Biomedical subjects

H Sheng

Publications and source records attributed to H Sheng.

At least 19 recordsLinked to original sources

PubMed2006

Epimedium-derived phytoestrogen exert beneficial effect on preventing steroid-associated osteonecrosis in rabbits with inhibition of both thrombosis and lipid-deposition.

OBJECTIVES: This study tested the effect of Epimedium-derived phytoestrogen (PE) on preventing steroid-associated osteonecrosis (ON) in rabbit model. METHODS: Thirty 28-week-old male New-Zealand white rabbits were divided into control group (CON; n=14) and PE group (PE; n=16; 5 mg/kg body weight/day) after receiving an established inductive protocol for inducing steroid-associated ON. Before and after inductive protocol, Dynamic-MRI was employed on bilateral femora for local intra-osseous perfusion, blood samples were examined for coagulation, fibrinolysis and lipid-transportation, and marrow samples were quantified for adipogenesis-gene mRNA expression. Six weeks later, bilateral femora were dissected for Micro-CT-based micro-angiography, and then ON lesion, intravascular thrombosis and extravascular fat-cell-size were examined histopathologically. RESULTS: The incidence of ON in the PE group (31%) was significantly lower than that in the CON group (93%). Compared to the CON group, local intra-osseous perfusion was maintained in the PE group. Blocked trunk vessels were seldom found in micro-angiography of the PE-treated rabbits. Thrombosis incidence and fat-cell-size were both significantly lower in the PE group than those in the CON group. During the early period after induction, indicator of coagulation, fibrinolysis, lipid-transportation and adipogenesis-gene expression were found with significantly changing pattern in the PE group compared to the CON group. CONCLUSION: PE was able to exert beneficial effect on preventing steroid-associated ON in rabbits with inhibition of both thrombosis and lipid deposition.

Adrenal Cortex Hormones↗

PubMed2006

Multiple bioimaging modalities in evaluation of an experimental osteonecrosis induced by a combination of lipopolysaccharide and methylprednisolone.

AIMS: The present study employed both static and dynamic imaging modalities to study both intra- and extravascular events attributing to steroid-associated osteonecrosis (ON) using an experimental protocol with a single low-dose lipopolysaccharide (LPS) injection and subsequently three injections of high-dose methylprednisolone (MPS). METHODS: Fourteen 28-week-old male New Zealand white rabbits received one intravenous injection of LPS (10 microg/kg). 24 h later, three injections of 20 mg/kg of MPS were given intramuscularly at a time interval of 24 h. Additional 6 rabbits were used as controls. Dynamic MRI was performed on bilateral femora for local intraosseous perfusion before and after LPS injection. Blood samples were collected for hematological examinations before and after LPS injection. Bilateral femora were dissected and decalcified for microCT-based microangiography. ON lesion, intravascular thrombus and extravascular marrow fat cell size were examined histopathologically. RESULTS: Intravascular thrombus was observed in all ON rabbits. Extravascular marrow fat cell size was significantly increased in ON rabbits than that of the controls (P<0.05). Compared to baseline, a significant decrease in ratio of tissue-type plasminogen activator/plasminogen activator inhibitor 1, activated partial thromboplatin time and a significant increase in ratio of low-density lipoprotein/high-density lipoprotein were only found in ON rabbits (P<0.05). Dynamic MRI showed a significant decrease in the perfusion index 'maximum enhancement' in the ON rabbits (P<0.05), and microCT-based microangiography showed blocked stem vessels in ON samples. Overall, 93% of the rabbits (13/14) developed ON, and no rabbits died throughout the experiment period. CONCLUSION: Both intra- and extravascular events were found attributing to the steroid-associated ON based on our experimental protocol with a single low-dose LPS injection and subsequent three injections of high-dose MPS. Both high ON incidence and no mortality in rabbits treated with this inductive protocol suggested its effectiveness for future studies on evaluation of therapeutic efficacy of interventions developed for prevention of steroid-associated ON.

Animals↗

PubMed2006

Clustered gases as a medium for efficient plasma waveguide generation.

