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Nitric Oxide Synthase Expression (nitric + oxide_synthase_expression)
Kinds of Nitric Oxide Synthase Expression Selected AbstractsInducible Nitric Oxide Synthase Expression in Pneumocystis carinii PneumoniaTHE JOURNAL OF EUKARYOTIC MICROBIOLOGY, Issue 2003MARK E. LASBURY No abstract is available for this article. [source] Effect of porto-systemic shunting on NOS expression after extended hepatectomy in ratsHEPATOLOGY RESEARCH, Issue 1 2009Hironori Hayashi Aim:, Several surgical procedures have been developed for reducing portal vein pressure to prevent postoperative liver injury. Nitric oxide synthase expression (NOS) induced by elevation of portal vein pressure is thought to play an important role in liver regeneration, but the details are not well understood. Methods:, Rats in the control group and in the subcutaneous splenic transposition (SST) group underwent 90% partial hepatectomy. Survival and portal vein pressure were analyzed. The serum IL-6 and TNF-, levels were measured by enzyme-linked immunosorbent assay (ELISA). Hepatocyte proliferation and apoptosis 12 hours after hepatectomy were analyzed immunohistochemically. The protein and messenger RNA expression of inducible and endothelial NOS were analyzed using Western blotting and quantitative reverse transcriptase polymerase chain reaction, respectively. Results:, The survival rate of the SST group was significantly higher. Portal vein pressure, TNF-, level and the apoptotic index were significantly lower in the SST group. Twelve hours after surgery, liver inducible NOS (iNOS) protein expression was significantly lower in the SST group. However, protein expression of endothelial NOS was not significantly different between the groups. Conclusion:, Inducible NOS expression after extended hepatectomy is related to the effects of porto-systemic shunting on the splanchnic circulation. Also, iNOS induction and concomitant nitric oxide generation appear to participate in the cytotoxicity of excessive portal pressure after extended hepatectomy. [source] The effect of ultraviolet B irradiation on nitric oxide synthase expression in murine keratinocytesEXPERIMENTAL DERMATOLOGY, Issue 6 2000M. Sasaki Abstract: Nitric oxide (NO), which has several physiological functions in skin, is generated by NO synthase (NOS). NOS has at least three isoforms; endothelial NOS (eNOS), brain NOS (bNOS), and inducible NOS (iNOS). Ultraviolet B (UVB) irradiation has been reported to stimulate NO production in skin via induction or activation of NOS, however, the exact mechanism of NOS induction by UVB irradiation remains obscure. In this study, we investigated the direct effect of UVB on the expression of NOS isoforms in murine keratinocytes, and found a significant increase in NO production within 48 h. mRNA and protein expressions of bNOS were both enhanced by UVB irradiation in murine keratinocytes, whereas iNOS mRNA expression was suppressed at 4 and 12 h after UVB irradiation. These results suggest that the enhancement of NO production observed after UVB irradiation in murine keratinocytes may be explained in part by the upregulation of bNOS expression, but not iNOS expression. [source] Inducible nitric oxide synthase expression in laryngeal neoplasia: Correlation with angiogenesisHEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 1 2002Alessandro Franchi MD Abstract Background The nitric oxide (NO) pathway plays a relevant role in angiogenesis and tumor progression in squamous cell carcinoma (SCC) of the head and neck. The aim of this study was to assess whether the NO pathway may be correlated with angiogenesis in the transition from laryngeal dysplasia to invasive carcinoma. Methods We investigated the expression of the inducible NO synthase (iNOS) in 26 laryngeal precancerous lesions and 35 squamous cell carcinomas with respect to microvessel density. In addition, we determined iNOS activity and cGMP levels in specimens from SCCs. Results There was a significant increase of iNOS levels detected immunohistochemically passing from hyperplastic/mild dysplastic to moderate/severe dysplastic lesions to SCC (p = .04). Accordingly, Northern and Western analyses demonstrated higher iNOS mRNA and protein levels in SCCs than dysplastic mucosa. iNOS expression was significantly correlated with microvessel counts both in the group of preneoplastic lesions (p = .02) and