Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To clarify the induction pathway of inducible nitric oxide (NO) synthase in the brain, we examined the effects of interferon-gamma and lipopolysaccharide on the induction of inducible NO synthase in glial cells cultured from neonatal rats, compared to those in the macrophage cell line RAW264.7 which was derived from Abelson leukemia virus-induced BALB/c lymphocytic lymphoma. NO synthase activity (NO2- accumulation) and 130 kDa protein of inducible NO synthase were induced 24 h after treatment with interferon-gamma or lipopolysaccharide in both glial cells and RAW264.7 macrophages. These induction activities were inhibited by a tyrosine kinase inhibitor, herbimycin A. Immunoprecipitation assay using antibodies against Janus kinases, and the signal transducer and activator of transcription-1 (STAT1), revealed that interferon-gamma induced tyrosine phosphorylation of the just another kinase-2 (Jak2) and STAT1 alpha but did not induced the phosphorylation of Jak1, the non-receptor tyrosine kinase-2 (Tyk2) and STAT1 beta. Tyrosine phosphorylation of Jak2 and STAT1 alpha induced by interferon-gamma was also inhibited by herbimycin A, while lipopolysaccharide did not induce any tyrosine phosphorylation of Janus kinases and STAT1 at all. These results suggest that the interferon-gamma-induced inducible NO synthase induction involves activation of Jak2-STAT1 alpha pathway in both glial cells and macrophages.
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PMID:Possible involvement of Janus kinase Jak2 in interferon-gamma induction of nitric oxide synthase in rat glial cells. 881 44

Because of the involvement of nitric oxide (NO) in inflammatory states such as parasitic and hypersensitivity disorders and the fact that eosinophils are one of the cell types implicated, we asked whether eosinophils were able to express mRNA specific to inducible NO synthase (iNOS) and iNOS protein and to secrete nitric oxide. iNOS protein was detected on eosinophil preparations by immunocytochemistry using iNOS mAb. Expression of iNOS protein was also detected by immunoblotting in human purified eosinophils and an eosinophilic leukemia cell line, Eol-3. Nitrite production was detected in the supernatant of human eosinophils and Eol-3 cells cultured for 24 h, and was completely inhibited in the presence of the NOS inhibitor N-methylester-L-arginine. iNOS cDNA was obtained by reverse transcription-PCR. After subcloning, sequencing of the 259-bp fragment from three different human eosinophils cDNAs revealed 97% identity with macrophage/monocyte iNOS. Our studies describe for the first time the presence of iNOS on eosinophil and a putative new role for this cell in inflammatory states such as asthma and parasitic disease.
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PMID:Eosinophils transcribe and translate messenger RNA for inducible nitric oxide synthase. 899 4

We studied the role of IL-6 and nitric oxide (NO) in IL-1 and leukaemia inhibitory factor (LIF) induced suppression of proteoglycan synthesis. Cartilage explants of patellae and femoral heads were incubated with IL-1 or LIF. Conditioned media were analysed for IL-6 activity (B9-assay) and NO content (Griess). Proteoglycan synthesis was assessed using [35S]sulfate incorporation. IL-1 dose dependently induced IL-6 synthesis and neutralizing IL-6 with antibodies did not reduce proteoglycan synthesis suppression, neither in explants nor in isolated chondrocytes. IL-6 independence was confirmed using cartilage from IL-6 deficient mice. IL-1 significantly increased NO release in normal and IL-6 deficient chondrocytes and addition of the NO synthase inhibitor, N(G)-monomethyl-L-arginine markedly alleviated proteoglycan synthesis suppression. LIF also induced proteoglycan synthesis suppression in cartilage from normal and IL-6 deficient mice, but the suppression was neither accompanied by nor dependent on NO release. Furthermore, proteoglycan synthesis suppression during experimental arthritis was similar in both normal and IL-6 deficient mice. We concluded that IL-6 is not a necessary cofactor in IL-1 and LIF induced suppression of proteoglycan synthesis. Furthermore, only the IL-1 induced suppression was mediated by NO, suggesting that inhibition of proteoglycan synthesis may occur through different pathways.
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PMID:Effect of interleukin 1 and leukaemia inhibitory factor on chondrocyte metabolism in articular cartilage from normal and interleukin-6-deficient mice: role of nitric oxide and IL-6 in the suppression of proteoglycan synthesis. 923 7

