Effects and mediators of psychosocial work characteristics on somatic symptoms six years later: Prospective findings from the Mannheim Industrial Cohort Studies (MICS).

PubMed

Herr, Raphael M; Li, Jian; Loerbroks, Adrian; Angerer, Peter; Siegrist, Johannes; Fischer, Joachim E

2017-07-01

Ample evidence documented the adverse health effects of work stressors, and recent research has increasingly focused on somatic symptoms which are very common and costly. Prospective evidence is however sparse and yielded mixed findings. Furthermore, there is reason to assume that depression and anxiety might mediate the effects of adverse psychosocial work conditions on somatic symptoms. This study aimed to investigate longitudinal effects of work stressors on somatic symptoms and the potential mediation by anxiety and/or depression. Six year follow-up data from 352 individuals - free of potentially stress-related chronic disease - were utilized. Somatic symptoms were assessed by 19 items of an established list of complaints at baseline and follow-up. The effort-reward-imbalance (ERI) model measured adverse psychosocial work conditions and over-commitment (OC). Linear regressions adjusted for socio-demographics, social status, lifestyle, and baseline symptoms estimated the effects of the ERI ratio, effort, reward, OC, and the ERI ratio×OC interaction on somatic symptoms six years later. Furthermore, single and multiple mediation by anxiety and/or depression was investigated. There was a strong longitudinal effect of the ERI ratio, as well as of its subcomponents, and OC on somatic symptoms (all Bs≥|0.49|; p-values ≤0.004). Moreover, the ERI ratio×OC interaction was significant (p-value=0.047). Multiple mediation analyses revealed especially anxiety to mediate the effect of work stressors on somatic symptoms (Sobel test=0.007). Adverse psychosocial work conditions seem to longitudinally affect somatic symptoms, potentially moderated by OC, and mediated by anxiety. Copyright © 2017 Elsevier Inc. All rights reserved.

Assessing Omitted Confounder Bias in Multilevel Mediation Models.

PubMed

Tofighi, Davood; Kelley, Ken

2016-01-01

To draw valid inference about an indirect effect in a mediation model, there must be no omitted confounders. No omitted confounders means that there are no common causes of hypothesized causal relationships. When the no-omitted-confounder assumption is violated, inference about indirect effects can be severely biased and the results potentially misleading. Despite the increasing attention to address confounder bias in single-level mediation, this topic has received little attention in the growing area of multilevel mediation analysis. A formidable challenge is that the no-omitted-confounder assumption is untestable. To address this challenge, we first analytically examined the biasing effects of potential violations of this critical assumption in a two-level mediation model with random intercepts and slopes, in which all the variables are measured at Level 1. Our analytic results show that omitting a Level 1 confounder can yield misleading results about key quantities of interest, such as Level 1 and Level 2 indirect effects. Second, we proposed a sensitivity analysis technique to assess the extent to which potential violation of the no-omitted-confounder assumption might invalidate or alter the conclusions about the indirect effects observed. We illustrated the methods using an empirical study and provided computer code so that researchers can implement the methods discussed.

Active video games: the mediating effect of aerobic fitness on body composition

PubMed Central

2012-01-01

Background Increased understanding of why and how physical activity impacts on health outcomes is needed to increase the effectiveness of physical activity interventions. A recent randomized controlled trial of an active video game (PlayStation EyeToy™) intervention showed a statistically significant treatment effect on the primary outcome, change from baseline in body mass index (BMI), which favored the intervention group at 24 weeks. In this short paper we evaluate the mediating effects of the secondary outcomes. Objective To identify mediators of the effect of an active video games intervention on body composition. Methods Data from a two-arm parallel randomized controlled trial of an active video game intervention (n = 322) were analyzed. The primary outcome was change from baseline in BMI. A priori secondary outcomes were considered as potential mediators of the intervention on BMI, including aerobic fitness (VO2Max), time spent in moderate-to-vigorous physical activity (MVPA), and food snacking at 24 weeks. Results Only aerobic fitness at 24 weeks met the conditions for mediation, and was a significant mediator of BMI. Conclusion Playing active video games can have a positive effect on body composition in overweight or obese children and this effect is most likely mediated through improved aerobic fitness. Future trials should examine other potential mediators related to this type of intervention. Trial registration Australian New Zealand Clinical Trials Registry Website: http://www.anzctr.org.au Study ID number: ACTRN12607000632493 PMID:22554052

Effects of exogenous nicotinamide adenine dinucleotide (NAD+) in the rat heart are mediated by P2 purine receptors.

PubMed

Kuzmin, Vladislav S; Pustovit, Ksenia B; Abramochkin, Denis V

2016-06-27

Recently, NAD+ has been considered as an essential factor, participating in nerve control of physiological functions and intercellular communication. NAD+ also has been supposed as endogenous activator of P1 and P2 purinoreceptors. Effects of extracellular NAD+ remain poorly investigated in cardiac tissue. This study aims to investigate the effects of extracellular NAD+ in different types of supraventricular and ventricular working myocardium from rat and their potential mechanisms. The standard technique of sharp microelectrode action potential recording in cardiac multicellular preparations was used to study the effects of NAD+. Extracellular NAD+ induced significant changes in bioelectrical activity of left auricle (LA), right auricle (RA), pulmonary veins (PV) and right ventricular wall (RV) myocardial preparations. 10-100 μM NAD+ produced two opposite effects in LA and RA - quickly developing and transient prolongation of action potentials (AP) and delayed sustained AP shortening, which follows the initial positive effect. In PV and RV only AP shortening was observed in response to NAD+ application. In PV preparations AP shortening induced by NAD+ may be considered as a potential proarrhythmic effect. Revealed cardiotropic effects of NAD+ are likely to be mediated by P2 purine receptors, since P1 blocker DPCPX failed to affect them and P2 antagonist suramin abolished NAD + -induced alterations of electrical activity. P2X receptors may be responsible for NAD + -induced short-lasting AP prolongation, while P2Y receptors mediate persistent AP shortening. The latter effect is partially removed by PLC inhibitor U73122 showing the potential involvement of phosphoinositide signaling pathway in mediation of NAD+ cardiotropic effects. Extracellular NAD+ is supposed to be a novel regulator of cardiac electrical activity. P2 receptors represent the main target of NAD+ at least in the rat heart.

Associations of Organizational Justice with Tinnitus and the Mediating Role of Depressive Symptoms and Burnout-Findings from a Cross-Sectional Study.

PubMed

Herr, Raphael M; Loerbroks, Adrian; Bosch, Jos A; Seegel, Max; Schneider, Michael; Schmidt, Burkhard

2016-04-01

Tinnitus refers to the perception of a sound while an external source is absent. Research has identified work-related stress and its potential mental health-related sequelaes, i.e., depression and burnout, as risk factors for tinnitus. Perceived unfairness at work (organizational injustice), which is considered a psychosocial occupational stressor, has been shown to predict depression and burnout but its potential associations with tinnitus remains unaddressed. The aim was to determine the relationship of organizational injustice with tinnitus, and to examine depression and burnout as potential mediators. Cross-sectional data from a sample of 1632 employees were used. Tinnitus was assessed by self-report (n = 207; 13.9 %). Organizational justice and its subcomponents (interactional and procedural justice), burnout, and depressive symptoms were measured by validated questionnaires. Associations were assessed by logistic regressions, and mediation was assessed by maximum likelihood logistic regression estimations. Overall organizational justice, interactional and procedural justice were inversely related to tinnitus (z-score for overall justice: OR = 0.754; 95 % CI = 0.649 to 0.876). These associations were independent of demographics, socioeconomic status, job characteristics (including potential noise exposure), and health behaviors. Mediation analyses suggested a potential mediation by burnout (95 % CI indirect effect -0.188 to -0.066) and depressive symptoms (95 % CI indirect effect -0.160 to -0.043). Parallel multiple mediation analysis revealed that mediation through burnout was significantly larger than through depressive symptoms. Organizational justice appeared inversely related to tinnitus and this association was explained by individual differences in burnout symptoms, suggesting mediation. Longitudinal studies may further help to strengthen the evidence base for prevention of tinnitus through promotion of organizational justice and prevention of burnout.

Under What Assumptions Do Site-by-Treatment Instruments Identify Average Causal Effects?

ERIC Educational Resources Information Center

Reardon, Sean F.; Raudenbush, Stephen W.

2013-01-01

The increasing availability of data from multi-site randomized trials provides a potential opportunity to use instrumental variables methods to study the effects of multiple hypothesized mediators of the effect of a treatment. We derive nine assumptions needed to identify the effects of multiple mediators when using site-by-treatment interactions…

Parental modeling, education and children's sports and TV time: the ENERGY-project.

PubMed

Fernández-Alvira, Juan M; Te Velde, Saskia J; Singh, Amika; Jiménez-Pavón, David; De Bourdeaudhuij, Ilse; Bere, Elling; Manios, Yannis; Kovacs, Eva; Jan, Nataša; Moreno, Luis A; Brug, Johannes

2015-01-01

We assessed whether differences in children's sports participation and television time according to parental education were mediated by parental modeling. Moreover, we explored the differences between parental and child reports on parental sports participation and television time as potential mediators. 5729 children and 5183 parents participating in the EuropeaN Energy balance Research to prevent excessive weight Gain among Youth (ENERGY-project) during 2010 in seven European countries provided information on sports participation and television time using validated self-report questionnaires. Multilevel country-specific mediation models analyzed the potential mediation effect of parental self-reports and child-reports on parental sports participation and television time. Significant mediation effect was found for parental self-reported television time in four countries (Greece, Hungary, The Netherlands and Slovenia), with the highest proportion for Slovenia (40%) and the lowest for Greece (21%). Child-reported parental television time showed mediation effect in Greece only. Parental self-reported sports participation showed significant mediation effect only in Greece. With child-reported parental sports participation, significant mediation was observed in Greece and Norway. Parental behaviors appear to be important in explaining parental educational differences in children's sports participation and television time. However, child reports on parental behavior appear to be more relevant than parents' self-reports as correlates of children's own sports participation and television time. Copyright © 2014 Elsevier Inc. All rights reserved.

Mediators of the effect of the JUMP-in intervention on physical activity and sedentary behavior in Dutch primary schoolchildren from disadvantaged neighborhoods

PubMed Central

2012-01-01

Background Important health benefits can be achieved when physical activity in children from low socio-economic status is promoted and sedentariness is limited. By specifying the mediating mechanisms of existing interventions one can improve future physical activity interventions. This study explored potential mediators of the long-term effect of the school-based multicomponent JUMP-in intervention on sport participation, outdoor play and screen time in Dutch primary schoolchildren from disadvantaged neighborhoods. Methods In total, 600 primary schoolchildren (aged 9.8 ± 0.7, 51% girls, 13% Dutch ethnicity, 35% overweight) from 9 intervention and 10 control schools were included in the analyses. JUMP-in was developed using Intervention Mapping, and targeted psychological and environmental determinants of physical activity. Outcome behaviors were self-reported sport participation, outdoor play, TV-viewing behavior and computer use. Potential mediators were self-reported psychological, social and physical environmental factors. Results JUMP-in was effective in improving sport participation after 20 months, but not in improving outdoor play, or reducing TV-viewing or computer time. JUMP-in was not effective in changing hypothesized mediators so no significant mediated effects could be identified. However, changes in self-efficacy, social support and habit strength were positively associated with changes in sport participation, and changes in social support, self-efficacy, perceived planning skills, enjoyment and habit strength were positively associated with changes in outdoor play. Changes in enjoyment was positively associated with changes in TV-viewing while parental rules were negatively associated. Having a computer in the bedroom and enjoyment were positively associated with changes in computer use, while changes in parental rules were negatively associated. Conclusions Besides a significant positive effect on sports participation, no significant intervention effect on outdoor play, screen time or any of the potential mediators was found. This suggest that other (unmeasured) factors operated as mediating mechanisms of the intervention, that we used unsuccessful intervention strategies, that the strategies were inappropriately implemented, or that children are unable to accurately recall past activities and cognitions. Additionally, the school setting might not be the sole channel to influence leisure time activities. Still, several personal and environmental constructs were found to be relevant in predicting change in sport participation, outdoor play and screen behavior and seem to be potential mediators. Future interventions are recommended including more effective strategies targeting these relevant constructs, addressing different constructs (e.g. pedagogic skills of parents), and focusing on different implementation settings. Trail registration ISRCTN17489378 PMID:23130806

Why is social network drinking associated with college students' alcohol use? Focus on psychological mediators.

PubMed

Reid, Allecia E; Carey, Kate B

2018-06-01

Level of drinking in the social network is strongly associated with college students' alcohol use. However, mechanisms through which networks are associated with personal drinking have been underexplored thus far. The present study examined theoretically derived constructs-sociability outcome expectancies, attitudes toward heavy drinking, self-efficacy for use of protective strategies, and descriptive norms-as potential mediators of the association between egocentric social network drinking and personal consumption. College students (N = 274) self-reported their social network's level of alcohol consumption, all mediators, drinks per week, and consequences at both baseline (Time 1) and a 1-month follow-up (Time 2). Autoregressive mediation models focused on the longitudinal associations between Time 1 network drinking and the Time 2 mediators and between the Time 1 mediators and the Time 2 outcomes. Consistent with hypotheses, Time 1 social network drinking was significantly associated with Time 2 drinks per week and consequences. Only attitudes significantly mediated social network associations with drinks per week and consequences, though the proportion of the total effects accounted for by attitudes was small. After accounting for the stability of constructs over time, social network drinking was generally un- or weakly related to sociability expectancies, self-efficacy, and descriptive norms. Results support reducing attitudes toward heavy drinking as a potential avenue for mitigating network effects, but also highlight the need to evaluate additional potential mechanisms of network effects. Intervention efforts that aim to address the social network have the potential to substantially reduce alcohol consumption, thereby enhancing the overall efficacy of alcohol risk-reduction interventions. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Interventions to Reduce College Student Drinking: State of the Evidence for Mechanisms of Behavior Change

PubMed Central

Reid, Allecia E.; Carey, Kate B.

2015-01-01

Interventions to reduce college student drinking, although efficacious, generally yield only small effects on behavior change. Examining mechanisms of change may help to improve the magnitude of intervention effects by identifying effective and ineffective active ingredients. Informed by guidelines for establishing mechanisms of change, we conducted a systematic review of alcohol interventions for college students to identify (a) which constructs have been examined and received support as mediators, (b) circumstances that enhance the likelihood of detecting mediation, and (c) the extent of evidence for mechanisms of change. We identified 61 trials that examined 22 potential mediators of intervention efficacy. Descriptive norms consistently mediated normative feedback interventions. Motivation to change consistently failed to mediate motivational interviewing interventions. Multiple active ingredient interventions were not substantially more likely to find evidence of mediation than single ingredient interventions. Delivering intervention content remotely reduced likelihood of finding support for mediation. With the exception of descriptive norms, there is inadequate evidence for the psychosocial constructs purported as mechanisms of change in the college drinking literature. Evidence for mechanisms will be yielded by future studies that map all active ingredients to targeted psychosocial outcomes and that assess potential mediators early, inclusively, and at appropriate intervals following interventions. PMID:26164065

Causal Mediation Analysis for the Cox Proportional Hazards Model with a Smooth Baseline Hazard Estimator.

PubMed

Wang, Wei; Albert, Jeffrey M

2017-08-01

An important problem within the social, behavioral, and health sciences is how to partition an exposure effect (e.g. treatment or risk factor) among specific pathway effects and to quantify the importance of each pathway. Mediation analysis based on the potential outcomes framework is an important tool to address this problem and we consider the estimation of mediation effects for the proportional hazards model in this paper. We give precise definitions of the total effect, natural indirect effect, and natural direct effect in terms of the survival probability, hazard function, and restricted mean survival time within the standard two-stage mediation framework. To estimate the mediation effects on different scales, we propose a mediation formula approach in which simple parametric models (fractional polynomials or restricted cubic splines) are utilized to approximate the baseline log cumulative hazard function. Simulation study results demonstrate low bias of the mediation effect estimators and close-to-nominal coverage probability of the confidence intervals for a wide range of complex hazard shapes. We apply this method to the Jackson Heart Study data and conduct sensitivity analysis to assess the impact on the mediation effects inference when the no unmeasured mediator-outcome confounding assumption is violated.

Housing mobility and adolescent mental health: The role of substance use, social networks, and family mental health in the Moving to Opportunity Study.

PubMed

Schmidt, Nicole M; Glymour, M Maria; Osypuk, Theresa L

2017-12-01

The Moving to Opportunity (MTO) experiment was a housing mobility program begun in the mid-nineties that relocated volunteer low income families from public housing to rental units in higher opportunity neighborhoods in 5 US cities, using the Section 8 affordable housing voucher program. Compared to the control group who stayed behind in public housing, the MTO voucher group exhibited a harmful main effect for boys' mental health, and a beneficial main effect for girls' mental health. But no studies have examined how this social experiment caused these puzzling, opposite gender effects. The present study tests potential mediating mechanisms of the MTO voucher experiment on adolescent mental health (n=2829, aged 12-19 in 2001-2002). Using Inverse Odds Ratio Weighting causal mediation, we tested whether adolescent substance use comorbidity, social networks, or family mental health acted as potential mediators. Our results document that comorbid substance use (e.g. past 30 day alcohol use, cigarette use, and number of substances used) significantly partially mediated the effect of MTO on boys' behavior problems, resulting in -13% to -18% percent change in the total effect. The social connectedness domain was a marginally significant mediator for boys' psychological distress. Yet no tested variables mediated MTO's beneficial effects on girls' psychological distress. Confounding sensitivity analyses suggest that the indirect effect of substance use for mediating boys' behavior problems was robust, but social connectedness for mediating boys' psychological distress was not robust. Understanding how housing mobility policies achieve their effects may inform etiology of neighborhoods as upstream causes of health, and inform enhancement of future affordable housing programs.

Targeting the link between loneliness and paranoia via an interventionist-causal model framework.

PubMed

Gollwitzer, Anton; Wilczynska, Magdalena; Jaya, Edo S

2018-05-01

Targeting the antecedents of paranoia may be one potential method to reduce or prevent paranoia. For instance, targeting a potential antecedent of paranoia - loneliness - may reduce paranoia. Our first research question was whether loneliness heightens subclinical paranoia and whether negative affect may mediate this effect. Second, we wondered whether this potential effect could be targeted via two interventionist pathways in line with an interventionist-causal model approach: (1) decreasing loneliness, and (2) intervening on the potential mediator - negative affect. In Study 1 (N = 222), recollecting an experience of companionship reduced paranoia in participants high in pre-manipulation paranoia but not in participants low in pre-manipulation paranoia. Participants recollecting an experience of loneliness, on the other hand, exhibited increased paranoia, and this effect was mediated by negative affect. In Study 2 (N = 196), participants who utilized an emotion-regulation strategy, cognitive reappraisal, to regulate the negative affect associated with loneliness successfully attenuated the effect of loneliness on paranoia. Targeting the effect of loneliness on paranoia by identifying interventionist pathways may be one promising route for reducing and preventing subclinical paranoia. Copyright © 2018 Elsevier B.V. All rights reserved.

Pathways from fear of falling to quality of life: the mediating effect of the self-concept of health and physical independence.

PubMed

Hsu, Yawen; Alfermann, Dorothee; Lu, Frank J H; Lin, Linda L

2013-01-01

Fear of falling leads to many adverse consequences and may compromise the quality of life of older adults. Psychological factors are potential mediators between the fear of falling and quality of life, but have yet to be explored in detail. This study presents results from examining the mediating effect of the self-concept of health and physical independence. Data from Western and Eastern countries were compared. Concerns about falling, the level of participation in physical activities, the self-concept of health and physical independence, and health-related quality of life were measured using samples from Taiwan (n = 193) and Germany (n = 182). Multiple regression models were used to test the mediating effects. The relationship between fear of falling and quality of life was partially mediated through participation in physical activities and the self-concept of health and physical independence in both the Taiwanese and German samples. In particular, the self-concept of health and physical independence of the Taiwanese sample resulted in the strongest mediating effect. Potential mediating mechanisms through both participation in physical activities and the self-concept of health and physical independence provide useful information for understanding related theories and for explicating interventions. Cultural factors should also be accounted for when conducting research and programs related to the fear of falling.

Locus of Control and Self-Efficacy: Potential Mediators of Stress, Illness, and Utilization of Health Services in College Students

ERIC Educational Resources Information Center

Roddenberry, Angela; Renk, Kimberly

2010-01-01

Although many studies examine the biological phenomena that mediate the relationship between stress and illness, more research is needed regarding psychological variables that may mediate this relationship. Thus, the current study investigates the mediating effects of locus of control and self-efficacy in the relationships among stress, illness,…

Participation in Athletics and Female Sexual Risk Behavior: The Evaluation of Four Causal Structures.

ERIC Educational Resources Information Center

Dodge, Tonya; Jaccard, James

2002-01-01

Compared sexual risk behavior of female athletes and nonathletes. Examined mediation, reverse mediation, spurious effects, and moderated causal models, using as potential mediators physical development, educational aspirations, self-esteem, attitudes toward pregnancy, involvement in a romantic relationship, age, ethnicity, and social class. Found…

Empirical solvent-mediated potentials hold for both intra-molecular and inter-molecular inter-residue interactions.

PubMed Central

Keskin, O.; Bahar, I.; Badretdinov, A. Y.; Ptitsyn, O. B.; Jernigan, R. L.

1998-01-01

Whether knowledge-based intra-molecular inter-residue potentials are valid to represent inter-molecular interactions taking place at protein-protein interfaces has been questioned in several studies. Differences in the chain connectivity effect and in residue packing geometry between interfaces and single chain monomers have been pointed out as possible sources of distinct energetics for the two cases. In the present study, the interfacial regions of protein-protein complexes are examined to extract inter-molecular inter-residue potentials, using the same statistical methods as those previously adopted for intra-molecular residue pairs. Two sets of energy parameters are derived, corresponding to solvent-mediation and "average residue" mediation. The former set is shown to be highly correlated (correlation coefficient 0.89) with that previously obtained for inter-residue interactions within single chain monomers, while the latter exhibits a weaker correlation (0.69) with its intra-molecular counterpart. In addition to the close similarity of intra- and inter-molecular solvent-mediated potentials, they are shown to be significantly more residue-specific and thereby discriminative compared to the residue-mediated ones, indicating that solvent-mediation plays a major role in controlling the effective inter-residue interactions, either at interfaces, or within single monomers. Based on this observation, a reduced set of energy parameters comprising 20 one-body and 3 two-body terms is proposed (as opposed to the 20 x 20 tables of inter-residue potentials), which reproduces the conventional 20 x 20 tables with a correlation coefficient of 0.99. PMID:9865952

Mediation of an efficacious HIV risk reduction intervention for South African men.

PubMed

O'Leary, Ann; Jemmott, John B; Jemmott, Loretta S; Bellamy, Scarlett; Icard, Larry D; Ngwane, Zolani

2015-10-01

"Men, Together Making a Difference!" is an HIV/STD risk-reduction intervention that significantly increased self-reported consistent condom use during vaginal intercourse compared with a health-promotion attention-control intervention among men (N = 1181) in Eastern Cape Province, South Africa. The present analyses were designed to identify mediators of the intervention's efficacy. The potential mediators were Social Cognitive Theory (SCT) constructs that the intervention targeted, including several aspects of condom-use self-efficacy, outcome expectancies, and knowledge. Mediation was assessed using a product-of-coefficients approach where an α path (the intervention's effect on the potential mediator) and a β path (the potential mediator's effect on the outcome of interest, adjusting for intervention) were estimated independently in a generalized estimating equations framework. Condom-use negotiation self-efficacy, technical-skill self-efficacy, and impulse-control self-efficacy were significant mediators. Although not mediators, descriptive norm and expected friends' approval of condom use predicted subsequent self-reported condom use, whereas the expected approval of sexual partner did not. The present results suggest that HIV/STD risk-reduction interventions that draw upon SCT and that address self-efficacy to negotiate condom use, to apply condoms correctly, and to exercise sufficient control when sexually aroused to use condoms may contribute to efforts to reduce sexual risk behavior among South African men. Future research must examine whether approaches that build normative support for condom use among men's friends are also efficacious.

Longitudinal study of diet quality and change in asthma symptoms in adults, according to smoking status.

PubMed

Li, Zhen; Kesse-Guyot, Emmanuelle; Dumas, Orianne; Garcia-Aymerich, Judith; Leynaert, Bénédicte; Pison, Christophe; Le Moual, Nicole; Romieu, Isabelle; Siroux, Valérie; Camargo, Carlos A; Nadif, Rachel; Varraso, Raphaëlle

2017-02-01

It has been hypothesised that increased asthma prevalence in westernised countries is associated with changes in lifestyle factors, including a poorer diet. However, little is known regarding the association between diet quality and asthma. In the diet-asthma association, the role of BMI as a potential mediator needs clarification; moreover, potential effect modification by non-diet sources of oxidants, such as smoking, merits investigation. We investigated the association between diet quality and change in asthma symptoms, as well as assessed effect modification by smoking, while accounting for BMI as a potential mediator. Using data from the French prospective Epidemiological study on the Genetics and Environment of Asthma study, we assessed diet quality using the Alternate Healthy Eating Index 2010 (AHEI-2010) at baseline and change in asthma symptoms (stable (reference), worsening, improved; mean follow-up time: 7 years). Mediation analysis was used to disentangle total and direct effects and the indirect effect mediated by BMI. The analyses included 969 adults (mean age 43 years; 49 % men; 42 % ever asthma). We observed a significant interaction between smoking and AHEI-2010 on change in asthma symptoms (P for interaction=0·04). Among never smokers (n 499), we observed a positive total effect (multivariable OR 1·39; 95 % CI 1·07, 1·80) and a positive direct effect (OR 1·41; 95 % CI 1·09, 1·80) of the AHEI-2010 (per ten-point increment) on improved symptoms. No indirect effect mediated through BMI was observed (OR 0·99; 95 % CI 0·91, 1·07). Among former and current smokers, all effects were statistically non-significant. Better diet quality was associated with improved asthma symptoms over time in never smokers, independently of BMI.

Causal mediation analysis with a latent mediator.

PubMed

Albert, Jeffrey M; Geng, Cuiyu; Nelson, Suchitra

2016-05-01

Health researchers are often interested in assessing the direct effect of a treatment or exposure on an outcome variable, as well as its indirect (or mediation) effect through an intermediate variable (or mediator). For an outcome following a nonlinear model, the mediation formula may be used to estimate causally interpretable mediation effects. This method, like others, assumes that the mediator is observed. However, as is common in structural equations modeling, we may wish to consider a latent (unobserved) mediator. We follow a potential outcomes framework and assume a generalized structural equations model (GSEM). We provide maximum-likelihood estimation of GSEM parameters using an approximate Monte Carlo EM algorithm, coupled with a mediation formula approach to estimate natural direct and indirect effects. The method relies on an untestable sequential ignorability assumption; we assess robustness to this assumption by adapting a recently proposed method for sensitivity analysis. Simulation studies show good properties of the proposed estimators in plausible scenarios. Our method is applied to a study of the effect of mother education on occurrence of adolescent dental caries, in which we examine possible mediation through latent oral health behavior. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Pathological prolongation of action potential duration as a cause of the reduced alpha-adrenoceptor-mediated negative inotropy in streptozotocin-induced diabetic mice myocardium.

PubMed

Kanae, Haruna; Hamaguchi, Shogo; Wakasugi, Yumi; Kusakabe, Taichi; Kato, Keisuke; Namekata, Iyuki; Tanaka, Hikaru

2017-11-01

Effect of pathological prolongation of action potential duration on the α-adrenoceptor-mediated negative inotropy was studied in streptozotocin-induced diabetic mice myocardium. In streptozotocin-treated mouse ventricular myocardium, which had longer duration of action potential than that in control mice, the negative inotropic response induced by phenylephrine was smaller than that in control mice. 4-Aminopyridine prolonged the action potential duration and decreased the negative inotropy in control mice. Cromakalim shortened the action potential duration and increased the negative inotropy in streptozotocin-treated mice. These results suggest that the reduced α-adrenoceptor-mediated inotropy in the diabetic mouse myocardium is partly due to its prolonged action potential. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Post-Traumatic Symptomatology and Compulsions as Potential Mediators of the Relation Between Child Sexual Abuse and Auditory Verbal Hallucinations.

PubMed

McCarthy-Jones, Simon

2018-05-01

Whilst evidence is mounting that childhood sexual abuse (CSA) can be a cause of auditory verbal hallucinations (AVH), it is unclear what factors mediate this relation. Recent evidence suggests that post-traumatic symptomatology may mediate the CSA-AVH relation in clinical populations, although this hypothesis has not yet been tested in the general population. There is also reason to believe that obsessive ideation could mediate the CSA-AVH relation. To test for evidence to falsify the hypotheses that post-traumatic symptomatology, obsessions, compulsions, anxiety and depression mediate the relation between CSA and AVH in a general population sample. Indirect effects of CSA on AVH via potential mediators were tested for, using a regression-based approach employing data from the 2007 Adult Psychiatric Morbidity Survey (n = 5788). After controlling for demographics, IQ and child physical abuse, it was found that CSA, IQ, post-traumatic symptomatology and compulsions predicted lifetime experience of AVH. Mediation analyses found significant indirect effects of CSA on AVH via post-traumatic symptomatology [odds ratio (OR): 1.11; 95% confidence interval (CI):1.00-1.29] and compulsions (OR: 1.10, 95% CI: 1.01-1.28). These findings offer further support for the hypothesis that post-traumatic symptomatology is a mediator of the CSA-AVH relation. Although no evidence was found for obsessional thoughts as a mediating variable, a potential mediating role for compulsions is theoretically intriguing. This study's findings reiterate the need to ask about experiences of childhood adversity and post-traumatic symptomology in people with AVH, as well as the likely therapeutic importance of trauma-informed and trauma-based interventions for this population.

The Effect of Religious Involvement on Life Satisfaction among Korean Christians: Focused on the Mediating Effect of Spiritual Well-Being and Self-Esteem.

PubMed

Yoo, Jieun

2017-12-01

The present study examined the relationship between two categories of religious involvement, namely religious belief and religious behavior, and life satisfaction among Korean Christians (N = 278) with spiritual well-being and self-esteem as potential mediators in this relationship by using structural equation modeling (SEM). The results supported the full mediated structural model and indicated that religious belief had a significant indirect effect on life satisfaction through the mediators, spiritual well-being and self-esteem. Religious behavior did not have an indirect or direct effect on life satisfaction among Korean Christians. The significance, implications, and limitations of the study were discussed.

An amodal shared resource model of language-mediated visual attention

PubMed Central

Smith, Alastair C.; Monaghan, Padraic; Huettig, Falk

2013-01-01

Language-mediated visual attention describes the interaction of two fundamental components of the human cognitive system, language and vision. Within this paper we present an amodal shared resource model of language-mediated visual attention that offers a description of the information and processes involved in this complex multimodal behavior and a potential explanation for how this ability is acquired. We demonstrate that the model is not only sufficient to account for the experimental effects of Visual World Paradigm studies but also that these effects are emergent properties of the architecture of the model itself, rather than requiring separate information processing channels or modular processing systems. The model provides an explicit description of the connection between the modality-specific input from language and vision and the distribution of eye gaze in language-mediated visual attention. The paper concludes by discussing future applications for the model, specifically its potential for investigating the factors driving observed individual differences in language-mediated eye gaze. PMID:23966967

Mediators of the relationship between maternal education and children's TV viewing.

PubMed

Hesketh, Kylie; Ball, Kylie; Crawford, David; Campbell, Karen; Salmon, Jo

2007-07-01

Maternal education is consistently found to be inversely related to children's television viewing and is associated with aspects of the family television environment. This study investigates whether family television environment mediates the relationship between maternal education and children's television viewing. Parents of 1484 children reported maternal education, time their child spends watching television, and 21 aspects of the family television environment (potential mediators) during 2002 and 2003. Separate regression analyses were conducted in 2006 for each potential mediator that met two initial conditions for mediation (associated with both maternal education and children's television viewing (p<0.10)), to assess whether inclusion reduced the association between maternal education and children's television viewing. Multivariable regression assessed the combined impact of all mediators. Twelve of 21 potential mediators met the initial conditions for mediation. Inclusion of each resulted in decreased beta values (3.2% to 15.2%) for the association between maternal education and television viewing. Number and placement of televisions in the home appeared to have the greatest mediating effect, followed by frequency of eating dinner in front of the television with the child and rules about television viewing during mealtimes. Together, the 12 mediators accounted for more than one-third of the association between maternal education and children's television viewing time. This study suggests the strong inverse relationship between maternal education and children's television viewing is partly mediated by aspects of the family television environment.

Factor Xa Mediates Calcium Flux in Endothelial Cells and is Potentiated by Igg From Patients With Lupus and/or Antiphospholipid Syndrome.

PubMed

Artim-Esen, Bahar; Smoktunowicz, Natalia; McDonnell, Thomas; Ripoll, Vera M; Pericleous, Charis; Mackie, Ian; Robinson, Eifion; Isenberg, David; Rahman, Anisur; Ioannou, Yiannis; Chambers, Rachel C; Giles, Ian

2017-09-07

Factor (F) Xa reactive IgG isolated from patients with antiphospholipid syndrome (APS) display higher avidity binding to FXa with greater coagulant effects compared to systemic lupus erythematosus (SLE) non APS IgG. FXa signalling via activation of protease-activated receptors (PAR) leads to increased intracellular calcium (Ca 2+ ). Therefore, we measured alterations in Ca 2+ levels in human umbilical vein endothelial cells (HUVEC) following FXa-mediated PAR activation and investigated whether FXa reactive IgG from patients with APS or SLE/APS- alter these responses. We observed concentration-dependent induction of Ca 2+ release by FXa that was potentiated by APS-IgG and SLE/APS- IgG compared to healthy control subjects' IgG, and FXa alone. APS-IgG and SLE/APS- IgG increased FXa mediated NFκB signalling and this effect was fully-retained in the affinity purified anti-FXa IgG sub-fraction. Antagonism of PAR-1 and PAR-2 reduced FXa-induced Ca 2+ release. Treatment with a specific FXa inhibitor, hydroxychloroquine or fluvastatin significantly reduced FXa-induced and IgG-potentiated Ca 2+ release. In conclusion, PAR-1 and PAR-2 are involved in FXa-mediated intracellular Ca 2+ release in HUVEC and FXa reactive IgG from patients with APS and/or SLE potentiate this effect. Further work is required to explore the potential use of IgG FXa reactivity as a novel biomarker to stratify treatment with FXa inhibitors in these patients.

Maternal care mediates the effects of nutrition and responsive stimulation interventions on young children's growth.

PubMed

Brown, N; Finch, J E; Obradović, J; Yousafzai, A K

2017-07-01

Undernutrition contributes to at least half the estimated six million annual childhood deaths worldwide. Furthermore, one in three children fails to meet their developmental potential because of risks including stunting, illness, under-stimulation, poor responsive interactions and maternal depressive symptoms. Our study investigates the role of caregiving processes on children's height-for-age at 2 and 4 years. The Pakistan Early Child Development Scale-up study assessed the longitudinal effectiveness of early nutrition and responsive stimulation interventions on growth and development at 4 years of age. In total, 1302 children were followed up from birth to 4 years. We leveraged path analyses to explore potential mediators of early intervention effects on children's height-for-age at 4 years, including maternal depressive symptoms, mother-child interaction quality, diarrhoeal illness and height-for-age at 2 years. Our final model had excellent model fit (comparative fix index = 0.999, Tucker-Lewis index = 0.998, root mean square error of approximation = 0.008) and showed that mother-child interaction quality mediated the effects of both enhanced nutrition and responsive stimulation interventions on height-for-age at 4 years via its longitudinal stability from 2 years of age (β = 0.016, p = 0.005; β = 0.048, p < 0.001, respectively). Further, diarrhoeal illness mediated the effects of maternal depressive symptoms at 1 year post partum on children's height-for-age at 4 years via the longitudinal stability of height-for-age z-score from 2 years of age onwards (β = -0.007, p = 0.019). The quality of early caregiving experience mediated the association between both interventions and height-for-age. The effect of maternal depressive symptoms on growth was mediated by diarrhoeal illness. Programmatic approaches to child nutrition and growth must address all these potentially modifiable factors. © 2017 John Wiley & Sons Ltd.

Achievement goals and emotions: The mediational roles of perceived progress, control, and value.

PubMed

Hall, Nathan C; Sampasivam, Lavanya; Muis, Krista R; Ranellucci, John

2016-06-01

The link between achievement goals and achievement emotions is well established; however, research exploring potential mediators of this relationship is lacking. The control-value theory of achievement emotions (Pekrun, 2006, Educational Psychology Review, 18, 315) posits that perceptions of control and value mediate the relationship between achievement goals and achievement emotions, whereas the bidirectional theory of affect (Linnenbrink & Pintrich, 2002, Educational Psychologist, 37, 69) proposes that perceived progress mediates this relationship. The present study empirically evaluated three hypothesized mediators of the effects of achievement goals on learning-related emotions as proposed in the control-value theory and the bidirectional theory of affect. Undergraduate students (N = 273) from humanities, social science, and STEM disciplines participated. Participants completed web-based questionnaires evaluating academic achievement goals, perceptions of control, perceived task value, and achievement emotions. Results provided empirical support primarily for perceived progress as a mediator of mastery-approach goal effects on positive emotions (enjoyment, hope), showing indirect effects of mastery- and performance-approach goals on outcome-related emotions (hope, anxiety) via perceived control. Indirect effects of mastery- and performance-approach goals were further observed on anxiety via perceived value, with higher value levels predicting greater anxiety. Study findings partially support Linnenbrink and Pintrich's (2002, Educational Psychologist, 37, 69) bidirectional theory of affect while underscoring the potential for indirect effects of goals on emotions through perceived control as proposed by Pekrun (2006, Educational Psychology Review, 18, 315). © 2016 The British Psychological Society.

[Effects of Korean proficiency and parent-child cohesion on self-esteem and acculturation among children from multicultural families].

PubMed

Kim, Mi Ye; Lim, Ji Young; Chung, Grace H

2012-12-01

There is evidence that parent-child cohesion is a potentially influential factor in children's self-esteem and acculturation. However, no research to date has examined cohesion with parents as a potential pathway between Korean proficiency and self-esteem or acculturation among children from multicultural families. This study was done to address these limitations by examining whether and to what extent cohesion with parents mediated the effect of Korean proficiency on self-esteem and acculturation among children from multicultural families. Data were collected from a sample of 138 mothers and their children living in Seoul, Daegu, Kyungi province, and Kyungpook province. Multiple regression analysis was used to examine the relationships between the variables of interest. Mediation effects of cohesion with parents were tested by following the procedure recommended by Baron and Kenny (1986). Cohesion with parents partially mediated the relationship between Korean proficiency and self-esteem. For children's acculturation, the effect of Korean proficiency was partially mediated through father-child cohesion. Mother-child cohesion completely mediated the relationship between Korean proficiency and acculturation. These findings suggest that to help children from multicultural families experiencing difficulties with self-esteem or acculturation, it might be useful to develop programs that are aimed at strengthen cohesion with parents.

Probing Long-Range Neutrino-Mediated Forces with Atomic and Nuclear Spectroscopy.

PubMed

Stadnik, Yevgeny V

2018-06-01

The exchange of a pair of low-mass neutrinos between electrons, protons, and neutrons produces a "long-range" 1/r^{5} potential, which can be sought for in phenomena originating on the atomic and subatomic length scales. We calculate the effects of neutrino-pair exchange on transition and binding energies in atoms and nuclei. In the case of atomic s-wave states, there is a large enhancement of the induced energy shifts due to the lack of a centrifugal barrier and the highly singular nature of the neutrino-mediated potential. We derive limits on neutrino-mediated forces from measurements of the deuteron binding energy and transition energies in positronium, muonium, hydrogen, and deuterium, as well as isotope-shift measurements in calcium ions. Our limits improve on existing constraints on neutrino-mediated forces from experiments that search for new macroscopic forces by 18 orders of magnitude. Future spectroscopy experiments have the potential to probe long-range forces mediated by the exchange of pairs of standard-model neutrinos and other weakly charged particles.

Probing Long-Range Neutrino-Mediated Forces with Atomic and Nuclear Spectroscopy

NASA Astrophysics Data System (ADS)

Stadnik, Yevgeny V.

2018-06-01

The exchange of a pair of low-mass neutrinos between electrons, protons, and neutrons produces a "long-range" 1 /r5 potential, which can be sought for in phenomena originating on the atomic and subatomic length scales. We calculate the effects of neutrino-pair exchange on transition and binding energies in atoms and nuclei. In the case of atomic s -wave states, there is a large enhancement of the induced energy shifts due to the lack of a centrifugal barrier and the highly singular nature of the neutrino-mediated potential. We derive limits on neutrino-mediated forces from measurements of the deuteron binding energy and transition energies in positronium, muonium, hydrogen, and deuterium, as well as isotope-shift measurements in calcium ions. Our limits improve on existing constraints on neutrino-mediated forces from experiments that search for new macroscopic forces by 18 orders of magnitude. Future spectroscopy experiments have the potential to probe long-range forces mediated by the exchange of pairs of standard-model neutrinos and other weakly charged particles.

Integrating mediation and moderation to advance theory development and testing.

PubMed

Karazsia, Bryan T; Berlin, Kristoffer S; Armstrong, Bridget; Janicke, David M; Darling, Katherine E

2014-03-01

The concepts and associated analyses of mediation and moderation are important to the field of psychology. Although pediatric psychologists frequently incorporate mediation and moderation in their theories and empirical research, on few occasions have we integrated mediation and moderation. In this article, conceptual reasons for integrating mediation and moderation are offered. We illustrate a model that integrates mediation and moderation. In our illustration, the strength of an indirect or a mediating effect varied as a function of a moderating variable. Clinical implications of the integration of mediation and moderation are discussed, as is the potential of integrated models to advance research programs in pediatric psychology.

Exploring the Mediating Effects of Trust on Principal Leadership and Teacher Professional Learning in Hong Kong Primary Schools

ERIC Educational Resources Information Center

Li, Lijuan; Hallinger, Philip; Walker, Allan

2016-01-01

This study attempted to identify effects of trust between principal leadership and teacher professional learning in Hong Kong primary schools. To verify the potential mediating effects of trust as a component of school capacity, survey data with a sample of 970 teachers from 32 local primary schools was used. Two questionnaires were combined to…

Causal mediation analysis for longitudinal data with exogenous exposure

PubMed Central

Bind, M.-A. C.; Vanderweele, T. J.; Coull, B. A.; Schwartz, J. D.

2016-01-01

Mediation analysis is a valuable approach to examine pathways in epidemiological research. Prospective cohort studies are often conducted to study biological mechanisms and often collect longitudinal measurements on each participant. Mediation formulae for longitudinal data have been developed. Here, we formalize the natural direct and indirect effects using a causal framework with potential outcomes that allows for an interaction between the exposure and the mediator. To allow different types of longitudinal measures of the mediator and outcome, we assume two generalized mixed-effects models for both the mediator and the outcome. The model for the mediator has subject-specific random intercepts and random exposure slopes for each cluster, and the outcome model has random intercepts and random slopes for the exposure, the mediator, and their interaction. We also expand our approach to settings with multiple mediators and derive the mediated effects, jointly through all mediators. Our method requires the absence of time-varying confounding with respect to the exposure and the mediator. This assumption is achieved in settings with exogenous exposure and mediator, especially when exposure and mediator are not affected by variables measured at earlier time points. We apply the methodology to data from the Normative Aging Study and estimate the direct and indirect effects, via DNA methylation, of air pollution, and temperature on intercellular adhesion molecule 1 (ICAM-1) protein levels. Our results suggest that air pollution and temperature have a direct effect on ICAM-1 protein levels (i.e. not through a change in ICAM-1 DNA methylation) and that temperature has an indirect effect via a change in ICAM-1 DNA methylation. PMID:26272993

Cognitive and affective mechanisms of pain and fatigue in multiple sclerosis.

PubMed

Arewasikporn, Anne; Turner, Aaron P; Alschuler, Kevin N; Hughes, Abbey J; Ehde, Dawn M

2018-06-01

To examine the extent to which pain catastrophizing, fatigue catastrophizing, positive affect, and negative affect simultaneously mediated the associations between common symptoms of multiple sclerosis (MS; i.e., pain, fatigue) and impact on daily life, depressive symptoms, and resilience. Participants were community-dwelling adults with MS (N = 163) reporting chronic pain, fatigue, and/or moderate depressive symptoms. Multiple mediation path analysis was used to model potential mediators of pain and fatigue separately, using baseline data from a randomized controlled trial comparing two symptom self-management interventions. In the pain model, pain catastrophizing was a mediator of pain intensity with pain interference and depression. Negative affect was a mediator of pain intensity with depression and resilience. In the fatigue model, fatigue catastrophizing was a mediator of fatigue intensity with fatigue impact and depression. Positive affect was a mediator of fatigue intensity with depression and resilience. These findings provide preliminary support for the presence of differential effects of cognitive-affective mediators and suggest potential targets for psychological interventions based on an individual's clinical presentation. The differential mediating effects also support the inclusion of both positive and negative aspects of psychological health in models of pain and fatigue, which would not be otherwise apparent if negative constructs were examined in isolation. To our knowledge, this is the first study to utilize a multivariate path analysis approach to examine cognitive-affective mediators of pain and fatigue in MS, while also examining positive and negative constructs concurrently. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

The Mediation of Mothers’ Self-Fulfilling Effects on Their Children’s Alcohol Use: Self-Verification, Informational Conformity and Modeling Processes

PubMed Central

Madon, Stephanie; Guyll, Max; Buller, Ashley A.; Scherr, Kyle C.; Willard, Jennifer; Spoth, Richard

2010-01-01

This research examined whether self-fulfilling prophecy effects are mediated by self-verification, informational conformity, and modeling processes. The authors examined these mediational processes across multiple time frames with longitudinal data obtained from two samples of mother – child dyads (N1 = 487; N2 = 287). Children’s alcohol use was the outcome variable. The results provided consistent support for the mediational process of self-verification. In both samples and across several years of adolescence, there was a significant indirect effect of mothers’ beliefs on children’s alcohol use through children’s self-assessed likelihood of drinking alcohol in the future. Comparatively less support was found for informational conformity and modeling processes as mediators of mothers’ self-fulfilling effects. The potential for self-fulfilling prophecies to produce long lasting changes in targets’ behavior via self-verification processes are discussed. PMID:18665708

The mediation of mothers' self-fulfilling effects on their children's alcohol use: self-verification, informational conformity, and modeling processes.

PubMed

Madon, Stephanie; Guyll, Max; Buller, Ashley A; Scherr, Kyle C; Willard, Jennifer; Spoth, Richard

2008-08-01

This research examined whether self-fulfilling prophecy effects are mediated by self-verification, informational conformity, and modeling processes. The authors examined these mediational processes across multiple time frames with longitudinal data obtained from two samples of mother-child dyads (N-sub-1 = 486; N-sub-2 = 287), with children's alcohol use as the outcome variable. The results provided consistent support for the mediational process of self-verification. In both samples and across several years of adolescence, there was a significant indirect effect of mothers' beliefs on children's alcohol use through children's self-assessed likelihood of drinking alcohol in the future. Comparatively less support was found for informational conformity and modeling processes as mediators of mothers' self-fulfilling effects. The potential for self-fulfilling prophecies to produce long-lasting changes in targets' behavior via self-verification processes are discussed. (c) 2008 APA, all rights reserved

Hypnotherapy to Reduce Hot Flashes: Examination of Response Expectancies as a Mediator of Outcomes

PubMed Central

Sliwinski, Jim R.; Elkins, Gary R.

2017-01-01

The mechanism of action responsible for hypnotherapy’s effect in reducing hot flashes is not yet known. The purpose of this study was to examine the role of response expectancies as a potential mediator. Hypnotizability was also tested as an effect moderator. Data were collected from a sample of 172 postmenopausal women, who had been randomized to receive either a 5-week hypnosis intervention or structured attention counseling. Measures of response expectancies were analyzed to determine if the relationship between group assignment and hot flashes frequency was mediated by expectancies for treatment efficacy. A series of simple mediation and conditional process analyses did not support mediation of the relationship between treatment condition and hot flash frequency through response expectancy. The effect of hypnotherapy in reducing hot flashes does not appear to be due to placebo effects as determined by response expectancies. Implications for clinical practice and future research are discussed. PMID:28528570

A novel measure of effect size for mediation analysis.

PubMed

Lachowicz, Mark J; Preacher, Kristopher J; Kelley, Ken

2018-06-01

Mediation analysis has become one of the most popular statistical methods in the social sciences. However, many currently available effect size measures for mediation have limitations that restrict their use to specific mediation models. In this article, we develop a measure of effect size that addresses these limitations. We show how modification of a currently existing effect size measure results in a novel effect size measure with many desirable properties. We also derive an expression for the bias of the sample estimator for the proposed effect size measure and propose an adjusted version of the estimator. We present a Monte Carlo simulation study conducted to examine the finite sampling properties of the adjusted and unadjusted estimators, which shows that the adjusted estimator is effective at recovering the true value it estimates. Finally, we demonstrate the use of the effect size measure with an empirical example. We provide freely available software so that researchers can immediately implement the methods we discuss. Our developments here extend the existing literature on effect sizes and mediation by developing a potentially useful method of communicating the magnitude of mediation. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Child abuse potential in mothers with early life maltreatment, borderline personality disorder and depression.

PubMed

Dittrich, Katja; Boedeker, Katja; Kluczniok, Dorothea; Jaite, Charlotte; Hindi Attar, Catherine; Fuehrer, Daniel; Herpertz, Sabine C; Brunner, Romuald; Winter, Sibylle Maria; Heinz, Andreas; Roepke, Stefan; Heim, Christine; Bermpohl, Felix

2018-05-24

Early life maltreatment (ELM), borderline personality disorder (BPD) and major depressive disorder (MDD) have been shown to increase the potential of abuse. Emotion regulation is an identified mediator for the association of ELM and BPD with abuse potential. Until now, there has been no study to account for the co-occurrence of these risk factors in one analysis, although BPD and MDD are known as common sequelae of ELM. This is paired with a lack of studies investigating the effects of abuse potential on child well-being.AimsOur study aims at (a) disentangling the effects of maternal ELM, MDD and BPD on abuse potential; (b) exploring the role of emotion regulation as a mediator; and (c) testing for intergenerational effects of abuse potential on child psychopathology. The research design included 114 mothers with/without ELM, BPD and MDD in remission and their children, all of which were between 5 and 12 years of age. A path analysis was conducted to investigate the multiple associations between our variables. ELM, MDD and BPD were all associated with abuse potential, with emotion regulation acting as a mediator for BPD and MDD. Furthermore, an elevated abuse potential was related to higher psychopathology in the child. History of ELM as well as the common sequelae, BPD and MDD, pose risks for child abuse. Our findings suggest improvement of emotion regulation as a potential target for intervention programs. These programs should also aim at non-substantiated cases because even an elevated abuse potential affected child mental health.Declaration of interestNone.

