Protaminhyperlipämie und Stress

Ohne Zusammenfassung     

Oxidative Stress and DNA Damage Signaling

S41Intracellularsignalingresponsetooxida tiveandnitrosativestress?YoungJoonSURH(NationalResearchLaboratoryofMolecularCarcino genesisandChemoprevention,CollegeofPharmacy,SeoulNationalUniversity,Seoul151742,Korea;E mail:surh@plaza.snu.ac.kr)Reactiveoxygenspecies(ROS)andreactiveni trogenspecies(RNS)cancausecellulardamageim plicatedinpathogenesisofawiderangeofhumandis orders,includingcancer,autoimmunedisease,diabe tes,cardiovasculardiseaseandneurodegenerativedis ease.Whileexcessiveoxidat…     

Stress and the α7 nicotinic acetylcholine receptor

Nicotine is well known for its deleterious effects on human health, and it has long been known that nicotine interacts with the stress axis in both man and in laboratory animals. Nicotine also has beneficial effects upon cognition, and an emerging literature has demonstrated that it may play a protective or palliative role in diseases such as Alzheimer's disease and schizophrenia. Recent advances have permitted scientists to identify the specific subtypes of nicotinic receptors responsible for the drugs varied physiological effects. The α7 subunit of the nicotinic acetylcholine receptor (NAchRα7), has been identified as a significant mediator of nicotine's interactions with the stress axis and human disease. The NAchRα7 has also been shown to have neuroprotective effects via multiple pathways, making it a logical target for the treatment of a number of brain disorders.     

Social Stress and Psychosis Risk: Common Neurochemical Substrates?

Environmental risk factors have been implicated in the etiology of psychotic disorders, with growing evidence showing the adverse effects of migration, social marginalization, urbanicity, childhood trauma, social defeat, and other adverse experiences on mental health in vulnerable populations. Collectively, social stress may be one mechanism that could link these environmental risk factors. The exact mechanism(s) by which social stress can affect brain function, and in particular the molecular targets involved in psychosis (such as the dopaminergic (DA) system), is (are) not fully understood. In this review, we will discuss the interplay between social environmental risk factors and molecular changes in the human brain; in particular, we will highlight the impact of social stress on three specific neurochemical systems: DA, neuroinflammation/immune, and endocannabinoid (eCB) signaling. We have chosen the latter two molecular pathways based on emerging evidence linking schizophrenia to altered neuroinflammatory processes and cannabis use. We further identify key developmental periods in which social stress interacts with these pathways, suggesting window(s) of opportunities for novel interventions. Taken together, we suggest that they may have a key role in the pathogenesis and disease progression, possibly provide novel treatment options for schizophrenia, and perhaps even prevent it.Psychosis is characterized by a constellation of symptoms that includes abnormal perceptions and beliefs, usually called positive symptoms. Negative symptoms (eg, anhedonia, social withdrawal, etc) and cognitive deficits (eg, impaired memory, attention, executive functions, etc) are also evident, and represent major predictors of functional outcome. Epidemiological data have consistently demonstrated a well-replicated association between early environmental social risk factors and psychosis. The exact mechanism(s) by which social stress can affect brain function, and in particular the molecular targets involved in psychosis (such as the dopaminergic (DA) system), are not fully understood. In this review, we will discuss the interplay between social environmental risk factors and molecular changes in the human brain; in particular, we will highlight the impact of social stress on three specific neurochemical systems: DA, neuroinflammation/immune, and endocannabinoid (eCB) signaling. We have chosen the latter two molecular pathways based on emerging evidence linking schizophrenia to altered neuroinflammatory processes (Carter et al, 2014) and cannabis use (Andreasson et al, 1987; Arseneault et al, 2002; Harley et al, 2010; Leweke et al, 2007; Morgan et al, 2013). Although a number of other neurochemical systems have been implicated in schizophrenia, such as the glutamate system (Carter et al, 2014; Coyle, 2012; Javitt, 2012), the scope of this review is limited to the molecular systems with existing human data on the effects of psychosocial stress, notwithstanding encouraging findings regarding stress-induced glutamate alterations obtained in animal studies (Gan et al, 2014; Jiang et al, 2013). In this article, stress is broadly defined as either cortisol alterations or social manipulations, which are appraised to exceed the adaptive capacity to cope.     

