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

A newborn female, the second child of consanguineous parents, exhibited general muscle hypotonia, apathy, hepatomegaly and failure to thrive from birth and signs of craniofacial dysmorphia were present. Pipecolic and trihydroxicoprostanoic acid were excreted in the urine and serum transferrin, ferritin and iron were markedly elevated. At the age of 7 weeks the baby died of respiratory insufficiency. Besides malformations of the brain, renal cysts, liver damage with hypoplastic intrahepatic bile ducts and cholestasis, increased storage of iron and cytochemically proven deficiency of peroxisomes in liver and kidney, morphological studied provided evidence of a mitochondrial myopathy in striated muscle with the accumulation of enlarged bizarre mitochondria, showing only minor structural abnormalities. No defects of NADH-reductase, succinate-dehydrogenase or cytochrome-c-oxidase were demonstrated histochemically. Cytochemical-ultrastructural investigation of mitochondrial ATPase revealed activation of the ATP-synthesising enzyme even before the addition of an uncoupler, this indicating loosely coupled oxidative phosphorylation. In addition a high rate of subcellular autophagy with segregation of mitochondria and focal loss of fibrils was present. Muscle damage in Zellweger syndrome appears to be the consequence of complex, interacting metabolic processes. The mitochondrial myopathy thereby induced allows a better understanding of general muscle hypotonia, one of the leading symptoms of this disorder.
Virchows Arch B Cell Pathol Incl Mol Pathol 1984
PMID:Mitochondrial myopathy with loosely coupled oxidative phosphorylation in a case of Zellweger syndrome. A cytochemical-ultrastructural study. 614 41

Resolution of the total evidence (i.e., character congruence) versus consensus (i.e., taxonomic congruence) debate has been impeded by (1) a failure to employ validation methods consistently across both tree-building and consensus analyses, (2) the incomparability of methods for constructing as opposed to those for combining trees, and (3) indifference to aspects of trees other than their topologies. We demonstrate a uniform, distance-based approach which allows for comparability among the results of character- and taxonomic-congruence studies, whether or not an identical suite of taxa has been included in all contributing data sets. Our results indicate that total-evidence and consensus trees differ little in topology if branch lengths are taken into account when combining two or more trees. In addition, when character-state data are converted to distances, our method permits their combination with information produced by techniques which generate distances directly. Moreover, treating all data sets or trees as distance matrices avoids the problem that different numbers of characters in contributing studies may confound the conclusions of a total-evidence or consensus analysis. Our protocol is illustrated with an example involving bats, in which the three component studies based on serology, DNA hybridization, and anatomy imply distinct phylogenies. However, the total-evidence and consensus trees support a fourth, somewhat different, topology resolved at all but one node and which conforms closely to the currently accepted higher category classification of Chiroptera.
Mol Phylogenet Evol 1999 Feb
PMID:Total evidence, consensus, and bat phylogeny: A distance-based approach. 1008 10

Although dementia is described as one of the constituent characteristics of normal pressure hydrocephalus (NPH), alongside gait disturbances and urinary incontinence, there is a rather limited number of controlled studies concerning neuropsychological deficits in the disease. A wide range of psychopathologically relevant symptoms have been described, but the common features of most cases include mental and motor slowing, apathy, emotional indifference, anosognosia, memory and attentional impairment. A number of other functional deficits such as dyslexia, dysgraphia, acalculia, apraxia can also frequently be found. Some emphasis is put on the work of J. de Mol (Brussels) which appears to be most important for the study of neuropsychological symptoms in NPH patients. The methodological standard of a number of studies has been found to be rather low, and yet a sound neuropsychological investigation may be of utmost importance for the diagnosis and neurosurgical outcome assessment. Concerning morphological correlates of the functional deficits in NPH, various hypotheses have been formulated, but it is argued that symptoms can neither be described as predominantly "diffuse" in nature, nor can they be reduced to unilocular dysfunctions. Recommendations for future research strategies are formulated.
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PMID:[Neuropsychology of normal pressure hydrocephalus]. 1041 93

