Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Most previous researches on neurotrophins including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) have focused on the nervous system, because their receptors are widely distributed in neuronal tissues. Recently, however, the participation of neurotrophins in inflammation and atherosclerosis has been proposed. Therefore, the gene expression of neurotrophins is now an urgent issue is to be investigated in nonneuronal tissues. Here, we evaluated the gene expression of neurotrophins and their receptors in rat cultured vascular smooth muscle cells (VSMCs) by the reverse transcriptase-polymerase chain reaction method. The transcripts of NGF, NT-3, and TrkC (high-affinity receptor for NT-3), and two BDNF alternative spliced transcript variants with exons 3 and 4 were clearly detected in VSMCs cultured under conventional culture conditions. The upregulation of mRNA levels for NGF, two BDNF variants with exons 1 and 2, low-affinity neurotrophin receptor, and high-affinity receptors, TrkA (for NGF) and TrkB (for BDNF), was observed in response to the treatment with serum and phorbol-ester following the serum-starvation. In contrast, the expression of NT-3 and TrkC genes was downregulated under these conditions. Co-expression of these factors and their receptors and the characteristic regulation of their gene transcriptions suggest that these factors play crucial roles in the function of VSMCs through an autocrine mechanism.
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PMID:Gene expression of neurotrophins and their receptors in cultured rat vascular smooth muscle cells. 953 23

The cachexia-anorexia syndrome occurs in chronic pathophysiologic processes including cancer, infection with human immunodeficiency virus, bacterial and parasitic diseases, inflammatory bowel disease, liver disease, obstructive pulmonary disease, cardiovascular disease, and rheumatoid arthritis. Cachexia makes an organism susceptible to secondary pathologies and can result in death. Cachexia-anorexia may result from pain, depression or anxiety, hypogeusia and hyposmia, taste and food aversions, chronic nausea, vomiting, early satiety, malfunction of the gastrointestinal system (delayed digestion, malabsorption, gastric stasis and associated delayed emptying, and/or atrophic changes of the mucosa), metabolic shifts, cytokine action, production of substances by tumor cells, and/or iatrogenic causes such as chemotherapy and radiotherapy. The cachexia-anorexia syndrome also involves metabolic and immune changes (mediated by either the pathophysiologic process, i.e., tumor, or host-derived chemical factors, e.g., peptides, neurotransmitters, cytokines, and lipid-mobilizing factors) and is associated with hypertriacylglycerolemia, lipolysis, and acceleration of protein turnover. These changes result in the loss of fat mass and body protein. Increased resting energy expenditure in weight-losing cachectic patients can occur despite the reduced dietary intake, indicating a systemic dysregulation of host metabolism. During cachexia, the organism is maintained in a constant negative energy balance. This can rarely be explained by the actual energy and substrate demands by tumors in patients with cancer. Overall, the cachectic profile is significantly different than that observed during starvation. Cachexia may result not only from anorexia and a decreased caloric intake but also from malabsorption and losses from the body (ulcers, hemorrhage, effusions). In any case, the major deficit of a cachectic organism is a negative energy balance. Cytokines are proposed to participate in the development and/or progression of cachexia-anorexia; interleukin-1, interleukin-6 (and its subfamily members such as ciliary neurotrophic factor and leukemia inhibitory factor), interferon-gamma, tumor necrosis factor-alpha, and brain-derived neurotrophic factor have been associated with various cachectic conditions. Controversy has focused on the requirement of increased cytokine concentrations in the circulation or other body fluids (e.g., cerebrospinal fluid) to demonstrate cytokine involvement in cachexia-anorexia. Cytokines, however, also act in paracrine, autocrine, and intracrine manners, activities that cannot be detected in the circulation. In fact, paracrine interactions represent a predominant cytokine mode of action within organs, including the brain. Data show that cytokines may be involved in cachectic-anorectic processes by being produced and by acting locally in specific brain regions. Brain synthesis of cytokines has been shown in peripheral models of cancer, peripheral inflammation, and during peripheral cytokine administration; these data support a role for brain cytokines as mediators of neurologic and neuropsychiatric manifestations of disease and in the brain-to-peripheral communication (e.g., through the autonomic nervous system). Brain mechanisms that merit significant attention in the cachexia-anorexia syndrome are those that result from interactions among cytokines, peptides/neuropeptides, and neurotransmitters. These interactions could result in additive, synergistic, or antagonistic activities and can involve modifications of transducing molecules and intracellular mediators. Thus, the data show that the cachexia-anorexia syndrome is multifactorial, and understanding the interactions between peripheral and brain mechanisms is pivotal to characterizing the underlying integrative pathophysiology of this disorder.
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PMID:Central nervous system mechanisms contributing to the cachexia-anorexia syndrome. 1105 8

