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)

The actions of CRF in the brain and in the periphery are mediated through multiple binding sites. There are three receptors, CRF1, CRF2 alpha and CRF2 beta, which encode 411, 415 and 431 amino acid proteins and transduce signals via the stimulation of intracellular cAMP production. The recent identification of high-affinity non-peptide CRF receptor antagonists should allow for rapid progress in drug development of CRF receptor antagonists. In addition to the receptors, the actions of CRF in brain and in the periphery can also be modulated by a binding protein of 322 amino acids. Ligands of CRF-BP, such as CRF (6-33) can elevate brain levels of 'free' CRF and improve learning and memory without stress-like side effects of CRF receptor agonists. Urocortin, a mammalian CRF-related peptide with close sequence homology to fish urotensin, interacts with CRF1, CRF2 receptors and with CRF-BP. These data indicate that CRF receptor antagonists may be useful for the treatment of the disease states where CRF is elevated such as anxiety and depression, anorexia nervosa and stroke and that ligand inhibitors of CRF-BP may be used to elevate brain levels of 'free' urocortin and other CRF-related peptides.
Mol Psychiatry 1996 Sep
PMID:Neurobiology of corticotropin releasing factor (CRF) receptors and CRF-binding protein: implications for the treatment of CNS disorders. 911 53

Transgenic mice overexpressing the human beta 2-adrenergic receptor gene were compared with wild mice type in terms of cardiac function, using a modified work-performing isolated murine heart preparation and on-line computer analysis. A preload-dependent experiment was performed, in which venous return was gradually increased in 5 mmHg increments from 5 mmHg to 25 mmHg. At each preload, aortic flow, left atrial pressure and aortic pressure were measured in all hearts, and from these parameters stroke volume, contractility, and cardiac index (cardiac output divided by body weight in g) were calculated and compared between groups. At increasing preload levels, the heart rates ranged from 322 beats/min (+/-29) to 369 beats/min (+/-39) in control mice and from 469 beats/min (+/-36) to 540 beats/min (+/-39) in transgenic mice. Cardiac index increased from 138 microliters/min/g (+/-13) and 48 microliters/min/g (+/-5) for transgenic and control mice, respectively at 5 mmHg preload to 262 microliters/min/g (+/-51) and 167 microliters/min/g (+/-15), respectively at 20 mmHg preload. The contractility in the transgenic mice were significantly increased at lower preload levels compared to control mice (1420 mmHg/s +/- 204 v 1187 mmHg/s +/- 127). An increase in myocardial adrenergic receptor density (100-200 fold) leads to significantly higher indices of cardiac function in transgenic mice compared to control mice. The increased heart rate leading to a positive inotropic effect in the hearts of transgenic mice is, at least in part, due to the overexpression of adrenergic receptors. These findings suggest a possible alternative method of establishing a positive chronotropic and inotropic state without the use of pharmacological agents.
J Mol Cell Cardiol 1997 Mar
PMID:Functional analysis of myocardial performance in murine hearts overexpressing the human beta 2-adrenergic receptor. 915 57

Dysthymia is characterized by long-lasting periods of lowered mood. Epidemiological studies in the USA and Europe have demonstrated that the prevalence of dysthymia is at least 3% of the general population. Its pervasive occurrence makes dysthymia a public health problem worldwide. One feature of this disorder is its co-occurrence with medical and neurological disorders. A World Health Organization meeting on dysthymia in neurological disorders was held in Geneva, 1-3 July 1996 to address this topic. Some of the major goals of this meeting were to clarify the definition of dysthymia in the presence of neurological disorders and to evaluate current research in the field, to point out new areas for investigation, and to discuss current psychological and pharmacological treatments for dysthymia in neurological disorders. The potential roles of neuroendocrine and molecular mechanisms in dysthymia were identified through specific problems related to dysthymia occurring in disorders such as Parkinson's disease, Alzheimer's disease, stroke, multiple sclerosis and epilepsy. This meeting provided direction and opportunity for future studies in the under-recognized and under-investigated relationship between dysthymia and neurological disorders.
Mol Psychiatry 1996 Dec
PMID:Dysthymia in neurological disorders. 915 50

Breakdown or disruption of the cytoskeleton has been implicated in the neurodegenerative processes of a variety of diseases, including Alzheimer disease (AD) and stroke. Studies of such diseases in the human involve the use of postmortem brain tissue. Postmortem delay may vary considerably from a few hours to a few days, and within this period, a degree of cytoskeletal breakdown may occur. It is therefore crucial to examine alterations occurring in the cytoskeleton as a result of postmortem delay and subtract these from those caused by the disease. In this study, the distribution of tau, MAP2, and MAP5 immunohistochemistry was examined following postmortem intervals of 0-72 h in the rat cerebral cortex, corpus callosum, caudate nucleus, and hippocampus. Each microtubule-associated protein (MAP) underwent unique changes that were dependent both on postmortem interval and the brain region examined. Following long postmortem delays, some of the changes in these proteins were similar to those seen in rodent models of cerebral ischemia. These results demonstrate that MAPs are not stable during postmortem delay in the rat. Therefore, caution must be exercised when interpreting changes in MAPs in human postmortem tissue, especially in cases where ischemic injury may be involved. Examination of control tissue carefully matched for postmortem delay is therefore essential to allow meaningful interpretation of cytoskeletal abnormalities in human neurodegenerative disease.
Mol Chem Neuropathol 1997 Apr
PMID:The effect of postmortem delay on the distribution of microtubule-associated proteins tau, MAP2, and MAP5 in the rat. 916 90

