UMLS:C0011570 - FACTA Search

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)

A number of malignant tumors interact with the host to cause a syndrome of cachexia, characterized by extensive loss of adipose tissue and skeletal muscle mass, but with preservation of proteins in visceral tissues. Although anorexia is frequently present, the body composition changes in cancer cachexia cannot be explained by nutritional deprivation alone. Loss of skeletal muscle mass is a result of depression in protein synthesis and an increase in protein degradation. The main degradative pathway that has been found to have increased expression and activity in the skeletal muscle of cachectic patients is the ubiquitin-proteasome proteolytic pathway. Cachexia-inducing tumors produce catabolic factors such as proteolysis-inducing factor (PIF), a 24 kDa sulfated glycoprotein, which inhibit protein synthesis and stimulate degradation of intracellular proteins in skeletal muscle by inducing an increased expression of regulatory components of the ubiquitin-proteasome proteolytic pathway. While the oligosaccharide chains in PIF are required to initiate protein degradation the central polypeptide core may act as a growth and survival factor. Only cachexia-inducing tumors are capable of elaborating fully glycosylated PIF, and the selectivity of production possibly rests with the acquisition of the necessary glycosylating enzymes, rather than expressing the gene for the polypeptide core. Loss of adipose tissue is probably the result of an increase in catabolism rather than a defect in anabolism. A lipid mobilizing factor (LMF), identical with the plasma protein Zn-alpha2-glycoprotein (ZAG) is found in the urine of cachectic cancer patients and is produced by tumors causing a decrease in carcass lipid. LMF causes triglyceride hydrolysis in adipose tissue through a cyclic AMP-mediated process by interaction with a beta3-adrenoreceptor. Thus, by producing circulating factors certain malignant tumors are able to interfere with host metabolism even without metastasis to that particular site.
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PMID:Tumor-host interactions. 1544 22

Ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCH-L1) is a deubiquitinating enzyme that is responsible for making ubiquitin, which is required to target proteins for degradation by the ubiquitin-proteasome pathway in neurons, available. We investigated whether UCH-L1 plays a neuroprotective role at the rostral ventrolateral medulla (RVLM), the origin of sympathetic neurogenic vasomotor tone in the medulla oblongata where the organophosphate insecticide mevinphos (Mev) acts to elicit cardiovascular toxicity. In Sprague-Dawley rats maintained under propofol anesthesia, Mev (960 microg/kg, i.v.) induced a parallel and progressive augmentation in UCH-L1 or ubiquitin expression at the ventrolateral medulla during the course of Mev intoxication. The increase in UCH-L1 level was significantly blunted on pretreatment with bilateral microinjection into the RVLM of a transcription inhibitor, actinomycin D (5 nmol), or a translation inhibitor, cycloheximide (20 nmol). Compared with aCSF or sense oligonucleotide (100 pmol) pretreatment, microinjection of an antisense uch-L1 oligonucleotide (100 pmol) bilaterally into the RVLM significantly increased mortality, reduced the duration of the "pro-life" phase, blunted the increase in ubiquitin expression in ventrolateral medulla, and augmented the induced hypotension in rats that received Mev. These findings suggest that de novo synthesis of UCH-L1, leading to an enhanced disassembly of ubiquitin-protein conjugates in the RVLM, is essential to maintenance of the "pro-life" phase of Mev intoxication via prevention of cardiovascular depression, leading to neuroprotection.
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PMID:De novo synthesis of ubiquitin carboxyl-terminal hydrolase isozyme l1 in rostral ventrolateral medulla is crucial to survival during mevinphos intoxication. 1554 31

The introduction of acetylcholine esterase (AChE) inhibitors as a symptomatic treatment of Alzheimer's disease (AD) has made patients seek medical advice at an earlier stage of the disease. This has highlighted the importance of diagnostic markers for early AD. However, there is no clinical method to determine which of the patients with mild cognitive impairment (MCI) will progress to AD with dementia, and which have a benign form of MCI without progression. In this paper, the performance of cerebrospinal fluid (CSF) protein biomarkers for AD is reviewed. The diagnostic performance of the three biomarkers, total tau, phospho-tau, and the 42 amino acid form of beta-amyloid have been evaluated in numerous studies and their ability to identify incipient AD in MCI cases has also been studied. Some candidate AD biomarkers including ubiquitin, neurofilament proteins, growth-associated protein 43 (neuromodulin), and neuronal thread protein (AD7c) show interesting results but have been less extensively studied. It is concluded that CSF biomarkers may have clinical utility in the differentiation between AD and several important differential diagnoses, including normal aging, depression, alcohol dementia, and Parkinson's disease, and also in the identification of Creutzfeldt-Jakob disease in cases with rapidly progressive dementia. Early diagnosis of AD is not only of importance to be able to initiate symptomatic treatment with AChE inhibitors, but will be the basis for initiation of treatment with drugs aimed at slowing down or arresting the degenerative process, such as gamma-secretase inhibitors, if these prove to affect AD pathology and to have a clinical effect.
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PMID:Cerebrospinal fluid protein biomarkers for Alzheimer's disease. 1571 22

