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PubMed2005

An overview of chagasic cardiomyopathy: pathogenic importance of oxidative stress.

There is growing evidence to suggest that chagasic myocardia are exposed to sustained oxidative stress-induced injuries that may contribute to disease progression. Pathogen invasion- and replication-mediated cellular injuries and immune-mediated cytotoxic reactions are the common source of reactive oxygen species (ROS) in infectious etiologies. However, our understanding of the source and role of oxidative stress in chagasic cardiomyopathy (CCM) remains incomplete. In this review, we discuss the evidence for increased oxidative stress in chagasic disease, with emphasis on mitochondrial abnormalities, electron transport chain dysfunction and its role in sustaining oxidative stress in myocardium. We discuss the literature reporting the consequences of sustained oxidative stress in CCM pathogenesis.

Animals↗
PubMed2000

Social rhythm disruption and stressful life events in the onset of bipolar and unipolar episodes.

BACKGROUND: An association between social rhythm disruption (SRD) and onset of manic episodes has recently been observed. Whether other types of bipolar (depressive and cycling) or unipolar depressive episodes are similarly related to SRD is unclear, as is the association between severely threatening life events and onset of bipolar manic, depressed and cycling episodes. METHODS: Bipolar patients with purely manic (N= 21), purely depressed (N = 21) and cycling (N = 24) episodes, and 44 patients with recurrent unipolar depression, were interviewed with the Bedford College Life Events and Difficulties Schedule. The presence of severe and SRD events during the year prior to index episode onset was then determined. RESULTS: More manic than cycling and unipolar subjects experienced SRD events during 8- and 20-week pre-onset periods, and severe events during 20-week pre-onset periods. Controlling for age and prior number of episodes left most findings unchanged. An earlier finding of more manic subjects with SRD events in an 8-week pre-onset versus control period was also replicated. CONCLUSIONS: It appears that manic onsets are influenced by stressful life events, especially those involving SRD, in a unique manner compared to onsets of other types of bipolar and unipolar episodes. Onset of bipolar cycling episodes, in contrast, seems to be relatively unaffected by SRD or severe life events. These findings refine the hypothesis that SRD may precipitate onset of affective episodes to be specific to manic onsets.

Adult↗
PubMed1991

Controlled prospective study of postpartum mood disorders: psychological, environmental, and hormonal variables.

Demographic, psychiatric, social, cognitive, and life stress variables were used to determine the etiology of depression in childbearing (CB; n = 182) and nonchildbearing (NCB; n = 179) women. Hormonal variables in postpartum depression were also evaluated. In the CB group predictors of depression diagnosis were previous depression, depression during pregnancy, and a Vulnerability (V) x Life Stress (LS) interaction; predictors of depressive symptomatology were previous depression, depressive symptoms during pregnancy, life events, and V x LS. Only estradiol was associated with postpartum depression diagnosis. In the NCB group V X LS was the only predictor of depression diagnosis; depressive symptoms during pregnancy and life events were predictors of depressive symptomatology. Previous findings about depression vulnerability were replicated. The significant V x LS interactions support the vulnerability-stress model of postpartum depression.

Adult↗
PubMedDate not supplied

How Fanconi anemia proteins promote the four Rs: replication, recombination, repair, and recovery.

The genetically complex disease Fanconi anemia (FA) comprises cancer predisposition, developmental defects, and bone marrow failure due to elevated apoptosis. The FA cellular phenotype includes universal sensitivity to DNA crosslinking damage, symptoms of oxidative stress, and reduced mutability at the X-linked HPRT gene. In this review article, we present a new heuristic molecular model that accommodates these varied features of FA cells. In our view, the FANCA, -C, and -G proteins, which are both cytoplasmic and nuclear, have an integrated dual role in which they sense and convey information about cytoplasmic oxidative stress to the nucleus, where they participate in the further assembly and functionality of the nuclear core complex (NCCFA= FANCA/B/C/E/F/G/L). In turn, NCCFA facilitates DNA replication at sites of base damage and strand breaks by performing the critical monoubiquitination of FANCD2, an event that somehow helps stabilize blocked and broken replication forks. This stabilization facilitates two kinds of processes: translesion synthesis at sites of blocking lesions (e.g., oxidative base damage), which produces point mutations by error-prone polymerases, and homologous recombination-mediated restart of broken forks, which arise spontaneously and when crosslinks are unhooked by the ERCC1-XPF endonuclease. In the absence of the critical FANCD2 monoubiquitination step, broken replication forks further lose chromatid continuity by collapsing into a configuration that is more difficult to restart through recombination and prone to aberrant repair through nonhomologous end joining. Thus, the FA regulatory pathway promotes chromosome integrity by monitoring oxidative stress and coping efficiently with the accompanying oxidative DNA damage during DNA replication.