Smoking Cessation Leads to Reduced Stress,but Why?

Recent longitudinal studies have demonstrated that smoking cessation leads to reduced feelings of stress. This finding is not predicted by either of the two main models for smoking behavior. The nicotine resource model (Warburton) states that nicotine is used to cope with external stressors, and predicts that smokers will suffer from increased stress when they quit smoking. The deprivation reversal model (Schachter), suggests that smoking reverses the deleterious effects of deprivation; cessation will then lead to a period of increased stress, followed by a return to baseline. Although the stress/cessation data agree with neither model, they are consistent with a third explanation, namely that smoking causes stress. This model states that acute nicotine deprivation (i.e., between cigarettes) leads to increased stress. Smokers then use cigarettes to reverse these withdrawal effects and “normalize” their mood. This model explains some paradoxical aspects of the smoking/mood relationship. First, why smokers are calmed by smoking, yet report high average levels of stress. Second, why stress levels become reduced after smoking cessation; this is because the former smoker no longer suffers from the adverse mood effects of acute nicotine depletion.     

Neuronal and Vascular Oxidative Stress in Alzheimer��s Disease

The brain is a highly metabolically active organ producing large amounts of reactive oxygen species (ROS). These ROS are kept in check by an elaborate network of antioxidants. Although ROS are necessary for signaling and synaptic plasticity, their uncontrolled levels cause oxidation of essential macromolecules such as membrane lipids, nucleic acids, enzymes and cytoskeletal proteins. Indeed, overproduction of ROS and/or failure of the antioxidant network lead to neuronal oxidative stress, a condition associated with not only aging but also Alzheimer’s disease (AD). However, the specific source of excessive ROS production has not yet been identified. On one hand, amyloid beta (Aβ) has been extensively shown to act as an oxidant molecule. On the other hand, oxidative stress has been shown to precede and exacerbate Aβ pathology. This review will address the involvement of oxidative stress in the context of neuronal as well as vascular dysfunction associated with AD.     

Stress — the neglected variable in experimental pharmacology and toxicology

In experimental pharmacology and toxicology it is preferable to use nonstressed animals to study the mode of action of drugs and toxins. However, animals and humans are seldom nonstressed but are frequently challenged by stressful events in real life, responding with ‘stress’ manifested as many biochemical and physiological changes. Thus, drugs and toxins acting at specific biochemical sites or on physiological processes will encounter different biological conditions during rest and stress resulting in differences in their actions and effects. In addition, the true action of some drugs might only be revealed during stress. Thus, this variable should be included during experimentation to simulate more closely various real life situations and to predict more accurately the actions and effects of drugs and toxins under all types of environmental conditions. In this review, W. Vogel describes some of the biochemical and physiological changes seen during stress, reviews differences seen in the effects of some drugs and toxins between nonstressed and stressed animals and illustrates how the use of stressed animals can clarify the action of certain drugs.     

Prefrontal–Amygdala Dysregulation to Threat in Pediatric Posttraumatic Stress Disorder

Functional abnormalities in fear circuitry are likely to underlie the pathophysiology of pediatric posttraumatic stress disorder (PTSD), but the few studies to date have yielded conflicting findings. Furthermore, network level functional connectivity and age-related disruptions in fear circuitry have not been thoroughly explored. In a cross-sectional design, 24 healthy and 24 medication-free youth with severe PTSD completed an event-related emotion-processing task during functional MRI. Youth viewed threat and neutral images, half of which were paired with a neutral male face. Group- and age-related differences in brain activation were examined in the medial prefrontal cortex (mPFC), amygdala, and hippocampus. Amygdala functional connectivity was examined using a seed-based approach. PTSD youth showed hyperactivation of the dorsal anterior cingulate cortex (dACC) to threat images. In the dorsomedial PFC (dmPFC), age positively predicted activation in healthy youth but negatively predicted activation in PTSD youth. In the amygdala functional connectivity analysis, PTSD youth showed decreased amygdala–mPFC connectivity to threat images. Furthermore, age positively predicted amygdala–vmPFC connectivity in healthy youth, but negatively predicted connectivity in PTSD youth. Finally, dmPFC activation and amygdala–mPFC connectivity were inversely related to PTSD severity. Pediatric PTSD involves abnormal functional activation and connectivity in fear circuitry. Specifically, dACC hyperactivation is consistent with abnormal promotion of fear responses, whereas reduced amygdala–mPFC connectivity suggests impaired regulation of amygdala responses to threat. Importantly, age-dependent decreases in dmPFC activation and amygdala–vmPFC connectivity may indicate abnormal developmental processes in key emotion pathways in pediatric PTSD.     

