Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The stability of proteins that constitute the neurofibrillary tangles and senile plaques of Alzheimer disease suggests that they would be ideal substrates for nonenzymatic glycation, a process that occurs over long times, even at normal levels of glucose, ultimately resulting in the formation of advanced glycation end products (AGEs). AGE-modified proteins aggregate, and they generate reactive oxygen intermediates. Using monospecific antibody to AGEs, we have colocalized these AGEs with paired helical filament tau in neurofibrillary tangles in sporadic Alzheimer disease. Such neurons also exhibited evidence of oxidant stress: induction of malondialdehyde epitopes and heme oxygenase 1 antigen. AGE-recombinant tau generated reactive oxygen intermediates and, when introduced into the cytoplasm of SH-SY5Y neuroblastoma cells, induced oxidant stress. We propose that in Alzheimer disease, AGEs in paired helical filament tau can induce oxidant stress, thereby promoting neuronal dysfunction.
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PMID:Glycated tau protein in Alzheimer disease: a mechanism for induction of oxidant stress. 805 61

To explore the involvement of nitric oxide (NO) in the induction of heme oxygenase-1, an essential enzyme in heme catabolism, we studied the effects of NO donors on the expression of heme oxygenase-1 mRNA in HeLa human cervical cancer cells. Treatment with each of three NO donors, sodium nitroprusside, 3-morpholinosydnonimine, and S-nitroso-L-glutathione, caused noticeable increases in the expression levels of heme oxygenase- mRNA, but not heme oxygenase-2 mRNA. On the other hand, nitrite or 8-bromo cGMP exerted no noticeable effect on the levels of heme oxygenase-1 mRNA. We showed that sodium nitroprusside also increased the levels of heme oxygenase-1 protein. The sodium nitroprusside-mediated increase in heme oxygenase-1 mRNA levels was abolished by treatment with actinomycin D. The expression levels of heme oxygenase-1 mRNA were also increased by NO donors in human melanoma and neuroblastoma cell lines. Thus, the observed induction of heme oxygenase-1 may represent an important response to NO or NO-related oxidative stress. The half lives of heme oxygenase-1 and heme oxygenase-2 mRNAs were estimated to be about 3.2 h and more than 5 h, respectively.
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PMID:Possible implications of the induction of human heme oxygenase-1 by nitric oxide donors. 935 92

Increased expression of heme oxygenase-1 (HO-1) is a common feature in a number of neurodegenerative diseases. Interestingly, the spatial distribution of HO-1 expression in diseased brain is essentially identical to that of pathological expression of tau. In this study, we explored the relationship between HO-1 and tau, using neuroblastoma cells stably transfected with sense and antisense HO-1 constructs as well as with the vector alone. In transfected cells overexpressing HO-1, the activity of heme oxygenase was increased, and conversely, the level of tau protein was dramatically decreased when compared with antisense HO-1 or CEP transfected cells. The suppression of tau protein expression was almost completely reversed by zinc-deuteroporphyrin, a specific inhibitor of heme oxygenase activity. The activated forms of ERKs (extracellular signal-regulated kinases) were also decreased in cells overexpressing HO-1 although no changes in the expression of total ERK-1/2 proteins were observed. These data are in agreement with the finding that the expression of tau is regulated through signal cascades including the ERKs, whose activities are modulated by oxidative stresses. The expression of tau and HO-1 may be regulated by oxidative stresses in a coordinated manner and play a pivotal role in the cytoprotection of neuronal cells.
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PMID:Overexpression of heme oxygenase in neuronal cells, the possible interaction with Tau. 1068 14

Ebselen (2-phenyl-1,2-benzisoselenazol-3[2H]-one) mimics the activity of glutathione peroxidase [Biochem. Pharmacol. 33 (1984) 3235], acts as a substrate for thioredoxin reductase [Proc. Natl. Acad. Sci. U.S.A. 99 (2002) 8579]. The present study focused on the cellular mechanism of its action against oxidative stress by using HT22 cells, a mouse neuroblastoma of hippocampal origin. Ebselen protected HT22 cells against death induced by glutamate and hydrogen peroxide but not against that by tumor necrosis factor alpha. Oxidative glutamate toxicity is initiated by depletion of total glutathione, and ebselen inhibited the decrease in glutathione and increased its basal level. Although glutamate increased intracellular levels of reactive oxygen species (ROS), ebselen suppressed their increase. Ebselen reduced the basal levels of ROS when it was applied in control cells. Ebselen also removed ROS from cells that had accumulated a level of them. The compound had a significant trolox equivalent activity concentration value in a cell-free system, suggesting that it has a direct ROS-scavenging capacity. Finally, ebselen-induced heme oxygenase-1 (HO-1) protein. These results indicate that ebselen protects neuronal cells against the oxidative stress at multiple steps, including an increase in glutathione, a ROS-scavenging activity and the induction of HO-1 protein.
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PMID:Protective effects on neuronal cells of mouse afforded by ebselen against oxidative stress at multiple steps. 1550 Sep 56