Cell Cycle Proteins↗
PubMed1986

Relationships among negative life events, physiological reactivity, and health symptomatology.

College undergraduates classified as high (n = 25) and low (n = 25) on recent life stress participated in an experiment involving a novel laboratory stressor. Heart rate and pulse arrival time (PAT) were measured during baseline, anticipation, testing, and recovery periods of the experiment. The results did not replicate those obtained by Pardine and Napoli in that high and low life stress subjects did not show differential physiological reactions. In addition, regression analyses failed to demonstrate that physiological reactivity moderated the relationship between life stress and subsequent self-reported psychiatric or physical health symptomatology. The present findings demonstrated neither the stress-buffering effects of physiological reactivity nor a relationship between life stress and reactivity when the latter was conceptualized as an outcome.

Adult↗
PubMed2000

Stressful manipulations that elevate corticosterone reduce blood-brain barrier permeability to pyridostigmine in the Rat.

Pyridostigmine bromide (PB), a reversible inhibitor of acetylcholinesterase (AChE), is used for the treatment of myasthenia gravis. PB has also been provided to military personnel for preexposure protection against potential soman release. The entry of PB into the brain is typically minimal, but recently published data in mice suggest that a brief forced swim stress increases the permeability of the blood-brain barrier to PB. From these results, PB administered under stressful conditions was proposed to induce long-lasting central cholinergic deficits, potentially explaining the neurological and neuropsychological symptoms presented by some Gulf War veterans. In undertaking to replicate these results in the Long-Evans rat, no evidence of a stress-potentiated central effect of PB, administered at doses up 5.0 mg/kg ip, was found. Three stress protocols were used: restraint, forced swim, or a combined restraint/forced swim. Wistar rats were also tested in some of the protocols to ensure that the results were generalizable across rat strains, and plasma corticosterone levels were measured to test the effectiveness of the stressors employed. In contrast to the previously reported findings in the mouse, stress significantly reduced the entry of PB into rat brain, as measured by reduced inhibition of AChE activity: a 12.5% reduction in whole brain AChE activity after treatment with 5.0 mg/kg PB under control conditions declined to 9% after stress exposure. It is apparent, therefore, that the interaction between stress and PB requires further study, and previous data should be reassessed before they are used as a basis for interpreting symptoms presented by veterans.

Acetylcholinesterase↗
PubMedDate not supplied

Altered cortisol response in sober alcoholics: an examination of contributing factors.

We have previously reported an attenuated plasma cortisol stress response in alcoholics abstinent from alcohol up to 4 weeks. The present study replicates and extends these findings by examining urinary cortisol levels in detoxified alcoholics (n = 40) and controls (n = 14) at rest and following mental arithmetic and isometric handgrip stress. Although the groups had similar baseline cortisol levels, the alcoholics showed an attenuated cortisol response to the combined stressors. This cortisol response reduction was unrelated to potential confounds such as smoking, liver function, age, depression, or anxiety. A multivariate model showed a trend for an association between severity of withdrawal and alcoholics' poststress cortisol levels. Although these results indicate decreased adrenocortical response to biobehavioral stress in alcoholics abstinent up to four weeks, higher stress cortisol values were seen in the patients with the most severe withdrawal symptoms.

Adult↗
PubMed1995

Cell type-specific expression of human 8-oxo-7,8-dihydroguanosine triphosphatase in normal breast and skin tissues in vivo.