Alzheimer's disease is a neurodegenerative disorder associated with a decline in cognitive abilities. Patients also frequently have noncognitive symptoms, such as anxiety, depression, apathy, and psychosis, that impair daily living. The most commonly prescribed treatments for Alzheimer's disease are acetylcholinesterase inhibitors, such as donepezil and galantamine. Enhanced cholinergic functions caused by these compounds are believed to underlie improvements in learning, memory, and attention. The noncognitive aspects of dementia, however, are usually linked to serotonin and dopamine rather than acetylcholine because those neurotransmitter systems most directly influence mood, emotional balance, and psychosis. Fast-scan cyclic voltammetry applied to mouse striatal brain slices was used to measure the real-time release of dopamine arising from spontaneous activity or from single electrical stimulations. At concentrations that include their prescribed dosage ranges, donepezil (1-1000 nM) and galantamine (50-1000 nM) increase action potential-dependent dopamine release. Consistent with previous literature, the data support slightly different modes of action for donepezil and galantamine. The ability of these commonly prescribed drugs to alter catecholamine release may underlie their influence over noncognitive symptoms of dementia. Furthermore, these results suggest that acting via nicotinic receptors, these drugs may serve presently untapped therapeutic roles by altering dopamine release in other disorders involving dopaminergic systems.
Mol Pharmacol 2004 Sep
PMID:Cholinergic drugs for Alzheimer's disease enhance in vitro dopamine release. 1532 45

Ambiguity in the mutual manipulation between the immune system, more appropriately termed integrated defense system, on the one hand and microbes and incipient tumors on the other, is to be taken into account. Such ambiguity may also apply to autoimmune infighting. Here we consider the association of its increased incidence with modern ways of living. Indifference about fate implies that longstanding, evolutionary regulated, immune/tissue relationships are no impediment for asymmetric estrangement promoted by ongoing globalization.
Cell Mol Biol (Noisy-le-grand) 2004
PMID:Asymmetry alters immune-partner relationship. 1555 15

The invertebrate tachykinin-related peptides (TKRPs) constitute a conserved family, structurally related to the mammalian tachykinins, including members such as substance P and neurokinins A and B. Although their expression has been documented in the brains of insects and mammals, their neural functions remain largely unknown, particularly in behavior. Here, we have studied the role of TKRPs in Drosophila. We have analyzed the olfactory perception and the locomotor activity of individuals in which TKRPs are eliminated in the nervous system specifically, by using RNAi constructs to silence gene expression. The perception of specific odorants and concentrations is modified towards a loss of sensitivity, thus resulting in a significant change of the behavioral response towards indifference. In locomotion assays, the TKRP-deficient flies show hyperactivity. We conclude that these peptides are modulators of olfactory perception and locomotion activity in agreement with their abundant expression in the olfactory lobes and central complex. In these brain centers, TKRPs seem to enhance the regulatory inhibition of the neurons in which they are expressed.
Mol Cell Neurosci 2006 Mar
PMID:Tachykinin-related peptides modulate odor perception and locomotor activity in Drosophila. 1628 99

Schizophrenia is a serious and disabling mental disorder with symptoms such as auditory hallucinations, disordered thinking and delusions, avolition, anhedonia, blunted affect and apathy. In this review article we seek to present the current scientific findings from linkage studies and susceptible genes and the pathophysiology of white matter in schizophrenia. The article has been reviewed in two parts. The first part deals with the linkage studies and susceptible genes in schizophrenia in order to have a clear-cut picture of the involvement of chromosomes and their genes in schizophrenia. The genetic linkage results seem to be replicated in some cases but in others are not. From these results, we cannot draw a fine map to a single locus or gene, leading to the conclusion that schizophrenia is not caused by a single factor/gene. In the second part of the article we present the oligodendrocyte-related genes that are associated with schizophrenia, as we hypothesize a potential role of oligodendrocyte-related genes in the pathology of the disorder.
Mol Psychiatry 2008 Mar
PMID:The myelin-pathogenesis puzzle in schizophrenia: a literature review. 1792 96