We have previously shown that human leukaemia inhibitory factor (hLIF) inhibits perivascular cuff-induced neointimal formation in the rabbit carotid artery. Since nitric oxide (NO) is a known inhibitor of smooth muscle growth, NO synthase (NOS) activity in the presence of hLIF was examined in vivo and in vitro. In rabbit aortic smooth muscle cell (SMC) culture, significant NOS activity was observed at 50 pg/ml hLIF, with maximal activity at 5 ng/ml. In the presence of the NOS inhibitor L-NAME, hLIF-induced activation of NOS was greatly decreased, however it was still 63-fold higher than in control (p < 0.05). SMC-DNA synthesis was significantly reduced (-47%) following incubation with hLIF plus L-arginine, the substrate required for NO production (p < 0.05), with no effect observed in the absence of L-arginine. Silastic cuff placement over the right carotid artery of rabbits resulted in a neointima 19.3 +/- 5.4% of total wall cross-sectional area, which was increased in the presence of L-NAME (27.0 +/- 2.0%; p < 0.05) and reduced in the presence of L-arginine (11.3 +/- 2.0%; p < 0.05). The effect of L-arginine was ameliorated by co-administration of L-NAME (16.4 +/- 1.5%). However, administration of L-NAME with hLIF had no effect on the potent inhibition of neointimal formation by hLIF (3.2 +/- 2.5 vs. 2.1 +/- 5.4%, respectively). Similarly, with hLIF administration, NOS activity in the cuffed carotid increased to 269.0 +/- 14.0% of saline-treated controls and remained significantly higher with co-administration of L-NAME (188.5 +/- 14.7%). These results indicate that hLIF causes superinduction of NO by SMC, and that it is, either partially or wholly, through this mechanism that hLIF is a potent inhibitor of neointimal formation in vivo and of smooth muscle proliferation in vitro.
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PMID:Induction of smooth muscle cell nitric oxide synthase by human leukaemia inhibitory factor: effects in vitro and in vivo. 934 31

Tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) exert a wide array of immunoregulatory, partly related effects. We examined the production of these two mediators by the human hairy cell leukemia cell line Eskol. Combined cell lysate and supernatant of Eskol cells (0.5 x 10(6) cells ml(-1)) incubated for 18 h, contained a mean of 1.5 ng ml(-1) TNF-alpha. This spontaneous TNF-alpha synthesis was enhanced by phorbol ester (PMA) and phytohemagglutinin (PHA) and decreased by dexamethasone. Nitrite, the stable product of NO, accumulated in the supernatant of Eskol cells after prolonged incubation. Maximal nitrite concentrations (range: 0.8-3.5 microM at 2 x 10(6) cells ml(-1)) were detected after 7 days of incubation. NO production was augmented by PHA and reduced by PMA. The inhibitors of NO synthase N(G)-monomethyl-L-arginine (L-NMMA) and aminoguanidine decreased NO synthesis. Simultaneous activation with the proinflammatory cytokines, interferon-gamma, interleukin-1beta and TNF-alpha, increased NO synthesis. These results suggest that NO production in Eskol cells results from inducible NO synthase activity. This is the first direct demonstration of NO formation in human lymphoid cells. The cell line, Eskol, may serve as a model to study regulation of TNF-alpha and NO synthesis in human B-cell leukemia.
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PMID:The hairy cell leukemia cell line Eskol spontaneously synthesizes tumor necrosis factor-alpha and nitric oxide. 967 16

