Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In vitro assessment was made of the hormone-release capability of splenic pancreatic tissue 16 days after adult chickens had 99% of the pancreatic mass surgically removed. The objective of this study was to evaluate if the enlargement of the splenic lobe remnant after 99% pancreatectomy was attended by alterations in the responsivity of hormone release and, if so, were such changes reflective of all pancreatic hormones. After a 24-hr fast, splenic lobe tissue was obtained from young adult chickens on Postoperative Day 16, diced into 18-22 mg cubes, and incubated in vitro in media containing varying amounts of glucose with or without added somatostatin (SRIF). At 15-min intervals, the tissue cubes were transferred to fresh media and samples of each medium measured for insulin, glucagon, and APP. Viability of the tissue after 75 min was tested by tissue response to added 5 mM phenylalanine. The results obtained indicated that while total content of all four hormones (including SRIF) increased with tissue enlargement, the concentration of each decreased significantly except for SRIF, which remained at control levels. Further, the sensitivity of the B-cell in releasing insulin when confronted by a glucose challenge was not altered by previous pancreatectomy, while that of glucagon release from the A-cell was depressed. A-cell responsivity to SRIF does not appear to be adversely affected by previous 99% pancreatectomy. APP release was least affected by SRIF addition to the media, although depression by high glucose occurred. It is concluded that differential alterations occur in chicken pancreatic hormone-releasing cells as a result of 99% pancreatectomy. The efficacy in maintaining low, but still adequate, plasma I/G molar ratios (reported earlier) by the splenic remnant tissue either reflects a remarkable functional readjustment to surgical removal of 99% of the pancreatic mass in chickens or, alternatively, suggests the existence of extrapancreatic sources of insulin and glucagon, but not APP.
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PMID:In vitro release of pancreatic hormones following 99% pancreatectomy in the chicken. 256 76

In vivo studies were carried out in adult chickens in an attempt to evaluate the effectiveness of somatostatin (SRIF) in regulating hormone secretion from the splenic pancreatic lobe after 99% of the pancreatic mass was surgically ablated. Sixteen days after either sham operation or 99% pancreatectomy, birds were infused iv with SRIF (420 ng/min) alone and then glucose (59 mg/Kg/min) was superimposed on the infusate, or birds were infused iv with glucose alone and then SRIF was superimposed on the infusate. Serial blood samples were taken during the 16-day postoperative period and also at regular intervals during the 75-min observation period. Plasma was analyzed for glucose, insulin (IRI), glucagon (IRG), pancreatic polypeptide (IRAPP), and somatostatin (IRSRIF). Careful standardization of the SRIF radioimmunoassay, as well as analysis of the molecular form of circulating SRIF, indicated that "true" SRIF levels were being estimated in plasma of both groups of chickens. Normal-fed chickens have plasma SRIF levels of 1.12 +/- 0.07 ng/ml which increases 16 days after 99% pancreatectomy to 2.39 +/- 0.15 ng/ml plasma. The latter decreases by 55% with an overnight fast. Glucose infusion, superimposed upon a preexisting SRIF infusion in adult chickens, did not evoke an IRI response in the 99% depancreatized birds equal to that observed in sham-op controls. Although a full SRIF dose-response curve was not generated, the glucose data strongly suggest a reduced sensitivity of insulin-secreting cells to SRIF in pancreoprivic birds. Both bird groups were equally--and markedly--sensitive to the IRG-depressant effects of SRIF; in contrast, the depancreatized chickens were significantly more resistant to the APP-inhibitory effects of SRIF when compared to the sham-op control birds. Thus, 16 days after partial pancreatectomy, the hormone-release mechanisms appeared altered for IRI and IRAPP in response to SRIF. Data obtained when glucose infusions preceded SRIF infusions indicated that A-cell release of glucagon was much more sensitive to glucose (as a depression) in the partially depancreatized birds than in control birds. These same birds were significantly less responsive to the glucose-depressant effect on plasma APP levels. Thus, it appears that 99% pancreatectomy increases the sensitivity of the SRIF, IRI, and IRG release mechanisms in response to glucose 16 days after surgery. The insulin-to-glucagon (I/G) molar ratios indicative of metabolic anabolism can still be achieved by nutrients 16 days after partial pancreatectomy.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effectiveness of somatostatin in regulating pancreatic splenic lobe hormone secretion following 99% pancreatectomy in adult chickens. 287 20