8-Oxo-7,8-dihydroguanosine triphosphate (8-oxo-dGTP) is formed from the oxidation of GTP in the nucleotide pools of cells during normal cellular metabolism and from exogenous sources. 8-Oxo-dGTP is a potent mutagenic substrate for DNA synthesis causing transversion mutations. In human cells this oxidized base is hydrolyzed to 8-oxo-7,8-dihydroguanosine monophosphate by 8-oxo-7,8-dihydroguanosine triphosphatase (8-oxo-dGTPase) to prevent the misincorporation of 8-oxo-dGTP into cellular DNA. In order to better understand specific human tissue and cell type responses to oxidative stress, we used colorimetric in situ hybridization, with an 8-oxo-dGTPase-specific antisense oligomer probe, to map, for the first time, the cellular distribution of 8-oxo-dGTPase mRNA in tissue sections of normal neonatal foreskin and adult human breast tissues. Paraffin embedded tissue sections were hybridized with a digoxigenin-labeled 39 base oligomer, antisense to 8-oxo-dGTPase cDNA. Hybridization of the probe to cells expressing the 8-oxo-dGTPase gene was visualized following immunodetection with an alkaline phosphatase-conjugated anti-digoxigenin antibody. Following color development, we were able to simultaneously identify tissue architecture and cell types with expression of the 8-oxo-dGTPase gene. There was no hybridization-specific color when sections were 'mock' hybridized, hybridized with a sense probe or treated with RNase. In skin dermis, fibroblasts express high levels of 8-oxo-dGTPAse mRNA. Within the epidermis, a gradient of expression was observed, from high to moderate levels in the replicating basal epithelial cells to undetectable in the non-mitotic suprabasal and granular epithelial cells. In the breast tissue, fibroblasts in the loosely connective tissue and myoepithelial cells expressed high levels of 8-oxo-dGTPase mRNA, while expression in the luminal epithelial cells was not detectable. Our data suggest that expression of 8-oxo-dGTP is heterogenous between cell types within an organ and may help to explain cell type-specific responses to oxidative stress, especially in replicating and potentially replicating cells with low levels of this protective protein.

Adult↗
PubMed1995

Heat stress alters the virulence of a rifampin-resistant mutant of Francisella tularensis LVS.

We have studied the stress response of a rifampin-resistant mutant of Francisella tularensis LVS. This mutant, Rif 7, was avirulent with an intraperitoneally administered 50% lethal dose greater than 10(7) CFU in a murine model of infection. Exposure of Rif 7 to heat stress for 5 h in vitro resulted in a 2-log decrease in its 50% lethal dose (P < 0.02). The increase in virulence was dependent on the time of exposure to high temperature and was maximal at 5 h. Envelope preparations from heat-stressed cells showed increased levels of several proteins. Notable among these were polypeptides with approximate molecular masses of 16, 60, and 75 kDa. Increases in both virulence and envelope protein levels were reversed when heat-treated cells were subsequently grown at 37 degrees C. Inhibition of protein synthesis by actinomycin D during heat stress blocked the increase in virulence of Rif 7. Cell-free media from the heat-stressed Rif 7 reacted with the whole spectrum of bacterial proteins were not toxic to mice. Hyperimmune serum against Rif 7 reacted with the whole spectrum of bacterial proteins in Western blots (immunoblots), although its reaction with 34- and 45-kDa proteins and two 60- and 75-kDa proteins upregulated during heat stress was weak. Other stress conditions, low iron and low pH, caused similar increases in the virulence of Rif 7. However, examination of the protein profile did not reveal any major common polypeptides induced by different stresses. Heat-treated Rif 7 bacteria were fully able to replicate in macrophages in vitro and in the host tissues, even though heat treatment only partially restored virulence.

Animals↗
PubMed2026

Biological Mechanisms Underlying the Cardiovascular Effects of Branched-Chain Amino Acids: A Proteome-Wide Mendelian Randomization Study.