Tissue plasminogen activator (tPA), the serine protease that converts inactive plasminogen to the protease plasmin, was recently shown to mediate neurodegeneration in the mouse hippocampus. Mice deficient in tissue plasminogen activator (tPA) display a dramatic resistance to a paradigm of excitotoxic neuronal death that involves intrahippocampal injection of the excitotoxin. This model is thought to reproduce the mechanism of neuronal death observed during acute (such as ischemic stroke) and degenerative (such as amyotrophic lateral sclerosis) diseases of the nervous system. The requirement for the proteolytic activity of tPA to mediate neuronal death is acute in the adult mouse. Serine protease inhibitors, specific for tPA or the tPA/plasmin proteolytic cascade, are effective in conferring extensive neuroprotection following the excitotoxic injection. These findings suggest possible new ways for interfering with the neuronal death observed in the hippocampus as a result of excitotoxicity. In addition, tPA is produced in the hippocampus primarily by microglial cells, which become activated in response to the neuronal injury. Blocking microglial activation has been shown in other injury paradigms to protect against neuronal death, therefore suggesting another way to retard neurodegeneration in the CNS. Furthermore, after the insult has been inflicted and in the presence of a compromised blood-brain barrier macrophages (cells deriving from the same lineage as microglia) migrate into the brain, where they are thought to contribute to the neuronal cell loss by secreting neurotoxic molecules. If these macrophages/microglia expressed, however, a tPA inhibitor, rather than the possibly neurotoxic tPA, they might be able to protect the neurons from dying.
J Mol Med (Berl) 1997 May
PMID:Clinical implications of the involvement of tPA in neuronal cell death. 918 75

Urokinase-type plasminogen activator (uPA) is an inducible extracellular serine protease implicated in fibrinolysis and in tissue remodeling. Recently, we have localized uPA mRNA strictly in limbic structures and the parietal cortex of the adult mouse brain. Here, we tested whether the systemic treatment of mice with kainic acid (KA), an amino acid inducing limbic seizures, could elevate in the brain mRNAs encoding uPA and its specific inhibitor, plasminogen activator inhibitor-1 (PAI-1), a major antifibrinolytic agent. Brain sections encompassing the hippocampus were tested through in situ hybridization using radiolabeled riboprobes specific for the two mRNA species. The results showed that KA greatly enhanced both mRNA species in sites of limbic structures and cortex. However, in the hypothalamus and brain blood vessels only PAI-1 mRNA was elevated. Those were also the only two locations where PAI-1 mRNA was detected in the non-treated control brain, although at a low level. For both mRNAs, KA enhancement was first evident 2-4 h after treatment, and it was most prolonged in the hippocampal area, where prominent hybridization signals persisted for three days. Here, both mRNAs were initially elevated in the hilar region of the dentate gyrus and in the molecular and oriens layers; however, PAI-1 mRNA became evident throughout the area, while uPA mRNA became especially pronounced in the CA3/CA4 subfield. In the cortex both mRNA types were induced, but only uPA mRNA was elevated in the retrosplenial cortex, and also in the subiculum. In the amygdaloid complex, uPA mRNA was restricted to the basolateral nucleus, whereas PAI-1 mRNA was seen throughout the structure, however, excluding this nucleus. These data show that seizure activity enhances the expression of uPA and PAI-1 genes in the brain; the patterns of enhancement suggest that the protease and its inhibitor may act in brain plasticity in synchrony, however, also independently of each other. Furthermore, the results suggest that by elevating PAI-1 mRNA in brain blood vessels, limbic seizures generate a risk for stroke.
Brain Res Mol Brain Res 1997 Jul
PMID:mRNAs encoding urokinase-type plasminogen activator and plasminogen activator inhibitor-1 are elevated in the mouse brain following kainate-mediated excitation. 922 13

In patients with a load-induced cardiac dysfunction (LCD), the left ventricular (LV) stroke work is supernormal at rest, but then becomes subnormal during handgrip (HG). The LCD usually occurs in children with the mitral valve prolapse (MVP). Our catheterization study revealed that the end-diastolic pressure (EDP) of both ventricles was elevated in LCD patients. In this study, the LV and right ventricular (RV) systolic time (ET) were measured by echocardiograms. The mitral inflow peak velocities, E and A, were also measured by the pulsed Doppler method. Subjects were divided into four groups, each consisting of 16 individuals: group 1, normal children; group 2, LCD patients; group 3, recovered children from LCD, the same individuals as group 2, but after coenzyme Q10 (CoQ) therapy; and group 4, asymptomatic children with MVP. In group 2, the mean PEP and PEP/ET were significantly smaller and the peak A velocity was significantly larger than in groups 1, 3 and 4. Among groups 1, 3 and 4, no intergroup differences were found regarding the PEP/ET and A. In LCD patients, a depressed inotropic state of the myocardium may result in a high EDP due to the Frank-Starling mechanism, and such a high EDP may then cause STI changes and a large A velocity. CoQ may also return abnormal STIs in LCD patients to normal, probably by improving the inotropic state and, as a consequence, reducing the high EDP of the LV and RV to a normal level.
Mol Aspects Med 1997
PMID:Recovery of the systolic time intervals by coenzyme Q10 in patients with a load-induced cardiac dysfunction. 926 17

