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)

The short term cardiac side-effects of AZT (3'-azido-3'-deoxythymidine, zidovudine) was studied in rats to understand the biochemical events contributing to the development of AZT-induced cardiomyopathy. Developing rats were treated with AZT (50 mg/kg/day) for 2 wk and the structural and functional changes were monitored in the cardiac muscle. AZT treatment provoked a surprisingly fast appearance of cardiac malfunctions in developing animals characterized by prolonged RR, PR and QT intervals and J point depression. Electron microscopy showed abnormal mitochondrial structure but the cardiomyocyte had normal myofibers. The AZT treatment of rats significantly increased ROS and peroxynitrite formation in heart tissues as determined by the oxidation of nonfluorescent dihydrorhodamine123 and dichlorodihydro-fluorescein diacetate (H2DCFDA) to fluorescent dyes, and induced single-strand DNA breaks. Lipid peroxidation and oxidation of cellular proteins determined from protein carbonyl content were increased as a consequence of AZT treatment. Activation of the nuclear poly-ADP-ribose polymerase and the accelerated NAD+ catabolism were also observed in AZT-treated animals. Western blot analysis showed that mono-ADP-ribosylation of glucose regulated protein (GRP78/BIP) was enhanced by AZT treatment, that process inactivates GRP78. In this way moderate decrease in the activity of respiratory complexes was detected in the heart of AZT-treated animals indicating a damaged mitochondrial energy production. There was a significant decrease in creatine phosphate concentration resulting in a decrease in creatine phosphate/creatine ratio from 2.08 to 0.58. ATP level remained close to normal but the total extractable ADP increased with 45%. The calculated free ATP/ADP ratio decreased from 340 to 94 in the heart of AZT-treated rats as a consequence of increased free ADP concentration. It was assumed that the increased free ADP in AZT-treated cardiomyocyte may help cells to compensate the defective ATP production in damaged mitochondria by activating the ATP synthesis in undamaged mitochondria. Southern blot analysis did not show decreased quantity of mtDNA deriving from AZT-treated rat hearts indicating that under our experimental conditions AZT-induced heart abnormalities are not the direct consequence of the mtDNA depletion. These data show that ROS-mediated oxidative damages, activated ADP-ribosylation reactions and accelerated NAD+ catabolism play basic roles in the development of AZT-induced cardiomyopathy in our animal model and indicated that these ROS-mediated processes can be important factors in the development of myopathy and cardiomyopathy in zidovudine-treated AIDS patients.
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PMID:Role of reactive oxygen species and poly-ADP-ribose polymerase in the development of AZT-induced cardiomyopathy in rat. 989 21

Parkinson's disease (PD) is characterized by pathological changes which include degeneration of dopaminergic neurons in the substantia nigra pars compacta coupled with intracytoplasmic inclusions known as Lewy bodies. Neurodegeneration and Lewy bodies can also be found in the locus coeruleus, nucleus basalis, hypothalamus, cerebral cortex, cranial nerve motor nuclei, and central and peripheral components of the autonomic nervous system. PD progression is associated with the development of dementia, autonomic dysfunction, and postural instability, which do not respond well to conventional therapy. Therapeutic efforts aimed at preventing or at least delaying PD progression by reducing the overload of iron and generation of ROS, correcting the zinc deficiency may be of great benefit. Current pharmacotherapy of PD, in addition to symptomatic L-dopa treatment, includes the neuroprotective strategies with dopamine agonists, monoamine oxidase-B inhibitors (MAO-B), glutamate antagonists, catechol O-methyltransferase (COMT) inhibitors and other antioxidants or free radical scavengers. Depression, anxiety disorder and stress are all associated with PD and it is therefore necessary to include treatment regimens for these ailments in addition to the traditional pharmacotherapy for the symptoms of PD, as well as the neuroprotective measures noted above, in order to ensure the greatest possible benefit to PD patients.
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PMID:Importance of treatment of depression in assuring the most efficacious management of Parkinson's disease. 1090 82