Protein synthesis is depressed during mammalian hibernation in concordance with metabolic demands. In the absence of significant protein synthesis, continued proteolysis would rapidly deplete protein pools. Since ubiquitin-dependent proteolysis is implicated in the turnover of most regulatory proteins, we examined the fate of this system during hibernation. Ubiquitin-dependent proteolysis consists of two major steps: (1) the tagging of a protein substrate by ubiquitin and (2) the protein substrate's subsequent degradation by the 26S proteasome. An earlier study revealed a two to threefold elevation of ubiquitin conjugate concentrations during hibernation: an unexpected result that seemingly would suggest increased proteolytic activity. A more likely explanation for these data would be that proteolysis per se was depressed and that the increased levels of ubiquitylated proteins reflect an inability to degrade tagged proteins. We employed an assay based on the cleavage of fluorogenic substrates to address the well characterized proteolytic activities of the proteasome. All activities show little to no activity at temperatures associated with deep torpor. Coordinated depression of proteolytic activities by low temperature supports the hypothesis that the increased levels of ubiquitylated proteins during hibernation is explained by a net accumulation due to an inability to degrade the tagged proteins.
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PMID:Proteolysis is depressed during torpor in hibernators at the level of the 20S core protease. 1591 63

Muscle protein degradation is thought to play a major role in muscle atrophy in cancer cachexia. To investigate the importance of the ubiquitin-proteasome pathway, which has been suggested to be the main degradative pathway mediating progressive protein loss in cachexia, the expression of mRNA for proteasome subunits C2 and C5 as well as the ubiquitin-conjugating enzyme, E2(14k), has been determined in gastrocnemius and pectoral muscles of mice bearing the MAC16 adenocarcinoma, using competitive quantitative reverse transcriptase polymerase chain reaction. Protein levels of proteasome subunits and E2(14k) were determined by immunoblotting, to ensure changes in mRNA were reflected in changes in protein expression. Muscle weights correlated linearly with weight loss during the course of the study. There was a good correlation between expression of C2 and E2(14k) mRNA and protein levels in gastrocnemius muscle with increases of 6-8-fold for C2 and two-fold for E2(14k) between 12 and 20% weight loss, followed by a decrease in expression at weight losses of 25-27%, although loss of muscle protein continued. In contrast, expression of C5 mRNA only increased two-fold and was elevated similarly at all weight losses between 7.5 and 27%. Both proteasome functional activity, and proteasome-specific tyrosine release as a measure of total protein degradation was also maximal at 18-20% weight loss and decreased at higher weight loss. Proteasome expression in pectoral muscle followed a different pattern with increases in C2 and C5 and E2(14k) mRNA only being seen at weight losses above 17%, although muscle loss increased progressively with increasing weight loss. These results suggest that activation of the ubiquitin-proteasome pathway plays a major role in protein loss in gastrocnemius muscle, up to 20% weight loss, but that other factors such as depression in protein synthesis may play a more important role at higher weight loss.
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PMID:Expression of the ubiquitin-proteasome pathway and muscle loss in experimental cancer cachexia. 1616 Jun 95

The ubiquitin-proteasome system contributes to regulation of apoptosis degrading apoptosis-regulatory proteins. Marked accumulation of ubiquitinated proteins in cardiomyocytes of human failing hearts suggested impaired ubiquitin-proteasome system in heart failure. Since cardiomyocyte apoptosis contributes to the progression of cardiac dysfunction in pressure-overloaded hearts, we investigated the role of ubiquitin-proteasome system in such conditions. We found that proteasome activities already depressed before the onset of cardiac dysfunction in pressure-overloaded hearts of mice. Cardiomyocyte apoptosis was observed along with depression of proteasome activities and elevation of proapoptotic/antiapoptotic protein ratio in failing hearts. In cultured cardiomyocytes, pharmacological inhibition of proteasome accumulated proapoptotic proteins such as p53 and Bax. Gene silencing of these proapoptotic proteins by RNA interference prevented the accumulation of respective proteins and attenuated cardiomyocyte apoptosis induced by proteasome inhibition. We conclude that depression of proteasome activities contributes to cardiac dysfunction resulting from cardiomyocyte apoptosis through accumulation of proapoptotic proteins by impaired degradation.
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PMID:Depression of proteasome activities during the progression of cardiac dysfunction in pressure-overloaded heart of mice. 1640 36

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a rare autosomal dominant disorder characterized by cerebral white matter degeneration with axonal spheroids leading to progressive cognitive and motor dysfunction. We report clinical and pathological features, as well as molecular genetic analysis, of a family with HDLS. A pedigree consisting of 27 persons in 5 generations contained 6 affected individuals. Dementia and depression were common; two individuals presented with a syndrome resembling corticobasal degeneration (CBD). Postmortem neuropathologic evaluation of three affected individuals revealed enlargement of the lateral ventricles and marked attenuation of cerebral white matter, but preservation of white matter in brainstem and cerebellum, except for the corticospinal tract. Histopathologic studies showed a loss of myelinated fibers, lipid-laden macrophages and bizarre astrocytes, as well as abundant axonal spheroids that were immunoreactive for phosphorylated neurofilament protein and amyloid precursor protein (APP), but not alphaB-crystallin and variably with ubiquitin. By electron microscopy, axonal spheroids contained aggregates of intermediate filaments or of organelles that were predominantly vesicular and lamellar. The cerebral cortex had focal neuronal degeneration with alphaB-crystallin-immunoreactive ballooned neurons. In summary, the present report describes a previously unreported kindred with HDLS with individuals presenting as CBD. Immunohistochemistry for APP and alphaB-crystallin demonstrates distinctive neurodegeneration in cerebral axons and perikarya.
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PMID:Hereditary diffuse leukoencephalopathy with spheroids: clinical, pathologic and genetic studies of a new kindred. 1652 41