BACKGROUND: Ischemic heart disease (IHD) is the leading cause of morbidity and mortality. Branched-chain amino acids (BCAAs) are associated with higher IHD risk, but the underlying biological pathways remain unclear. OBJECTIVES: This study aims to explore these pathways using 2-step proteome-wide Mendelian randomization. METHODS: We examined the associations between genetic proxies for BCAAs and 2922 proteins in the United Kingdom Biobank Pharma Proteomics Project, supplemented by a meta-analysis with data from deCODE to identify proteins associated with BCAAs. Next, we tested their effects on IHD risk using Coronary Artery Disease Genome-wide Replication and Meta-analysis plus Coronary Artery Disease Genetics Consortium (122,733 cases and 424,528 controls) and replicated in FinnGen (31,640 cases and 187,152 controls). We conducted sensitivity analyses using genetic instruments from deCODE. Proteins associated with IHD risk and, in a consistent direction, with genetically predicted BCAAs were considered potential mediators. RESULTS: Genetic proxies for BCAAs were associated with 40 proteins. Among these, 6 proteins showed consistent evidence of mediation, including complement C1s subcomponent, coagulation factor II, granulin, proprotein convertase subtilisin/kexin type 9, sex hormone-binding globulin, and V-set and transmembrane domain-containing protein 2-like. These proteins are involved in inflammation, coagulation, lipid metabolism, and cellular stress response. All associations were robust across different analytical methods and replicated in independent datasets. Mediation analysis showed that these proteins accounted for 6.5% to 32.1% of the association between BCAAs and IHD risk. CONCLUSIONS: This study identified 6 proteins that potentially link BCAAs to IHD, implicating pathways related to inflammation, coagulation, lipid metabolism, and cellular stress responses. To our knowledge, these findings provide novel mechanistic insights into the BCAA-IHD relationship and highlight potential protein targets for future prevention and intervention strategies.

Amino Acids, Branched-Chain↗
PubMed2003

Lipopolysaccharide stimulates mitochondrial biogenesis via activation of nuclear respiratory factor-1.

Exposure to bacterial lipopolysaccharide (LPS) in vivo damages mitochondrial DNA (mtDNA) and interferes with mitochondrial transcription and oxidative phosphorylation (OXPHOS). Because this damage accompanies oxidative stress and is reversible, we postulated that LPS stimulates mtDNA replication and mitochondrial biogenesis via expression of factors responsive to reactive oxygen species, i.e. nuclear respiratory factor-1 (NRF-1) and mitochondrial transcription factor-A. In testing this hypothesis in rat liver, we found that LPS induces NRF-1 protein expression and activity accompanied by mRNA expression for mitochondrial transcription factor-A, mtDNA polymerase gamma, NRF-2, and single-stranded DNA-binding protein. These events restored the loss in mtDNA copy number and OXPHOS gene expression caused by LPS and increased hepatocyte mitotic index, nuclear cyclin D1 translocation, and phosphorylation of pro-survival kinase, Akt. Thus, NRF-1 was implicated in oxidant-mediated mitochondrial biogenesis to provide OXPHOS for proliferation. This implication was tested in novel mtDNA-deficient cells generated from rat hepatoma cells that overexpress NRF-1. Depletion of mtDNA (rhoo clones) diminished oxidant production and caused loss of NRF-1 expression and growth delay. NRF-1 expression and growth were restored by exogenous oxidant exposure indicating that oxidative stress stimulates biogenesis in part via NRF-1 activation and corresponding to recovery events after LPS-induced liver damage.

Active Transport, Cell Nucleus↗
PubMed1982

Critical job events, acute stress, and strain: a multiple interrupted time series.

A critical job event (CJE) is defined as a time-bounded peak of performance demand made on the individual as an integral part of his job. Though such events are an important source of acute job stress and are amenable to longitudinal study, relevant research has been scant. In the present study, the effects of acute objective stress on subjective stress and on psychological and physiological strain were assessed among 39 first-year nursing students in an interrupted time series with multiple replications. Strain was measured five times, twice in anticipation of CJE interspersed by three low-stress occasions. The CJEs were providing the first comprehensive patient care and the final exam in nursing. A consistently confirmatory pattern of significantly rising and falling strain was found for anxiety, systolic blood pressure, and pulse rate: qualitative overload and serum uric acid changed as predicted four times out of five. CJE research can redress past overemphasis on chronic organizational stress and strengthen causal interpretation.

