Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxidative stress, bioenergetic impairment and mitochondrial failure have all been implicated in the etiology of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD), as well as retinal degeneration in glaucoma and retinitis pigmentosa. Moreover, at least 75 debilitating, and often lethal, diseases are directly attributable to deletions or mutations in mitochondrial DNA, or in nuclear-encoded proteins destined for delivery to the mitochondria. Such widespread mitochondrial involvement in disease reflects the regulatory position mitochondrial failure plays in both acute necrotic cell death, and in the less catastrophic process of apoptosis. The potent feminizing hormone, 17 beta-estradiol (E2), has shown cytoprotective activities in a host of cell and animal models of stroke, myocardial infarct and neurodegenerative diseases. The discovery that 17alpha-estradiol, an isomer of E2, is equally as cytoprotective as E2 yet is >200-fold less active as a hormone, has permitted development of novel, more potent analogs where cytoprotection is independent of hormonal potency. Studies of structure-activity-relationships, glutathione interactions and mitochondrial function have led to a mechanistic model in which these steroidal phenols intercalate into cell membranes where they block lipid peroxidation reactions, and are in turn recycled via glutathione. Such a mechanism would be particularly germane in mitochondria where function is directly dependent on the impermeability of the inner membrane, and where glutathione levels are maintained at extraordinarily high 8-10mM concentrations. Indeed, the parental estrogens and novel analogs stabilize mitochondria under Ca(2+) loading otherwise sufficient to collapse membrane potential. The cytoprotective and mitoprotective potencies for 14 of these analogs are significantly correlated, suggesting that these compounds prevent cell death in large measure by maintaining functionally intact mitochondria. This therapeutic strategy is germane not only to sudden mitochondrial failure in acute circumstances, such as during a stroke or myocardial infarction, but also to gradual mitochondrial dysfunction associated with chronic degenerative disorders such as AD, PD and HD.
 ...
PMID:Mitochondria play a central role in estrogen-induced neuroprotection. 1572 15

Disease-causing mutations in mitochondrial DNA (mtDNA) are typically heteroplasmic and therefore interpretation of genetic tests for mitochondrial disorders can be problematic. Detection of low level heteroplasmy is technically demanding and it is often difficult to discriminate between the absence of a mutation or the failure of a technique to detect the mutation in a particular tissue. The reliable measurement of heteroplasmy in different tissues may help identify individuals who are at risk of developing specific complications and allow improved prognostic advice for patients and family members. We have evaluated Pyrosequencing technology for the detection and estimation of heteroplasmy for six mitochondrial point mutations associated with the following diseases: Leber's hereditary optical neuropathy (LHON), G3460A, G11778A, and T14484C; mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS), A3243G; myoclonus epilepsy with ragged red fibers (MERRF), A8344G, and neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP)/Leighs: T8993G/C. Results obtained from the Pyrosequencing assays for 50 patients with presumptive mitochondrial disease were compared to those obtained using the commonly used diagnostic technique of polymerase chain reaction (PCR) and restriction enzyme digestion. The Pyrosequencing assays provided accurate genotyping and quantitative determination of mutational load with a sensitivity and specificity of 100%. The MELAS A3243G mutation was detected reliably at a level of 1% heteroplasmy. We conclude that Pyrosequencing is a rapid and robust method for detecting heteroplasmic mitochondrial point mutations.
 ...
PMID:Accurate detection and quantitation of heteroplasmic mitochondrial point mutations by pyrosequencing. 1622 98

Congenital disorder of glycosylation Ia is the most common defect of glycosylation and is due to mutations in phosphomannomutase 2. This leads to aberrant N-linked oligosaccharides. The phenotype of CDG Ia reflects the essential nature of glycosylation and patients typically present with multiple organs affected, with hypotonia, developmental delay, inverted nipples and abnormal fat pads. Later features include retinitis pigmentosa, stroke, cerebellar atrophy and malabsorption. Approximately 20% of patients die in the first year of life and infection is the most common cause of death. Immunological function has not previously been investigated in these patients and the critical role of oligosaccharides on adhesion molecules suggested that haematopoietic cell migration and communication could be disrupted by mutations in phosphomannomutase 2. We characterized the clinical features, performed standard immunological evaluations, and performed specific analyses of neutrophil adhesion molecules on two patients to address this question. Patient neutrophils had diminished chemotaxis but expressed comparable levels of adhesion molecules and rolled on artificial endothelium equivalently to control neutrophils. The most significant feature of the patients' immunological function was poor vaccine responses. These two affected patients were begun on intravenous immunoglobulin with some improvement in their infections.
 ...
PMID:Recurrent infections and immunological dysfunction in congenital disorder of glycosylation Ia (CDG Ia). 1682 48