in the group of SCCs (p = .01). In addition, iNOS activity was correlated with iNOS immunohistochemical expression (p = .1) and was significantly associated with increased vascularization (p = .03) in SCCs. Similarly, iNOS expression was significantly correlated with cGMP levels in SCC (p = .02) and increased tumor vascularization correlated with higher cGMP levels (rs = .4; p = .01). Conclusions Our data indicate that the NO pathway may play a relevant role in the angiogenesis associated with the progression from laryngeal dysplasia to laryngeal SCC. © 2002 John Wiley & Sons, Inc. Head Neck 24: 16,23, 2002. [source] Sulphasalazine inhibits macrophage activation: inhibitory effects on inducible nitric oxide synthase expression, interleukin-12 production and major histocompatibility complex II expressionIMMUNOLOGY, Issue 4 2001György Haskó Summary The anti-inflammatory agent sulphasalazine is an important component of several treatment regimens in the therapy of ulcerative colitis, Crohn's disease and rheumatoid arthritis. Sulphasalazine has many immunomodulatory actions, including modulation of the function of a variety of cell types, such as lymphocytes, natural killer cells, epithelial cells and mast cells. However, the effect of this agent on macrophage (M,) function has not been characterized in detail. In the present study, we investigated the effect of sulphasalazine and two related compounds , sulphapyridine and 5-aminosalicylic acid , on M, activation induced by bacterial lipopolysaccharide (LPS) and interferon-, (IFN-,). In J774 M, stimulated with LPS (10 µg/ml) and IFN-, (100 U/ml), sulphasalazine (50,500 µm) suppressed nitric oxide (NO) production in a concentration-dependent manner. The expression of the inducible NO synthase (iNOS) was suppressed by sulphasalazine at 500 µm. Sulphasalazine inhibited the LPS/IFN-,-induced production of both interleukin-12 (IL-12) p40 and p70. The suppression of both NO and IL-12 production by sulphasalazine was superior to that by either sulphapyridine or 5-aminosalicylic acid. Although the combination of LPS and IFN-, induced a rapid expression of the active forms of p38 and p42/44 mitogen-activated protein kinases and c-Jun terminal kinase, sulphasalazine failed to interfere with the activation of any of these kinases. Finally, sulphasalazine suppressed the IFN-,-induced expression of major histocompatibility complex class II. These results demonstrate that the M, is an important target of the immunosuppressive effect of sulphasalazine. [source] Inhibition of CCAAT/enhancer binding protein , expression by chrysin in microglial cells results in anti-inflammatory and neuroprotective effectsJOURNAL OF NEUROCHEMISTRY, Issue 2 2010Núria Gresa-Arribas J. Neurochem. (2010) 115, 526,536. Abstract The control of neuroinflammation is a potential target to be considered in the treatment of neurodegenerative diseases. It is therefore important to find anti-inflammatory drugs and study new targets that inhibit neuroinflammation. We designed an experimental model of neuroinflammation in vitro to study the anti-inflammatory and neuroprotective effects of the flavonoid chrysin and the involvement of nuclear factor-,B p65 and CCAAT/enhancer binding proteins (C/EBPs) , and , transcription factors in its mechanism of action. We used primary cultures of mouse embryonic cortical neurons and cultures of BV2 (murine microglial cell line) or mouse primary microglia. We induced neuronal death in neuronal-BV2/microglial co-cultures using lipopolysaccharide of Escherichia coli and interferon-,. Chrysin pre-treatment inhibited nitric oxide and tumor necrosis factor-, production, as well as inducible nitric oxide synthase expression in lipopolysaccharide E. coli and interferon-,-treated microglial cells, but did not affect cyclooxygenase-2 expression. Chrysin pre-treatment also protected neurons against the neurotoxicity induced by reactive microglial cells. These effects were associated to a decrease in C/EBP, protein level, mRNA expression, and DNA-binding activity, with no effect on C/EBP, and p65 nuclear protein levels or DNA-binding activity, pointing out C/EBP, as a possible mediator of chrysin effects. Consequently, C/EBP, is a possible target to act against neuroinflammation in neurodegenerative processes. [source] Attenuation of proliferation in oligodendrocyte precursor cells by activated microgliaJOURNAL OF NEUROSCIENCE