Brain-derived neurotrophic factor has been associated previously with the regulation of food intake. To help elucidate the role of this neurotrophin in weight regulation, we have generated conditional mutants in which brain-derived neurotrophic factor has been eliminated from the brain after birth through the use of the cre-loxP recombination system. Brain-derived neurotrophic factor conditional mutants were hyperactive after exposure to stressors and had higher levels of anxiety when evaluated in the light/dark exploration test. They also had mature onset obesity characterized by a dramatic 80-150% increase in body weight, increased linear growth, and elevated serum levels of leptin, insulin, glucose, and cholesterol. In addition, the mutants had an abnormal starvation response and elevated basal levels of POMC, an anorexigenic factor and the precursor for alpha-MSH. Our results demonstrate that brain derived neurotrophic factor has an essential maintenance function in the regulation of anxiety-related behavior and in food intake through central mediators in both the basal and fasted state.
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PMID:Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity. 1157 7

Lens epithelium derived growth factor (LEDGF) has been shown to rescue embryonic chick photoreceptor cells from serum starvation and heat stress, light damaged photoreceptor cells in Lewis rats, and photoreceptor cells in RCS rats. The aim of our study is to study the rescue effect of LEDGF on photoreceptor cells in the rd/rd mouse using our long-term serum free organ culture. At the end of this culture period of 21-26 days LEDGF treated rd mouse retina showed an increased photoreceptor survival compared to the untreated controls. LEDGF has no effect on expression and localization of opsin and arrestin in the rod photoreceptor cells when RPE is present. The protective potency of LEDGF on the retinal photoreceptor cells is similar to that of BDNF. LEDGF is known to activate heat shock proteins (Hsps) and the elevated Hsps are also reported to suppress apoptosis.
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PMID:Lens epithelium-derived growth factor (LEDGF) delays photoreceptor degeneration in explants of rd/rd mouse retina. 1158 9

Eating disorders (ED), such as anorexia nervosa (AN) and bulimia nervosa (BN), are complex psychiatric disorders where different genetic and environmental factors are involved. Several lines of evidence support that brain-derived neurotrophic factor (BDNF) plays an essential role in eating behaviour and that alterations on this neurotrophic system participates in the susceptibility to both AN and BN. Accordingly, intraventricular administration of BDNF in rats determines food starvation and body weight loss, while BDNF or its specific receptor NTRK2 knockout mice develop obesity and hyperphagia. Case-control studies also suggest a BDNF contribution in the aetiology of ED: we have previously reported a strong association between the Met66 variant within the BDNF gene, restricting AN (ANR) and minimum body mass index (minBMI) in a Spanish sample, and a positive association between the Val66Met and -270C/T BDNF SNPs and ED in six different European populations. To replicate these results, avoiding population stratification effects, we recruited 453 ED trios from eight European centres and performed a family-based association study. Both haplotype relative risk (HRR) and haplotype-based haplotype relative risk (HHRR) methods showed a positive association between the Met66 allele and ANR. Consistently, we also observed an effect of the Met66 variant on low minBMI and a preferential transmission of the -270C/Met66 haplotype to the affected ANR offspring. These results support the involvement of BDNF in eating behaviour and further suggest its participation in the genetic susceptibility to ED, mainly ANR and low minBMI.
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PMID:Association of BDNF with restricting anorexia nervosa and minimum body mass index: a family-based association study of eight European populations. 1565 4

