hydrochloride 5 mg on the whole unstimulated and stimulated salivary flow in patients suffering from thyroid cancer treated with radioiodine therapy, and to investigate the changes in vital signs during the treatment. Subjects and methods:, Five such patients were referred with complaints of dry mouth, rampant caries, and pain in the parotid gland region or history of chronic recurrent suppurative sialodenitis. A single dose of 5 mg pilocarpine hydrochloride was administered to each patient and blood pressure, heart rate, body temperature and salivary secretion rate were monitored at 1, 2 and 3 h. Results:, A significant elevation of unstimulated and stimulated saliva flow rate was observed in four patients without significant alteration of the monitored vital signs. Conclusions:, Treatment with pilocarpine hydrochloride may be beneficial in the case of impaired salivary function in patients treated with radioiodine. [source] Cytokine profile of sickle cell disease in OmanAMERICAN JOURNAL OF HEMATOLOGY, Issue 4 2004Anil Pathare Abstract The aim of our study was to assess the cytokine profile of sickle cell disease (SCD) patients in steady state and in vaso-occlusive crisis (VOC). VOC has a complex nature, involving interactions between sickle red blood cells (RBC), the endothelium, and leucocytes. Endothelial damage due to recurrent adhesion of sickle RBCs may disrupt endothelial function, leading to altered cytokine release. It is therefore pertinent to study the cytokine profile of SCD patients in steady state and in crisis prior to exploring its contribution to vaso-occlusive manifestations, since it is believed that an altered balance of proinflammatory and anti-inflammatory cytokines plays an important role in painful crisis. Cytokines including IL-1,, IL-2, IL-4, IL-6, IL-8, TNF-,, and IFN-, were measured by commercially available ELISA kits in SCD patients (n = 60); in steady state (n = 26) and in painful crisis (n = 34) and compared with nonanemic age- and sex-matched normal Omani controls (n = 20). SCD patients in crisis showed elevated levels of TNF-, (P < 0.092) and IL-6 (P < 0.024) when compared with steady state. It was also observed that SCD patients in steady state showed a significant elevation in IL-1, (P < 0.04), IL-6 (P < 0.0001), and IFN-, (P < 0.02) as compared to normal subjects. It is thus evident that both type I and type II cytokines are significantly altered in SCD patients. In steady state, type II proinflammatory cytokines are elevated, whereas in crisis, an additional augmentation of type I cytokines occurs, with persistent elevation of type II cytokines, emphasizing the role of perturbed endothelium and activated monocytes in the pathophysiology of vaso-occlusion in sickle cell crisis. Am. J. Hematol. 77:323,328, 2004 © 2004 Wiley-Liss, Inc. [source] Proanthocyanidin protects against cisplatin-induced nephrotoxicityPHYTOTHERAPY RESEARCH, Issue 12 2009Ahmed Amir Radwan Sayed Abstract Cisplatin (CP) [cis -diamminedichloroplatinum (II)] is one of the most widely therapeutic agents used for treating many types of cancer. At effective doses, CP causes nephrotoxicity which has been attributed to the induction of reactive oxygen species (ROS). In the present investigation proanthocyanidin (PA) was studied to demonstrate its therapeutic efficacy against CP-induced nephrotoxicity in mice. Cp treatment caused significant elevation of urea, creatinine and IL-6. In addition, CP enhanced malondialdehyde (MDA) levels and lowered the glutathione (GSH) content in kidney. On the other hand, superoxide dismutase (SOD) activity was decreased. These alterations were reversed by PA in a dose-dependent manner. These findings suggested a beneficial role of PA in attenuating CP-induced oxidative renal toxicity. Copyright © 2009 John Wiley & Sons, Ltd. [source] A cohort mortality study of chemical laboratory workers at Department of Energy Nuclear Plants,AMERICAN JOURNAL OF INDUSTRIAL MEDICINE, Issue 9 2008Travis Kubale PhD Abstract Objective This study evaluates the mortality experience of 6,157 chemical laboratory workers employed at United States Department of Energy facilities. Methods All cause, all cancer and cause-specific standardized mortality ratios were calculated. Cox regression analyses were conducted to further evaluate the relation between chemical exposure and mortality risk due to selected cancers. Results The mortality due to all causes combined and all cancers combined were below expectation for the cohort. There were no statistically significant elevations reported among males for any specific cancer or non-cancer outcome. There no statistically significant elevations among females for any specific non-cancer and most specific cancers; however, multiple myeloma deaths were significantly elevated (SMR,=,3.56; 95% CI,=,1.43,7.33; number of observed deaths, n,=,7). Statistically significant elevations were seen among workers employed 20+ years for leukemia using both 2- and 5-year lag periods. Also, a statistically significant positive trend