RESEARCH, Issue 8 2010Deanna L. Taylor Abstract Activated microglia can influence the survival of neural cells through the release of cytotoxic factors. Here, we investigated the interaction between Toll-like receptor 4 (TLR4)-activated microglia and oligodendrocytes or their precursor cells (OPC). Primary rat or N9 microglial cells were activated by exposure to TLR4-specifc lipopolysaccharide (LPS), resulting in mitogen-activated protein kinase activation, increased CD68 and inducible nitric oxide synthase expression, and release of the proinflammatory cytokines tumor necrosis factor (TNF) and interleukin-6 (IL-6). Microglial conditioned medium (MGCM) from LPS-activated microglia attenuated primary OPC proliferation without inducing cell death. The microglial-induced inhibition of OPC proliferation was reversed by stimulating group III metabotropic glutamate receptors in microglia with the agonist L-AP4. In contrast to OPC, LPS-activated MGCM enhanced the survival of mature oligodendrocytes. Further investigation suggested that TNF and IL-6 released from TLR4-activated microglia might contribute to the effect of MGCM on OPC proliferation, insofar as TNF depletion of LPS-activated MGCM reduced the inhibition of OPC proliferation, and direct addition of TNF or IL-6 attenuated or increased proliferation, respectively. OPC themselves were also found to express proteins involved in TLR4 signalling, including TLR4, MyD88, and MAL. Although LPS stimulation of OPC did not induce proinflammatory cytokine release or affect their survival, it did trigger JNK phosphorylation, suggesting that TLR4 signalling in these cells is active. These findings suggest that OPC survival may be influenced not only by factors released from endotoxin-activated microglia but also through a direct response to endotoxins. This may have consequences for myelination under conditions in which microglial activation and cerebral infection are both implicated. © 2010 Wiley-Liss, Inc. [source] Distinct pattern of microglial response, cyclooxygenase-2, and inducible nitric oxide synthase expression in the aged rat brain after excitotoxic damageJOURNAL OF NEUROSCIENCE RESEARCH, Issue 14 2008O. Campuzano Abstract Microglial and inflammatory responses to acute damage in aging are still poorly understood, although the aged brain responds differently to injury, showing poor lesion outcome. In this study, excitotoxicity was induced by intrastriatal injection of N-methyl-D-aspartate in adult (3,4 months) and aged (22,24 months) rats. Cryostat brain sections were processed for the analysis of microglial response by lectin histochemistry and cyclooxygenase 2 (COX2) and inducible nitric oxide synthase (iNOS) expression by immunohistochemistry and confocal analysis. Aged injured animals showed more widespread area of microglial response at 12 hr postlesion (hpl) and greater microglia/macrophage density at 3 days postlesion (dpl). However, aged reactive microglia showed prevalence of ramified morphologies and fewer amoeboid/round forms. Aged injured animals presented a diminished area of COX2 expression, but a significantly larger density of COX2+ cells, with higher numbers of COX2+ neurons during the first 24 hpl and COX2+ microglia/macrophages later. In contrast, the amount of COX2+ neutrophils was diminished in the aged. iNOS was more rapidly induced in the aged injured striatum, with higher cell density at 12 hpl, when expression was mainly neuronal. From 1 dpl, both the iNOS+ area and the density of iNOS+ cells were reduced in the aged, with lower numbers of iNOS+ neurons, microglia/macrophages, neutrophils, and astrocytes. In conclusion, excitotoxic damage in aging induces a distinct pattern of microglia/macrophage response and expression of inflammatory enzymes, which may account for the changes in lesion outcome in the aged, and highlight the importance of using aged animals for the study of acute age-related insults. © 2008 Wiley-Liss, Inc. [source] Loss of lipopolysaccharide-induced nitric oxide production and inducible nitric oxide synthase expression in scrapie-infected N2a cellsJOURNAL OF NEUROSCIENCE RESEARCH, Issue 2 2003Heléne Lindegren Abstract In scrapie-infected cells, the conversion of the cellular prion protein to the pathogenic prion has been shown to occur in lipid rafts, which are suggested to function as signal transduction platforms. Neuronal cells may respond to bacterial