Clustered gas jets are shown to be an efficient means for plasma waveguide generation, for both femtosecond and picosecond generation pulses. These waveguides enable significantly lower on-axis plasma density (less than 10(18) cm(-3)) than in conventional hydrodynamic plasma waveguides generated in unclustered gases. Using femtosecond pump pulses, self-guided propagation and strong absorption (more than 70%) are used to produce long centimetre scale channels in an argon cluster jet, and a subsequent intense pulse is coupled into the guide with 50% efficiency and guided at above 10(17)W cm(-2) intensity over 40 Rayleigh lengths. We also demonstrate efficient generation of waveguides using 100 ps axicon-generated Bessel-beam pump pulses. Despite the expected sub-picosecond cluster disassembly time, we observe long pulse absorption efficiencies up to a maximum of 35%. Simulations show that in the far leading edge of the long laser pulse, the volume of heated clusters evolves to a locally uniform and cool plasma already near ionization saturation, which is then efficiently heated by the remainder of the pulse.

Journal Article↗

PubMed2006

Comparison of a waterless hand-hygiene preparation and soap-and-water hand washing to reduce coliforms on hands in animal exhibit settings.

Outbreaks of enteric disease associated with exposure to live animals on exhibit have occurred with increasing frequency in recent years. Possibly the most important pathogen causing such outbreaks is Escherichia coli O157:H7, because of the serious illness it can cause. Hand hygiene is consistently protective against disease among persons exposed to animals implicated in these outbreaks. Livestock barns have limited hand-washing facilities, therefore a waterless hand-sanitizing gel would be a potentially preventive measure readily available to visitors and animal exhibitors. This study compared the reduction of bacterial counts on hands of animal exhibitors when soap and water was used or when an ethanol-based hand gel was used after animal handling. Participants were youth and adults involved with showing livestock. The sanitation methods were similar in reducing the total bacteria and coliform counts on the hands of the participants (Wilcoxon rank sum test P values 0.12 and 0.69 respectively).

Animals↗

PubMed2006

Comparison of expression of TGF-beta1, its receptors TGFbeta1R-I and TGFbeta1R-II in rat kidneys during chronic nephropathy induced by cyclosporine and tacrolimus.

OBJECTIVE: Chronic rejection is a major cause of graft dysfunction after kidney transplantation. Long-term treatment with cyclosporine (CsA) or tacrolimus (FK506) results in chronic nephrotoxicity. Transforming growth factor-beta1 (TGFbeta1) and its receptors type I (TR-I) and type II (TR-II) have been known to contribute to this side effect. The expression of TGF-beta1, TR-I, and TR-II in rat kidneys has not been compared during chronic nephropathy induced by CsA or FK506. METHODS: Rat models of chronic CsA- or FK506-induced nephropathy were established using Sandimun Neoral or Prograf administration. The kidneys were dissected and TGF-beta1, TR-I, and TR-II proteins and TR-I and TR-II mRNAs measured by immunohistochemistry and in situ hybridization, respectively, to compare the results of the two groups. RESULTS: The functional and morphologic studies showed that in the rats the nephrotoxic effects of FK506 were not as significant as those of CsA. The results of immunohistochemistry and in situ hybridization showed that the expression of renal TGFbeta1, TR I, TR-II proteins and TR and TR II mRNA in the FK506 group were lower than those in the CsA groups. CONCLUSION: These results showed that both FK506 and CSA display nephrotoxicity, but that the nephrotoxicity of FK506 was less than that of CsA in chronic nephropathy.

Activin Receptors, Type I↗

PubMed2006

Expression of renal transforming growth factor-beta and its receptors in a rat model of chronic cyclosporine-induced nephropathy.