Ischemic stress causes neuronal death and functional impairment. Evidence has suggested that cells in the ischemic core first lose viability due to the decline in blood flow and cellular energy metabolism and then die by necrosis. Although inhibition of necrosis could be a potent therapeutic target for brain ischemia, known neurotrophic factors are ineffective for neuronal necrosis. We previously reported that insulin, but not brain-derived neurotrophic factor or insulin like-growth factor-1, inhibited neuronal necrosis under serum-free starvation stress. Although insulin receptors are abundant in the central nervous system as well as in peripheral tissues, neurons are not dependent upon insulin for their glucose supply, indicating that insulin receptors have other roles in the central nervous system. In the present study, by using hypoxia-reperfusion stress, we showed that cortical neurons rapidly died by necrosis as evaluated by propidium iodide staining and transmission electron microscopic analysis. As expected, insulin treatment significantly inhibited neuronal necrosis, although this effect was blocked by pretreatment with an antisense oligonucleotide for the insulin receptor. Furthermore, an inhibitor of protein kinase C (PKC) eliminated the insulin-induced antinecrotic effect. The addition of insulin induced significant translocation of only the PKC-gamma isoform, whereas antisense oligonucleotide treatment for this isoform abolished the insulin-induced inhibition of necrosis. Together, these results suggest that insulin mediates inhibition of neuronal necrosis through a novel mechanism involving PKC-gamma activation.
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PMID:Insulin receptor-protein kinase C-gamma signaling mediates inhibition of hypoxia-induced necrosis of cortical neurons. 1570 36

Famine and viral infection, as well as interferon therapy have been reported to increase the risk of developing bipolar disorder. In addition, almost 100 polymorphic genes have been associated with this disease. Several form most of the components of a phosphatidyl-inositol signalling/AKT1 survival pathway (PIK3C3, PIP5K2A, PLCG1, SYNJ1, IMPA2, AKT1, GSK3B, TCF4) which is activated by growth factors (BDNF, NRG1) and also by NMDA receptors (GRIN1, GRIN2A, GRIN2B). Various other protein products of genes associated with bipolar disorder either bind to or are affected by phosphatidyl-inositol phosphate products of this pathway (ADBRK2, HIP1R, KCNQ2, RGS4, WFS1), are associated with its constituent elements (BCR, DUSP6, FAT, GNAZ) or are downstream targets of this signalling cascade (DPYSL2, DRD3, GAD1, G6PD, GCH1, KCNQ2, NOS3, SLC6A3, SLC6A4, SST, TH, TIMELESS). A further pathway relates to endoplasmic reticulum-stress (HSPA5, XBP1), caused by problems in protein glycosylation (ALG9), growth factor receptor sorting (PIK3C3, HIP1R, SYBL1), or aberrant calcium homoeostasis (WFS1). Key processes relating to these pathways appear to be under circadian control (ARNTL, CLOCK, PER3, TIMELESS). DISC1 can also be linked to many of these pathways. The growth factor pathway promotes protein synthesis, while the endoplasmic reticulum stress pathway, and other stress pathways activated by viruses and cytokines (IL1B, TNF, Interferons), oxidative stress or starvation, all factors associated with bipolar disorder risk, shuts down protein synthesis via control of the EIF2 alpha and beta translation initiation complex. For unknown reasons, oligodendrocytes appear to be particularly prone to defects in the translation initiation complex (EIF2B) and the convergence of these environmental and genomic signalling pathways on this area might well explain their vulnerability in bipolar disorder.
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PMID:Multiple genes and factors associated with bipolar disorder converge on growth factor and stress activated kinase pathways controlling translation initiation: implications for oligodendrocyte viability. 1723 88

Bipolar disorder and schizophrenia share common chromosomal susceptibility loci and many risk-promoting genes. Oligodendrocyte cell loss and hypomyelination are common to both diseases. A number of environmental risk factors including famine, viral infection, and prenatal or childhood stress may also predispose to schizophrenia or bipolar disorder. In cells, related stressors (starvation, viruses, cytokines, oxidative, and endoplasmic reticulum stress) activate a series of eIF2-alpha kinases, which arrest protein synthesis via the eventual inhibition, by phosphorylated eIF2-alpha, of the translation initiation factor eIF2B. Growth factors increase protein synthesis via eIF2B activation and counterbalance this system. The control of protein synthesis by eIF2-alpha kinases is also engaged by long-term potentiation and repressed by long-term depression, mediated by N-methyl-D-aspartate (NMDA) and metabotropic glutamate receptors. Many genes reportedly associated with both schizophrenia and bipolar disorder code for proteins within or associated with this network. These include NMDA (GRIN1, GRIN2A, GRIN2B) and metabotropic (GRM3, GRM4) glutamate receptors, growth factors (BDNF, NRG1), and many of their downstream signaling components or accomplices (AKT1, DAO, DAOA, DISC1, DTNBP1, DPYSL2, IMPA2, NCAM1, NOS1, NOS1AP, PIK3C3, PIP5K2A, PDLIM5, RGS4, YWHAH). They also include multiple gene products related to the control of the stress-responsive eIF2-alpha kinases (IL1B, IL1RN, MTHFR, TNF, ND4, NDUFV2, XBP1). Oligodendrocytes are particularly sensitive to defects in the eIF2B complex, mutations in which are responsible for vanishing white matter disease. The convergence of natural and genetic risk factors on this area in bipolar disorder and schizophrenia may help to explain the apparent vulnerability of this cell type in these conditions. This convergence may also help to reconcile certain arguments related to the importance of nature and nurture in the etiology of these psychiatric disorders. Both may affect common stress-related signaling pathways that dictate oligodendrocyte viability and synaptic plasticity.
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PMID:eIF2B and oligodendrocyte survival: where nature and nurture meet in bipolar disorder and schizophrenia? 1732 32