lipopolysaccharide (LPS) treatment with a sustained and elevated nitric oxide (NO) release. Because prions and the major LPS receptor CD14 are colocalized in lipid rafts, the LPS-induced NO production in scrapie-infected neuroblastoma cells was studied. This study shows that LPS induces a dose- and time-dependent increase in NO release in the murine neuroblastoma cell line N2a, with a 50-fold increase in NO production at 1 ,g/ml LPS after 96 hr, as measured by nitrite in the medium. This massive NO release was not caused by activation of the neuronal NO synthase (nNOS), but by increased expression of the inducible NOS (iNOS) mRNA and protein. However, in scrapie-infected N2a cells (ScN2a), the LPS-induced NO production was completely abolished. The absence of LPS-induced NO production in ScN2a was due not to abolished enzymatic activity of iNOS but to a complete inhibition of the LPS-induced iNOS gene expression as measured by Western blot and RT-PCR. These results indicate that scrapie infection inhibits the LPS-mediated signal transduction upstream of the transcriptional step in the signaling cascade and may reflect the important molecular and cellular changes induced by scrapie infection. © 2002 Wiley-Liss, Inc. [source] A study to assess inducible nitric oxide synthase expression in oral lichen planusJOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 6 2000Peter A. Brennan Abstract: Nitric oxide (NO) has been implicated in a variety of diseases but has not been previously studied in oral lichen planus (OLP). Since OLP has a complex immunogenesis with abundant macrophage infiltration, this study determined by immunohistochemistry whether or not the expression of the inducible form of nitric oxide synthase (iNOS) was increased in this condition relative to normal mucosa. Thirty cases of OLP and 10 normal buccal mucosa biopsies were studied utilising primary antibodies to iNOS and CD68, a myelomonocytic marker. iNOS activity was additionally assessed using a [14,C]-labelled arginine to citrulline assay. CD68 expression was significantly increased in the cellular infiltrate of all 30 cases of OLP compared with normal mucosa (P<0.009). Although iNOS staining was seen in a minority of cells in nine cases, this was not statistically significant when compared with the absent staining in normal oral mucosa (P=0.26). Furthermore, the minimal iNOS activity found in OLP was similar to that in normal mucosa. We conclude that expression of iNOS by macrophages is downregulated in OLP and discuss the possible reasons for this finding. [source] Early changes in rectal nitric oxide and mucosal inflammatory mediators in Crohn's colitis in response to infliximab treatmentALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 8 2007T. LJUNG SUMMARY Background Treatment with tumor necrosis factor-, monoclonal antibody (infliximab) reduces clinical activity and intestinal inflammation in Crohn's disease. Aim To study the time-course of the effects of infliximab with reference to mucosal cytokine and inducible nitric oxide synthase expression. Methods Thirty-two patients with Crohn's disease were treated with single dose infliximab (5 mg/kg). Disease activity was assessed days 1, 3, 7 and 28 using Harvey,Bradshaw index. Rectal nitric oxide levels were determined and rectal biopsies collected before treatment, 1 h after infusion and on days 3, 7 and 28. Immunohistochemical staining against inducible nitric oxide synthase, tumor necrosis factor-,, interleukin-1, and interferon-, were performed. Results Clinical response was seen in 14 patients with down-regulation of global immunohistochemistry expression, reaching nadir day 3. Rectal nitric oxide was increased at baseline (3578 ± 1199 parts per billion, ppb) compared with controls (89 ± 13 ppb) (P < 0.001). In patients with clinical response, rectal nitric oxide decreased from 3926 ± 1687 ppb to 1050 ± 428 ppb day 28 (P < 0.05). Conclusions Down-regulation of mucosal inflammatory mediators occurs after infliximab. Rectal nitric oxide levels parallel down-regulation of inducible nitric oxide synthase, tumor necrosis factor-,, interleukin-1, and interferon-, and may serve as a quantitative biomarker of intestinal inflammation. [source] The cytoprotective effects of addition of activated protein C into preservation solution on small-for-size grafts in ratsLIVER TRANSPLANTATION, Issue 1 2010Naohisa Kuriyama Small-for-size liver