OBJECTIVE: We sought to detect expression of transforming growth factor-beta 1 (TGF-beta1) as well as its receptors type I (TRI) and type II (TRII) in rat kidneys during chronic cyclosporine (CsA)-induced nephropathy. METHODS: Twenty four rats were randomly divided into three experimental groups: group 1; NSD (control, n = 8) were administered a normal sodium diet, group 2; LSD (n = 8) were administered a low sodium diet, group 3; CsA (n = 8) were sodium-depleted rats administered Neoral by gastric gavage in a model of chronic CsA-induced nephropathy. TGF-beta1, TRI, and TRII proteins, as well as TRI and TRII mRNAs were measured in the CsA-treated rat kidneys by immunohistochemistry and in situ hybridization, respectively. Semiquantitative results were shown by image analysis. RESULTS: The expression of TGF-beta1, TRI, TRII, TRI mRNA, and TRII mRNA were all increased in CsA-treated rat kidneys, compared with NSD or LSD (P < .05). CONCLUSION: Our study showed that the ligand of TGF-beta1 and its receptors TRI, TRII were all up-regulated. It may be important to inhibit the expression of TGF-beta1 or its receptors in patients who suffer from chronic CsA-induced nephropathy.

Animals↗

PubMed2005

Plasma waveguides efficiently generated by Bessel beams in elongated cluster gas jets.

We demonstrate the efficient generation of plasma waveguides in elongated cluster gas jets using 100 ps axicon-generated Bessel beam pump pulses. The plasma waveguide space and time evolution is measured using picosecond interferometry. Small radius waveguides with central densities as low as approximately 10(18) cm(-3) can be generated with this technique. Despite the expected subpicosecond cluster disassembly time, we observe long pulse absorption efficiencies that can be more than a factor of 10 greater than in unclustered gas targets of the same volume average atomic density. The maximum long pulse absorption observed in cluster jets under our range of conditions was 35%. The explanation for the enhanced absorption is that in the far-leading edge of the laser pulse, the volume of heated clusters evolves to a locally uniform and cool plasma already near ionization saturation, which is then heated by the remainder of the pulse. From this perspective, the use of clustered gases is equivalent to a supercharged preionization scheme for long duration laser pulses.

Journal Article↗

PubMed2005

HOXB13 is downregulated in colorectal cancer to confer TCF4-mediated transactivation.

Mutations in the Wnt signalling cascade are believed to cause aberrant proliferation of colorectal cells through T-cell factor-4 (TCF4) and its downstream growth-modulating factors. HOXB13 is exclusively expressed in prostate and colorectum. In prostate cancers, HOXB13 negatively regulates beta-catenin/TCF4-mediated transactivation and subsequently inhibits cell growth. To study the role of HOXB13 in colorectal tumorigenesis, we evaluated the expression of HOXB13 in 53 colorectal tumours originated from the distal left colon to rectum with their matching normal tissues using quantitative RT-PCR analysis. Expression of HOXB13 is either lost or diminished in 26 out of 42 valid tumours (62%), while expression of TCF4 RNA is not correlated with HOXB13 expression. TCF4 promoter analysis showed that HOXB13 does not regulate TCF4 at the transcriptional level. However, HOXB13 downregulated the expression of TCF4 and its target gene, c-myc, at the protein level and consequently inhibited beta-catenin/TCF-mediated signalling. Functionally, forced expression of HOXB13 drove colorectal cancer (CRC) cells into growth suppression. This is the first description of the downregulation of HOXB13 in CRC and its mechanism of action is mediated through the regulation of TCF4 protein stability. Our results suggest that loss of HOXB13 may be an important event for colorectal cell transformation, considering that over 90% of colorectal tumours retain mutations in the APC/beta-catenin pathway.

Cell Proliferation↗

PubMed2003

Phosphatidylinositol 3-kinase mediates proliferative signals in intestinal epithelial cells.