Prostaglandin E2 (PGE2), one product of inflammatory reactions, and PGA1, which is formed during PGE2 extraction, induce degeneration in adenosine 3',5'-cyclic monophosphate (cAMP)-induced differentiated neuroblastoma (NB) cells in culture. The mechanisms of action of PGE2 on neurodegeneration are not well understood. To investigate this, we have utilized PGA(1), which mimics the effect of PGE2 and is very stable in solution. We have assayed selected markers of oxidative stress such as heme oxygenase-1 (HO-1), catalase, glutathione peroxidase (GPx1), mitochondrial superoxide dismutase (Mn-SOD-2) and cytosolic superoxide dismutase (Cu/Zn-SOD-1). The results showed that the treatment of differentiated NB cells with PGA1 for a period of 48 hr increased the expression of HO-1 and catalase, decreased the expression of GPx1 and Mn-SOD-2, and did not change the expression of Cu/Zn-SOD-1 as measured by gene array and confirmed by real-time PCR. The protein levels of HO-1 and GPx1 increased; however, the protein level of Mn-SOD-2 decreased and the levels of catalase and Cu/Zn-SOD-1 did not change as determined by Western blot. The increases in the levels of HO-1 and GPx1 reflected an adaptive response to increased oxidative stress, whereas decrease in the level of Mn-SOD-2 may make cells more sensitive to oxidative damage. These data suggest that one of the mechanisms of action of PGA1 on neurodegeneration may involve increased oxidative stress. This was supported further by the fact that a mixture of antioxidants (alpha-tocopherol, vitamin C, selenomethionine, and reduced glutathione), but not the individual antioxidants, reduced the level of PGA1-induced degeneration in differentiated NB cells. The addition of a single antioxidant at two or four times the concentration used in the mixture was toxic.
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PMID:Prostaglandin-induced neurodegeneration is associated with increased levels of oxidative markers and reduced by a mixture of antioxidants. 1592 Jul 43

Carboxyl-terminal fragments (CTs) of the amyloid precursor protein have been shown to be highly neurotoxic and are though to contribute to the neuropathology of Alzheimer's disease. We compared the effects of expressing CT99 in the human neuroblastoma MC65 with the effects of hydrogen peroxide on the parental SK-N-MC cells. CT99 and hydrogen peroxide generated a different pattern of free radicals and their toxic effects were differentially protected by a battery of antioxidants. Hydrogen peroxide caused a cell cycle arrest at phase S and apoptosis mediated through caspase-3 activation in a pattern similar to that described for amyloid-beta neurotoxicity. However, CT99 apoptosis appeared to be mediated through an unidentified mitochondrial pathway. Both oxidative injury types induced heme oxygenase-1 expression as a neuroprotective response. Overall we found a coincidence in the nonespecific stress oxidative effects of CT99 and hydrogen peroxide, but clear differences on their respective potencies and pathways of neurotoxicity.
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PMID:Carboxyl-terminal fragment of amyloid precursor protein and hydrogen peroxide induce neuronal cell death through different pathways. 1675 47

NF-E2-related factor-2 (Nrf2), a basic leucine zipper transcription factor, is involved in the expression of numerous detoxifying and antioxidant genes via the antioxidant response element (ARE). Apomorphine (Apo), a dopamine D(1)/D(2) receptor agonist, is used for clinical therapy of Parkinson's disease. On the other hand, Apo is a potent radical scavenger and has protective effects on oxidative stress-induced cell death. Previously, we have reported that pretreatment of human neuroblastoma SH-SY5Y cells with Apo enhances protection against 6-hydroxydopamine (6-OHDA)-induced cell death. In this study, we investigated whether the Nrf2-ARE system is involved in the protection by Apo. Pretreatment of SH-SY5Y cells with Apo suppressed 6-OHDA-induced cell death in a dose-dependent manner. However, neither SCH23390, a dopamine D(1) receptor antagonist, nor sulpiride, a dopamine D(2) receptor antagonist, prevented the protective effect of Apo. Apo stimulated the translocation of Nrf2 into the nucleus and the transactivation of the ARE. The expression of heme oxygenase-1 (HO-1) was dose dependently induced by Apo. Moreover, we found that the activation of the ARE and the induction of HO-1 mRNA caused by Apo were suppressed in the presence of the antioxidant N-acetylcysteine and also that Apo produced intracellular reactive oxygen species (ROS), indicating that the low level of ROS produced by Apo may play a critical role in this phenomenon. Taken together, our findings suggest that not only the function as a radical scavenger but also the function as an Nrf2-ARE pathway activator may be involved in the neuroprotective effects of Apo.
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PMID:Apomorphine protects against 6-hydroxydopamine-induced neuronal cell death through activation of the Nrf2-ARE pathway. 1680 48