grafts are a serious obstacle for partial orthotopic liver transplantation. Activated protein C (APC), a potent anticoagulant serine protease, is known to have cell-protective properties due to its anti-inflammatory and antiapoptotic activities. This study was designed to examine the cytoprotective effects of a preservation solution containing APC on small-for-size liver grafts, with special attention paid to ischemia-reperfusion injury and shear stress in rats. APC exerted cytoprotective effects, as evidenced by (1) increased 7-day graft survival; (2) decreased initial portal pressure and improved hepatic microcirculation; (3) decreased levels of aminotransferase and improved histological features of hepatic ischemia-reperfusion injury; (4) suppressed infiltration of neutrophils and monocytes/macrophages; (5) reduced hepatic expression of tumor necrosis factor , and interleukin 6; (6) decreased serum levels of hyaluronic acid, which indicated attenuation of sinusoidal endothelial cell injury; (7) increased hepatic levels of nitric oxide via up-regulated hepatic endothelial nitric oxide synthesis expression together with down-regulated hepatic inducible nitric oxide synthase expression; (8) decreased hepatic levels of endothelin 1; and (9) reduced hepatocellular apoptosis by down-regulated caspase-8 and caspase-3 activities. These results suggest that a preservation solution containing APC is a potential novel and safe product for small-for-size liver transplantation, alleviating graft injury via anti-inflammatory and antiapoptotic effects and vasorelaxing conditions. Liver Transpl 16:1,11, 2010. © 2009 AASLD. [source] Nitric oxide synthesis and nitric oxide synthase expression in the kidney of rats treated by FK506NEPHROLOGY, Issue 1 2002LiMing WANG SUMMARY: FK506-induced nephrotoxicity is characterized by a disturbance in renal haemody-namics that is attributed to an imbalance between the various modulators of renal vascular tone. It has not been well defined whether nitric oxide (NO), as an important vasoactive factor, is involved in FK506-induced nephrotoxicity. This study was designed to evaluate the involvement of nitric oxide in FK506-induced nephrotoxicity by investigating NO synthesis and NO synthase (NOS) expression in the kidney of rats treated with FK506. Male Wistar rats weighing 240,260 g, aged 11 weeks, were administered with FK506 (3.2mg/kg per day i.m.) for 4 weeks. Renal function and urinary NOx was measured using biochemical methods at the end of both 2 and 4 weeks of treatment. Expression of NOS protein and NOS mRNA in the kidney was also investigated using Western blot analysis and reverse transcription/polymerase chain reaction, respectively. FK506 administration induced nephrotoxicity, which was indicated by renal dysfunction (elevated blood urea nitrogen and creatinine, and reduced creatinine clearance, P < 0.05 vs control). FK506-induced nephrotoxicity was accompanied by higher urinary NOx excretion at the end of 2 weeks' treatment. In parallel with an increase in NO synthesis, increased eNOS protein and mRNA expression were also found in the renal medulla and renal cortex at week 2. the expression remained at higher levels in the renal medulla and returned to normal levels in the renal cortex at week 4. FK506 treatment induced nephrotoxicity in rats, which was accompanied by a temporal increase in NO synthesis in the kidney. Increased eNOS protein and mRNA expression were also found in the kidney of treated rats, which may be responsible for the enhanced NO synthesis. [source] Morphine tolerance increases [3H]MK-801 binding affinity and constitutive neuronal nitric oxide synthase expression in rat spinal cord. (National Medical Defense Center, Taipei, Taiwan) Br J Anaesth 2000;85:587,591.PAIN PRACTICE, Issue 2 2001Chih-Shung Wong N -Methyl-D-aspartate (NMDA) receptor antagonists and nitric oxide synthase (NOS) inhibitors inhibit morphine tolerance. In the present study, a lumbar subarachnoid polyethylene (PE10) catheter was implanted for drug administration to study alterations in NMDA receptor activity and NOS protein expression in a morphine-tolerant rat spinal model. Antinociceptive tolerance induced by intrathecal morphine infusion (10 ,g h,1) for 5 days. Co-administered MK801 with morphine was used to inhibit the development of morphine tolerance. Lumbar spinal cord segments were removed and prepared for [3H]MK-801 binding