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)

We reported previously that sera from patients with type 2 diabetes and neuropathy induce autophagy in human neuroblastoma (SH-SY5Y) cells. Here we report that enriched immunoglobulin fractions from a subpopulation of these patients induce autophagy and colocalization with Fas-activated death domain (FADD), a component of the Fas-activated death domain receptor signaling pathway. These effects were replicated by treatment of SY5Y cells with Fas ligand, tumor necrosis factor alpha and an agonist anti-Fas antibody. Preincubation of these sera with a soluble Fas receptor chimera (extracellular domain) markedly decreased the stimulation of autophagy. The results suggest that sera from subset of individuals with type 2 diabetes and neuropathy contain autoantibodies that activate the Fas cascade.
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PMID:Type 2 diabetes with neuropathy: autoantibody stimulation of autophagy via Fas. 1830 64

In the process of glycation, methylglyoxal is a reactive dicarbonyl compound physiologically generated as an intermediate of glycolysis, and is found in high levels in blood or tissue of diabetic models. Biological glycation has been commonly implicated in the development of diabetic microvascular complications of neuropathy. Increasing evidence suggests that neuronal cell cycle regulatory failure followed by apoptosis is an important mechanism in the development of diabetic neuropathy complication. Naturally occurring antioxidants, especially phenolic acids have been recommended as the major bioactive compounds to prevent chronic diseases and promote health benefits. The objective of this study was to investigate the inhibitory abilities of phenolic acids (chlorogenic acid, syringic acid and vanillic acid) on methylglyoxal-induced mouse Neuro-2A neuroblastoma (Neuro-2A) cell apoptosis in the progression of diabetic neuropathy. The data indicated that methylglyoxal induced mouse Neuro-2A neuroblastoma (Neuro-2A) cell apoptosis via alternation of mitochondria membrane potential and Bax/Bcl-2 ratio, activation of caspase-3, and cleavage of poly (ADP-ribose) polymerase. Furthermore, the results demonstrated that activation of mitogen-activated protein kinase signal pathways (JNK and p38) participated in the methylglyoxal-induced Neuro-2A cell apoptosis process. Treatment of Neuro-2A cells with phenolic acids markedly suppresses cell apoptosis induced by methylglyoxal, suggesting that phenolic acids possess cytoprotective ability in the prevention of diabetic neuropathy complication.
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PMID:Cytoprotective effects of phenolic acids on methylglyoxal-induced apoptosis in Neuro-2A cells. 1848 34

Activation of membrane death receptors has been connected to apoptosis and, recently, other non-apoptotic events. For example, we reported recently that sera from either a subset of patients with type 2 diabetes with neuropathy or a subpopulation of patients with neurogenic chronic intestinal pseudo-obstruction (CIP) stimulate autophagy in SH-SY5Y human neuroblastoma cells via complement-independent, autoantibody-mediated activation of Fas (CD95). Activation of the Fas pathway causes minimal activation of apoptosis in these cells since procaspase-8 shows low constitutive levels of expression in neuroblastoma cells. The observation that anti-Fas autoantibodies induce autophagy is novel and provocative. This finding has implications regarding the pathophysiology of diabetic neuropathy, CIP and, perhaps, other autoimmune disorders. For example, recent reports suggest that expression or activity of proapoptotic caspases can be enhanced by activation of more than one membrane death receptor, as could happen by combinations of cytokines and autoantibodies. The observation that autophagy, a putative cytoprotective pathway that has also been implicated in non-apoptotic cell death, is activated by autoantibodies against Fas, may represent an early cellular protective response. An increase in cytotoxic cytokine levels or the ratio of agonist:antagonist autoantibodies may "tip" the balance of the cellular response to activation of programmed cell death pathways.
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PMID:Stimulation of autophagy by autoantibody-mediated activation of death receptor cascades. 1856 Feb 72

Complex regional pain syndrome, which is characterised by pain and trophic disturbances, develops frequently after peripheral limb trauma. There is an increasing evidence of an involvement of the immune system in CRPS, and recently we showed that CRPS patients have autoantibodies against nervous system structures. Therefore we tested the sera of CRPS patients, neuropathy patients and healthy volunteers for surface-binding autoantibodies to primary cultures of autonomic neurons and differentiated neuroblastoma cell lines using flow cytometry. Thirteen of 30 CRPS patients, but none of 30 healthy controls and only one of the 20 neuropathy sera had specific surface binding to autonomic neurons (p<0.001). The majority of the sera reacted with both sympathetic and myenteric plexus neurons. Interestingly, 6/30 CRPS sera showed binding to undifferentiated SH-SY5Y neuroblastoma cells. However, differentiation of SH-SY5Y into a cholinergic phenotype induced a surface antigen, which is recognised by 60% of CRPS sera (18/30), but not by controls (p<0.001). Our data show that about 30-40% of CRPS patients have surface-binding autoantibodies against an inducible autonomic nervous system autoantigen. These data support an autoimmune hypothesis in CRPS patients. Further studies must elucidate origin and function of these autoantibodies in CRPS.
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PMID:Autoantibodies in complex regional pain syndrome bind to a differentiation-dependent neuronal surface autoantigen. 1937 22