The purpose of this was to investigate the effect of coenzyme Q10 (CoQ10) in patients with congestive heart failure (CHF) by measuring the possible improvement of certain relevant hemodynamic heart parameters. A statistic aggregation method know as a meta-analysis was used to measure the changes in the cardiac parameters. To begin with we collected the total number of randomized controlled trials and from a total of 14 studies published in the period of 1984-1994, eight studies met our inclusion criteria. The rest were excluded because of a lack of data which made a meta-analysis impossible. The relevant effect parameters investigated were stroke volume (SV), cardiac output (CO), ejection fraction (EF), cardiac index (CI), end diastolic volume index (EDVI), systolic time intervals (PEP/LVET) and total work capacity (Wmax). Seven meta-analyses were performed, one for each of the parameters, and the calculated effect sizes were all positive. Statistical significance could be demonstrated for all of the parameters except the PEP/LVET and Wmax thereby indicating an improvement of greater or lesser magnitude in the CoQ10 group as opposed to the placebo group. Accordingly, the average patient in the CoQ10 group had a better score with regard to SV and CO than 76 and 73% respectively of the patients in the placebo group. In conclusion, supplemental treatment of CHF with CoQ10 is consistent with an improvement of SV, EF, CO, CI and EDVI. Homogeneity could be established for SV and CO. Additional clinical trials of the effect of CoQ10 on CHF are necessary, but, on the basis of the evidence currently available, the possibility remains that CoQ10 will receive a well-documented role as an adjunctive treatment of CHF.
Mol Aspects Med 1997
PMID:Treatment of congestive heart failure with coenzyme Q10 illuminated by meta-analyses of clinical trials. 926 18

Diabetes mellitus associated with mitochondrial tRNA mutation at position 3243(DM-Mt3243) is a new disease. Patients have a distinctly different picture from MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). During observations at the Saiseikai Central Hospital, the following findings were noted in DM-Mt3243 patients: DM-Mt3243 patients are diagnosed earlier with diabetes, compared to NIDDM (non-insulin dependent diabetes mellitus) controls without family history. DM-Mt3243 patients often need insulin more often than NIDDM controls without family history. Post-treatment neuropathy and insulin edema are often found in DM-Mt3243, and the two phenomena possibly have a similar pathophysiology related to mitochondrial dysfunction. Ambiguous psychiatric disorders of functional psychosis are observed frequently in DM-Mt3243. Mild headache is common in DM-Mt3243 cases. Ambiguous neuromuscular abnormalities such as sleep disturbance, paresthesia of the legs, edema of the legs, and palpitation may be symptoms associated with mitochondrial dysfunction in DM-Mt3243. Coenzyme Q may be effective in the relief of these neuromuscular symptoms.
Mol Aspects Med 1997
PMID:Diabetes mellitus associated with 3243 mitochondrial tRNA(Leu(UUR)) mutation: clinical features and coenzyme Q10 treatment. 926 20

Anesthetic agent, arterial pCO2 level, and opioid peptides have all been implicated in the pathophysiology of experimental stroke models. The effects of halothane, alpha-chloralose, and differing concentrations of arterial pCO2 on injury volume and CSF beta-endorphin levels were studied in a feline model of experimental focal cerebral ischemia. The type of anesthetic agent used had no effect on injury volume following 6 h of focal cerebral ischemia. Over a 6-h period, beta-endorphin levels significantly increased from 10.1 +/- 5.0 fmol/mL at zero time to 14.4 +/- 7.2 fmol/mL at 6 h under halothane anesthesia (p < 0.05), whereas they did not significantly change (10.1 +/- 6.7 to 7.8 +/- 4.7 fmol/mL) under alpha-chloralose anesthesia. In contrast, hypercapnia had no effect on beta-endorphin levels, but significantly increased injury volume from 30.6 +/- 5.7% of the ipsilateral hemisphere under normocapnic conditions to 37.1 +/- 5.9% under hypercapnic conditions (p < 0.05). These results suggest that hypercapnia increases injury volume in a feline model of focal cerebral ischemia, and pCO2 should be controlled in experimental focal cerebral ischemia models.
Mol Chem Neuropathol 1997 May
PMID:Effects of halothane, alpha-chloralose, and pCO2 on injury volume and CSF beta-endorphin levels in focal cerebral ischemia. 927 Oct 3


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