assays and NOS western blotting. The binding affinity of [3H]MK-801 was higher in spinal cords of morphine-related rats than in control rats. There was no difference in Bmax. Western blot analysis showed that constitutive expression of neuronal NOS protein in the morphine-tolerant group was twice that in the control group. This up-regulation was partially prevented by MK-801. The results suggest that morphine tolerance affects NMDA receptor binding activity and increases nNOS expression in the rat spinal cord. Comment by Octavio Calvillo, M.D., Ph.D. Morphine tolerance may be due to receptor down-regulation or receptor uncoupling; activation of the NMDA-dependent pain-facilitatory system may also play a role. It has been proposed that NMDA receptor activation may play a role in morphine tolerance. NMDA receptor antagonists and nitric oxide synthase [NOS] inhibitors may prevent morphine tolerance. Tolerance was induced in rats by intrathecal injection of morphine [10 ug/h] for 5 days, co-administration of MK801 [NMDA antagonist] with morphine was used to prevent morphine tolerance. Lumbar spinal cord segments were removed and prepared for [H3]MK801 binding assays and NOS western blotting. The binding affinity of labeled MK801 was higher in spinal cords of morphine tolerant rats than in control rats. Western blot analysis showed that constitutive expression of neuronal NOS protein in the morphine tolerant rats was twice that in the control group, thus, up-regulation was prevented by MK801. The results suggest that morphine tolerance affect NMDA receptor binding activity and increase neuronal protein expression in rat the spinal cord. [source] Transgenic neuronal nitric oxide synthase expression induces axotomy-like changes in adult motoneuronsTHE JOURNAL OF PHYSIOLOGY, Issue 18 2010Fernando Montero Dysregulation of protein expression, function and/or aggregation is a hallmark of a number of neuropathological conditions. Among them, upregulation and/or de novo expression of the neuronal isoform of nitric oxide (NO) synthase (nNOS) commonly occurs in diverse neurodegenerative diseases and in axotomized motoneurons. We used adenoviral (AVV) and lentiviral (LVV) vectors to study the effects of de novo nNOS expression on the functional properties and synaptic array of motoneurons. AVV-nNOS injection into the genioglossus muscle retrogradely transduced neonatal hypoglossal motoneurons (HMNs). Ratiometric real-time NO imaging confirmed that transduced HMNs generated NO gradients in brain parenchyma (space constant: ,12.3 ,m) in response to a glutamatergic stimulus. Unilateral AVV-nNOS microinjection in the hypoglossal nucleus of adult rats induced axotomy-like changes in HMNs. Specifically, we found alterations in axonal conduction properties and the recruitment order of motor units and reductions in responsiveness to synaptic drive and in the linear density of synaptophysin-positive puncta opposed to HMN somata. Functional alterations were fully prevented by chronic treatment with nNOS or soluble guanylyl cyclase inhibitors. Synaptic and functional changes were also completely avoided by prior intranuclear injection of a neuron-specific LVV system for miRNA-mediated nNOS knock-down (LVV-miR-shRNA/nNOS). Furthermore, synaptic and several functional changes evoked by XIIth nerve injury were to a large extent prevented by intranuclear administration of LVV-miR-shRNA/nNOS. We suggest that nNOS up-regulation creates a repulsive NO gradient for synaptic boutons underlying most of the functional impairment undergone by injured motoneurons. This further strengthens the case for nNOS targeting as a plausible strategy for treatment of peripheral neuropaties and neurodegenerative disorders. [source] Inducible nitric oxide synthase expression and its prognostic significance in colorectal cancerAPMIS, Issue 2 2010KYRIAKOS ZAFIRELLIS Zafirellis K, Zachaki A, Agrogiannis G, Gravani K. Inducible nitric oxide synthase expression and its prognostic significance in colorectal cancer. APMIS 2010; 118: 115,24. Nitric oxide synthases (NOS) are expressed in colorectal cancer. The aim of this study was to examine the inducible NOS (iNOS) expression in colorectal cancer and to investigate its prognostic relevance. Tissue sections of primary tumors from 132 patients undergoing curative resection for colorectal cancer were immunohistochemically examined for iNOS expression. The expression