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)

Immunotherapy with interferon-alpha (IFN-alpha) induces neuropsychiatric side effects, most notably depression. In hepatitis patients treated with IFN-alpha, severity of depression correlates with a decrease in serum activity of dipeptidyl peptidase IV (DPP-IV, EC 3.4.14.5), a membrane-bound protease involved in the cleavage of cytokines and neuroactive peptides. Abnormal serum activity of the cytosolic peptidase prolyl endopeptidase (PEP, EC 3.4.21.26, postprolyl cleaving enzyme, prolyl oligopeptidase) has been documented in patients with a variety of psychiatric disorders, most consistently in mood disorders. The serum activity of PEP and DPP-IV was measured before and after 4 weeks of high-dose induction treatment with IFN-alpha in 18 patients with high-risk melanoma. In this exploratory study, we show a clear decrease in the serum activity of PEP after 4 weeks of treatment with IFN-alpha. This decrease was not related to changes in hematologic parameters. In contrast, serum activity of DPP-IV did not change. Further studies focusing on a possible role of PEP in the pathophysiology of IFN-alpha-induced depression are warranted.
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PMID:Serum activity of prolyl endopeptidase, but not of dipeptidyl peptidase IV, is decreased by immunotherapy with IFN-alpha in high-risk melanoma patients. 1529 52

The trans-10, cis-12 CLA isomer has been causally related to milk fat depression in dairy cows, although no molecular mechanism has been established. Sterol response element-binding protein (SREBP)-1 is a transcription factor synthesized and retained as a membrane-bound precursor in the endoplasmic reticulum and proteolytically cleaved to release an active fragment that migrates to the nucleus to stimulate lipogenic gene transcription. Certain lipid molecules (i.e., PUFA) were shown to inhibit the proteolytic activation of SREBP-1 in rodent liver models, although there has been no previous demonstration of its presence in bovine tissues or in mammary tissue of any species. We used a bovine mammary cell line (MAC-T) to assess the involvement of SREBP-1 in the regulation of lipid synthesis in bovine mammary cells by trans-10, cis-12 CLA. Treatment with 75 micromol/L trans-10, cis-12 CLA for 48 h resulted in an approximately 50% reduction of (14)C-acetate incorporation into total lipid and corresponding reductions in mRNA abundance for acetyl CoA carboxylase, fatty acid synthase, and stearoyl CoA desaturase, whereas cis-9, trans-11 CLA had no effect on these genes. There was no reduction in SREBP-1 mRNA or precursor protein, but the abundance of the activated nuclear fragment of the protein was significantly reduced by treatment with 75 micromol/L trans-10, cis-12 CLA. These results indicate that trans-10, cis-12 CLA reduces lipid synthesis in the bovine mammary gland through inhibition of the proteolytic activation of SREBP-1 and subsequent reduction in transcriptional activation of lipogenic genes.
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PMID:The inhibitory effect of trans-10, cis-12 CLA on lipid synthesis in bovine mammary epithelial cells involves reduced proteolytic activation of the transcription factor SREBP-1. 1546 41

The past 5 years have seen unprecedented advances in our knowledge about the neurobiology of depression. Significant breakthroughs have been made in genomics, imaging, and the identification of key neural systems involved in cognition, emotion, and behavior. In addition, novel targets have been identified for the development of new pharmacological and behavioral treatments. Genetic variations associated with most mental disorders are being identified, and reliable tests for early detection of risk and disease are now on the horizon. New neurobiological concepts have emerged, as they relate to these advances in mental health research such as the serotonin transporter receptor, a genetic variant of which doubles the risk of depression. Brain neurochemicals, including neurotropic factors (implicated in several mental disorders), and anatomical studies involving imaging of the amygdala and the hippocampus and prefrontal cortex are now at the forefront. Several brain neurotransmitters systems: glutamate, gamma -aminobutyric acid, serotonin, norepinephrine, and dopamine have been implicated in depression and mania. These transmitter systems, as well as other neurochemical systems such as membrane-bound signal transduction systems and intracellular signaling systems that modulate gene transcription and protein synthesis, play an important role in the etiology of depression. This new knowledge is expected to provide important clues for the development of selective pharmacological interventions. Neuroimaging studies of depressed patients have shown several abnormalities of regional cerebral blood flow and glucose metabolism--a surrogate of neuronal function--in various brain regions, including the limbic cortex, the prefrontal cortex, the hippocampus, the amygdala, and the anterior cingulate cortex. At this time, a considerable amount of new information is converging--derived from animal models of mood disorders, genetics, basic behavioral research, and neuroscience. It is inevitable that the next step in this progression will be the integration of these basic advances in clinical management and the application of this new information in the context of the depressed patient.
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PMID:Neurobiological basis of depression: an update. 1587 9