BACKGROUND AND AIMS: Determination of intracellular signalling pathways that mediate intestinal epithelial proliferation is fundamental to the understanding of the integrity and function of the intestinal tract under normal and diseased conditions. The phosphoinositide 3-kinase (PI3K)/Akt pathway transduces signals initiated by growth factors and is involved in cell proliferation and differentiation. In this study, we assessed the role of PI3K/Akt in transduction of proliferative signals in intestinal epithelial cells. METHODS: A rat intestinal epithelial (RIE) cell line and human colorectal cancer HCA-7 and LS-174 cell lines served as in vitro models. The Balb/cJ mouse was the in vivo model. RESULTS: PI3K activation was critical for G1 cell cycle progression of intestinal epithelial cells. Ectopic expression of either active p110alpha or Akt-1 increased RIE cell proliferation. In vivo experiments demonstrated that PI3K activation was closely associated with the proliferative activity of intestinal mucosa. Treatment of mice with PI3K inhibitors blocked induction of PI3K activity and attenuated intestinal mucosal proliferation associated with oral intake. Epidermal growth factor and transforming growth factor alpha stimulated PI3K activation which was required for growth factor induced expression of cyclin D1. CONCLUSIONS: The PI3K/Akt pathway transduces mitogenic signals from growth factor receptors to the cell cycle machinery and plays a critical role in regulation of intestinal epithelial proliferation.

Animals↗

PubMed2001

Neuroprotection from delayed postischemic administration of a metalloporphyrin catalytic antioxidant.

Reactive oxygen species contribute to ischemic brain injury. This study examined whether the porphyrin catalytic antioxidant manganese (III) meso-tetrakis (N-ethylpyridinium-2-yl)porphyrin (MnTE-2-PyP(5+)) reduces oxidative stress and improves outcome from experimental cerebral ischemia. Rats that were subjected to 90 min focal ischemia and 7 d recovery were given MnTE-2-PyP(5+) (or vehicle) intracerebroventricularly 60 min before ischemia, or 5 or 90 min or 6 or 12 hr after reperfusion. Biomarkers of brain oxidative stress were measured at 4 hr after postischemic treatment (5 min or 6 hr). MnTE-2-PyP(5+), given 60 min before ischemia, improved neurologic scores and reduced total infarct size by 70%. MnTE-2-PyP(5+), given 5 or 90 min after reperfusion, reduced infarct size by 70-77% and had no effect on temperature. MnTE-2-PyP(5+) treatment 6 hr after ischemia reduced total infarct volume by 54% (vehicle, 131 +/- 60 mm(3); MnTE-2-PyP(5+), 300 ng, 60 +/- 68 mm(3)). Protection was observed in both cortex and caudoputamen, and neurologic scores were improved. No MnTE-2-PyP(5+) effect was observed if it was given 12 hr after ischemia. MnTE-2-PyP(5+) prevented mitochondrial aconitase inactivation and reduced 8-hydroxy-2'-deoxyguanosine formation when it was given 5 min or 6 hr after ischemia. In mice, MnTE-2-PyP(5+) reduced infarct size and improved neurologic scores when it was given intravenously 5 min after ischemia. There was no effect of 150 or 300 ng of MnTE-2-PyP(5+) pretreatment on selective neuronal necrosis resulting from 10 min forebrain ischemia and 5 d recovery in rats. Administration of a metalloporphyrin catalytic antioxidant had marked neuroprotective effects against focal ischemic insults when it was given up to 6 hr after ischemia. This was associated with decreased postischemic superoxide-mediated oxidative stress.

Aconitate Hydratase↗

PubMed2001

Transforming growth factor-beta1 promotes invasiveness after cellular transformation with activated Ras in intestinal epithelial cells.