When cows develop endometritis after birth, Escherichia coli and Arcanobacterium pyogenes are usually the most prominent bacteria present in bovine uterine lochial secretions. A. pyogenes alone is rarely found in the course of a disturbed puerperium. This was confirmed in this study, since average and high-grade uterine contaminations were always associated with the presence of both bacteria. The contamination grade was positively correlated with uterine polymorphonuclear granulocyte (PMN) numbers and negatively correlated with blood PMN numbers. Whether E. coli and A. pyogenes affect the phenotype and function of bovine PMN in a similar or differential way was subject to in vitro studies. PMN were tested in the presence of washed bacterial fragments or culture supernatants taken as a source for soluble and/or secreted bacterial products. Fragments and soluble products differed only quantitatively in their effects on PMN. Usually, long-time exposure (24h) of PMN to fragments induced the strongest effects. Accelerated death of granulocytes was only moderately induced by both E. coli and A. pyogenes products. Both E. coli and A. pyogenes products induced the enhanced expression of a membrane molecule detected by mAb IL-A110 and of CD11b. Expression of other surface structures remained largely unchanged (MHC class I, CD11c). Functional parameters of PMN (phagocytosis; generation of reactive oxygen species, ROS; antibody-independent cellular cytotoxicity, AICC) generally declined after pre-incubation for 24h with products of E. coli or A. pyogenes. Interestingly, soluble products of A. pyogenes stimulated the phagocytosis of PMN. However, co-incubation with E. coli products abrogated this stimulatory effect. The results supply evidence for similar modes of action of the gram-negative E. coli and the gram-positive A. pyogenes on bovine PMN. Alterations in PMN function and phenotype are mainly triggered by direct contact between bacterial fragments and PMN. Inhibition experiments with polymyxin B demonstrated that E. coli-mediated effects were not solely due to the action of lipopolysaccharide. The dominant functional depression of neutrophils by E. coli products strengthens the suggestion that the earlier appearance of E. coli in the uterus may support the co-infection of this organ by A. pyogenes at later times.
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PMID:Influence of Escherichia coli and Arcanobacterium pyogenes isolated from bovine puerperal uteri on phenotypic and functional properties of neutrophils. 1126 94

Nebivolol is a new and selective beta1-adrenergic receptor antagonist whose haemodynamic profile is different from that of classical beta-blockers. The blood pressure lowering effects of nebivolol are, at least partially, due to the direct vasodilation as a result of nitric oxide (NO) release from endothelial cells. Several in vitro studies unequivocally show that, at least in certain vascular districts (particularly in small diameter, non-conduit vessels) and in platelets, nebivolol can stimulate an increase of endothelial NO, which becomes available at the smooth muscle layers and induces vasorelaxation. Nebivolol appears to interact with the endothelial NO pathway in two complementary ways: it increases NO synthase (NOS) activity and reduces the NO-scavenging radical superoxide anion, by re-directing deranged NOS activity, from superoxide to NO production. Nebivolol appears also to possess a complementary antioxidant activity, through which the pathological ROS-induced depression of intracellular NO levels can be prevented. Depending on the studies, evidences for a role of different receptors have been obtained. Although the interaction of nebivolol with cell receptors and the mechanisms of signal transduction into eNOS activation are not yet fully delineated, that nebivolol increases NO production and extracellular release has been proved not only by confirming its inhibition by NOS blockers, but also by measuring NO levels in mediums and cells in several different experimental settings.
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PMID:Experimental evidences of nitric oxide-dependent vasodilatory activity of nebivolol, a third-generation beta-blocker. 1558 7