of elevated lung cancer mortality with increasing employment duration was seen using both 5- and 10-year lags. A similar trend was seen for smoking related cancers among men. Conclusion While lymphatic and hematopoietic cancer mortality was below expectation, a significant elevation of multiple myeloma deaths among females and an elevation of leukemia among workers employed 20+ years (possibly due to radiation and benzene exposure) were observed. A NIOSH case,control study is underway to examine more closely the relation between multiple myeloma and a variety of chemical exposures among workers employed at the Oak Ridge K-25 facility. Am. J. Ind. Med. 51:656,667, 2008. Published 2008 Wiley-Liss, Inc. [source] A comparative proteomic analysis of HepG2 cells incubated by S(,) and R(+) enantiomers of anti-coagulating drug warfarinPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 7 2010Jing Bai Abstract Warfarin is a commonly prescribed oral anti-coagulant with narrow therapeutic index. It interferes with vitamin K cycle to achieve anti-coagulating effects. Warfarin has two enantiomers, S(,) and R(+) and undergoes stereoselective metabolism, with the S(,) enantiomer being more effective. We reported that the intracellular protein profile in HepG2 cells incubated with S(,) and R(+) warfarin, using iTRAQ-coupled 2-D LC-MS/MS. In samples incubated with S(,) and R(+) warfarin alone, the multi-task protein Protein SET showed significant elevation in cells incubated with S(,) warfarin but not in those incubated with R(+) warfarin. In cells incubated with individual enantiomers of warfarin in the presence of vitamin K, protein disulfide isomerase A3 which is known as a glucose-regulated protein, in cells incubated with S(,) warfarin was found to be down-regulated compared to those incubated with R(+) warfarin. In addition, Protein DJ-1 and 14-3-3 Protein, were down-regulated in cells incubated with either S(,) or R(+) warfarin regardless of the presence of vitamin K. Our results indicated that Protein DJ-1 may act as an enzyme for expression of essential enzymes in vitamin K cycle. Taken together, our findings provided molecular evidence on a comprehensive protein profile on warfarin,cell interaction, which may shed new lights on future improvement of warfarin therapy. [source] Interleukin-21 triggers both cellular and humoral immune responses leading to therapeutic antitumor effects against head and neck squamous cell carcinomaTHE JOURNAL OF GENE MEDICINE, Issue 1 2006Hiroshi Nakano Abstract Background Interleukin-21 (IL-21) plays important roles in the regulation of T, B, and natural killer (NK) cells. We hypothesized that the cytokine may provide a novel immunotherapy strategy for cancer by stimulating both Th1 and Th2 immune responses. In this context, antitumor immunity induced by IL-21 was examined in mice bearing subcutaneous head and neck squamous cell carcinomas (HNSCC). Methods A plasmid vector encoding murine IL-21 was injected intravenously into mice with pre-established HNSCC tumors, either alone or in combination with a vector construct expressing IL-15. Cytotoxic T lymphocyte (CTL) and NK killing activities were evaluated by chrome release assays, while HNSCC-specific antibody was examined by flow cytometry and ELISA. Results Significant antitumor effects were obtained by repeated transfection with either the IL-21 or the IL-15 gene. Co-administration of both cytokine genes resulted in increased suppression of tumor growth, significantly prolonging the survival periods of the animals. Thirty percent of the tumor-bearing mice that received the combination therapy survived for more than 300 days, completely rejecting rechallenge with the tumor at a distant site. IL-21 induced significant elevation of HNSCC-specific CTL activity, while IL-21 and IL-15 augmented NK activity in an additive manner. IL-21 gene transfer also promoted the production of tumor-specific IgG. Conclusions In vivo transduction of the IL-21 gene elicits powerful antitumor immunity, including both humoral and cellular arms of the immune response, and results in significant suppression of pre-established HNSCC. Co-transfer of the IL-15 gene further improved the therapeutic outcome, mainly by augmenting NK tumoricidal activity. The biological effects of IL-21 may be in sharp contrast to those of conventional Th1 and Th2 cytokines, suggesting intriguing implications of this cytokine for the classical concept of Th1 vs. Th2 paradigm. Copyright © 2005 John Wiley & Sons, Ltd. [source] Candidate's Thesis: Platelet-Activating Factor,Induced Hearing Loss: Mediated by Nitric Oxide?,THE LARYNGOSCOPE, Issue 12 2003Chung-Ku Rhee MD Abstract Objectives/Hypothesis Platelet-activating factor (PAF)in middle ear effusion is thought to induce hearing loss. The purpose of this study is to investigate the role of nitric oxide (NO) in the mechanism of PAF-induced hearing loss by studying the effects of PAF application on the round window membrane (RWM) with and without PAF-antagonist NO-blocker. Study Design