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NO Inhibition (no + inhibition)
Selected AbstractsIschemic preconditioning affects interleukin release in fatty livers of rats undergoing ischemia/reperfusionHEPATOLOGY, Issue 3 2004Anna Serafín The present study evaluates the effect of ischemic preconditioning on interleukin-1 (IL-1) and interleukin-10 (IL-10) generation following hepatic ischemia/reperfusion (I/R) in normal and steatotic livers as well as the role of nitric oxide (NO) in this process. Increased IL-1, and IL-10 levels were observed in normal livers after I/R. Steatotic livers showed higher IL-1, levels than normal livers, and IL-10 at control levels. The injurious role of IL-1, and the benefits of IL-10 on hepatic I/R injury was shown with the use of IL-1 receptor antagonist (IL-1ra), anti-IL-10 polyclonal antibody against IL-10 (anti-IL-10) and exogenous IL-10. The effective dose of these treatments was different in both types of livers. Preconditioning prevented IL-1, release and increased IL-10 generation after I/R in normal and steatotic livers. IL-1, or anti-IL-10 pretreatments reversed the benefits of preconditioning. IL-1, action inhibition in a preconditioned group that was pretreated with anti-IL-10 did not modify the benefits of preconditioning. In addition, anti-IL-10 pretreatment in the preconditioned group resulted in IL-1, levels comparable to those observed after I/R. NO inhibition eliminated the benefits of preconditioning on IL-10 release, IL-1, levels, and hepatic injury. In conclusion, preconditioning, through IL-10 overproduction, inhibits IL-1, release and the ensuing hepatic I/R injury in normal and steatotic livers. IL-10 generation induced by preconditioning could be mediated by NO. (HEPATOLOGY 2004;39:688,698.) [source] Tumoricidal activity of high-dose tumor necrosis factor-, is mediated by macrophage-derived nitric oxide burst and permanent blood flow shutdownINTERNATIONAL JOURNAL OF CANCER, Issue 2 2008Chandrakala Menon Abstract This study investigates the role of tumor nitric oxide (NO) and vascular regulation in tumor ulceration following high-dose tumor necrosis factor-, (TNF) treatment. Using TNF-responsive (MethA) and nonresponsive (LL2) mouse tumors, tumor NO concentration was measured with an electrochemical sensor and tumor blood flow by Doppler ultrasound. Mice were also pretreated with a selective inducible nitric oxide synthase (iNOS) inhibitor, 1400 W. Tumors harvested from TNF-treated mice were cryosectioned and immunostained for murine macrophages, or/and iNOS. MethA tumor-bearing mice were depleted of macrophages. Pre- and post-TNF tumor NO levels were measured continuously, and mice were followed for gross tumor response. In MethA tumors, TNF caused a 96% response rate, and tumor NO concentration doubled. Tumor blood flow decreased to 3% of baseline by 4 hr and was sustained at 24 hr and 10 days post-TNF. Selective NO inhibition with 1400 W blocked NO rise and decreased response rate to 38%. MethA tumors showed tumor infiltration by macrophages post-TNF and the pattern of macrophage immunostaining overlapped with iNOS immunostaining. Depletion of macrophages inhibited tumor NO increase and response to TNF. LL2 tumors had a 0% response rate to TNF and exhibited no change in NO concentration. Blood flow decreased to 2% of baseline by 4 hr, recovered to 56% by 24 hr and increased to 232% by 10 days. LL2 tumors showed no infiltration by macrophages post-TNF. We conclude that TNF causes tumor infiltrating, macrophage-derived iNOS-mediated tumor NO rise and sustained tumor blood flow shutdown, resulting in tumor ulceration in the responsive tumor. © 2008 Wiley-Liss, Inc. [source] Nitric Oxide, Mitochondria, and Cell DeathIUBMB LIFE, Issue 3-5 2001Guy C. Brown Abstract NO or its derivatives (reactive nitrogen species: RNS) have three types of actions on mitochondria: 1) reversible inhibition of mitochondrial respiration at cytochrome oxidase by NO, and irreversible inhibition at multiple sites by RNS; 2) stimulation of mitochondrial production of superoxide, hydrogen peroxide, and peroxynitrite by NO; and 3) induction of mitochondrial permeability transition (MPT) by RNS. Similarly there are three main roles of mitochondria in NO-induced cell death: a) NO inhibition of respiration can induce necrosis (or excitotoxicity in neurons) and inhibit apoptosis if glycolysis is insufficient to compensate, b) RNS- or oxidant-induced signal transduction or DNA damage may activate the mitochondrial pathway to apoptosis, and c) RNS-induced MPT may induce apoptosis or necrosis. [source] Nitric oxide scavenging and detoxification by the Mycobacterium tuberculosis haemoglobin, HbN in Escherichia coliMOLECULAR MICROBIOLOGY, Issue 5 2002Ranjana Pathania Summary Nitric oxide (NO), generated in large amounts within the macrophages, controls and restricts the growth of internalized human pathogen, Mycobacterium tuberculosis H37Rv. The molecular mechanism by which tubercle bacilli survive within macrophages is currently of intense interest. In