Microglial cells account for approximately 20% of the total glial population in the central nervous system. They are distributed with no significant local differences in the white and grey matters. In contrast to astrocytes they cover non-overlapping territories. They belong to the mononuclear phagocyte system and form the resident macrophages in the brain tissue, the spinal cord and the retina. Their function in the normal neural parenchyma is unknown. However, in various pathologies they form a most reactive sensor to threats to the nervous system. Within a few hours they exhibit an activation program that we have studied in seven different experimental paradigms, e.g. following nerve section, direct brain trauma, toxic lesion, spreading depression, ischemic lesion, fiber degeneration, autoimmune diseases. Activated microglial cells become immuno-competent and are MHC (major histocompatibility complex) class 1 and class 2 positive. They express the amyloid precursor protein, APP. The complement receptor CR3bi is quickly upregulated. The mitotic activity depends on the colony stimulating factors M-CSF and GM-CSF and the appropriate receptors. Molecules discussed as signals in the activation process of microglia are cytokines such as IL-1, IL-2, IL-6, TGF beta 1. An important role could also be attributed to the unique potassium channel of microglia. Brain macrophages of microglial origin have a strong respiratory burst activity, meaning that they produce oxygen radicals. They also possess Cathepsin B and L and thus are potentially cytotoxic. Taken together, microglia are highly reactive, mobile and multifunctional immune cells of the CNS that can play a universal role in the defence of the neural parenchyma.
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PMID:Microglia, the first line of defence in brain pathologies. 776 26

This study deals with the influence of oxygen radicals on the contraction of skinned muscle fibres from pig myocardium. The radicals were generated by xanthine-xanthine oxidase (X/XO) or by Fe2+/H2O2 (Fenton system). Addition of the X/XO to the incubation medium (KCl/imidazole) induced a depression of the contractility which was dependent from the incubation time and the X/XO concentration. The maximum contraction in the presence of high concentrations of free calcium ions (pCa 4.32) decreased to 52.0 +/- 15.5% (p < 0.01). The EC50 of calcium ions inducing fibre contraction increased from 2.82 +/- 0.66 mumol/l to 5.47 +/- 2.06 mumol/l (p < 0.05). The Hill plot of contraction versus concentration of calcium ions was shifted to the right and the maximum of contractility was attenuated. Replacement of X/XO by the Fenton system was without significant effects on the fibre contractility. Addition of 5.10(-4) mol/l APP 210-533 (3-amino-6-methyl-5-phenyl-1,2- dihydropyrid-2-on), a known "calcium sensitizer", increased the fibre contractility in radical impaired fibres, too. This may indicate that the radicals did not impair the troponine complex. Oxygen radicals were detected by electron spin resonance spectroscopy spin trapping using 5,5-dimethylpyrroline-1-oxide. Superoxide radicals were found in the presence of X/XO whereas addition of Fe2/H2O2 to the incubation medium resulted in the formation of hydroxyl radical adducts. The appearance of additional adducts observed in both system is discussed. The experiments indicate that free radicals can interact with components of the skinned fibre (probably with contractile proteins of the myocardial muscle cells) resulting in an impairment of the contractility.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Oxygen radicals attenuate the contractility of skinned muscle fibres from the pig myocardium. 783 69

