Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The metabolism of nitrovasodilators such as glyceryl trinitrate and nitroprusside provides the active moiety of these drugs (that is, nitric oxide). This process is not limited to the known nitrovasodilators, but also occurs with nitroaromatic antimicrobials. Here we report that the administration of hydroxyurea, an antitumor drug, to rats at pharmacological doses formed detectable nitrosyl hemoglobin, which increased with dose. At higher doses, nitrosyl hemoprotein complexes could also be detected in liver tissue. [15N]hydroxyurea was synthesized and compared with [14N]hydroxyurea. These observations verified that nitric oxide detected as nitrosyl hemoglobin or nitrosyl hemoprotein complexes in rats was the result of the metabolism of hydroxyurea. The time course and dose-dependence of nitric oxide generation were also investigated. Hydroxyurea's antineoplastic activity is caused by its direct action on ribonucleotide reductase, the rate-limiting enzyme in DNA synthesis. Because nitric oxide also inhibits ribonucleotide reductase, this metabolite may supplement this action of hydroxyurea. In addition, the known ability of hydroxyurea to ease the pain of sickle cell anemia patients may be the result of vasodilation by the drug-derived nitric oxide.
Mol Pharmacol 1997 Dec
PMID:In vivo production of nitric oxide in rats after administration of hydroxyurea. 941 18

Rheumatoid arthritis (RA) is an inflammatory disease targeting the synovial membrane and extra-articular tissues. The most feared consequences are significant levels of pain, functional disability, and rheumatoid organ involvement. Molecular investigations of RA have markedly changed the understanding of the pathogenesis although the etiology remains unresolved. Despite the failure of intense efforts to confirm the presence of an infectious micro-organism in rheumatoid synovium, the concept that RA is infectious in origin has continued to be attractive. Theories on the autoimmune nature of RA have benefited from the enormous progress made in understanding the cellular and molecular components of normal immune responses. However, convincing experimental evidence of a joint-specific endogenous antigen in the synovial lesions is still lacking. The viewpoint that RA represents the sequelae of systemic lymphoproliferation has recently been supported by the finding of autoreactive T cells with atypical growth and differentiation behavior. Significant cross-fertilization for the understanding of RA can be expected by studies elucidating cell cycle control and the role of proto-oncogenes. The realization that RA is a genetic disease has had and will have a major impact on investigating pathological events. As in other common genetic disorders, multiple genetic determinants contribute to the risk of an individual developing chronic inflammatory rheumatoid synovitis. Individual genetic elements are seldom mutated or abnormal, but a risk threshold is reached by their accumulation and combination. Genes encoded in the HLA region are recognized as RA risk genes. Recent studies have emphasized that a gene dosing effect for RA-associated HLA alleles is functional, and that HLA polymorphisms act as progression factors rather than as initiation factors in the disease process. These data have challenged the traditional paradigm that disease-associated HLA molecules function solely through their capability to select, bind, and present an arthritogenic antigen. Current efforts focus on identifying the spectrum and nature of genes associated with various RA phenotypes. The future will likely see a broadening of biological systems involved in the pathogenesis of RA with anomalies other than immunoresponsiveness contributing to mechanisms driving articular and extra-articular RA.
J Mol Med (Berl)
PMID:The molecular basis of rheumatoid arthritis. 942 8

Increased voltage-gated sodium channel activity may contribute to the hyperexcitability of sensory neurons in inflammatory and neuropathic pain states. We examined the levels of the transcript encoding the tetrodotoxin-resistant sodium channel SNS in dorsal root ganglion neurons in a range of inflammatory and neuropathic pain models in the rat. Local Freund's adjuvant or systemic nerve growth factor-induced inflammation did not substantially alter the total levels of SNS mRNA. When NGF-treated adult rat DRG neurons in vitro were compared with NGF-depleted control neurons, SNS total mRNA levels and the levels of membrane-associated immunoreactive SNS showed a small increase (17 and 25%, respectively), while CGRP levels increased fourfold. SNS expression is thus little dependent on NGF even though SNS transcript levels dropped by more than 60% 7-14 days after axotomy. In the streptozotocin diabetic rat SNS levels fell 25%, while in several manipulations of the L5/6 tight nerve ligation rat neuropathic pain model, SNS levels fell 40-80% in rat strains that are either susceptible or relatively resistant to the development of allodynia. Increased expression of SNS mRNA is thus unlikely to underlie sensory neuron hyperexcitability associated with inflammation, while lowered SNS transcript levels are associated with peripheral nerve damage.
Mol Cell Neurosci 1997
PMID:Regulation of expression of the sensory neuron-specific sodium channel SNS in inflammatory and neuropathic pain. 953 81