Ab affinity maturation in vivo is always accompanied by negative selection to maintain Ag specificity. In contrast, in vitro affinity maturation can lead to epitope spread, resulting in loss of specificity. Anti-ganglioside-GD2 mAbs are clinically effective against neuroblastoma; pain and neuropathy are major side effects. We used structural relatives of GD2 to define epitope spread during in vitro affinity maturation of an anti-GD2 single-chain variable fragment (scFv) called 5F11-scFv. Clonal dominance identified by polyclonal sequencing was confirmed by analyzing individual clones. Affinity-matured mutations were introduced into scFv-streptavidin for functional studies. Without a negative selector, 19-fold affinity improvement (clone Q, where Q is the symbol for glutamine) was associated with strong cross-reactivity with GM2 and GD1b and moderate cross-reactivity with GD3, resulting in positive immunohistochemical staining of all 13 non-neural normal human tissues, in contrast to none of 13 tissues with parental clone P. With GM2 as a negative selector, clone Y (where Y is the symbol for tyrosine) was generated with only weak cross-reactivity with GD1b, adrenal and thyroid glands, and no staining of other non-neural normal tissues. Even though there was only a 3-fold affinity improvement, clone Y showed significantly higher tumor uptake over parental clone P (134%, p = 0.04), whereas clone Q was inferior (54% of clone P; p = 0.05) as confirmed by tumor-to-normal tissue ratios across 16 organs (41% of clone P; p < 0.0001). Using the less efficient negative selector GD3, a clone mixture (Q, V, and Y, where V is the symbol for valine) emerged. We conclude that epitope spread during affinity maturation can be reduced by negative selection. Furthermore, efficiency of the negative selector depends on its cross-reactive affinity with the matured scFv.
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PMID:Reducing epitope spread during affinity maturation of an anti-ganglioside GD2 antibody. 1981 1

Microtubule-targeting agents (MTAs), anticancer drugs widely used in the clinic, often induce peripheral neuropathy, a main dose-limiting side effect. The mechanism for this neurotoxicity remains poorly understood and there are still no approved therapies for neuropathies triggered by MTAs. Olesoxime (cholest-4-en-3-one, oxime; TRO19622) has shown marked neuroprotective properties in animals treated with paclitaxel and vincristine. The purpose of this study was to investigate its mechanism of neuroprotection against MTA neurotoxicity by using rat and human differentiated neuronal cells. We first showed that olesoxime prevented neurite shrinkage induced by MTAs in differentiated PC-12 and SK-N-SH neuroblastoma cell lines by up to 90%. This neuroprotective effect was correlated with enhanced EB1 accumulation at microtubule plus-ends, increased growth cone microtubule growing rate (20%) and decreased microtubule attenuation duration (54%). The effects of olesoxime on EB comets were specific for differentiated neuronal cells and were not seen either in proliferating neuroblastoma cells, glioblastoma cells or primary endothelial cells. Importantly, olesoxime did not alter MTA cytotoxic properties in a wide range of MTA-sensitive tumor cells, a prerequisite for future clinical application. Finally, olesoxime also counteracted MTA inhibition of microtubule-dependent mitochondria trafficking. These results provide additional insight into the neuroprotective properties of olesoxime, highlighting a role for microtubule dynamics in preservation of neurite architecture and axoplasmic transport, which are both disturbed by MTAs. The neuron-specific protective properties of olesoxime support its further development to treat MTA-induced neuropathy.
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PMID:Olesoxime prevents microtubule-targeting drug neurotoxicity: selective preservation of EB comets in differentiated neuronal cells. 2041 91