Infections caused by multidrug-resistant Gram-negative pathogens play a major role in the morbidity and mortality of hospitalized patients. The rise of resistance to current antibiotic therapies has made the discovery of new agents urgent. One of the major antibiotic resistance mechanisms utilized by more than 15 species of Gram-negative bacterial cells is the Resistance Nodulation Division (RND) efflux pump, which eliminates several classes of antibiotics such as penicillins and cephalosporin macrolides aminoglycosides, fluoroquinolonesx and tetracyclines. Here we describe a multistep process to identify compounds that inhibit the RND-type efflux pumps. This involves measuring the inhibition of accumulation of ethidium bromide in E. coli or Haemophilus influenzae cells and confirming that the inhibition is specific for the efflux pumps by using genetic constructs and biochemical methods to measure nonspecific inhibition due to e.g. intrinsic antibacterial activity or membrane disruption. In whole bacterial cells synergism antagonism or indifference of the combination of an antibiotic with the putative inhibitor is determined and this is then confirmed by quantitating viable bacterial cells in liquid culture over 24 h.
Methods Mol Med 2008
PMID:Bacterial efflux pump inhibitors. 1843 15

Voltage-gated sodium (Na(V)1) channels play a critical role in modulating the excitability of sensory neurons, and human genetic evidence points to Na(V)1.7 as an essential contributor to pain signaling. Human loss-of-function mutations in SCN9A, the gene encoding Na(V)1.7, cause channelopathy-associated indifference to pain (CIP), whereas gain-of-function mutations are associated with two inherited painful neuropathies. Although the human genetic data make Na(V)1.7 an attractive target for the development of analgesics, pharmacological proof-of-concept in experimental pain models requires Na(V)1.7-selective channel blockers. Here, we show that the tarantula venom peptide ProTx-II selectively interacts with Na(V)1.7 channels, inhibiting Na(V)1.7 with an IC(50) value of 0.3 nM, compared with IC(50) values of 30 to 150 nM for other heterologously expressed Na(V)1 subtypes. This subtype selectivity was abolished by a point mutation in DIIS3. It is interesting that application of ProTx-II to desheathed cutaneous nerves completely blocked the C-fiber compound action potential at concentrations that had little effect on Abeta-fiber conduction. ProTx-II application had little effect on action potential propagation of the intact nerve, which may explain why ProTx-II was not efficacious in rodent models of acute and inflammatory pain. Mono-iodo-ProTx-II ((125)I-ProTx-II) binds with high affinity (K(d) = 0.3 nM) to recombinant hNa(V)1.7 channels. Binding of (125)I-ProTx-II is insensitive to the presence of other well characterized Na(V)1 channel modulators, suggesting that ProTx-II binds to a novel site, which may be more conducive to conferring subtype selectivity than the site occupied by traditional local anesthetics and anticonvulsants. Thus, the (125)I-ProTx-II binding assay, described here, offers a new tool in the search for novel Na(V)1.7-selective blockers.
Mol Pharmacol 2008 Nov
PMID:ProTx-II, a selective inhibitor of NaV1.7 sodium channels, blocks action potential propagation in nociceptors. 1872

Psychosis has been recognized as a common feature in neurodegenerative diseases and a core feature of dementia that worsens most clinical courses. It includes hallucinations, delusions including paranoia, aggressive behaviour, apathy and other psychotic phenomena that occur in a wide range of degenerative disorders including Alzheimer's disease, synucleinopathies (Parkinson's disease, dementia with Lewy bodies), Huntington's disease, frontotemporal degenerations, motoneuron and prion diseases. Many of these psychiatric manifestations may be early expressions of cognitive impairment, but often there is a dissociation between psychotic/behavioural symptoms and the rather linear decline in cognitive function, suggesting independent pathophysiological mechanisms. Strictly neuropathological explanations are likely to be insufficient to explain them, and a large group of heterogeneous factors (environmental, neurochemical changes, genetic factors, etc.) may influence their pathogenesis. Clinico-pathological evaluation of behavioural and psychotic symptoms (PS) in the setting of neurodegenerative and dementing disorders presents a significant challenge for modern neurosciences. Recognition and understanding of these manifestations may lead to the development of more effective preventive and therapeutic options that can serve to delay long-term progression of these devastating disorders and improve the patients' quality of life. A better understanding of the pathophysiology and distinctive pathological features underlying the development of PS in neurodegenerative diseases may provide important insights into psychotic processes in general.
J Cell Mol Med 2012 May
PMID:Cerebral correlates of psychotic syndromes in neurodegenerative diseases. 2141 22


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