Differences in Electronic Exchanges in Synchronous and Asynchronous Computer-Mediated Communication: The Effect of Culture as a Mediating Variable

ERIC Educational Resources Information Center

Angeli, Charoula; Schwartz, Neil H.

2016-01-01

Two hundred and eighty undergraduates from universities in two countries were asked to read didactic material, and then think and write about potential solutions to an ill-defined problem. The writing was conducted within a synchronous or asynchronous computer-mediated communication (CMC) environment. Asynchronous CMC took the form of email…

Single-Participant Assessment of Treatment Mediators: Strategy Description and Examples from a Behavioral Activation Intervention for Depressed Adolescents

ERIC Educational Resources Information Center

Gaynor, Scott T.; Harris, Amanda

2008-01-01

Determining the means by which effective psychotherapy works is critical. A generally recommended strategy for identifying the potential causal variables is to conduct group-level statistical tests of treatment mediators. Herein the case is made for also assessing mediators of treatment outcome at the level of the individual participant.…

High-Potential Electrocatalytic O2 Reduction with Nitroxyl/NOx Mediators: Implications for Fuel Cells and Aerobic Oxidation Catalysis

PubMed Central

2015-01-01

Efficient reduction of O2 to water is a central challenge in energy conversion and many aerobic oxidation reactions. Here, we show that the electrochemical oxygen reduction reaction (ORR) can be achieved at high potentials by using soluble organic nitroxyl and nitrogen oxide (NOx) mediators. When used alone, neither organic nitroxyls, such as 2,2,6,6-tetramethyl-1-piperidinyl-N-oxyl (TEMPO), nor NOx species, such as sodium nitrite, are effective ORR mediators. The combination of nitroxyl/NOx species, however, mediates sustained O2 reduction with overpotentials as low as 300 mV in acetonitrile containing trifluoroacetic acid. Mechanistic analysis of the coupled redox reactions supports a process in which the nitrogen oxide catalyst drives aerobic oxidation of a nitroxyl mediator to an oxoammonium species, which then is reduced back to the nitroxyl at the cathode. The electrolysis potential is dictated by the oxoammonium/nitroxyl reduction potential. The overpotentials accessible with this ORR system are significantly lower than widely studied molecular metal-macrocycle ORR catalysts and benefit from the mechanism-based specificity for four-electron reduction of oxygen to water mediated by NOx species, together with kinetically efficient reduction of oxidized NOx species by TEMPO and other organic nitroxyls. PMID:27162977

RNA sequencing supports distinct reactive oxygen species-mediated pathways of apoptosis by high and low size mass fractions of Bay leaf (Lauris nobilis) in HT-29 cells.

PubMed

Rodd, Annabelle L; Ververis, Katherine; Sayakkarage, Dheeshana; Khan, Abdul W; Rafehi, Haloom; Ziemann, Mark; Loveridge, Shanon J; Lazarus, Ross; Kerr, Caroline; Lockett, Trevor; El-Osta, Assam; Karagiannis, Tom C; Bennett, Louise E

2015-08-01

Anti-proliferative and pro-apoptotic effects of Bay leaf (Laurus nobilis) in mammalian cancer and HT-29 adenocarcinoma cells have been previously attributed to effects of polyphenolic and essential oil chemical species. Recently, we demonstrated differentiated growth-regulating effects of high (HFBL) versus low molecular mass (LFBL) aqueous fractions of bay leaf and now confirm by comparative effects on gene expression, that HFBL and LFBL suppress HT-29 growth by distinct mechanisms. Induction of intra-cellular lesions including DNA strand breakage by extra-cellular HFBL, invoked the hypothesis that iron-mediated reactive oxygen species with capacity to penetrate cell membrane, were responsible for HFBL-mediated effects, supported by equivalent effects of HFBL in combination with γ radiation. Activities of HFBL and LFBL were interpreted to reflect differentiated responses to iron-mediated reactive oxygen species (ROS), occurring either outside or inside cells. In the presence of LFBL, apoptotic death was relatively delayed compared with HFBL. ROS production by LFBL mediated p53-dependent apoptosis and recovery was suppressed by promoting G1/S phase arrest and failure of cellular tight junctions. In comparison, intra-cellular anti-oxidant protection exerted by LFBL was absent for extra-cellular HFBL (likely polysaccharide-rich), which potentiated more rapid apoptosis by producing DNA double strand breaks. Differentiated effects on expression of genes regulating ROS defense and chromatic condensation by LFBL versus HFBL, were observed. The results support ferrous iron in cell culture systems and potentially in vivo, can invoke different extra-cellular versus intra-cellular ROS-mediated chemistries, that may be regulated by exogenous, including dietary species.

Harsh parenting and academic achievement in Chinese adolescents: Potential mediating roles of effortful control and classroom engagement.

PubMed

Wang, Mingzhong; Deng, Xueli; Du, Xiuxiu

2018-04-01

This study examined (a) the potential mediating roles of effortful control and classroom engagement in the association between harsh parenting and adolescent academic achievement, and (b) the potential moderating role of gender. Sixth through eighth graders in rural China (n=815, mean age=12.55years) reported on harsh parenting, effortful control, and classroom engagement. Parents also reported on each other's harsh parenting. Academic achievement was assessed by students' test scores and teacher-rated academic performance. Results of structural equation modeling revealed gender differences in patterns of association among the model variables. Harsh parenting was negatively and directly associated with academic achievement for both boys and girls. It was also negatively and indirectly associated with academic achievement via effortful control and classroom engagement sequentially, forming a common indirect "path" for boys and girls. The indirect negative effect of harsh parenting on boys' academic achievement was mainly realized through the mediator of effortful control, whereas this same indirect effect for girls was mainly realized through the mediator of classroom engagement. Jointly, effortful control and classroom engagement precipitates more indirect effects for boys than for girls in the association between harsh parenting and academic achievement. The discussion analyzes the potential "paths" from harsh parenting to adolescent academic achievement, as well as gender differences in these "paths." The current study has implications for teachers and parents eager to improve students' classroom engagement and academic achievement. Copyright © 2017. Published by Elsevier Ltd.

Parent-Reported Behavioral and Psychiatric Problems Mediate the Relationship between Sleep-Disordered Breathing and Cognitive Deficits in School-Aged Children.

PubMed

Smith, Dale L; Gozal, David; Hunter, Scott J; Kheirandish-Gozal, Leila

2017-01-01

Numerous studies over the past several decades have illustrated that children who suffer from sleep-disordered breathing (SDB) are at greater risk for cognitive, behavioral, and psychiatric problems. Although behavioral problems have been proposed as a potential mediator between SDB and cognitive functioning, these relationships have not been critically examined. This analysis is based on a community-based cohort of 1,115 children who underwent overnight polysomnography, and cognitive and behavioral phenotyping. Structural model of the relationships between SDB, behavior, and cognition, and two recently developed mediation approaches based on propensity score weighting and resampling were used to assess the mediational role of parent-reported behavior and psychiatric problems in the relationship between SDB and cognitive functioning. Multiple models utilizing two different SDB definitions further explored direct effects of SDB on cognition as well as indirect effects through behavioral pathology. All models were adjusted for age, sex, race, BMI z -score, and asthma status. Indirect effects of SDB through behavior problems were significant in all mediation models, while direct effects of SDB on cognition were not. The findings were consistent across different mediation procedures and remained essentially unaltered when different criteria for SDB, behavior, and cognition were used. Potential effects of SDB on cognitive functioning appear to occur through behavioral problems that are detectable in this pediatric population. Thus, early attentional or behavioral pathology may be implicated in the cognitive functioning deficits associated with SDB, and may present an early morbidity-related susceptibility biomarker.

Causal mediation analysis for longitudinal data with exogenous exposure.

PubMed

Bind, M-A C; Vanderweele, T J; Coull, B A; Schwartz, J D

2016-01-01

Mediation analysis is a valuable approach to examine pathways in epidemiological research. Prospective cohort studies are often conducted to study biological mechanisms and often collect longitudinal measurements on each participant. Mediation formulae for longitudinal data have been developed. Here, we formalize the natural direct and indirect effects using a causal framework with potential outcomes that allows for an interaction between the exposure and the mediator. To allow different types of longitudinal measures of the mediator and outcome, we assume two generalized mixed-effects models for both the mediator and the outcome. The model for the mediator has subject-specific random intercepts and random exposure slopes for each cluster, and the outcome model has random intercepts and random slopes for the exposure, the mediator, and their interaction. We also expand our approach to settings with multiple mediators and derive the mediated effects, jointly through all mediators. Our method requires the absence of time-varying confounding with respect to the exposure and the mediator. This assumption is achieved in settings with exogenous exposure and mediator, especially when exposure and mediator are not affected by variables measured at earlier time points. We apply the methodology to data from the Normative Aging Study and estimate the direct and indirect effects, via DNA methylation, of air pollution, and temperature on intercellular adhesion molecule 1 (ICAM-1) protein levels. Our results suggest that air pollution and temperature have a direct effect on ICAM-1 protein levels (i.e. not through a change in ICAM-1 DNA methylation) and that temperature has an indirect effect via a change in ICAM-1 DNA methylation. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Long-Term Effects of Child Corporal Punishment on Depressive Symptoms in Young Adults: Potential Moderators and Mediators

ERIC Educational Resources Information Center

Turner, Heather A.; Muller, Paul A.

2004-01-01

Based on a sample of 649 students from 3 New England colleges, this study examined the long-term effects of childhood corporal punishment on symptoms of depression and considered factors that may moderate or mediate the association. Similar to national studies, approximately 40% of the sample reported experiencing some level of corporal punishment…

The role of proteosome-mediated proteolysis in modulating potentially harmful transcription factor activity in Saccharomyces cerevisiae

PubMed Central

Bonzanni, Nicola; Zhang, Nianshu; Oliver, Stephen G.; Fisher, Jasmin

2011-01-01

Motivation: The appropriate modulation of the stress response to variable environmental conditions is necessary to maintain sustained viability in Saccharomyces cerevisiae. Particularly, controlling the abundance of proteins that may have detrimental effects on cell growth is crucial for rapid recovery from stress-induced quiescence. Results: Prompted by qualitative modeling of the nutrient starvation response in yeast, we investigated in vivo the effect of proteolysis after nutrient starvation showing that, for the Gis1 transcription factor at least, proteasome-mediated control is crucial for a rapid return to growth. Additional bioinformatics analyses show that potentially toxic transcriptional regulators have a significantly lower protein half-life, a higher fraction of unstructured regions and more potential PEST motifs than the non-detrimental ones. Furthermore, inhibiting proteasome activity tends to increase the expression of genes induced during the Environmental Stress Response more than those in the rest of the genome. Our combined results suggest that proteasome-mediated proteolysis of potentially toxic transcription factors tightly modulates the stress response in yeast. Contact: jasmin.fisher@microsoft.com Supplementary information: Supplementary data are available at Bioinformatics online. PMID:21685082

Relationship authenticity partially mediates the effects of attachment on relationship satisfaction.

PubMed

Rasco, Danney; Warner, Rebecca M

2017-01-01

Individuals with anxious and avoidant attachment tend to experience less satisfaction in their relationships. Past research suggests the negative effects of attachment on relationship satisfaction may be partially mediated by self-disclosure and self-concealment; the present study evaluated relationship authenticity as a potential additional mediator. Confirmatory factor analysis indicated that relationship authenticity is distinct from self-disclosure and self-concealment. Relationship authenticity predicted additional variance in relationship satisfaction controlling for attachment, self-disclosure, and self-concealment. The results were consistent with relationship authenticity, along with self-disclosure and self-concealment, partially mediating the effects of attachment on relationship satisfaction. These findings suggest that relationship authenticity may play a unique role in understanding how attachment influences relationship satisfaction. Theoretical and clinical implications are discussed.

Implementation and reporting of causal mediation analysis in 2015: a systematic review in epidemiological studies.

PubMed

Liu, Shao-Hsien; Ulbricht, Christine M; Chrysanthopoulou, Stavroula A; Lapane, Kate L

2016-07-20

Causal mediation analysis is often used to understand the impact of variables along the causal pathway of an occurrence relation. How well studies apply and report the elements of causal mediation analysis remains unknown. We systematically reviewed epidemiological studies published in 2015 that employed causal mediation analysis to estimate direct and indirect effects of observed associations between an exposure on an outcome. We identified potential epidemiological studies through conducting a citation search within Web of Science and a keyword search within PubMed. Two reviewers independently screened studies for eligibility. For eligible studies, one reviewer performed data extraction, and a senior epidemiologist confirmed the extracted information. Empirical application and methodological details of the technique were extracted and summarized. Thirteen studies were eligible for data extraction. While the majority of studies reported and identified the effects of measures, most studies lacked sufficient details on the extent to which identifiability assumptions were satisfied. Although most studies addressed issues of unmeasured confounders either from empirical approaches or sensitivity analyses, the majority did not examine the potential bias arising from the measurement error of the mediator. Some studies allowed for exposure-mediator interaction and only a few presented results from models both with and without interactions. Power calculations were scarce. Reporting of causal mediation analysis is varied and suboptimal. Given that the application of causal mediation analysis will likely continue to increase, developing standards of reporting of causal mediation analysis in epidemiological research would be prudent.

Effect of dietary supplementation with Spirulina platensis on Atrazine-induced oxidative stress- mediated hepatic damage and inflammation in the common carp (Cyprinus carpio L.).

PubMed

Toughan, Hosam; Khalil, Samah R; El-Ghoneimy, Ashraf Ahmed; Awad, Ashraf; Seddek, A Sh

2018-03-01

The present study evaluated the potential modulatory effect(s) of dietary supplementation with Spirulina platensis (SP) on Atrazine (ATZ)-induced oxidative stress and inflammation in common carp (Cyprinus carpio L.). Common carp was exposed to ATZ (428μg/L) and SP (1%), either alone or in combination, for 40 days. Subsequently, the treatment groups were evaluated for ATZ-induced oxidative stress-mediated hepatic damage and the potential antioxidant effect(s) of SP supplementation. The results indicated that ATZ exposure led to a significant increase in the oxidative stress as suggested by the increased levels of lipid and DNA oxidative damage markers and the significant decline of antioxidant status biomarkers. Further, a real-time PCR analysis of the liver tissues revealed that the ATZ exposure resulted in the significant modulation of the mRNA expression of cytokines involved in the inflammatory response pathway in the liver, such as Interleukin (IL)-1ß and IL-10. The expression of IL-1ß mRNA was up-regulated while that of IL-10 mRNA was down-regulated. The group subjected to supplementation with SP exhibited a significant decrease in ATZ-induced oxidative stress-mediated hepatotoxic and inflammatory responses; however, these did not attain the levels of the control group. Owing to its ability for protecting against ATZ-induced oxidative stress-mediated hepatic damage in carps, SP could be a potentially effective and promising candidate as a feed additive for carps in aquaculture. Copyright © 2017 Elsevier Inc. All rights reserved.

Mediation Analysis: A Practitioner's Guide.

PubMed

VanderWeele, Tyler J

2016-01-01

This article provides an overview of recent developments in mediation analysis, that is, analyses used to assess the relative magnitude of different pathways and mechanisms by which an exposure may affect an outcome. Traditional approaches to mediation in the biomedical and social sciences are described. Attention is given to the confounding assumptions required for a causal interpretation of direct and indirect effect estimates. Methods from the causal inference literature to conduct mediation in the presence of exposure-mediator interactions, binary outcomes, binary mediators, and case-control study designs are presented. Sensitivity analysis techniques for unmeasured confounding and measurement error are introduced. Discussion is given to extensions to time-to-event outcomes and multiple mediators. Further flexible modeling strategies arising from the precise counterfactual definitions of direct and indirect effects are also described. The focus throughout is on methodology that is easily implementable in practice across a broad range of potential applications.

The Pathways from a Behavior Change Communication Intervention to Infant and Young Child Feeding in Bangladesh Are Mediated and Potentiated by Maternal Self-Efficacy.

PubMed

Zongrone, Amanda A; Menon, Purnima; Pelto, Gretel H; Habicht, Jean-Pierre; Rasmussen, Kathleen M; Constas, Mark A; Vermeylen, Francoise; Khaled, Adiba; Saha, Kuntal K; Stoltzfus, Rebecca J

2018-02-01

Although self-efficacy is a potential determinant of feeding and care behaviors, there is limited empirical analysis of the role of maternal self-efficacy in low- and middle-income countries. In the context of behavior change interventions (BCIs) addressing complementary feeding (CF), it is possible that maternal self-efficacy can mediate or enhance intervention impacts. In the context of a BCI in Bangladesh, we studied the role of maternal self-efficacy for CF (MSE-CF) for 2 CF behaviors with the use of a theoretically grounded empirical model of determinants to illustrate the potential roles of MSE-CF. We developed and tested a locally relevant scale for MSE-CF and included it in a survey (n = 457 mothers of children aged 6-24 mo) conducted as part of a cluster-randomized evaluation. Qualitative research was used to inform the selection of 2 intervention-targeted behaviors: feeding green leafy vegetables in the last 24 h (GLV) and on-time introduction of egg (EGG) between 6 and 8 mo of age. We then examined direct, mediated, and potentiated paths of MSE-CF in relation to the impacts of the BCI on these behaviors with the use of regression and structural equation modeling. GLV and EGG were higher in the intensive group than in the nonintensive control group (16.0 percentage points for GLV; P < 0.001; 11.2 percentage points for EGG; P = 0.037). For GLV, MSE-CF mediated (β = 0.345, P = 0.010) and potentiated (β = 0.390, P = 0.038) the effect of the intensive group. In contrast, MSE-CF did not mediate or potentiate the effect of the intervention on EGG. MSE-CF was a significant mediator and potentiator for GLV but not for EGG. The divergent findings highlight the complex determinants of individual specific infant and young child feeding behaviors. The study shows the value of measuring behavioral determinants, such as MSE-CF, that affect a caregiver's capability to adopt intervention-targeted behaviors.

Drug-Gut Microbiota Interactions: Implications for Neuropharmacology.

PubMed

Walsh, Jacinta; Griffin, Brendan T; Clarke, Gerard; Hyland, Niall P

2018-05-21

The fate and activity of drugs are frequently dictated not only by the host per se but also by the microorganisms present in the gastrointestinal tract. The gut microbiome is known to, both directly and indirectly, affect drug metabolism. More evidence now hints at the impact that drugs can have on the function and composition of the gut microbiome. Both microbiota-mediated alterations in drug metabolism and drug-mediated alterations in the gut microbiome can have beneficial or detrimental effects on the host. Greater insights into the mechanisms driving these reciprocal drug-gut microbiota interactions are needed, to guide the development of microbiome-targeted dietary or pharmacological interventions, with the potential to enhance drug efficacy or reduce drug side-effects. In this review, we explore the relationship between drugs and the gut microbiome, with a specific focus on potential mechanisms underpinning the drug-mediated alterations on the gut microbiome and the potential implications for psychoactive drugs. This article is protected by copyright. All rights reserved.

From CNTNAP2 to Early Expressive Language in Infancy: The Mediation Role of Rapid Auditory Processing.

PubMed

Riva, Valentina; Cantiani, Chiara; Benasich, April A; Molteni, Massimo; Piazza, Caterina; Giorda, Roberto; Dionne, Ginette; Marino, Cecilia

2018-06-01

Although it is clear that early language acquisition can be a target of CNTNAP2, the pathway between gene and language is still largely unknown. This research focused on the mediation role of rapid auditory processing (RAP). We tested RAP at 6 months of age by the use of event-related potentials, as a mediator between common variants of the CNTNAP2 gene (rs7794745 and rs2710102) and 20-month-old language outcome in a prospective longitudinal study of 96 Italian infants. The mediation model examines the hypothesis that language outcome is explained by a sequence of effects involving RAP and CNTNAP2. The ability to discriminate spectrotemporally complex auditory frequency changes at 6 months of age mediates the contribution of rs2710102 to expressive vocabulary at 20 months. The indirect effect revealed that rs2710102 C/C was associated with lower P3 amplitude in the right hemisphere, which, in turn, predicted poorer expressive vocabulary at 20 months of age. These findings add to a growing body of literature implicating RAP as a viable marker in genetic studies of language development. The results demonstrate a potential developmental cascade of effects, whereby CNTNAP2 drives RAP functioning that, in turn, contributes to early expressive outcome.

High-Potential Electrocatalytic O2 Reduction with Nitroxyl / NOx Mediators: Implications for Fuel Cells and Aerobic Oxidation Catalysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gerken, James B.; Stahl, Shannon S.

2015-07-15

Efficient reduction of O2 to water is a central challenge in energy conversion and aerobic oxidation catalysis. In the present study, we investigate the electrochemical reduction of O2 with soluble organic nitroxyl and nitrogen oxide (NOx) mediators. When used alone, neither organic nitroxyls, such as TEMPO (2,2,6,6-tetramethyl-1-piperidinyl-N-oxyl), nor NOx species, such as sodium nitrite, are effective mediators of electrochemical O2 reduction. The combination of nitroxyl/NOx species, however, mediates sustained O2 reduction at electrochemical potentials of 0.19–0.33 V (vs. Fc/Fc+) in acetonitrile containing trifluoroacetic acid. Mechanistic analysis of the coupled redox reactions supports a process in which the nitrogen oxide catalystmore » drives aerobic oxidation of a nitroxyl mediator to an oxoammonium species, which then is reduced back to the nitroxyl at the cathode. The electrolysis potential is dictated by the oxoammonium/nitroxyl reduction potential. The high potentials observed with this ORR system benefit from the mechanism-based specificity for four-electron reduction of oxygen to water mediated by NOx species, together with kinetically efficient reduction of oxidized NOx species by TEMPO and other organic nitroxyls. This research was supported as part of the Center for Molecular Electrocatalysis, an Energy Frontier Research Center, funded by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences.« less

Nonlinear Predictive Models for Multiple Mediation Analysis: With an Application to Explore Ethnic Disparities in Anxiety and Depression Among Cancer Survivors.

PubMed

Yu, Qingzhao; Medeiros, Kaelen L; Wu, Xiaocheng; Jensen, Roxanne E

2018-04-02

Mediation analysis allows the examination of effects of a third variable (mediator/confounder) in the causal pathway between an exposure and an outcome. The general multiple mediation analysis method (MMA), proposed by Yu et al., improves traditional methods (e.g., estimation of natural and controlled direct effects) to enable consideration of multiple mediators/confounders simultaneously and the use of linear and nonlinear predictive models for estimating mediation/confounding effects. Previous studies find that compared with non-Hispanic cancer survivors, Hispanic survivors are more likely to endure anxiety and depression after cancer diagnoses. In this paper, we applied MMA on MY-Health study to identify mediators/confounders and quantify the indirect effect of each identified mediator/confounder in explaining ethnic disparities in anxiety and depression among cancer survivors who enrolled in the study. We considered a number of socio-demographic variables, tumor characteristics, and treatment factors as potential mediators/confounders and found that most of the ethnic differences in anxiety or depression between Hispanic and non-Hispanic white cancer survivors were explained by younger diagnosis age, lower education level, lower proportions of employment, less likely of being born in the USA, less insurance, and less social support among Hispanic patients.

The effect, moderators, and mediators of resistance and aerobic exercise on health-related quality of life in older long-term survivors of prostate cancer.

PubMed

Buffart, Laurien M; Newton, Robert U; Chinapaw, Mai J; Taaffe, Dennis R; Spry, Nigel A; Denham, James W; Joseph, David J; Lamb, David S; Brug, Johannes; Galvão, Daniel A

2015-08-15

The current study examined effects, moderators (for whom), and mediators (working mechanisms) of 12 months of exercise on health-related quality of life (HRQoL) in older long-term survivors of prostate cancer. In total, 100 men aged 71.7 years (standard deviation, 6.4 years) were randomly assigned to 6 months of supervised aerobic and resistance exercise followed by 6 months of a home-based exercise maintenance program (EX group) or printed education material regarding physical activity for 12 months (PA group). Assessments took place at baseline and after 6 and 12 months. Generalized estimating equations were used to study the effects of EX versus PA on HRQoL at 6 and 12 months, adjusting for baseline HRQoL. The authors examined potential sociodemographic and clinical moderators by adding interaction terms, and potential physical and psychological mediators using the product-of-coefficients test. At 6 months, significant beneficial effects were found for global QoL, physical function, and social function in the EX group compared with the PA group. For physical function, beneficial effects were sustained at 12 months. Moderation analyses demonstrated larger effects of EX versus PA for patients who were married, started exercising sooner after their diagnosis, and previously used bisphosphonates. Changes in lower body functional performance significantly mediated the effect of EX on global QoL, physical function, and social function. No mediating effects on HRQoL were found for aerobic fitness, physical activity, fatigue, distress, or falls self-efficacy. Aerobic and resistance exercise appears to have beneficial effects on HRQoL among older, long-term survivors of prostate cancer. Effects were moderated by marital status, time since diagnosis, and use of bisphosphonates, and were mediated by lower body functional performance. © 2015 American Cancer Society.

Endomorphins potentiate acid-sensing ion channel currents and enhance the lactic acid-mediated increase in arterial blood pressure: effects amplified in hindlimb ischaemia.

PubMed

Farrag, Mohamed; Drobish, Julie K; Puhl, Henry L; Kim, Joyce S; Herold, Paul B; Kaufman, Marc P; Ruiz-Velasco, Victor

2017-12-01

Chronic limb ischaemia, characterized by inflammatory mediator release and a low extracellular pH, leads to acid-sensing ion channel (ASIC) activation and reflexively increases mean arterial pressure; endomorphin release is also increased under inflammatory conditions. We examined the modulation of ASIC currents by endomorphins in sensory neurons from rats with freely perfused and ligated femoral arteries: peripheral artery disease (PAD) model. Endomorphins potentiated sustained ASIC currents in both groups of dorsal root ganglion neurons, independent of mu opioid receptor stimulation or G protein activation. Intra-arterial administration of lactic acid (to simulate exercising muscle and evoke a pressor reflex), endomorphin-2 and naloxone resulted in a significantly greater pressor response than lactic acid alone, while administration of APETx2 inhibited endomorphin's enhancing effect in both groups. These results suggest a novel role for endomorphins in modulating ASIC function to effect lactic acid-mediated reflex increase in arterial pressure in patients with PAD. Chronic muscle ischaemia leads to accumulation of lactic acid and other inflammatory mediators with a subsequent drop in interstitial pH. Acid-sensing ion channels (ASICs), expressed in thin muscle afferents, sense the decrease in pH and evoke a pressor reflex known to increase mean arterial pressure. The naturally occurring endomorphins are also released by primary afferents under ischaemic conditions. We examined whether high affinity mu opioid receptor (MOR) agonists, endomorphin-1 (E-1) and -2 (E-2), modulate ASIC currents and the lactic acid-mediated pressor reflex. In rat dorsal root ganglion (DRG) neurons, exposure to E-2 in acidic solutions significantly potentiated ASIC currents when compared to acidic solutions alone. The potentiation was significantly greater in DRG neurons isolated from rats whose femoral arteries were ligated for 72 h. Sustained ASIC current potentiation was also observed in neurons pretreated with pertussis toxin, an uncoupler of G proteins and MOR. The endomorphin-mediated potentiation was a result of a leftward shift of the activation curve to higher pH values and a slight shift of the inactivation curve to lower pH values. Intra-arterial co-administration of lactic acid and E-2 led to a significantly greater pressor reflex than lactic acid alone in the presence of naloxone. Finally, E-2 effects were inhibited by pretreatment with the ASIC3 blocker APETx2 and enhanced by pretreatment with the ASIC1a blocker psalmotoxin-1. These findings have uncovered a novel role of endomorphins by which the opioids can enhance the lactic acid-mediated reflex increase in arterial pressure that is MOR stimulation-independent and APETx2-sensitive. © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.

Attitudinal Ambivalence as a Protective Factor Against Junk Food Advertisements: A Moderated Mediation Model of Behavioral Intention.

PubMed

Ran, Weina; Yamamoto, Masahiro

2015-08-01

This study investigates the role of attitudinal ambivalence in moderating the effects of junk food advertisements on behavioral intentions by tapping different facets of this construct-felt ambivalence, potential ambivalence, and affective-cognitive ambivalence. Results based on an online survey of college students indicate that attention to junk food advertisements has an indirect positive effect on intentions to eat junk food through its positive effect on attitudes toward junk food. A moderated mediation model reveals that this indirect effect of junk food advertisements is weakened as respondents' levels of felt ambivalence increase. This moderating role is not observed for the measures of potential ambivalence and affective-cognitive ambivalence. Implications are discussed for health interventions.

On their best behavior: how animal behavior can help determine the combined effects of species interactions and climate change.

PubMed

Harmon, Jason P; Barton, Brandon T

2013-09-01

The increasingly appreciated link between climate change and species interactions has the potential to help us understand and predict how organisms respond to a changing environment. As this connection grows, it becomes even more important to appreciate the mechanisms that create and control the combined effect of these factors. However, we believe one such important set of mechanisms comes from species' behavior and the subsequent trait-mediated interactions, as opposed to the more often studied density-mediated effects. Behavioral mechanisms are already well appreciated for mitigating the separate effects of the environment and species interactions. Thus, they could be at the forefront for understanding the combined effects. In this review, we (1) show some of the known behaviors that influence the individual and combined effects of climate change and species interactions; (2) conceptualize general ways behavior may mediate these combined effects; and (3) illustrate the potential importance of including behavior in our current tools for predicting climate change effects. In doing so, we hope to promote more research on behavior and other mechanistic factors that may increase our ability to accurately predict climate change effects. © 2013 New York Academy of Sciences.

Theory of Mind as a mediator variable between neurocognition and functioning in young individuals in treatment with secondary services for non-psychotic disorders.

PubMed

Francesconi, Marta; Minichino, Amedeo; Carrión, Ricardo E; Chiaie, Roberto Delle; Bevilacqua, Arturo; Parisi, Maurizio; Rullo, Santo; Bersani, Francesco Saverio; Biondi, Massimo; Cadenhead, Kristin

2016-12-30

A large body of studies provides evidence for a link between neurocognition, theory of mind (ToM) and functioning in psychotic spectrum disorders (PSDs), with ToM mediating the effect that neurocognition has on functioning. These three constructs and the related mediation effect may characterize different psychiatric syndromes other than PSDs. Structural equation modelling (SEM) was applied to baseline data from a longitudinal study of 138 young individuals with a recent-onset psychiatric disorder. Using SEM, we tested the hypothesis that ToM mediates the effect of neurocognition on functioning independent of the level of psychosis risk and the diagnostic category. In the mediation model the bootstrapping estimate revealed a significant indirect effect that was the association of social cognition with neurocognition and with functional outcome. ToM was significantly associated with neurocognition and the path from neurocognition to functioning was no longer significant as soon as the mediator (ToM) was entered into the mediation model consistent with a complete mediation effect through ToM. This mediation was independent of the psychosis-risk status and the psychiatric diagnoses. Our results provide useful information on a young psychiatric sample, in which specific therapeutic interventions have the potential to significantly limit functional disability. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Statistical grand rounds: understanding the mechanism: mediation analysis in randomized and nonrandomized studies.

PubMed

Mascha, Edward J; Dalton, Jarrod E; Kurz, Andrea; Saager, Leif

2013-10-01

In comparative clinical studies, a common goal is to assess whether an exposure, or intervention, affects the outcome of interest. However, just as important is to understand the mechanism(s) for how the intervention affects outcome. For example, if preoperative anemia was shown to increase the risk of postoperative complications by 15%, it would be important to quantify how much of that effect was due to patients receiving intraoperative transfusions. Mediation analysis attempts to quantify how much, if any, of the effect of an intervention on outcome goes though prespecified mediator, or "mechanism" variable(s), that is, variables sitting on the causal pathway between exposure and outcome. Effects of an exposure on outcome can thus be divided into direct and indirect, or mediated, effects. Mediation is claimed when 2 conditions are true: the exposure affects the mediator and the mediator (adjusting for the exposure) affects the outcome. Understanding how an intervention affects outcome can validate or invalidate one's original hypothesis and also facilitate further research to modify the responsible factors, and thus improve patient outcome. We discuss the proper design and analysis of studies investigating mediation, including the importance of distinguishing mediator variables from confounding variables, the challenge of identifying potential mediators when the exposure is chronic versus acute, and the requirements for claiming mediation. Simple designs are considered, as well as those containing multiple mediators, multiple outcomes, and mixed data types. Methods are illustrated with data collected by the National Surgical Quality Improvement Project (NSQIP) and utilized in a companion paper which assessed the effects of preoperative anemic status on postoperative outcomes.

Facial Redness Increases Men's Perceived Healthiness and Attractiveness.

PubMed

Thorstenson, Christopher A; Pazda, Adam D; Elliot, Andrew J; Perrett, David I

2017-06-01

Past research has shown that peripheral and facial redness influences perceptions of attractiveness for men viewing women. The current research investigated whether a parallel effect is present when women rate men with varying facial redness. In four experiments, women judged the attractiveness of men's faces, which were presented with varying degrees of redness. We also examined perceived healthiness and other candidate variables as mediators of the red-attractiveness effect. The results show that facial redness positively influences ratings of men's attractiveness. Additionally, perceived healthiness was documented as a mediator of this effect, independent of other potential mediator variables. The current research emphasizes facial coloration as an important feature of social judgments.

Potentiation of pulmonary reflex response to capsaicin 24h following whole-body acrolein exposure is mediated by TRPV1.

PubMed

Hazari, Mehdi S; Rowan, William H; Winsett, Darrell W; Ledbetter, Allen D; Haykal-Coates, Najwa; Watkinson, William P; Costa, Daniel L

2008-02-01

Pulmonary C-fibers are stimulated by irritant air pollutants producing apnea, bronchospasm, and decrease in HR. Chemoreflex responses resulting from C-fiber activation are sometimes mediated by TRPV1 and release of substance P. While acrolein has been shown to stimulate C-fibers, the persistence of acrolein effects and the role of C-fibers in these responses are unknown. These experiments were designed to determine the effects of whole-body acrolein exposure and pulmonary chemoreflex response post-acrolein. Rats were exposed to either air or 3 ppm acrolein for 3 h while ventilatory function and HR were measured; 1-day later response to capsaicin challenge was measured in anesthetized rats. Rats experienced apnea and decrease in HR upon exposure to acrolein, which was not affected by either TRPV1 antagonist or NK(1)R antagonist pretreatment. Twenty-four hours later, capsaicin caused apnea and bronchoconstriction in control rats, which was potentiated in rats exposed to acrolein. Pretreatment with TRPV1 antagonist or NK(1)R antagonist prevented potentiation of apneic response and bronchoconstriction 24h post-exposure. These data suggest that although potentiation of pulmonary chemoreflex response 24h post-acrolein is mediated by TRPV1 and release of substance P, cardiopulmonary inhibition during whole-body acrolein exposure is mediated through other mechanisms.

Anti-neuroinflammatory effects of grossamide from hemp seed via suppression of TLR-4-mediated NF-κB signaling pathways in lipopolysaccharide-stimulated BV2 microglia cells.

PubMed

Luo, Qian; Yan, Xiaoli; Bobrovskaya, Larisa; Ji, Mei; Yuan, Huiqing; Lou, Hongxiang; Fan, Peihong

2017-04-01

Grossamide, a representative lignanamide in hemp seed, has been reported to possess potential anti-inflammatory effects. However, the potential anti-neuroinflammatory effects and underlying mechanisms of action of grossamide are still unclear. Therefore, the present study investigated the possible effects and underlying mechanisms of grossamide against lipopolysaccharide (LPS)-induced inflammatory response in BV2 microglia cells. BV2 microglia cells were pre-treated with various concentrations of grossamide before being stimulated with LPS to induce inflammation. The levels of pro-inflammatory cytokines were determined using the enzyme-linked immunoassay (ELISA) and mRNA expression levels were measured by real-time PCR. The translocation of nuclear factor-kappa B (NF-κB) and contribution of TLR4-mediated NF-κB activation on inflammatory effects were evaluated by immunostaining and Western blot analysis. This study demonstrated that grossamide significantly inhibited the secretion of pro-inflammatory mediators such as interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α), and decreased the level of LPS-mediated IL-6 and TNF-α mRNA. In addition, it significantly reduced the phosphorylation levels of NF-κB subunit p65 in a concentration-dependent manner and suppressed translocation of NF-κB p65 into the nucleus. Furthermore, grossamide markedly attenuated the LPS-induced expression of Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88). Taken together, these data suggest that grossamide could be a potential therapeutic candidate for inhibiting neuroinflammation in neurodegenerative diseases.

Metabolic changes of cultured DRG neurons induced by adenosine using confocal microscopy imaging

NASA Astrophysics Data System (ADS)

Zheng, Liqin; Huang, Yimei; Chen, Jiangxu; Wang, Yuhua; Yang, Hongqin; Zhang, Yanding; Xie, Shusen

2012-12-01

Adenosine exerts multiple effects on pain transmission in the peripheral nervous system. This study was performed to use confocal microscopy to evaluate whether adenosine could affect dorsal root ganglia (DRG) neurons in vitro and test which adenosine receptor mediates the effect of adenosine on DRG neurons. After adding adenosine with different concentration, we compared the metabolic changes by the real time imaging of calcium and mitochondria membrane potential using confocal microscopy. The results showed that the effect of 500 μM adenosine on the metabolic changes of DRG neurons was more significant than others. Furthermore, four different adenosine receptor antagonists were used to study which receptor mediated the influences of adenosine on the cultured DRG neurons. All adenosine receptor antagonists especially A1 receptor antagonist (DPCPX) had effect on the Ca2+ and mitochondria membrane potential dynamics of DRG neurons. The above studies demonstrated that the effect of adenosine which may be involved in the signal transmission on the sensory neurons was dose-dependent, and all the four adenosine receptors especially the A1R may mediate the transmission.

Depression moderates smoking behavior in response to a sad mood induction.

PubMed

Fucito, Lisa M; Juliano, Laura M

2009-09-01

Stress and anxiety have been shown to increase smoking motivation. There is limited experimental data on depressed or sad mood and smoking. This study investigated the effects of two induced moods on smoking behavior. Depression scores were examined as a potential moderator and mood changes were tested as a potential mediator. Smokers (N = 121) were randomly assigned to receive either a sad induction or a neutral induction via standardized film clips. Among participants with higher depression scores, smoking duration and the number of cigarette puffs were greater in response to the sad condition. There was also a marginal interactive effect on the change in expired air carbon monoxide among this subsample; however, no differences in smoking latency or craving were observed. Changes in positive mood partially mediated the effect of condition on smoking behavior among participants with high depression scores. There was no modifying effect of gender or mediating effect of negative mood changes. The results provide preliminary support that decreases in positive mood may have a greater influence on smoking behavior among depression-prone smokers than less psychiatrically vulnerable smokers. 2009 APA, all rights reserved.

Interrupting violence: how the CeaseFire Program prevents imminent gun violence through conflict mediation.

PubMed

Whitehill, Jennifer M; Webster, Daniel W; Frattaroli, Shannon; Parker, Elizabeth M

2014-02-01

Cities are increasingly adopting CeaseFire, an evidence-based public health program that uses specialized outreach workers, called violence interrupters (VIs), to mediate potentially violent conflicts before they lead to a shooting. Prior research has linked conflict mediation with program-related reductions in homicides, but the specific conflict mediation practices used by effective programs to prevent imminent gun violence have not been identified. We conducted case studies of CeaseFire programs in two inner cities using qualitative data from focus groups with 24 VIs and interviews with eight program managers. Study sites were purposively sampled to represent programs with more than 1 year of implementation and evidence of program effectiveness. Staff with more than 6 months of job experience were recruited for participation. Successful mediation efforts were built on trust and respect between VIs and the community, especially high-risk individuals. In conflict mediation, immediate priorities included separating the potential shooter from the intended victim and from peers who may encourage violence, followed by persuading the parties to resolve the conflict peacefully. Tactics for brokering peace included arranging the return of stolen property and emphasizing negative consequences of violence such as jail, death, or increased police attention. Utilizing these approaches, VIs are capable of preventing gun violence and interrupting cycles of retaliation.

The applied model of imagery use: Examination of moderation and mediation effects.

PubMed

Koehn, S; Stavrou, N A M; Young, J A; Morris, T

2016-08-01

The applied model of mental imagery use proposed an interaction effect between imagery type and imagery ability. This study had two aims: (a) the examination of imagery ability as a moderating variable between imagery type and dispositional flow, and (b) the testing of alternative mediation models. The sample consisted of 367 athletes from Scotland and Australia, who completed the Sport Imagery Questionnaire, Sport Imagery Ability Questionnaire, and Dispositional Flow Scale-2. Hierarchical regression analysis showed direct effects of imagery use and imagery ability on flow, but no significant interaction. Mediation analysis revealed a significant indirect path, indicating a partially mediated relationship (P = 0.002) between imagery use, imagery ability, and flow. Partial mediation was confirmed when the effect of cognitive imagery use and cognitive imagery ability was tested, and a full mediation model was found between motivational imagery use, motivational imagery ability, and flow. The results are discussed in conjunction with potential future research directions on advancing theory and applications. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

P2X1 Receptor-Mediated Ca2+ Influx Triggered by DA-9801 Potentiates Nerve Growth Factor-Induced Neurite Outgrowth.

PubMed

Back, Moon Jung; Lee, Hae Kyung; Lee, Joo Hyun; Fu, Zhicheng; Son, Mi Won; Choi, Sang Zin; Go, Hyo Sang; Yoo, Sungjae; Hwang, Sun Wook; Kim, Dae Kyong

2016-11-16

Nerve growth factor (NGF)-induced neuronal regeneration has emerged as a strategy to treat neuronal degeneration-associated disorders. However, direct NGF administration is limited by the occurrence of adverse effects at high doses of NGF. Therefore, development of a therapeutic strategy to promote the NGF trophic effect is required. In view of the lack of understanding of the mechanism for potentiating the NGF effect, this study investigated molecular targets of DA-9801, a well-standardized Dioscorea rhizome extract, which has a promoting effect on NGF. An increase in intracellular calcium ion level was induced by DA-9801, and chelation of extracellular calcium ions with ethylene-bis(oxyethylenenitrilo)tetraacetic acid (EGTA) suppressed the potentiating effect of DA-9801 on NGF-induced neurite outgrowth. In addition, EGTA treatment reduced the DA-9801-induced phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2), the major mediators of neurite outgrowth. To find which calcium ion-permeable channel contributes to the calcium ion influx induced by DA-9801, we treated PC12 cells with various inhibitors of calcium ion-permeable channels. NF449, a P2X1 receptor selective antagonist, significantly abolished the potentiating effect of DA-9801 on NGF-induced neurite outgrowth and abrogated the DA-9801-induced ERK1/2 phosphorylation. In addition, transfection with siRNA of P2X1 receptor significantly reduced the DA-9801-enhanced neurite outgrowth. In conclusion, calcium ion influx through P2X1 receptor mediated the promoting effect of DA-9801 on NGF-induced neurite outgrowth via ERK1/2 phosphorylation.

Potential mediating pathways through which sports participation relates to reduced risk of suicidal ideation.

PubMed

Taliaferro, Lindsay A; Rienzo, Barbara A; Miller, M David; Pigg, R Morgan; Dodd, Virginia J

2010-09-01

Suicide ranks as the third leading cause of death for American youth. Researchers examining sport participation and suicidal behavior have regularly found inverse relationships. This study represents the first effort to test a model depicting potential mechanisms through which sport participation relates to reduced risk of suicidal ideation. The participants were 450 undergraduate students. Measures assessed participants' involvement in university-run sports and other activities; frequency of physical activity; and perceived social support, self-esteem, depression, hopelessness, loneliness, and suicidal ideation. Regression analyses confirmed a path model and tested for mediation effects. Vigorous activity mediated relationships between sport participation and self-esteem and depression; and self-esteem and depression mediated the relationship between vigorous activity and suicidal ideation. Social support mediated relationships between sport participation and depression, hopelessness, and loneliness; and each of these risk factors partially mediated the relationship between social support and suicidal ideation. However no variable fully mediated the relationship between sport participation and suicidal ideation. This study provides a foundation for research designed to examine pathways through which sport participation relates to reduced risk of suicidal behavior.

Moderated mediation analysis: An illustration using the association of gender with delinquency and mental health.

PubMed

Miles, Jeremy N V; Kulesza, Magdalena; Ewing, Brett; Shih, Regina A; Tucker, Joan S; D'Amico, Elizabeth J

When researchers find an association between two variables, it is useful to evaluate the role of other constructs in this association. While assessing these mediation effects, it is important to determine if results are equal for different groups. It is possible that the strength of a mediation effect may differ for males and females, for example - such an effect is known as moderated mediation. Participants were 2532 adolescents from diverse ethnic/racial backgrounds and equally distributed across gender. The goal of this study was to investigate parental respect as a potential mediator of the relationship between gender and delinquency and mental health, and to determine whether observed mediation is moderated by gender. Parental respect mediated the association between gender and both delinquency and mental health. Specifically, parental respect was a protective factor against delinquency and mental health problems for both females and males. Demonstrated the process of estimating models in Lavaan, using two approaches (i.e. single group regression and multiple group regression model), and including covariates in both models.

Moderated mediation analysis: An illustration using the association of gender with delinquency and mental health

PubMed Central

Miles, Jeremy N.V.; Kulesza, Magdalena; Ewing, Brett; Shih, Regina A.; Tucker, Joan S.; D’Amico, Elizabeth J.

2015-01-01

Purpose When researchers find an association between two variables, it is useful to evaluate the role of other constructs in this association. While assessing these mediation effects, it is important to determine if results are equal for different groups. It is possible that the strength of a mediation effect may differ for males and females, for example – such an effect is known as moderated mediation. Design Participants were 2532 adolescents from diverse ethnic/racial backgrounds and equally distributed across gender. The goal of this study was to investigate parental respect as a potential mediator of the relationship between gender and delinquency and mental health, and to determine whether observed mediation is moderated by gender. Findings Parental respect mediated the association between gender and both delinquency and mental health. Specifically, parental respect was a protective factor against delinquency and mental health problems for both females and males. Practical implications Demonstrated the process of estimating models in Lavaan, using two approaches (i.e. single group regression and multiple group regression model), and including covariates in both models. PMID:26500722

The inverse relationship between prostate-specific antigen (PSA) and obesity.

PubMed

Aref, Adel; Vincent, Andrew D; O'Callaghan, Michael; Martin, Sean; Sutherland, Peter; Hoy, Andrew; Butler, Lisa M; Wittert, Gary

2018-06-25

Obese men have lower serum prostate-specific antigen (PSA) than comparably aged lean men, but the underlying mechanism remains unclear. The aim of this study was to determine the effect of obesity on PSA and the potential contributing mechanisms. A cohort of 1195 men aged 35 years and over at recruitment, with demographic, anthropometric (body mass index (BMI), waist circumference (WC)) and serum hormone (serum testosterone (T), estradiol (E2)), PSA and hematology assessments obtained over two waves was assessed. Men with a history of prostate cancer or missing PSA were excluded, leaving 970 men for the final analysis. Mixed-effects regressions and mediation analyses adjusting for hormonal and volumetric factors explore the potential mechanisms relating obesity to PSA. After adjusting for age, PSA levels were lower in men with greater WC (p=0.001). In a multivariable model including WC, age, E2/T and PlasV as predictors, no statistically significant associations were observed between with PSA and either WC (p=0.36) or PlasV (p=0.49), while strong associations were observed with both E2/T (p<0.001) and age (p<0.001). In the mediation analyses with PlasV as the mediator, the average causal mediation effect (ACME) explained roughly 0.2 of the total effect of WC on PSA (p=0.31), while when E2/T is a mediator; the ACME explained roughly 0.5 of the effect (p<0.001). Our findings indicate that lower PSA levels in obese men, as compared to normal weight men, can be explained both by hormonal changes (elevated E2/T ratio) and haemodilution. Hormonal factors therefore represent a substantial but underappreciated mediating pathway.

Pre- and Perinatal Risk for Attention-Deficit Hyperactivity Disorder: Does Neuropsychological Weakness Explain the Link?

PubMed

Wiggs, Kelsey; Elmore, Alexis L; Nigg, Joel T; Nikolas, Molly A

2016-11-01

Etiological investigations of attention-deficit hyperactivity disorder (ADHD) and disruptive behavior problems support multiple causal pathways, including involvement of pre- and perinatal risk factors. Because these risks occur early in life, well before observable ADHD and externalizing symptoms emerge, the relation between risk and symptoms may be mediated by neurodevelopmental effects that manifest later in neuropsychological functioning. However, potential dissociable effects of pre/perinatal risk elements on ADHD and familial confounds must also be considered to test alternative hypotheses. 498 youth aged 6-17 years (55.0 % male) completed a multi-stage, multi-informant assessment including parent and teacher symptom reports of symptoms and parent ratings of pre/perinatal health risk indicators. Youth completed a neuropsychological testing battery. Multiple mediation models examined direct effects of pre- and perinatal health risk on ADHD and other disruptive behavior disorder symptoms and indirect effects via neuropsychological functioning. Parental ADHD symptoms and externalizing status was covaried to control for potential familial effects. Effects of prenatal substance exposure on inattention were mediated by memory span and temporal processing deficits. Further, effects of perinatal health risk on inattention, hyperactivity-impulsivity, and ODD were mediated by deficits in response variability and temporal processing. Further, maternal health risks during pregnancy appeared to exert direct rather than indirect effects on outcomes. Results suggest that after controlling for familial relatedness of ADHD between parent and child, early developmental health risks may influence ADHD via effects on neuropsychological processes underpinning the disorder.

Asymptotic and resampling strategies for assessing and comparing indirect effects in multiple mediator models.

PubMed

Preacher, Kristopher J; Hayes, Andrew F

2008-08-01

Hypotheses involving mediation are common in the behavioral sciences. Mediation exists when a predictor affects a dependent variable indirectly through at least one intervening variable, or mediator. Methods to assess mediation involving multiple simultaneous mediators have received little attention in the methodological literature despite a clear need. We provide an overview of simple and multiple mediation and explore three approaches that can be used to investigate indirect processes, as well as methods for contrasting two or more mediators within a single model. We present an illustrative example, assessing and contrasting potential mediators of the relationship between the helpfulness of socialization agents and job satisfaction. We also provide SAS and SPSS macros, as well as Mplus and LISREL syntax, to facilitate the use of these methods in applications.