The paper discusses therapeutical approaches to Alzheimer's disease on the basis of pathological mechanisms responsible for neurodegeneration. Amyloid plaques called also senile plaques situated extracellularly cause loss of neurons, especially cholinergic neurons, that begin in Nucleus of Meynert. However, recent evidence from postmortem brain and fibroblast studies suggests that both adenylyl cyclase and phosphatidylinositol hydrolysis signal transduction cascades are disrupted in AD. Such disruption may limit cholinergic pharmacotherapy. Other disorders, like disturbances in releasing Neuronal Growth Factor (NGF), oxidative stress, free Ca 2+, neuroimmunologic reactions are also important in AD brain changer. Only use of acetylcholine inhibitors: tacrine, donepezil and Gingko Biloba as well as nimodipine improved mental functions (MMSE screening). Neuroprotection of selegiline and NGF was observed. Behavioral symptoms often associated with dementia, like depression, anxiety, irritability, delusions, aggressiveness were treated with: olazepine, risperidone, haloperidol, clozapine, fluoxetine, paroxetine, sertraline, trazodon, dezypramine, lithium, benzodiazepines, carbamazepine and valproic acid. Drugs with strong anticholinergic effects, such as amitriptyline or imipramine should not be administered. Future studies on therapy to regulate metabolism of amyloid precursor-beta-APP are necessary to discover new efficient strategies.
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PMID:[Trials and perspectives in pharmacotherapy of Alzheimer's disease]. 1078 33

The Alzheimer's disease-related beta-amyloid precursor protein (beta-APP) is metabolized to a number of potentially amyloidogenic peptides that are believed to be pathogenic. Application of relatively low concentrations of the soluble forms of these peptides has previously been shown to block high-frequency stimulation-induced long-term potentiation (LTP) of glutamatergic transmission in the hippocampus. The present experiments examined how these peptides affect low-frequency stimulation-induced long-term depression (LTD) and the reversal of LTP (depotentiation). We discovered that beta-amyloid peptide (Abeta1-42) and the Abeta-containing C -terminus of beta-APP (CT) facilitate the induction of LTD in the CA1 area of the intact rat hippocampus. The LTD was frequency- and NMDA receptor-dependent. Thus, although low-frequency stimulation alone was ineffective, after intracerebroventricular injection of Abeta1-42, it induced an LTD that was blocked by d-(-)-2-amino-5-phosphonopentanoic acid. Furthermore, an NMDA receptor-dependent depotentiation was induced in a time-dependent manner, being evoked by injection of CT 10 min, but not 1 hr, after LTP induction. These use- and time-dependent effects of the amyloidogenic peptides on synaptic plasticity promote long-lasting reductions in synaptic strength and oppose activity-dependent strengthening of transmission in the hippocampus. This will result in a profound disruption of information processing dependent on hippocampal synaptic plasticity.
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PMID:Use-dependent effects of amyloidogenic fragments of (beta)-amyloid precursor protein on synaptic plasticity in rat hippocampus in vivo. 1116 Apr 3

Recently, a novel risk gene protein expressed in elderly patients with the diagnosis of Alzheimer disease (AD) was discovered on chromosome 21 within the APP (amyloid precursor protein) region. This 79 amino acid protein, ALZAS (Alzheimer Associated Protein) contains the beta-amyloid peptide 1-42 fragment, the APP transmembrane signal, and a unique 12 amino acid c-terminal which is not present in any known allele of the APP gene. Reverse transcription-PCR revealed that the transcript of ALZAS was expressed in cortical and hippocampal regions of human Alzheimer disease brain as well as in leukocytes derived from AD patients. Most specifically, an endogenous antibody was found in patients with confirmed AD, in patients with depression, and in subjects suggested to have presymptomatic AD, where it was directed against epitopes within the intron encoded amino acid c-terminal sequence.
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PMID:A broader horizon of Alzheimer pathogenesis: ALZAS--an early serum biomarker? 1245 54