Ethanol has deleterious effects on neuronal cells both in vivo and in vitro, but the mechanisms are unknown. Here, treatment with increasing doses of ethanol (from 20 up to 600mM) decreased the viability of a mouse hippocampal neuroblastoma cell line, HT22. The glutathione concentration decreased and intracellular reactive oxygen species (ROS) increased in a dose-and time-dependent manner, suggesting that the neurotoxicity was due to oxidative stress. Expression of heme oxygenase (HO)-1, a redox regulator and heat shock protein, increased with time after ethanol treatment, but HO-2 was expressed constitutively. The addition of 5microM zinc protoporphyrin IX (ZnPP IX), a competitive HO inhibitor, with the ethanol further reduced cell viability and increased intracellular ROS, but these effects were reversed by co-treatment with 50nM bilirubin, a well-known antioxidant and a product of HO catalysis. These results suggest that HO has a protective role in hippocampal neurons as an intrinsic factor against ethanol-induced oxidative stress and the protection depends on the degree of oxidative stress.
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PMID:Heme oxygenase protects hippocampal neurons from ethanol-induced neurotoxicity. 1685 15

Up-regulation of heme oxygenase-1 (HO-1) and altered cholesterol metabolism are characteristic of Alzheimer-diseased (AD) neural tissues. Central oxidation of cholesterol to oxysterols has been implicated in neuroembryogenesis, synaptic plasticity, and membrane repair. In the current study, we demonstrated that transient transfection of rat astroglia with human (h)ho-1 cDNA for 3 days significantly decreased intracellular cholesterol concentrations and increased levels of four oxysterol species (measured by GC/MS) compared to untreated control cultures and HO-1-transfected cells exposed to the HO inhibitor, tin mesoporphyrin (SnMP). Relative to control preparations, oxidative stress was augmented in mitochondria (isolated by subcellular fractionation) and culture media derived from HO-1-transfected astrocytes, as evidenced by enhanced oxidation of the synthetic reporter molecules, linoleoyl tyrosine (LT), linoleoyl tyrosine cholesterol ester (LTC), or linoleoyl tyrosine deoxyguanosyl ester (LTG; measured by GC/MS and LC/MS/MS). We also observed enhanced oxidation of exogenous LTC in human neuroblastoma (M17) cells exposed for 18 h to conditioned media collected from HO-1-transfected astrocytes relative to control media. In AD and other pathological states, glial HO-1 induction may transduce ambient noxious stimuli (e.g., beta-amyloid) into altered patterns of glial sterol metabolism which, in turn, may affect neuronal membrane turnover, survival, and adaptability.
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PMID:Effects of heme oxygenase-1 expression on sterol homeostasis in rat astroglia. 1732 Jul 68

Glyceryl nonivamide (GLNVA), a vanilloid receptor (VR) agonist, has been reported to have calcitonin gene-related peptide-associated vasodilatation and to prevent subarachnoid hemorrhage-induced cerebral vasospasm. In this study, we investigated the neuroprotective effects of GLNVA on activated microglia-like cell mediated- and proparkinsonian neurotoxin 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in human dopaminergic neuroblastoma SH-SY5Y cells. In coculture conditions, we used lipopolysaccharide (LPS)-stimulated BV-2 cells as a model of activated microglia. LPS-induced neuronal death was significantly inhibited by diphenylene iodonium (DPI), an inhibitor of NADPH oxidase. However, capsazepine, the selective VR1 antagonist, did not block the neuroprotective effects of GLNVA. GLNVA reduced LPS-activated microglia-mediated neuronal death, but it lacked protection in DPI-pretreated cultures. GLNVA also decreased LPS activated microglia induced overexpression of neuronal nitric-oxide synthase (nNOS) and glycoprotein 91 phagocyte oxidase (gp91(phox)) on SH-SY5Y cells. Pretreatment of BV-2 cells with GLNVA diminished LPS-induced nitric oxide production, overexpression of inducible nitric-oxide synthase (iNOS), and gp91(phox) and intracellular reactive oxygen species (iROS). GLNVA also reduced cyclooxygenase (COX)-2 expression, inhibitor of nuclear factor (NF)-kappaB (IkappaB)alpha/IkappaBbeta degradation, NF-kappaB activation, and the overproduction of tumor necrosis factor-alpha, interleukin (IL)-1beta, and prostaglandin E2 in BV-2 cells. However, GLNVA augmented anti-inflammatory cytokine IL-10 production on LPS-stimulated BV-2 cells. Furthermore, in 6-OHDA-treated SH-SY5Y cells, GLNVA rescued the changes in condensed nuclear and apoptotic bodies, prevented the decrease in mitochondrial membrane potential, and reduced cells death. GLNVA also suppressed accumulation of iROS and up-regulated heme oxygenase-1 expression. 6-OHDA-induced overexpression of nNOS, iNOS, COX-2, and gp91(phox) was also reduced by GLNVA. In summary, the neuroprotective effects of GLNVA are mediated, at least in part, by decreasing the inflammation- and oxidative stress-associated factors induced by microglia and 6-OHDA.
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PMID:Neuroprotective effects of glyceryl nonivamide against microglia-like cells and 6-hydroxydopamine-induced neurotoxicity in SH-SY5Y human dopaminergic neuroblastoma cells. 1785 75


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