It is generally accepted that the vascular endothelial growth factor (VEGF) signal system has no role in the maintenance of normal blood cell formation, although it obviously regulates the development of primitive hematopoiesis during an early stage of embryogenesis. The VEGF signaling pathway, however, might have some role in malignant hematopoiesis, since malignant hematopoietic cells, including acute myeloid leukemia (AML) cells, have been shown to express VEGF and its receptors. In endothelial cells, the VEGF/Flk-1/KDR signal system is a very important generator of nitric oxide (NO) through the activation of its downstream effectors phosphatidylinositol-3-OH-kinase (PI3-K), Akt kinase and endothelial NO synthase (eNOS). It is known that NO regulates hematopoiesis and modulates AML cell growth. The role of the VEGF signaling pathway in the control of AML cell growth through eNOS, however, has not been studied. By using the OCI/AML-2 cell line, which expresses VEGF receptor-2, ie Flk-1/KDR, eNOS and VEGF, as analyzed by flow cytometry, and produces VEGF into growth medium, as analyzed by ELISA, we showed that the Akt kinase and NOS activities in these cells were decreased by the inhibitors of VEGF, Flk-1/KDR and PI3-K, and NOS activity also by the direct inhibitor of NOS. The decreased NOS activity led to inhibition of clonogenic cell growth and, to some extent, induction of apoptosis. We also found that blast cells of bone marrow samples randomly taken from 14 AML patients uniformly expressed Flk-1/KDR and to varying degrees eNOS and VEGF, as analyzed by immunohistochemistry. We conclude that autocrine VEGF through Flk-1/KDR, by activating eNOS to produce NO through PI3-K/Akt kinase, maintains clonogenic cell growth in the OCI/AML-2 cell line. Since the patient samples did not express VEGF in all cases, it is possible that in vivo the regulatory connection between these two signal systems is also mediated via endocrine VEGF in addition to autocrine or paracrine VEGF.
Leukemia 2001 Sep
PMID:Regulation of the acute myeloid leukemia cell line OCI/AML-2 by endothelial nitric oxide synthase under the control of a vascular endothelial growth factor signaling system. 1151 4

Flavopiridol, an inhibitor of cyclin-dependent kinases and other protein kinases, induces in vitro apoptosis of malignant cells from B-cell chronic lymphocytic leukemia (B-CLL). Previously, we reported that nitric oxide (NO), produced by an inducible NO synthase (iNOS), spontaneously expressed by the B-CLL cells, contributed to their deficiency in apoptosis. In the present work, we show that ex vivo treatment of leukemic cells from B-CLL patients with flavopiridol results in the inhibition of iNOS expression, as determined by immunofluorescence and Western blotting, and in a marked inhibition of NO production measured in situ with a specific fluorescent probe (DAF-2 DA). These effects are accompanied by membrane, mitochondrial and nuclear events of apoptosis. Flavopiridol exposure also results in the stimulation of caspase 3 activity and in caspase-dependent cleavage of p27(kip1), a negative regulator of the cell cycle, which is overexpressed in B-CLL. Thus, flavopiridol is capable of downregulating both iNOS and p27(kip1) expression in B-CLL cells. Furthermore, flavopiridol-promoted apoptosis is partly reverted by an NO donor, suggesting that inhibition of the NO pathway could participate in the apoptotic effects of flavopiridol on the leukemic cells.
Leukemia 2003 Dec
PMID:Flavopiridol downregulates the expression of both the inducible NO synthase and p27(kip1) in malignant cells from B-cell chronic lymphocytic leukemia. 1467 37

Some murine leukemia viruses (MuLVs), among them Cas-Br-E and ts-1 MuLVs, are neurovirulent, inducing spongiform myeloencephalopathy and hind limb paralysis in susceptible mice. It has been shown that the env gene of these viruses harbors the determinant of neurovirulence. It appears that neuronal loss occurs by an indirect mechanism, since the target motor neurons have not been found to be infected. However, the pathogenesis of the disease remains unclear. Several lymphokines, cytokines, and other cellular effectors have been found to be aberrantly expressed in the brains of infected mice, but whether these are required for the development of the neurodegenerative lesions is not known. In an effort to identify the specific effectors which are indeed required for the initiation and/or development of spongiform myeloencephalopathy, we inoculated gene-deficient (knockout [KO]) mice with ts-1 MuLV. We show here that interleukin-6 (IL-6), inducible nitric oxide synthetase (iNOS), ICE, Fas, Fas ligand (FasL), and TNF-R1 KO mice still develop signs of disease. However, transgenic mice overexpressing Bcl-2 in neurons (NSE/Bcl-2) were largely protected from hind limb paralysis and had less-severe spongiform lesions. These results indicate that motor neuron death occurs in this disease at least in part by a Bcl-2-inhibitable pathway not requiring the ICE, iNOS, Fas/FasL, TNF-R1, and IL-6 gene products.
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PMID:Protection against murine leukemia virus-induced spongiform myeloencephalopathy in mice overexpressing Bcl-2 but not in mice deficient for interleukin-6, inducible nitric oxide synthetase, ICE, Fas, Fas ligand, or TNF-R1 genes. 1464 73