Invasive insect herbivores as disrupters of chemically-mediated tritrophic interactions: effects of herbivore density and parasitoid learning

USDA-ARS?s Scientific Manuscript database

Invasive species of insect herbivores have the potential to interfere with native multitrophic interactions when they invade new environments. For instance, exotic herbivores can affect the chemical cues emitted by plants and disrupt attraction of natural enemies mediated by herbivore-induced plant ...

Religiousness and Alcohol Use in College Students: Examining Descriptive Drinking Norms as Mediators

ERIC Educational Resources Information Center

Brechting, Emily H.; Carlson, Charles R.

2015-01-01

Religiousness has consistently emerged in the literature as a protective factor for alcohol use. Relatively few studies have empirically explored possible mechanisms for this robust effect. The present study examines descriptive drinking norms as a potential mediator of the religiousness--alcohol consumption association. Consistent with the…

Mindfulness and Counseling Self-Efficacy: The Mediating Role of Attention and Empathy

ERIC Educational Resources Information Center

Greason, Paige Bentley; Cashwell, Craig S.

2009-01-01

This study examined the predictive relationship between mindfulness and counseling self-efficacy and the potential mediating effects of attention and empathy. Master's-level counseling interns and doctoral counseling students (N = 179) were surveyed to determine levels of mindfulness, attention, empathy, and counseling self-efficacy. Pearson…

Reduced expression IRF7 in nasal epithelial cells from smokers as a potential mechanism mediating enhanced susceptibility to influenza

EPA Science Inventory

Rationale: Smokers are more susceptible to viral infections, including influenza virus, yet the mechanisms mediating this effect are not known. Methods: We have established an in vitro model of differentiated nasal epithelial cells from smokers, which maintain enhanced levels...

Inhibitors of bacterial multidrug efflux pumps potentiate antimicrobial photoinactivation.

PubMed

Tegos, George P; Masago, Kayo; Aziz, Fatima; Higginbotham, Andrew; Stermitz, Frank R; Hamblin, Michael R

2008-09-01

Antimicrobial photodynamic inactivation (APDI) combines a nontoxic photoactivatable dye or photosensitizer (PS) with harmless visible light to generate singlet oxygen and reactive oxygen species that kill microbial cells. Cationic phenothiazinium dyes, such as toluidine blue O (TBO), are the only PS used clinically for APDI, and we recently reported that this class of PS are substrates of multidrug efflux pumps in both gram-positive and gram-negative bacteria. We now report that APDI can be significantly potentiated by combining the PS with an efflux pump inhibitor (EPI). Killing of Staphylococcus aureus mediated by TBO and red light is greatly increased by coincubation with known inhibitors of the major facilitator pump (NorA): the diphenyl urea INF271, reserpine, 5'-methoxyhydnocarpin, and the polyacylated neohesperidoside, ADH7. The potentiation effect is greatest in the case of S. aureus mutants that overexpress NorA and least in NorA null cells. Addition of the EPI before TBO has a bigger effect than addition of the EPI after TBO. Cellular uptake of TBO is increased by EPI. EPI increased photodynamic inactivation killing mediated by other phenothiazinium dyes, such as methylene blue and dimethylmethylene blue, but not that mediated by nonphenothiazinium PS, such as Rose Bengal and benzoporphyrin derivative. Killing of Pseudomonas aeruginosa mediated by TBO and light was also potentiated by the resistance nodulation division pump (MexAB-OprM) inhibitor phenylalanine-arginine beta-naphthylamide but to a lesser extent than for S. aureus. These data suggest that EPI could be used in combination with phenothiazinium salts and light to enhance their antimicrobial effect against localized infections.

Mitochondria-targeted esculetin alleviates mitochondrial dysfunction by AMPK-mediated nitric oxide and SIRT3 regulation in endothelial cells: potential implications in atherosclerosis.

PubMed

Karnewar, Santosh; Vasamsetti, Sathish Babu; Gopoju, Raja; Kanugula, Anantha Koteswararao; Ganji, Sai Krishna; Prabhakar, Sripadi; Rangaraj, Nandini; Tupperwar, Nitin; Kumar, Jerald Mahesh; Kotamraju, Srigiridhar

2016-04-11

Mitochondria-targeted compounds are emerging as a new class of drugs that can potentially alter the pathophysiology of those diseases where mitochondrial dysfunction plays a critical role. We have synthesized a novel mitochondria-targeted esculetin (Mito-Esc) with an aim to investigate its effect during oxidative stress-induced endothelial cell death and angiotensin (Ang)-II-induced atherosclerosis in ApoE(-/-) mice. Mito-Esc but not natural esculetin treatment significantly inhibited H2O2- and Ang-II-induced cell death in human aortic endothelial cells by enhancing NO production via AMPK-mediated eNOS phosphorylation. While L-NAME (NOS inhibitor) significantly abrogated Mito-Esc-mediated protective effects, Compound c (inhibitor of AMPK) significantly decreased Mito-Esc-mediated increase in NO production. Notably, Mito-Esc promoted mitochondrial biogenesis by enhancing SIRT3 expression through AMPK activation; and restored H2O2-induced inhibition of mitochondrial respiration. siSIRT3 treatment not only completely reversed Mito-Esc-mediated mitochondrial biogenetic marker expressions but also caused endothelial cell death. Furthermore, Mito-Esc administration to ApoE(-/-) mice greatly alleviated Ang-II-induced atheromatous plaque formation, monocyte infiltration and serum pro-inflammatory cytokines levels. We conclude that Mito-Esc is preferentially taken up by the mitochondria and preserves endothelial cell survival during oxidative stress by modulating NO generation via AMPK. Also, Mito-Esc-induced SIRT3 plays a pivotal role in mediating mitochondrial biogenesis and perhaps contributes to its anti-atherogenic effects.

Analysis of Individual Social-ecological Mediators and Moderators and Their Ability to Explain Effect of a Randomized Neighborhood Walking Intervention.

PubMed

Michael, Yvonne L; Carlson, Nichole E

2009-07-30

Using data from the SHAPE trial, a randomized 6-month neighborhood-based intervention designed to increase walking activity among older adults, this study identified and analyzed social-ecological factors mediating and moderating changes in walking activity. Three potential mediators (social cohesion, walking efficacy, and perception of neighborhood problems) and minutes of brisk walking were assessed at baseline, 3-months, and 6-months. One moderator, neighborhood walkability, was assessed using an administrative GIS database. The mediating effect of change in process variables on change in brisk walking was tested using a product-of-coefficients test, and we evaluated the moderating effect of neighborhood walkability on change in brisk walking by testing the significance of the interaction between walkability and intervention status. Only one of the hypothesized mediators, walking efficacy, explained the intervention effect (product of the coefficients (95% CI) = 8.72 (2.53, 15.56). Contrary to hypotheses, perceived neighborhood problems appeared to suppress the intervention effects (product of the coefficients (95% CI = -2.48, -5.6, -0.22). Neighborhood walkability did not moderate the intervention effect. Walking efficacy may be an important mediator of lay-lead walking interventions for sedentary older adults. Social-ecologic theory-based analyses can support clinical interventions to elucidate the mediators and moderators responsible for producing intervention effects.

Intergenerational Transmission of Maladaptive Parenting Strategies in Families of Adolescent Mothers: Effects from Grandmothers to Young Children

PubMed Central

Seay, Danielle M.; Jahromi, Laudan B.; Umaña-Taylor, Adriana J.; Updegraff, Kimberly A.

2015-01-01

The current longitudinal study examined the effect of the transmission of maladaptive parenting strategies from grandmothers to adolescent mothers on children’s subsequent development. Mexican-origin adolescent mothers (N = 204) participated in home interviews when the adolescent’s child (89 boys, 60 girls) was 2, 3, 4, and 5 years old. Grandmothers’ psychological control toward the adolescent mother was positively related to adolescents’ potential for abuse 1 year later, which was subsequently positively related to adolescents’ punitive discipline toward their young child. In addition, adolescent mothers’ punitive discipline subsequently predicted greater externalizing problems and less committed compliance among their children. Adolescent mothers’ potential for abuse and punitive discipline mediated the effects of grandmothers’ psychological control on children’s externalizing problems. Finally, adolescent mothers’ potential for abuse mediated the effect of grandmothers’ psychological control on adolescent mothers’ punitive discipline. Results highlight the salience of long-term intergenerational effects of maladaptive parenting on children’s behavior. PMID:26521948

Unpacking personalized feedback: an exploratory study of the impact of its components and the reactions it elicits among problem drinking men who have sex with men.

PubMed

Kuerbis, Alexis Noel; Schaumberg, Katherine; Davis, Christine M; Hail, Lisa; Morgenstern, Jon

2014-03-01

Personalized feedback (PF) has demonstrated effectiveness in reducing drinking. Few studies have examined its effectiveness with adult problem drinkers or its potential mediators or moderators, including developing discrepancy. This study aimed to identify potential mediators and moderators of PF provided to adult problem drinking men who have sex with men (PDMSM). An exploratory analysis of PF provided to PDMSM in the context of modified behavioral self-control therapy (N = 90). The association of individual items of PF, severity of PF, and independently rated, in-session participant reactions to PF with drinking outcomes (mean drinks per drinking day, MDDD) were examined using correlations and logistic and linear regression. Significant pre-post differences in MDDD emerged. Other drug risk, family risk, and having an abnormal liver enzyme test result were significantly associated with proxies for developed discrepancy in expected directions; however, no PF item or reaction to PF predicted drinking outcomes. Severity of PF was not associated with participant reactions or drinking outcome. PF may be an effective intervention for PDMSM. Further research is needed to identify potential mediators and moderators of PF among adults.

Physical Injury and Somatic Complaints: The Mediating Role of Posttraumatic Stress Symptoms in Young Survivors of a Terror Attack.

PubMed

Bugge, Ingrid; Dyb, Grete; Stensland, Synne Øien; Ekeberg, Øivind; Wentzel-Larsen, Tore; Diseth, Trond H

2017-06-01

Physically injured trauma survivors have particularly high risk for later somatic complaints and posttraumatic stress symptoms (PTSS). However, the potential mediating role of PTSS linking injury to later somatic complaints has been poorly investigated. In this study, survivors (N = 255) were interviewed longitudinally at 2 timepoints after the terror attack on Utøya Island, Norway, in 2011. Assessments included injury sustained during the attack, PTSS (after 4-5 months), somatic complaints (after 14-15 months), and background factors. Causal mediation analysis was conducted to evaluate the potential mediating role of PTSS in linking injury to somatic complaints comparing 2 groups of injured survivors with noninjured survivors. For the nonhospitalized injured versus the noninjured survivors, the mediated pathway was significant (average causal mediation effect; ACME = 0.09, p = .028, proportion = 55.8%). For the hospitalized versus the noninjured survivors, the mediated pathway was not significant (ACME = 0.04, p = .453, proportion = 11.6%). PTSS may play a significant mediating role in the development of somatic complaints among nonhospitalized injured trauma survivors. Intervening health professionals should be aware of this possible pathway to somatic complaints. Copyright © 2017 International Society for Traumatic Stress Studies.

Reduced Osmotic Potential Inhibition of Photosynthesis 1

PubMed Central

Berkowitz, Gerald A.; Gibbs, Martin

1983-01-01

The effects of reduced reaction medium osmotic potential (0.67 molar sorbitol as compared to a control treatment with 0.33 molar sorbitol) on the enzymic steps of the photosynthetic carbon reduction cycle were investigated using isolated spinach (Spinacia oleracea L. var Longstanding Bloomsdale) chloroplasts. Reversal of reduced osmotic potential inhibition of photosynthetic rates by a stromal alkalating agent (NH4Cl) was associated with specific steps of the cycle. Low osmotic potential induced stromal acidification was found to be facilitated by osmotically induced chloroplast shrinkage. However, the action of the alkalating agent was found not to be associated with reversal of osmotically induced morphological changes of the stromal compartment. Labeled metabolite analyses indicated that the osmotic stress treatment caused the substrate for fructose 1,6-bisphosphatase (FBPase) to build up in the absence of NH4Cl, and the substrate for phosphoribulokinase to increase in the presence of NH4Cl. These data were interpreted as indicating that the most severe effect of osmotic stress on photosynthesis is at the site of FBPase, and that this inhibition is mediated by osmotically induced stromal acidification. Phosphoribulokinase activity inhibition at the low osmotic potential treatment was apparently less severe and not mediated by stromal acidification. A third site of osmotic inhibition, which was reversed by NH4Cl, and therefore was assumed to be mediated by stromal acidification, was at the step of ribulose 1,5-bisphosphate carboxylase. Additions of NH4Cl also enhanced the activity of the pH-insensitive phase of the photosynthetic carbon reduction cycle, 3-phosphoglyceric acid reduction, at the stress treatment. This effect was thought to be mediated by the removal of the block at FBPase. A model was proposed to outline the relative severity of osmotic stress effects at various sites of the photosynthetic carbon reduction cycle. Images Fig. 1 PMID:16663127

Power in Bayesian Mediation Analysis for Small Sample Research

PubMed Central

Miočević, Milica; MacKinnon, David P.; Levy, Roy

2018-01-01

It was suggested that Bayesian methods have potential for increasing power in mediation analysis (Koopman, Howe, Hollenbeck, & Sin, 2015; Yuan & MacKinnon, 2009). This paper compares the power of Bayesian credibility intervals for the mediated effect to the power of normal theory, distribution of the product, percentile, and bias-corrected bootstrap confidence intervals at N≤ 200. Bayesian methods with diffuse priors have power comparable to the distribution of the product and bootstrap methods, and Bayesian methods with informative priors had the most power. Varying degrees of precision of prior distributions were also examined. Increased precision led to greater power only when N≥ 100 and the effects were small, N < 60 and the effects were large, and N < 200 and the effects were medium. An empirical example from psychology illustrated a Bayesian analysis of the single mediator model from prior selection to interpreting results. PMID:29662296

Power in Bayesian Mediation Analysis for Small Sample Research.

PubMed

Miočević, Milica; MacKinnon, David P; Levy, Roy

2017-01-01

It was suggested that Bayesian methods have potential for increasing power in mediation analysis (Koopman, Howe, Hollenbeck, & Sin, 2015; Yuan & MacKinnon, 2009). This paper compares the power of Bayesian credibility intervals for the mediated effect to the power of normal theory, distribution of the product, percentile, and bias-corrected bootstrap confidence intervals at N≤ 200. Bayesian methods with diffuse priors have power comparable to the distribution of the product and bootstrap methods, and Bayesian methods with informative priors had the most power. Varying degrees of precision of prior distributions were also examined. Increased precision led to greater power only when N≥ 100 and the effects were small, N < 60 and the effects were large, and N < 200 and the effects were medium. An empirical example from psychology illustrated a Bayesian analysis of the single mediator model from prior selection to interpreting results.

Inhibition of CD26/dipeptidyl peptidase IV enhances CCL11/eotaxin-mediated recruitment of eosinophils in vivo.

PubMed

Forssmann, Ulf; Stoetzer, Carsten; Stephan, Michael; Kruschinski, Carsten; Skripuletz, Thomas; Schade, Jutta; Schmiedl, Andreas; Pabst, Reinhard; Wagner, Leona; Hoffmann, Torsten; Kehlen, Astrid; Escher, Sylvia E; Forssmann, Wolf-Georg; Elsner, Jörn; von Hörsten, Stephan

2008-07-15

Chemokines mediate the recruitment of leukocytes to the sites of inflammation. N-terminal truncation of chemokines by the protease dipeptidyl peptidase IV (DPPIV) potentially restricts their activity during inflammatory processes such as allergic reactions, but direct evidence in vivo is very rare. After demonstrating that N-terminal truncation of the chemokine CCL11/eotaxin by DPPIV results in a loss of CCR3-mediated intracellular calcium mobilization and CCR3 internalization in human eosinophils, we focused on the in vivo role of CCL11 and provide direct evidence for specific kinetic and rate-determining effects by DPPIV-like enzymatic activity on CCL11-mediated responses of eosinophils. Namely, it is demonstrated that i.v. administration of CCL11 in wild-type F344 rats leads to mobilization of eosinophils into the blood, peaking at 30 min. This mobilization is significantly increased in DPPIV-deficient F344 rats. Intradermal administration of CCL11 is followed by a dose-dependent recruitment of eosinophils into the skin and is significantly more effective in DPPIV-deficient F344 mutants as well as after pharmacological inhibition of DPPIV. Interestingly, CCL11 application leads to an up-regulation of DPPIV, which is not associated with negative feedback inhibition via DPPIV-cleaved CCL11((3-74)). These findings demonstrate regulatory effects of DPPIV for the recruitment of eosinophils. Furthermore, they illustrate that inhibitors of DPPIV have the potential to interfere with chemokine-mediated effects in vivo including but not limited to allergy.

Effects of Exposure to Community Violence and Family Violence on School Functioning Problems among Urban Youth: The Potential Mediating Role of Posttraumatic Stress Symptoms

PubMed Central

McGill, Tia M.; Self-Brown, Shannon R.; Lai, Betty S.; Cowart-Osborne, Melissa; Tiwari, Ashwini; LeBlanc, Monique; Kelley, Mary Lou

2014-01-01

Adolescents who are exposed to violence during childhood are at an increased risk for developing posttraumatic stress (PTS) symptoms. The literature suggests that violence exposure might also have negative effects on school functioning, and that PTS might serve as a potential mediator in this association. The purpose of the current study was to replicate and extend prior research by examining PTS symptoms as a mediator of the relationship between two types of violence exposure and school functioning problems among adolescent youth from an urban setting. Participants included a sample of 121 junior high and high school students (M = 15 years; range = 13–16 years; 60 males, 61 females) within high-crime neighborhoods. Consistent with our hypotheses, community violence and family violence were associated with PTS symptoms and school functioning problems. Our data suggest that community and family violence were indirectly related to school functioning problems through PTS symptoms. Findings from this study demonstrate that PTS symptoms potentially mediate the relationship between violence exposure and school functioning problems across two settings (community and home). Future research should further examine protective factors that can prevent youth violence exposure as well as negative outcomes related to violence. PMID:24570897

Adolescent survivors of childhood sexual abuse: the mediating role of attachment style and coping in psychological and interpersonal functioning.

PubMed

Shapiro, D L; Levendosky, A A

1999-11-01

To examine attachment style and coping strategies as potential mediating variables between childhood sexual abuse (CSA) and psychological and interpersonal functioning in an attempt to explain variability in extent of disorder and level of functioning. Eighty adolescent females, aged 14-16 years, answered questions regarding abuse history, attachment style, coping with an interpersonal stressor, depression and trauma symptomatology, and conflict with a best friend. Structural equation modeling analyses indicated that attachment style mediates the effects of CSA and child abuse and neglect on coping and psychological distress. The indirect effects of CSA and other abuse through attachment accounted for most of the effects on coping and psychological distress. Avoidant and cognitive coping strategies also served as mediators in the models, accounting for most of the effects of the other variables on interpersonal conflict. The findings indicate that attachment style and coping strategies influence psychological and interpersonal functioning, mediating the direct effects of CSA and other types of child abuse and neglect. These results have implications for therapeutic intervention with children and adolescents who have experienced child abuse.

Creatine Protects against Excitoxicity in an In Vitro Model of Neurodegeneration

PubMed Central

Genius, Just; Geiger, Johanna; Bender, Andreas; Möller, Hans-Jürgen; Klopstock, Thomas; Rujescu, Dan

2012-01-01

Creatine has been shown to be neuroprotective in aging, neurodegenerative conditions and brain injury. As a common molecular background, oxidative stress and disturbed cellular energy homeostasis are key aspects in these conditions. Moreover, in a recent report we could demonstrate a life-enhancing and health-promoting potential of creatine in rodents, mainly due to its neuroprotective action. In order to investigate the underlying pharmacology mediating these mainly neuroprotective properties of creatine, cultured primary embryonal hippocampal and cortical cells were challenged with glutamate or H2O2. In good agreement with our in vivo data, creatine mediated a direct effect on the bioenergetic balance, leading to an enhanced cellular energy charge, thereby acting as a neuroprotectant. Moreover, creatine effectively antagonized the H2O2-induced ATP depletion and the excitotoxic response towards glutamate, while not directly acting as an antioxidant. Additionally, creatine mediated a direct inhibitory action on the NMDA receptor-mediated calcium response, which initiates the excitotoxic cascade. Even excessive concentrations of creatine had no neurotoxic effects, so that high-dose creatine supplementation as a health-promoting agent in specific pathological situations or as a primary prophylactic compound in risk populations seems feasible. In conclusion, we were able to demonstrate that the protective potential of creatine was primarily mediated by its impact on cellular energy metabolism and NMDA receptor function, along with reduced glutamate spillover, oxidative stress and subsequent excitotoxicity. PMID:22347384

Adolescent impulsivity and soft drink consumption: The role of parental regulation.

PubMed

Melbye, Elisabeth L; Bergh, Ingunn H; Hausken, Solveig E S; Sleddens, Ester F C; Glavin, Kari; Lien, Nanna; Bjelland, Mona

2016-01-01

The present study aimed to explore the process in which impulsivity might influence soft drink consumption in adolescents, addressing potential mediating effects of perceived parental regulation regarding unhealthy eating. A cross-sectional survey was performed among 440 13-15-year-olds in Eastern Norway. The survey questionnaire included measures of impulsivity, six types of maternal and paternal regulation (as perceived by the adolescents), and consumption of sugar-sweetened beverages (SSB). Parallel multiple-mediator analyses were performed to reveal potential mediating effects of perceived parental regulatory behaviors on the association between adolescent impulsivity and SSB consumption. Separate models were run for maternal and paternal regulation. Results from our model analyses (both maternal and paternal models) indicated that all the six measured parental regulatory behaviors jointly acted as mediators on the association between adolescent impulsivity and SSB consumption. However, only perceived maternal and paternal legitimacy of regulation showed a unique contribution to the mediated effect. This finding suggests that adolescents' perception of parental legitimate authority is of particular importance in explaining the relationship between impulsivity and unhealthy eating behaviors in adolescents. Future nutrition interventions targeting adolescents and their parents should take personal factors such as adolescents' level of impulsivity into account. Ultimately; what may be an appropriate approach to impulsive individuals and their parents may diverge from what may be an appropriate approach to less impulsive individuals and their parents. Copyright © 2015 Elsevier Ltd. All rights reserved.

Understanding the link between exposure to violence and aggression in justice-involved adolescents.

PubMed

Wall Myers, Tina D; Salcedo, Abigail; Frick, Paul J; Ray, James V; Thornton, Laura C; Steinberg, Laurence; Cauffman, Elizabeth

2018-05-01

The current study advanced research on the link between community violence exposure and aggression by comparing the effects of violence exposure on different functions of aggression and by testing four potential (i.e., callous-unemotional traits, consideration of others, impulse control, and anxiety) mediators of this relationship. Analyses were conducted in an ethnically/racially diverse sample of 1,216 male first-time juvenile offenders (M = 15.30 years, SD = 1.29). Our results indicated that violence exposure had direct effects on both proactive and reactive aggression 18 months later. The predictive link of violence exposure to proactive aggression was no longer significant after controlling for proactive aggression at baseline and the overlap with reactive aggression. In contrast, violence exposure predicted later reactive aggression even after controlling for baseline reactive aggression and the overlap with proactive aggression. Mediation analyses of the association between violence exposure and reactive aggression indicated indirect effects through all potential mediators, but the strongest indirect effect was through impulse control. The findings help to advance knowledge on the consequences of community violence exposure on justice-involved youth.

Radioprotection by polysaccharides alone and in combination with aminothiols

NASA Astrophysics Data System (ADS)

Patchen, Myra L.; Macvittie, Thomas J.; Solberg, Brian D.; D'Alesandro, Michele M.; Brook, Itzhak

We demonstrated that glucan, a beta-1,3 polysaccharide immunomodulator, enhances survival of mice when administered before radiation exposure. Glucan's prophylactic survival-enhancing effects are mediated by several mechanisms including (1) increasing macrophage-mediated resistance to potentially lethal postirradiation opportunistic infections, (2) increasing the Do of hematopoietic progenitor cells, and (3) accelerating hematopoietic reconstitution. In addition, even when administered shortly after some otherwise lethal doses of radiation, glucan increases survival. Glucan's therapeutic survival-enhancing effects are also mediated through its ability to enhance macrophage function and to accelerate hematopoietic reconstitution; glucan's therapeutic potential, however, is ultimately dependent on the survival of a critical number of hematopoietic stem cells capable of responding to glucan's stimulatory effects. Preirradiation administration of the traditional aminothiol radioprotectants WR-2721 and WR-3689 has been previously demonstrated to be an extremely effective means to increase hematopoietic stem cell survival. Therapeutic glucan treatment administered in combination with preirradiation WR-2721 or WR-3689 treatment synergistically increases both hematopoietic reconstitution and survival. Such combined modality treatments offer new promise in treating acute radiation injury.

Mediators of Psychological Well-being in Adolescent Boys.

PubMed

Lubans, David R; Smith, Jordan J; Morgan, Philip J; Beauchamp, Mark R; Miller, Andrew; Lonsdale, Chris; Parker, Philip; Dally, Kerry

2016-02-01

The aim of this study was to explore the effect of the Active Teen Leaders Avoiding Screen-time (ATLAS) intervention on psychological well-being in adolescent boys and to examine the potential mediating mechanisms that might explain this effect. ATLAS was evaluated using a cluster randomized controlled trial in 14 secondary schools located in low-income communities (N = 361 adolescent boys, mean age = 12.7 ± .5 years). The 20-week intervention was guided by self-determination theory and involved: professional development for teachers, provision of fitness equipment to schools, enhanced school sport sessions, researcher-led seminars, a smartphone application, and parental strategies for reducing screen time. Assessments were conducted at baseline and immediately post intervention (8 months). Psychological well-being was measured using the Flourishing Scale. Motivational regulations (intrinsic, identified, introjected, controlled, and amotivation) and basic psychological needs (autonomy, competence, and relatedness) in school sport, muscular fitness, resistance training skill competency, and recreational screen time were examined as potential mediating mechanisms of the intervention effect. The intervention effect on well-being was small but statistically significant. Within a multiple mediator model, changes in autonomy needs satisfaction, recreational screen time, and muscular fitness significantly mediated the effect of the intervention on psychological well-being. In addition to the physical health benefits, targeted physical activity programs for adolescent boys may have utility for mental health promotion through the mechanisms of increasing autonomy support and muscular fitness and reducing screen time. Copyright © 2016 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.

Childhood abuse and psychotic experiences - evidence for mediation by adulthood adverse life events.

PubMed

Bhavsar, V; Boydell, J; McGuire, P; Harris, V; Hotopf, M; Hatch, S L; MacCabe, J H; Morgan, C

2017-10-09

We have previously reported an association between childhood abuse and psychotic experiences (PEs) in survey data from South East London. Childhood abuse is related to subsequent adulthood adversity, which could form one pathway to PEs. We aimed to investigate evidence of mediation of the association between childhood abuse and PEs by adverse life events. Data were analysed from the South East London Community Health Study (SELCoH, n = 1698). Estimates of the total effects on PEs of any physical or sexual abuse while growing up were partitioned into direct (i.e. unmediated) and indirect (total and specific) effects, mediated via violent and non-violent life events. There was strong statistical evidence for direct (OR 1.58, 95% CI: 1.19-2.1) and indirect (OR 1.51, 95% CI: 1.32-1.72) effects of childhood abuse on PEs after adjustment for potential confounders, indicating partial mediation of this effect via violent and non-violent life events. An estimated 47% of the total effect of abuse on PEs was mediated via adulthood adverse life events, of which violent life events made up 33% and non-violent life events the remaining 14%. The association between childhood abuse and PEs is partly mediated through the experience of adverse life events in adulthood. There is some evidence that a larger proportion of this effect was mediated through violent life events than non-violent life events.

Leptin: a potential anxiolytic by facilitation of fear extinction.

PubMed

Wang, Wei; Liu, Song-Lin; Li, Kuan; Chen, Yu; Jiang, Bo; Li, Yan-Kun; Xiao, Jun-Li; Yang, Si; Chen, Tao; Chen, Jian-Guo; Li, Jia-Geng; Wang, Fang

2015-05-01

Anxiety disorders are characterized by a deficient extinction of fear memory. Evidence is growing that leptin influences numerous neuronal functions. The aims of this study were to investigate the effects and the mechanism of leptin on fear extinction. Leptin (1 mg/kg, i.p) was applied to evaluate the anxiolytic effect in rat behavioral tests. Field potentials recording were used to investigate the changes in synaptic transmission in the thalamic-lateral amygadala (LA) pathway of rat. We found that leptin produced strong anxiolytic effects under basal condition and after acute stress. Systemic administration and intra-LA infusions of leptin facilitated extinction of conditioned fear responses. The antagonist of NMDA receptor, MK-801, blocked the effect of leptin on fear extinction completely. Furthermore, these effects of leptin on fear extinction were accompanied by a reversal of conditioning-induced synaptic potentiation in the LA. Leptin facilitated NMDA receptor-mediated synaptic transmission, and reversed amygdala long-term potentiation (LTP) in a dose-dependent manner in vitro, and this LTP depotentiation effect was mediated by NMDA receptor and MAPK signaling pathway. These results identify a key role of leptin in dampening fear conditioning-induced synaptic potentiation in the LA through NMDA receptor and indicate a new strategy for treating anxiety disorders. © 2015 John Wiley & Sons Ltd.

Revisiting Synchronous Computer-Mediated Communication: Learner Perception and the Meaning of Corrective Feedback

ERIC Educational Resources Information Center

Kim, Hye Yeong

2014-01-01

Effectively exploring the efficacy of synchronous computer-mediated communication (SCMC) for pedagogical purposes can be achieved through the careful investigation of potentially beneficial, inherent attributes of SCMC. This study provides empirical evidence for the capacity of task-based SCMC to draw learner attention to linguistic forms by…

Family Conflict as a Mediator of Caregiver Strain

ERIC Educational Resources Information Center

Scharlach, Andrew; Li, Wei; Dalvi, Tapashi B.

2006-01-01

The present study used structural equation modeling to examine the potential mediating effect of family conflict on caregiver strain in a randomly drawn household sample of 650 adults with primary care responsibility for an adult age 50 or older with a mental disability. Caregiver strain was directly influenced by the conflict, disagreements, and…

POTENTIATION OF PULMONARY REFLEX RESPONSE TO CAPSAICIN 24 HOURS FOLLOWING WHOLE-BODY ACROLEIN EXPOSURE IS MEDIATED BY TRPV1

EPA Science Inventory

Pulmonary C-fibers are stimulated by irritant air pollutants producing apnea, bronchospasm, and decrease in HR. C-fiber chemoreflex activation is mediated by TRPV1 and release of substance P. While acrolein has been shown to stimulate C-fibers, the persistence of acrolein effect...

A Weighting Method for Assessing Between-Site Heterogeneity in Causal Mediation Mechanism

ERIC Educational Resources Information Center

Qin, Xu; Hong, Guanglei

2017-01-01

When a multisite randomized trial reveals between-site variation in program impact, methods are needed for further investigating heterogeneous mediation mechanisms across the sites. We conceptualize and identify a joint distribution of site-specific direct and indirect effects under the potential outcomes framework. A method-of-moments procedure…

Processes of change in a school-based mindfulness programme: cognitive reactivity and self-coldness as mediators.

PubMed

Van der Gucht, Katleen; Takano, Keisuke; Raes, Filip; Kuppens, Peter

2018-05-01

The underlying mechanisms of the effectiveness of mindfulness-based interventions for emotional well-being remain poorly understood. Here, we examined the potential mediating effects of cognitive reactivity and self-compassion on symptoms of depression, anxiety and stress using data from an earlier randomised controlled school trial. A moderated time-lagged mediation model based on multilevel modelling was used to analyse the data. The findings showed that post-treatment changes in cognitive reactivity and self-coldness, an aspect of self-compassion, mediated subsequent changes in symptoms of depression, anxiety and stress. These results suggest that cognitive reactivity and self-coldness may be considered as transdiagnostic mechanisms of change of a mindfulness-based intervention programme for youth.

Two-step estimation in ratio-of-mediator-probability weighted causal mediation analysis.

PubMed

Bein, Edward; Deutsch, Jonah; Hong, Guanglei; Porter, Kristin E; Qin, Xu; Yang, Cheng

2018-04-15

This study investigates appropriate estimation of estimator variability in the context of causal mediation analysis that employs propensity score-based weighting. Such an analysis decomposes the total effect of a treatment on the outcome into an indirect effect transmitted through a focal mediator and a direct effect bypassing the mediator. Ratio-of-mediator-probability weighting estimates these causal effects by adjusting for the confounding impact of a large number of pretreatment covariates through propensity score-based weighting. In step 1, a propensity score model is estimated. In step 2, the causal effects of interest are estimated using weights derived from the prior step's regression coefficient estimates. Statistical inferences obtained from this 2-step estimation procedure are potentially problematic if the estimated standard errors of the causal effect estimates do not reflect the sampling uncertainty in the estimation of the weights. This study extends to ratio-of-mediator-probability weighting analysis a solution to the 2-step estimation problem by stacking the score functions from both steps. We derive the asymptotic variance-covariance matrix for the indirect effect and direct effect 2-step estimators, provide simulation results, and illustrate with an application study. Our simulation results indicate that the sampling uncertainty in the estimated weights should not be ignored. The standard error estimation using the stacking procedure offers a viable alternative to bootstrap standard error estimation. We discuss broad implications of this approach for causal analysis involving propensity score-based weighting. Copyright © 2018 John Wiley & Sons, Ltd.

A Mechanism for the Temporal Potentiation of Genipin to the Cytotoxicity of Cisplatin in Colon Cancer Cells.

PubMed

Wang, Ruihua; MoYung, K C; Zhao, Y J; Poon, Karen

2016-01-01

To investigate the potentiation effect of Genipin to Cisplatin induced cell senescence in HCT-116 colon cancer cells in vitro. Cell viability was estimated by Propidium iodide and Hoechst 3342, reactive oxygen species (ROS) with DHE, mitochondrial membrane potential (MMP) with JC-1 MMP assay Kit and electron current production with microbial fuel cells (MFC). Genipin inhibited the UCP2 mediated anti-oxidative proton leak significantly promoted the Cisplatin induced ROS and subsequent cell death, which was similar to that of UCP2-siRNA. Cells treated with Cisplatin alone or combined with Genipin, ROS negatively, while MMP positively correlated with cell viability. Cisplatin induced ROS was significantly decreased by detouring electrons to MFC, or increased by Genipin combined treatment. Compensatory effects of UCP2 up-regulation with time against Genipin treatment were suggested. Shorter the Genipin treatment before Cisplatin better promoted the Cisplatin induced ROS and subsequent cell death. The interaction of leaked electron with Cisplatin was important during ROS generation. Inhibition of UCP2-mediated proton leak with Genipin potentiated the cytotoxicity of Cisplatin. Owing to the compensatory effects against Genipin, shorter Genipin treatment before Cisplatin was recommended in order to achieve better potentiation effect.

γ-Aminobutyric Acid Type A Receptor Potentiation Inhibits Learning in a Computational Network Model.

PubMed

Storer, Kingsley P; Reeke, George N

2018-04-17

Propofol produces memory impairment at concentrations well below those abolishing consciousness. Episodic memory, mediated by the hippocampus, is most sensitive. Two potentially overlapping scenarios may explain how γ-aminobutyric acid receptor type A (GABAA) potentiation by propofol disrupts episodic memory-the first mediated by shifting the balance from excitation to inhibition while the second involves disruption of rhythmic oscillations. We use a hippocampal network model to explore these scenarios. The basis for these experiments is the proposal that the brain represents memories as groups of anatomically dispersed strongly connected neurons. A neuronal network with connections modified by synaptic plasticity was exposed to patterned stimuli, after which spiking output demonstrated evidence of stimulus-related neuronal group development analogous to memory formation. The effect of GABAA potentiation on this memory model was studied in 100 unique networks. GABAA potentiation consistent with moderate propofol effects reduced neuronal group size formed in response to a patterned stimulus by around 70%. Concurrently, accuracy of a Bayesian classifier in identifying learned patterns in the network output was reduced. Greater potentiation led to near total failure of group formation. Theta rhythm variations had no effect on group size or classifier accuracy. Memory formation is widely thought to depend on changes in neuronal connection strengths during learning that enable neuronal groups to respond with greater facility to familiar stimuli. This experiment suggests the ability to form such groups is sensitive to alteration in the balance between excitation and inhibition such as that resulting from administration of a γ-aminobutyric acid-mediated anesthetic agent.

DKK1 rescues osteogenic differentiation of mesenchymal stem cells isolated from periodontal ligaments of patients with diabetes mellitus induced periodontitis

PubMed Central

Liu, Qi; Hu, Cheng-Hu; Zhou, Cui-Hong; Cui, Xiao-Xia; Yang, Kun; Deng, Chao; Xia, Jia-Jia; Wu, Yan; Liu, Lu-Chuan; Jin, Yan

2015-01-01

Multiple studies have shown that diabetes mellitus is an established risk factor for periodontitis. Recently mesenchymal stem cells derived from periodontal ligament (PDLSCs) have been utilized to reconstruct tissues destroyed by chronic inflammation. However, impact of periodontitis with diabetes mellitus on PDLSCs and mechanisms mediating effects of complex microenvironments remain poorly understood. In this study, we found multiple differentiation potential of PDLSCs from chronic periodontitis with diabetes mellitus donors (D-PDLSCs) was damaged significantly. Inhibition of NF-κB signaling could rescue osteogenic potential of PDLSCs from simple chronic periodontitis patients (P-PDLSCs), whereas did not promote D-PDLSCs osteogenesis. In addition, we found expression of DKK1 in D-PDLSCs did not respond to osteogenic signal and decreased osteogenic potential of D-PDLSCs treated with DKK1 could be reversed. To further elucidate different character between P-PDLSCs and D-PDLSCs, we treated PDLSCs with TNF-α and advanced glycation end products (AGEs), and find out AGEs which enhance effect of TNF-α in PDLSCs might mediate special personality of D-PDLSCs. The adverse effect of AGEs in PDLSCs could be reversed when PDLSCs were treated with DKK1. These results suggested DKK1 mediating WNT signaling might be a therapy target to rescue potential of PDLSCs in periodontitis with diabetes mellitus. PMID:26278788

Pre-incubation with cyclosporine A potentiates its inhibitory effects on pitavastatin uptake mediated by recombinantly expressed cynomolgus monkey hepatic organic anion transporting polypeptide.

PubMed

Takahashi, Tsuyoshi; Ohtsuka, Tatsuyuki; Uno, Yasuhiro; Utoh, Masahiro; Yamazaki, Hiroshi; Kume, Toshiyuki

2016-11-01

Cyclosporine A, an inhibitor of hepatic organic anion transporting polypeptides (OATPs), reportedly increased plasma concentrations of probe substrates, although its maximum unbound blood concentrations were lower than the experimental half-maximal inhibitory (IC 50 ) concentrations. Pre-incubation with cyclosporine A in vitro before simultaneous incubation with probes has been reported to potentiate its inhibitory effects on recombinant human OATP-mediated probe uptake. In the present study, the effects of cyclosporine A and rifampicin on recombinant cynomolgus monkey OATP-mediated pitavastatin uptake were investigated in pre- and simultaneous incubation systems. Pre-incubation with cyclosporine A, but not with rifampicin, decreased the apparent IC 50 values on recombinant cynomolgus monkey OATP1B1- and OATP1B3-mediated pitavastatin uptake. Application of the co-incubated IC 50 values toward R values (1 + [unbound inhibitor] inlet to the liver, theoretically maximum /inhibition constant) in static models, 1.1 in monkeys and 1.3 in humans, for recombinant cynomolgus monkey and human OATP1B1-mediated pitavastatin uptake might result in the poor prediction of drug interaction magnitudes. In contrast, the lowered IC 50 values after pre-incubation with cyclosporine A provided better prediction with R values of 3.9 for monkeys and 2.7 for humans when the estimated maximum cyclosporine A concentrations at the inlet to the liver were used. These results suggest that the enhanced inhibitory potential of perpetrator medicines by pre-incubation on cynomolgus monkey OATP-mediated pitavastatin uptake in vitro could be of value for the precise estimation of drug interaction magnitudes in silico, in accordance with the findings from pre-administration of inhibitors on pitavastatin pharmacokinetics validated in monkeys. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

WRKY23 is a component of the transcriptional network mediating auxin feedback on PIN polarity

PubMed Central

Vasileva, Mina; Sauer, Michael

2018-01-01

Auxin is unique among plant hormones due to its directional transport that is mediated by the polarly distributed PIN auxin transporters at the plasma membrane. The canalization hypothesis proposes that the auxin feedback on its polar flow is a crucial, plant-specific mechanism mediating multiple self-organizing developmental processes. Here, we used the auxin effect on the PIN polar localization in Arabidopsis thaliana roots as a proxy for the auxin feedback on the PIN polarity during canalization. We performed microarray experiments to find regulators of this process that act downstream of auxin. We identified genes that were transcriptionally regulated by auxin in an AXR3/IAA17- and ARF7/ARF19-dependent manner. Besides the known components of the PIN polarity, such as PID and PIP5K kinases, a number of potential new regulators were detected, among which the WRKY23 transcription factor, which was characterized in more detail. Gain- and loss-of-function mutants confirmed a role for WRKY23 in mediating the auxin effect on the PIN polarity. Accordingly, processes requiring auxin-mediated PIN polarity rearrangements, such as vascular tissue development during leaf venation, showed a higher WRKY23 expression and required the WRKY23 activity. Our results provide initial insights into the auxin transcriptional network acting upstream of PIN polarization and, potentially, canalization-mediated plant development. PMID:29377885

Anger and health in dementia caregivers: exploring the mediation effect of optimism.

PubMed

López, J; Romero-Moreno, R; Márquez-González, M; Losada, A

2015-04-01

Although previous studies indicate a negative association between caregivers' anger and health, the potential mechanisms linking this relationship are not yet fully understood. The aim of this study was to explore the potential mediating role of optimism in the relationship between anger and caregivers' physical health. Dementia caregivers (n = 108) were interviewed and filled out instruments assessing their anger (reaction), optimism and health (vitality). A mediational model was tested to determine whether optimism partially mediated the relationship between anger and vitality. Angry reaction was negatively associated with optimism and vitality; optimism was positively associated with vitality. Finally, the relationship between angry reaction and vitality decreased when optimism was entered simultaneously. A non-parametric bootstrap approach confirmed that optimism significantly mediated some of the relationship between angry reaction and vitality. These findings suggest that low optimism may help explain the association between caregivers' anger and reduced sense of vitality. The results provide a specific target for intervention with caregivers. Copyright © 2013 John Wiley & Sons, Ltd.

Potential Mediators in Parenting and Family Intervention: Quality of Mediation Analyses

PubMed Central

Patel, Chandni C.; Fairchild, Amanda J.; Prinz, Ronald J.

2017-01-01

Parenting and family interventions have repeatedly shown effectiveness in preventing and treating a range of youth outcomes. Accordingly, investigators in this area have conducted a number of studies using statistical mediation to examine some of the potential mechanisms of action by which these interventions work. This review examined from a methodological perspective in what ways and how well the family-based intervention studies tested statistical mediation. A systematic search identified 73 published outcome studies that tested mediation for family-based interventions across a wide range of child and adolescent outcomes (i.e., externalizing, internalizing, and substance-abuse problems; high-risk sexual activity; and academic achievement), for putative mediators pertaining to positive and negative parenting, family functioning, youth beliefs and coping skills, and peer relationships. Taken as a whole, the studies used designs that adequately addressed temporal precedence. The majority of studies used the product of coefficients approach to mediation, which is preferred, and less limiting than the causal steps approach. Statistical significance testing did not always make use of the most recently developed approaches, which would better accommodate small sample sizes and more complex functions. Specific recommendations are offered for future mediation studies in this area with respect to full longitudinal design, mediation approach, significance testing method, documentation and reporting of statistics, testing of multiple mediators, and control for Type I error. PMID:28028654

[6]-Gingerol Affects Glucose Metabolism by Dual Regulation via the AMPKα2-Mediated AS160-Rab5 Pathway and AMPK-Mediated Insulin Sensitizing Effects.

PubMed

Lee, Jung Ok; Kim, Nami; Lee, Hye Jeong; Moon, Ji Wook; Lee, Soo Kyung; Kim, Su Jin; Kim, Joong Kwan; Park, Sun Hwa; Kim, Hyeon Soo

2015-07-01

[6]-Gingerol has been used to control diabetes and dyslipidemia; however, its metabolic role is poorly understood. In this study, [6]-gingerol increased adenosine monophosphate (AMP)-activated protein kinase (AMPK) phosphorylation in mouse skeletal muscle C2C12 cells. Stimulation of glucose uptake by [6]-gingerol was dependent on AMPKα2. Moreover, both Inhibition and knockdown of AMPKα2 blocked [6]-gingerol-induced glucose uptake. [6]-Gingerol significantly decreased the activity of protein phosphatase 2A (PP2A). Inhibition of PP2A activity with okadaic acid enhanced the phosphorylation of AMPKα2. Moreover, the interaction between AMPKα2 and PP2A was increased by [6]-gingerol, suggesting that PP2A mediates the effect of [6]-gingerol on AMPK phosphorylation. In addition, [6]-gingerol increased the phosphorylation of Akt-substrate 160 (AS160), which is a Rab GTPase-activating protein. Inhibition of AMPKα2 blocked [6]-gingerol-induced AS160 phosphorylation. [6]-gingerol increased the Rab5, and AMPKα2 knockdown blocked [6]-gingerol-induced expression of Rab5, indicating AMPK play as an upstream of Rab5. It also increased glucose transporter 4 (GLUT4) mRNA and protein expression and stimulated GLUT4 translocation. Furthermore, insulin-mediated glucose uptake and Akt phosphorylation were further potentiated by [6]-gingerol treatment. This potentiation was not observed in the presence of AMPK inhibitor compound C. In summary, our results suggest that [6]-gingerol plays an important role in glucose metabolism via the AMPKα2-mediated AS160-Rab5 pathway and through potentiation of insulin-mediated glucose regulation. © 2015 Wiley Periodicals, Inc.

Relationships among race, education, criminal thinking, and recidivism: moderator and mediator effects.

PubMed

Walters, Glenn D

2014-02-01

Moderator and mediator relationships linking variables from three different theoretical traditions-race (subcultural theory), education (life-course theory), and criminal thinking (social learning theory)-and recidivism were examined in 1,101 released male federal prison inmates. Preliminary regression analyses indicated that racial status (White, Black, Hispanic) moderated the relationship between criminal thinking, as measured by the General Criminal Thinking (GCT) score of the Psychological Inventory of Criminal Thinking Styles (PICTS), and recidivism. Further analysis, however, revealed that it was not racial status, per se, that moderated the relationship between the PICTS and recidivism, but educational attainment. Whereas the PICTS was largely effective in predicting recidivism in inmates with 12 or more years of education, it was largely ineffective in predicting recidivism in inmates with fewer than 12 years of education. When education and the GCT score were compared as possible mediators of the race-recidivism relationship only the GCT successfully mediated this relationship. Sensitivity testing showed that the GCT mediating effect was moderately robust to violations of the sequential ignorability assumption on which causal mediation analysis rests. Moderator and mediator analyses are potentially important avenues through which theoretical constructs can be integrated and assessment strategies devised.

Therapeutic potential of Mediator complex subunits in metabolic diseases.

PubMed

Ranjan, Amol; Ansari, Suraiya A

2018-01-01

The multisubunit Mediator is an evolutionary conserved transcriptional coregulatory complex in eukaryotes. It is needed for the transcriptional regulation of gene expression in general as well as in a gene specific manner. Mediator complex subunits interact with different transcription factors as well as components of RNA Pol II transcription initiation complex and in doing so act as a bridge between gene specific transcription factors and general Pol II transcription machinery. Specific interaction of various Mediator subunits with nuclear receptors (NRs) and other transcription factors involved in metabolism has been reported in different studies. Evidences indicate that ligand-activated NRs recruit Mediator complex for RNA Pol II-dependent gene transcription. These NRs have been explored as therapeutic targets in different metabolic diseases; however, they show side-effects as targets due to their overlapping involvement in different signaling pathways. Here we discuss the interaction of various Mediator subunits with transcription factors involved in metabolism and whether specific interaction of these transcription factors with Mediator subunits could be potentially utilized as therapeutic strategy in a variety of metabolic diseases. Copyright © 2017 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Oxotremorine-M potentiates NMDA receptors by muscarinic receptor dependent and independent mechanisms.

PubMed

Zwart, Ruud; Reed, Hannah; Sher, Emanuele

2018-01-01

Muscarinic acetylcholine M1 receptors play an important role in synaptic plasticity in the hippocampus and cortex. Potentiation of NMDA receptors as a consequence of muscarinic acetylcholine M1 receptor activation is a crucial event mediating the cholinergic modulation of synaptic plasticity, which is a cellular mechanism for learning and memory. In Alzheimer's disease, the cholinergic input to the hippocampus and cortex is severely degenerated, and agonists or positive allosteric modulators of M1 receptors are therefore thought to be of potential use to treat the deficits in cognitive functions in Alzheimer's disease. In this study we developed a simple system in which muscarinic modulation of NMDA receptors can be studied in vitro. Human M1 receptors and NR1/2B NMDA receptors were co-expressed in Xenopus oocytes and various muscarinic agonists were assessed for their modulatory effects on NMDA receptor-mediated responses. As expected, NMDA receptor-mediated responses were potentiated by oxotremorine-M, oxotremorine or xanomeline when the drugs were applied between subsequent NMDA responses, an effect which was fully blocked by the muscarinic receptor antagonist atropine. However, in oocytes expressing NR1/2B NMDA receptors but not muscarinic M1 receptors, oxotremorine-M co-applied with NMDA also resulted in a potentiation of NMDA currents and this effect was not blocked by atropine, demonstrating that oxotremorine-M is able to directly potentiate NMDA receptors. Oxotremorine, which is a close analogue of oxotremorine-M, and xanomeline, a chemically distinct muscarinic agonist, did not potentiate NMDA receptors by this direct mechanism. Comparing the chemical structures of the three different muscarinic agonists used in this study suggests that the tri-methyl ammonium moiety present in oxotremorine-M is important for the compound's interaction with NMDA receptors. Copyright © 2017 Elsevier Inc. All rights reserved.