Best Practices for Drug Substance Stress and Stability Studies During Early-Stage Development Part I—Conducting Drug Substance Solid Stress to Support Phase Ia Clinical Trials

Regulatory guidances for drug stability testing during early development stages lack specifics. Consequently, companies either conduct more stability studies than necessary just to avoid regulatory questions or perform insufficient stability work resulting in regulatory questions and delays in drug development. Hence, there exist a pressing need and a great opportunity for pharmaceutical companies to share drug stability testing practices, rationales, and regulatory experiences for the early stages of development. This paper describes a quick, streamlined solid stress practice to support drug development from pre-clinical to Phase Ia Clinical Trials. By subjecting a few grams of drug substance to high temperature and high humidity (e.g., 70?°C/75?% RH, in open and closed containers, for three weeks) and to the ICH Q1B confirmatory photostability testing condition, the initial DS retest period and the initial shelf life of powder for oral solution can be reliably extrapolated, and a bulk packaging choice is made. In addition, the solid stress results can be used for multifaceted purposes. The solid stress practice offers a quick turnaround in obtaining adequate stability information for new drug development and achieves an optimum balance between risk and cost for Phase Ia clinical development.     

Stress induced desensitization of lymphocyte β-adrenoceptors in young and aged rats

The effects of different times of immobilization stress on intact lymphocyte β-adrenoceptors and plasma corticosterone were compared in 3-month and 24-month-old rats. In young animals after 30 min restraint ³H-dihydroalprenolol specific binding was significantly reduced (61% of control value) and plasma corticosterone significantly raised (186% of control). The effect on β-adrenoceptors was due to changes in receptor number (Bmax) without any effect on affinity (K_D). In aged rats both effects were only seen after 180 min restraint and were less pronounced. Isoproterenol treatment in vitro reduced β-adrenoceptors on lymphocytes. This effect was less pronounced in lymphocytes from aged rats. Corticosterone in vitro increased ³H-dihydroalprenolol specific binding. We therefore suggest that the decrease of β-adrenoceptors reflects an adaptive response to the stress-induced catecholamine release and that corticosterobe could play a role in reversing this effect. This adaptive response to stress seems to be impaired in aged animals.     

17β-Estradiol Differentially Regulates Stress Circuitry Activity in Healthy and Depressed Women

Many regions within stress neurocircuitry, including the anterior hypothalamus, amygdala, hippocampus, and medial prefrontal cortex, are densely populated with sex steroid receptors. Substantial evidence from animal studies indicates that the gonadal hormone 17β-estradiol (E₂) impacts the structure and function of these regions, but human studies are limited. Characterizing estradiol''s role in stress circuitry in vivo in humans may have important clinical implications given the comorbidity between major depressive disorder (MDD), stress circuitry dysfunction and endocrine dysregulation. In this study, we determined estradiol''s role in modulating activity within cortical and subcortical stress circuitry regions in healthy and MDD women. Subjects were part of a population-based birth cohort, the New England Family Study. Capitalizing on the endogenous fluctuation in E₂ during the menstrual cycle, we conducted a within-person repeated-measures functional neuroimaging study in which 15 women with recurrent MDD, in remission, and 15 healthy control women underwent hormonal evaluations, behavioral testing, and fMRI scanning on two occasions, under low and high E₂ conditions. Subjects completed an fMRI scan while undergoing a mild visual stress challenge that reliably activated stress neural circuitry. Results demonstrate that E₂ modulates activity across key stress circuitry regions, including bilateral amygdala, hippocampus, and hypothalamus. In healthy women, robust task-evoked BOLD signal changes observed under low E₂ conditions were attenuated under high E₂ conditions. This hormonal capacity to regulate activity in stress circuitry was not observed in MDD women, despite their remitted status, suggesting that dysregulation of gonadal hormone function may be a characteristic trait of the disease. These findings serve to deepen our understanding of estradiol''s actions in the healthy brain and the neurobiological mechanisms that may underlie the pronounced sex difference in MDD risk.     