Septic shock is the most common cause of death in intensive care units, and no effective treatment is available at present. Lipopolysaccharide (LPS) is the primary mediator of Gram-negative sepsis by inducing the production of macrophage-derived proinflammatory cytokines, in which activation of nuclear factor-kappaB (NF-kappaB) plays an important role. PC-SPES is an eight-herb mixture active against a variety of malignancies, including prostate cancer and leukemia. In this study, we demonstrated that PC-SPES inhibited the LPS-induced NF-kappaB reporter activity in RAW264.7 macrophages. Electrophoretic mobility shift assay showed that PC-SPES inhibited the binding of NF-kappaB to specific DNA sequences; however, it did not affect either degradation of inhibitory kappaBalpha or nuclear translocation of NF-kappaB. Also, we explored the effect of PCSPES on LPS-induced mitogen-activated protein (MAP) kinase signaling; PC-SPES did not affect LPS-induced phosphorylation of MAP kinases, including c-Jun NH2-terminal kinase, p38, and extracellular signal-regulated kinase 1/2. Moreover, PC-SPES decreased the production of proinflammatory cytokines and inducible enzymes, such as tumor necrosis factor (TNF) alpha, interleukin (IL)-1beta, IL-6, cyclooxygenase-2, as well as inducible nitric-oxide synthase in RAW264.7 macrophages and peritoneal macrophages from C57BL/6 mice after the cells were stimulated by either LPS or LPS and interferon-gamma. Furthermore, PC-SPES rescued C57BL/6 mice from death caused by LPS-induced septic shock in conjunction with decreased serum levels of TNFalpha and IL-1beta. Together, PC-SPES is a potent inhibitor of NF-kappaB and might be useful for the treatment of sepsis and inflammatory diseases.
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PMID:PC-SPES: a potent inhibitor of nuclear factor-kappa B rescues mice from lipopolysaccharide-induced septic shock. 1464 83

The therapeutic effects of melatonin against viral infections, with emphasis on the Venezuelan equine encephalomyelitis (VEE), are reviewed. Melatonin has been shown to prevent paralysis and death in mice infected with the encephalomyocarditis virus and to decrease viremia. Melatonin also postpones the onset of the disease produced by Semliki Forest virus inoculation and reduces the mortality of West Nile virus-infected mice stressed by either isolation or dexamethasone injection. An increase in the host resistance to the virus via a peripheral immunostimulatory activity is considered responsible for these effects. It has also been demonstrated that melatonin protects some strains of mink against Aleutian disease, and prevents the reduction of B- and T-cells as well as Th1 cytokine secretion in mice infected with leukemia retrovirus. In VEE-infected mice, melatonin postpones the onset of the disease and death for several days and reduces the mortality rate. This protective effect seems to be due to the increase in the production of interleukin-1beta (IL-1beta), as 100% of the infected mice treated with melatonin die when IL-1beta is blocked with antimurine IL-1beta antibodies. Although melatonin administration raises serum levels of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), the mortality observed in neutralization experiments with the corresponding anticytokine antibodies, suggests that neither TNF-alpha nor IFN-gamma are essential for the protective effect of melatonin on murine VEE virus infection. Melatonin treatment also enhances the efficiency of immunization against the VEE virus. Reactive oxygen species have been implicated in the dissemination of this virus, and their deleterious effects may be diminished by melatonin. This indole inhibits nitric oxide synthetase activity and it is a potent scavenger of nitric oxide, which also plays an important role in the spread of the VEE virus. In conclusion, the immunomodulatory, antioxidant, and neuroprotective effects of melatonin suggest that this indole must be considered as an additional therapeutic alternative to fight viral diseases.
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PMID:Melatonin and viral infections. 1496 57


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