Mediated moderation of the relation between maternal and adolescent depressive symptoms: role of adolescent physical health.

PubMed

Ferro, Mark A

2015-11-01

To examine the mediating effect of family functioning on the relation between maternal and adolescent depressive symptoms and determine whether the magnitude of the mediating effect is different for adolescents with and without chronic physical health conditions. Data come from the National Longitudinal Survey of Children and Youth. A representative survey of 11,813 adolescents and their mothers was included. Maternal and adolescent depressive symptoms were measured using the 12-item Center for Epidemiological Studies Depression Scale. Family functioning was measured using the McMaster Family Assessment Device. Multilevel multiple-group path analysis was used to examine potential mediating and moderating effects. Family functioning measured when adolescents were 14-15 years mediated the relation between maternal depressive symptoms (measured at 10-13 years) and adolescent depressive symptoms (measured at 16-19 years) for both adolescents with [αβ = 0.02 (0.02, 0.03)] and without chronic health conditions [αβ = 0.01 (0.00, 0.01)]. These findings provided evidence to suggest mediated moderation, Δαβ = 0.02 (0.01, 0.03), that is, the mediating effect of family functioning was significantly larger for adolescents with chronic health conditions. The mediating effect of family functioning in the relation between maternal and adolescent depressive symptoms is larger for adolescents with chronic health conditions. Within the framework of family-centered care, maternal depressive symptoms and family functioning are suitable targets for preventive intervention for adolescents with chronic health conditions.

Discrimination, Subjective Wellbeing, and the Role of Gender: A Mediation Model of LGB Minority Stress.

PubMed

Conlin, Sarah E; Douglass, Richard P; Ouch, Staci

2017-10-26

The present study examined the link between discrimination and the three components of subjective wellbeing (positive and negative affect and life satisfaction) among a cisgender sample of lesbian, gay, and bisexual (LGB) adults. Specifically, we investigated internalized homonegativity and expectations of rejection as potential mediators of the links between discrimination and subjective wellbeing among a sample of 215 participants. Results from our structural equation model demonstrated a strong, positive direct link between discrimination and negative affect. Discrimination also had small, negative indirect effects on life satisfaction through our two mediators. Interestingly, neither discrimination nor our two mediators were related with positive affect, demonstrating the need for future research to uncover potential buffers of this link. Finally, our model evidenced configural, metric, and scalar invariance, suggesting that our model applies well for both women and men. Practical implications and future directions for research are discussed.

Timing is Essential for Rapid Effects of Corticosterone on Synaptic Potentiation in the Mouse Hippocampus

ERIC Educational Resources Information Center

Joels, Marian; Krugers, Harm; Wiegert, Olof

2006-01-01

Stress facilitates memory formation, but only when the stressor is closely linked to the learning context. These effects are, at least in part, mediated by corticosteroid hormones. Here we demonstrate that corticosterone rapidly facilitates synaptic potentiation in the mouse hippocampal CA1 area when high levels of the hormone and high-frequency…

Adolescent mothers and child abuse potential: an evaluation of risk factors.

PubMed

Dukewich, T L; Borkowski, J G; Whitman, T L

1996-11-01

This research examines maternal and child factors that place adolescent mothers at risk for abusing their children. Using a longitudinal design, relationships among four risk factors (social supports, maternal psychological adjustment, maternal preparation for parenting, and child temperament), maternal psychological predisposition for aggressive coping (perceptions of stress and endorsements of punitive parenting), and maternal abuse potential were examined in a sample of 75 primiparous adolescent mothers and their children. Preparation for parenting, a construct which included knowledge and attitudes about children's development, was the strongest direct predictor of abuse potential; however, its effects were also partially mediated by the mother's psychological predisposition for aggressive coping. Similarly, the effects of child temperament on abuse were mediated by the mother's psychological predisposition for aggressive coping. Implications for designing intervention programs, and identifying at-risk adolescents, were also discussed.

Oxygen and indocyanine green loaded phase-transition nanoparticle-mediated photo-sonodynamic cytotoxic effects on rheumatoid arthritis fibroblast-like synoviocytes.

PubMed

Tang, Qin; Cui, Jianyu; Tian, Zhonghua; Sun, Jiangchuan; Wang, Zhigang; Chang, Shufang; Zhu, Shenyin

2017-01-01

Photodynamic therapy and sonodynamic therapy are developing, minimally invasive, and site-specific modalities for cancer therapy. A combined strategy PSDT (photodynamic therapy followed by sonodynamic therapy) has been proposed in this study. Here, we aimed to develop novel biodegradable poly(DL-lactide- co -glycolic acid) phase-transition nanoparticles simultaneously loaded with oxygen and indocyanine green (OI-NPs) and to investigate the cytotoxic effects and the potential mechanisms of OI-NP-mediated PSDT on MH7A synoviocytes. The OI-NPs were prepared using a modified double emulsion method and the physicochemical properties were determined. The cellular uptake of OI-NPs was detected by confocal microscopy and flow cytometry. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide assay, flow cytometry, and Hoechst 33342/propidium iodide double staining were used to determine the cytotoxic effect of OI-NP-mediated PSDT on MH7A cells. Fluorescence microscope and fluorescence microplate reader were used to detect reactive oxygen species (ROS) generation. The OI-NPs were a stable and efficient carrier to deliver oxygen and indocyanine green, and enhanced cellular uptake was observed in MH7A cells with the nanoparticles. OI-NP-mediated PSDT caused more serious cell damage and more evident cell apoptosis, compared with other groups. Furthermore, increased generation of intracellular ROS was detected in MH7A cells treated with PSDT. Interestingly, the OI-NP-mediated PSDT-induced cell viability loss was effectively rescued by pretreatment with the ROS scavenger N -acetylcysteine. Multifunctional OI-NPs were successfully developed and characterized for the combined delivery of oxygen and indocyanine green, and OI-NP-mediated PSDT would be a potential cytotoxic treatment for MH7A cells. This study may provide a novel strategy for the treatment of RA and develop a model of theranostic application through phase-transition nanoparticle-mediated PSDT in the future.

Oxygen and indocyanine green loaded phase-transition nanoparticle-mediated photo-sonodynamic cytotoxic effects on rheumatoid arthritis fibroblast-like synoviocytes

PubMed Central

Tang, Qin; Cui, Jianyu; Tian, Zhonghua; Sun, Jiangchuan; Wang, Zhigang; Chang, Shufang; Zhu, Shenyin

2017-01-01

Background Photodynamic therapy and sonodynamic therapy are developing, minimally invasive, and site-specific modalities for cancer therapy. A combined strategy PSDT (photodynamic therapy followed by sonodynamic therapy) has been proposed in this study. Here, we aimed to develop novel biodegradable poly(DL-lactide-co-glycolic acid) phase-transition nanoparticles simultaneously loaded with oxygen and indocyanine green (OI-NPs) and to investigate the cytotoxic effects and the potential mechanisms of OI-NP–mediated PSDT on MH7A synoviocytes. Methods The OI-NPs were prepared using a modified double emulsion method and the physicochemical properties were determined. The cellular uptake of OI-NPs was detected by confocal microscopy and flow cytometry. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide assay, flow cytometry, and Hoechst 33342/propidium iodide double staining were used to determine the cytotoxic effect of OI-NP–mediated PSDT on MH7A cells. Fluorescence microscope and fluorescence microplate reader were used to detect reactive oxygen species (ROS) generation. Results The OI-NPs were a stable and efficient carrier to deliver oxygen and indocyanine green, and enhanced cellular uptake was observed in MH7A cells with the nanoparticles. OI-NP–mediated PSDT caused more serious cell damage and more evident cell apoptosis, compared with other groups. Furthermore, increased generation of intracellular ROS was detected in MH7A cells treated with PSDT. Interestingly, the OI-NP–mediated PSDT-induced cell viability loss was effectively rescued by pretreatment with the ROS scavenger N-acetylcysteine. Conclusion Multifunctional OI-NPs were successfully developed and characterized for the combined delivery of oxygen and indocyanine green, and OI-NP–mediated PSDT would be a potential cytotoxic treatment for MH7A cells. This study may provide a novel strategy for the treatment of RA and develop a model of theranostic application through phase-transition nanoparticle-mediated PSDT in the future. PMID:28123298

I think therefore I om: cognitive distortions and coping style as mediators for the effects of mindfulness meditation on anxiety, positive and negative affect, and hope.

PubMed

Sears, Sharon; Kraus, Sue

2009-06-01

This study examined cognitive distortions and coping styles as potential mediators for the effects of mindfulness meditation on anxiety, negative affect, positive affect, and hope in college students. Our pre- and postintervention design had four conditions: control, brief meditation focused on attention, brief meditation focused on loving kindness, and longer meditation combining both attentional and loving kindness aspects of mindfulness. Each group met weekly over the course of a semester. Longer combined meditation significantly reduced anxiety and negative affect and increased hope. Changes in cognitive distortions mediated intervention effects for anxiety, negative affect, and hope. Further research is needed to determine differential effects of types of meditation. Copyright 2009 Wiley Periodicals, Inc.

The Mediating Roles of Anxiety Depression, and Hopelessness on Adolescent Suicidal Behaviors

ERIC Educational Resources Information Center

Thompson, Elaine Adams; Mazza, James J.; Herting, Jerald R.; Randell, Brooke P.; Eggert, Leona L.

2005-01-01

The purpose of this study was to explore the roles of anxiety, depression, and hopelessness as mediators between known risk factors and suicidal behaviors among 1,287 potential high school dropouts. As a step toward theory development, a model was tested that posited the relationships among these variables and their effects on suicidal behaviors.…

Sulforaphane-induced autophagy flux prevents prion protein-mediated neurotoxicity through AMPK pathway.

PubMed

Lee, J-H; Jeong, J-K; Park, S-Y

2014-10-10

Prion diseases are neurodegenerative and infectious disorders that involve accumulation of misfolded scrapie prion protein, and which are characterized by spongiform degeneration. Autophagy, a major homeostatic process responsible for the degradation of cytoplasmic components, has garnered attention as the potential target for neurodegenerative diseases such as prion disease. We focused on protective effects of sulforaphane found in cruciferous vegetables on prion-mediated neurotoxicity and the mechanism of sulforaphane related to autophagy. In human neuroblastoma cells, sulforaphane protected prion protein (PrP) (106-126)-mediated neurotoxicity and increased autophagy flux marker microtubule-associated protein 1 light chain 3-II protein levels, following a decrease of p62 protein level. Pharmacological and genetical inhibition of autophagy by 3MA, wortmannin and knockdown of autophagy-related 5 (ATG5) led to block the effect of sulforaphane against PrP (106-126)-induced neurotoxicity. Furthermore we demonstrated that both sulforaphane-induced autophagy and protective effect of sulforaphane against PrP (106-126)-induced neurotoxicity are dependent on the AMP-activated protein kinase (AMPK) signaling. The present results indicated that sulforaphane of cruciferous vegetables enhanced autophagy flux led to the protection effects against prion-mediated neurotoxicity, which was regulated by AMPK signaling pathways in human neuron cells. Our data also suggest that sulforaphane has a potential value as a therapeutic tool in neurodegenerative disease including prion diseases. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Modulation of opioid analgesia by agmatine.

PubMed

Kolesnikov, Y; Jain, S; Pasternak, G W

1996-01-18

Administered alone, agmatine at doses of 0.1 or 10 mg/kg is without effect in the mouse tailflick assay. However, agmatine enhances morphine analgesia in a dose-dependent manner, shifting morphine's ED50 over 5-fold. A far greater effect is observed when morphine is given intrathecally (9-fold shift) than after intracerebroventricular administration (2-fold). In contrast to the potentiation of morphine analgesia, agmatine (10 mg/kg) has no effect on morphine's inhibition of gastrointestinal transit. delta-Opioid receptor-mediated analgesia also is potentiated by agmatine, but kappa1-receptor-mediated (U50,488H; trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetemide) and kappa3-opioid receptor-mediated (naloxone benzoylhydrazone) analgesia is not significantly enhanced by any dose of agmatine tested in this acute model. In chronic studies, agmatine at a low dose (0.1 mg/kg) which does not affect morphine analgesia acutely prevents tolerance following chronic morphine dosing for 10 days. A higher agmatine dose (10 mg/kg) has a similar effect. Agmatine also blocks tolerance to the delta-opioid receptor ligand [D-Pen2,D-Pen5]enkephalin given intrathecally, but not to the kappa3-opioid receptor agonist naloxone benzoylhydrazone. Despite its inactivity on kappa1-opioid analgesia in the acute model, agmatine prevents kappa1-opioid receptor-mediated tolerance. These studies demonstrate the dramatic interactions between agmatine and opioid analgesia and tolerance.

Quercetin Potentiates Doxorubicin Mediated Antitumor Effects against Liver Cancer through p53/Bcl-xl

PubMed Central

Wang, Guanyu; Sharma, Sherven; Dong, Qinghua

2012-01-01

Background The dose-dependent toxicities of doxorubicin (DOX) limit its clinical applications, particularly in drug-resistant cancers, such as liver cancer. In this study, we investigated the role of quercetin on the antitumor effects of DOX on liver cancer cells and its ability to provide protection against DOX-mediated liver damage in mice. Methodology and Results The MTT and Annexin V/PI staining assay demonstrated that quercetin selectively sensitized DOX-induced cytotoxicity against liver cancer cells while protecting normal liver cells. The increase in DOX-mediated apoptosis in hepatoma cells by quercetin was p53-dependent and occurred by downregulating Bcl-xl expression. Z-VAD-fmk (caspase inhibitor), pifithrin-α (p53 inhibitor), or overexpressed Bcl-xl decreased the effects of quercetin on DOX-mediated apoptosis. The combined treatment of quercetin and DOX significantly reduced the growth of liver cancer xenografts in mice. Moreover, quercetin decreased the serum levels of alanine aminotransferase and aspartate aminotransferase that were increased in DOX-treated mice. Quercetin also reversed the DOX-induced pathological changes in mice livers. Conclusion and Significance These results indicate that quercetin potentiated the antitumor effects of DOX on liver cancer cells while protecting normal liver cells. Therefore, the development of quercetin may be beneficial in a combined treatment with DOX for increased therapeutic efficacy against liver cancer. PMID:23240061

Mediating pathways and gender differences between shift work and subjective cognitive function.

PubMed

Wong, Imelda S; Smith, Peter M; Ibrahim, Selahadin; Mustard, Cameron A; Gignac, Monique A M

2016-11-01

Increased injury risk among shift workers is often attributed to cognitive function deficits that come about as a result of sleep disruptions. However, little is known about the intermediate influences of other factors (eg, work stress, health) which may affect this relationship. In addition, gender differences in these the complex relationships have not been fully explored. The purpose of this study is to (1) identify the extent to which work and non-work factors mediate the relationship between shift work, sleep and subsequent subjective cognitive function; and (2) determine if the mediating pathways differ for men and women. Data from the 2010 National Population Health Survey was used to create a cross-sectional sample of 4255 employed Canadians. Using path modelling, we examined the direct and indirect relationships between shift work, sleep duration, sleep quality and subjective cognitive function. Multigroup analyses tested for significantly different pathways between men and women. Potential confounding effects of age and self-reported health and potential mediating effects of work stress were simultaneously examined. Work stress and sleep quality significantly mediated the effects of shift work on cognition. Age and health confounded the relationship between sleep quality and subjective cognition. No differences were found between men and women. Occupational health and safety programmes are needed to address stress and health factors, in addition to sleep hygiene, to effectively address cognitive function among shift workers. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Computational nanomedicine: modeling of nanoparticle-mediated hyperthermal cancer therapy

PubMed Central

Kaddi, Chanchala D; Phan, John H; Wang, May D

2016-01-01

Nanoparticle-mediated hyperthermia for cancer therapy is a growing area of cancer nanomedicine because of the potential for localized and targeted destruction of cancer cells. Localized hyperthermal effects are dependent on many factors, including nanoparticle size and shape, excitation wavelength and power, and tissue properties. Computational modeling is an important tool for investigating and optimizing these parameters. In this review, we focus on computational modeling of magnetic and gold nanoparticle-mediated hyperthermia, followed by a discussion of new opportunities and challenges. PMID:23914967

Abusive supervision, leader-member exchange and moral disengagement: a moderated-mediation model of organizational deviance.

PubMed

Valle, Matthew; Kacmar, K Michele; Zivnuska, Suzanne; Harting, Troy

2018-04-20

This paper draws from social exchange theory and social cognitive theory to explore moral disengagement as a potential mediator of the relationship between abusive supervision and organizational deviance. We also explore the moderating effect of leader-member exchange (LMX) on this mediated relationship. Results indicate that employees with abusive supervisors engaged in moral disengagement strategies and subsequently in organizational deviance behaviors. Additionally, this relationship was stronger for those higher in LMX. Important implications for management research and practice are discussed.

Tai Chi exercise in improving cardiorespiratory capacity.

PubMed

Thornton, Everard W

2008-01-01

To evaluate evidence relating to effects of Tai Chi on cardiovascular outcomes, with emphasis on randomised control designs. Studies reviewed in 2004 were re-examined, together with more recent controlled trials of Tai Chi relating to cardiovascular outcome. The analysis provided comment on problems associated with randomised control design, including sources of bias in such trials. With a single exception, data support reduction of baseline systolic/diastolic blood pressure (BP). While there may be positive bias in these studies, data are from diverse ethnic groups, different gender, age, and level of functional ability. There are no data relating to BP reactive change to subsequent stressors. Few studies consider potential mediating mechanisms through which Tai Chi may provide these benefits. Caution is advocated in using randomised controlled trials as the only effective type of study. Such designs are difficult to conduct and effective trials are more likely given a better understanding of the mediating mechanism(s) through which benefits may be derived. It is currently unclear how changes in BP are derived. Some data indicate a shift to increased vagal relative to sympathetic dominance and there may be other potential physiological mediators. No study has examined relationships between potential psychological gains such as self-efficacy and BP change, or individual differences in outcomes.

Mental health consequences of international migration for Vietnamese Americans and the mediating effects of physical health and social networks: results from a natural experiment approach.

PubMed

Fu, Hongyun; VanLandingham, Mark J

2012-05-01

Although the existing literature on immigrant mental health is extensive, major substantive and methodological gaps remain. Substantively, there is little population-based research that focuses on the mental health consequences of migration for Vietnamese Americans. More generally, although a wide range of mental health problems among immigrants has been identified, the potential causal or mediating mechanisms underlying these problems remain elusive. This latter substantive shortcoming is related to a key methodological challenge involving the potentially confounding effects of selection on migration-related outcomes. This article addresses these challenges by employing a "natural experiment" design, involving comparisons among three population-based samples of Vietnamese immigrants, never-leavers, and returnees (N=709). Data were collected in Ho Chi Minh City and in New Orleans between 2003 and 2005. The study investigates the long-term impact of international migration on Vietnamese mental health, and the potential mediating effects of social networks and physical health on these migration-related outcomes. The results reveal both mental health advantages and disadvantages among Vietnamese immigrants relative to the two groups of Vietnamese nationals. Selection can be ruled out for some of these differences, and both social networks and physical health are found to play important explanatory roles.

Computational Identification of Mechanistic Factors That Determine the Timing and Intensity of the Inflammatory Response

PubMed Central

Nagaraja, Sridevi; Reifman, Jaques; Mitrophanov, Alexander Y.

2015-01-01

Timely resolution of inflammation is critical for the restoration of homeostasis in injured or infected tissue. Chronic inflammation is often characterized by a persistent increase in the concentrations of inflammatory cells and molecular mediators, whose distinct amount and timing characteristics offer an opportunity to identify effective therapeutic regulatory targets. Here, we used our recently developed computational model of local inflammation to identify potential targets for molecular interventions and to investigate the effects of individual and combined inhibition of such targets. This was accomplished via the development and application of computational strategies involving the simulation and analysis of thousands of inflammatory scenarios. We found that modulation of macrophage influx and efflux is an effective potential strategy to regulate the amount of inflammatory cells and molecular mediators in both normal and chronic inflammatory scenarios. We identified three molecular mediators − tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), and the chemokine CXCL8 − as potential molecular targets whose individual or combined inhibition may robustly regulate both the amount and timing properties of the kinetic trajectories for neutrophils and macrophages in chronic inflammation. Modulation of macrophage flux, as well as of the abundance of TNF-α, TGF-β, and CXCL8, may improve the resolution of chronic inflammation. PMID:26633296

Microneedle-mediated vaccine delivery: Harnessing cutaneous immunobiology to improve efficacy

PubMed Central

Al-Zahrani, S; Zaric, M; McCrudden, C; Scott, C; Kissenpfennig, A; Donnelly, Ryan F.

2014-01-01

Introduction We describe the use of microneedle arrays for delivery to targets within the skin itself. Breaching the skin’s stratum corneum barrier raises the possibility of administration of vaccines, gene vectors, antibodies and even nanoparticles, all of which have at least their initial effect on populations of skin cells. Areas Covered Intradermal vaccine delivery, in particular, holds enormous potential for improved therapeutic outcomes for patients, particularly those in the developing world. Various vaccine-delivery strategies have been employed and here we discuss each one in turn. We also describe the importance of cutaneous immunobiology on the effect produced by microneedle-mediated intradermal vaccination. Expert Opinion Microneedle-mediated vaccine holds enormous potential for patient benefit. In order for microneedle vaccine strategies to fulfil their potential, however, the proportion of an immune response that is due to local action of delivered vaccines on skin antigen presenting cells and what is due to a systemic effect from vaccine reaching the systemic circulation must be determined. Moreover, industry will need to invest significantly in new equipment and instrumentation in order to mass produce microneedle vaccines consistently. Finally, microneedles will need to demonstrate consistent dose delivery across patient groups and match this to reliable immune responses before they will replace tried- and-tested needle-and-syringe based-approaches. PMID:22475249

Self-Efficacy and Social Support as Mediators Between Culturally Specific Dance and Lifestyle Physical Activity

PubMed Central

Murrock, Carolyn J.; Madigan, Elizabeth

2013-01-01

Culturally specific dance has the potential to generate health benefits but is seldom used even among studies advocating culturally specific interventions. This study examined the components of self-efficacy and social support as mediators between culturally specific dance and lifestyle physical activity in African American women (N = 126). An experimental design compared intervention and control groups for mediating effects of self-efficacy and social support on lifestyle physical activity. Findings indicated that only outcome expectations and social support from friends mediated effects. Culturally specific dance is a first step in encouraging African American women to become more physically active and improve health outcomes. The implications are that culturally specific dance programs can improve health outcomes by including members of underserved populations. PMID:18763475

Self-efficacy and social support as mediators between culturally specific dance and lifestyle physical activity.

PubMed

Murrock, Carolyn J; Madigan, Elizabeth

2008-01-01

Culturally specific dance has the potential to generate health benefits but is seldom used even among studies advocating culturally specific interventions. This study examined the components of self-efficacy and social support as mediators between culturally specific dance and lifestyle physical activity in African American women (N = 126). An experimental design compared intervention and control groups for mediating effects of self-efficacy and social support on lifestyle physical activity. Findings indicated that only outcome expectations and social support from friends mediated effects. Culturally specific dance is a first step in encouraging African American women to become more physically active and improve health outcomes. The implications are that culturally specific dance programs can improve health outcomes by including members of underserved populations.

Improvements in emotion regulation following mindfulness meditation: Effects on depressive symptoms and perceived stress in younger breast cancer survivors.

PubMed

Boyle, Chloe C; Stanton, Annette L; Ganz, Patricia A; Crespi, Catherine M; Bower, Julienne E

2017-04-01

Mindfulness meditation reduces psychological distress among individuals with cancer. However, mechanisms for intervention effects have not been fully determined. This study tested emotion regulation strategies as mediators of intervention effects in a sample of younger women treated for breast cancer, a group at risk for psychological distress. We focused on two distinct strategies targeted by the intervention-rumination and self-kindness-and further examined the broader construct of mindfulness as a potential mediator. Women (n = 71) with Stage 0-III breast cancer diagnosed at or before age 50 who had completed cancer treatment were randomly assigned to a 6-week mindfulness intervention or wait-list control group. Assessments occurred at study entry, postintervention, and a 3-month follow-up. In single mediator analyses, increases in self-kindness (CIB [-7.83, -1.93]), decreases in rumination (CIB [-5.05, -.31]), and increases in mindfulness (CIB [-6.58, -.82]) each mediated reductions in depressive symptoms from pre- to postintervention. Increases in self-kindness also mediated reductions in perceived stress (CIB [-5.37, -.62]) from pre- to postintervention, and increases in self-kindness (CIB [-5.67, -.22]) and in mindfulness (CIB [-5.51, -.16]) each mediated intervention effects on perceived stress from preintervention to 3-month follow-up. In multiple mediator analysis, only self-kindness mediated intervention effects on depressive symptoms from pre- to postintervention (CIB [-6.41, -.61]), and self-kindness and mindfulness together mediated intervention effects on perceived stress from preintervention to follow-up (CIB [-6.77, -.35]). Self-kindness played a consistent role in reducing distress in younger women with breast cancer. The efficacy of this understudied emotion regulation strategy should be evaluated in other clinical populations. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Differentiation of direct and indirect socioeconomic effects on suicide attempts in South Korea

PubMed Central

Ki, Myung; Seong Sohn, Eui; An, Byungduck; Lim, Jiseun

2017-01-01

Abstract Despite the wide recognition of the inverse association between socioeconomic position (SEP) and suicidal behaviors, its underlying process and potential mediators are little known. This study investigated the pathway from SEP to suicide attempts with attention to potential mediators. From the Korean Health and Nutrition Examination Survey 2007–2013, which is a nationwide cross-sectional survey of the health and nutritional status, a total of 34,565 participants (≥30 years) were included in the analysis. To unfold the pathways linking SEP to suicide attempts, the direct and indirect effects of 3 SEP measures (educational attainment, household income, and occupational group) and 3 mediators (physical illness, mental health problems, and problematic drinking) were differentiated using structured equation model (SEM). Most of direct and indirect effects of educational attainment, household income, and occupational group on suicide attempts were significant; Nonemployment status had the largest total (β = 0.291, P < .01) and direct effects (β = 0.212, P < .01), while educational attainment had the largest indirect effect (β = −0.124, P < .01). Educational attainment was mainly mediated by physical illness and problem drinking, whereas household income and occupational group were mainly mediated by anxious or depressed mood and problem drinking. Physical illness played a major role in explaining suicide attempts, compared to mental health problem and problem drinking. Overall, experience of socioeconomic disadvantage increased suicide attempts independently of mental and physical problems. An extension of suicide prevention program is required for comprehensively targeting people with general problems such as physical illness and low SEP, complemented to narrowly targeting high risk group with, such as mental health problem. PMID:29390510

Elicitors aboveground: an alternative for control of a belowground pest

USDA-ARS?s Scientific Manuscript database

Plant defense pathways mediate multitrophic interactions above and belowground. Understanding the effects of these pathways on pests and natural enemies above and belowground holds great potential for designing effective control strategies. Here we investigate the effects of aboveground stimulation ...

Maternally Mediated Developmental Toxicity

EPA Science Inventory

The current practice for the assessment of an agent’s potential effects on the developing embryo/fetus includes administration of high, maternally toxic doses to pregnant laboratory animals. For most agents evaluated, developmental effects occur concomitant with maternal toxicity...

Maternally Mediated Developmental Toxicity

EPA Science Inventory

The current practice for the assessment of an agent’s potential effects on the developing embryo/fetus includes administration of high, maternally toxic doses to pregnant laboratory animals. For most agents evaluated, developmental effects occur concomitant with maternal to...

Mediation pathways and effects of green structures on respiratory mortality via reducing air pollution

NASA Astrophysics Data System (ADS)

Shen, Yu-Sheng; Lung, Shih-Chun Candice

2017-02-01

Previous studies have shown both health and environmental benefits of green spaces, especially in moderating temperature and reducing air pollution. However, the characteristics of green structures have been overlooked in previous investigations. In addition, the mediation effects of green structures on respiratory mortality have not been assessed. This study explores the potential mediation pathways and effects of green structure characteristics on respiratory mortality through temperature, primary and secondary air pollutants separately using partial least squares model with data from Taiwan. The measurable characteristics of green structure include the largest patch percentage, landscape proportion, aggregation, patch distance, and fragmentation. The results showed that mortality of pneumonia and chronic lower respiratory diseases could be reduced by minimizing fragmentation and increasing the largest patch percentage of green structure, and the mediation effects are mostly through reducing air pollutants rather than temperature. Moreover, a high proportion of but fragmented green spaces would increase secondary air pollutants and enhance health risks; demonstrating the deficiency of traditional greening policy with primary focus on coverage ratio. This is the first research focusing on mediation effects of green structure characteristics on respiratory mortality, revealing that appropriate green structure planning can be a useful complementary strategy in environmental health management.

Mediation pathways and effects of green structures on respiratory mortality via reducing air pollution.

PubMed

Shen, Yu-Sheng; Lung, Shih-Chun Candice

2017-02-23

Previous studies have shown both health and environmental benefits of green spaces, especially in moderating temperature and reducing air pollution. However, the characteristics of green structures have been overlooked in previous investigations. In addition, the mediation effects of green structures on respiratory mortality have not been assessed. This study explores the potential mediation pathways and effects of green structure characteristics on respiratory mortality through temperature, primary and secondary air pollutants separately using partial least squares model with data from Taiwan. The measurable characteristics of green structure include the largest patch percentage, landscape proportion, aggregation, patch distance, and fragmentation. The results showed that mortality of pneumonia and chronic lower respiratory diseases could be reduced by minimizing fragmentation and increasing the largest patch percentage of green structure, and the mediation effects are mostly through reducing air pollutants rather than temperature. Moreover, a high proportion of but fragmented green spaces would increase secondary air pollutants and enhance health risks; demonstrating the deficiency of traditional greening policy with primary focus on coverage ratio. This is the first research focusing on mediation effects of green structure characteristics on respiratory mortality, revealing that appropriate green structure planning can be a useful complementary strategy in environmental health management.

The working mechanism of manual therapy in participants with chronic tension-type headache.

PubMed

Castien, René; Blankenstein, Annette; van der Windt, Daniëlle; Heymans, Martijn W; Dekker, Joost

2013-10-01

Prospective longitudinal study. To explore the working mechanism of manual therapy, we investigated whether 3 cervical spine variables were mediators of the effect of manual therapy on headache frequency. Background Manual therapy has been shown to reduce headache frequency in participants with chronic tension-type headache (CTTH). To what extent specific elements of treatment contribute to the effectiveness of manual therapy in CTTH is unknown. One hundred eighty-two participants with CTTH participated in a prospective longitudinal study: 142 underwent manual therapy and 40 participants received usual care by their general practitioner. Regression analysis was performed according to the steps described by Baron and Kenny, and the proportion of mediated effect was estimated for 3 potential mediators: (1) cervical range of motion, (2) neck flexor endurance, and (3) forward head posture. Outcome was defined as a 50% or greater reduction in headache days. Neck flexor endurance mediated 24.5% of the effect of manual therapy. Cervical range of motion and forward head posture showed no mediated effect. Increased neck flexor endurance appears to be a working mechanism of manual therapy. This finding supports isometric training of neck flexors in participants with CTTH. Trial registered with Netherlands Trial Register (TR 1074).

New insights into the effects of onion consumption on lipid mediators using a diet-induced model of hypercholesterolemia.

PubMed

González-Peña, Diana; Checa, Antonio; de Ancos, Begoña; Wheelock, Craig E; Sánchez-Moreno, Concepción

2017-04-01

The levels and roles of lipid mediators can be modified in response to nutritional stimuli. The aim of this study was to investigate shifts in oxylipin and sphingolipid profiles stimulated by a hypercholesterolemic (HC) diet along with the modulating effects of onion introduced as an antioxidant functional ingredient characterized in the diet (HCO). Oxylipin and sphingolipid profiles were determined in plasma and tissues from Wistar rats using LC-MS/MS. Plasma ω-3 and ω-6 PUFA-derived oxylipins decreased in rats after 7 weeks of HC feeding, but did not evidence a further shift with HCO diet. Onion ingredient supplementation modulated the hepatic concentrations of prostaglandins and enhanced ω-3 oxylipins in the liver of HCO-fed rats relative to the HC group. The HC diet induced shifts in plasma sphingolipids, increasing sphingoid bases, dihydroceramides and ceramides, whilst the sphingomyelin, hexosylceramide and lactosylceramide families decreased. The HCO diet modified some HC diet-induced changes in sphingolipids in liver and spleen tissue. Onion supplementation effected changes in lipid mediator levels in diet-induced hypercholesterolemic Wistar rats. The potential of onion as regulator of pro-inflammatory mediators, and possible enhancer of pro-resolution pathways, warrants further study of the interaction of functional ingredients with bioactive lipid mediators and their potential impact on inflammation, oxidative stress and organ dysfunction. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Bax Translocation Mediated Mitochondrial Apoptosis and Caspase Dependent Photosensitizing Effect of Ficus religiosa on Cancer Cells

PubMed Central

Thankayyan R, Santhosh Kumar; Sithul, Hima; Sreeharshan, Sreeja

2012-01-01

The main aim of the present work was to investigate the potential effect of acetone extract of Ficus religosa leaf (FAE) in multiple apoptosis signalling in human breast cancer cells. FAE treatment significantly induced dose and time dependent, irreversible inhibition of breast cancer cell growth with moderate toxicity to normal breast epithelial cells. This observation was validated using Sulforhodamine B assay. Cell cycle analysis by Flow cytometry showed cell cycle arrest in G1 phase and induction of sub-G0 peak. FAE induced chromatin condensation and displayed an increase in apoptotic population in Annexin V-FITC/PI (Fluorescein isothiocyanate/Propidium iodide) double staining. FAE stimulated the loss of mitochondrial membrane potential in multiple breast cancer cell lines when compared to normal diploid cells. To understand the role of Bax in FAE induced apoptosis, we employed a sensitive cell based platform of MCF-7 cells expressing Bax-EGFP. Bax translocation to mitochondria was accompanied by the disruption of mitochondrial membrane potential and marked elevation in LEHDase activity (Caspase 9). Consistent with this data, FAE induced Caspase activation as evidenced by ratio change in FRET Caspase sensor expressing MCF-7 cell line and cleavage of prominent Caspases and PARP. Interestingly, FAE accelerated cell death in a mitochondrial dependent manner in continuous live cell imaging mode indicating its possible photosensitizing effect. Intracellular generation of reactive oxygen species (ROS) by FAE played a critical role in mediating apoptotic cell death and photosensitizing activity. FAE induced dose and time dependent inhibition of cancer cell growth which was associated with Bax translocation and mitochondria mediated apoptosis with the activation of Caspase 9 dependent Caspase cascade. FAE also possessed strong photosensitizing effect on cancer cell line that was mediated through rapid mitochondrial transmembrane potential loss and partial Caspase activation involving generation of intracellular ROS. PMID:22792212

Injection Drug Use, Unemployment, and Severe Food Insecurity Among HIV-HCV Co-Infected Individuals: A Mediation Analysis.

PubMed

McLinden, Taylor; Moodie, Erica E M; Hamelin, Anne-Marie; Harper, Sam; Walmsley, Sharon L; Paradis, Gilles; Aibibula, Wusiman; Klein, Marina B; Cox, Joseph

2017-12-01

Severe food insecurity (FI), which indicates reduced food intake, is common among HIV-hepatitis C virus (HCV) co-infected individuals. Given the importance of unemployment as a proximal risk factor for FI, this mediation analysis examines a potential mechanism through which injection drug use (IDU) is associated with severe FI. We used biannual data from the Canadian Co-infection Cohort (N = 429 with 3 study visits, 2012-2015). IDU in the past 6 months (exposure) and current unemployment (mediator) were self-reported. Severe FI in the following 6 months (outcome) was measured using the Household Food Security Survey Module. An overall association and a controlled direct effect were estimated using marginal structural models. Among participants, 32% engaged in IDU, 78% were unemployed, and 29% experienced severe FI. After adjustment for confounding and addressing censoring through weighting, the overall association (through all potential pathways) between IDU and severe FI was: risk ratio (RR) = 1.69 (95% confidence interval [CI] = 1.15-2.48). The controlled direct effect (the association through all potential pathways except that of unemployment) was: RR = 1.65 (95% CI = 1.08-2.53). We found evidence of an overall association between IDU and severe FI and estimated a controlled direct effect that is suggestive of pathways from IDU to severe FI that are not mediated by unemployment. Specifically, an overall association and a controlled direct effect that are similar in magnitude suggests that the potential impact of IDU on unemployment is not the primary mechanism through which IDU is associated with severe FI. Therefore, while further research is required to understand the mechanisms linking IDU and severe FI, the strong overall association suggests that reductions in IDU may mitigate severe FI in this vulnerable subset of the HIV-positive population.

Potentially modifiable lifestyle factors, cognitive reserve, and cognitive function in later life: A cross-sectional study

PubMed Central

Wu, Yu-Tzu

2017-01-01

Background Potentially modifiable lifestyle factors may influence cognitive health in later life and offer potential to reduce the risk of cognitive decline and dementia. The concept of cognitive reserve has been proposed as a mechanism to explain individual differences in rates of cognitive decline, but its potential role as a mediating pathway has seldom been explored using data from large epidemiological studies. We explored the mediating effect of cognitive reserve on the cross-sectional association between lifestyle factors and cognitive function in later life using data from a population-based cohort of healthy older people. Methods and findings We analysed data from 2,315 cognitively healthy participants aged 65 y and over in the Cognitive Function and Ageing Study Wales (CFAS-Wales) cohort collected in 2011–2013. Linear regression modelling was used to investigate the overall associations between five lifestyle factors—cognitive and social activity, physical activity, diet, alcohol consumption, and smoking—and cognition, adjusting for demographic factors and chronic conditions. Mediation analysis tested for indirect effects of the lifestyle factors on cognition via cognitive reserve. After controlling for age, gender, and the presence of chronic conditions, cognitive and social activity, physical activity, healthy diet, and light-to-moderate alcohol consumption were positively associated with cognitive function, together accounting for 20% (95% CI 17%–23%) of variance in cognitive test scores. Cognitive reserve was an important mediator of this association, with indirect effects via cognitive reserve contributing 21% (95% CI 15%–27%) of the overall effect on cognition. The main limitations of the study derive from the cross-sectional nature of the data and the challenges of accurately measuring the latent construct of cognitive reserve. Conclusions Cross-sectional associations support the view that enhancing cognitive reserve may benefit cognition, and maintenance of cognitive health may be supported by a healthy and active lifestyle, in later life. PMID:28323829

Experimental Evidence of ω-3 Polyunsaturated Fatty Acid Modulation of Inflammatory Cytokines and Bioactive Lipid Mediators: Their Potential Role in Inflammatory, Neurodegenerative, and Neoplastic Diseases

PubMed Central

Calviello, Gabriella; Su, Hui-Min; Weylandt, Karsten H.; Fasano, Elena; Serini, Simona; Cittadini, Achille

2013-01-01

A large body of evidence has emerged over the past years to show the critical role played by inflammation in the pathogenesis of several diseases including some cardiovascular, neoplastic, and neurodegenerative diseases, previously not considered inflammation-related. The anti-inflammatory action of ω-3 polyunsaturated fatty acids (PUFAs), as well as their potential healthy effects against the development and progression of the same diseases, has been widely studied by our and others' laboratories. As a result, a rethinking is taking place on the possible mechanisms underlying the beneficial effects of ω-3 PUFAs against these disorders, and, in particular, on the influence that they may exert on the molecular pathways involved in inflammatory process, including the production of inflammatory cytokines and lipid mediators active in the resolving phase of inflammation. In the present review we will summarize and discuss the current knowledge regarding the modulating effects of ω-3 PUFAs on the production of inflammatory cytokines and proresolving or protective lipid mediators in the context of inflammatory, metabolic, neurodegenerative, and neoplastic diseases. PMID:23691510

Natural outdoor environments and mental health: Stress as a possible mechanism.

PubMed

Triguero-Mas, Margarita; Donaire-Gonzalez, David; Seto, Edmund; Valentín, Antònia; Martínez, David; Smith, Graham; Hurst, Gemma; Carrasco-Turigas, Glòria; Masterson, Daniel; van den Berg, Magdalena; Ambròs, Albert; Martínez-Íñiguez, Tania; Dedele, Audrius; Ellis, Naomi; Grazulevicius, Tomas; Voorsmit, Martin; Cirach, Marta; Cirac-Claveras, Judith; Swart, Wim; Clasquin, Eddy; Ruijsbroek, Annemarie; Maas, Jolanda; Jerret, Michael; Gražulevičienė, Regina; Kruize, Hanneke; Gidlow, Christopher J; Nieuwenhuijsen, Mark J

2017-11-01

Better mental health has been associated with exposure to natural outdoor environments (NOE). However, comprehensive studies including several indicators of exposure and outcomes, potential effect modifiers and mediators are scarce. We used novel, objective measures to explore the relationships between exposure to NOE (i.e. residential availability and contact) and different indicators of mental health, and possible modifiers and mediators. A nested cross-sectional study was conducted in: Barcelona, Spain; Stoke-on-Trent, United Kingdom; Doetinchem, Netherlands; Kaunas, Lithuania. Participants' exposure to NOE (including both surrounding greenness and green and/or blue spaces) was measured in terms of (a) amount in their residential environment (using Geographical Information Systems) and (b) their contact with NOE (using smartphone data collected over seven days). Self-reported information was collected for mental health (psychological wellbeing, sleep quality, vitality, and somatisation), and potential effect modifiers (gender, age, education level, and city) and mediators (perceived stress and social contacts), with additional objective NOE physical activity (potential mediator) derived from smartphone accelerometers. Analysis of data from 406 participants showed no statistically significant associations linking mental health and residential NOE exposure. However, NOE contact, especially surrounding greenness, was statistically significantly tied to better mental health. There were indications that these relationships were stronger for males, younger people, low-medium educated, and Doetinchem residents. Perceived stress was a mediator of most associations, and physical activity and social contacts were not. Our findings indicate that contact with NOE benefits mental health. Our results also suggest that having contact with NOE that can facilitate stress reduction could be particularly beneficial. Copyright © 2017 Elsevier Inc. All rights reserved.

Working conditions, burnout and stress symptoms in university professors: validating a structural model of the mediating effect of perceived personal competence.

PubMed

Avargues Navarro, María Luisa; Borda Mas, Mercedes; López Jiménez, Ana María

2010-05-01

The purpose of this study has been to test, with a sample of 193 Professors of the University of Seville, a structural model on the mediating role of personal perceived competence in the appearance of burnout syndrome and stress symptoms under potentially stressful work conditions. The instruments used to evaluate were a socio-demographic and work-related data questionnaire, The Maslach Burnout Inventory (M.B.I.), The Labour Scale of Stress and the Magallanes Stress Scale. The model of strategy implementation and LISREL 8.71 were used. The estimated model was adjusted satisfactorily, ascertaining the mediating effect of perceived competence in the effect exerted by the work conditions studied on the depersonalization and personal fulfillment, as well as in the appearance of stress symptoms. The effect on the emotional exhaustion dimension was not confirmed. The latter also acted on the estimated model as a mediating variable, facilitating the negative impact of stressors on emotional exhaustion, depersonalization and personal accomplishment.

Does Social Support Mediate the Moderating Effect of Intrinsic Religiosity on the Relationship between Physical Health and Depressive Symptoms Among Jews?

PubMed Central

Pirutinsky, Steven; Rosmarin, David H.; Holt, Cheryl L.; Feldman, Robert H.; Caplan, Lee S.; Midlarsky, Elizabeth; Pargament, Kenneth I.

2018-01-01

Previous research in the general population suggests that intrinsic religiosity moderates (mitigates) the effect of poor physical health on depression. However, few studies have focused specifically on the Jewish community. We therefore examined these variables in a cross-sectional sample of 89 Orthodox and 123 non-Orthodox Jews. Based on previous research suggesting that non-Orthodox Judaism values religious mental states (e.g., beliefs) less and a collectivist social religiosity more, as compared to Orthodox Judaism, we hypothesized that the moderating effect of intrinsic religiosity would mediated by social support among non-Orthodox but not Orthodox Jews. As predicted, results indicated that the relationship between physical health and depression was moderated by intrinsic religiosity in the sample as a whole. Furthermore, this effect was mediated by social support among non-Orthodox Jews, but not among the Orthodox. The importance of examining religious affiliation and potential mediators in research on spirituality and health is discussed. PMID:21308407

Evidence for a role of MRCK in mediating HeLa cell elongation induced by the C1 domain ligand HMI-1a3.

PubMed

Talman, Virpi; Gateva, Gergana; Ahti, Marja; Ekokoski, Elina; Lappalainen, Pekka; Tuominen, Raimo K

2014-05-13

Diacylglycerol (DAG) is a central mediator of signaling pathways that regulate cell proliferation, survival and apoptosis. Therefore, C1 domain, the DAG binding site within protein kinase C (PKC) and other DAG effector proteins, is considered a potential cancer drug target. Derivatives of 5-(hydroxymethyl)isophthalic acid are a novel group of C1 domain ligands with antiproliferative and differentiation-inducing effects. Our previous work showed that these isophthalate derivatives exhibit antiproliferative and elongation-inducing effects in HeLa human cervical cancer cells. In this study we further characterized the effects of bis(3-trifluoromethylbenzyl) 5-(hydroxymethyl)isophthalate (HMI-1a3) on HeLa cell proliferation and morphology. HMI-1a3-induced cell elongation was accompanied with loss of focal adhesions and actin stress fibers, and exposure to HMI-1a3 induced a prominent relocation of cofilin-1 into the nucleus regardless of cell phenotype. The antiproliferative and morphological responses to HMI-1a3 were not modified by pharmacological inhibition or activation of PKC, or by RNAi knock-down of specific PKC isoforms, suggesting that the effects of HMI-1a3 were not mediated by PKC. Genome-wide gene expression microarray and gene set enrichment analysis suggested that, among others, HMI-1a3 induces changes in small GTPase-mediated signaling pathways. Our experiments revealed that the isophthalates bind also to the C1 domains of β2-chimaerin, protein kinase D (PKD) and myotonic dystrophy kinase-related Cdc42-binding kinase (MRCK), which are potential mediators of small GTPase signaling and cytoskeletal reorganization. Pharmacological inhibition of MRCK, but not that of PKD attenuated HMI-1a3-induced cell elongation, suggesting that MRCK participates in mediating the effects of HMI-1a3 on HeLa cell morphology. Copyright © 2014 Elsevier B.V. All rights reserved.

Side effects, adherence self-efficacy, and adherence to antiretroviral treatment: a mediation analysis in a Chinese sample.

PubMed

Zhang, Liying; Li, Xiaoming; Lin, Zhenping; Jacques-Tiura, Angela J; Xu, Jinping; Zhou, Yuejiao; Qiao, Shan; Shen, Zhiyong; Stanton, Bonita

2016-07-01

Antiretroviral therapy (ART) is a lifelong treatment. To date, ART adherence is suboptimal for most patients in resource-poor settings. Previous research indicates that medication side effects are perceived to be a significant barrier of high ART adherence. Data regarding the role of adherence self-efficacy in mediating the relationship between side effects from ART and adherence to ART are limited; thus, this study examines this potential mediational role of self-efficacy. A cross-sectional survey of 2987 people living with HIV aged ≥18 years was conducted in 2012-2013 in Guangxi Autonomous Region (Guangxi) which has one of the fastest-growing HIV rates in China. Of the total sample, 2146 (72.1%) participants had initiated ART. Participants reported the number of days of completing the daily dose of ART in the past month; adherence was defined as completing the daily dose at least 28 days in the last month (≥90%). Side effects were significantly negatively related to adherence to ART. Mediation analyses indicated that adherence self-efficacy significantly mediated the side effects-adherence relationship. Future interventions to increase adherence self-efficacy and effective coping with side effects among HIV patients are needed in order to improve their ART adherence.

Mediating effects of resistance training skill competency on health-related fitness and physical activity: the ATLAS cluster randomised controlled trial.

PubMed

Smith, Jordan J; Morgan, Philip J; Plotnikoff, Ronald C; Stodden, David F; Lubans, David R

2016-01-01

The purpose of this study was to examine the mediating effect of resistance training skill competency on percentage of body fat, muscular fitness and physical activity among a sample of adolescent boys participating in a school-based obesity prevention intervention. Participants were 361 adolescent boys taking part in the Active Teen Leaders Avoiding Screen-time (ATLAS) cluster randomised controlled trial: a school-based program targeting the health behaviours of economically disadvantaged adolescent males considered "at-risk" of obesity. Body fat percentage (bioelectrical impedance), muscular fitness (hand grip dynamometry and push-ups), physical activity (accelerometry) and resistance training skill competency were assessed at baseline and post-intervention (i.e., 8 months). Three separate multi-level mediation models were analysed to investigate the potential mediating effects of resistance training skill competency on each of the study outcomes using a product-of-coefficients test. Analyses followed the intention-to-treat principle. The intervention had a significant impact on the resistance training skill competency of the boys, and improvements in skill competency significantly mediated the effect of the intervention on percentage of body fat and the combined muscular fitness score. No significant mediated effects were found for physical activity. Improving resistance training skill competency may be an effective strategy for achieving improvements in body composition and muscular fitness in adolescent boys.

Adenoviral mediated interferon-alpha 2b gene therapy suppresses the pro-angiogenic effect of vascular endothelial growth factor in superficial bladder cancer.