Invasion is a defining event in carcinoma progression. In general, invasive carcinoma is characterized by an epithelial-fibroblastoid conversion associated with loss of cell-cell adhesion receptors such as E-cadherin and beta-catenin. We report here that TGF-beta1 promotes the invasiveness by modulating the alterations of cellular plasticity including a loss of cell-cell contact in Ras-transformed epithelial cells. In order to examine the role of TGF-beta1 in the Ras-induced responses, intestinal epithelial cells expressing a conditionally activated Ha-Ras(Val12) (RIE-iRas cells) were used in this study. Induced expression of activated Ha-Ras(Val12) caused morphologic transformation of the RIE-iRas cells with an increase in vimentin expression and a decrease of E-cadherin levels. There was also redistribution of beta-catenin from the cytoplasm to the nucleus after the induction of Ras. TGF-beta1 treatment enhanced both the decrease in E-cadherin levels and the redistribution of beta-catenin. Interestingly, the activation of Ras markedly decreased the level of TGF-beta receptor type II (TbetaRII) in RIE-iRas cells. However, the expression of plasminogen activator inhibitor-1, which is known to be transcriptionally induced by TGF-beta1, was strongly induced by TGF-beta1 despite the marked downregulation of TbetaRII. The induction of Ha-Ras(Val12) markedly increased the invasiveness in RIE-iRas cells, as evaluated by a collagen type I-coated Boyden-chamber assay, and the Ras-mediated invasiveness was significantly enhanced by TGF-beta1 treatment. Expression of a dominant-negative form of TbetaRII in the RIE-iRas cells abrogated both growth-inhibitory and invasion responses to TGF-beta1. Collectively, these results suggest that TGF-beta1 and oncogenic Ras collaborate in promoting cellular invasiveness in intestinal epithelial cells. The enhancement of invasiveness was correlated with decreased E-cadherin levels and subcellular distribution of beta-catenin. The enhancement of oncogenic Ras-mediated cell transformation by TGF-beta1 occurs via TbetaRII.

Adherens Junctions↗

PubMed2001

K-Ras-mediated increase in cyclooxygenase 2 mRNA stability involves activation of the protein kinase B1.

Cyclooxygenase (COX) 2 expression is regulated via the Ras signaling pathway, and induction of mutated Ras rapidly increases COX-2 levels in intestinal epithelial cells. Protein kinase B (Akt/PKB) is an important effector of Ras signaling and a critical component of Ras-mediated transformation. Here we investigate the role of Akt/PKB in K-Ras-mediated induction of COX-2. Rat intestinal epithelial cells (IEC-6) were transfected with an inducible K-RasVal12 cDNA (IEC-iK-Ras cells). Addition of 5 mM isopropyl-1-thio-beta-D-galactopyranoside induced the expression of K-RasVal12, followed by increased activity of extracellular signal-regulated kinase and Akt/PKB. COX-2 levels were dramatically increased after induction of K-RasVal12. Inhibition of MAPK/ERK kinase activity by PD 98059 completely blocked the K-Ras-mediated induction of COX-2, whereas inhibition of PI3K/Akt/PKB activity with LY 294002 or by expressing a dominant negative Akt (Akt-K179M) partially blocked the induction of COX-2 by K-Ras. Transient transfection of cells with phosphatidylinositol 3-kinase and Akt expression vectors revealed that PI3/Akt/PKB activity predominantly regulates the stability of COX-2 mRNA. Thus, Akt/PKB activity is involved in K-Ras-induced expression of COX-2 and stabilization of COX-2 mRNA largely depends on the activation of Akt/PKB.

Animals↗

PubMed2001

Prostaglandin E2 increases growth and motility of colorectal carcinoma cells.

Chronic use of nonsteroidal anti-inflammatory drugs results in a significant reduction of risk and mortality from colorectal cancer in humans. All of the mechanism(s) by which nonsteroidal anti-inflammatory drugs exert their protective effects are not completely understood, but they are known to inhibit cyclooxygenase activity. The cyclooxygenase enzymes catalyze a key reaction in the conversion of arachidonic acid to prostaglandins, such as prostaglandin E(2) (PGE(2)). Here we demonstrate that PGE(2) treatment of LS-174 human colorectal carcinoma cells leads to increased motility and changes in cell shape. The prostaglandin EP(4) receptor signaling pathway appears to play a role in transducing signals which regulate these effects. PGE(2) treatment results in an activation of phosphatidylinositol 3-kinase/protein kinase B pathway that is required for the PGE(2)-induced changes in carcinoma cell motility and colony morphology. Our results suggest that PGE(2) might enhance the invasive potential of colorectal carcinoma cells via activation of major intracellular signal transduction pathways not previously reported to be regulated by prostaglandins.