The Psychopharmacology of ±3,4 Methylenedioxymethamphetamine and its Role in the Treatment of Posttraumatic Stress Disorder

Abstract

Prior to 1985, ± 3,4-methylenedioxymethamphetamine (MDMA) was readily used as a psychotherapeutic adjunct. As MDMA became popular in treating various psychiatric illnesses by mental health professionals, the public started to abuse the MDMA-containing recreational drug “ecstasy.” This alarmed the DEA, which led to emergency scheduling of MDMA as a Schedule I drug. Due to its scheduling in 1985, human research and clinical use has been limited. The majority of research on MDMA has been focused on the drug’s potential harmful effects rather than its possible therapeutic effects. The limitations on retrospective human studies and preclinical animal models of MDMA neurotoxicity are examined in this analysis. New research has shown that MDMA, used as a catalyst in psychotherapy, is effective in treating posttraumatic stress disorder (PTSD). This review also examines the psychopharmacological basis for the efficacy of MDMA-assisted psychotherapy. Specifically, the brain regions involved with both PTSD and those activated by MDMA (i.e., amygdala, anterior cingulate cortex, and hippocampus) are examined. Also, the possible neurochemical mechanisms involved in MDMA’s efficacy in treating PTSD are reviewed.     

通过冷觉负荷检查（Cold Stress Test，CST）诊断手部位冷症

目的冷症由于是主观症状评价其严重程度比较困乱。利用Digital Infrared Thermal Imaging (DITI)可以了解体表的冷症状态。但是客观的掌握其程度也不容易，为了客观性的评价冷症，我们对冷症通过Visual Analogue Scale(VAS和Cold Stress Test(CST)研究了有关手的温度变化之间的相关性。方法从2002年5月至8月为止。我们选择了以冷症为主诉的来庆熙大学江南韩医院女性科外来就诊的23名患者为研究对象，其中将合并有肥胖症，皮肤病，脊髓神经病变，外伤等患者排除在外。红外织体热摄影是利数码红外线皮肤湿度测定仪进行三次摄影检查。首先摄部位不触及任何物体状态下，在室温保持在25℃环境中等待15分钟以后进行第一次照影部位为两手的手背与手心。第二次照影是在第一次照影后的即刻可上冷负荷以后进行的，第三次照影是在第二次照影10分钟以后进行的。其部位同第一次。检查结果来以后测定了每张摄影照片上的各手指、手心、手背部位的温度，并计算其平均值，还计算出加上冷负荷以后各部位的恢复率与恢复率与手指、手心、手背等部位的温度差值。结果男性1名，女性22名参加本试验，年龄在18—66名。CST后手指温恢复率与冷症伽VAS score具有负性相关关系。手指与手心及手背的温度差值与冷症VAS score之间具有统计学意义伽正性相关关系。结论对冷症患者利用DITI与CST，对症并行客观性评价并决定症状的严重程度是有效的。在临床上作为评价冷症的方法尚需要进一步深入研究。     

Stress–restress evokes sustained iNOS activity and altered GABA levels and NMDA receptors in rat hippocampus

Rationale Stress-related glucocorticoid and glutamate release have been implicated in hippocampal atrophy evident in patients with post-traumatic stress disorder (PTSD). Glutamatergic mechanisms activate nitric oxide synthase (NOS), while gamma-amino-butyric acid (GABA) may inhibit both glutamatergic and nitrergic transmission. Animal studies support a role for NOS in stress.Objectives We have studied the role of NOS and glucocorticoids, as well as inhibitory and excitatory transmitters, in a putative animal model of PTSD that emphasizes repeated trauma.Methods Hippocampal NOS activity, N-methyl-d-aspartate (NMDA) receptor binding characteristics and GABA levels were studied in Sprague-Dawley rats 21 days after exposure to a stress–restress paradigm, using radiometric analysis, radioligand studies and high-performance liquid chromatography (HPLC) analysis with electrochemical detection, respectively. The NOS isoform involved, and the role of stress-mediated corticosterone release in NOS activation, was verified with the administration of selective iNOS and nNOS inhibitors, aminoguanidine (50 mg/kg/day i.p.) and 7-nitroindazole (12.5 mg/kg/day i.p.), and the steroid synthesis inhibitor, ketoconazole (24 mg/kg/day i.p.), administered for 21 days prior to and during the stress procedure.Results Stress evoked a sustained increase in NOS activity, but reduced NMDA receptor density and total GABA levels. Aminoguanidine or ketoconazole, but not 7-nitroindazole or saline, blocked stress-induced NOS activation.Conclusions Stress–restress-mediated glucocorticoid release activates iNOS, followed by a reactive downregulation of hippocampal NMDA receptors and dysregulation of inhibitory GABA pathways. The role of NO in neuronal toxicity, and its regulation by glutamate and GABA has important implications in stress-related hippocampal degeneration.     