Mitochondrial respiratory chain disorders are clinically and genetically heterogeneous. There are several mitochondrial DNA (mtDNA) point mutations responsible for common mitochondrial diseases such as mitochondrial encephalopathy, lactic acidosis, stroke-like events, myoclonic epilepsy and ragged red fibers, neuropathy, ataxia, retinitis pigmentosa, and Leber's hereditary optic neuropathy. As a result of the clinical overlap, it is usually necessary to analyze more than one mutation for a patient suspected of a mitochondrial disorder. Molecular diagnosis is often performed using polymerase chain reaction (PCR)/restriction fragment length polymorphism (RFLP) analysis of the most likely point mutations. However, this method is time-consuming and often produces problems associated with incomplete restriction enzyme digestion. In addition, PCR/RFLP analysis may not be able to detect a low percentage of heteroplasmy. For a more effective method of diagnosing mtDNA disorders, we have developed a multiplex PCR/ allele-specific oligonucleotide (ASO) dot blot hybridization method to simultaneously analyze 11 point mutations. The PCR products from a DNA sample containing a homoplasmic wild-type or mutant mtDNA sequence will hybridize to either the wild-type or the mutant ASO probe. The PCR products of a heteroplasmic DNA sample will hybridize to both wild-type and mutant ASO probes. This PCR/ASO method allows the detection of low percentage mutant heteroplasmy.
 ...
PMID:Molecular analysis of mitochondrial DNA point mutations by polymerase chain reaction. 1691 59

The central nervous system (CNS) is, after the peripheral nervous system, the second most frequently affected organ in mitochondrial disorders (MCDs). CNS involvement in MCDs is clinically heterogeneous, manifesting as epilepsy, stroke-like episodes, migraine, ataxia, spasticity, extrapyramidal abnormalities, bulbar dysfunction, psychiatric abnormalities, neuropsychological deficits, or hypophysial abnormalities. CNS involvement is found in syndromic and non-syndromic MCDs. Syndromic MCDs with CNS involvement include mitochondrial encephalomyopathy, lactacidosis, stroke-like episodes syndrome, myoclonic epilepsy and ragged red fibers syndrome, mitochondrial neuro-gastrointestinal encephalomyopathy syndrome, neurogenic muscle weakness, ataxia, and retinitis pigmentosa syndrome, mitochondrial depletion syndrome, Kearns-Sayre syndrome, and Leigh syndrome, Leber's hereditary optic neuropathy, Friedreich's ataxia, and multiple systemic lipomatosis. As CNS involvement is often subclinical, the CNS including the spinal cord should be investigated even in the absence of overt clinical CNS manifestations. CNS investigations comprise the history, clinical neurological examination, neuropsychological tests, electroencephalogram, cerebral computed tomography scan, and magnetic resonance imaging. A spinal tap is indicated if there is episodic or permanent impaired consciousness or in case of cognitive decline. More sophisticated methods are required if the CNS is solely affected. Treatment of CNS manifestations in MCDs is symptomatic and focused on epilepsy, headache, lactacidosis, impaired consciousness, confusion, spasticity, extrapyramidal abnormalities, or depression. Valproate, carbamazepine, corticosteroids, acetyl salicylic acid, local and volatile anesthetics should be applied with caution. Avoiding certain drugs is often more beneficial than application of established, apparently indicated drugs.
 ...
PMID:Central nervous system manifestations of mitochondrial disorders. 1694 41

Congenital disorders of glycosylation (CDG) are a group of metabolic disorders resulting from defective synthesis of N-linked oligosaccharides. CDG-Ia is the most common of the 21 known types defined by defects in different steps of the synthetic pathway. An increasing number of American adults with CDG-Ia are being recognized but little is documented on the morbidity and mortality in this population. These adults have moderate mental retardation, ataxia, retinitis pigmentosa, peripheral neuropathy, kyphoscoliosis, and endocrinopathies. Four adults with CDG-Ia, ages 19-36 years old are presented. All are active, dysarthric conversant adults with moderate cognitive impairment. They are ataxic and wheelchair dependent, however, only the oldest man shows significant muscle atrophy. All have diagnosed peripheral neuropathy. Three of four remain on anticonvulsants with only occasional seizures, none have had stroke-like episodes since their teen years. Their skeletal issues include significant kyphoscoliosis, joint contractures, and osteopenia. Retinitis pigmentosa and myopia complicate their functional vision. The women do not menstruate and the men have small testes resulting from hypogonadotropic hypogonadism. Documentation of clinical complications and successful management strategies in adults with CDG will improve their quality of life and allow more informed prognostic discussions with families of younger affected individuals.
 ...
PMID:Clinical features in adults with congenital disorders of glycosylation type Ia (CDG-Ia). 1763 95