Endogenous catecholamines released during myocardial ischemia have been considered both to aggravate cell injury and exacerbate arrhythmias and to exert a protective action on the post-ischemic contractile function. The present work was addressed to look for evidence to explain this controversy. The effects of cardiac catecholamine depletion and of alpha- and beta-adrenoceptor (AR) blockade on the post-ischemic contractile dysfunction, as well as its possible relationship with cardiac oxidative stress, were studied in isolated and perfused rat hearts submitted to 20 min of ischemia and 30 min of reperfusion (stunning). Catecholamine depletion improves the contractile recovery in the stunned heart. This mechanical effect was associated with decreased levels of lipid peroxidation. A similar enhancement of the contractile function during reperfusion was detected after the simultaneous blockade of alpha 1- and beta-ARs with prazosin plus propranolol. To ascertain which specific AR pathway was involved in the effects of catecholamines on the stunned heart, selective AR blockers, prazosin (alpha 1-blocker), atenolol (beta 1-blocker), ICI 118,551 (beta 2-blocker) and selective inhibitors of Gi-PI3K pathway (pertussis toxin and wortmannin) were alternatively combined. The results indicate that catecholamines released during ischemia exert a dual action on the contractile behavior of the stunned heart: a deleterious effect, related to the activation of the beta 2-AR-Gi-PI3K-pathway, which was counteracted by a beneficial effect, triggered by the stimulation of alpha 1-AR. Neither the depression nor the enhancement of the post-ischemic contractile recovery were related with the increase in ROS formation induced by endogenous catecholamines.
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PMID:beta 2-Adrenergic stimulation is involved in the contractile dysfunction of the stunned heart. 1657 88

Depression is a condition with a complex biologic pattern in etiology. Environmental stressors modulate subsequent vulnerability to depression. In particular, early adversity seems to induce heightened reactivity to stress through several possible mechanisms, both biologic and psychologic. This increased reactivity results in an enhancement of biologic stress-response mechanisms, especially the HPA axis. Regulators of this system, particularly signal transduction pathways involving PKA and PKC, may be important in the regulation of key genes in this system including genes for GR, BDNF, and trk-b. This system potentially is vulnerable to ROS and therefore, indirectly, to the effects of cytokines. Finally, some of these effects may be controlled by chemical modification of DNA, specifically, methylation of promoters or other gene regions. This modification is a mechanism by which long-term biologic change can be induced by environmental stressors. The brain is homeostatic, and it is possible that alterations at multiple points in this system may induce dysregulation and, as a result, vulnerability to stress. Therefore, a person may be vulnerable to depression, which may be a final common "pathway" for this family of conditions. Individuals may very considerably with regard to the locus of the problem, however. For example, functional variants in a set of genes might predispose some people to depression; others may have epigenetic imprinting; and yet different causes may be at work in others. Although this mix is complicated, it can be unraveled. Doing so could lead to the development of novel interventions that could target specific points of vulnerability, allowing an improved matching of patient to treatment based on differential abnormalities at the cellular level.
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PMID:The molecular neurobiology of depression. 1736 99

Treatment of murine myotubes with high glucose concentrations (10 and 25 mM) stimulated protein degradation through the ubiquitin-proteasome pathway, and also caused activation (autophosphorylation) of PKR (double-stranded-RNA-dependent protein kinase) and eIF2alpha (eukaryotic initiation factor 2alpha). Phosphorylation of PKR and eIF2alpha was also seen in the gastrocnemius muscle of diabetic ob/ob mice. High glucose levels also inhibited protein synthesis. The effect of glucose on protein synthesis and degradation was not seen in myotubes transfected with a catalytically inactive variant (PKRDelta6). High glucose also induced an increased activity of both caspase-3 and -8, which led to activation of PKR, since this was completely attenuated by the specific caspase inhibitors. Activation of PKR also led to activation of p38MAPK (mitogen activated protein kinase), leading to ROS (reactive oxygen species) formation, since this was attenuated by the specific p38MAPK inhibitor SB203580. ROS formation was important in protein degradation, since it was completely attenuated by the antioxidant butylated hydroxytoluene. These results suggest that high glucose induces muscle atrophy through the caspase-3/-8 induced activation of PKR, leading to phosphorylation of eIF2alpha and depression of protein synthesis, together with PKR-mediated ROS production, through p38MAPK and increased protein degradation.
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PMID:Mechanism of induction of muscle protein loss by hyperglycaemia. 1897 55