Cell Division↗

PubMed2001

Akt/PKB activity is required for Ha-Ras-mediated transformation of intestinal epithelial cells.

Phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/Akt) is thought to serve as an oncogenic signaling pathway which can be activated by Ras. The role of PI3K/Akt in Ras-mediated transformation of intestinal epithelial cells is currently not clear. Here we demonstrate that inducible expression of oncogenic Ha-Ras results in activation of PKB/Akt in rat intestinal epithelial cells (RIE-iHa-Ras), which was blocked by treatment with inhibitors of PI3K activity. The PI3K inhibitor, LY-294002, partially reversed the morphological transformation induced by Ha-Ras and resulted in a modest stimulation of apoptosis. The most pronounced phenotypic alteration following inhibition of PI3K was induction of G(1) phase cell cycle arrest. LY-294002 blocked the Ha-Ras-induced expression of cyclin D1, cyclin-dependent kinase (CDK) 2, and increased the levels of p27(kip). Both LY-294002 and wortmannin significantly reduced anchorage-independent growth of RIE-iHa-Ras cells. Forced expression of both the constitutively active forms of Raf (DeltaRaf-22W or Raf BXB) and Akt (Akt-myr) resulted in transformation of RIE cells that was not achieved by transfection with either the Raf mutant construct or Akt-myr alone. These findings delineate an important role for PI3K/Akt in Ras-mediated transformation of intestinal epithelial cells.

Androstadienes↗

PubMed2001

Tracking brain volume changes in C57BL/6J and ApoE-deficient mice in a model of neurodegeneration: a 5-week longitudinal micro-MRI study.

Magnetic resonance imaging (MRI)-based volume measurements of brain structures are useful indicators of pending cognitive decline in humans suffering from neurodegenerative diseases. Transgenic mouse models that mimic the clinical conditions of these disorders have been developed. Noninvasive methods that can follow progression and regression of relevant pathology in these mice are therefore in great demand. In this study we tested whether high-resolution MRI (micro-MRI) in a mouse model of neurodegeneration (cerebral ischemia) could reliably track development of brain atrophy. We first established that diffusion imaging at a spatial resolution of 1.6 x 10(-3) mm(3) allowed superior visualization of forebrain, ventricles, and dorsal hippocampus in the mouse brain compared to either T2*- or T1-weighted MR imaging. Using this predetermined protocol we subsequently scanned C56BL/6J (C57) and ApoE-deficient (ApoE(-/-)) mice before and after ischemia. Four groups were studied: C57/sham (n = 9), ApoE(-/-)/sham (n = 9), C57/ischemia (n = 9), and ApoE(-/-)/ischemia (n = 11). All mice received a baseline 3D diffusion scan. One week later C57/ischemia and ApoE(-/-)/ischemia mice were exposed to 10 min of ischemia and scanned again on the 3rd and 30th postischemic day. The C57/sham and ApoE(-/-)/sham mice served as controls and were scanned at corresponding time points. Diffusion images of ApoE(-/-)/ischemia mice on the 3rd postischemic day revealed multiple localized high signal intensity areas. An increase in ventricle and a decrease in dorsal hippocampal volumes (which included the associated cortex laterally) at 30 days confirmed brain atrophy in C57 mice after ischemia. Excessive mortality of ApoE(-/-)/ischemia mice restricted statistical analysis, but ventricle enlargement postischemia was demonstrated. Our results show that volume changes in the brain of a 30-g mouse can be tracked by micro-MRI in a model of neurodegeneration. Clearly the ability to follow progression of pathology in mice will greatly aid our understanding of neurodegenerative diseases and facilitate the many possibilities to intervene pharmacologically.

Animals↗

PubMed2001

Targeting cyclooxygenase 2 and HER-2/neu pathways inhibits colorectal carcinoma growth.