Defects of the oxidative ATP production pathway lead to an amazing variety of disease phenotypes, ranging from childhood encephalomyopathies to hereditary tumor formation. A key enzyme of tricarboxylic cycle, fumarate hydratase (FH), is involved in encephalopathies, but also in leiomyoma formation, and occasionally also in various types of cancer. MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) and NARP (neuropathy ataxia retinitis pigmentosa) are progressive neurological disorders, caused by mitochondrial DNA mutations and respiratory chain (RC) deficiency. These diseases lead to disability and premature death, but not to tumorigenesis. We studied the cellular consequences of FH and RC deficiencies, aiming to identify general responses to energy metabolism defect and those specific for FH-deficiency, suggestively connected to tumorigenesis. Unlike in RC deficiency, the FH-deficient diploid human fibroblasts showed no signs of oxidative stress, but had a reduced redox state with high glutathione levels. The cytoplasmic FH isoform, previously described, but with an unknown function, was completely lacking in all FH-deficient lines. Fumarate was increased in two of our FH-lines, but accumulation of HIF-1alpha was not detected. Glycolysis was induced in both MELAS and in FH-deficiency. Accumulation of fumarate in primary fibroblasts did not activate a hypoxia response, suggesting that hypoxia activation due to fumarate accumulation may be a tissue-specific response. The lack of cytoplasmic form of FH and the reduced redox environment were typical for all FH-mutant lines, and their role in FH-related tumorigenesis requires further attention.
 ...
PMID:Differential metabolic consequences of fumarate hydratase and respiratory chain defects. 1831 10

Photoreceptor cells are incessantly bombarded with photons of light, which, along with the cells' high rate of oxygen metabolism, continuously exposes them to elevated levels of toxic reactive oxygen intermediates (ROIs). Vacancy-engineered mixed-valence-state cerium oxide nanoparticles (nanoceria particles) scavenge ROIs. Our data show that nanoceria particles prevent increases in the intracellular concentrations of ROIs in primary cell cultures of rat retina and, in vivo, prevent loss of vision due to light-induced degeneration of photoreceptor cells. These data indicate that the nanoceria particles may be effective in inhibiting the progression of ROI-induced cell death, which is thought to be involved in macular degeneration, retinitis pigmentosa and other blinding diseases, as well as the ROI-induced death of other cell types in diabetes, Alzheimer's disease, atherosclerosis, stroke and so on. The use of nanoceria particles as a direct therapy for multiple diseases represents a novel strategy and suggests that they may represent a unique platform technology.
 ...
PMID:Rare earth nanoparticles prevent retinal degeneration induced by intracellular peroxides. 1865 54

Mitochondrial genomes with deleterious mutations can replicate in cells along with wild-type genomes in a state of heteroplasmy, and are a cause of severe inherited syndromes, such as mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS), neuropathy, ataxia, retinitis pigmentosa-maternally inherited Leigh syndrome (NARP-MILS), and Leber's hereditary optic neuropathy (LHON). The cytosolic E3 ligase, Parkin, commonly mutated in recessive familial parkinsonism, translocates to depolarized mitochondria and induces their autophagic elimination, suggesting that Parkin may signal the selective removal of defective mitochondria within the cell. We report that long-term overexpression of Parkin can eliminate mitochondria with deleterious COXI mutations in heteroplasmic cybrid cells, thereby enriching cells for wild-type mtDNA and restoring cytochrome c oxidase activity. After relieving cybrid cells of Parkin overexpression, a more favorable wild-type to mutant mitochondrial genome ratio is stably maintained. These data support the model that Parkin functions in a mitochondrial quality control pathway. Additionally, they suggest that transiently increasing levels of Parkin expression might ameliorate certain mitochondrial diseases.
 ...
PMID:Parkin overexpression selects against a deleterious mtDNA mutation in heteroplasmic cybrid cells. 2054 44

The syndrome of mitochondrial encephalopathy, lactic acidosis, and stroke-like episode (MELAS) is characterized clinically by recurrent focal neurological deficits, epilepsy, and short stature. The phenotypic spectrum is extremely diverse, with multisystemic organ involvement leading to isolated diabetes, deafness, renal tubulopathy, hypertrophic cardiomyopathy, and retinitis pigmentosa. In 80% of cases, the syndrome is associated with an AG transmission mutation (A3243G) in the tRNALeu gene of the mitochondrial DNA (mtDNA). We describe a woman with a unique combination of the MELAS A3243G mutation and multiple mtDNA deletions with normal POLG sequence. The patient presented with diabetes mellitus, sensorineural deafness, short stature, and mental disorientation. All her three children died in early adolescence.
 ...
PMID:MELAS syndrome associated with both A3243G-tRNALeu mutation and multiple mitochondrial DNA deletions. 2065 66


<< Previous 1 2 3 4 Next >>