PubMed

Adam, Liana; Black, Peter C; Kassouf, Wassim; Eve, Beryl; McConkey, David; Munsell, Mark F; Benedict, William F; Dinney, Colin P N

2007-05-01

Intravesical adenovirus mediated interferon-alpha gene transfer has a potent therapeutic effect against superficial human bladder carcinoma xenografts growing in the bladder of athymic nude mice. We determined whether the inhibition of angiogenesis might contribute to the antitumor effect. We treated several human urothelial carcinoma cells with adenovirus mediated interferon-alpha 2b and monitored its effects on the production of angiogenic factors using real-time reverse-transcription polymerase chain reaction, Western blotting, and immunohistochemical analysis and a gel shift based transcription factor array. To assess the role of adenovirus mediated interferon 2b in angiogenic activity we used in vitro invasion assays and evaluated the anti-angiogenic effects of adenovirus mediated interferon gene therapy in an orthotopic murine model of human superficial bladder cancer. In adenovirus mediated interferon-alpha infected 253J B-V cells vascular endothelial growth factor was decreased and anti-angiogenic interferon-gamma inducible protein 10 was up-regulated. In contrast, the addition of as much as 100,000 IU recombinant interferon had no apparent effect on vascular endothelial growth factor production. Conditioned medium derived from adenovirus mediated interferon 2b infected 253J B-V cells greatly decreased the invasive potential of human endothelial cells and down-regulated their matrix metalloproteinase 2 expression compared to controls. Furthermore, adenovirus mediated interferon 2b blocked pro-angiogenic nuclear signals, such as the transcription factors activating protein-1 and 2, stimulating protein-1, nuclear factor kappaB and c-myb. In vivo experiments revealed significant vascular endothelial growth factor down-regulation and decreased tumor vessel density in the adenovirus mediated interferon 2b treated group compared to controls. Treatment with adenovirus mediated interferon 2b increases the angiostatic activity of the bladder cancer microenvironment. This inhibition may prove beneficial for treating superficial bladder cancer with adenovirus mediated interferon-alpha and hopefully contribute to a decreased recurrence rate of this neoplasm.

Type D personality and coronary atherosclerotic plaque vulnerability: The potential mediating effect of health behavior.

PubMed

Cheng, Fangman; Lin, Ping; Wang, Yini; Liu, Guojie; Li, Ling; Yu, Huai; Yu, Bo; Zhao, Zhenjuan; Gao, Xueqin

2018-05-01

The association between type D personality and coronary plaque vulnerability has been suggested. The objective of the study was to evaluate the potential mediating effects of health behavior on the association between type D personality and plaque vulnerability in coronary artery disease (CAD) patients. A total of 319 CAD patients were assessed for type D personality and health behavior via self-administered questionnaires. The plaque vulnerability, evaluated according to characteristics, accompaniment, and outcomes of plaque, was assessed by optical coherence tomography. Regression analysis showed that type D personality was independently associated with lipid plaque (odds ratio [OR] = 2.387, p = 0.001), thin cap fibroatheroma (TCFA) (OR = 2.366, p = 0.001), rupture (OR = 2.153, p = 0.002), and lipid arc (β = -0.291, p < 0.001). Mediation analyses showed that aspects of health behavior were significant mediators of the relationship between type D personality and plaque vulnerability. Psychological stress mediated the relationship between type D and lipid plaque (p = 0.030), TCFA (p = 0.034), and rupture (p = 0.013). Living habits significantly mediated the relationship between type D and lipid plaque (p = 0.028), TCFA (p = 0.036), but not rupture (p = 0.066). Participating in activities was not a significant mediator of the relationship between type D personality and lipid plaque (p = 0.115), TCFA (p = 0.115), or rupture (p = 0.077). Health behaviors (psychological stress and living habits) may be mediators of the association between type D personality and plaque vulnerability. Copyright © 2018 Elsevier Inc. All rights reserved.

The Role of AhR in Autoimmune Regulation and Its Potential as a Therapeutic Target against CD4 T Cell Mediated Inflammatory Disorder

PubMed Central

Zhu, Conghui; Xie, Qunhui; Zhao, Bin

2014-01-01

AhR has recently emerged as a critical physiological regulator of immune responses affecting both innate and adaptive systems. Since the AhR signaling pathway represents an important link between environmental stimulators and immune-mediated inflammatory disorder, it has become the object of great interest among researchers recently. The current review discusses new insights into the mechanisms of action of a select group of inflammatory autoimmune diseases and the ligand-activated AhR signaling pathway. Representative ligands of AhR, both exogenous and endogenous, are also reviewed relative to their potential use as tools for understanding the role of AhR and as potential therapeutics for the treatment of various inflammatory autoimmune diseases, with a focus on CD4 helper T cells, which play important roles both in self-immune tolerance and in inflammatory autoimmune diseases. Evidence indicating the potential use of these ligands in regulating inflammation in various diseases is highlighted, and potential mechanisms of action causing immune system effects mediated by AhR signaling are also discussed. The current review will contribute to a better understanding of the role of AhR and its signaling pathway in CD4 helper T cell mediated inflammatory disorder. Considering the established importance of AhR in immune regulation and its potential as a therapeutic target, we also think that both further investigation into the molecular mechanisms of immune regulation that are mediated by the ligand-specific AhR signaling pathway, and integrated research and development of new therapeutic drug candidates targeting the AhR signaling pathway should be pursued urgently. PMID:24905409

Testing covariates of Type 2 diabetes-cognition associations in older adults: moderating or mediating effects?

PubMed

McFall, G Peggy; Geall, Bonnie P; Fischer, Ashley L; Dolcos, Sanda; Dixon, Roger A

2010-09-01

The general goal of this study was to advance our understanding of Type 2 diabetes (T2D)-cognition relationships in older adults by linking and testing comprehensive sets of potential moderators, potential mediators, and multiple cognitive outcomes. We identified in the literature 13 health-related (but T2D-distal) potential covariates, representing four informal domains (i.e., biological vitality, personal affect, subjective health, lifestyle activities). Cross-sectional data from the Victoria Longitudinal Study (age range = 53-90 years; n = 41 T2D and n = 458 control participants) were used. We first examined whether any of the 13 potential covariates influenced T2D-cognition associations, as measured by a comprehensive neuropsychological battery (15 measures). Next, using standard regression-based moderator and mediator analyses, we systematically tested whether the identified covariates would significantly alter observed T2D-cognition relationships. Six potential covariates were found to be sensitive to T2D associations with performance on seven cognitive measures. Three factors (systolic blood pressure, gait-balance composite, subjective health) were significant mediators. Each mediated multiple cognitive outcomes, especially measures of neurocognitive speed, executive functioning, and episodic memory. Our findings offer a relatively comprehensive perspective of T2D-related cognitive deficits, comorbidities, and modulating influences. The implications for future research reach across several fields of study and application. These include (1) neuropsychological research on neural and biological bases of T2D-related cognitive decline, (2) clinical research on intervention and treatment strategies, and (3) larger-scale longitudinal studies examining the potential multilateral and dynamic relationships among T2D status, related comorbidities, and cognitive outcomes. Copyright 2010 APA, all rights reserved.

Within-subject mediation analysis for experimental data in cognitive psychology and neuroscience.

PubMed

Vuorre, Matti; Bolger, Niall

2017-12-15

Statistical mediation allows researchers to investigate potential causal effects of experimental manipulations through intervening variables. It is a powerful tool for assessing the presence and strength of postulated causal mechanisms. Although mediation is used in certain areas of psychology, it is rarely applied in cognitive psychology and neuroscience. One reason for the scarcity of applications is that these areas of psychology commonly employ within-subjects designs, and mediation models for within-subjects data are considerably more complicated than for between-subjects data. Here, we draw attention to the importance and ubiquity of mediational hypotheses in within-subjects designs, and we present a general and flexible software package for conducting Bayesian within-subjects mediation analyses in the R programming environment. We use experimental data from cognitive psychology to illustrate the benefits of within-subject mediation for theory testing and comparison.

Enhanced Radiotherapy using Bismuth Sulfide Nanoagents Combined with Photo-thermal Treatment.

PubMed

Cheng, Xiaju; Yong, Yuan; Dai, Yiheng; Song, Xin; Yang, Gang; Pan, Yue; Ge, Cuicui

2017-01-01

Nanotechniques that can improve the effectiveness of radiotherapy (RT) by integrating it with multimodal imaging are highly desirable. Results In this study, we fabricated Bi 2 S 3 nanorods that have attractive features such as their ability to function as contrast agents for X-ray computed tomography (CT) and photoacoustic (PA) imaging as well as good biocompatibility. Both in vitro and in vivo studies confirmed that the Bi 2 S 3 nanoagents could potentiate the lethal effects of radiation via amplifying the local radiation dose and enhancing the anti-tumor efficacy of RT by augmenting the photo-thermal effect. Furthermore, the nanoagent-mediated hyperthermia could effectively increase the oxygen concentration in hypoxic regions thereby inhibiting the expression of hypoxia-inducible factor ( HIF -1α). This, in turn, interfered with DNA repair via decreasing the expression of DNA repair-related proteins to overcome radio-resistance. Also, RT combined with nanoagent-mediated hyperthermia could substantially suppress tumor metastasis via down-regulating angiogenic factors. Conclusion In summary, we constructed a single-component powerful nanoagent for CT/PA imaging-guided tumor radiotherapy and, most importantly, explored the potential mechanisms of nanoagent-mediated photo-thermal treatment for enhancing the efficacy of RT in a synergistic manner.

The anorexic agents, sibutramine and fenfluramine, depress GABAB-induced inhibitory postsynaptic potentials in rat mesencephalic dopaminergic cells

PubMed Central

Ledonne, Ada; Sebastianelli, Luca; Federici, Mauro; Bernardi, Giorgio; Mercuri, Nicola Biagio

2009-01-01

Background and purpose Nutrition is the result of a complex interaction among environmental, homeostatic and reward-related processes. Accumulating evidence supports key roles for the dopaminergic neurons of the ventral midbrain in regulating feeding behaviour. For this reason, in the present study, we have investigated the electrophysiological effects of two centrally acting anorexic agents, fenfluramine and sibutramine, on these cells. Experimental approach Rat midbrain slices were used to make intracellular recordings from dopaminergic neurons of the substantia nigra and the ventral tegmental area. Gamma-aminobutyric acid (GABA)-mediated synaptic transmission was assessed from the inhibitory postsynaptic potentials (IPSPs) mediated by GABAA and GABAB receptors. Key results Fenfluramine and sibutramine reduced, concentration-dependently, the GABAB IPSPs, without affecting the GABAA-mediated potentials. This effect is presynaptic, as postsynaptic membrane responses induced by application of a GABAB receptor agonist, baclofen, were not affected by the two drugs. Furthermore, the selective 5-hydroxytriptamine 1B (5-HT1B) receptor antagonist, SB216641, blocked the reduction of GABAB IPSPs caused by fenfluramine and sibutramine, indicating that the receptor mediating this effect is 5-HT1B. Conclusions and implications Two anorexic agents, fenfluramine and sibutramine, induced the activation of 5-HT1B receptors located on presynaptic GABAergic terminals, thus reducing the release of GABA. This action can alter the strength of synaptic afferents that modify the activity of dopaminergic neurons, inducing neuronal excitation. Our results reveal an additional mechanism of action for fenfluramine and sibutramine that might contribute to reducing food intake, by influencing the pleasurable and motor aspects of feeding behaviour. PMID:19298257

Bimolecular Rate Constants for FAD-Dependent Glucose Dehydrogenase from Aspergillus terreus and Organic Electron Acceptors.

PubMed

Tsuruoka, Nozomu; Sadakane, Takuya; Hayashi, Rika; Tsujimura, Seiya

2017-03-10

The flavin adenine dinucleotide-dependent glucose dehydrogenase (FAD-GDH) from Aspergillus species require suitable redox mediators to transfer electrons from the enzyme to the electrode surface for the application of bioelectrical devices. Although several mediators for FAD-GDH are already in use, they are still far from optimum in view of potential, kinetics, sustainability, and cost-effectiveness. Herein, we investigated the efficiency of various phenothiazines and quinones in the electrochemical oxidation of FAD-GDH from Aspergillus terreus . At pH 7.0, the logarithm of the bimolecular oxidation rate constants appeared to depend on the redox potentials of all the mediators tested. Notably, the rate constant of each molecule for FAD-GDH was approximately 2.5 orders of magnitude higher than that for glucose oxidase from Aspergillus sp. The results suggest that the electron transfer kinetics is mainly determined by the formal potential of the mediator, the driving force of electron transfer, and the electron transfer distance between the redox active site of the mediator and the FAD, affected by the steric or chemical interactions. Higher k ₂ values were found for ortho-quinones than for para-quinones in the reactions with FAD-GDH and glucose oxidase, which was likely due to less steric hindrance in the active site in the case of the ortho-quinones.

Network Mendelian randomization: using genetic variants as instrumental variables to investigate mediation in causal pathways

PubMed Central

Burgess, Stephen; Daniel, Rhian M; Butterworth, Adam S; Thompson, Simon G

2015-01-01

Background: Mendelian randomization uses genetic variants, assumed to be instrumental variables for a particular exposure, to estimate the causal effect of that exposure on an outcome. If the instrumental variable criteria are satisfied, the resulting estimator is consistent even in the presence of unmeasured confounding and reverse causation. Methods: We extend the Mendelian randomization paradigm to investigate more complex networks of relationships between variables, in particular where some of the effect of an exposure on the outcome may operate through an intermediate variable (a mediator). If instrumental variables for the exposure and mediator are available, direct and indirect effects of the exposure on the outcome can be estimated, for example using either a regression-based method or structural equation models. The direction of effect between the exposure and a possible mediator can also be assessed. Methods are illustrated in an applied example considering causal relationships between body mass index, C-reactive protein and uric acid. Results: These estimators are consistent in the presence of unmeasured confounding if, in addition to the instrumental variable assumptions, the effects of both the exposure on the mediator and the mediator on the outcome are homogeneous across individuals and linear without interactions. Nevertheless, a simulation study demonstrates that even considerable heterogeneity in these effects does not lead to bias in the estimates. Conclusions: These methods can be used to estimate direct and indirect causal effects in a mediation setting, and have potential for the investigation of more complex networks between multiple interrelated exposures and disease outcomes. PMID:25150977

The Effects of Anti-Vaccine Conspiracy Theories on Vaccination Intentions

PubMed Central

Jolley, Daniel; Douglas, Karen M.

2014-01-01

The current studies investigated the potential impact of anti-vaccine conspiracy beliefs, and exposure to anti-vaccine conspiracy theories, on vaccination intentions. In Study 1, British parents completed a questionnaire measuring beliefs in anti-vaccine conspiracy theories and the likelihood that they would have a fictitious child vaccinated. Results revealed a significant negative relationship between anti-vaccine conspiracy beliefs and vaccination intentions. This effect was mediated by the perceived dangers of vaccines, and feelings of powerlessness, disillusionment and mistrust in authorities. In Study 2, participants were exposed to information that either supported or refuted anti-vaccine conspiracy theories, or a control condition. Results revealed that participants who had been exposed to material supporting anti-vaccine conspiracy theories showed less intention to vaccinate than those in the anti-conspiracy condition or controls. This effect was mediated by the same variables as in Study 1. These findings point to the potentially detrimental consequences of anti-vaccine conspiracy theories, and highlight their potential role in shaping health-related behaviors. PMID:24586574

The effects of anti-vaccine conspiracy theories on vaccination intentions.

PubMed

Jolley, Daniel; Douglas, Karen M

2014-01-01

The current studies investigated the potential impact of anti-vaccine conspiracy beliefs, and exposure to anti-vaccine conspiracy theories, on vaccination intentions. In Study 1, British parents completed a questionnaire measuring beliefs in anti-vaccine conspiracy theories and the likelihood that they would have a fictitious child vaccinated. Results revealed a significant negative relationship between anti-vaccine conspiracy beliefs and vaccination intentions. This effect was mediated by the perceived dangers of vaccines, and feelings of powerlessness, disillusionment and mistrust in authorities. In Study 2, participants were exposed to information that either supported or refuted anti-vaccine conspiracy theories, or a control condition. Results revealed that participants who had been exposed to material supporting anti-vaccine conspiracy theories showed less intention to vaccinate than those in the anti-conspiracy condition or controls. This effect was mediated by the same variables as in Study 1. These findings point to the potentially detrimental consequences of anti-vaccine conspiracy theories, and highlight their potential role in shaping health-related behaviors.

N-acetylcysteine potentiates platelet inhibition by endothelium-derived relaxing factor.

PubMed

Stamler, J; Mendelsohn, M E; Amarante, P; Smick, D; Andon, N; Davies, P F; Cooke, J P; Loscalzo, J

1989-09-01

Recent evidence suggests that endothelium-derived relaxing factor exhibits properties of nitric oxide. Like nitric oxide, it inhibits platelet function and mediates its effects by elevating intracellular cyclic GMP. In this study we have investigated the role of reduced thiol in the mechanism of action of endothelium-derived relaxing factor on platelets. Bovine aortic endothelial cells were grown on microcarrier beads and pretreated with aspirin before use. Endothelial cells stimulated with bradykinin or exposed to stirred medium expressed a dose-dependent inhibition of platelet aggregation that was potentiated by the reduced thiol, N-acetylcysteine. Endothelial cell-mediated platelet inhibition was attenuated by methylene blue. Inhibition of platelet aggregation by endothelial cells was associated with a rise in platelet intracellular cyclic GMP, an effect that was enhanced by N-acetylcysteine. These data show that 1) the reduced thiol N-acetylcysteine potentiates platelet inhibition by endothelium-derived relaxing factor and 2) this effect is associated with increasing intracellular platelet cyclic GMP levels.

Social Skills and Depressive Symptoms across Adolescence: Social Support as a Mediator in Girls versus Boys

ERIC Educational Resources Information Center

Nilsen, Wendy; Karevold, Evalill; Roysamb, Espen; Gustavson, Kristin; Mathiesen, Kristin S.

2013-01-01

The current population-based study of Norwegian adolescents examined gender-specific patterns in the prospective association between social skills in early adolescence (age 12.5; n = 566) and changes in depressive symptoms from early to late adolescence (age 16.5; n = 375). Further, a potential mediation effect of social support (from peers,…

Victimization in Early Life and Mental Health in Adulthood: An Examination of the Mediating and Moderating Influences of Psychosocial Resources

ERIC Educational Resources Information Center

Hill, Terrence D.; Kaplan, Lauren M.; French, Michael T.; Johnson, Robert J.

2010-01-01

Although numerous studies have documented the long-term effects of childhood victimization on mental health in adulthood, few have directly examined potential mediators and moderators of this association. Using data from the Welfare, Children, and Families project (1999)--a probability sample of 2,402 predominantly black and Hispanic low-income…

Vitamin D-Prostaglandin Interactions and Effects in Prostate Cancer

DTIC Science & Technology

2006-10-01

combining high doses of calcitriol and naproxen in PCa patients with advanced androgen-independent disease who have failed other therapies. The initial...growth inhibitory actions of calcitriol. Potential Mediators of the Enhanced Growth Inhibition by the combined treatment with Calcitriol and Naproxen ...specific NSAIDs ( naproxen and ibuprofen). To explore the possible molecular mechanisms mediating this enhanced growth inhibition, we analyzed the

Transient receptor potential cation channel A1 (TRPA1) mediates decrements in cardiac mechanical function and dysrhythmia caused by a single air pollution exposure in mice

EPA Science Inventory

This work, which will be presented at SOT 2014, demonstrates that a single exposure to either ozone or acrolein causes decrements in cardiac function and altered electrical activity (i.e. arrhythmia). The results suggest that this effect is mediated by the airway sensor TRPA1. ...

A Proteomic Approach to Analyze the Aspirin-mediated Lysine Acetylome*

PubMed Central

Tatham, Michael H.; Cole, Christian; Scullion, Paul; Wilkie, Ross; Westwood, Nicholas J.; Stark, Lesley A.; Hay, Ronald T.

2017-01-01

Aspirin, or acetylsalicylic acid is widely used to control pain, inflammation and fever. Important to this function is its ability to irreversibly acetylate cyclooxygenases at active site serines. Aspirin has the potential to acetylate other amino acid side-chains, leading to the possibility that aspirin-mediated lysine acetylation could explain some of its as-yet unexplained drug actions or side-effects. Using isotopically labeled aspirin-d3, in combination with acetylated lysine purification and LC-MS/MS, we identified over 12000 sites of lysine acetylation from cultured human cells. Although aspirin amplifies endogenous acetylation signals at the majority of detectable endogenous sites, cells tolerate aspirin mediated acetylation very well unless cellular deacetylases are inhibited. Although most endogenous acetylations are amplified by orders of magnitude, lysine acetylation site occupancies remain very low even after high doses of aspirin. This work shows that while aspirin has enormous potential to alter protein function, in the majority of cases aspirin-mediated acetylations do not accumulate to levels likely to elicit biological effects. These findings are consistent with an emerging model for cellular acetylation whereby stoichiometry correlates with biological relevance, and deacetylases act to minimize the biological consequences of nonspecific chemical acetylations. PMID:27913581

Taurine-induced attenuation of MPP+ neurotoxicity in vitro: a possible role for the GABA(A) subclass of GABA receptors.

PubMed

O'Byrne, M B; Tipton, K F

2000-05-01

Taurine is a sulphur-containing beta-amino acid found in high (millimolar) concentrations in excitable tissues such as brain and heart. Its suggested roles include osmoregulator, thermoregulator, neuromodulator, and potential neurotransmitter. This amino acid has also been shown to be released in large concentrations during ischaemia and excitotoxin-induced neuronal damage. Here we report a protective effect of taurine against MPP(+)-induced neurotoxicity in coronal slices from rat brain. Significant protective effects were observed at taurine concentrations of 20 and 1 mM, suggesting a potential role for taurine in cases of neuronal insult. Studies with the synthetic taurine analogues taurine phosphonate, guanidinoethane sulphonate, and trimethyltaurine suggested the observed effect to be mediated via an extracellular mechanism. The use of GABA receptor ligands muscimol and bicuculline indicated the effect to be mediated through activation of GABA(A) receptors.

Evidence That GABA Mediates Dopaminergic and Serotonergic Pathways Associated with Locomotor Activity in Juvenile Chinook Salmon (Oncorhynchus tshawytscha)

USGS Publications Warehouse

Clements, S.; Schreck, C.B.

2004-01-01

The authors examined the control of locomotor activity in juvenile salmon (Oncorhynchus tshawytscha) by manipulating 3 neurotransmitter systems-gamma-amino-n-butyric acid (GABA), dopamine, and serotonin-as well as the neuropeptide corticotropin releasing hormone (CRH). Intracerebroventricular (ICV) injections of CRH and the GABAAagonist muscimol stimulated locomotor activity. The effect of muscimol was attenuated by administration of a dopamine receptor antagonist, haloperidol. Conversely, the administration of a dopamine uptake inhibitor (4???,4??? -difluoro-3-alpha-[diphenylmethoxy] tropane hydrochloride [DUI]) potentiated the effect of muscimol. They found no evidence that CRH-induced hyperactivity is mediated by dopaminergic systems following concurrent injections of haloperidol or DUI with CRH. Administration of muscimol either had no effect or attenuated the locomotor response to concurrent injections of CRH and fluoxetine, whereas the GABAA antagonist bicuculline methiodide potentiated the effect of CRH and fluoxetine.

Free Recall Enhances Subsequent Learning

PubMed Central

Arnold, Kathleen M.; McDermott, Kathleen B.

2013-01-01

Testing, or retrieval practice, has become a central topic in memory research. One potentially important effect of retrieval practice has received little attention, however: Retrieval practice may enhance, or potentiate, subsequent learning. We introduce a paradigm that can measure the indirect, potentiating effect of free recall tests on subsequent learning, and then test a hypothesis for why tests have this potentiating effect. In two experiments, the benefit of a restudy trial was enhanced when prior free recall tests had been taken. Results from a third correlational study suggest that this effect may be mediated by the effect of testing on organization. Not only do encoding conditions impact later retrievability, but also retrieval attempts impact subsequent encoding effectiveness. PMID:23297100

Cooperative Electrocatalytic O 2 Reduction Involving Co(salophen) with p- Hydroquinone as an Electron–Proton Transfer Mediator

DOE Office of Scientific and Technical Information (OSTI.GOV)

Anson, Colin W.; Stahl, Shannon S.

2017-12-01

The molecular cobalt complex, Co(salophen), and para-hydroquinone (H2Q) serve as effective cocatalysts for the electrochemical reduction of O2 to water. Mechanistic studies reveal redox cooperativity between Co(salophen) and H2Q. H2Q serves as an electron-proton transfer mediator (EPTM) that enables electrochemical O2 reduction at higher potentials and with faster rates than is observed with Co(salophen) alone. Replacement of H2Q with the higher potential EPTM, 2-chloro-H2Q, allows for faster O2 reduction rates at higher applied potential. These results demonstrate a unique strategy to achieve improved performance with molecular electrocatalyst systems.

Covariate Measurement Error Correction Methods in Mediation Analysis with Failure Time Data

PubMed Central

Zhao, Shanshan

2014-01-01

Summary Mediation analysis is important for understanding the mechanisms whereby one variable causes changes in another. Measurement error could obscure the ability of the potential mediator to explain such changes. This paper focuses on developing correction methods for measurement error in the mediator with failure time outcomes. We consider a broad definition of measurement error, including technical error and error associated with temporal variation. The underlying model with the ‘true’ mediator is assumed to be of the Cox proportional hazards model form. The induced hazard ratio for the observed mediator no longer has a simple form independent of the baseline hazard function, due to the conditioning event. We propose a mean-variance regression calibration approach and a follow-up time regression calibration approach, to approximate the partial likelihood for the induced hazard function. Both methods demonstrate value in assessing mediation effects in simulation studies. These methods are generalized to multiple biomarkers and to both case-cohort and nested case-control sampling design. We apply these correction methods to the Women's Health Initiative hormone therapy trials to understand the mediation effect of several serum sex hormone measures on the relationship between postmenopausal hormone therapy and breast cancer risk. PMID:25139469

Covariate measurement error correction methods in mediation analysis with failure time data.

PubMed

Zhao, Shanshan; Prentice, Ross L

2014-12-01

Mediation analysis is important for understanding the mechanisms whereby one variable causes changes in another. Measurement error could obscure the ability of the potential mediator to explain such changes. This article focuses on developing correction methods for measurement error in the mediator with failure time outcomes. We consider a broad definition of measurement error, including technical error, and error associated with temporal variation. The underlying model with the "true" mediator is assumed to be of the Cox proportional hazards model form. The induced hazard ratio for the observed mediator no longer has a simple form independent of the baseline hazard function, due to the conditioning event. We propose a mean-variance regression calibration approach and a follow-up time regression calibration approach, to approximate the partial likelihood for the induced hazard function. Both methods demonstrate value in assessing mediation effects in simulation studies. These methods are generalized to multiple biomarkers and to both case-cohort and nested case-control sampling designs. We apply these correction methods to the Women's Health Initiative hormone therapy trials to understand the mediation effect of several serum sex hormone measures on the relationship between postmenopausal hormone therapy and breast cancer risk. © 2014, The International Biometric Society.

Abdominal adiposity is not a mediator of the protective effect of Mediterranean diet on colorectal cancer.

PubMed

Fasanelli, Francesca; Zugna, Daniela; Giraudo, Maria Teresa; Krogh, Vittorio; Grioni, Sara; Panico, Salvatore; Mattiello, Amalia; Masala, Giovanna; Caini, Saverio; Tumino, Rosario; Frasca, Graziella; Sciannameo, Veronica; Ricceri, Fulvio; Sacerdote, Carlotta

2017-05-15

Adherence to the Mediterranean diet (MD) has a preventive effect on colorectal cancer (CRC). Several biological mechanisms have been hypothesized to explain this effect, but the involvement of clinical mediators has not been experimentally proven. We examined the role of abdominal adiposity (i.e., waist-to-hip ratio, WHR) as a potential mediator of the relationship between the MD and CRC in the Italian centres of the European Prospective Investigation into Cancer and Nutrition. We evaluated the effect of the Italian Mediterranean Index (IMI) on WHR and of WHR on CRC risk. We then estimated the natural indirect effect (NIE, mediated by WHR) and the pure direct effect (PDE, unmediated) of IMI on CRC risk using mediation analyses, considering age, sex, education, physical activity, smoking and EPIC centre as confounders. Increased IMI was associated with significantly decreased odds of high WHR (odds ratio [OR] for an IMI of 6-11 vs. 0-1: 0.88, 95% confidence interval [CI]: 0.81-0.97). There was a positive relationship between WHR and CRC (hazard ratio [HR] for high vs. low WHR: 1.34, 95%CI: 1.09-1.66). The total effect of IMI was protective on CRC risk and was mainly explained by the PDE (HR for an IMI of 6-11 vs. 0-1: 0.51, 95%CI: 0.31-0.83), whereas the NIE was 1.00 (95%CI: 0.94-1.10). In this Mediterranean cohort, the protective effect of the MD on the development of CRC was not mediated by abdominal adiposity. Since this is the first study to investigate the mediating effect of abdominal obesity, other studies are needed to replicate this result. © 2017 UICC.

Understanding how pain education causes changes in pain and disability: protocol for a causal mediation analysis of the PREVENT trial.

PubMed

Lee, Hopin; Moseley, G Lorimer; Hübscher, Markus; Kamper, Steven J; Traeger, Adrian C; Skinner, Ian W; McAuley, James H

2015-07-01

Pain education is a complex intervention developed to help clinicians manage low back pain. Although complex interventions are usually evaluated by their effects on outcomes, such as pain or disability, most do not directly target these outcomes; instead, they target intermediate factors that are presumed to be associated with the outcomes. The mechanisms underlying treatment effects, or the effect of an intervention on an intermediate factor and its subsequent effect on outcome, are rarely investigated in clinical trials. This leaves a gap in the evidence for understanding how treatments exert their effects on outcomes. Mediation analysis provides a method for identifying and quantifying the mechanisms that underlie interventions. To determine whether the effect of pain education on pain and disability is mediated by changes in self-efficacy, catastrophisation and back pain beliefs. Causal mediation analysis of the PREVENT randomised controlled trial. Two hundred and two participants with acute low back pain from primary care clinics in the Sydney metropolitan area. Participants will be randomised to receive either 'pain education' (intervention group) or 'sham education' (control group). All outcome measures (including patient characteristics), primary outcome measures (pain and disability), and putative mediating variables (self-efficacy, catastrophisation and back pain beliefs) will be measured prior to randomisation. Putative mediators and primary outcome measures will be measured 1 week after the intervention, and primary outcome measures will be measured 3 months after the onset of low back pain. Causal mediation analysis under the potential outcomes framework will be used to test single and multiple mediator models. A sensitivity analysis will be conducted to evaluate the robustness of the estimated mediation effects on the influence of violating sequential ignorability--a critical assumption for causal inference. Mediation analysis of clinical trials can estimate how much the total effect of the treatment on the outcome is carried through an indirect path. Using mediation analysis to understand these mechanisms can generate evidence that can be used to tailor treatments and optimise treatment effects. In this study, the causal mediation effects of a pain education intervention for acute non-specific low back pain will be estimated. This knowledge is critical for further development and refinement of interventions for conditions such as low back pain. Copyright © 2015 Australian Physiotherapy Association. Published by Elsevier B.V. All rights reserved.

PDE3, but not PDE4, reduces β1- and β2-adrenoceptor-mediated inotropic and lusitropic effects in failing ventricle from metoprolol-treated patients

PubMed Central

Molenaar, Peter; Christ, Torsten; Hussain, Rizwan I; Engel, Andreas; Berk, Emanuel; Gillette, Katherine T; Chen, Lu; Galindo-Tovar, Alejandro; Krobert, Kurt A; Ravens, Ursula; Levy, Finn Olav; Kaumann, Alberto J

2013-01-01

Background and Purpose PDE3 and/or PDE4 control ventricular effects of catecholamines in several species but their relative effects in failing human ventricle are unknown. We investigated whether the PDE3-selective inhibitor cilostamide (0.3–1 μM) or PDE4 inhibitor rolipram (1–10 μM) modified the positive inotropic and lusitropic effects of catecholamines in human failing myocardium. Experimental Approach Right and left ventricular trabeculae from freshly explanted hearts of 5 non-β-blocker-treated and 15 metoprolol-treated patients with terminal heart failure were paced to contract at 1 Hz. The effects of (-)-noradrenaline, mediated through β1 adrenoceptors (β2 adrenoceptors blocked with ICI118551), and (-)-adrenaline, mediated through β2 adrenoceptors (β1 adrenoceptors blocked with CGP20712A), were assessed in the absence and presence of PDE inhibitors. Catecholamine potencies were estimated from –logEC50s. Key Results Cilostamide did not significantly potentiate the inotropic effects of the catecholamines in non-β-blocker-treated patients. Cilostamide caused greater potentiation (P = 0.037) of the positive inotropic effects of (-)-adrenaline (0.78 ± 0.12 log units) than (-)-noradrenaline (0.47 ± 0.12 log units) in metoprolol-treated patients. Lusitropic effects of the catecholamines were also potentiated by cilostamide. Rolipram did not affect the inotropic and lusitropic potencies of (-)-noradrenaline or (-)-adrenaline on right and left ventricular trabeculae from metoprolol-treated patients. Conclusions and Implications Metoprolol induces a control by PDE3 of ventricular effects mediated through both β1 and β2 adrenoceptors, thereby further reducing sympathetic cardiostimulation in patients with terminal heart failure. Concurrent therapy with a PDE3 blocker and metoprolol could conceivably facilitate cardiostimulation evoked by adrenaline through β2 adrenoceptors. PDE4 does not appear to reduce inotropic and lusitropic effects of catecholamines in failing human ventricle. Linked Article This article is commented on by Eschenhagen, pp 524–527 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12168 PMID:23489141

Stress eating and sleep disturbance as mediators in the relationship between depression and obesity in low-income, minority women.

PubMed

Yu, Jessica; Fei, Kezhen; Fox, Ashley; Negron, Rennie; Horowitz, Carol

2016-01-01

The purpose of this study was to explore potential mediators of the relationship between depression and obesity in a sample of low-income, minority women. Data were extracted from a sample of 535 women enrolled in a weight loss intervention for the prevention of type 2 diabetes. Using a non-parametric bootstrapping procedure, the potential mediation effects of stress eating and sleep disturbance on the relationship between depression and obesity were tested. Results of a single mediation model indicated that depressive symptomatology was significantly associated with obesity (β=0.800, SE=0.290, p=0.006), and that stress eating (β=0.166, 95% CI [0.046, 0.328]) and sleep disturbance (β=1.032, 95% CI [0.612, 1.427]) were significant independent mediators of this relationship. Sleep disturbance remained a significant mediator in a combined mediation model (β=1.009, 95% CI [0.653, 1.399]). Findings add to the growing literature on the psychosocial factors implicated in the link between depression and obesity, particularly among disadvantaged populations. Future longitudinal research should aim to establish causal pathways between obesity, stress eating, sleep disturbance, and depression. Copyright © 2015 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

The effect of psychological capital between work-family conflict and job burnout in Chinese university teachers: Testing for mediation and moderation.

PubMed

Pu, Jun; Hou, Hanpo; Ma, Ruiyang; Sang, Jinyan

2017-12-01

In this study, we investigated the relationship between work-family conflict and job burnout as well as the potential mediation/moderation effects of psychological capital. Participants were 357 university teachers who completed a questionnaire packet containing a work-family conflict scale, psychological capital questionnaire, and Maslach Burnout Inventory-General survey. According to the results, work-family conflict and psychological capital were both significantly correlated with job burnout. In addition, psychological capital cannot mediate-but can moderate-the relationship between work-family conflict and job burnout. Taken together, our findings shed light on the psychological capital underlying the association of work-family conflict and job burnout.

INTRACELLULAR SIGNALING BY BILE ACIDS

PubMed Central

Anwer, Mohammed Sawkat

2014-01-01

Bile acids, synthesized from cholesterol, are known to produce beneficial as well as toxic effects in the liver. The beneficial effects include choleresis, immunomodulation, cell survival, while the toxic effects include cholestasis, apoptosis and cellular toxicity. It is believed that bile acids produce many of these effects by activating intracellular signaling pathways. However, it has been a challenge to relate intracellular signaling to specific and at times opposing effects of bile acids. It is becoming evident that bile acids produce different effects by activating different isoforms of phosphoinositide 3-kinase (PI3K), Protein kinase Cs (PKCs), and mitogen activated protein kinases (MAPK). Thus, the apoptotic effect of bile acids may be mediated via PI3K-110γ, while cytoprotection induce by cAMP-GEF pathway involves activation of PI3K-p110α/β isoforms. Atypical PKCζ may mediate beneficial effects and nPKCε may mediate toxic effects, while cPKCα and nPKCδ may be involved in both beneficial and toxic effects of bile acids. The opposing effects of nPKCδ activation may depend on nPKCδ phosphorylation site(s). Activation of ERK1/2 and JNK1/2 pathway appears to mediate beneficial and toxic effects, respectively, of bile acids. Activation of p38α MAPK and p38β MAPK may mediate choleretic and cholestatic effects, respectively, of bile acids. Future studies clarifying the isoform specific effects on bile formation should allow us to define potential therapeutic targets in the treatment of cholestatic disorders. PMID:25378891

PUMA mediates the anti-cancer effect of osimertinib in colon cancer cells.

PubMed

Guo, Lingchuan; Huang, Shan; Wang, Xinwei

2017-01-01

Osimertinib, an irreversible EGFR/HER2 inhibitor, has been found to be effective in the cancer cell with EGFR gene mutations in preclinical lung cancer models. However, the effect of osimertinib in colorectal cancer (CRC) cells is unclear. In the present study, we investigated how osimertinib suppresses CRC cells growth and potentiates effects of other chemotherapeutic drugs. We found that p73-mediated osimertinib-induced p53 upregulated modulator of apoptosis (PUMA) expression irrespective of p53 status following PI3K/AKT pathway inhibition in CRC cells. Furthermore, PUMA is required for osimertinib-induced apoptosis. In addition, osimertinib also synergized with 5-FU to induce significant apoptosis via PUMA in CRC cells. These results demonstrated a critical role of PUMA in mediating the anticancer effects of osimertinib and suggest that PUMA induction can be used as an indicator of osimertinib sensitivity.

PUMA mediates the anti-cancer effect of osimertinib in colon cancer cells

PubMed Central

Wang, Xinwei

2017-01-01

Osimertinib, an irreversible EGFR/HER2 inhibitor, has been found to be effective in the cancer cell with EGFR gene mutations in preclinical lung cancer models. However, the effect of osimertinib in colorectal cancer (CRC) cells is unclear. In the present study, we investigated how osimertinib suppresses CRC cells growth and potentiates effects of other chemotherapeutic drugs. We found that p73-mediated osimertinib-induced p53 upregulated modulator of apoptosis (PUMA) expression irrespective of p53 status following PI3K/AKT pathway inhibition in CRC cells. Furthermore, PUMA is required for osimertinib-induced apoptosis. In addition, osimertinib also synergized with 5-FU to induce significant apoptosis via PUMA in CRC cells. These results demonstrated a critical role of PUMA in mediating the anticancer effects of osimertinib and suggest that PUMA induction can be used as an indicator of osimertinib sensitivity. PMID:29138581

The Effect of Psychological Suzhi on Problem Behaviors in Chinese Adolescents: The Mediating Role of Subjective Social Status and Self-esteem

PubMed Central

Liu, Guangzeng; Zhang, Dajun; Pan, Yangu; Ma, Yuanxiao; Lu, Xingyue

2017-01-01

In this study, we examined subjective social status (SSS) and self-esteem as potential mediators between the association of psychological suzhi and problem behaviors in a sample of 1271 Chinese adolescents (44.5% male, grades 7–12). The results showed that SSS and self-esteem were fully mediating the relationship between psychological suzhi and problem behaviors. Moreover, the indirect effect was stronger via self-esteem than via SSS. These findings perhaps provide insight into the preliminary effect that SSS and self-esteem underlie psychological suzhi’s effect on adolescents’ problem behaviors, and also are important in helping school-teachers and administrators to develop a better understanding of problem behaviors in their schools as a pre-requisite to the development of more effective behaviors management practices from the perspective of psychological suzhi. Implications and limitations in the present study have also been discussed. PMID:28912744

The Effect of Psychological Suzhi on Problem Behaviors in Chinese Adolescents: The Mediating Role of Subjective Social Status and Self-esteem.

PubMed

Liu, Guangzeng; Zhang, Dajun; Pan, Yangu; Ma, Yuanxiao; Lu, Xingyue

2017-01-01

In this study, we examined subjective social status (SSS) and self-esteem as potential mediators between the association of psychological suzhi and problem behaviors in a sample of 1271 Chinese adolescents (44.5% male, grades 7-12). The results showed that SSS and self-esteem were fully mediating the relationship between psychological suzhi and problem behaviors. Moreover, the indirect effect was stronger via self-esteem than via SSS. These findings perhaps provide insight into the preliminary effect that SSS and self-esteem underlie psychological suzhi 's effect on adolescents' problem behaviors, and also are important in helping school-teachers and administrators to develop a better understanding of problem behaviors in their schools as a pre-requisite to the development of more effective behaviors management practices from the perspective of psychological suzhi. Implications and limitations in the present study have also been discussed.

The role of exercise dependence for the relationship between exercise behavior and eating pathology: mediator or moderator?

PubMed

Cook, Brian J; Hausenblas, Heather A

2008-05-01

Our study examined the potential mediating or moderating effect of exercise dependence on the exercise-eating pathology relationship. Female university students (N = 330) completed Internet-based self-report measures of exercise behavior, exercise dependence, and eating pathology. Exercise dependence served as a mediator for the relationship between exercise and eating pathology. This unidirectional causal model suggests that an individual's pathological motivation or compulsion to exercise is the critical mediating component in the exercise-eating pathology relationship. The best target for removing the link between exercise behavior and eating pathology may be reformulating exercise dependence symptoms.

Comparative study of hop-containing products on human cytochrome p450-mediated metabolism.

PubMed

Foster, Brian C; Kearns, Nikia; Arnason, John T; Saleem, Ammar; Ogrodowczyk, Carolina; Desjardins, Suzanne

2009-06-10

Thirty-five national and international brands of beer were examined for their potential to affect human cytochrome P450 (CYP)-mediated metabolism. They represented the two main categories of beer, ales and lagers, and included a number of specialty products including bitter (porter, stout), coffee, ice, wheat, Pilsner, and hemp seed. Aliquots were examined for nonvolatile soluble solids, effect on CYP metabolism and P-glycoprotein (Pgp) transport, and major alpha- and beta-hop acids. Wide variance was detected in contents of alcohol, nonvolatile suspended solids, and hop acids and in the potential to affect CYP-mediated metabolism and Pgp-mediated efflux transport. Many of the products affected CYP2C9-mediated metabolism, and only two (NRP 306 and 307) markedly affected CYP3A4; hence, some products have the capacity to affect drug safety. CYP3A4, CYP3A5, CYP3A7, and CYP19 (aromatase) inhibition to the log concentration of beta-acid content was significant with r(2) > 0.37, suggesting that these components can account for some of the variation in inhibition of CYP metabolism.

Functional limitations as potential mediators of the effects of self-reported vision status on fall risk of older adults.

PubMed

Steinman, Bernard A; Allen, Susan M; Chen, Jie; Pynoos, Jon

2015-02-01

To test whether limitations in mobility and large-muscle functioning mediate self-reported vision status to increase fall risk among respondents age 65 and above. This study used two waves from the Health and Retirement Study. We conducted binary logistic and negative binomial regression analyses to test indirect paths leading from self-reported vision status to falls, via indices of mobility and large-muscle functioning. Limited evidence was found for a mediating effect among women; however, large-muscle groups were implicated as partially mediating risk factors for falls among men with fair self-reported vision status. Implications of these findings are discussed including the need for prioritizing improved muscle strength of older men and women with poor vision as a preventive measure against falls. © The Author(s) 2014.

Father's and mother's perceptions of parenting styles as mediators of the effects of parental psychopathology on antisocial behavior in outpatient children and adolescents.

PubMed

Vera, Juan; Granero, Roser; Ezpeleta, Lourdes

2012-06-01

The aim was to examine the potential mediating role of father's and mother's parenting styles in the association between parental psychopathology and antisocial behavior in children, and whether this pathway was moderated by child's sex. Participants included both parents and 338 Spanish outpatient children between 8 and 17 years (56.5% boys). Parenting style had a mediating effect on the studied relationships. Maternal psychopathology was positively associated with antisocial behavior in children, either directly or partially by parenting style, while paternal psychopathology was positively associated with offspring antisocial behavior only through the mediator role of parenting style. Child's sex did not moderate these relationships. Parenting style could be a target for prevention and intervention of antisocial behavior in the offspring of parents with mental health problems.

Molecular simulation of the effect of cholesterol on lipid-mediated protein-protein interactions.

PubMed

de Meyer, Frédérick J-M; Rodgers, Jocelyn M; Willems, Thomas F; Smit, Berend

2010-12-01

Experiments and molecular simulations have shown that the hydrophobic mismatch between proteins and membranes contributes significantly to lipid-mediated protein-protein interactions. In this article, we discuss the effect of cholesterol on lipid-mediated protein-protein interactions as function of hydrophobic mismatch, protein diameter and protein cluster size, lipid tail length, and temperature. To do so, we study a mesoscopic model of a hydrated bilayer containing lipids and cholesterol in which proteins are embedded, with a hybrid dissipative particle dynamics-Monte Carlo method. We propose a mechanism by which cholesterol affects protein interactions: protein-induced, cholesterol-enriched, or cholesterol-depleted lipid shells surrounding the proteins affect the lipid-mediated protein-protein interactions. Our calculations of the potential of mean force between proteins and protein clusters show that the addition of cholesterol dramatically reduces repulsive lipid-mediated interactions between proteins (protein clusters) with positive mismatch, but does not affect attractive interactions between proteins with negative mismatch. Cholesterol has only a modest effect on the repulsive interactions between proteins with different mismatch. Copyright © 2010 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Ultrasound-mediated drug delivery for cardiovascular disease

PubMed Central

Sutton, Jonathan T; Haworth, Kevin J; Pyne-Geithman, Gail; Holland, Christy K

2014-01-01

Introduction Ultrasound (US) has been developed as both a valuable diagnostic tool and a potent promoter of beneficial tissue bioeffects for the treatment of cardiovascular disease. These effects can be mediated by mechanical oscillations of circulating microbubbles, or US contrast agents, which may also encapsulate and shield a therapeutic agent in the bloodstream. Oscillating microbubbles can create stresses directly on nearby tissue or induce fluid effects that effect drug penetration into vascular tissue, lyse thrombi or direct drugs to optimal locations for delivery. Areas covered The present review summarizes investigations that have provided evidence for US-mediated drug delivery as a potent method to deliver therapeutics to diseased tissue for cardiovascular treatment. In particular, the focus will be on investigations of specific aspects relating to US-mediated drug delivery, such as delivery vehicles, drug transport routes, biochemical mechanisms and molecular targeting strategies. Expert opinion These investigations have spurred continued research into alternative therapeutic applications, such as bioactive gas delivery and new US technologies. Successful implementation of US-mediated drug delivery has the potential to change the way many drugs are administered systemically, resulting in more effective and economical therapeutics, and less-invasive treatments. PMID:23448121

Size-Dependent Effects of Gold Nanoparticles Uptake on Maturation and Antitumor Functions of Human Dendritic Cells In Vitro

PubMed Central

Tomić, Sergej; Đokić, Jelena; Vasilijić, Saša; Ogrinc, Nina; Rudolf, Rebeka; Pelicon, Primož; Vučević, Dragana; Milosavljević, Petar; Janković, Srđa; Anžel, Ivan; Rajković, Jelena; Rupnik, Marjan Slak; Friedrich, Bernd; Čolić, Miodrag

2014-01-01

Gold nanoparticles (GNPs) are claimed as outstanding biomedical tools for cancer diagnostics and photo-thermal therapy, but without enough evidence on their potentially adverse immunological effects. Using a model of human dendritic cells (DCs), we showed that 10 nm- and 50 nm-sized GNPs (GNP10 and GNP50, respectively) were internalized predominantly via dynamin-dependent mechanisms, and they both impaired LPS-induced maturation and allostimulatory capacity of DCs, although the effect of GNP10 was more prominent. However, GNP10 inhibited LPS-induced production of IL-12p70 by DCs, and potentiated their Th2 polarization capacity, while GNP50 promoted Th17 polarization. Such effects of GNP10 correlated with a stronger inhibition of LPS-induced changes in Ca2+ oscillations, their higher number per DC, and more frequent extra-endosomal localization, as judged by live-cell imaging, proton, and electron microscopy, respectively. Even when released from heat-killed necrotic HEp-2 cells, GNP10 inhibited the necrotic tumor cell-induced maturation and functions of DCs, potentiated their Th2/Th17 polarization capacity, and thus, impaired the DCs' capacity to induce T cell-mediated anti-tumor cytotoxicity in vitro. Therefore, GNP10 could potentially induce more adverse DC-mediated immunological effects, compared to GNP50. PMID:24802102

Pain and symptoms of depression in older adults living in community and in nursing homes: the role of activity restriction as a potential mediator and moderator.

PubMed

López-Lopez, Almudena; González, José L; Alonso-Fernández, Miriam; Cuidad, Noelia; Matías, Borja

2014-10-01

Chronic pain is likely to lead to depressive symptoms, but the nature of this relationship is not completely clear. The aim of the present study is to analyze the role of activity restriction in the pain-depression relationship in older people, and to test the hypothesis that this role is more relevant in community-dwelling older people than in nursing home residents. Depressive symptoms, pain intensity, and activity restriction were measured in a sample of 208 older adults with osteoarthritis, 102 living in nursing homes (NH), and 106 in the community. Analyses were carried out using moderation and moderated mediation analyses approach, treating activity restriction as a confounder. RESULTS showed a significant confounding effect of activity restriction, interaction effect between pain intensity and activity restriction on depression, and modifying effect of pain intensity on depression by adding activity restriction into the model. These results suggest a potential mediating and moderating effects of activity restriction. Moreover, analyses suggest that, surprisingly, the strength of the mediation could be higher in nursing homes. Overall, it may be that what is really important to emotional well-being is not so much pain itself, but rather the way in which the pain alters older people's lives. The greater strength of the mediation in NH might be understood within the scope of self-determination theory. Generally speaking, the NH context has been considered as a coercive setting, promoting non-autonomous orientation. In this context, when events are objectively coercive, people may lack perceived autonomy and hence be at greater risk of depression.

Development of Gene Therapy for Thalassemia

PubMed Central

Nienhuis, Arthur W.; Persons, Derek A.

2012-01-01

Retroviral vector–mediated gene transfer into hematopoietic stem cells provides a potentially curative therapy for severe β-thalassemia. Lentiviral vectors based on human immunodeficiency virus have been developed for this purpose and have been shown to be effective in curing thalassemia in mouse models. One participant in an ongoing clinical trial has achieved transfusion independence after gene transfer into bone marrow stem cells owing, in part, to a genetically modified, dominant clone. Ongoing efforts are focused on improving the efficiency of lentiviral vector–mediated gene transfer into stem cells so that the curative potential of gene transfer can be consistently achieved. PMID:23125203

Underpotential deposition-mediated layer-by-layer growth of thin films

DOEpatents

Wang, Jia Xu; Adzic, Radoslav R.