Cyclic GMP (cGMP) is synthesized by guanylyl cyclase (GC) in response to nitric oxide (NO) and carbon monoxide (CO) or natiuretic peptides (NPs); atrial, brain and C-type (ANP, BNP and CNP). cGMP is degraded by several cGMP-specific phosphodiesterases (PDEs). Guanylate cyclases (GC) are differentiated into: membrane-bound/particulate (pGC) and cytosolic/soluble (sGC). In recent years evidence has accumulated that NO is the main activator of sGC and NO/cGMP plays important role in glutaminergic, cholinergic and dopaminergic signaling pathways. cGMP in the nervous system is involved in long term potentiation and depression (LTP, LTD) suggesting its participation in learning and memory mechanism. cGMP regulates calcium homeostasis and phototransduction. Its level is regulated by PDEs and their specific inhibitors protect cGMP level in cells and are very important from clinical point of view.
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PMID:Cyclic GMP metabolism and its role in brain physiology. 1607 88

Since trivalent chromium (Cr(3+)) enhances glucose metabolism, interest in the use of Cr(3+)as a therapy for type 2 diabetes has grown in the mainstream medical community. Moreover, accumulating evidence suggests that Cr(3+) may also benefit cardiovascular disease (CVD) and atypical depression. We have found that cholesterol, a lipid implicated in both CVD and neurodegenerative disorders, also influences cellular glucose uptake. A recent study in our laboratory shows that exposure of 3T3-L1 adipocytes to chromium picolinate (CrPic, 10 nM) induces a loss of plasma membrane cholesterol. Concomitantly, accumulation of intracellularly sequestered glucose transporter GLUT4 at the plasma membrane was dependent on the CrPic-induced cholesterol loss. Since CrPic supplementation has the greatest benefit on glucose metabolism in hyperglycemic insulin-resistant individuals, we asked here if the CrPic effect on cells was glucose-dependent. We found that GLUT4 redistribution in cells treated with CrPic occurs only in cells cultured under high glucose (25 mM) conditions that resemble the diabetic-state, and not in cells cultured under non-diabetic (5.5 mM glucose) conditions. Examination of the effect of CrPic on proteins involved in cholesterol homeostasis revealed that the activity of sterol regulatory element-binding protein (SREBP), a membrane-bound transcription factor ultimately responsible for controlling cellular cholesterol balance, was upregulated by CrPic. In addition, ABCA1, a major player in mediating cholesterol efflux was decreased, consistent with SREBP transcriptional repression of the ABCA1 gene. Although the exact mechanism of Cr(3+)-induced cholesterol loss remains to be determined, these cellular responses highlight a novel and significant effect of chromium on cholesterol homeostasis. Furthermore, these findings provide an important clue to our understanding of how chromium supplementation might benefit hypercholesterolemia-associated disorders.
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PMID:Chromium picolinate positively influences the glucose transporter system via affecting cholesterol homeostasis in adipocytes cultured under hyperglycemic diabetic conditions. 1687 Apr 93