Longitudinal study on randomized guinea pigs using PAF to induce hearing loss. Methods Guinea pigs were divided into four groups: PBS, PAF, PAF-antagonist, and L-NAME. The PBS group received phosphate buffered saline (PBS) and the PAF groups received 10, 20, and 40 ,g of PAF soaked into gelfoam and placed on the RWM. PAF-antagonist (WEB 2170) and NOS inhibitor NG-nitro-l-arginine-methylester (L-NAME) were injected intraperitoneally prior to PAF 20 ,g application on the RWM. The following three tests were performed on each animal group: Hearing was tested with an auditory brainstem response (ABR) test over 24 hours. At the end of 24 hours, cochlear hair cells were examined by scanning electron microscopy (SEM) and immunohistochemistry was carried out on the cochlea to test the expression of inducible nitric oxide synthase (iNOS). Results The PAF group developed significant elevation of ABR threshold and cochlear hair cell damage in the SEM group as compared with the PBS control group. The PAF-antagonist (WEB 2170) and the L-NAME groups did not show significant elevation of ABR threshold and cochlear hair cell damage compared with the group administered PAF 20 ,g, but in the PAF-antagonist group, the elevation of ABR threshold was significant compared with that of the PBS control group, whereas it was not significant compared with the PBS group in the L-NAME group. Strong expression of iNOS on cochlea was observed in the PAF group and lighter expression was seen in PBS, WEB 2170, and L-NAME groups. Conclusions This study demonstrated that PAF placed on the RWM induced hearing loss and cochlear hair cell damage. The PAF-antagonists and L-NAME prevented the PAF-induced hearing loss and inhibited iNOS expression in the cochlea. These findings suggest that the PAF-induced hearing loss caused by cochlear hair cell damage may have been mediated by NO. PAF-antagonists and L-NAME may have future therapeutic implications in preventing sensorineural hearing loss associated with chronic otitis media. The results of this study have significant potential clinical application. [source] Effects of testosterone and vitamin E on the antioxidant system in rabbit testisANDROLOGIA, Issue 5 2004N. Aydilek Summary. The aim of the study was to investigate the effects of testosterone propionate and vitamin E on the antioxidant system in the testis. Thirty-two male New Zealand White rabbits were randomly divided into four groups. The first group was used as control. The second group was injected with testosterone propionate, the third group vitamin E and the fourth group vitamin E and testosterone propionate combination. All treatments were carried out during 6 weeks and oxidative parameters were evaluated in homogenized testicular tissue. The levels of vitamin E and the activity of glutathione peroxidase were lower (P < 0.05) in the testosterone group than in controls. However, vitamin C and malondialdehyde levels were higher (P < 0.05) in this group than in controls. The levels of reduced glutathione, , -carotene, vitamin C and E increased, but malondialdehyde levels decreased in the vitamin E group, when compared with controls (P < 0.05). Vitamin E and , -carotene levels were significantly higher (P < 0.05) in the combination group than in testosterone group. However, MDA levels were lower (P < 0.05) in combination group than in the testosterone group. In conclusion, administration of testosterone propionate led to a significant elevation of oxidative stress. Vitamin E is quite an effective antioxidant which protects rabbit testis against lipid peroxidation, and, testosterone-induced lipid peroxidation could be improved by additional vitamin E treatment. [source] Short-term physiological response of the Pacific oyster, Crassostrea gigas, on exposure to varying levels of polycyclic aromatic hydrocarbonAQUACULTURE RESEARCH, Issue 15 2007Mu-Chan Kim Abstract In the present study, we investigate the short-term adaptive physiological strategies to polycyclic aromatic hydrocarbon (PAH) of Pacific oysters, Crassostrea gigas, by exposing the oysters to varying levels of PAH (0, 50, 100 and 200 ,g L,1) for 7 days with a 3-day acclimation period under laboratory conditions. The filtration rate (FR) and respiration rate (R) increased significantly at 50 ,g L,1 PAH and decreased at 100 and 200 ,g L,1 compared with the control. The absorption efficiency (Abs. eff.) was significantly impaired at 200 ,g L,1 PAH. Ammonia excretion (E) increased with increasing PAH levels, with a significant elevation at 200 ,g L,1. Although a significantly elevated FR was observed, oysters exposed to 50 ,g L,1 PAH showed scope for growth (SFG) similar to the control. This indicates that even at nominal levels, PAH contamination is a possible cause of reduced oyster production because of increased food demand. The oysters exposed to 200 ,g L,1 PAH showed negative SFG values, which could be a possible cause of growth stagnation or even mortality when the exposure is chronic. [source] | |||||||||||||||||||||||||||||||