Analysis of Variance↗
PubMed2007

Granulocyte-monocyte colony-stimulating factor upregulates HIV-1 replication in monocyte-derived macrophages cultured at low density.

The effects that granulocyte-monocyte colony-stimulating factor (GM-CSF) has on HIV-1 replication in monocyte-derived macrophage are controversial. We noted that groups reporting that GM-CSF inhibits HIV-1 replication performed their experiments at relatively high cell densities. To address this issue, we performed experiments at different macrophage densities. In cultures seeded at low cell densities, we find that adding GM-CSF during the first week of culture (ie, before infection, during maturation) increased viral replication compared with that in untreated controls in 10 of 11 donors with quantifiable HIV-1 replication. (No effects were observed if GM-CSF was added after the first week of culture.) In cultures seeded at the higher cell densities representative of those in some previous studies, adding GM-CSF during the first week reduced subsequent viral replication in 8 of 12 donors. In all cases in which GM-CSF reduced viral replication, however, the pH in the wells containing GM-CSF-treated cells dropped dramatically. Macrophages in these acidified cultures had numerous dark granules, suggesting that they were under stress. We conclude, contrary to previous reports, that GM-CSF usually enhances viral replication when cells are grown at low densities in which excessive medium acidification can be prevented. Our results illustrate the dramatic effects that in vitro tissue culture conditions can have when studying the effect of cytokines on HIV-1 replication.

Cell Count↗
PubMed1998

Differential expression of mitochondrial DNA replication factors in mammalian tissues.

Mitochondrial biogenesis and mitochondrial DNA (mtDNA) replication are regulated during development and in response to physiological stresses, but the regulatory events that control the abundance of mtDNA in cells of higher eukaryotes have not been defined at a molecular level. In this study, we observed that expression of the catalytic subunit of DNA polymerase gamma (POLgammaCAT) mRNA varies little among different tissues and is not increased by continuous neural activation of skeletal muscle, a potent stimulus to mitochondrial biogenesis. Increased copy number for the POLgamma locus in a human cell line bearing a partial duplication of chromosome 15 increased the abundance of POLgammaCAT mRNA without up-regulation of mtDNA. In contrast, expression of mitochondrial single-stranded DNA-binding (mtSSB) mRNA is regulated coordinately with variations in the abundance of mtDNA among tissues of mammalian organisms and is up-regulated in association with the enhanced mitochondrial biogenesis that characterizes early postnatal development of the heart and the adaptive response of skeletal myofibers to motor nerve stimulation. In addition, we noted that expression of mtSSB is concentrated within perinuclear mitochondria that constitute active sites of mtDNA replication. We conclude that constitutive expression of the gene encoding the catalytic subunit of mitochondrial DNA polymerase is sufficient to support physiological variations in mtDNA replication among specialized cell types, whereas expression of the mtSSB gene is controlled by molecular mechanisms acting to regulate mtDNA replication or stability in mammalian cells.

Animals↗
PubMed1998

Autonomic, neuroendocrine, and immune responses to psychological stress: the reactivity hypothesis.

We examined the effects of brief psychological stressors on cardiovascular, neuroendocrine, and cellular immune response in 22 older women to investigate the common effects of stress across systems. Results revealed that psychological stressors heightened cardiac sympathetic activation, elevated plasma catecholamine concentrations, and affected the cellular immune response (ps < 0.05). In a replication and extension, 27 women caring for a spouse with a progressive dementia (high chronic stress) and 37 controls category matched for age and family income (low chronic stress) performed the 12-min laboratory stressor. Measures were taken before (low acute stress) and immediately following (high acute stress) exposure to the laboratory stressors as well as 30 min after termination of the stressor (recovery period). Acute stress again heightened cardiac sympathetic activation, elevated plasma catecholamine concentrations, and affected cellular immune responses (ps < 0.05), whereas chronic stress was associated with higher reports of negative affect, enhanced cardiac sympathetic activation, elevated blood pressure and plasma levels of ACTH, and diminished production of interleukin-1 beta (ps < 0.05). Correlational analyses in both studies further suggested that individuals who showed the greatest stress-related changes in HPA activation also exhibited the greatest diminution in cellular immune response.