Microencapsulated genetically engineered cells have the potential to treat a wide range of diseases. For example, in experimental animals, implanted microencapsulated cells have been used to secrete growth hormone to treat dwarfism, neurotrophic factors for amyotrophic lateral sclerosis, beta-endorphin to decrease pain, factor XI for hemophilia B, and nerve growth factors to protect axotomized neurons. For some applications, microencapsulated cells can even be given orally. They can be engineered to remove unwanted molecules from the body as they travel through the intestine, and are finally excreted in the stool without being retained in the body. This application has enormous potential for the removal of urea in kidney failure, ammonia in liver failure and amino acids such as phenylalanine in phenylketonuria and other inborn errors of metabolism.
Mol Med Today 1998 May
PMID:Therapeutic uses of microencapsulated genetically engineered cells. 961 2

The human mu opioid receptor (hMOR) interacts with endogenous and exogenous ligands to mediate its characteristic effects, reward, dependence, and analgesia. Specifically binding morphine, it represents the target of the most valuable pain killer in contemporary medicine. Analysis of its structure, regulation, and expression will elucidate molecular processes involved in opioid/morphine-induced actions. Thus we have contributed significant information on the genomic organization of hMOR, extending the previously known cDNA sequence information (2162 bp) up to a total of 6968 bp: we have determined 2412 bp of 5' regulatory region, identified one major and three minor transcription initiation sites 216, 285, 358, and 373 bp upstream from the translation start codon, as well as potential binding sites for transcriptional regulatory factors, including putative cis-acting enhancer motifs for a glucocorticoid response element, cAMP response elements, activator proteins 1, and Yin Yang-1 boxes. Moreover, we have analyzed the 5' and 3' nucleotide sequences of introns 1 and 3 and the complete sequence of intron 2. In addition to the classical consensus sequences involved in RNA splicing, we have identified intronic repeats (A/T GGG) found to regulate alternative splicing, mutations of which cause human disease. A similar genetic variant is observed in the hMOR gene. Taken together, the sequence information presented will allow comprehensive analysis of this gene for allelic variations associated with vulnerability to drug abuse or individual differences in opiate mediated analgesia.
J Mol Med (Berl) 1998 Jun
PMID:The human mu opioid receptor gene: 5' regulatory and intronic sequences. 966 Jan 63

The latencies of pain threshold to different subhypnotic doses (12.5, 25 and 50 mg kg-1) of propofol, an anaesthetic, administered intraperitoneally (i.p.) into male mice were measured using a hot plate method. The possible mechanism of pain control by propofol was also investigated through blocking beta-endorphin receptors and measuring serum level of beta-endorphin. Morphine (1.5 mg kg-1; i.p.) was used as a reference of reduction of pain sensation. The results showed that propofol in doses of 25 and 50 mg kg-1 significantly (P < 0.01) increased the latency of pain threshold but a lower dose (12.5 mg kg-1) failed to produce any significant change. This indicates that propofol reduced pain and this effect is dose-dependent. Propofol prevents hyperalgesia produced by prostaglandin PGE2, (0.5 mg kg-1, i.p.; P < 0.01). Pretreatment with naloxone (1.0 mg kg-1, i.p.) abolished significantly (P < 0.01) the antinociceptive action of propofol. Furthermore, serum level of beta-endorphin was increased (P < 0.01) after propofol injection particularly at the peak time of propofol action. The serum level of corticosterone was also increased (P < 0.01) at the time of beta-endorphin release. It was concluded that propofol can control pain and this action may be centrally modulated through the opioid system rather than at the level of the spinal cord.
Comp Biochem Physiol A Mol Integr Physiol 1998 Jun
PMID:Effect of propofol on perception of pain in mice: mechanisms of action. 977 4