Charcot-Marie-Tooth (CMT) disease is the most frequent peripheral neuropathy affecting the Schwann cells and neurons. CMT disease type 2 (CMT2) neuropathies are characterized by peripheral nerve aberrance. Four missense mutations of Rab7, a small GTPase of the Rab family involved in intracellular vesicular trafficking, are associated with the CMT2B phenotype. Despite a growing body of evidence concerning the gene structures responsible for genetically heterogenous CMT2B and other CMT2 neuropathies, little is known about the in vitro neuropathy model and how CMT2B-associated mutation-caused aberrant neuritogenesis is properly reversed. Here, we show that valproic acid (VPA), a classical mood-stabilizing drug, improves defective neurite formation in N1E-115 neuroblastoma cells regardless of which CMT2B-associated Rab7 mutant protein is expressed. The effect is mediated by c-Jun N-terminal kinase (JNK) signaling, but not by deacetylase inhibition activity of VPA itself. Furthermore, VPA has similar effects in dorsal root ganglion (DRG) neurons expressing any of the four mutant Rab7 proteins. Thus, VPA has a previously unknown potential to improve defective neuritogenesis associated with CMT2B in vitro, indicating that JNK should be a potential therapeutic target for treatments aimed at improving neuritogenesis.
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PMID:The mood stabilizer valproic acid improves defective neurite formation caused by Charcot-Marie-Tooth disease-associated mutant Rab7 through the JNK signaling pathway. 2064 6

Organophosphates have previously been tested for the induction of delayed neuropathy in adult hens. An alternative in vitro test, which avoids the severe suffering caused by the test in hens, has been developed using permanent cell lines from a rat-brain glioma (C-6) or from a mouse-brain neuroblastoma (N-18). Addition of dibutyryl cAMP to these cell cultures triggers the development of neurite-like processes; the development of these processes is inhibited by the addition of various organophosphate compounds and this inhibition serves as an indicator of neurotoxicity. 26 compounds with positive results in the in vivo test in hens, and eight analogues with negative results were tested in vitro. An almost perfect correlation between the in vivo and in vitro results was found; two compounds with weak positive results in vitro (O,O,S-trimethyl phosphorothioate and O,S,S-trimethyl phosphorothioate) yielded negative results in hens but this discrepancy may be related to their bioavailability in hens. The in vitro test is recommended to avoid the pain and stress caused by testing in vivo in hens.
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PMID:The inhibitory effect of neuropathic organophosphate esters on neurite outgrowth in cell cultures: A basis for screening for delayed neurotoxicity. 2073 29

The primary aim of this phase 1 study was to determine the maximum tolerated dose (MTD) and evaluate the safety of nifurtimox alone and in combination with cyclophosphamide and topotecan in multiple relapsed/refractory neuroblastoma pediatric patients. The secondary aim was to evaluate the pharmacokinetics of nifurtimox and the treatment response. To these ends, we performed a phase 1 dose escalation trial of daily oral nifurtimox with toxicity monitoring to determine the MTD, followed by 3 cycles of nifurtimox in combination with cyclophosphamide and topotecan. Samples were collected to determine the pharmacokinetic parameters maximum concentration, time at which maximum concentration is reached, and area under the curve between 0 and 8 hours. Treatment response was evaluated by radiographic and radionuclide (I-metaiodobenzylguanidine) imaging, measurement of urinary catecholamines, and clearance of bone marrow disease. We determined the MTD of nifurtimox to be 30 mg/kg/d. The non-dose-limiting toxicities were mainly nausea and neuropathy. The dose-limiting toxicities of 2 patients at 40 mg/kg/d were a grade 3 pulmonary hemorrhage and a grade 3 neuropathy (reversible). Overall, nifurtimox was well tolerated by pediatric patients at a dose of 30 mg/kg/d, and tumor responses were seen both as a single agent and in combination with chemotherapy. A Phase 2 study to determine the antitumor efficacy of nifurtimox is currently underway.
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PMID:A phase 1 study of nifurtimox in patients with relapsed/refractory neuroblastoma. 2106 21

Seven children with sciatic neuropathy associated with an underlying neoplasm are reported. Clinical presentation, electrophysiological data, imaging, pathology, and/or autopsy results are described. Pain and weakness, primarily foot drop, were the most common presenting symptoms. The mechanism of sciatic neuropathy was varied and included: nerve infiltration by the adjacent neoplasm (neuroblastoma, rhabdomyosarcoma, and leukemic or lymphomatous infiltration); an expanding, intrinsic neurogenic tumor (perineurioma); or intraoperative stretch injury (osteosarcoma resection). The prognosis for sciatic nerve recovery was good among children who survived their associated cancer. Three children died from the cancer or complications of treatment. One child with perineurioma remained clinically stable, and two children improved after treatment of their neoplasm.
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PMID:Pediatric sciatic neuropathy associated with neoplasms. 2125 82


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