Genetic deletion of fragile X mental retardation protein (FMRP) has been shown to enhance mGluR-dependent long-term depression (LTD). Herein, we demonstrate that mGluR-LTD induces a transient, translation-dependent increase in FMRP that is rapidly degraded by the ubiquitin-proteasome pathway. Moreover, proteasome inhibitors abolished mGluR-LTD, and LTD was absent in mice that overexpress human FMRP. Neither translation nor proteasome inhibitors blocked the augmentation of mGluR-LTD in FMRP-deficient mice. In addition, mGluR-LTD is associated with rapid increases in the protein levels of FMRP target mRNAs in wild-type mice. Interestingly, the basal levels of these proteins were elevated and their synthesis was improperly regulated during mGluR-LTD in FMRP-deficient mice. Our findings indicate that hippocampal mGluR-LTD requires the rapid synthesis and degradation of FMRP and that mGluR-LTD triggers the synthesis of FMRP binding mRNAs. These findings indicate that the translation, ubiquitination, and proteolysis of FMRP functions as a dynamic regulatory system for controlling synaptic plasticity.
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PMID:Dynamic translational and proteasomal regulation of fragile X mental retardation protein controls mGluR-dependent long-term depression. 1690 10

The entorhinal cortex (EC) serves as a gateway to the hippocampus and plays a pivotal role in memory processing in the brain. Superficial layers of the EC convey the cortical input projections to the hippocampus, whereas deep layers of the EC relay hippocampal output projections back to the superficial layers of the EC or to other cortical regions. Whereas the EC expresses long-term potentiation (LTP) and depression (LTD), the underlying cellular and molecular mechanisms have not been determined. Because the axons of the stellate neurons in layer II of the EC form the perforant path that innervates the dentate gyrus granule cells of the hippocampus, we studied the mechanisms underlying the long-term plasticity in identified stellate neurons. Application of high-frequency stimulation (100 Hz for 1 s, repeated 3 times at an interval of 10 s) or forskolin (50 microM) failed to induce significant changes in synaptic strength, whereas application of pairing (presynaptic stimulation at 0.33 Hz paired with postsynaptic depolarization from -60 to -10 mV for 5 min) or low-frequency stimulation (LFS, 1 Hz for 15 min) paradigm-induced LTD. Pairing- or LFS-induced LTDs were N-methyl-D-aspartate receptor-dependent and occluded each other suggesting that they have the similar cellular mechanism. Pairing-induced LTD required the activity of calcineurin and involved AMPA receptor endocytosis that required the function of ubiquitin-proteasome system. Our study provides a cellular mechanism that might in part explain the role of the EC in memory.
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PMID:Long-term depression in identified stellate neurons of juvenile rat entorhinal cortex. 1713 66

Both proteolysis-inducing factor (PIF) and angiotensin II have been shown to produce a depression in protein synthesis in murine myotubes concomitant with an increased phosphorylation of eukaryotic initiation factor 2 (eIF2alpha). Both PIF and angiotensin II were shown to induce autophosphorylation of the RNA-dependent protein kinase (PKR), and an inhibitor of this enzyme completely attenuated the depression in protein synthesis and prevented the induction of eIF2alpha phosphorylation. The PKR inhibitor also completely attenuated the increase in protein degradation induced by PIF and angiotensin II and prevented the increase in proteasome expression and activity. To confirm these results myotubes were transfected with plasmids that express either wild-type PKR, or a catalytically inactive PKR variant, PKRDelta6. Myotubes expressing PKRDelta6 showed no increase in eIF2alpha phosphorylation in response to PIF or angiotensin II, no depression in protein synthesis, and no increase in protein degradation or increase in proteasome expression. Induction of the ubiquitin-proteasome pathway by PIF and angiotensin II has been linked to activation of the transcription factor nuclear factor-kappaB (NF-kappaB). Inhibition of PKR prevented nuclear migration of NF-kappaB in response to both PIF and angiotensin II, by preventing degradation of the inhibitor protein I-kappaB. Phosphorylation of PKR and eIF2alpha was also significantly increased in the gastrocnemius muscle of weight losing mice bearing the MAC16 tumor, suggesting that a similar process may be operative in cancer cachexia. These results provide a link between the depression of protein synthesis in skeletal muscle and the increase in protein degradation.
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PMID:Skeletal muscle atrophy, a link between depression of protein synthesis and increase in degradation. 1721 91

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