Following stroke or traumatic damage, neuronal death via both necrosis and apoptosis causes loss of functions including memory, sensory perception and motor skills. Since necrosis has the nature to expand, while apoptosis stops the cell death cascade in the brain, necrosis is considered to be a promising target for rapid treatment for stroke. Pure neuronal necrosis occurs when cortical neurons are cultured under serum-free and low-density conditions. Prothymosin alpha (ProTalpha) isolated from conditioned medium after serum-free culture was found to prevent necrosis by recovering the energy crisis due to endocytosed glucose transporters. At a later time point under the same starvation conditions, ProTalpha causes apoptosis, which in turn seems to inhibit the rapidly occurring necrosis by cleaving poly (ADP-ribose) polymerase, a major machinery involved in ATP consumption. Indeed, ProTalpha administered via systemic routes markedly inhibits the histological and functional damage induced by cerebral and retinal ischemia. Although ProTalpha also causes a cell death mode switch from necrosis to apoptosis in vivo, the induced apoptosis was found to be completely inhibited by endogenously occurring brain-derived neurotrophic factor or erythropoietin. Since forced downregulation of ProTalpha deteriorates the ischemic damage, it is evident that ProTalpha plays in vivo neuroprotective roles after ischemic events. Analyses in terms of the therapeutic time window and potency suggest that ProTalpha could be the prototypic compound to develop the medicine useful for treatment of stroke in clinics.
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PMID:Prothymosin alpha and cell death mode switch, a novel target for the prevention of cerebral ischemia-induced damage. 1950 Jun 18

Our previous studies have shown that brain-derived neurotrophic factor (BDNF) enhances bone/cementum-related protein gene expression through the TrkB-c-Raf-ERK1/2-Elk-1 signaling pathway in cementoblasts, which play a critical role in the establishment of a functional periodontal ligament. To clarify how BDNF regulates survival in cementoblasts, we examined its effects on cell death induced by serum starvation in immortalized human cementoblast-like (HCEM) cells. BDNF inhibited the death of HCEM cells. Small-interfering RNA (siRNA) for TRKB, a high affinity receptor for BDNF, and for Bcl-2, countered the BDNF-induced decrease in dead cell number. In addition, LY294002, a PI3-kinase inhibitor; SH-6, an Akt inhibitor; and PDTC, a nuclear factor kappa B (NF-kappaB) inhibitor, but not PD98059, an ERK1/2 inhibitor, abolished the protective effect of BDNF against cell death. BDNF enhanced phosphorylated Akt levels, NF-kappaB activity in the nucleus, Bcl-2 mRNA levels, and mitochondrial membrane potential. The blocking of BDNF's actions by treatment with siRNA in all cases for TRKB and Bcl-2, LY294002, SH-6, and PDTC suppressed the enhancement. These findings provide the first evidence that a TrkB-PI3-kinase-Akt-NF-kappaB-Bcl-2 signaling pathway triggered by BDNF and the subsequent protective effect of BDNF on mitochondrial membrane potential are required to rescue HCEM cells from serum starvation-induced cell death. Furthermore, the survival and increased expression of bone/cementum-related proteins induced by BDNF in HCEM cells occur through different signaling pathways.
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PMID:Brain-derived neurotrophic factor protects cementoblasts from serum starvation-induced cell death. 1971 59


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