this work, we have demonstrated that dimeric haemoglobin, HbN, from M. tuberculosis exhibits distinct nitric oxide dioxygenase (NOD) activity and protects growth and cellular respiration of heterologous hosts, Escherichia coli and Mycobacterium smegmatis, from the toxic effect of exogenous NO and the NO-releasing compounds. A flavohaemoglobin (HMP)-deficient mutant of E. coli, unable to metabolize NO, acquired an oxygen-dependent NO consumption activity in the presence of HbN. On the basis of cellular haem content, the specific NOD activity of HbN was nearly 35-fold higher than the single-domain Vitreoscilla haemoglobin (VHb) but was sevenfold lower than the two-domain flavohaemoglobin. HbN-dependent NO consumption was sustained with repeated addition of NO, demonstrating that HbN is catalytically reduced within E. coli. Aerobic growth and respiration of a flavohaemoglobin (HMP) mutant of E. coli was inhibited in the presence of exogenous NO but remained insensitive to NO inhibition when these cells produced HbN, VHb or flavohaemoglobin. M. smegmatis, carrying a native HbN very similar to M. tuberculosis HbN, exhibited a 7.5-fold increase in NO uptake when exposed to gaseous NO, suggesting NO-induced NOD activity in these cells. In addition, expression of plasmid-encoded HbN of M. tuberculosis in M. smegmatis resulted in 100-fold higher NO consumption activity than the isogenic control cells. These results provide strong experimental evidence in support of NO scavenging and detoxification function for the M. tuberculosis HbN. The catalytic NO scavenging by HbN may be highly advantageous for the survival of tubercle bacilli during infection and pathogenesis. [source] Nimbidin suppresses functions of macrophages and neutrophils: relevance to its antiin,ammatory mechanismsPHYTOTHERAPY RESEARCH, Issue 5 2004Gurpreet Kaur Abstract Nimbidin is a mixture of tetranortriterpenes and is the major active principle of the seed oil of Azadirachta indica A. Juss (Meliaceae) possessing potent antiin,ammatory and antiarthritic activities. The present study revealed that nimbidin signi,cantly inhibited some of the functions of macrophages and neutrophils relevant to the in,ammatory response following both in vivo and in vitro exposure. Oral administration of 5,25 mg/kg nimbidin to rats for 3 consecutive days signi,cantly inhibited the migration of macrophages to their peritoneal cavities in response to in,ammatory stimuli and also inhibited phagocytosis and phorbol-12-myristate-13-acetate (PMA) stimulated respiratory burst in these cells. In vitro exposure of rat peritoneal macrophages to nimbidin also inhibited phagocytosis and PMA stimulated respiratory burst in these cells. Nimbidin also inhibited nitric oxide (NO) and prostaglandin E2 (PGE2) production in lipopolysaccharide (LPS) stimulated macrophages following in vitro exposure, whereas interleukin 1 (IL-1) was only weakly inhibited. Probing the mechanism of NO inhibition revealed that nimbidin ameliorated the induction of inducible NO synthase (iNOS) without any inhibition in its catalytic activity. In addition, nimbidin also attenuated degranulation in neutrophils assessed in terms of release of , -glucuronidase, myeloperoxidase and lysozyme. The results suggest that nimbidin suppresses the functions of macrophages and neutrophils relevant to in,ammation. Thus nimbidin can be valuable in treating in,ammation/in,ammatory diseases. Copyright © 2004 John Wiley & Sons, Ltd. [source] Therapeutic Targets in Liver Transplantation: Angiotensin II in Nonsteatotic Grafts and Angiotensin-(1,7) in Steatotic GraftsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 3 2009I. Alfany-Fernandez Numerous steatotic livers are discarded as unsuitable for transplantation because of their poor tolerance of ischemia-reperfusion(I/R). The injurious effects of angiotensin (Ang)-II and the benefits of Ang-(1,7) in various pathologies are well documented. We examined the generation of Ang II and Ang-(1,7) in steatotic and nonsteatotic liver grafts from Zucker rats following transplantation. We also studied in both liver grafts the effects of Ang-II receptors antagonists and Ang-(1,7) receptor antagonists on hepatic I/R damage associated with transplantation. Nonsteatotic grafts showed higher Ang II levels than steatotic grafts, whereas steatotic grafts showed higher Ang-(1,7) levels than nonsteatotic grafts. Ang II receptor antagonists protected only nonsteatotic grafts against damage, whereas Ang-(1,7) receptor antagonists were effective only in steatotic grafts. The protection conferred by Ang II receptor antagonists in nonsteatotic grafts was associated with ERK 1/2 overexpression, whereas the beneficial effects of Ang-(1,7) receptor antagonists in steatotic grafts may be mediated by NO inhibition. Our results show that Ang II receptor antagonists are effective only in nonsteatotic liver transplantation and point to a novel therapeutic target in liver transplantation based on Ang-(1,7), which is specific for steatotic liver grafts. [source] | |||||||||||||