Interleukin-6 (IL-6) is a multifunctional cytokine whose actions include modulation of proliferation, differentiation, and maturation of hemapoietic progenitors and other cell lineages; growth regulation of certain carcinoma cell lines; and control of cellular metabolic activities. Initially described in terms of its activities in the immune system and inflammation, accumulating evidence supports an essential role of IL-6 in the development, differentiation, regeneration and degeneration of neurons in the peripheral and central nervous system. We have previously demonstrated that immunoreactive-like IL-6 protein is significantly elevated in the spinal cord in response to peripheral nerve injury that results in neuropathic pain behaviors in the rat. In the current study, our objective was to determine if the source of IL-6 protein was endogenous to the central nervous system by measuring any detectable increases in spinal IL-6 mRNA expression following established mononeuropathy procedures associated with neuropathic pain: spinal nerve cryoneurolysis (SPCN) or spinal nerve tight ligation (SPTL). Using in situ hybridization and a digoxigenin-labeled oligonucleotide, IL-6 mRNA in neurons was significantly elevated at 3 and 7 days post SPCN and 7 days post SPTL in both dorsal and ventral horns. The cellular localization of the IL-6 mRNA expression was predominately neuronal as confirmed by NeuN serial staining. For example, in the SPCN 7 day group, IL-6 mRNA cell profiles in the ipsilateral dorsal horn were significantly different from the normal group (38.7+/-12.8 vs. 4.89+/-1.6, p<0.001). These data demonstrate the central, spinal production of a proinflammatory cytokine in response to a peripheral nerve injury. In addition, these results add to the growing body of literature implicating these immune products, cytokines, as potential neuromodulators/neurotransmitters and provides further evidence for their role in the nociceptive processing which leads to chronic pain.
Brain Res Mol Brain Res 1998 Nov 20
PMID:Increase of interleukin-6 mRNA in the spinal cord following peripheral nerve injury in the rat: potential role of IL-6 in neuropathic pain. 981 45

Induction of the prodynorphin gene has been implicated in medium and long-term adaptation during memory acquisition and pain. By 5' deletion mapping and site-directed mutagenesis of the human prodynorphin promoter, we demonstrate that both basal transcription and protein kinase A (PKA)-induced transcription in NB69 and SK-N-MC human neuroblastoma cells are regulated by the GAGTCAAGG sequence centered at position +40 in the 5' untranslated region of the gene (named the DRE, for downstream regulatory element). The DRE repressed basal transcription in an orientation-independent and cell-specific manner when placed downstream from the heterologous thymidine kinase promoter. Southwestern blotting and UV cross-linking experiments with nuclear extracts from human neuroblastoma cells or human brain revealed a protein complex of approximately 110 kDa that specifically bound to the DRE. Forskolin treatment reduced binding to the DRE, and the time course paralleled that for an increase in prodynorphin gene expression. Our results suggest that under basal conditions, expression of the prodynorphin gene is repressed by occupancy of the DRE site. Upon PKA stimulation, binding to the DRE is reduced and transcription increases. We propose a model for human prodynorphin activation through PKA-dependent derepression at the DRE site.
Mol Cell Biol 1998 Dec
PMID:Protein kinase A-dependent derepression of the human prodynorphin gene via differential binding to an intragenic silencer element. 981 80

Islet amyloid polypeptide (IAPP or amylin) is predominantly expressed by insulin cells, but occurs also in primary sensory neurons in the rat. Here, using mice targeted for a null mutation in the IAPP gene, we establish murine expression of IAPP in sensory neurons; its distribution in a population of calcitonin gene-related peptide-containing neurons in the spinal cord and dorsal root ganglion is similar to that previously described in the rat. We also report the IAPP mutant mice display a reduced pain response in the paw formalin test. Adjuvant-induced joint inflammation was not altered in IAPP mutants, arguing against a peripheral inflammatory abnormality. These findings lead us to suggest that IAPP has a pro-nociceptive function in primary sensory neurons.
Brain Res Mol Brain Res 1998 Dec 10
PMID:Reduced nociceptive behavior in islet amyloid polypeptide (amylin) knockout mice. 983 1

The serotonin neural system originates from ten nuclei in the mid- and hindbrain regions. The cells of the rostral nuclei project to almost every area of the forebrain, including the hypothalamus, limbic regions, basal ganglia, thalamic nuclei, and cortex. The caudal nuclei project to the spinal cord and interact with numerous autonomic and sensory systems. This article reviews much of the available literature from basic research and relevant clinical research that indicates that ovarian steroid hormones, estrogens and progestins, affect the function of the serotonin neural system. Experimental results in nonhuman primates from this laboratory are contrasted with studies in rodents and humans. The sites of action of ovarian hormones on the serotonin neural system include effects within serotonin neurons as well as effects on serotonin afferent neurons and serotonin target neurons. Therefore, information on estrogen and progestin receptor-containing neurons was synthesized with information on serotonin afferent and efferent circuits. The ability of estrogens and progestins to alter the function of the serotonin neural system at various levels provides a cellular mechanism whereby ovarian hormones can impact mood, cognition, pain, and numerous other autonomic functions.
Mol Neurobiol 1998 Oct
PMID:Ovarian steroids and serotonin neural function. 1006 76


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>