pattern of iNOS was correlated with various clinicopathological characteristics and survival. iNOS immunoreactivity was observed in the cytoplasm of tumor epithelial cells in 60 patients (45.5%) and positively correlated with lymph node involvement (p = 0.019). No significant correlation was found between iNOS expression and various clinicopathological characteristics, including age, gender, tumor location, tumor size, tumor grade, T stage, and Union International Contra la Cancrum (UICC) stage. Survival analysis showed a significant correlation between iNOS-positive tumors and poor disease-specific survival (p < 0.0001), with independent prognostic significance in multivariate analysis (HR = 4.42; p < 0.0001). Patients with stage II disease and iNOS-positive tumors had significantly worse disease-specific survival than those with iNOS-negative tumors (p < 0.0001). In addition, patients with stage III disease and iNOS-positive tumors had significantly worse disease-specific survival than those with iNOS-negative tumors (p = 0.001). The ability of iNOS to predict outcome in colorectal cancer patients may be independent of other known prognostic factors, providing a new molecular marker with significant potential for clinical utility. [source] Targeted tumor necrosis factor receptor I preligand assembly domain improves skin lesions in MRL/lpr miceARTHRITIS & RHEUMATISM, Issue 8 2010Guo-Min Deng Objective Skin disease is the second most common manifestation in patients with systemic lupus erythematosus (SLE). Tumor necrosis factor receptor (TNFR) preligand assembly domain (PLAD) has been found to block the effect of TNF,, and TNFRI PLAD (p60 PLAD) inhibits inflammatory arthritis. This study was undertaken to investigate whether TNFR PLAD limits inflammatory skin injury in a mouse model of SLE. Methods Female MRL/lpr mice received p60 PLAD (100 ,g/mouse intraperitoneally), p80 PLAD (100 ,g/mouse intraperitoneally), or phosphate buffered saline (100 ,l/mouse intraperitoneally) 3 times a week for 26 weeks, starting at age 6 weeks. Results Immunohistochemistry studies demonstrated that TNFRI but not TNFRII was dominantly expressed in skin lesions in MRL/lpr mice. We found that TNFRI PLAD (p60 PLAD) but not TNFRII PLAD (p80 PLAD) protein significantly inhibited skin injury in the MRL/lpr mouse model of lupus. NF-,B, monocyte chemotactic protein 1, and inducible nitric oxide synthase expression in skin lesions were significantly inhibited by p60 PLAD. Lupus serum,induced monocyte differentiation into dendritic cells was reduced by p60 PLAD, but p60 PLAD did not reduce IgG deposition in the skin or improve the progression of kidney damage in MRL/lpr mice. Conclusion Our results indicate that TNFRI is involved in the expression of skin injury in MRL/lpr mice with lupus and that p60 PLAD or similar biologics may be of clinical value if applied locally. [source] Chemical induction of HO-1 suppresses lupus nephritis by reducing local iNOS expression and synthesis of anti-dsDNA antibodyCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 2 2004Y. TAKEDA SUMMARY There is accumulating evidence that haem oxygenase (HO)-1 plays a protective role in various disorders. The beneficial efficacy of HO-1 induction therapy has been shown in renal diseases such as glomerulonephritis, interstitial nephritis and drug induced nephrotoxicity. However, involvement of HO-1 in the development of autoimmune renal diseases remains uncertain. To assess the clinical efficacy of HO-1 induction therapy for lupus glomerulonephritis, MRL/lpr mice were intraperitoneally injected with 100 µmol/kg hemin, a potent HO-1 inducer, or PBS as controls, once a week from 6 weeks of age to 21,24 weeks-old. We found that treatment with hemin led to a significant reduction of proteinuria and remarkable amelioration of glomerular lesions accompanied by decreased immune depositions. In addition, the circulating IgG anti-double-stranded DNA antibody level was significantly decreased in hemin treated mice when compared with controls. A single intraperitoneal injection with hemin resulted in reduction of inducible nitric oxide synthase expression in the kidney and spleen, and serum interferon- , level. Our results suggest that HO-1 induction therapy ameliorates lupus nephritis by suppressing nitric oxide (NO) dependent inflammatory responses and attenuating production of pathogenic autoantibodies. [source] |