Multiple Biomarker Comparison in <Emphasis Type="Italic">Mytilus galloprovincialis</Emphasis> from the Greece Coast: “Lysosomal Membrane Stability,Neutral Red Retention,Micronucleus Frequency and Stress on Stress”

The lysosomal membrane stability test applied on the digestive cells (LMS) and the neutral red lysosomal retention assay (NRR) performed on hemocytes have been evaluated on mussels Mytilus galloprovincialis collected from Thermaikos and Strymonikos gulfs (Nothern Greece) in June and December 2000. The correlation analysis indicated that there was a strong positive relationship between the above mentioned biomarkers in both sampling seasons, supporting the validity of their application in water quality assessment. The evaluation of micronucleus frequency (MN) has been also performed in hemocytes of the same mussels and, according to the results, it requires additional validation before using it as a stress index. The results obtained in parallel by the stress on stress (SOS) technique do not support the application of this biomarker in biomonitoring, showing, however, negative correlation with LMS and NRR in one sampling season. Finally, morphological observations were performed on cryosections stained for the enzyme N-acetyl-β-hexosaminidase, revealing differences in the epithelial cell-layer thickness, as well as changes in the digestive lysosomal system of mussels, obtained from different sampling sites in the two sampling seasons.     

Protective Effect of Fisetin (3,7,3',4'-Tetrahydroxyflavone) against γ-Irradiation-Induced Oxidative Stress and Cell Damage

Ionizing radiation can induce cellular oxidative stress through the generation of reactive oxygen species, resulting in cell damage and cell death. The aim of this study was to determine whether the antioxidant effects of the flavonoid fisetin (3,7,3'',4''-tetrahydroxyflavone) included the radioprotection of cells exposed to γ-irradiation. Fisetin reduced the levels of intracellular reactive oxygen species generated by γ-irradiation and thereby protected cells against γ-irradiation-induced membrane lipid peroxidation, DNA damage, and protein carbonylation. In addition, fisetin maintained the viability of irradiated cells by partially inhibiting γ-irradiation-induced apoptosis and restoring mitochondrial membrane potential. These effects suggest that the cellular protective effects of fisetin against γ-irradiation are mainly due to its inhibition of reactive oxygen species generation.     

Failure Mode Identification of Insulin Drug Products – Impact of Relevant Stress Conditions on the Quality of the Drug

Fast-acting insulin drug products (DPs) are carried and administered by diabetic patients to maintain their blood glucose level throughout the day, exposing the DPs to stress conditions. Apidra, Novolog, and Humalog insulin DPs were tested under various stress conditions. Dynamic light scattering (DLS), and size exclusion chromatography (SEC) were used to monitor the stability and aggregation. Thermal stress alone did not influence the stability. However, 24 hr exposure to vigorous mechanical stress shifted the DLS size peaks of Novolog and Humalog from 5 ± 1 nm to > 50.9 ± 25.6 nm, and the SEC native protein peak areas decreased 52% for Novolog and 18.4% for Humalog. Combined stress accelerated protein aggregation more drastically. Novolog and Humalog size shifted (>75 nm) after 3 hr and the peak area decreased > 97.9% after 6 hr exposure, indicating that high temperature accelerated the aggregation triggered by agitation. Soluble aggregates were captured by DLS early on compared to SEC. Apidra was comparably stable indicating DP formulation plays a critical role in stability. Our study provides a greater understanding of potential failure modes patients and care givers may encounter while handling insulin DPs.