Sympathetic premotor neurons for the maintenance of vasomotor tone are located in rostral ventrolateral medulla (RVLM). We demonstrated previously that overproduction of nitric oxide (NO) by inducible NO synthase (iNOS) in RVLM, leading to caspase 3-dependent apoptotic cell death, plays a pivotal role in cardiovascular depression during endotoxemia induced by intravenous administration of Escherichia coli lipopolysaccharide. The interposing intracellular events remain unknown. We evaluated the hypothesis that these events encompass protein kinase C (PKC) activation, which triggers activation and translocation of Bax that opens mitochondrial permeability transition pore by interacting with adenine nucleotide translocase (ANT) or voltage-dependent anion protein (VDAC), followed by cytosolic release of cytochrome c. In Sprague-Dawley rats, coimmunoprecipitation and Western blot analyses revealed sequential manifestations during endotoxemia of membrane-bound translocation of PKC, dissociation of cytosolic PKC/Bax complex, mitochondrial translocation of activated Bax, augmented Bax/ANT or Bax/VDAC association, elevated cytosolic cytochrome c and caspase 3, and DNA fragmentation in ventrolateral medulla. Microinjection of iNOS inhibitor into bilateral RVLM significantly retarded PKC and Bax activation. The induced association of translocated Bax with ANT or VDAC and the triggered mitochondrial apoptotic signaling cascade were blunted by blockade in RVLM of PKC, mitochondrial translocation of Bax, Bax channels, ANT, or caspase 3, alongside significant amelioration of cardiovascular depression. We conclude that formation of mitochondrial Bax/ANT or Bax/VDAC complex that initiates caspase 3-dependent apoptosis in the RVLM as a result of PKC-dependent mitochondrial translocation of activated Bax activated by iNOS-derived NO plays a pivotal role in the manifestation of endotoxin-induced cardiovascular depression.
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PMID:Protein kinase C-dependent mitochondrial translocation of proapoptotic protein Bax on activation of inducible nitric-oxide synthase in rostral ventrolateral medulla mediates cardiovascular depression during experimental endotoxemia. 1722 55

Nitric oxide (NO) is a multifunctional messenger in the CNS that can signal both in antero- and retrograde directions across synapses. Many effects of NO are mediated through its canonical receptor, the soluble guanylyl cyclase, and the second messenger cyclic guanosine-3',5'-monophosphate (cGMP). An increase of cGMP can also arise independently of NO via activation of membrane-bound particulate guanylyl cyclases by natriuretic peptides. The classical targets of cGMP are cGMP-dependent protein kinases (cGKs), cyclic nucleotide hydrolysing phosphodiesterases, and cyclic nucleotide-gated (CNG) cation channels. The NO/cGMP/cGK signalling cascade has been linked to the modulation of transmitter release and synaptic plasticity by numerous pharmacological and genetic studies. This review focuses on the role of NO as a retrograde messenger in long-term potentiation of transmitter release in the hippocampus. Presynaptic mechanisms of NO/cGMP/cGK signalling will be discussed with recently identified potential downstream components such as CaMKII, the vasodilator-stimulated phosphoprotein, and regulators of G protein signalling. NO has further been suggested to increase transmitter release through presynaptic clustering of a-synuclein. Alternative modes of NO/cGMP signalling resulting in inhibition of transmitter release and long-term depression of synaptic activity will also be addressed, as well as anterograde NO signalling in the cerebellum. Finally, emerging evidence for cGMP signalling through CNG channels and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels will be discussed.
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PMID:NO/cGMP-dependent modulation of synaptic transmission. 1806 24