2015-05-19

A method of depositing contiguous, conformal submonolayer-to-multilayer thin films with atomic-level control is described. The process involves the use of underpotential deposition of a first element to mediate the growth of a second material by overpotential deposition. Deposition occurs between a potential positive to the bulk deposition potential for the mediating element where a full monolayer of mediating element forms, and a potential which is less than, or only slightly greater than, the bulk deposition potential of the material to be deposited. By cycling the applied voltage between the bulk deposition potential for the mediating element and the material to be deposited, repeated desorption/adsorption of the mediating element during each potential cycle can be used to precisely control film growth on a layer-by-layer basis. This process is especially suitable for the formation of a catalytically active layer on core-shell particles for use in energy conversion devices such as fuel cells.

SAD-A potentiates glucose-stimulated insulin secretion as a mediator of glucagon-like peptide 1 response in pancreatic β cells.

PubMed

Nie, Jia; Lilley, Brendan N; Pan, Y Albert; Faruque, Omar; Liu, Xiaolei; Zhang, Weiping; Sanes, Joshua R; Han, Xiao; Shi, Yuguang

2013-07-01

Type 2 diabetes is characterized by defective glucose-stimulated insulin secretion (GSIS) from pancreatic β cells, which can be restored by glucagon-like peptide 1 (GLP-1), an incretin hormone commonly used for the treatment of type 2 diabetes. However, molecular mechanisms by which GLP-1 affects glucose responsiveness in islet β cells remain poorly understood. Here we investigated a role of SAD-A, an AMP-activated protein kinase (AMPK)-related kinase, in regulating GSIS in mice with conditional SAD-A deletion. We show that selective deletion of SAD-A in pancreas impaired incretin's effect on GSIS, leading to glucose intolerance. Conversely, overexpression of SAD-A significantly enhanced GSIS and further potentiated GLP-1's effect on GSIS from isolated mouse islets. In support of SAD-A as a mediator of incretin response, SAD-A is expressed exclusively in pancreas and brain, the primary targeting tissues of GLP-1 action. Additionally, SAD-A kinase is activated in response to stimulation by GLP-1 through cyclic AMP (cAMP)/Ca(2+)-dependent signaling pathways in islet β cells. Furthermore, we identified Thr443 as a key autoinhibitory phosphorylation site which mediates SAD-A's effect on incretin response in islet β cells. Consequently, ablation of Thr443 significantly enhanced GLP-1's effect on GSIS from isolated mouse islets. Together, these findings identified SAD-A kinase as a pancreas-specific mediator of incretin response in islet β cells.

SAD-A Potentiates Glucose-Stimulated Insulin Secretion as a Mediator of Glucagon-Like Peptide 1 Response in Pancreatic β Cells

PubMed Central

Nie, Jia; Lilley, Brendan N.; Pan, Y. Albert; Faruque, Omar; Liu, Xiaolei; Zhang, Weiping; Sanes, Joshua R.

2013-01-01

Type 2 diabetes is characterized by defective glucose-stimulated insulin secretion (GSIS) from pancreatic β cells, which can be restored by glucagon-like peptide 1 (GLP-1), an incretin hormone commonly used for the treatment of type 2 diabetes. However, molecular mechanisms by which GLP-1 affects glucose responsiveness in islet β cells remain poorly understood. Here we investigated a role of SAD-A, an AMP-activated protein kinase (AMPK)-related kinase, in regulating GSIS in mice with conditional SAD-A deletion. We show that selective deletion of SAD-A in pancreas impaired incretin's effect on GSIS, leading to glucose intolerance. Conversely, overexpression of SAD-A significantly enhanced GSIS and further potentiated GLP-1's effect on GSIS from isolated mouse islets. In support of SAD-A as a mediator of incretin response, SAD-A is expressed exclusively in pancreas and brain, the primary targeting tissues of GLP-1 action. Additionally, SAD-A kinase is activated in response to stimulation by GLP-1 through cyclic AMP (cAMP)/Ca2+-dependent signaling pathways in islet β cells. Furthermore, we identified Thr443 as a key autoinhibitory phosphorylation site which mediates SAD-A's effect on incretin response in islet β cells. Consequently, ablation of Thr443 significantly enhanced GLP-1's effect on GSIS from isolated mouse islets. Together, these findings identified SAD-A kinase as a pancreas-specific mediator of incretin response in islet β cells. PMID:23629625

[Adolescent Use of Digital Media and Parental Mediation - A Research Review].

PubMed

Pfetsch, Jan

2018-02-01

Adolescent Use of Digital Media and Parental Mediation - A Research Review Digital media are wide spread, frequently used, and highly relevant in the lives of children, adolescents and their parents. Because parents aim to reduce or prevent potential risks of media use for their children, many parents apply different strategies of parental mediation of children's media use: restrictive parental mediation, active parental mediation, co-media use, technical monitoring, and participatory learning. These forms of parental mediation have differential impact on children and adolescents. Different types of media (e. g. television, video games, internet, and mobile phones) have common features but also specific characteristics that lead to partially inconsistent research findings that are not only due to age differences of children and adolescents. Concerning an impact model of parental mediation, the current contribution presents overarching and divergent empirical findings, approaches the effectiveness of parental mediation for cyberbullying, and discusses practical implications as well as research gaps in the analysis of parental mediation.

[Prevention of overweight and obesity in children and adolescents : Critical appraisal of the evidence base].

PubMed

Pigeot, Iris; Baranowski, Tom; Lytle, Leslie; Ahrens, Wolfgang

2016-11-01

Despite careful planning and implementation, overweight/obesity prevention interventions in children and adolescents typically show no, inconsistent or merely weak effects. Such programs usually aim at behavior changes, rarely also at environmental changes, that draw upon conventional wisdom regarding the commonly accepted determinants of childhood overweight/obesity. This paper evaluates the evidence base of the apparently overweight-/obesity-related determinants diet, physical activity and stress. The results of international intervention studies are discussed against this background. Based on the mediating-moderating variable model, we investigate the effect of theory specified mediating variables and how potential moderating variables may impact these relationships. Contrary to common beliefs, recent research has revealed inconsistent evidence regarding associations between potentially obesogenic behaviors and overweight/obesity in youth. Moreover, the evidence for strong and causal relationships between mediating variables and targeted behaviors seems to be inconsistent. In addition, inadequate attention is paid to moderating effects. The etiology of overweight/obesity in youth is likely the result of a complex interplay of multi-causal influences. Future prevention interventions would benefit from a more thorough understanding of the complex relationships that have been hypothesized and of the mechanisms of suspected behaviors for affecting overweight/obesity. Only if substantial change can be demonstrated in mediators with reasonable effort under real world circumstances, it will make sense to progress to community behavior change trials.

The effect of sleep quality on academic performance is mediated by Internet use time: DADOS study.

PubMed

Adelantado-Renau, Mireia; Diez-Fernandez, Ana; Beltran-Valls, Maria Reyes; Soriano-Maldonado, Alberto; Moliner-Urdiales, Diego

2018-05-19

The aims of the present study were to analyze the association of sleep patterns with academic and cognitive performance in adolescents, and to test the potential mediating effect of different activities of screen media usage on this association. A sample of 269 adolescents (140 boys) aged 14 years from the baseline data of the Deporte, ADOlescencia y Salud study completed questionnaires about sleep quality, cognitive performance, and leisure-time sedentary behaviors. Sleep duration was objectively computed using a wrist-worn GENEActiv accelerometer and academic performance was analyzed through school records. Sleep quality (but not sleep duration) was associated with all the academic performance indicators (all p<0.05). Analysis of covariance revealed higher grades among adolescents with better sleep quality (PSQI≤5; all p<0.05). These analyses showed no differences regarding cognitive performance. Internet use time was revealed as a mediator of the association between sleep quality and academic performance, being significant for all academic performance indicators (P M ranging from 15.5% to 16.0%). The association between sleep quality and academic performance in adolescents is mediated by time of Internet use. Overall, reducing Internet use in adolescents could be an achievable intervention for improving sleep quality, with potentially positive effects on academic performance. Copyright © 2018 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

Involvement of brain-derived neurotrophic factor (BDNF) in the functional elimination of synaptic contacts at polyinnervated neuromuscular synapses during development.

PubMed

Garcia, N; Santafe, M M; Tomàs, M; Lanuza, M A; Besalduch, N; Tomàs, J

2010-05-15

We use immunohistochemistry to describe the localization of brain-derived neurotrophic factor (BDNF) and its receptors trkB and p75(NTR) in the neuromuscular synapses of postnatal rats (P6-P7) during the synapse elimination period. The receptor protein p75(NTR) is present in the nerve terminal, muscle cell and glial Schwann cell whereas BDNF and trkB proteins can be detected mainly in the pre- and postsynaptic elements. Exogenously applied BDNF (10 nM for 3 hr or 50 nM for 1 hr) increases ACh release from singly and dually innervated synapses. This effect may be specific for BDNF because the neurotrophin NT-4 (2-8 nM) does not modulate release at P6-P7. Blocking the receptors trkB and p75(NTR) (with K-252a and anti-p75-192-IgG, respectively) completely abolishes the potentiating effect of exogenous BDNF. In addition, exogenous BDNF transiently recruits functionally depressed silent terminals, and this effect seems to be mediated by trkB. Calcium ions, the L-type voltage-dependent calcium channels and protein kinase C are involved in BDNF-mediated nerve ending recruitment. Blocking experiments suggest that endogenous BDNF could operate through p75(NTR) receptors coupled to potentiate ACh release in all nerve terminals because the anti-p75-192-IgG reduces release. However, blocking the trkB receptor (K-252a) or neutralizing endogenous BDNF with the trkB-IgG fusion protein reveals a trkB-mediated release inhibition on almost mature strong endings in dual junctions. Taken together these results suggest that a BDNF-induced p75(NTR)-mediated ACh release potentiating mechanism and a BDNF-induced trkB-mediated release inhibitory mechanism may contribute to developmental synapse disconnection. (c) 2009 Wiley-Liss, Inc.

Glutamate Receptor GluA1 Subunit Is Implicated in Capsaicin Induced Modulation of Amygdala LTP but Not LTD

ERIC Educational Resources Information Center

Gebhardt, Christine; Albrecht, Doris

2018-01-01

Capsaicin has been shown to modulate synaptic plasticity in various brain regions including the amygdala. Whereas in the lateral amygdala the modulatory effect of capsaicin on long-term potentiation (LA-LTP) is mediated by TRPV1 channels, we have recently shown that capsaicin-induced enhancement of long term depression (LA-LTD) is mediated by…

Amino terminus of substance P potentiates kainic acid-induced activity in the mouse spinal cord.

PubMed

Larson, A A; Sun, X

1992-12-01

Sensitization to the behavioral effects produced by repeated injections of kainic acid (KA) into the mouse spinal cord area has been previously shown to be abolished by pretreatment with capsaicin, a neurotoxin of substance P (SP)-containing primary afferent C-fibers. While SP has a variety of well characterized biological actions that are mediated by interactions of its COOH terminus with neurokinin receptors, more recently we have characterized an amino-terminally directed SP binding site. The present studies were initiated to determine whether behavioral sensitization to repeated injections of intrathecally administered KA is mediated by the COOH or NH2 terminal of SP. In the present studies, pretreatment with SP(1-7), an NH2-terminal fragment of SP, but not SP(5-11), a COOH-terminal fragment, potentiated KA-induced behavioral activity in mice. Pretreatment with [D-Pro2,D-Phe7]SP(1-7), an inhibitor of SP NH2-terminal binding, blocked the potentiative effect of SP(1-7) as well as the sensitization to repeated injections of KA. In contrast, [D-Pro2,D-Trp7,9]SP, a neurokinin antagonist, had little effect on behavioral sensitization to KA. The present study suggests that SP has an important modulatory role on excitatory amino acid activity in the spinal cord that is mediated by an action of the NH2 terminal of SP at a non-neurokinin receptor.

A Successful Multifaceted Trial to Improve Hypertension Control in Primary Care: Why Did it Work?

PubMed

Margolis, Karen L; Asche, Stephen E; Bergdall, Anna R; Dehmer, Steven P; Maciosek, Michael V; Nyboer, Rachel A; O'Connor, Patrick J; Pawloski, Pamala A; Sperl-Hillen, JoAnn M; Trower, Nicole K; Tucker, Ann D; Green, Beverly B

2015-11-01

It is important to understand which components of successful multifaceted interventions are responsible for study outcomes, since some components may be more important contributors to the intervention effect than others. We conducted a mediation analysis to determine which of seven factors had the greatest effect on change in systolic blood pressure (BP) after 6 months in a trial to improve hypertension control. The study was a preplanned secondary analysis of a cluster-randomized clinical trial. Eight clinics in an integrated health system were randomized to provide usual care to their patients (n = 222), and eight were randomized to provide a telemonitoring intervention (n = 228). Four hundred three of 450 trial participants completing the 6-month follow-up visit were included. Intervention group participants received home BP telemonitors and transmitted measurements to pharmacists, who adjusted medications and provided advice to improve adherence to medications and lifestyle modification via telephone visits. Path analytic models estimated indirect effects of the seven potential mediators of intervention effect (defined as the difference between the intervention and usual care groups in change in systolic BP from baseline to 6 months). The potential mediators were change in home BP monitor use, number of BP medication classes, adherence to BP medications, physical activity, salt intake, alcohol use, and weight. The difference in change in systolic BP was 11.3 mmHg. The multivariable mediation model explained 47 % (5.3 mmHg) of the intervention effect. Nearly all of this was mediated by two factors: an increase in medication treatment intensity (24 %) and increased home BP monitor use (19 %). The other five factors were not significant mediators, although medication adherence and salt intake improved more in the intervention group than in the usual care group. Most of the explained intervention effect was attributable to the combination of self-monitoring and medication intensification. High adherence at baseline and the relatively low intensity of resources directed toward lifestyle change may explain why these factors did not contribute to the improvement in BP.

Health-Related Behavior Mediates the Association Between Personality and Memory Performance in Older Adults.

PubMed

Allen, Mark S; Laborde, Sylvain; Walter, Emma E

2017-03-01

This prospective study explored the potential mediating role of health-related behavior (alcohol involvement, diet, television viewing, and physical activity) in the association between personality and change in memory performance over 2 years. A nationally representative sample of 8,376 U.K. participants aged 55 years and older (4,572 women, 3,804 men) completed self-report measures of personality and health-related behavior in 2010, and completed a memory performance task in 2010 and 2012. After removing variance associated with potential confounding variables, neuroticism and agreeableness had negative associations, and openness and conscientiousness positive associations with change in memory performance. There were no moderation effects by age, sex, education level, or ethnicity. Multiple mediator models demonstrated that physical activity, television viewing, and alcohol intake mediated associations between personality and change in memory performance. These findings provide evidence that the association between personality and memory performance in older adults can be explained, in part, through health-related behavior.

Do nurses who work in a fair organization sleep and perform better and why? Testing potential psychosocial mediators of organizational justice.

PubMed

Hietapakka, Laura; Elovainio, Marko; Heponiemi, Tarja; Presseau, Justin; Eccles, Martin; Aalto, Anna-Mari; Pekkarinen, Laura; Kuokkanen, Liisa; Sinervo, Timo

2013-10-01

We examined whether organizational justice is associated with sleep quality and performance in a population-based sample of 1,729 Finnish registered nurses working full time. In addition, we tested psychological mechanisms mediating the potential association. The results of multivariate linear regression analyses showed higher organizational justice to be associated with fewer sleeping problems (β values range from -.20 to -.11) and higher self-reported performance (β values range from .05 to .35). Furthermore, psychological distress (related to the psychological stress model) and job involvement (related to the psychosocial resource model) mediated the association between organizational justice and sleep. Sleeping problems partly mediated the association between organizational justice and performance. Psychological distress explained 51% to 83% and job involvement explained 10% to 15% of the total effects of justice variables on sleeping problems. The findings provide support for the psychological stress model and offer practical implications for reducing nurses' sleeping problems.

Pinocembrin, a novel histidine decarboxylase inhibitor with anti-allergic potential in in vitro.

PubMed

Hanieh, Hamza; Hairul Islam, Villianur Ibrahim; Saravanan, Subramanian; Chellappandian, Muthiah; Ragul, Kessavane; Durga, Arumugam; Venugopal, Kaliyamoorthy; Senthilkumar, Venugopal; Senthilkumar, Palanisamy; Thirugnanasambantham, Krishnaraj

2017-11-05

Pinocembrin (5, 7- dihydroxy flavanone) is the most abundant chiral flavonoid found in propolis, exhibiting antioxidant, antimicrobial and anti-inflammatory properties. However, the effect of Pinocembrin on allergic response is unexplored. Thus, current study aimed at investigating the effects of Pinocembrin on IgE-mediated allergic response in vitro. A special emphasis was directed toward histidine decarboxylase (HDC) and other pro-allergic and pro-inflammatory mediators. Preliminary studies, using a microbiological model of Klebsiella pneumoniae, provided first evidences that suggest Pinocembrin as a potential thermal stable inhibitor for HDC. Applying docking analysis revealed possible interaction between Pinocembrin and mammalian HDC. In vitro studies validated the predicted interaction and showed that Pinocembrin inhibits HDC activity and histamine in IgE-sensitized RBL-2H3 in response to dinitrophenol (DNP)-bovine serum albumin (BSA) stimulation. In addition, Pinocembrin mitigated the damage in the mitochondrial membrane, formation of cytoplasmic granules and degranulation as indicated by lower β-hexoseaminidase level. Interestingly, it reduced range of pro-inflammatory mediators in the IgE-mediated allergic response including tumor necrosis factor (TNF)-α, interleukin (IL)-6, nitric oxide (NO), inducible NO synthase (iNOS), phosphorylation of inhibitory kappa B (IкB)-α, prostaglandin (PGE)-2 and cyclooxygenase (COX)-2. In conclusion, current study suggests Pinocembrin as a potential HDC inhibitor, and provides the first evidences it is in vitro anti-allergic properties, suggesting Pinocembrin as a new candidate for natural anti-allergic drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

Potential hepatic toxicity of buprofezin at sublethal concentrations: ROS-mediated conversion of energy metabolism.

PubMed

Ji, Xiaotong; Ku, Tingting; Zhu, Na; Ning, Xia; Wei, Wei; Li, Guangke; Sang, Nan

2016-12-15

Buprofezin is known for its broad-spectrum action and environmental safety. The popularity of buprofezin has raised concerns about its potentially adverse effects on human health and risk to the environment. In this study, we first identified the liver as one of the major organs in which buprofezin accumulated, and we detected a severe oxidative stress response. Next, we demonstrated that sublethal concentrations of buprofezin promoted the conversion of energy metabolism from the aerobic tricarboxylic acid (TCA) cycle and oxidative phosphorylation to anaerobic glycolysis. Importantly, reactive oxygen species (ROS) generation partially accounted for the shunting of the energy metabolism through the buprofezin-mediated inhibition of cytochrome c oxidase activity. ROS directly perturbed the activities of several key TCA cycle enzymes, stimulated glycolysis, and indirectly disturbed the activity of the respiratory chain complex by altering mitochondrial DNA (mtDNA). These findings clarify the potential mechanisms of buprofezin toxicity and provide biomarkers for buprofezin-mediated hepatotoxicity at sublethal concentrations. Copyright © 2016 Elsevier B.V. All rights reserved.

Children's appraisals as mediators of the relationship between domestic violence and child adjustment.

PubMed

Fortin, Andrée; Doucet, Martin; Damant, Dominique

2011-01-01

This study examines the relationships among variables that were likely to mediate the effects of exposure to domestic violence on children's internalizing problems (i.e., children's appraisals of domestic violence and their perceptions of family relationships). The study was conducted with 79 children exposed to domestic violence, including 41 boys and 38 girls, aged between 9 and 12 years old. Indicators used for children's appraisals of violence were attribution of blame and perceived threat. Children's perceptions of family relationships were based on their levels of parentification and the degree of their loyalty conflicts. A path analysis was used to verify the predictive model's pathways and to test the multiple mediator effects. Findings confirm the contribution of mediating variables and also reflect the association between self-blame and children's parentification. The results stress the relevance of evaluating the combined role of different potential mediators to provide a better understanding of the impact of domestic violence on children.

Advancing coalition theory: the effect of coalition factors on community capacity mediated by member engagement

PubMed Central

Kegler, Michelle C.; Swan, Deanne W.

2012-01-01

Community coalitions have the potential to enhance a community’s capacity to engage in effective problem solving for a range of community concerns. Although numerous studies have documented correlations between member engagement and coalition processes and structural characteristics, fewer have examined associations between coalition factors and community capacity outcomes. The current study uses data from an evaluation of the California Healthy Cities and Communities program to examine pathways between coalition factors (i.e. membership, processes), member engagement (i.e. participation, satisfaction) and community capacity as hypothesized by the Community Coalition Action Theory (CCAT). Surveys were completed by 231 members of 19 healthy cities and communities coalitions. Multilevel mediation analyses were used to examine possible mediating effects of member engagement on three community capacity indicators: new skills, sense of community and social capital. Results generally supported CCAT. Member engagement mediated the effects of leadership and staffing on community capacity outcomes. Results also showed that member engagement mediated several relationships between process variables (i.e. task focus, cohesion) and community capacity, but several unmediated direct effects were also observed. This suggests that although member engagement does explain some relationships, it alone is not sufficient to explain how coalition processes influence indicators of community capacity. PMID:21911845

The COMMAND trial of cognitive therapy to prevent harmful compliance with command hallucinations: predictors of outcome and mediators of change.

PubMed

Birchwood, Max; Dunn, Graham; Meaden, Alan; Tarrier, Nicholas; Lewis, Shon; Wykes, Til; Davies, Linda; Michail, Maria; Peters, Emmanuelle

2017-12-05

Acting on harmful command hallucinations is a major clinical concern. Our COMMAND CBT trial approximately halved the rate of harmful compliance (OR = 0.45, 95% CI 0.23-0.88, p = 0.021). The focus of the therapy was a single mechanism, the power dimension of voice appraisal, was also significantly reduced. We hypothesised that voice power differential (between voice and voice hearer) was the mediator of the treatment effect. The trial sample (n = 197) was used. A logistic regression model predicting 18-month compliance was used to identify predictors, and an exploratory principal component analysis (PCA) of baseline variables used as potential predictors (confounders) in their own right. Stata's paramed command used to obtain estimates of the direct, indirect and total effects of treatment. Voice omnipotence was the best predictor although the PCA identified a highly predictive cognitive-affective dimension comprising: voices' power, childhood trauma, depression and self-harm. In the mediation analysis, the indirect effect of treatment was fully explained by its effect on the hypothesised mediator: voice power differential. Voice power and treatment allocation were the best predictors of harmful compliance up to 18 months; post-treatment, voice power differential measured at nine months was the mediator of the effect of treatment on compliance at 18 months.

Mediation analysis of relationships between chronic inflammation and quality of life in older adults.

PubMed

Nowakowski, Alexandra C H; Graves, Katelyn Y; Sumerau, J E

2016-03-22

This article summarizes exploratory analyses of relationships between chronic inflammation, its physical consequences, and quality of life (QoL). It summarizes key findings from preliminary analyses, and contextualizes these results with extant sociomedical literature to recommend directions for future research. Cross-sectional data from the National Social Life, Health, and Aging Project (NSHAP) were used to explore these relationships. Inflammation was assessed via the biomarker C-reactive protein (CRP). We examined associations between CRP levels and two different domains of QoL: happiness with life in general and happiness with intimate relationships. We used ordinal logistic regression with companion OLS models and Sobel-Goodman tests to assess potential mediation, and also conducted a variety of sensitivity analyses. Findings suggest that mediation pathways for the overall association between chronic inflammation and QoL may differ markedly across particular outcome constructs. Specifically, it shows mediation potential for the clinical sequelae of chronic inflammation in frameworks using happiness as an outcome measure, but not in those using relationship satisfaction. Disability appears to mediate the effect of inflammation by 27 %; chronic pain appears to exert a similar mediation effect of 21 %. Pain and disability linked to chronic inflammation appear to play a small but significant mediating role in the overall reduction in QoL observed among older adults with biomarker evidence of chronic inflammation. We note that these patterns are best framed as dynamic elements of a complex causal fabric, rather than powerful determinants that override other factors contributing to QoL. Hypotheses for further exploration using longitudinal data from the NSHAP are thus offered, pending availability of Wave III data in future years.

Lactoferricin mediates Anti-Inflammatory and Anti-Catabolic Effects via Inhibition of IL-1 and LPS Activity in the Intervertebral Disc†

PubMed Central

Kim, Jae-Sung; Ellman, Michael B.; Yan, Dongyao; An, Howard S.; Kc, Ranjan; Li, Xin; Chen, Di; Xiao, Guozhi; Cs-Zabo, Gabriella; Hoskin, David W.; Buechter, D.D.; Van Wijnen, Andre J.; Im, Hee-Jeong

2013-01-01

The catabolic cytokine interleukin-1 (IL-1) and endotoxin lipopolysaccharide (LPS) are well-known inflammatory mediators involved in degenerative disc disease, and inhibitors of IL-1 and LPS may potentially be used to slow or prevent disc degeneration in vivo. Here, we elucidate the striking anti-catabolic and anti-inflammatory effects of bovine lactoferricin (LfcinB) in the intervertebral disc (IVD) via antagonism of both IL-1 and LPS-mediated catabolic activity using in vitro and ex vivo analyses. Specifically, we demonstrate the biological counteraction of LfcinB against IL-1 and LPS-mediated proteoglycan (PG) depletion, matrix-degrading enzyme production and enzyme activity in long-term (alginate beads) and short-term (monolayer) culture models using bovine and human nucleus pulposus (NP) cells. LfcinB significantly attenuates the IL-1 and LPS-mediated suppression of PG production and synthesis, and thus restores PG accumulation and pericellular matrix formation. Simultaneously, LfcinB antagonizes catabolic factor mediated induction of multiple cartilage-degrading enzymes, including MMP-1, MMP-3, MMP-13, ADAMTS-4, and ADAMTS-5, in bovine NP cells at both mRNA and protein levels. LfcinB also suppresses the catabolic factor-induced stimulation of oxidative and inflammatory factors such as iNOS, IL-6, and toll-like receptor-2 (TLR-2) and TLR-4. Finally, the ability of LfcinB to antagonize IL-1 and LPS-mediated suppression of PG is upheld in an en bloc intradiscal microinjection model followed by ex vivo organ culture using both mouse and rabbit IVD tissue, suggesting a potential therapeutic benefit of LfcinB on degenerative disc disease in the future. PMID:23460134

Lactoferricin mediates anti-inflammatory and anti-catabolic effects via inhibition of IL-1 and LPS activity in the intervertebral disc.

PubMed

Kim, Jae-Sung; Ellman, Michael B; Yan, Dongyao; An, Howard S; Kc, Ranjan; Li, Xin; Chen, Di; Xiao, Guozhi; Cs-Szabo, Gabriella; Hoskin, David W; Buechter, Doug D; Van Wijnen, Andre J; Im, Hee-Jeong

2013-09-01

The catabolic cytokine interleukin-1 (IL-1) and endotoxin lipopolysaccharide (LPS) are well-known inflammatory mediators involved in degenerative disc disease, and inhibitors of IL-1 and LPS may potentially be used to slow or prevent disc degeneration in vivo. Here, we elucidate the striking anti-catabolic and anti-inflammatory effects of bovine lactoferricin (LfcinB) in the intervertebral disc (IVD) via antagonism of both IL-1 and LPS-mediated catabolic activity using in vitro and ex vivo analyses. Specifically, we demonstrate the biological counteraction of LfcinB against IL-1 and LPS-mediated proteoglycan (PG) depletion, matrix-degrading enzyme production, and enzyme activity in long-term (alginate beads) and short-term (monolayer) culture models using bovine and human nucleus pulposus (NP) cells. LfcinB significantly attenuates the IL-1 and LPS-mediated suppression of PG production and synthesis, and thus restores PG accumulation and pericellular matrix formation. Simultaneously, LfcinB antagonizes catabolic factor mediated induction of multiple cartilage-degrading enzymes, including MMP-1, MMP-3, MMP-13, ADAMTS-4, and ADAMTS-5, in bovine NP cells at both mRNA and protein levels. LfcinB also suppresses the catabolic factor-induced stimulation of oxidative and inflammatory factors such as iNOS, IL-6, and toll-like receptor-2 (TLR-2) and TLR-4. Finally, the ability of LfcinB to antagonize IL-1 and LPS-mediated suppression of PG is upheld in an en bloc intradiscal microinjection model followed by ex vivo organ culture using both mouse and rabbit IVD tissue, suggesting a potential therapeutic benefit of LfcinB on degenerative disc disease in the future. Copyright © 2013 Wiley Periodicals, Inc.

Method of making ionic liquid mediated sol-gel sorbents

DOEpatents

Malik, Abdul; Shearrow, Anne M.

2017-01-31

Ionic liquid (IL)-mediated sol-gel hybrid organic-inorganic materials present enormous potential for effective use in analytical microextraction. One obstacle to materializing this prospect arises from high viscosity of ILs significantly slowing down sol-gel reactions. A method was developed which provides phosphonium-based, pyridinium-based, and imidazolium-based IL-mediated advanced sol-gel organic-inorganic hybrid materials for capillary microextraction. Scanning electron microscopy results demonstrate that ILs can serve as porogenic agents in sol-gel reactions. IL-mediated sol-gel coatings prepared with silanol-terminated polymers provided up to 28 times higher extractions compared to analogous sol-gel coatings prepared without any IL in the sol solution. This study shows that IL-generated porous morphology alone is not enough to provide effective extraction media: careful choice of the organic polymer and the precursor with close sol-gel reactivity must be made to ensure effective chemical bonding of the organic polymer to the created sol-gel material to be able to provide the desired sorbent characteristics.

The mediating role of social support in the relationship between psychological well-being and health-risk behaviors among Chinese university students

PubMed Central

Lai, Catie CW; Ma, Cecilia MS

2016-01-01

While literature has displayed a link between psychological well-being (i.e. depression, hopelessness, and life satisfaction) and health-risk behaviors (i.e. smoking, drinking, suicide, and physical inactivity), the mechanisms underlying this relationship have received little empirical attention. This study examines the mediation effects of social support (from family, friends, and significant others) that accounted for the link. Participants were 2023 university students (47.7% male). Structural equation modeling showed partial mediation effect of social support between psychological well-being and health-risk behaviors. In particular, social support from family and friends jointly mediated about 80 percent of the effect of life satisfaction and hopelessness on drinking. These results offered novel evidence that helps improve theorizing the mechanisms of the relationship between psychological well-being and health-risk behaviors. They also highlighted the potential benefits of social support for university students to help them stay healthy. The implications of these results are discussed. PMID:28070409

Immunomodulatory and therapeutic properties of the Nigella sativa L. seed.

PubMed

Salem, Mohamed Labib

2005-12-01

A larger number of medicinal plants and their purified constituents have been shown beneficial therapeutic potentials. Seeds of Nigella sativa, a dicotyledon of the Ranunculaceae family, have been employed for thousands of years as a spice and food preservative. The oil and seed constituents, in particular thymoquinine (TQ), have shown potential medicinal properties in traditional medicine. In view of the recent literature, this article lists and discusses different immunomodulatory and immunotherapeutic potentials for the crude oil of N. sativa seeds and its active ingredients. The published findings provide clear evidence that both the oil and its active ingredients, in particular TQ, possess reproducible anti-oxidant effects through enhancing the oxidant scavenger system, which as a consequence lead to antitoxic effects induced by several insults. The oil and TQ have shown also potent anti-inflammatory effects on several inflammation-based models including experimental encephalomyelitis, colitis, peritonitis, oedama, and arthritis through suppression of the inflammatory mediators prostaglandins and leukotriens. The oil and certain active ingredients showed beneficial immunomodulatory properties, augmenting the T cell- and natural killer cell-mediated immune responses. Most importantly, both the oil and its active ingredients expressed anti-microbial and anti-tumor properties toward different microbes and cancers. Coupling these beneficial effects with its use in folk medicine, N. sativa seed is a promising source for active ingredients that would be with potential therapeutic modalities in different clinical settings. The efficacy of the active ingredients, however, should be measured by the nature of the disease. Given their potent immunomodulatory effects, further studies are urgently required to explore bystander effects of TQ on the professional antigen presenting cells, including macrophages and dendritic cells, as well as its modulatory effects upon Th1- and Th2-mediated inflammatory immune diseases. Ultimately, results emerging from such studies will substantially improve the immunotherapeutic application of TQ in clinical settings.

Polylysine-modified polyethylenimine (PEI-PLL) mediated VEGF gene delivery protects dopaminergic neurons in cell culture and in rat models of Parkinson's Disease (PD).

PubMed

Sheikh, Muhammad Abid; Malik, Yousra Saeed; Xing, Zhenkai; Guo, Zhaopei; Tian, Huayu; Zhu, Xiaojuan; Chen, Xuesi

2017-05-01

Parkinson's Disease (PD) is a chronic neurodegenerative disorder characterized by motor deficits which result from the progressive loss of dopaminergic neurons. Gene therapy using growth factors such as VEGF seems to be a viable approach for potential therapeutic treatment of PD. In this study, we utilized a novel non-viral gene carrier designated as PEI-PLL synthesized by our laboratory to deliver VEGF gene to study its effect by using both cell culture as well as animal models of PD. For cell culture experiments, we utilized 6-hydroxydopamine (6-OHDA) mediated cell death model of MN9D cells following transfection with either a control plasmid or VEGF expressing plasmid. As compared to control transfected cells, PEI-PLL mediated VEGF gene delivery to MN9D cells resulted in increased cell viability, increase in the number of Tyrosine hydroxylase (TH) positive cells and decreased apoptosis following 6-OHDA insult. Next, we studied the therapeutic potential of PEI-PLL mediated VEGF gene delivery in SNPc by using unilateral 6-OHDA Medial forebrain bundle (MFB) lesion model of PD in rats. VEGF administration prevented the loss of motor functions induced by 6-OHDA as determined by behavior analysis. Similarly, VEGF inhibited the 6-OHDA mediated loss of DA neurons in Substantia Nigra Pars Compacta (SNPc) as well as DA nerve fibers in striatum as determined by TH immunostaining. In addition, PEI-PLL mediated VEGF gene delivery also prevented apoptosis and microglial activation in PD rat models. Together, these results clearly demonstrated the beneficial effects of PEI-PLL mediated VEGF gene delivery on dopaminergic system in both cell culture and animal models of PD. In this report, we exploited the potential of PEI-PLL to deliver VEGF gene for the potential therapeutic treatment of PD by using both cell culture and animal models of PD. To the best of our knowledge, this is the first report describing the use of novel polymeric gene carriers for the delivery of VEGF gene to DA neurons with improved transfection efficiency. Finally, the study will lead to a significant advancement in the field of non-viral PD gene therapy treatment. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Exploring individual cognitions, self-regulation skills, and environmental-level factors as mediating variables of two versions of a Web-based computer-tailored nutrition education intervention aimed at adults: A randomized controlled trial.

PubMed

Springvloet, Linda; Lechner, Lilian; Candel, Math J J M; de Vries, Hein; Oenema, Anke

2016-03-01

This study explored whether the determinants that were targeted in two versions of a Web-based computer-tailored nutrition education intervention mediated the effects on fruit, high-energy snack, and saturated fat intake among adults who did not comply with dietary guidelines. A RCT was conducted with a basic (tailored intervention targeting individual cognitions and self-regulation), plus (additionally targeting environmental-level factors), and control group (generic nutrition information). Participants were recruited from the general Dutch adult population and randomly assigned to one of the study groups. Online self-reported questionnaires assessed dietary intake and potential mediating variables (behavior-specific cognitions, action- and coping planning, environmental-level factors) at baseline and one (T1) and four (T2) months post-intervention (i.e. four and seven months after baseline). The joint-significance test was used to establish mediating variables at different time points (T1-mediating variables - T2-intake; T1-mediating variables - T1-intake; T2-mediating variables - T2-intake). Educational differences were examined by testing interaction terms. The effect of the plus version on fruit intake was mediated (T2-T2) by intention and fruit availability at home and for high-educated participants also by attitude. Among low/moderate-educated participants, high-energy snack availability at home mediated (T1-T1) the effect of the basic version on high-energy snack intake. Subjective norm mediated (T1-T1) the effect of the basic version on fat intake among high-educated participants. Only some of the targeted determinants mediated the effects of both intervention versions on fruit, high-energy snack, and saturated fat intake. A possible reason for not finding a more pronounced pattern of mediating variables is that the educational content was tailored to individual characteristics and that participants only received feedback for relevant and not for all assessed mediating variables. Netherlands Trial Registry NTR3396. Copyright © 2015. Published by Elsevier Ltd.

Angiotensin-Converting Enzyme 2 Metabolizes and Partially Inactivates Pyr-Apelin-13 and Apelin-17: Physiological Effects in the Cardiovascular System.

PubMed

Wang, Wang; McKinnie, Shaun M K; Farhan, Maikel; Paul, Manish; McDonald, Tyler; McLean, Brent; Llorens-Cortes, Catherine; Hazra, Saugata; Murray, Allan G; Vederas, John C; Oudit, Gavin Y

2016-08-01

Apelin peptides mediate beneficial effects on the cardiovascular system and are being targeted as potential new drugs. However, apelin peptides have extremely short biological half-lives, and improved understanding of apelin peptide metabolism may lead to the discovery of biologically stable analogues with therapeutic potential. We examined the ability of angiotensin-converting enzyme 2 (ACE2) to cleave and inactivate pyr-apelin 13 and apelin 17, the dominant apelin peptides. Computer-assisted modeling shows a conserved binding of pyr-apelin 13 and apelin 17 to the ACE2 catalytic site. In ACE2 knockout mice, hypotensive action of pyr-apelin 13 and apelin 17 was potentiated, with a corresponding greater elevation in plasma apelin levels. Similarly, pharmacological inhibition of ACE2 potentiated the vasodepressor action of apelin peptides. Biochemical analysis confirmed that recombinant human ACE2 can cleave pyr-apelin 13 and apelin 17 efficiently, and apelin peptides are degraded slower in ACE2-deficient plasma. The biological relevance of ACE2-mediated proteolytic processing of apelin peptides was further supported by the reduced potency of pyr-apelin 12 and apelin 16 on the activation of signaling pathways and nitric oxide production from endothelial cells. Importantly, although pyr-apelin 13 and apelin 17 rescued contractile function in a myocardial ischemia-reperfusion model, ACE2 cleavage products, pyr-apelin 12 and 16, were devoid of these cardioprotective effects. We designed and synthesized active apelin analogues that were resistant to ACE2-mediated degradation, thereby confirming that stable apelin analogues can be designed as potential drugs. We conclude that ACE2 represents a major negative regulator of apelin action in the vasculature and heart. © 2016 American Heart Association, Inc.

Hippocampal A-type current and Kv4.2 channel modulation by the sulfonylurea compound NS5806.

PubMed

Witzel, Katrin; Fischer, Paul; Bähring, Robert

2012-12-01

We examined the effects of the sulfonylurea compound NS5806 on neuronal A-type channel function. Using whole-cell patch-clamp we studied the effects of NS5806 on the somatodendritic A-type current (I(SA)) in cultured hippocampal neurons and the currents mediated by Kv4.2 channels coexpressed with different auxiliary β-subunits, including both Kv channel interacting proteins (KChIPs) and dipeptidyl aminopeptidase-related proteins (DPPs), in HEK 293 cells. The amplitude of the I(SA) component in hippocampal neurons was reduced in the presence of 20 μM NS5806. I(SA) decay kinetics were slowed and the recovery kinetics accelerated, but the voltage dependence of steady-state inactivation was shifted to more negative potentials by NS5806. The peak amplitudes of currents mediated by ternary Kv4.2 channel complexes, associated with DPP6-S (short splice-variant) and either KChIP2, KChIP3 or KChIP4, were potentiated and their macroscopic inactivation slowed by NS5806, whereas the currents mediated by binary Kv4.2 channels, associated only with DPP6-S, were suppressed, and the NS5806-mediated slowing of macroscopic inactivation was less pronounced. Neither potentiation nor suppression and no effect on current decay kinetics in the presence of NS5806 were observed for Kv4.2 channels associated with KChIP3 and the N-type inactivation-conferring DPP6a splice-variant. For all recombinant channel complexes, NS5806 slowed the recovery from inactivation and shifted the voltage dependence of steady-state inactivation to more negative potentials. Our results demonstrate the activity of NS5806 on native I(SA) and possible molecular correlates in the form of recombinant Kv4.2 channels complexed with different KChIPs and DPPs, and they shed some light on the mechanism of NS5806 action. Copyright © 2012 Elsevier Ltd. All rights reserved.

Stress and multiple sclerosis: A systematic review considering potential moderating and mediating factors and methods of assessing stress.

PubMed

Briones-Buixassa, Laia; Milà, Raimon; Mª Aragonès, Josep; Bufill, Enric; Olaya, Beatriz; Arrufat, Francesc Xavier

2015-07-01

Research about the effects of stress on multiple sclerosis has yielded contradictory results. This study aims to systematically review the evidence focusing on two possible causes: the role of stress assessment and potential moderating and mediating factors. The Web of Knowledge (MEDLINE and Web of Science), Scopus, and PsycINFO databases were searched for relevant articles published from 1900 through December 2014 using the terms "stress*" AND "multiple sclerosis." Twenty-three articles were included. Studies focused on the effect of stress on multiple sclerosis onset ( n  = 9) were mostly retrospective, and semi-structured interviews and scales yielded the most consistent associations. Studies focused on multiple sclerosis progression ( n  = 14) were mostly prospective, and self-reported diaries yielded the most consistent results. The most important modifying factors were stressor duration, severity, and frequency; cardiovascular reactivity and heart rate; and social support and escitalopram intake. Future studies should consider the use of prospective design with self-reported evaluations and the study of moderators and mediators related to amount of stress and autonomic nervous system reactivity to determine the effects of stress on multiple sclerosis.

Stress and multiple sclerosis: A systematic review considering potential moderating and mediating factors and methods of assessing stress

PubMed Central

Briones-Buixassa, Laia; Milà, Raimon; Mª Aragonès, Josep; Bufill, Enric; Olaya, Beatriz; Arrufat, Francesc Xavier

2015-01-01

Research about the effects of stress on multiple sclerosis has yielded contradictory results. This study aims to systematically review the evidence focusing on two possible causes: the role of stress assessment and potential moderating and mediating factors. The Web of Knowledge (MEDLINE and Web of Science), Scopus, and PsycINFO databases were searched for relevant articles published from 1900 through December 2014 using the terms “stress*” AND “multiple sclerosis.” Twenty-three articles were included. Studies focused on the effect of stress on multiple sclerosis onset (n = 9) were mostly retrospective, and semi-structured interviews and scales yielded the most consistent associations. Studies focused on multiple sclerosis progression (n = 14) were mostly prospective, and self-reported diaries yielded the most consistent results. The most important modifying factors were stressor duration, severity, and frequency; cardiovascular reactivity and heart rate; and social support and escitalopram intake. Future studies should consider the use of prospective design with self-reported evaluations and the study of moderators and mediators related to amount of stress and autonomic nervous system reactivity to determine the effects of stress on multiple sclerosis. PMID:28070374

Targeting interleukin-6 for noninfectious uveitis

PubMed Central

Lin, Phoebe

2015-01-01

Interleukin-6 (IL-6) is a pleiotropic cytokine implicated in the pathogenesis of many immune-mediated disorders including several types of non-infectious uveitis. These uveitic conditions include Vogt-Koyanagi-Harada syndrome, uveitis associated with Behçet disease, and sarcoidosis. This review summarizes the role of IL-6 in immunity, highlighting its effect on Th17, Th1, and plasmablast differentiation. It reviews the downstream mediators activated in the process of IL-6 binding to its receptor complex. This review also summarizes the biologics targeting either IL-6 or the IL-6 receptor, including tocilizumab, sarilumab, sirukumab, olokizumab, clazakizumab, and siltuximab. The target, dosage, potential side effects, and potential uses of these biologics are summarized in this article based on the existing literature. In summary, anti-IL-6 therapy for non-infectious uveitis shows promise in terms of efficacy and side effect profile. PMID:26392750

Child Negative Emotionality and Parental Harsh Discipline in Chinese Preschoolers: The Different Mediating Roles of Maternal and Paternal Anxiety

PubMed Central

Xing, Xiaopei; Zhang, Hongli; Shao, Shuhui; Wang, Meifang

2017-01-01

Previous research has suggested that harsh discipline is still prevalent in modern Chinese families and it is necessary to explore the cause and the potential mechanisms of Chinese parental use of harsh discipline. This study examined the mediating effects of parental anxiety in the relations between child negative emotionality and parental harsh discipline in China. Using a sample of 328 Chinese father-mother dyads with their young children, findings revealed that maternal anxiety mediated the relations between child negative emotionality and maternal psychological aggression and corporal punishment, but the mediating effects of paternal anxiety on the relations between child negative emotionality and paternal harsh discipline was not significant. The findings provide an important supplement and extension to previous examinations of the factors associated with Chinese parental use of harsh discipline and its mechanisms. PMID:28326056

Types of prayer and depressive symptoms among cancer patients: the mediating role of rumination and social support.

PubMed

Pérez, John E; Rex Smith, Amy; Norris, Rebecca L; Canenguez, Katia M; Tracey, Elizabeth F; Decristofaro, Susan B

2011-12-01

We examined the association between different types of prayer and depressive symptoms--with rumination and social support as potential mediators--in a sample of predominantly White, Christian, and female ambulatory cancer patients. In a cross-sectional design, 179 adult cancer outpatients completed measures of prayer, rumination, social support, depressive symptoms, and demographic variables. Type and stage of cancer were collected from electronic medical charts. Depressive symptoms were negatively correlated with adoration prayer (r = -.15), reception prayer (r = -.17), thanksgiving prayer (r = -.29), and prayer for the well-being of others (r = -.26). In the path analysis, rumination fully mediated the link between thanksgiving prayer and depressive symptoms (β for indirect effect = -.05), whereas social support partially mediated the link between prayer for others and depressive symptoms (β for indirect effect = -.05). These findings suggest that unique mechanisms may link different prayer types to lower depressive symptoms among cancer patients.

Child Negative Emotionality and Parental Harsh Discipline in Chinese Preschoolers: The Different Mediating Roles of Maternal and Paternal Anxiety.

PubMed

Xing, Xiaopei; Zhang, Hongli; Shao, Shuhui; Wang, Meifang

2017-01-01

Previous research has suggested that harsh discipline is still prevalent in modern Chinese families and it is necessary to explore the cause and the potential mechanisms of Chinese parental use of harsh discipline. This study examined the mediating effects of parental anxiety in the relations between child negative emotionality and parental harsh discipline in China. Using a sample of 328 Chinese father-mother dyads with their young children, findings revealed that maternal anxiety mediated the relations between child negative emotionality and maternal psychological aggression and corporal punishment, but the mediating effects of paternal anxiety on the relations between child negative emotionality and paternal harsh discipline was not significant. The findings provide an important supplement and extension to previous examinations of the factors associated with Chinese parental use of harsh discipline and its mechanisms.

Improving Our Ability to Evaluate Underlying Mechanisms of Behavioral Onset and Other Event Occurrence Outcomes: A Discrete-Time Survival Mediation Model

PubMed Central

Fairchild, Amanda J.; Abara, Winston E.; Gottschall, Amanda C.; Tein, Jenn-Yun; Prinz, Ronald J.

2015-01-01

The purpose of this article is to introduce and describe a statistical model that researchers can use to evaluate underlying mechanisms of behavioral onset and other event occurrence outcomes. Specifically, the article develops a framework for estimating mediation effects with outcomes measured in discrete-time epochs by integrating the statistical mediation model with discrete-time survival analysis. The methodology has the potential to help strengthen health research by targeting prevention and intervention work more effectively as well as by improving our understanding of discretized periods of risk. The model is applied to an existing longitudinal data set to demonstrate its use, and programming code is provided to facilitate its implementation. PMID:24296470

A multimodal instrument for real-time in situ study of ultrasound and cavitation mediated drug delivery.

PubMed

Bian, Shuning; Seth, Anjali; Daly, Dan; Carlisle, Robert; Stride, Eleanor

2017-03-01

The development of a multimodal instrument capable of real-time in situ measurements of cavitation activity and effect in tissue mimicking phantoms during ultrasound and cavitation mediated drug delivery experiments is described here. The instrument features an acoustic arm that can expose phantoms to high-intensity focused-ultrasound while measuring cavitation activity and an optical arm that monitors cavitation effect using confocal microscopy. This combination of modalities allows real-time in situ characterisation of drug delivery in tissue and tissue mimicking phantoms during ultrasound and cavitation mediated drug delivery experiments. A representative result, obtained with a tissue mimicking phantom and acoustically activated droplets, is presented here as a demonstration of the instrument's capabilities and potential applications.

Free Swimming in Ground Effect

NASA Astrophysics Data System (ADS)

Cochran-Carney, Jackson; Wagenhoffer, Nathan; Zeyghami, Samane; Moored, Keith

2017-11-01

A free-swimming potential flow analysis of unsteady ground effect is conducted for two-dimensional airfoils via a method of images. The foils undergo a pure pitching motion about their leading edge, and the positions of the body in the streamwise and cross-stream directions are determined by the equations of motion of the body. It is shown that the unconstrained swimmer is attracted to a time-averaged position that is mediated by the flow interaction with the ground. The robustness of this fluid-mediated equilibrium position is probed by varying the non-dimensional mass, initial conditions and kinematic parameters of motion. Comparisons to the foil's fixed-motion counterpart are also made to pinpoint the effect that free swimming near the ground has on wake structures and the fluid-mediated forces over time. Optimal swimming regimes for near-boundary swimming are determined by examining asymmetric motions.

Investigating the effect of child maltreatment on early adolescent peer-on-peer sexual aggression: testing a multiple mediator model in a non-incarcerated sample of Danish adolescents.

PubMed

Bramsen, Rikke Holm; Lasgaard, Mathias; Koss, Mary P; Elklit, Ask; Banner, Jytte

2014-01-01

The aim of the present study was to investigate the relationship between child maltreatment and severe early adolescent peer-on-peer sexual aggression, using a multiple mediator model. The study comprised 330 male Grade 9 students with a mean age of 14.9 years (SD=0.5). Estimates from the mediation model indicated significant indirect effects of child physical abuse on sexual aggression via peer influence and insecure-hostile masculinity. No significant total effect of child sexual abuse and child neglect on sexual aggression was found. Findings of the present study identify risk factors that are potentially changeable and therefore of value in informing the design of prevention programs aiming at early adolescent peer-on-peer sexual aggression in at-risk youth.