A sesquiterpene lactone, eupalinin A, found in Eupatorium chinense L., exhibited a marked inhibitory effect on cell growth in HL60 cells. In a previous study, it was indicated that the intracellular ROS generation accompanying mitochondrial dysfunction was closely related to the autophagic cell death induced by the treatment with eupalinin A. By glutathione (GSH) pre-treatment, eupalinin A-induced cell growth inhibition was markedly reduced in a time- and dose-dependent manner. Eupalinin A reduced the intracellular GSH level in the early phase, but the GSH pre-treatment reduced this depression. Interestingly, the supplementation of GSH changed the cell death type from autophagic cell death to apoptotic cell death. Pre-treatment with GSH plus p38 MAP kinase inhibitor (SB203580) strongly diminished the eupalinin A-induced autophagic cell death compared with GSH pre-treatment, suggesting a negative regulation of p38 MAP kinase in this cell death type conversion. Taken together, intracellular ROS levels, including GSH, are crucial for the susceptibility to cell death and the determination of type of eupalinin A-induced cell death.
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PMID:Intracellular glutathione regulates sesquiterpene lactone-induced conversion of autophagy to apoptosis in human leukemia HL60 cells. 1941 1

A summary is presented of the cellular function and topology of the protein products of genes whose mutations are associated with familial forms of parkinsonism, with particular emphasis on mitochondrial involvement. Observations are reviewed which show mitochondrial respiratory depression in the fibroblasts of a patient affected by familial parkinsonism associated with homozygous PINK1 mutation. The respiratory depression, which was due to loss of mitochondrial cytochrome c, was associated with decreased capacity of respiratory chain oxidative phosphorylation and enhanced cellular level of ROS. Sequence analysis of the overall mtDNA revealed coexistence with the PINK1 mutation of homoplasmic point mutations in the ND5 and ND6 genes of complex I. The presence of these mutations appears to have an impact on the development of the parkinsonism, which can also occur in the heterozygous PINK1 mutation state.
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PMID:Mitochondrial respiratory dysfunction and mutations in mitochondrial DNA in PINK1 familial parkinsonism. 1990 88

Sepsis is characterized by systematic inflammation where oxidative damage plays a key role in organ failure. This study was designed to examine the impact of the antioxidant metallothionein (MT) on lipopolysaccharide (LPS)-induced cardiac contractile and intracellular Ca(2+) dysfunction, oxidative stress, endoplasmic reticulum (ER) stress and autophagy. Mechanical and intracellular Ca(2+) properties were examined in hearts from FVB and cardiac-specific MT overexpression mice treated with LPS. Oxidative stress, activation of mitogen-activated protein kinase pathways (ERK, JNK and p38), ER stress, autophagy and inflammatory markers iNOS and TNFalpha were evaluated. Our data revealed enlarged end systolic diameter, decreased fractional shortening, myocyte peak shortening and maximal velocity of shortening/relengthening as well as prolonged duration of relengthening in LPS-treated FVB mice associated with reduced intracellular Ca(2+) release and decay. LPS treatment promoted oxidative stress (reduced glutathione/glutathione disulfide ratio and ROS generation). Western blot analysis revealed greater iNOS and TNFalpha, activation of ERK, JNK and p38, upregulation of ER stress markers GRP78, Gadd153, PERK and IRE1alpha, as well as the autophagy markers Beclin-1, LCB3 and Atg7 in LPS-treated mouse hearts without any change in total ERK, JNK and p38. Interestingly, these LPS-induced changes in echocardiographic, cardiomyocyte mechanical and intracellular Ca(2+) properties, ROS, stress signaling and ER stress (but not autophagy, iNOS and TNFalpha) were ablated by MT. Antioxidant N-acetylcysteine and the ER stress inhibitor tauroursodeoxycholic acid reversed LPS-elicited depression in cardiomyocyte contractile function. LPS activated AMPK and its downstream signaling ACC in conjunction with an elevated AMP/ATP ratio, which was unaffected by MT. Taken together, our data favor a beneficial effect of MT in the management of cardiac dysfunction in sepsis.
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PMID:Cardiac overexpression of metallothionein rescues cardiac contractile dysfunction and endoplasmic reticulum stress but not autophagy in sepsis. 1991 57


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