Hypoxia is a consequence of inadequate oxygen availability. At the cellular level, lowered oxygen concentration activates signal cascades including numerous receptors, ion channels, second messengers, as well as several protein kinases and phosphatases. This, in turn, activates trans-factors like transcription factors, RNA-binding proteins and miRNAs, mediating an alteration in gene expression control. Each cell type has its unique constellation of oxygen sensors, couplers and effectors that determine the activation and predominance of several independent hypoxia-sensitive pathways. Hence, altered gene expression patterns in hypoxia result from a complex regulatory network with multiple divergences and convergences. Although hundreds of genes are activated by transcriptional control in hypoxia, metabolic rate depression, as a consequence of reduced ATP level, causes inhibition of mRNA translation. In a multi-phase response to hypoxia, global protein synthesis is suppressed, mainly by phosphorylation of eIF2-alpha by PERK and inhibition of mTOR, causing suppression of 5'-cap-dependent mRNA translation. Growing evidence suggests that mRNAs undergo sorting at stress granules, which determines the fate of mRNA as to whether being translated, stored, or degraded. Data indicate that translation is suppressed only at 'free' polysomes, but is active at subsets of membrane-bound ribosomes. The recruitment of specific mRNAs into subcellular compartments seems to be crucial for local mRNA translation in prolonged hypoxia. Furthermore, ribosomes themselves may play a significant role in targeting mRNAs for translation. This review summarizes the multiple facets of the cellular adaptation to hypoxia observed in mammals.
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PMID:Cellular oxygen sensing, signalling and how to survive translational arrest in hypoxia. 1876 66

The membrane-bound proteins ephrins and their receptors, Eph receptor tyrosine kinases, are known for their key role during development of the central nervous system (CNS). Ligand/receptor interactions as a result of cell-cell contacts activate intracellular signalling pathways which mediate specific cellular responses. Activation can occur bidirectionally in both the receptor and the ligand-bearing cells. Eph receptor and ephrin families have been implicated in synaptic plasticity in the mature brain: effects include long-term potentiation/depression of excitatory transmission (LTP/LTD) and an action on the structure and number of synaptic contacts. However, due to the redundancy of binding between receptors and ligands, the role of individual proteins has not yet been completely elucidated. Ephrin-B1 has been suggested to play a role in synaptic plasticity in the hippocampus, but its expression and localization at pre- or post-synaptic sites has been poorly documented, most likely due to the apparent low activity of the corresponding gene in mature brain. Here we present immunohistochemical data demonstrating a broad but highly regulated cellular distribution of ephrin-B1 in the mature mouse brain. We show that ephrin-B1 is expressed post-synaptically on dendritic spines in the cortex, supporting a role in synaptic plasticity in this region. However, the prevalent extra-synaptic distribution in regions such as the hippocampus and cerebellum suggests an additional structural role, perhaps at the neuron/glia interface.
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PMID:Regional and cellular distribution of ephrin-B1 in adult mouse brain. 1897 46

Depression develops as an interaction between stress and an individual's vulnerability to stress. The effect of early life stress and a gene-environment interaction may play a role in the development of stress vulnerability as a risk factor for depression. The epigenetic regulation of the promoter of the glucocorticoid receptor gene has been suggested as a molecular basis of such stress vulnerability. It has also been suggested that antidepressive treatment, such as antidepressant medication and electroconvulsive therapy, may be mediated by histone modification on the promoter of the brain-derived neurotrophic factor gene. Clinical genetic studies in bipolar disorder suggest the role of genomic imprinting, although no direct molecular evidence of this has been reported. The role of DNA methylation in mood regulation is indicated by the antimanic effect of valproate, a histone deacetylase inhibitor, and the antidepressive effect of S-adenosyl methionine, a methyl donor in DNA methylation. Studies of postmortem brains of patients have implicated altered DNA meA methylation of the promoter region of membrane-bound catechol-O-methyltransferase in bipolar disorder. An altered DNA methylation status of PPIEL (peptidylprolyl isomerase E-like) was found in a pair of monozygotic twins discordant for bipolar disorder. Hypomethylation of PPIEL was also found in patients with bipolar II disorder in a case control analysis. These fragmentary findings suggest the possible role of epigenetics in mood disorders. Further studies of epigenetics in mood disorders are warranted.
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PMID:Epigenetics in mood disorders. 1956 75


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