The association of headache frequency with pain interference and the burden of disease is mediated by depression and sleep quality, but not anxiety, in chronic tension type headache.

PubMed

Palacios-Ceña, María; Fernández-Muñoz, Juan J; Castaldo, Matteo; Wang, Kelun; Guerrero-Peral, Ángel; Arendt-Nielsen, Lars; Fernández-de-Las-Peñas, César

2017-12-01

A better understanding of potential relationship between mood disorders, sleep quality, pain, and headache frequency may assist clinicians in determining optimal therapeutic programs. The aim of the current study was to analyze the effects of sleep quality, anxiety, depression on potential relationships between headache intensity, burden of headache, and headache frequency in chronic tension type headache (CTTH). One hundred and ninety-three individuals with CTTH participated. Headache features were collected with a 4-weeks headache diary. The Hospital Anxiety and Depression Scale was used for assessing anxiety and depression. Headache Disability Inventory evaluated the burden of headache. Pain interference was determined with the bodily pain domain (SF-36 questionnaire). Sleep quality was assessed with Pittsburgh Sleep Quality Index. Path analyses with maximum likelihood estimations were conducted to determine the direct and indirect effects of depression, anxiety, and sleep quality on the frequency of headaches. Two paths were observed: the first with depression and the second with sleep quality as mediators. Direct effects were noted from sleep quality, emotional burden of disease and pain interference on depression, and from depression to headache frequency. The first path showed indirect effects of depression from emotional burden and from sleep quality to headache frequency (first model R 2  = 0.12). Direct effects from the second path were from depression and pain interference on sleep quality and from sleep quality on headache frequency. Sleep quality indirectly mediated the effects of depression, emotional burden and pain interference on headache frequency (second model R 2  = 0.18). Depression and sleep quality, but not anxiety, mediated the relationship between headache frequency and the emotional burden of disease and pain interference in CTTH.

Lindane blocks GABAA-mediated inhibition and modulates pyramidal cell excitability in the rat hippocampal slice.

PubMed

Joy, R M; Walby, W F; Stark, L G; Albertson, T E

1995-01-01

An in vitro paired-pulse orthodromic stimulation technique was used to examine the effects of lindane on excitatory afferent terminals, CA1 pyramidal cells and recurrent collateral evoked inhibition in the rat hippocampal slice. This was done to establish simultaneous effects on a simple neural network and to develop procedures for more detailed analyses of the effects of lindane. Hippocampal slices 400 microns thick were perfused with oxygenated artificial cerebrospinal fluid. Electrodes were placed in the CA1 region to record extracellular population spike (PS) or excitatory postsynaptic potential (EPSP) responses to stimulation of Schaffer collateral/commissural (SC/C) fibers. Gamma-aminobutyric acid (GABA)-mediated recurrent inhibition was measured using a paired-pulse technique. Perfusion with lindane produced both time and dose dependent changes in a number of the responses measured. The most striking effect produced by lindane was the loss of GABAA-mediated recurrent collateral inhibition. This tended to occur rapidly, often before changes in EPSP or PS responses could be detected. With longer exposures to lindane, repetitive discharge of pyramidal cells developed resulting in multiple PSs to single stimuli. Lindane (50 microM) also completely reversed the effects of the injectable anesthetic, propofol, a compound known to potentiate GABAA-mediated inhibition via a direct action on the GABAA receptor-chloride channel complex. An analysis of input/output relationships at varying stimulus intensities showed that lindane increased EPSP and PS response amplitudes at any given stimulus intensity resulting in a leftward shift in the EPSP amplitude/stimulus intensity, PS amplitude/stimulus intensity and PS amplitude/EPSP amplitude relationships. This effect was most noticeable with low intensity stimuli and became progressively less so as stimulus intensities approached those yielding maximal responses. In addition lindane significantly increased paired pulse facilitation of EPSPs during paired stimulus presentation.

Paternal Lifestyle-Related Parenting Practices Mediate Changes in Children's Dietary and Physical Activity Behaviors: Findings From the Healthy Dads, Healthy Kids Community Randomized Controlled Trial.

PubMed

Lloyd, Adam B; Lubans, David R; Plotnikoff, Ronald C; Morgan, Philip J

2015-09-01

This study examined potential parenting-related mediators of children's physical activity and dietary behavior change in the Healthy Dads, Healthy Kids (HDHK) community program. A randomized controlled trial was conducted with 45 overweight/obese (mean [SD] age = 39.8 [5.4] years; BMI = 32.4 [3.8]) fathers and their children (n = 77; 58% boys; mean [SD] age = 7.7 [2.5] years). Families were randomized to either the HDHK program or wait-list control group. The program involved 7 sessions. Fathers and their children were assessed at baseline and at 14 weeks for physical activity (pedometery) and core food intake (Questionnaire). Fathers' lifestyle-related parenting practices included; self-efficacy, beliefs, modeling, logistic support, rules, cophysical activity, shared mealtime frequency and intentions. Significant intervention effects were found for cophysical activity and modeling physical activity. Cophysical activity mediated children's physical activity in the intervention ('mediated effect,' AB = 653, 95% CI = 4-2050) and was responsible for 59.5% of the intervention effect. Fathers' beliefs mediated children's percent energy from core foods (AB = 1.51, 95% CI = 0.05-5.55) and accounted for 72.9% of the intervention effect. Participation in the HDHK program positively impacted on fathers' cophysical activity with their child and beliefs about healthy eating which mediated changes in children's diet and physical activity behaviors.

Suppressive effects of lysozyme on polyphosphate-mediated vascular inflammatory responses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chung, Jiwoo; Ku, Sae-Kwang; Lee, Suyeon

Lysozyme, found in relatively high concentration in blood, saliva, tears, and milk, protects us from the ever-present danger of bacterial infection. Previous studies have reported proinflammatory responses of endothelial cells to the release of polyphosphate(PolyP). In this study, we examined the anti-inflammatory responses and mechanisms of lysozyme and its effects on PolyP-induced septic activities in human umbilical vein endothelial cells (HUVECs) and mice. The survival rates, septic biomarker levels, behavior of human neutrophils, and vascular permeability were determined in PolyP-activated HUVECs and mice. Lysozyme suppressed the PolyP-mediated vascular barrier permeability, upregulation of inflammatory biomarkers, adhesion/migration of leukocytes, and activation and/ormore » production of nuclear factor-κB, tumor necrosis factor-α, and interleukin-6. Furthermore, lysozyme demonstrated protective effects on PolyP-mediated lethal death and the levels of the related septic biomarkers. Therefore, these results indicated the therapeutic potential of lysozyme on various systemic inflammatory diseases, such as sepsis or septic shock. -- Highlights: •PolyP is shown to be an important mediator of vascular inflammation. •Lysozyme inhibited PolyP-mediated hyperpermeability. •Lysozyme inhibited PolyP-mediated septic response. •Lysozyme reduced PolyP-induced septic mortality.« less

Effects of Chronic Alcohol Exposure on Kainate Receptor-Mediated Neurotransmission in the Hippocampus

DTIC Science & Technology

2004-09-01

hippocampus and hypothalamus. J Neurosci Res 63:200-208. Thorpe GH et al. (1989) Chemiluminescent enzyme immunoassay of alpha - fetoprotein based on an...cells. Proc Natl Acad Sci USA 83:6213-6215. Montpied Pet al. (1991) Prolonged ethanol inhalation decreases gamma-aminobutyric acidA receptor alpha ...potentials mediated via alpha -bungarotoxin-sensitive nico- tinic acetylcholine receptors in rat hippocampal interneurons. J Neurosci 18:8228- 8235

Father's and Mother's Perceptions of Parenting Styles as Mediators of the Effects of Parental Psychopathology on Antisocial Behavior in Outpatient Children and Adolescents

ERIC Educational Resources Information Center

Vera, Juan; Granero, Roser; Ezpeleta, Lourdes

2012-01-01

The aim was to examine the potential mediating role of father's and mother's parenting styles in the association between parental psychopathology and antisocial behavior in children, and whether this pathway was moderated by child's sex. Participants included both parents and 338 Spanish outpatient children between 8 and 17 years (56.5% boys).…

Translational control by eIF2α phosphorylation regulates vulnerability to the synaptic and behavioral effects of cocaine

PubMed Central

Huang, Wei; Placzek, Andon N; Viana Di Prisco, Gonzalo; Khatiwada, Sanjeev; Sidrauski, Carmela; Krnjević, Krešimir; Walter, Peter; Dani, John A; Costa-Mattioli, Mauro

2016-01-01

Adolescents are especially prone to drug addiction, but the underlying biological basis of their increased vulnerability remains unknown. We reveal that translational control by phosphorylation of the translation initiation factor eIF2α (p-eIF2α) accounts for adolescent hypersensitivity to cocaine. In adolescent (but not adult) mice, a low dose of cocaine reduced p-eIF2α in the ventral tegmental area (VTA), potentiated synaptic inputs to VTA dopaminergic neurons, and induced drug-reinforced behavior. Like adolescents, adult mice with reduced p-eIF2α-mediated translational control were more susceptible to cocaine-induced synaptic potentiation and behavior. Conversely, like adults, adolescent mice with increased p-eIF2α became more resistant to cocaine's effects. Accordingly, metabotropic glutamate receptor-mediated long-term depression (mGluR-LTD)—whose disruption is postulated to increase vulnerability to drug addiction—was impaired in both adolescent mice and adult mice with reduced p-eIF2α mediated translation. Thus, during addiction, cocaine hijacks translational control by p-eIF2α, initiating synaptic potentiation and addiction-related behaviors. These insights may hold promise for new treatments for addiction. DOI: http://dx.doi.org/10.7554/eLife.12052.001 PMID:26928234

Self-perceived provision of patient centered care by healthcare professionals: The role of emotional intelligence and general self-efficacy.

PubMed

Sommaruga, Marinella; Casu, Giulia; Giaquinto, Francesco; Gremigni, Paola

2017-05-01

This study aimed to investigate whether healthcare professionals' emotional intelligence (EI) is associated with self-perceived provision of patient-centered care (PCC), taking into account the potential mediating effect of general self-efficacy (GSE). A sample of 318 healthcare professionals, recruited in 2015 among four hospitals in Italy, completed the Provider-Patient Relationship Questionnaire, the Emotional Intelligence Scale, and the General Self-Efficacy scale. A structural equation model was tested with GSE mediating the relationship between EI and self-perceived provision of PCC. Groups of participants based on gender, profession, and work setting were also compared on the study variables. EI had direct effects on the self-perceived provision of PCC dimensions. GSE partially mediated only the relationship between EI and involving the patient in care. Healthcare professionals in rehabilitation units showed higher self-perceived provision of PCC than those in acute care or ambulatory services. Self-perceived provision of PCC seems to have the potential to be improved by EI and to be distinguishable from GSE. Since EI can be developed, findings of this study have potential implications for improving PCC through continuing education interventions for healthcare professionals. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Gaba mediated long-term depression (LTD) in the rat medial vestibular nuclei.

PubMed

Grassi, S; Della Torre, G; Zampolini, M; Pettorossi, V E

1995-01-01

As previously demonstrated, high frequency stimulation (HFS) of the primary vestibular afferents always induces a clear, long lasting depression of the polysynaptic (N2) component of the field potentials recorded in the dorsal portion of the medial vestibular nuclei (MVN). The induction of the HFS effect was mediated by the activation of glutamate NMDA receptors, since it was blocked by AP5. The mechanisms at the basis of such a depression were studied. Our results demonstrate that Gaba, acting on both GabaA and GabaB receptors, is involved in mediating this phenomenon. In fact, HFS applied during Bicuculline and Saclofen perfusion, was no longer able to induce an N2 depression, but provoked a slight potentiation. However, the N2 depression clearly emerged after drug wash-out. Furthermore, Bicuculline and Saclofen fully abolished the N2 depression and highlighted the potentiation, when administered after HFS. The possibility that the N2 depression is the result of a homosynaptic LTD can be excluded on the basis of our results. On the contrary, our findings suggest that the depression is due to an enhancement of the Gaba inhibitory effect due to an HFS dependent increase in gabaergic interneuron activity, which resets vestibular neuron excitability at a lower level.

Selectivity in the potentiation of antibacterial activity of α-peptide/β-peptoid peptidomimetics and antimicrobial peptides by human blood plasma.

PubMed

Hein-Kristensen, Line; Knapp, Kolja M; Franzyk, Henrik; Gram, Lone

2013-11-01

Antimicrobial peptides (AMPs) are promising leads for novel antibiotics; however, their activity is often compromised under physiological conditions. The purpose of this study was to determine the activity of α-peptide/β-peptoid peptidomimetics and AMPs against Escherichia coli and Staphylococcus aureus in the presence of human blood-derived matrices and immune effectors. The minimum inhibitory concentration (MIC) of two peptidomimetics against E. coli decreased by up to one order of magnitude when determined in 50% blood plasma as compared to MHB media. The MIC of a membrane-active AMP, LL-I/3, also decreased, whereas two intracellularly acting AMPs were not potentiated by plasma. Blood serum had no effect on activity against E. coli and neither matrix had an effect on activity against S. aureus. Unexpectedly, physiological concentrations of human serum albumin did not influence activity. Plasma potentiation was not mediated by an LL-37 analogue, lysozyme or hydrogen peroxide; however, plasma potentiation of activity was abolished when the complement system was heat-inactivated. Time-course experiments indicated that potentiation was due to plasma-mediated effects on bacterial cells prior to activities of peptidomimetics. The unexpected enhancement of antibacterial activity of peptidomimetics and AMPs under physiological conditions significantly increases the therapeutic potential of these compounds. Copyright © 2013 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Air pollution exposure potentiates hypertension through reactive oxygen species-mediated activation of Rho/ROCK

EPA Science Inventory

OBJECTIVE: Fine particulate matter <2.5 microm (PM2.5) has been implicated in vasoconstriction and potentiation of hypertension in humans. We investigated the effects of short-term exposure to PM2.5 in the angiotensin II (AII) infusion model. METHODS AND RESULTS: Sprague-Dawley r...

Anti-mitotic potential of 7-diethylamino-3(2 Prime -benzoxazolyl)-coumarin in 5-fluorouracil-resistant human gastric cancer cell line SNU620/5-FU

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Nam Hyun; Kim, Su-Nam; Oh, Joa Sub

2012-02-24

Highlights: Black-Right-Pointing-Pointer DBC exerts antiproliferative potential against 5FU-resistant human gastric cancer cells. Black-Right-Pointing-Pointer This effect is mediated by destabilization of microtubules and subsequent mitotic arrest. Black-Right-Pointing-Pointer DBC enhances apoptosis via caspase activation and downregulation of antiapoptotic genes. -- Abstract: In this study, we investigate an anti-mitotic potential of the novel synthetic coumarin-based compound, 7-diethylamino-3(2 Prime -benzoxazolyl)-coumarin, in 5-fluorouracil-resistant human gastric cancer cell line SNU-620-5FU and its parental cell SNU-620. It exerts the anti-proliferative effects with similar potencies against both cancer cells, which is mediated by destabilization of microtubules and subsequent mitotic arrest. Furthermore, this compound enhances caspase-dependent apoptotic cell deathmore » via decreased expression of anti-apoptotic genes. Taken together, our data strongly support anti-mitotic potential of 7-diethylamino-3(2 Prime -benzoxazolyl)-coumarin against drug-resistant cancer cells which will prompt us to further develop as a novel microtubule inhibitor for drug-resistant cancer chemotherapy.« less

Coping Self-Efficacy Mediates the Effects of Negative Cognitions on Posttraumatic Distress

PubMed Central

Cieslak, Roman; Benight, Charles C.; Lehman, Victoria Caden

2008-01-01

Although cognitive distortions have predicted posttraumatic distress after various types of traumatic events, the mechanisms through which cognitive distortions influence posttraumatic distress remain unclear. We hypothesized that coping self-efficacy, the belief in one’s own ability to manage posttraumatic recovery demands, would operate as a mediator between negative cognitions (about self, about the world, and self-blame beliefs) and posttraumatic distress. In the cross-sectional Study 1, data collected among 66 adult female victims of child sexual abuse indicated that coping self-efficacy mediated the effects of negative cognitions about self and about the world on posttraumatic distress. The same pattern of results was found in a longitudinal Study 2, conducted among 70 survivors of motor vehicle accidents. Coping self-efficacy measured at 1 month after the trauma mediated the effects of 7-day negative cognitions about self and about the world on 3-month posttraumatic distress. In both studies self-blame was not related to posttraumatic distress and the effect of self-blame on posttraumatic distress was not mediated by coping self-efficacy. The results provide insight into a mechanism through which negative cognitions may affect posttraumatic distress and highlight the potential importance of interventions aimed at enhancing coping self-efficacy beliefs. PMID:18456241

Why and for Whom May Coping Planning Have Adverse Effects? A Moderated Mediation Analysis.

PubMed

Inauen, Jennifer; Stocker, Andrea; Scholz, Urte

2018-05-09

Coping planning, the formation of plans to overcome behavioral barriers is assumed to promote health behavior maintenance, but the literature on this is inconsistent. In this study, we aimed to investigate the mechanisms of a coping planning intervention that adversely affected maintained safe water consumption. We also explored perceived behavioral difficulty as a potential moderator of coping planning interventions. In the second phase of a cluster-randomised trial, households (N = 177 analyzed) were randomly allocated to a coping planning intervention or a comparison group (repetition of interventions from first intervention phase). Safe water consumption, the mechanisms of coping planning, and perceived difficulty were measured pre-post. The data were analyzed using mediation and moderated mediation analysis. Changes in behavioral intention mediated the intervention effects on behavioral maintenance (b = -0.36, 95% CI [-0.91, -0.03]). Changes in perceived coping planning (b = 0.08, 95% CI [-0.12, 0.34]), and maintenance self-efficacy (b = -0.13, 95% CI [-0.45, 0.01]) did not mediate the effects. Prior perceived difficulty moderated the coping planning intervention effects on maintenance via intention. Coping planning may decrease motivation for health behavior maintenance for persons who experienced few barriers prior to the planning intervention. © 2018 The International Association of Applied Psychology.

Mediators and Moderators of a School-Based Cognitive-Behavioral Depression Prevention Program.

PubMed

Duong, Mylien T; Kelly, Brynn M; Haaland, Wren L; Matsumiya, Brandon; Huey, Stanley J; McCarty, Carolyn A

2016-10-01

This study tested potential moderators and mediators of an indicated depression prevention program for middle school students, Positive Thoughts and Actions (PTA). Participants were 120 students randomly assigned to PTA, or a brief, individually administered supportive intervention (Individual Support Program, or ISP). Youths completed measures of depressive symptoms at baseline, post-intervention, and 12-month follow-up. Hierarchical regression was used to test three moderators-ethnic minority status, gender, and baseline depressive symptoms-and three mediators representing functional outcomes targeted by PTA-parent-child communication, attitude towards school, and health behavior. Ethnic minority status did not moderate PTA effects at post-intervention but did moderate PTA effects at 12-month follow-up. At 12 months, PTA appeared to be more effective for White participants than ethnic minority youth. Follow-up analyses suggested this moderation effect was due to the tendency of ethnic minority youth, especially those with fewer symptoms at baseline, to drop out by 12 months. Neither gender nor baseline depressive symptoms moderated the effects of PTA. Although PTA improved health behavior and attitudes toward school, there was no evidence that any of these functional outcomes measured mediated the impact of PTA on depressive symptoms. Future directions are discussed.

Oxytocin Stimulates Extracellular Ca2+ Influx Through TRPV2 Channels in Hypothalamic Neurons to Exert Its Anxiolytic Effects.

PubMed

van den Burg, Erwin H; Stindl, Julia; Grund, Thomas; Neumann, Inga D; Strauss, Olaf

2015-12-01

There is growing interest in anxiolytic and pro-social effects of the neuropeptide oxytocin (OXT), but the underlying intraneuronal mechanisms are largely unknown. Here we examined OXT-mediated anxiolysis in the hypothalamic paraventricular nucleus (PVN) of rats and effects of OXT administration on signaling events in hypothalamic primary and immortalized cells. In vivo, the application of SKF96365 prevented the anxiolytic activity of OXT in the PVN, suggesting that changes in intracellular Ca(2+) mediate the acute OXT behavioral effects. In vitro, mainly in the neurons with autonomous Ca(2+) oscillations, OXT increased intracellular Ca(2+) concentration and oscillation amplitude. Pharmacological intervention revealed OXT-dependent changes in Ca(2+) signaling that required activation of transient receptor potential vanilloid type-2 channel (TRPV2), mediated by phosphoinositide 3-kinase. TRPV2 induced the activation of the anxiolytic mitogen-activated protein kinase kinase (MEK1/2). In situ, immunohistochemistry revealed co-localization of TRPV2 and OXT in the PVN. Thus, functional and pharmacological analyses identified TRPV2 as a mediator of anxiolytic effects of OXT, conveying the OXT signal to MEK1/2 via modulation of intracellular Ca(2+).

Oxytocin Stimulates Extracellular Ca2+ Influx Through TRPV2 Channels in Hypothalamic Neurons to Exert Its Anxiolytic Effects

PubMed Central

van den Burg, Erwin H; Stindl, Julia; Grund, Thomas; Neumann, Inga D; Strauss, Olaf

2015-01-01

There is growing interest in anxiolytic and pro-social effects of the neuropeptide oxytocin (OXT), but the underlying intraneuronal mechanisms are largely unknown. Here we examined OXT-mediated anxiolysis in the hypothalamic paraventricular nucleus (PVN) of rats and effects of OXT administration on signaling events in hypothalamic primary and immortalized cells. In vivo, the application of SKF96365 prevented the anxiolytic activity of OXT in the PVN, suggesting that changes in intracellular Ca2+ mediate the acute OXT behavioral effects. In vitro, mainly in the neurons with autonomous Ca2+ oscillations, OXT increased intracellular Ca2+ concentration and oscillation amplitude. Pharmacological intervention revealed OXT-dependent changes in Ca2+ signaling that required activation of transient receptor potential vanilloid type-2 channel (TRPV2), mediated by phosphoinositide 3-kinase. TRPV2 induced the activation of the anxiolytic mitogen-activated protein kinase kinase (MEK1/2). In situ, immunohistochemistry revealed co-localization of TRPV2 and OXT in the PVN. Thus, functional and pharmacological analyses identified TRPV2 as a mediator of anxiolytic effects of OXT, conveying the OXT signal to MEK1/2 via modulation of intracellular Ca2+. PMID:26013963

Negative Life Events and Antenatal Depression among Pregnant Women in Rural China: The Role of Negative Automatic Thoughts.

PubMed

Wang, Yang; Wang, Xiaohua; Liu, Fangnan; Jiang, Xiaoning; Xiao, Yun; Dong, Xuehan; Kong, Xianglei; Yang, Xuemei; Tian, Donghua; Qu, Zhiyong

2016-01-01

Few studies have looked at the relationship between psychological and the mental health status of pregnant women in rural China. The current study aims to explore the potential mediating effect of negative automatic thoughts between negative life events and antenatal depression. Data were collected in June 2012 and October 2012. 495 rural pregnant women were interviewed. Depressive symptoms were measured by the Edinburgh postnatal depression scale, stresses of pregnancy were measured by the pregnancy pressure scale, negative automatic thoughts were measured by the automatic thoughts questionnaire, and negative life events were measured by the life events scale for pregnant women. We used logistic regression and path analysis to test the mediating effect. The prevalence of antenatal depression was 13.7%. In the logistic regression, the only socio-demographic and health behavior factor significantly related to antenatal depression was sleep quality. Negative life events were not associated with depression in the fully adjusted model. Path analysis showed that the eventual direct and general effects of negative automatic thoughts were 0.39 and 0.51, which were larger than the effects of negative life events. This study suggested that there was a potentially significant mediating effect of negative automatic thoughts. Pregnant women who had lower scores of negative automatic thoughts were more likely to suffer less from negative life events which might lead to antenatal depression.

Dehydroeffusol effectively inhibits human gastric cancer cell-mediated vasculogenic mimicry with low toxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Wenming; Meng, Mei; Zhang, Bin

Accumulated data has shown that various vasculogenic tumor cells, including gastric cancer cells, are able to directly form tumor blood vessels via vasculogenic mimicry, supplying oxygen and nutrients to tumors, and facilitating progression and metastasis of malignant tumors. Therefore, tumor vasculogenic mimicry is a rational target for developing novel anticancer therapeutics. However, effective antitumor vasculogenic mimicry-targeting drugs are not clinically available. In this study, we purified 2,7-dihydroxyl-1-methyl-5-vinyl-phenanthrene, termed dehydroeffusol, from the traditional Chinese medicinal herb Juncus effusus L., and found that dehydroeffusol effectively inhibited gastric cancer cell-mediated vasculogenic mimicry in vitro and in vivo with very low toxicity. Dehydroeffusol significantlymore » suppressed gastric cancer cell adhesion, migration, and invasion. Molecular mechanistic studies revealed that dehydroeffusol markedly inhibited the expression of a vasculogenic mimicry master gene VE-cadherin and reduced adherent protein exposure on the cell surface by inhibiting gene promoter activity. In addition, dehydroeffusol significantly decreased the expression of a key vasculogenic gene matrix metalloproteinase 2 (MMP2) in gastric cancer cells, and diminished MMP2 protease activity. Together, our results showed that dehydroeffusol effectively inhibited gastric cancer cell-mediated vasculogenic mimicry with very low toxicity, suggesting that dehydroeffusol is a potential drug candidate for anti-gastric cancer neovascularization and anti-gastric cancer therapy. - Highlights: • Dehydroeffusol markedly inhibits gastric cancer cell-mediated vasculogenic mimicry. • Dehydroeffusol suppresses the expression of vasculogenic mimicry key gene VE-cadherin. • Dehydroeffusol decreases the MMP2 expression and activity in gastric cancer cells. • Dehydroeffusol is a potential anti-cancer drug candidate with very low toxicity.« less

Developmental Regulation of NO-Mediated VEGF-Induced Effects in the Lung

PubMed Central

Bhandari, Vineet; Choo-Wing, Rayman; Lee, Chun G.; Yusuf, Kamran; Nedrelow, Jonathan H.; Ambalavanan, Namasivayam; Malkus, Herbert; Homer, Robert J.; Elias, Jack A.

2008-01-01

Vascular endothelial growth factor (VEGF) is known to have a pivotal role in lung development and in a variety of pathologic conditions in the adult lung. Our earlier studies have shown that NO is a critical mediator of VEGF-induced vascular and extravascular effects in the adult murine lung. As significant differences have been reported in the cytokine responses in the adult versus the neonatal lung, we hypothesized that there may be significant differences in VEGF-induced alterations in the developing as opposed to the mature lung. Furthermore, nitric oxide (NO) mediation of these VEGF-induced effects may be developmentally regulated. Using a novel externally regulatable lung-targeted transgenic murine model, we found that VEGF-induced pulmonary hemorrhage was mediated by NO-dependent mechanisms in adults and newborns. VEGF enhanced surfactant production in adults as well as increased surfactant and lung development in newborns, via an NO-independent mechanism. While the enhanced survival in hyperoxia in the adult was partly NO-dependent, there was enhanced hyperoxia-induced lung injury in the newborn. In addition, human amniotic fluid VEGF levels correlated positively with surfactant phospholipids. Tracheal aspirate VEGF levels had an initial spike, followed by a decline, and then a subsequent rise, in human neonates with an outcome of bronchopulmonary dysplasia or death. Our data show that VEGF can have injurious as well as potentially beneficial developmental effects, of which some are NO dependent, others NO independent. This opens up the possibility of selective manipulation of any VEGF-based intervention using NO inhibitors for maximal potential clinical benefit. PMID:18441284

Developmental regulation of NO-mediated VEGF-induced effects in the lung.

PubMed

Bhandari, Vineet; Choo-Wing, Rayman; Lee, Chun G; Yusuf, Kamran; Nedrelow, Jonathan H; Ambalavanan, Namasivayam; Malkus, Herbert; Homer, Robert J; Elias, Jack A

2008-10-01

Vascular endothelial growth factor (VEGF) is known to have a pivotal role in lung development and in a variety of pathologic conditions in the adult lung. Our earlier studies have shown that NO is a critical mediator of VEGF-induced vascular and extravascular effects in the adult murine lung. As significant differences have been reported in the cytokine responses in the adult versus the neonatal lung, we hypothesized that there may be significant differences in VEGF-induced alterations in the developing as opposed to the mature lung. Furthermore, nitric oxide (NO) mediation of these VEGF-induced effects may be developmentally regulated. Using a novel externally regulatable lung-targeted transgenic murine model, we found that VEGF-induced pulmonary hemorrhage was mediated by NO-dependent mechanisms in adults and newborns. VEGF enhanced surfactant production in adults as well as increased surfactant and lung development in newborns, via an NO-independent mechanism. While the enhanced survival in hyperoxia in the adult was partly NO-dependent, there was enhanced hyperoxia-induced lung injury in the newborn. In addition, human amniotic fluid VEGF levels correlated positively with surfactant phospholipids. Tracheal aspirate VEGF levels had an initial spike, followed by a decline, and then a subsequent rise, in human neonates with an outcome of bronchopulmonary dysplasia or death. Our data show that VEGF can have injurious as well as potentially beneficial developmental effects, of which some are NO dependent, others NO independent. This opens up the possibility of selective manipulation of any VEGF-based intervention using NO inhibitors for maximal potential clinical benefit.

Chronic Exposure to Anabolic Androgenic Steroids Alters Neuronal Function in the Mammalian Forebrain via Androgen Receptor- and Estrogen Receptor-Mediated Mechanisms

PubMed Central

Penatti, Carlos A A; Porter, Donna M; Henderson, Leslie P

2009-01-01

Anabolic androgenic steroids (AAS) can promote detrimental effects on social behaviors for which γ-aminobutyric acid type A (GABAA) receptor-mediated circuits in the forebrain play a critical role. While all AAS bind to androgen receptors (AR), they may also be aromatized to estrogens and thus potentially impart effects via estrogen receptors (ER). Chronic exposure of wild type male mice to a combination of chemically distinct AAS increased action potential (AP) frequency, selective GABAA receptor subunit mRNAs, and GABAergic synaptic current decay in the medial preoptic area (mPOA). Experiments performed with pharmacological agents and in AR-deficient Tfm mutant mice suggest that the AAS-dependent enhancement of GABAergic transmission in wild type mice is AR-mediated. In AR-deficient mice, the AAS elicited dramatically different effects, decreasing AP frequency, sIPSC amplitude and frequency and the expression of selective GABAA receptor subunit mRNAs. Surprisingly, in the absence of AR signaling, the data indicate that the AAS do not act as ER agonists, but rather suggest a novel in vivo action in which the AAS inhibit aromatase and impair endogenous ER signaling. These results show that the AAS have the capacity to alter neuronal function in the forebrain via multiple steroid signaling mechanisms and suggest that effects of these steroids in the brain will depend not only on the balance of AR- vs. ER-mediated regulation for different target genes, but also on the ability of these drugs to alter steroid metabolism and thus the endogenous steroid milieu. PMID:19812324

Opioid receptor mediated anticonvulsant effect of pentazocine.

PubMed

Khanna, N; Khosla, R; Kohli, J

1998-01-01

Intraperitoneal (i.p.) administration of (+/-) pentazocine (10, 30 & 50 mg/kg), a Sigma opioid agonist, resulted in a dose dependent anticonvulsant action against maximal electroshock seizures in mice. This anticonvulsant effect of pentazocine was not antagonized by both the doses of naloxone (1 and 10 mg/kg) suggesting thereby that its anticonvulsant action is probably mediated by Sigma opiate binding sites. Its anticonvulsant effect was potentiated by both the anticonvulsant drugs viz. diazepam and diphenylhydantoin. Morphine, mu opioid agonist, on the other hand, failed to protect the animals against maximal electroshock seizures when it was given in doses of 10-40 mg/kg body wt.

Potential Health Effects Associated with Dermal Exposure to Occupational Chemicals

PubMed Central

Anderson, Stacey E; Meade, B Jean

2014-01-01

There are a large number of workers in the United States, spanning a variety of occupational industries and sectors, who are potentially exposed to chemicals that can be absorbed through the skin. Occupational skin exposures can result in numerous diseases that can adversely affect an individual’s health and capacity to perform at work. In general, there are three types of chemical–skin interactions of concern: direct skin effects, immune-mediated skin effects, and systemic effects. While hundreds of chemicals (metals, epoxy and acrylic resins, rubber additives, and chemical intermediates) present in virtually every industry have been identified to cause direct and immune-mediated effects such as contact dermatitis or urticaria, less is known about the number and types of chemicals contributing to systemic effects. In an attempt to raise awareness, skin notation assignments communicate the potential for dermal absorption; however, there is a need for standardization among agencies to communicate an accurate description of occupational hazards. Studies have suggested that exposure to complex mixtures, excessive hand washing, use of hand sanitizers, high frequency of wet work, and environmental or other factors may enhance penetration and stimulate other biological responses altering the outcomes of dermal chemical exposure. Understanding the hazards of dermal exposure is essential for the proper implementation of protective measures to ensure worker safety and health. PMID:25574139

Potential health effects associated with dermal exposure to occupational chemicals.

PubMed

Anderson, Stacey E; Meade, B Jean

2014-01-01

There are a large number of workers in the United States, spanning a variety of occupational industries and sectors, who are potentially exposed to chemicals that can be absorbed through the skin. Occupational skin exposures can result in numerous diseases that can adversely affect an individual's health and capacity to perform at work. In general, there are three types of chemical-skin interactions of concern: direct skin effects, immune-mediated skin effects, and systemic effects. While hundreds of chemicals (metals, epoxy and acrylic resins, rubber additives, and chemical intermediates) present in virtually every industry have been identified to cause direct and immune-mediated effects such as contact dermatitis or urticaria, less is known about the number and types of chemicals contributing to systemic effects. In an attempt to raise awareness, skin notation assignments communicate the potential for dermal absorption; however, there is a need for standardization among agencies to communicate an accurate description of occupational hazards. Studies have suggested that exposure to complex mixtures, excessive hand washing, use of hand sanitizers, high frequency of wet work, and environmental or other factors may enhance penetration and stimulate other biological responses altering the outcomes of dermal chemical exposure. Understanding the hazards of dermal exposure is essential for the proper implementation of protective measures to ensure worker safety and health.

Working Alliance and Stages of Change for Employment: The Intermediary Role of Autonomous Motivation, Outcome Expectancy and Vocational Rehabilitation Engagement.

PubMed

Iwanaga, Kanako; Chan, Fong; Tansey, Timothy N; Strauser, David; Ritter, Ellen; Bishop, Malachy; Brooks, Jessica

2018-05-30

Purpose Working alliance is one of the most important common factors for successful counseling/psychotherapy outcomes. Based on the empirical literature about working alliance, it seems that self-determination and self-efficacy theory (SDT/SET) can potentially be used as a motivational model to explain the relationship between working alliance and vocational rehabilitation (VR) outcomes. The purpose of this study is to evaluate three primary SDT/SET constructs, autonomous motivation, expectancy and engagement, as mediators for the relationship between working alliance and stages of change (SOC) for employment. Methods A serial multiple mediation analysis (SMMA) was computed to evaluate autonomy, outcome expectancy, and VR engagement as mediators of the relationship between working alliance and SOC for employment in a sample of 277 people with chronic illness and disability (CID) receiving services from state VR agencies in the United States. Results The SMMA results indicated that working alliance was positively associated with SOC for employment (total effect), while the direct effect between working alliance and SOC for employment was not significant after controlling for the effects of the mediators, indicating significant mediation effects. The mediation effects were estimates of the indirect effects for working alliance on SOC for employment through (a) autonomous motivation, (b) outcome expectancy, (c) VR engagement, and (d) autonomous motivation, outcome expectancy and VR engagement together. Conclusions The results indicated that a strong working alliance has the benefit of helping consumers develop autonomous motivation to work and increasing their vocational outcome expectancy and engagement in VR services, leading to employment.

A multiple mediator analysis approach to quantify the effects of the ADH1B and ALDH2 genes on hepatocellular carcinoma risk.

PubMed

Shih, Stephannie; Huang, Yen-Tsung; Yang, Hwai-I

2018-06-01

Previous work suggested a genetic component affecting the risk of hepatocellular carcinoma (HCC) and mediation analyses have elucidated potential indirect pathways of these genetic effects. Specifically, the effects of alcohol dehydrogenase (ADH1B) and aldehyde dehydrogenase (ALDH2) genes on HCC risk vary based on alcohol consumption habits. However, alcohol consumption may not be the only mediator in the identified pathway: factors related to alcohol consumption may contribute to the same indirect pathway. Thus, we developed a multimediator model to quantify the genetic effects on HCC risk through sequential dichotomous mediators under the counterfactual framework. Our method provided a closed form formula for the mediation effects through different indirect paths, which requires no assumption for the rarity of outcome. In simulation studies of a finite sample, we presented the utility of the method with the variance of the effects estimated using the delta method and bootstrapping. We applied our method to data from participants in Taiwan (580 cases and 3,207 controls) and quantified the mediation effects of single nucleotide polymorphisms (SNPs) in the ADH1B and ALDH2 genes on HCC through alcohol consumption (yes/no) and high alanine transaminase (ALT) levels (greater than or equal to 45 U/L or below 45 U/L). Assuming a dominant risk model, we identified that the SNPs' effects through alcohol consumption is more significant than through ALT levels on HCC risk. This new method provides insight to the magnitude of various casual mechanisms as a closed form solution and can be readily applied in other genomic studies. © 2018 WILEY PERIODICALS, INC.

The effects of perceived racism on psychological distress mediated by venting and disengagement coping in Native Hawaiians.

PubMed

Kaholokula, Joseph Keawe'aimoku; Antonio, Mapuana C K; Ing, Claire K Townsend; Hermosura, Andrea; Hall, Kimberly E; Knight, Rebecca; Wills, Thomas A

2017-01-12

Studies have linked perceived racism to psychological distress via certain coping strategies in several different racial and ethnic groups, but few of these studies included indigenous populations. Elucidating modifiable factors for intervention to reduce the adverse effects of racism on psychological well-being is another avenue to addressing health inequities. We examined the potential mediating effects of 14 distinct coping strategies on the relationship between perceived racism and psychological distress in a community-based sample of 145 Native Hawaiians using structural equation modeling. Perceived racism had a significant indirect effect on psychological distress, mediated through venting and behavioral disengagement coping strategies, with control for age, gender, educational level, and marital status. The findings suggest that certain coping strategies may exacerbate the deleterious effects of racism on a person's psychological well-being. Our study adds Native Hawaiians to the list of U.S. racial and ethnic minorities whose psychological well-being is adversely affected by racism.

Dynamin-related Protein 1 Inhibition Mitigates Bisphenol A-mediated Alterations in Mitochondrial Dynamics and Neural Stem Cell Proliferation and Differentiation*

PubMed Central

Agarwal, Swati; Yadav, Anuradha; Tiwari, Shashi Kant; Seth, Brashket; Chauhan, Lalit Kumar Singh; Khare, Puneet; Ray, Ratan Singh

2016-01-01

The regulatory dynamics of mitochondria comprises well orchestrated distribution and mitochondrial turnover to maintain the mitochondrial circuitry and homeostasis inside the cells. Several pieces of evidence suggested impaired mitochondrial dynamics and its association with the pathogenesis of neurodegenerative disorders. We found that chronic exposure of synthetic xenoestrogen bisphenol A (BPA), a component of consumer plastic products, impaired autophagy-mediated mitochondrial turnover, leading to increased oxidative stress, mitochondrial fragmentation, and apoptosis in hippocampal neural stem cells (NSCs). It also inhibited hippocampal derived NSC proliferation and differentiation, as evident by the decreased number of BrdU- and β-III tubulin-positive cells. All these effects were reversed by the inhibition of oxidative stress using N-acetyl cysteine. BPA up-regulated the levels of Drp-1 (dynamin-related protein 1) and enhanced its mitochondrial translocation, with no effect on Fis-1, Mfn-1, Mfn-2, and Opa-1 in vitro and in the hippocampus. Moreover, transmission electron microscopy studies suggested increased mitochondrial fission and accumulation of fragmented mitochondria and decreased elongated mitochondria in the hippocampus of the rat brain. Impaired mitochondrial dynamics by BPA resulted in increased reactive oxygen species and malondialdehyde levels, disruption of mitochondrial membrane potential, and ATP decline. Pharmacological (Mdivi-1) and genetic (Drp-1siRNA) inhibition of Drp-1 reversed BPA-induced mitochondrial dysfunctions, fragmentation, and apoptosis. Interestingly, BPA-mediated inhibitory effects on NSC proliferation and neuronal differentiations were also mitigated by Drp-1 inhibition. On the other hand, Drp-1 inhibition blocked BPA-mediated Drp-1 translocation, leading to decreased apoptosis of NSC. Overall, our studies implicate Drp-1 as a potential therapeutic target against BPA-mediated impaired mitochondrial dynamics and neurodegeneration in the hippocampus. PMID:27252377

The molecular mechanism underlying the proliferating and preconditioning effect of vitamin C on adipose-derived stem cells.

PubMed

Kim, Ji Hye; Kim, Wang-Kyun; Sung, Young Kwan; Kwack, Mi Hee; Song, Seung Yong; Choi, Joon-Seok; Park, Sang Gyu; Yi, TacGhee; Lee, Hyun-Joo; Kim, Dae-Duk; Seo, Hyun Min; Song, Sun U; Sung, Jong-Hyuk

2014-06-15

Although adipose-derived stem cells (ASCs) show promise for cell therapy, there is a tremendous need for developing ASC activators. In the present study, we investigated whether or not vitamin C increases the survival, proliferation, and hair-regenerative potential of ASCs. In addition, we tried to find the molecular mechanisms underlying the vitamin C-mediated stimulation of ASCs. Sodium-dependent vitamin C transporter 2 (SVCT2) is expressed in ASCs, and mediates uptake of vitamin C into ASCs. Vitamin C increased the survival and proliferation of ASCs in a dose-dependent manner. Vitamin C increased ERK1/2 phosphorylation, and inhibition of the mitogen-activated protein kinase (MAPK) pathway attenuated the proliferation of ASCs. Microarray and quantitative polymerase chain reaction showed that vitamin C primarily upregulated expression of proliferation-related genes, including Fos, E2F2, Ier2, Mybl1, Cdc45, JunB, FosB, and Cdca5, whereas Fos knock-down using siRNA significantly decreased vitamin C-mediated ASC proliferation. In addition, vitamin C-treated ASCs accelerated the telogen-to-anagen transition in C3H/HeN mice, and conditioned medium from vitamin C-treated ASCs increased the hair length and the Ki67-positive matrix keratinocytes in hair organ culture. Vitamin C increased the mRNA expression of HGF, IGFBP6, VEGF, bFGF, and KGF, which may mediate hair growth promotion. In summary, vitamin C is transported via SVCT2, and increased ASC proliferation is mediated by the MAPK pathway. In addition, vitamin C preconditioning enhanced the hair growth promoting effect of ASCs. Because vitamin C is safe and effective, it could be used to increase the yield and regenerative potential of ASCs.

CD10/neutral endopeptidase 24.11 in developing human fetal lung. Patterns of expression and modulation of peptide-mediated proliferation.

PubMed

Sunday, M E; Hua, J; Torday, J S; Reyes, B; Shipp, M A

1992-12-01

The cell membrane-associated enzyme CD10/neutral endopeptidase 24.11 (CD10/NEP) functions in multiple organ systems to downregulate responses to peptide hormones. Recently, CD10/NEP was found to hydrolyze bombesin-like peptides (BLP), which are mitogens for normal bronchial epithelial cells and small cell lung carcinomas. Growth of BLP-responsive small cell lung carcinomas was potentiated by CD10/NEP inhibition, implicating CD10/NEP in regulation of BLP-mediated tumor growth. BLP are also likely to participate in normal lung development because high BLP levels are found in fetal lung, and bombesin induces proliferation and maturation of human fetal lung in organ cultures and murine fetal lung in utero. To explore potential roles for CD10/NEP in regulating peptide-mediated human fetal lung development, we have characterized temporal and cellular patterns of CD10/NEP expression and effects of CD10/NEP inhibition in organ cultures. Peak CD10/NEP transcript levels are identified at 11-13 wk gestation by Northern blots and localized to epithelial cells and mesenchyme of developing airways by in situ hybridization. CD10/NEP immunostaining is most intense in undifferentiated airway epithelium. In human fetal lung organ cultures, inhibition of CD10/NEP with either phosphoramidon or SCH32615 increases thymidine incorporation by 166-182% (P < 0.025). The specific BLP receptor antagonist, [Leu13-psi(CH2NH)Leu14]bombesin abolishes these effects on fetal lung growth, suggesting that CD10/NEP modulates BLP-mediated proliferation. CD10/NEP expression in the growing front of airway epithelium and the effects of CD10/NEP inhibitors in lung explants implicate the enzyme in the regulation of peptide-mediated fetal lung growth.

Potential for Chlorine Gas–induced Injury in the Extrapulmonary Vasculature

PubMed Central

Samal, Andrey; Honovar, Jaideep; White, C. Roger; Patel, Rakesh P.

2010-01-01

Exposure to chlorine gas (Cl2) primarily causes injury to the lung and is characterized by inflammation and oxidative stress mediated by reactive chlorine species. Reducing lung injury and improving respiratory function are the principal therapeutic goals in treating individuals exposed to Cl2 gas. Less is known on the potential for Cl2 gas exposure to cause injury to extrapulmonary tissues and specifically to mediate endothelial dysfunction. This concept is forwarded in this article on the basis that (1) many irritant gases whose reactivity is limited to the lung have now been shown to have effects that promote endothelial dysfunction in the systemic vasculature, and as such lead to the acute and chronic cardiovascular disease events (e.g., myocardial infarctions and atherosclerosis); and (2) that endogenously produced reactive chlorine species are now considered to be central in the development of cardiovascular diseases. This article discusses these two areas with the view of providing a framework in which potential extrapulmonary toxic effects of Cl2 gas exposure may be considered. PMID:20601634

Chemopreventive potential of the tannase-mediated biotransformation of green tea.

PubMed

Macedo, J A; Ferreira, L R; Camara, L E; Santos, J C; Gambero, A; Macedo, G A; Ribeiro, M L

2012-07-15

Green tea (Camellia sinensis) is one of the most widely consumed beverages in the world. The cancer chemopreventive qualities of green tea have been well documented. Epigallocatechin gallate (EGCG) is often described as the most potently chemopreventive green tea catechin; however, the low bioavailability of EGCG is a limiting factor for its biological effect. Thus, the aim of this work was to test the chemopreventive potential of green tea extract and EGCG after tannase-mediated hydrolysis. The results showed that the biotransformed compounds retained most of the beneficial properties of the original compounds, and some beneficial properties were improved in the biotransformed compounds. Biotransformation of EGCG decreased its toxicity without affecting its antiproliferative effects. Furthermore, human cells gene expression profiling showed that the biotransformed compounds modulated the expression of several genes related to carcinogenesis. These results demonstrate the benefits of the biotechnological modification of natural food molecules, allowing the improvement of the nutraceutical potential of a beverage as green tea. Copyright © 2012 Elsevier Ltd. All rights reserved.

Genetic moderators and psychiatric mediators of the link between sexual abuse and alcohol dependence.

PubMed

Copeland, William E; Magnusson, Asa; Göransson, Mona; Heilig, Markus A

2011-06-01

This study used a case-control female sample to test psychiatric mediators and genetic moderators of the effect of sexual abuse on later alcohol dependence. The study also tested differences between alcohol dependent women with or without a history of sexual abuse on variables that might affect treatment planning. A case-control design compared 192 treatment-seeking alcohol dependent women with 177 healthy population controls. All participants were assessed for alcohol-related behaviors, sexual abuse history, psychiatric problems, and personality functioning. Markers were genotyped in the CRHR1, MAO-A and OPRM1 genes. The association of sexual abuse with alcohol dependence was limited to the most severe category of sexual abuse involving anal or vaginal penetration. Of the five psychiatric disorders tested, anxiety, anorexia nervosa, and bulimia met criteria as potential mediators of the abuse-alcohol dependence association. Severe sexual abuse continued to have an independent effect on alcohol dependence status even after accounting for these potential mediators. None of the candidate genetic markers moderated the association between sexual abuse and alcohol dependence. Of alcohol dependent participants, those with a history of severe abuse rated higher on alcoholism severity, and psychiatric comorbidities. Sexual abuse is associated with later alcohol problems directly as well as through its effect on psychiatric problems. Treatment-seeking alcohol dependent women with a history of abuse have distinct features as compared to other alcohol dependent women. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Salinity-mediated cyanogenesis in white clover (Trifolium repens) affects trophic interactions

PubMed Central

Ballhorn, Daniel J.; Elias, Jacob D.

2014-01-01

Background and Aims Increasing soil salinity poses a major plant stress in agro-ecosystems worldwide. Surprisingly little is known about the quantitative effect of elevated salinity on secondary metabolism in many agricultural crops. Such salt-mediated changes in defence-associated compounds may significantly alter the quality of food and forage plants as well as their resistance against pests. In the present study, the effects of soil salinity on cyanogenesis in white clover (Trifolium repens), a forage crop of international importance, are analysed. Methods Experimental clonal plants were exposed to five levels of soil salinity, and cyanogenic potential (HCNp, total amount of accumulated cyanide in a given plant tissue), β-glucosidase activity, soluble protein concentration and biomass production were quantified. The attractiveness of plant material grown under the different salt treatments was tested using cafeteria-style feeding trials with a generalist (grey garden slug, Deroceras reticulatum) and a specialist (clover leaf weevil, Hypera punctata) herbivore. Key Results Salt treatment resulted in an upregulation of HCNp, whereas β-glucosidase activity and soluble protein concentration showed no significant variation among treatments. Leaf area consumption of both herbivore species was negatively correlated with HCNp, indicating bottom-up effects of salinity-mediated changes in HCNp on plant consumers. Conclusions The results suggest that soil salinity leads to an upregulation of cyanogenesis in white clover, which results in enhanced resistance against two different natural herbivores. The potential implications for such salinity-mediated changes in plant defence for livestock grazing remain to be tested. PMID:25006176

Genetic Moderators and Psychiatric Mediators of the link between Sexual Abuse and Alcohol Dependence

PubMed Central

Copeland, William E.; Magnusson, Åsa; Göransson, Mona; Heilig, Markus A.