Mints (also called X11-like proteins) are adaptor proteins composed of divergent N-terminal sequences that bind to synaptic proteins such as CASK (Mint 1 only) and Munc18-1 (Mints 1 and 2) and conserved C-terminal PTB- and PDZ-domains that bind to widely distributed proteins such as APP, presenilins, and Ca(2+) channels (all Mints). We find that Mints 1 and 2 are similarly expressed in most neurons except for inhibitory interneurons that contain selectively high levels of Mint 1. Using knockout mice, we show that deletion of Mint 1 does not impair survival or alter the overall brain architecture, arguing against an essential developmental function of the Mint 1-CASK complex. In electrophysiological recordings in the hippocampus, we observed no changes in short- or long-term synaptic plasticity in excitatory synapses from Mint 1-deficient mice and detected no alterations in the ratio of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) to N-methyl-d-aspartate (NMDA) receptor-mediated synaptic currents. Thus the Mint 1-CASK complex is not required for AMPA- and NMDA-receptor functions or for synaptic plasticity in excitatory synapses. In inhibitory synapses, however, we uncovered an approximately 3-fold increase in presynaptic paired-pulse depression, suggesting that deletion of Mint 1 impairs the regulation of gamma-aminobutyric acid release. Our data indicate that Mints 1 and 2 perform redundant synaptic functions that become apparent in Mint 1-deficient mice in inhibitory interneurons because these neurons selectively express higher levels of Mint 1 than Mint 2.
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PMID:A role for Mints in transmitter release: Mint 1 knockout mice exhibit impaired GABAergic synaptic transmission. 1254 17

Alzheimer's disease (AD) is characterised by progressive cognitive impairment with neuropsychiatric symptoms such as anomalous motor behaviour, depression, anxiety, weight loss, irritability and agitation. The effect of hAPP and PS1 overexpression on cognition has been well characterised in a variety of transgenic mouse models, however, non-cognitive behaviours have not been considered as systematically. The non-cognitive behaviour of the hAPP/PS1 transgenic mouse model (TASTPM) was observed at ages spanning the rapid progression of amyloid neuropathology. TASTPM transgenic mice, of both genders, exhibited decreased spontaneous motor activity, disinhibition, increased frequency and duration of feeding bouts, reduced body weight and, by 10 months, increased activity over a 24h period. In addition to the aforementioned behaviours, male transgenic mice also displayed enhanced aggression relative to wildtype controls. These data reveal previously unreported disease relevant behavioural changes that demonstrate the value of measuring behaviour in APP/PS1 transgenic models. These behavioural readouts could be useful in screening putative drug treatments for AD.
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PMID:Non-cognitive behaviours in an APP/PS1 transgenic model of Alzheimer's disease. 1722 72

Genetic factors have a variable impact on Alzheimer's Disease (AD), ranging from familial forms that are transmitted in an autosomal dominant fashion to sporadic AD, where a polygenic component is present. Most genes conferring susceptibility to AD are related to amyloid-beta deposition (APP; PS1; PS2; APOE; Cystatin-C; ubiquilin-1), oxidative stress (NOS2; NOS3) and inflammatory response (IL-1 alpha; IL-1 beta; IL-6; TNF-alpha). Genome-wide analyses, transcriptomics and proteomics approaches have pointed also to proapoptotic genes as increasing AD liability. Depression and psychotic symptoms that occur in a large proportion of AD patients have been associated with monoamine genes coding for metabolic enzymes (COMT), transporters (5-HTTLPR) and receptors (DRD1; DRD3). Genetic testing may be useful to confirm the diagnosis of AD in individuals with clinical signs of dementia, while it is generally not recommended as a predictive testing for AD in asymptomatic individuals. Drugs currently in use to treat AD are effective in only 20% of patients; their therapeutic effect is predominantly under genetic control (CYP26 gene; APOE). Environmental factors have been shown to moderate the effects of genes on psychiatric disorders such as depression, schizophrenia and ADHD. The study of gene-environment interactions in AD, that are still poorly understood, is essential to predict disease-risk in asymptomatic individuals. Genomics will provide a dynamic picture of biological processes in AD and new targets for the forthcoming anti-AD drugs.
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PMID:Genetics of Alzheimer's disease. A rapidly evolving field. 1785 Nov 96


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