BACKGROUND & AIMS: The cyclooxygenase 2 (COX-2) and ErbB/HER pathways are important modulators of cancer cell growth. We sought to determine the effects of treatment with a specific COX-2 inhibitor and/or a monoclonal antibody against the ErbB receptor subtype HER-2/neu on carcinoma cell growth. METHODS: A cell-proliferation assay was used to determine the response of HCA-7 cells to the HER-3/HER-4 ligand heregulin beta-1 (HRGbeta-1). Both in vitro and in vivo assays were used to determine the effects of the selective COX-2 inhibitor, celecoxib, and/or an anti-HER-2/neu monoclonal antibody (either Herceptin [Genetech Inc., S. San Francisco, CA] or 2C4) on cell growth. RESULTS: HCA-7 cells express HER-2/neu messenger RNA and protein, and exposure of these cells to HRGbeta-1 results in a significant stimulation of cell growth. Celecoxib or Herceptin inhibits HCA-7 cell growth in vitro and in vivo. Combination therapy with celecoxib plus Herceptin or celecoxib plus 2C4 resulted in additive effects that resulted in almost complete inhibition of tumor growth. CONCLUSIONS: Combined treatment with COX-2 and HER-2/neu inhibitors more effectively reduces colorectal carcinoma growth than either agent alone. Therefore, targeting of both the COX-2 and ErbB signaling pathways may represent a novel approach for the treatment and/or prevention of colorectal cancer in humans.

Animals↗

PubMed2001

Extracellular superoxide dismutase overexpression improves behavioral outcome from closed head injury in the mouse.

Oxidative stress is known to play an important role in the response of brain to traumatic insults. We tested the hypothesis that increased extracellular superoxide dismutase (EC-SOD) expression can reduce injury in a mouse model of closed head injury. Neurologic, cognitive, and histologic outcomes were compared between transgenic mice exhibiting a fivefold increase in EC-SOD activity and wild-type littermate controls. Severe or moderate transcranial impact was induced in anesthetized and physiologically controlled animals. After severe impact, transgenic mice had better neurological outcome at 24 hr postinjury (p = 0.038). Brain water content was increased, but there was no difference between groups. Moderate impact resulted in predominantly mild neurologic deficits in both groups at both 24 hr and 14 days postinjury. Morris water maze performance, testing cognitive function at 14-17 days after trauma, was better in EC-SOD overexpressors (p = 0.018). No differences were observed between groups for histologic damage in hippocampal CA1 and CA3. We conclude that EC-SOD has a beneficial effect on behavioral outcome after both severe and moderate closed head injury in mice. Because EC-SOD is believed to be predominantly located in the extracellular space, these data implicate an adverse effect of extracellular superoxide anion on outcome from closed head injury.

Animals↗

PubMed2000

Celecoxib prevents tumor growth in vivo without toxicity to normal gut: lack of correlation between in vitro and in vivo models.

Nonsteroidal anti-inflammatory drugs have potential for use in the prevention and/or treatment of colorectal cancer. We have studied the cytotoxic effect of a specific COX-2 inhibitor, celecoxib, against LLC, HCA-7, and HCT-15 cells grown in cell culture and have compared these results with its effect on HCA-7 cells grown as xenografts in nude mice. "High-dose" celecoxib (>20 microM) reduced the viability of all three cell lines in vitro as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Flow cytometric analysis demonstrated that this loss of viability was attributable to the induction of apoptosis. Significantly, concentrations of the drug <10 microM had no effect on cell viability in vitro. The cytotoxic effects of high-dose celecoxib were independent of COX-2 inhibition because similar effects were observed in cox-2 (+/+), cox-2 (+/-) and cox-2 (-/-) fibroblasts. A plasma concentration of 2.3+/-0.7 microM was achieved when celecoxib (1250 mg/kg of chow) was fed to animals ad libitum. Despite a lack of toxicity at 2-3 microM celecoxib in vitro, there was attenuation of HCA-7 xenograft growth in vivo. Celecoxib had no effect on apoptosis, cell division, or the epithelial architecture of the normal gut in treated mice. These results support the need for additional clinical evaluation of celecoxib for treatment and/or prevention of colorectal cancer in humans.

Animals↗