Autonomic Nervous System↗
PubMed1999

Enhancement of UV-induced cytotoxicity by the adeno-associated virus replication proteins.

Adeno-associated virus (AAV) normally requires co-infection of a helper virus to complete its life cycle. However, under conditions of cellular stress, such as treatment with carcinogens or ultraviolet (UV) light, a permissive intracellular environment is established and AAV completes its replicative cycle producing low levels of progeny virus. AAV DNA replication is dependent upon viral replication proteins, Rep78 and Rep68. The detailed mechanism by which these proteins interact with host cell factors is unknown. We have used a cell line (Neo6) that inducibly expresses the AAV Rep proteins to study their effects on cells that have undergone UV-induced DNA damage. Induction of Rep protein expression immediately after a sub-lethal dose of UV irradiation resulted in rapid cell killing. Those cells that die had chromatin condensation while cellular membranes remained intact, suggesting that concurrent Rep expression and UV damage induces an apoptosis-like response. However, we did not observe any DNA degradation. Thus we believe that the combination of Rep expression and UV irradiation induces cell death that shares some of the characteristics of apoptosis. UV irradiation and Rep expression induced an increase in the level of the CDK inhibitor, p21Cip, and the appearance of modified forms of both p21Cip and Bcl-2. Alteration of normal expression of these cytostatic/apoptotic proteins provides insight into the intracellular targets of the AAV replication proteins.

Apoptosis↗
PubMedDate not supplied

Intrusive traumatic recollections and comorbid posttraumatic stress disorder in depressed patients.

OBJECTIVE: Recent studies have found evidence of the presence and role of intrusive traumatic memories in depressed patients. In this study, we attempted to replicate these findings, examining the full range of early and later traumatic events, as well as comorbid posttraumatic stress disorder, in male and female depressed patients. METHODS: Sixty-nine outpatients meeting criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, for major depressive episode were recruited from the outpatient department of an academic hospital. RESULTS: Seventy-five percent of the depressed patients were found to have had one or more early and/or more recent traumatic experiences. The symptom category of reexperiencing was diagnosed in 48% of these trauma-exposed respondents. Comorbid posttraumatic stress disorder was diagnosed in 13% of the total sample. CONCLUSIONS: The findings show that depressed patients are highly likely to have experienced traumatic events and intrusive traumatic recollections. Future research should focus on the direction of any causal relationship between trauma, reexperiencing, posttraumatic stress disorder, and depression.

Adult↗
PubMed2004

Higher respiratory activity decreases mitochondrial reactive oxygen release and increases life span in Saccharomyces cerevisiae.

Increased replicative longevity in Saccharomyces cerevisiae because of calorie restriction has been linked to enhanced mitochondrial respiratory activity. Here we have further investigated how mitochondrial respiration affects yeast life span. We found that calorie restriction by growth in low glucose increased respiration but decreased mitochondrial reactive oxygen species production relative to oxygen consumption. Calorie restriction also enhanced chronological life span. The beneficial effects of calorie restriction on mitochondrial respiration, reactive oxygen species release, and replicative and chronological life span could be mimicked by uncoupling agents such as dinitrophenol. Conversely, chronological life span decreased in cells treated with antimycin (which strongly increases mitochondrial reactive oxygen species generation) or in yeast mutants null for mitochondrial superoxide dismutase (which removes superoxide radicals) and for RTG2 (which participates in retrograde feedback signaling between mitochondria and the nucleus). These results suggest that yeast aging is linked to changes in mitochondrial metabolism and oxidative stress and that mild mitochondrial uncoupling can increase both chronological and replicative life span.

Mitochondria↗