2011-01-01

Background/Objective This study used a case-control female sample to test psychiatric mediators and genetic moderators of the effect of sexual abuse on later alcohol dependence. The study also tested differences between alcohol dependent women with or without a history of sexual abuse on variables that that might affect treatment planning. Methods A case-control design compared 192 treatment-seeking alcohol dependent women with 177 healthy population controls. All participants were assessed for alcohol-related behaviors, sexual abuse history, psychiatric problems, and personality functioning. Markers were genotyped in the CRHR1, MAO-A and OPRM1 genes. Results The association of sexual abuse with alcohol dependence was limited to the most severe category of sexual abuse involving anal or vaginal penetration. Of the five psychiatric disorders tested, anxiety, anorexia nervosa, and bulimia met criteria as potential mediators of the abuse-alcohol dependence association. Severe sexual abuse continued to have an independent effect on alcohol dependence status even after accounting for these potential mediators. None of the candidate genetic markers moderated the association between sexual abuse and alcohol dependence. Of alcohol dependent participants, those with a history of severe abuse rated higher on alcoholism severity, and psychiatric comorbidities. Conclusion Sexual abuse is associated with later alcohol problems directly as well as through its effect on psychiatric problems. Treatment-seeking alcohol dependent women with a history of abuse have distinct features as compared to other alcohol dependent women. PMID:21193270

Aldosterone and parathyroid hormone interactions as mediators of metabolic and cardiovascular disease.

PubMed

Tomaschitz, Andreas; Ritz, Eberhard; Pieske, Burkert; Rus-Machan, Jutta; Kienreich, Katharina; Verheyen, Nicolas; Gaksch, Martin; Grübler, Martin; Fahrleitner-Pammer, Astrid; Mrak, Peter; Toplak, Hermann; Kraigher-Krainer, Elisabeth; März, Winfried; Pilz, Stefan

2014-01-01

Inappropriate aldosterone and parathyroid hormone (PTH) secretion is strongly linked with development and progression of cardiovascular (CV) disease. Accumulating evidence suggests a bidirectional interplay between parathyroid hormone and aldosterone. This interaction may lead to a disproportionally increased risk of CV damage, metabolic and bone diseases. This review focuses on mechanisms underlying the mutual interplay between aldosterone and PTH as well as their potential impact on CV, metabolic and bone health. PTH stimulates aldosterone secretion by increasing the calcium concentration in the cells of the adrenal zona glomerulosa as a result of binding to the PTH/PTH-rP receptor and indirectly by potentiating angiotensin 2 induced effects. This may explain why after parathyroidectomy lower aldosterone levels are seen in parallel with improved cardiovascular outcomes. Aldosterone mediated effects are inappropriately pronounced in conditions such as chronic heart failure, excess dietary salt intake (relative aldosterone excess) and primary aldosteronism. PTH is increased as a result of (1) the MR (mineralocorticoid receptor) mediated calciuretic and magnesiuretic effects with a trend of hypocalcemia and hypomagnesemia; the resulting secondary hyperparathyroidism causes myocardial fibrosis and disturbed bone metabolism; and (2) direct effects of aldosterone on parathyroid cells via binding to the MR. This adverse sequence is interrupted by mineralocorticoid receptor blockade and adrenalectomy. Hyperaldosteronism due to klotho deficiency results in vascular calcification, which can be mitigated by spironolactone treatment. In view of the documented reciprocal interaction between aldosterone and PTH as well as the potentially ensuing target organ damage, studies are needed to evaluate diagnostic and therapeutic strategies to address this increasingly recognized pathophysiological phenomenon. © 2013.

Cysteine-Accelerated Methanogenic Propionate Degradation in Paddy Soil Enrichment.

PubMed

Zhuang, Li; Ma, Jinlian; Tang, Jia; Tang, Ziyang; Zhou, Shungui

2017-05-01

Propionate degradation is a critical step during the conversion of complex organic matter under methanogenic conditions, and it requires a syntrophic cooperation between propionate-oxidizing bacteria and methanogenic archaea. Increasing evidences suggest that interspecies electron transfer for syntrophic metabolism is not limited to the reducing equivalents of hydrogen and formate. This study tested the ability of an electron shuttle to mediate interspecies electron transfer in syntrophic methanogenesis. We found that cysteine supplementation (100, 400, and 800 μM) accelerated CH 4 production from propionate in paddy soil enrichments. Of the concentrations tested, 100 μM cysteine was the most effective at enhancing propionate degradation to CH 4 , and the rates of CH 4 production and propionate degradation were increased by 109 and 79%, respectively, compared with the cysteine-free control incubations. We eliminated the possibility that the stimulatory effect of cysteine on methanogenesis was attributable to the function of cysteine as a methanogenic substrate in the presence of propionate. The potential catalytic effect involved cysteine serving as an electron carrier to mediate interspecies electron transfer in syntrophic propionate oxidization. The redox potential of cystine/cysteine, which is dependent on the concentration, might be more suitable to facilitate interspecies electron transfer between syntrophic partners at a concentration of 100 μM. Pelotomaculum, obligately syntrophic, propionate-oxidizing bacteria, and hydrogenotrophic methanogens of the family Methanobacteriaceae are predominant in cysteine-mediated methanogenic propionate degradation. The stimulatory effect of cysteine on syntrophic methanogenesis offers remarkable potential for improving the performance of anaerobic digestion and conceptually broaden strategies for interspecies electron transfer in syntrophic metabolism.

Child ADHD severity and positive and negative parenting as predictors of child social functioning: evaluation of three theoretical models.

PubMed

Kaiser, Nina M; McBurnett, Keith; Pfiffner, Linda J

2011-04-01

Prior research has established links between child social functioning and both parenting and child ADHD severity; however, research examining the way that these variables work together is lacking. The current article aims to test three possible models (main effects, mediation, and moderation) by which ADHD severity and positive and negative parenting on the part of both mothers and fathers may work together to predict child social functioning. In a combined sample of children ages 5 to 11 with and without ADHD (N = 143), multiple regression was used to assess: (a) the main effects of ADHD severity and of positive and negative parenting by both mothers and fathers on child social skill and aggressive behavior; (b) parenting as a potential mediator of the relation between ADHD severity and child social skill and aggressive behavior; and (c) ADHD severity as a potential moderator of the relation between parenting and child social skill and aggressive behavior dependent variables. Significant main effects of both ADHD severity and parenting on child social skill and aggression were found. There was some evidence to support parenting (particularly negative parenting) as a mediator of the relation between ADHD severity and child social skill and aggression. There was no evidence of significant moderational effects. Parenting and ADHD severity are independently associated with child social skill and aggressive behavior.To the extent that these associations are causal, multimodal treatment targeting both symptom reduction and improved parenting may be especially effective for the treatment of social problems related to childhood ADHD. Furthermore, evidence for parenting as a mediator of the relation between ADHD severity and child outcomes suggests that changes in child symptoms may also improve parenting practices, thus leading to improved child outcomes.

Potential health hazards from thermal degradation events - Particulate vs. gas phase effects

NASA Technical Reports Server (NTRS)

Oberdorster, Gunter; Ferin, Juraj; Finkelstein, Jacob; Baggs, Raymond; Stavert, D. M.; Lehnert, Bruce E.

1992-01-01

The effect of instillation of ultrafine TiO2 particles (10-nm anatase-TiO2 and 12-nm rutile-TiO2 (administered in doses from 60 to 1000 microg/rat and 500 microg/rat, respectively) on the respiratory tract of exposed rats was compared to the effects of larger (250 nm anatase-TiO2 and 220-nm rutile-TiO2 particles (given in doses 500 or 1000 microg/rat and 500 microg/rat, respectively). These effects were also compared to the effects of inhalation of 20-nm and 250-nm anatase-TiO2 particles and inhalation with surrogate gas phase components (HF and HCl). It was found that ultrafine TiO2 particles induced greater inflammatory reaction in the lung, had greater adverse effect on alveolar macrophage-mediated clearance function, and had a greater potential to induce mediators which can adversely affect other lung cells than did larger-sized particles. Inhalation of surrogate gas phase components caused injury only to the upper respiratory tract, in contrast to the ultrafine particles, which affected the deep lung.

When inflammation and depression go together: The longitudinal effects of parent-child relationships.

PubMed

Beach, Steven R H; Lei, Man Kit; Simons, Ronald L; Barr, Ashley B; Simons, Leslie G; Ehrlich, Katherine; Brody, Gene H; Philibert, Robert A

2017-12-01

Parent-child relationships have long-term effects on health, particularly later inflammation and depression. We hypothesized that these effects would be mediated by later romantic partner relationships and elevated stressors in young adulthood, helping promote chronic, low grade, inflammation as well as depressive symptoms, and driving their covariation. It has been proposed recently that youth experiencing harsher parenting may also develop a stronger association between inflammation and depressive symptoms in adulthood and altered effects of stressors on outcomes. In the current investigation, we test these ideas using an 18-year longitudinal study of N = 413 African American youth that provides assessment of the parent-child relationship (at age 10), pro-inflammatory cytokine profile and depressive symptoms (at age 28), and potential mediators in early young adulthood (assessed at ages 21 and 24). As predicted, the effect of harsher parent-child relationships (age 10) on pro-inflammatory state and increased depressive symptoms at age 28 were fully mediated through young adult stress and romantic partner relationships. In addition, beyond these mediated effects, parent-child relationships at age 10 moderated the concurrent association between inflammation and depressive symptoms, as well as the prospective association between romantic partner relationships and inflammation, and resulted in substantially different patterns of indirect effects from young adult mediators to outcomes. The results support theorizing that the association of depression and inflammation in young adulthood is conditional on earlier parenting, and suggest incorporating this perspective into models predicting long-term health outcomes.

Structural drivers and social protection: mechanisms of HIV risk and HIV prevention for South African adolescents.

PubMed

Cluver, Lucie Dale; Orkin, Frederick Mark; Meinck, Franziska; Boyes, Mark Edward; Sherr, Lorraine

2016-01-01

Social protection is high on the HIV-prevention agenda for youth in sub-Saharan Africa. However, questions remain: How do unconditional cash transfers work? What is the effect of augmenting cash provision with social care? And can "cash plus care" social protection reduce risks for adolescents most vulnerable to infection? This study tackles these questions by first identifying mediated pathways to adolescent HIV risks and then examining potential main and moderating effects of social protection in South Africa. This study was a prospective observational study of 3515 10-to-17-year-olds (56.7% female; 96.8% one-year retention). Within randomly selected census areas in four rural and urban districts in two South African provinces, all homes with a resident adolescent were sampled between 2009/2010 and 2011/2012. Measures included 1) potential structural drivers of HIV infection such as poverty and community violence; 2) HIV risk behaviours; 3) hypothesized psychosocial mediating factors; and 4) types of social protection involving cash and care. Using gender-disaggregated analyses, longitudinal mediation models were tested for potential main and moderating effects of social protection. Structural drivers were associated with increased onset of adolescent HIV risk behaviour (p<0.001, B=0.06, SE=0.01), fully mediated by increased psychosocial problems. Both cash and care aspects of social protection were associated with reductions in HIV risk behaviour and psychosocial deprivations. In addition, cash social protection moderated risk pathways: for adolescent girls and boys experiencing more acute structural deprivation, social protection had the greatest associations with HIV risk prevention (e.g. moderation effects for girls: B=-0.08, p<0.002 between structural deprivation and psychosocial problems, and B=-0.07, p<0.001 between psychosocial problems and HIV risk behaviour). Adolescents with the greatest structural deprivation are at higher risk of HIV, but social protection has the greatest prevention effects for the most vulnerable. Social protection comprising unconditional cash plus care was associated with reduced risk pathways through moderation and main effects, respectively. Our findings suggest the importance of social protection within a combination package of HIV-prevention approaches.

Structural drivers and social protection: mechanisms of HIV risk and HIV prevention for South African adolescents

PubMed Central

Cluver, Lucie Dale; Orkin, Frederick Mark; Meinck, Franziska; Boyes, Mark Edward; Sherr, Lorraine

2016-01-01

Introduction Social protection is high on the HIV-prevention agenda for youth in sub-Saharan Africa. However, questions remain: How do unconditional cash transfers work? What is the effect of augmenting cash provision with social care? And can “cash plus care” social protection reduce risks for adolescents most vulnerable to infection? This study tackles these questions by first identifying mediated pathways to adolescent HIV risks and then examining potential main and moderating effects of social protection in South Africa. Methods This study was a prospective observational study of 3515 10-to-17-year-olds (56.7% female; 96.8% one-year retention). Within randomly selected census areas in four rural and urban districts in two South African provinces, all homes with a resident adolescent were sampled between 2009/2010 and 2011/2012. Measures included 1) potential structural drivers of HIV infection such as poverty and community violence; 2) HIV risk behaviours; 3) hypothesized psychosocial mediating factors; and 4) types of social protection involving cash and care. Using gender-disaggregated analyses, longitudinal mediation models were tested for potential main and moderating effects of social protection. Results Structural drivers were associated with increased onset of adolescent HIV risk behaviour (p<0.001, B=0.06, SE=0.01), fully mediated by increased psychosocial problems. Both cash and care aspects of social protection were associated with reductions in HIV risk behaviour and psychosocial deprivations. In addition, cash social protection moderated risk pathways: for adolescent girls and boys experiencing more acute structural deprivation, social protection had the greatest associations with HIV risk prevention (e.g. moderation effects for girls: B=−0.08, p<0.002 between structural deprivation and psychosocial problems, and B=−0.07, p<0.001 between psychosocial problems and HIV risk behaviour). Conclusions Adolescents with the greatest structural deprivation are at higher risk of HIV, but social protection has the greatest prevention effects for the most vulnerable. Social protection comprising unconditional cash plus care was associated with reduced risk pathways through moderation and main effects, respectively. Our findings suggest the importance of social protection within a combination package of HIV-prevention approaches. PMID:27086838

Core–Shell Nanoparticle-Based Peptide Therapeutics and Combined Hyperthermia for Enhanced Cancer Cell Apoptosis

PubMed Central

2015-01-01

Mitochondria-targeting peptides have garnered immense interest as potential chemotherapeutics in recent years. However, there is a clear need to develop strategies to overcome the critical limitations of peptides, such as poor solubility and the lack of target specificity, which impede their clinical applications. To this end, we report magnetic core–shell nanoparticle (MCNP)-mediated delivery of a mitochondria-targeting pro-apoptotic amphipathic tail-anchoring peptide (ATAP) to malignant brain and metastatic breast cancer cells. Conjugation of ATAP to the MCNPs significantly enhanced the chemotherapeutic efficacy of ATAP, while the presence of targeting ligands afforded selective delivery to cancer cells. Induction of MCNP-mediated hyperthermia further potentiated the efficacy of ATAP. In summary, a combination of MCNP-mediated ATAP delivery and subsequent hyperthermia resulted in an enhanced effect on mitochondrial dysfunction, thus resulting in increased cancer cell apoptosis. PMID:25133971

The mediating sex-specific effect of psychological distress on the relationship between adverse childhood experiences and current smoking among adults

PubMed Central

2012-01-01

Background Research suggests that ACEs have a long-term impact on the behavioral, emotional, and cognitive development of children. These disruptions can lead to adoption of unhealthy coping behaviors throughout the lifespan. The present study sought to examine psychological distress as a potential mediator of sex-specific associations between adverse childhood experiences (ACEs) and adult smoking. Method Data from 7,210 Kaiser-Permanente members in San Diego California collected between April and October 1997 were used. Results Among women, psychological distress mediated a significant portion of the association between ACEs and smoking (21% for emotional abuse, 16% for physical abuse, 15% for physical neglect, 10% for parental separation or divorce). Among men, the associations between ACEs and smoking were not significant. Conclusions These findings suggest that for women, current smoking cessation strategies may benefit from understanding the potential role of childhood trauma. PMID:22788356

Association between social support and post-traumatic stress disorder symptoms among Chinese patients with ovarian cancer: A multiple mediation model

PubMed Central

Liu, Chunli; Zhang, Yi; Jiang, Hong; Wu, Hui

2017-01-01

Post-traumatic stress disorder (PTSD) symptoms can develop after person experiences one or more traumatic events. Little research, however, has been done on PTSD symptoms of patients with ovarian cancer. The present study aimed to estimate the prevalence of PTSD symptoms in patients with ovarian cancer in China; the effects of demographic and clinical variables on PTSD symptoms; multiple mediation roles in the association between social support and PTSD symptoms in patients with ovarian cancer in China. We collected demographic and clinical information of patients with ovarian cancer in the first and second hospitals of China Medical University between January 1, 2014 and December 31, 2015. Qualified patients were asked to complete the Posttraumatic Stress Disorder Checklist-Civilian Version (PCL-C), Duke-UNC Functional Social Support Questionnaire, Herth Hope Index (HHI), and Resilience Scale-14 (RS-14). 201 patients provided responses. We performed hierarchical linear regression to assess the correlation between social support and PTSD symptoms and bootstrapping to test the mediating role of hope and resilience as potential mediators. After controlling demographic and clinical characteristics, social support negatively correlated with PTSD symptoms (β = -0.406, P < 0.01). Social support explained 14.7% of the variance in PTSD symptoms. Hope and resilience explained 17.0% of the variance in PTSD symptoms. The proportion of the hope mediating effect was 43.37% for social support and the proportion of the resilience mediating effect was 10.64% for social support. Hope and resilience partly mediated the correlation between social support and PTSD symptoms despite accounting for different proportions of the mediating effect. Future intervention plans should pay more attention to social support as well as hope and resilience to prevent, relieve and treat PTSD symptoms. PMID:28475593

Association between social support and post-traumatic stress disorder symptoms among Chinese patients with ovarian cancer: A multiple mediation model.

PubMed

Liu, Chunli; Zhang, Yi; Jiang, Hong; Wu, Hui

2017-01-01

Post-traumatic stress disorder (PTSD) symptoms can develop after person experiences one or more traumatic events. Little research, however, has been done on PTSD symptoms of patients with ovarian cancer. The present study aimed to estimate the prevalence of PTSD symptoms in patients with ovarian cancer in China; the effects of demographic and clinical variables on PTSD symptoms; multiple mediation roles in the association between social support and PTSD symptoms in patients with ovarian cancer in China. We collected demographic and clinical information of patients with ovarian cancer in the first and second hospitals of China Medical University between January 1, 2014 and December 31, 2015. Qualified patients were asked to complete the Posttraumatic Stress Disorder Checklist-Civilian Version (PCL-C), Duke-UNC Functional Social Support Questionnaire, Herth Hope Index (HHI), and Resilience Scale-14 (RS-14). 201 patients provided responses. We performed hierarchical linear regression to assess the correlation between social support and PTSD symptoms and bootstrapping to test the mediating role of hope and resilience as potential mediators. After controlling demographic and clinical characteristics, social support negatively correlated with PTSD symptoms (β = -0.406, P < 0.01). Social support explained 14.7% of the variance in PTSD symptoms. Hope and resilience explained 17.0% of the variance in PTSD symptoms. The proportion of the hope mediating effect was 43.37% for social support and the proportion of the resilience mediating effect was 10.64% for social support. Hope and resilience partly mediated the correlation between social support and PTSD symptoms despite accounting for different proportions of the mediating effect. Future intervention plans should pay more attention to social support as well as hope and resilience to prevent, relieve and treat PTSD symptoms.

Anti-allergic activity of 2,4,6-trihydroxy-3-geranylacetophenone (tHGA) via attenuation of IgE-mediated mast cell activation and inhibition of passive systemic anaphylaxis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tan, Ji Wei; Israf, Daud Ahmad; Harith, Hanis Haze

tHGA, a geranyl acetophenone compound originally isolated from a local shrub called Melicope ptelefolia, has been previously reported to prevent ovalbumin-induced allergic airway inflammation in a murine model of allergic asthma by targeting cysteinyl leukotriene synthesis. Mast cells are immune effector cells involved in the pathogenesis of allergic diseases including asthma by releasing cysteinyl leukotrienes. The anti-asthmatic properties of tHGA could be attributed to its inhibitory effect on mast cell degranulation. As mast cell degranulation is an important event in allergic responses, this study aimed to investigate the anti-allergic effects of tHGA in cellular and animal models of IgE-mediated mastmore » cell degranulation. For in vitro model of IgE-mediated mast cell degranulation, DNP-IgE-sensitized RBL-2H3 cells were pre-treated with tHGA before challenged with DNP-BSA to induce degranulation. For IgE-mediated passive systemic anaphylaxis, Sprague Dawley rats were sensitized by intraperitoneal injection of DNP-IgE before challenged with DNP-BSA. Both in vitro and in vivo models showed that tHGA significantly inhibited the release of preformed mediators (β-hexosaminidase and histamine) as well as de novo mediators (interleukin-4, tumour necrosis factor-α, prostaglandin D{sub 2} and leukotriene C{sub 4}). Pre-treatment of tHGA also prevented IgE-challenged RBL-2H3 cells and peritoneal mast cells from undergoing morphological changes associated with mast cell degranulation. These findings indicate that tHGA possesses potent anti-allergic activity via attenuation of IgE-mediated mast cell degranulation and inhibition of IgE-mediated passive systemic anaphylaxis. Thus, tHGA may have the potential to be developed as a mast cell stabilizer for the treatment of allergic diseases in the future. - Highlights: • The in vitro and in vivo mast cell stabilizing effects of tHGA were examined. • tHGA counteracts the plasma membrane deformation in degranulating mast cells. • tHGA attenuates preformed and de novo mediators released by degranulating mast cells. • tHGA prevents in vivo mast cell activation and passive systemic anaphylaxis in rats. • tHGA could be a potential mast cell stabilizer for the treatment of allergic diseases.« less

Influence of testosterone on synaptic transmission in the rat medial vestibular nuclei: estrogenic and androgenic effects.

PubMed

Grassi, S; Frondaroli, A; Di Mauro, M; Pettorossi, V E

2010-12-15

In brainstem slices of young male rat, we investigated the influence of the neuroactive steroid testosterone (T) on the synaptic responses by analyzing the field potential evoked in the medial vestibular nucleus (MVN) by vestibular afferent stimulation. T induced three distinct and independent long-term synaptic changes: fast long-lasting potentiation (fLP), slow long-lasting potentiation (sLP) and long-lasting depression (LD). The fLP was mediated by 17β-estradiol (E(2)) since it was abolished by blocking the estrogen receptors (ERs) or the enzyme converting T to E(2). Conversely, sLP and LD were mediated by 5α-dihydrotestosterone (DHT) since they were prevented by blocking the androgen receptors (ARs) or the enzyme converting T to DHT. Therefore, the synaptic effects of T were mediated by its androgenic or estrogenic metabolites. The pathways leading to estrogenic and androgenic conversion of T might be co-localized since, the occurrence of fLP under block of androgenic pathway, and that of sLP and LD under estrogenic block, were higher than those observed without blocks. In case of co-localization, the effect on synaptic transmission should depend on the prevailing enzymatic activity. We conclude that circulating and neuronal T can remarkably influence synaptic responses of the vestibular neurons in different and opposite ways, depending on its conversion to estrogenic or androgenic metabolites. Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

Is Andrographis paniculata extract and andrographolide anaphylactic?

PubMed

Richard, Edwin Jothie; Murugan, Sasikumar; Bethapudi, Bharathi; Illuri, Ramanaiah; Mundkinajeddu, Deepak; Chinampudur Velusami, Chandrasekaran

2017-01-01

Andrographis paniculata, "King of bitters" is a popularly known medicinal plant extensively used in many parts of the world for treatment of various diseases. Since recent past, anaphylactic/allergic type adverse events were reported upon A. paniculata usage, the study aimed to evaluate the anaphylactic and anaphylactoid potential of A. paniculata extract and andrographolide (a major phytoactive of A. paniculata ). The anaphylactic potential was evaluated using active systemic anaphylaxis (ASA) assay in guinea pigs. Further, the release of allergic mediators was measured in immunoglobulin E (IgE) sensitized and non-IgE sensitized Rat Basophilic Leukemia (RBL-2H3) cell lines in-vitro . A. paniculata extract or andrographolide sensitized guinea pigs following the challenge antigen administration orally and intravenously did not demonstrate any clinical signs of anaphylaxis. IgE sensitized and non- IgE sensitized RBL-2H3 cells treated with A. paniculata extract did not induce release of allergic mediators. Whereas IgE sensitized and non- IgE sensitized RBL-2H3 cells treated with andrographolide demonstrated mild to moderate release of allergic mediators. A. paniculata extract has no anaphylactic and anaphylactoid potential in in-vivo and in-vitro studies. Whereas, andrographolide effects on allergic mediators in in-vitro studies needs to be scrutinized if they are of biologically important.

Mother Involvement as an Influence on Father Involvement with Early Adolescents

PubMed Central

Pleck, Joseph H.; Hofferth, Sandra L.

2009-01-01

This study hypothesized that father involvement is influenced by mothers' level of involvement as well as by marital conflict, mothers' work hours, and fathers' status as biological or step father. The analysis also tested hypotheses about mother involvement as a potential mediator of the effects of marital conflict and maternal work hours on father involvement, and hypotheses about factors influencing mother involvement. Children aged 10-14 from the NLSY79 who resided with their biological or step father and with their mother reported on each parent's involvement with them. As hypothesized, father involvement was predicted by mother involvement, and the reciprocal influence was not significant. Father involvement was associated with low marital conflict and being a biological father. Mothers' involvement partially mediated the effects of marital conflict on father involvement. If the mediating role of maternal involvement is not taken into account, the effect of marital conflict on father involvement is overestimated. PMID:21776195

Life stress and symptoms of anxiety and depression in women after cancer: The mediating effect of stress appraisal and coping.

PubMed

Seib, Charrlotte; Porter-Steele, Janine; Ng, Shu-Kay; Turner, Jane; McGuire, Amanda; McDonald, Nicole; Balaam, Sarah; Yates, Patsy; McCarthy, Alexandra; Anderson, Debra

2018-04-06

This paper examines the direct and intermediary relationships between life stress, stress appraisal, and resilience, and increased anxiety and depressive symptoms in Australian women after cancer treatment. Data examined from 278 women aged 18 years and older previously treated for breast, gynaecological, or blood cancer, participating in the Australian Women's Wellness after Cancer Program. Serial mediation models interrogated the effect of stressful life events (List of Threatening Experiences-Modified) mediated by appraisal and coping (Perceived Stress Scale and Connor-Davidson Resilience Scale), on symptoms of anxiety and depression (Zung Self-rating Anxiety Scale and Center for Epidemiologic Studies Depression Scale). Over one-quarter (30.2%) of participants reported 1 or more stressful life events, other than their cancer, in the previous 6 months. Results indicate that perceived stress fully mediated the relationships between life stress, anxiety (indirect effect = 0.09, Bias-corrected bootstrap 95% CI 0.02-0.18, Percent mediation = 0.51), and depressive symptoms (indirect effect = 0.11, Bias-corrected bootstrap 95% CI 0.02-0.23, Percent mediation = 0.71) and accounted for more than half of the relationship between predictor and outcome. Findings indicate that stress appraisal mediated the relationship between past life stressors and anxiety and depressive symptoms. This analysis also highlights the need to consider wellness within a broader care context to identify potentially vulnerable patients to possibly avert future health concerns. Copyright © 2018 John Wiley & Sons, Ltd.

Interdependence of depressive symptoms, school involvement, and academic performance between adolescent friends: A dyadic analysis.

PubMed

Chow, Chong Man; Tan, Cin Cin; Buhrmester, Duane

2015-09-01

Friendships play an important role in the development of school involvement and academic performance during adolescence. This study examined the interdependence of depressive symptoms, school involvement, and academic performance between adolescent same-sex friends. Using cross-sectional data, we examined whether the link between depressive symptoms and academic performance would be mediated by school involvement at the intrapersonal (actor) and interpersonal (partner) levels. Data came from 155 pairs of same-sex adolescent friends (80 boys; M(age) = 16.17, SD = 0.44). The actor-partner interdependence model was used to examine the dyadic data and mediation hypotheses. Mediated actor effects showed that adolescents who had more depressive symptoms reported lower academic performance, and such an association was mediated by their own and their friend's lower school involvement. Mediated partner effects showed that adolescents who had more depressive symptoms also had a friend with lower academic performance, and such an association was mediated by both individuals' lower school involvement. This study provided evidence to support the broader interpersonal framework for understanding school involvement and academic performance. The current findings also have potential practical implications, especially for programmes targeted at addressing adolescents' school problems. © 2015 The British Psychological Society.

Interdependence of Depressive Symptoms, School Involvement, and Academic Performance between Adolescent Friends: A Dyadic Analysis

PubMed Central

Chow, Chong Man; Tan, Cin Cin; Buhrmester, Duane

2015-01-01

Background Friendships play an important role in the development of school involvement and academic performance during adolescence. This study examined the interdependence of depressive symptoms, school involvement, and academic performance between adolescent same-sex friends. Aims Using cross-sectional data, we examined whether the link between depressive symptoms and academic performance would be mediated by school involvement at the intrapersonal (actor) and interpersonal (partner) levels. Sample Data came from 155 pairs of same-sex adolescent friends (80 boys; Mage = 16.17, SD = .44). The Actor-Partner Interdependence Model (APIM) was used to examine the dyadic data and mediation hypotheses. Results Mediated actor effects showed that adolescents who had more depressive symptoms reported lower academic performance, and such an association was mediated by their own and their friend’s lower school involvement. Mediated partner effects showed that adolescents who had more depressive symptoms also had a friend with lower academic performance, and such an association was mediated by both individuals’ lower school involvement. Conclusions This study provided evidence to support the broader interpersonal framework for understanding school involvement and academic performance. The current findings also have potential practical implications, especially for programs targeted at addressing adolescents’ school problems. PMID:25858014

Coping Skills Are Associated With Gastrointestinal Symptom Severity and Somatization in Patients With Irritable Bowel Syndrome.

PubMed

Wilpart, Katarina; Törnblom, Hans; Svedlund, Jan; Tack, Jan F; Simrén, Magnus; Van Oudenhove, Lukas

2017-10-01

Coping resources and processes are altered in patients with irritable bowel syndrome (IBS). We investigated the relationship between coping resources and gastrointestinal (GI) and extraintestinal symptom severity in patients with IBS and potential mediators of this relationship. We performed a cross-sectional study of 216 patients with IBS attending a secondary/tertiary care specialized outpatient center in Sweden from 2003 through 2007. We collected data on coping resources, levels of anxiety (general and GI specific), depressive symptoms, levels of GI symptoms, and extraintestinal somatic symptoms (somatization) by administering validated self-report questionnaires. General Linear Models were used to assess associations and mediation. GI symptoms: low levels of physical coping resources (practice of activities that are beneficial for health; P = .0016), high levels of general anxiety symptoms (P = .033), and GI-specific anxiety symptoms (P < .0001), but not depressive symptoms (P = .89), were independently associated with GI symptom levels (R 2  = 0.31). Anxiety and GI-specific anxiety partially mediated the effect of physical coping. Somatization: low levels of physical coping resources (P = .003), high levels of anxiety (P = .0147), depressive (P = .0005), and GI-specific anxiety symptoms (P = .06) were associated with somatization levels (R 2  = 0.35). Levels of general and GI-specific anxiety and depressive symptoms partially mediated this physical coping effect. The effect of psychological coping resources (including optimism, social support, and accepting/expressing emotions) on somatization levels was not significant (P = .98), but was fully mediated by levels of anxiety and depressive symptoms, and partially by levels of GI-specific anxiety symptoms. In a cross-sectional study of patients with IBS in Sweden, we found associations of levels of coping resources with GI and extraintestinal symptom severity; these associations were mediated by levels of anxiety and depressive symptoms. Although confirmation in longitudinal studies is needed, this identifies coping as a potential psychological treatment target in IBS. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Household food insecurity is associated with higher child undernutrition in Bangladesh, Ethiopia, and Vietnam, but the effect is not mediated by child dietary diversity.

PubMed

Ali, Disha; Saha, Kuntal K; Nguyen, Phuong H; Diressie, Michael T; Ruel, Marie T; Menon, Purnima; Rawat, Rahul

2013-12-01

Household food insecurity (HFI) is a recognized underlying determinant of child undernutrition, but evidence of associations between HFI and child undernutrition is mixed. The purpose of this study was to investigate if HFI is associated with undernutrition in children aged 6-59.9 mo in Bangladesh (n = 2356), Ethiopia (n = 3422), and Vietnam (n = 3075) and if child dietary diversity (DD) mediated this effect. We used baseline survey data from the Alive & Thrive project. Logistic regression, adjusting for potential confounding factors, was used to determine the magnitude and significance of the association of HFI with stunting, underweight, and wasting. The mediating effect of child DD was tested by using a Sobel-Goodman mediation test. The prevalences of HFI were 66%, 40%, and 32% in Ethiopia, Vietnam, and Bangladesh, respectively. The prevalences of stunting, underweight, and wasting were higher in Bangladesh (47.1%, 43.7%, and 19.1%, respectively) and Ethiopia (50.7%, 27.5%, and 5.9%, respectively) than in Vietnam (20.7%, 15.8%, and 5%, respectively). In the adjusted models, the odds of being stunted or underweight were significantly higher for children in severely food-insecure households in Bangladesh (stunting OR: 1.36; 95% CI: 1.05, 1.76; underweight OR: 1.28; 95% CI: 0.99, 1.65) and Ethiopia (stunting OR: 1.48; 95% CI: 1.09, 2.00; underweight OR: 1.68; 95% CI: 1.22, 2.30) and in moderately food-insecure households in Vietnam (stunting OR: 1.39; 95% CI: 1.16, 1.65; underweight OR: 1.69; 95% CI: 1.28, 2.23). HFI was significantly associated with wasting in Bangladesh where close to 1 in 5 children demonstrated wasting. Child DD did not mediate the relation between HFI and undernutrition in any of the countries. Further research is recommended to investigate potential mediators in this pathway.

The effects of anxiety and depression on stress-related growth among Chinese army recruits: Resilience and coping as mediators.

PubMed

Yu, Yongju; Peng, Li; Liu, Botao; Liu, Yunbo; Li, Min; Chen, Long; Xie, Junrun; Li, Jing; Li, Jiawen

2016-09-01

Stress-related growth can occur after various traumas or stressful events. In order to investigate how anxiety and depression relate to stress-related growth, this study was conducted with 443 Chinese army recruits who had just finished a 3-month recruit training program. Path analyses revealed that resilience and positive/negative coping partially mediated the effect of anxiety on perceived stress-related growth, while negative coping fully mediated the relationship between depression and perceived stress-related growth. Moreover, positive coping partially carried the influence of resilience on perceived stress-related growth. Anxiety and depression may be potential targets for intervention to enhance the development of stress-related growth among Chinese army recruits. © The Author(s) 2015.

Deleterious Effects of a Low Amount of Ethanol on LTP-Like Plasticity in Human Cortex

PubMed Central

Lücke, Caroline; Heidegger, Tonio; Röhner, Mirjam; Toennes, Stefan W; Krivanekova, Lucia; Müller-Dahlhaus, Florian; Ziemann, Ulf

2014-01-01

Ingesting ethanol (EtOH) at low doses during social drinking is a common human behavior for its facilitating effects on social interactions. However, low-dose EtOH may have also detrimental effects that so far are underexplored. Here we sought to test the effects of low-dose EtOH on long-term potentiation (LTP)-like plasticity in human motor cortex. Previous cellular experiments showed that low-dose EtOH potentiates extrasynaptic GABAAR and reduces NMDAR-mediated currents, processes that would limit the expression of LTP. Paired associative transcranial magnetic stimulation (PASLTP) was employed in nine healthy subjects for induction of LTP-like plasticity, indexed by a long-term increase in motor-evoked potential input–output curves. Synaptic α1-GABAAR function was measured by saccadic peak velocity (SPV). Very low doses of EtOH (resulting in blood concentrations of <5 mM) suppressed LTP-like plasticity but did not affect SPV when compared with a placebo condition. In contrast, 1 mg of alprazolam, a classical benzodiazepine, or 10 mg of zolpidem, a non-benzodiazepine hypnotic, decreased SPV but did not significantly affect LTP-like plasticity when compared with placebo. This double dissociation of low-dose EtOH vs alprazolam/zolpidem effects is best explained by the putatively high affinity of EtOH but not alprazolam/zolpidem to extrasynaptic GABAARs and to NMDARs. Findings suggest that enhancement of extrasynaptic GABAAR-mediated tonic inhibition and/or reduction of NMDAR-mediated neurotransmission by EtOH blocks LTP-like plasticity in human cortex at very low doses that are easily reached during social drinking. Therefore, low-dose EtOH may jeopardize LTP-dependent processes, such as learning and memory formation. PMID:24385131

Pathway Linking Internet Health Information Seeking to Better Health: A Moderated Mediation Study.

PubMed

Jiang, Shaohai; Street, Richard L

2017-08-01

The Internet increasingly has been recognized as an important medium with respect to population health. However, little is known about the mechanisms that underlie the potential impact of health-related Internet use on health outcomes. Based on the three-stage model of health promotion using interactive media, this study empirically tested a moderated mediation pathway model. Results showed that the effect of Internet health information seeking on three health outcomes (general, emotional, and physical) was completely mediated by respondents' access to social support resources. In addition, users' online health information seeking experience positively moderated this mediation path. The findings have significant theoretical and practical implications for the design of Internet-based health promotion resources to improve health outcomes.

Role of Rho/ROCK and p38 MAP kinase pathways in transforming growth factor-beta-mediated Smad-dependent growth inhibition of human breast carcinoma cells in vivo.

PubMed

Kamaraju, Anil K; Roberts, Anita B

2005-01-14

TGF-beta is a multifunctional cytokine known to exert its biological effects through a variety of signaling pathways of which Smad signaling is considered to be the main mediator. At present, the Smad-independent pathways, their interactions with each other, and their roles in TGF-beta-mediated growth inhibitory effects are not well understood. To address these questions, we have utilized a human breast cancer cell line MCF10CA1h and demonstrate that p38 MAP kinase and Rho/ROCK pathways together with Smad2 and Smad3 are necessary for TGF-beta-mediated growth inhibition of this cell line. We show that Smad2/3 are indispensable for TGF-beta-mediated growth inhibition, and that both p38 and Rho/ROCK pathways affect the linker region phosphorylation of Smad2/3. Further, by using Smad3 mutated at the putative phosphorylation sites in the linker region, we demonstrate that phosphorylation at Ser203 and Ser207 residues is required for the full transactivation potential of Smad3, and that these residues are targets of the p38 and Rho/ROCK pathways. We demonstrate that activation of the p38 MAP kinase pathway is necessary for the full transcriptional activation potential of Smad2/Smad3 by TGF-beta, whereas activity of Rho/ROCK is necessary for both down-regulation of c-Myc protein and up-regulation of p21waf1 protein, directly interfering with p21waf1 transcription. Our results not only implicate Rho/ROCK and p38 MAPK pathways as necessary for TGF-beta-mediated growth inhibition, but also demonstrate their individual contributions and the basis for their cooperation with each other.

Cisplatin-tethered gold nanospheres for multimodal chemo-radiotherapy of glioblastoma

NASA Astrophysics Data System (ADS)

Setua, Sonali; Ouberai, Myriam; Piccirillo, Sara G.; Watts, Colin; Welland, Mark

2014-08-01

Glioblastoma multiforme (GBM) remains the most aggressive and challenging brain tumour to treat. We report the first successful chemo-radiotherapy on patient derived treatment resistant GBM cells using a cisplatin-tethered gold nanosphere. After intracellular uptake, the nanosphere effects DNA damage which initiates caspase-mediated apoptosis in those cells. In the presence of radiation, both gold and platinum of cisplatin, serve as high atomic number radiosensitizers leading to the emission of ionizing photoelectrons and Auger electrons. This resulted in enhanced synergy between cisplatin and radiotherapy mediated cytotoxicity, and photo/Auger electron mediated radiosensitisation leading to complete ablation of the tumour cells in an in vitro model system. This study demonstrates the potential of designed nanoparticles to target aggressive cancers in the patient derived cell lines providing a platform to move towards treatment strategies.Glioblastoma multiforme (GBM) remains the most aggressive and challenging brain tumour to treat. We report the first successful chemo-radiotherapy on patient derived treatment resistant GBM cells using a cisplatin-tethered gold nanosphere. After intracellular uptake, the nanosphere effects DNA damage which initiates caspase-mediated apoptosis in those cells. In the presence of radiation, both gold and platinum of cisplatin, serve as high atomic number radiosensitizers leading to the emission of ionizing photoelectrons and Auger electrons. This resulted in enhanced synergy between cisplatin and radiotherapy mediated cytotoxicity, and photo/Auger electron mediated radiosensitisation leading to complete ablation of the tumour cells in an in vitro model system. This study demonstrates the potential of designed nanoparticles to target aggressive cancers in the patient derived cell lines providing a platform to move towards treatment strategies. Electronic supplementary information (ESI) available: Additional figures. See DOI: 10.1039/c4nr03693j

Anti-inflammatory effects of traditional mixed extract of medicinal herbs (MEMH) on monosodium urate crystal-induced gouty arthritis.

PubMed

Nam, Ju-Suk; Jagga, Supriya; Sharma, Ashish Ranjan; Lee, Joon-Hee; Park, Jong Bong; Jung, Jun-Sub; Lee, Sang-Soo

2017-08-01

Korean oriental medicine prescription is widely used for the treatment of gouty diseases. In the present study, we investigated anti-inflammatory effects of modified Korean herbal formulation, mixed extract of medicinal herbs (MEMH), and its modulatory effects on inflammatory mediators associated with gouty arthritis. Both in vitro and in vivo studies were carried out to assess the anti-inflammatory efficacy of MEMH on monosodium urate (MSU) crystals-induced gouty inflammation. MSU crystals stimulated human chondrosarcoma cell line, SW1353, and human primary chondrocytes were treated with MEMH in vitro. The expression levels of pro-inflammatory mediators and metalloproteases were analyzed. The effect of MEMH on NFκB signaling pathway in SW1353 cells was examined. Effect of MEMH on the mRNA expression level of pro-inflammatory mediators and chemotactic factor from human monocytic cell line, THP-1, was also analyzed. The probable role of MEMH in the differentiation process of osteoblast like cells, SaOS-2, after MSU treatment was also observed. To investigate the effects of MEMH in vivo, MSU crystals-induced ankle arthritic model was established. Histopathological changes in affected joints and plasma levels of pro-inflammatory mediators (IL-1β and TNFα) were recorded. MEMH inhibited NFκB signaling pathway and COX-2 protein expression in chondrocytes. MSU-induced mRNA expressions of pro-inflammatory mediators and chemotactic cytokines were suppressed by MEMH. In MSU crystals-induced ankle arthritic mouse model, administration of MEMH relieved inflammatory symptoms and decreased the plasma levels of IL-1β and TNFα. The results indicated that MEMH can effectively inhibit the expression of inflammatory mediators in gouty arthritis, demonstrating its potential for treating gouty arthritis. Copyright © 2017 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

Mediation and spillover effects in group-randomized trials: a case study of the 4Rs educational intervention

PubMed Central

VanderWeele, Tyler J.; Hong, Guanglei; Jones, Stephanie M.; Brown, Joshua L.

2013-01-01

Peer influence and social interactions can give rise to spillover effects in which the exposure of one individual may affect outcomes of other individuals. Even if the intervention under study occurs at the group or cluster level as in group-randomized trials, spillover effects can occur when the mediator of interest is measured at a lower level than the treatment. Evaluators who choose groups rather than individuals as experimental units in a randomized trial often anticipate that the desirable changes in targeted social behaviors will be reinforced through interference among individuals in a group exposed to the same treatment. In an empirical evaluation of the effect of a school-wide intervention on reducing individual students’ depressive symptoms, schools in matched pairs were randomly assigned to the 4Rs intervention or the control condition. Class quality was hypothesized as an important mediator assessed at the classroom level. We reason that the quality of one classroom may affect outcomes of children in another classroom because children interact not simply with their classmates but also with those from other classes in the hallways or on the playground. In investigating the role of class quality as a mediator, failure to account for such spillover effects of one classroom on the outcomes of children in other classrooms can potentially result in bias and problems with interpretation. Using a counterfactual conceptualization of direct, indirect and spillover effects, we provide a framework that can accommodate issues of mediation and spillover effects in group randomized trials. We show that the total effect can be decomposed into a natural direct effect, a within-classroom mediated effect and a spillover mediated effect. We give identification conditions for each of the causal effects of interest and provide results on the consequences of ignoring “interference” or “spillover effects” when they are in fact present. Our modeling approach disentangles these effects. The analysis examines whether the 4Rs intervention has an effect on children's depressive symptoms through changing the quality of other classes as well as through changing the quality of a child's own class. PMID:23997375

Mediation Analysis of the Efficacy of the Eban HIV/STD Risk-Reduction Intervention for African American HIV Serodiscordant Couples.

PubMed

El-Bassel, Nabila; Jemmott, John B; Bellamy, Scarlett L; Pequegnat, Willo; Wingood, Gina M; Wyatt, Gail E; Landis, J Richard; Remien, Robert H

2016-06-01

Targeting couples is a promising behavioral HIV risk-reduction strategy, but the mechanisms underlying the effects of such interventions are unknown. We report secondary analyses testing whether Social-Cognitive-Theory variables mediated the Eban HIV-risk-reduction intervention's effects on condom-use outcomes. In a multisite randomized controlled trial conducted in four US cities, 535 African American HIV-serodiscordant couples were randomized to the Eban HIV risk-reduction intervention or attention-matched control intervention. Outcomes were proportion condom-protected sex, consistent condom use, and frequency of unprotected sex measured pre-, immediately post-, and 6 and 12 months post-intervention. Potential mediators included Social-Cognitive-Theory variables: outcome expectancies and self-efficacy. Mediation analyses using the product-of-coefficients approach in a generalized-estimating-equations framework revealed that condom-use outcome expectancy, partner-reaction outcome expectancy, intention, self-efficacy, and safer-sex communication improved post-intervention and mediated intervention-induced improvements in condom-use outcomes. These findings underscore the importance of targeting outcome expectancies, self-efficacy, and safer-sex communication in couples-level HIV risk-reduction interventions.

Core self-evaluation and burnout among Nurses: the mediating role of coping styles.

PubMed

Li, Xiaofei; Guan, Lili; Chang, Hui; Zhang, Bo

2014-01-01

This study aimed to determine the potential association between core self-evaluation and the burnout syndrome among Chinese nurses, and the mediating role of coping styles in this relationship. A cross-sectional survey was conducted in Shenyang, China, from May to July, 2013. A questionnaire which consisted of the Maslach Burnout Inventory-General Survey (MBI-GS), the Core Self-Evaluation Scale (CSE), and the Simplified Coping Style Questionnaire (CSQ), was completed by a total of 1,559 nurses. Hierarchical linear regression analyses and the Sobel test were performed to determine the mediating role of coping styles on the relationship between CSE and burnout. Nurses who had higher self-evaluation characteristics, reported less emotional exhaustion and cynicism, and higher professional efficacy. Coping style had a partial mediating effect on the relationship between CSE and the burnout syndrome among nurses. Core self-evaluation had effects on burnout and coping style was a mediating factor in this relationship among Chinese nurses. Therefore, the improvement of coping strategies may be helpful in the prevention of burnout among nurses, thus enhancing professional performance.

Core Self-Evaluation and Burnout among Nurses: The Mediating Role of Coping Styles

PubMed Central

Li, Xiaofei; Guan, Lili; Chang, Hui; Zhang, Bo

2014-01-01

Objectives This study aimed to determine the potential association between core self-evaluation and the burnout syndrome among Chinese nurses, and the mediating role of coping styles in this relationship. Methods A cross-sectional survey was conducted in Shenyang, China, from May to July, 2013. A questionnaire which consisted of the Maslach Burnout Inventory-General Survey (MBI-GS), the Core Self-Evaluation Scale (CSE), and the Simplified Coping Style Questionnaire (CSQ), was completed by a total of 1,559 nurses. Hierarchical linear regression analyses and the Sobel test were performed to determine the mediating role of coping styles on the relationship between CSE and burnout. Results Nurses who had higher self-evaluation characteristics, reported less emotional exhaustion and cynicism, and higher professional efficacy. Coping style had a partial mediating effect on the relationship between CSE and the burnout syndrome among nurses. Conclusions Core self-evaluation had effects on burnout and coping style was a mediating factor in this relationship among Chinese nurses. Therefore, the improvement of coping strategies may be helpful in the prevention of burnout among nurses, thus enhancing professional performance. PMID:25541990

Dendritic sodium spikes are required for long-term potentiation at distal synapses on hippocampal pyramidal neurons

PubMed Central

Kim, Yujin; Hsu, Ching-Lung; Cembrowski, Mark S; Mensh, Brett D; Spruston, Nelson

2015-01-01

Dendritic integration of synaptic inputs mediates rapid neural computation as well as longer-lasting plasticity. Several channel types can mediate dendritically initiated spikes (dSpikes), which may impact information processing and storage across multiple timescales; however, the roles of different channels in the rapid vs long-term effects of dSpikes are unknown. We show here that dSpikes mediated by Nav channels (blocked by a low concentration of TTX) are required for long-term potentiation (LTP) in the distal apical dendrites of hippocampal pyramidal neurons. Furthermore, imaging, simulations, and buffering experiments all support a model whereby fast Nav channel-mediated dSpikes (Na-dSpikes) contribute to LTP induction by promoting large, transient, localized increases in intracellular calcium concentration near the calcium-conducting pores of NMDAR and L-type Cav channels. Thus, in addition to contributing to rapid neural processing, Na-dSpikes are likely to contribute to memory formation via their role in long-lasting synaptic plasticity. DOI: http://dx.doi.org/10.7554/eLife.06414.001 PMID:26247712

Antitumor effect of novel gallium compounds and efficacy of nanoparticle-mediated gallium delivery in lung cancer.

PubMed

Wehrung, Daniel; Oyewumi, Moses O

2012-02-01

The widespread application of gallium (Ga) in cancer therapy has been greatly hampered by lack of specificity resulting in poor tumor accumulation and retention. To address the challenge, two lipophilic gallium (III) compounds (gallium hexanedione; GaH and gallium acetylacetonate; GaAcAc) were synthesized and antitumor studies were conducted in human lung adenocarcinoma (A549) cells. Nanoparticles (NPs) containing various concentrations of the Ga compounds were prepared using a binary mixture of Gelucire 44/14 and cetyl alcohol as matrix materials. NPs were characterized based on size, morphology, stability and biocompatibility. Antitumor effects of free or NP-loaded Ga compounds were investigated based on cell viability, production of reactive oxygen species and reduction of mitochondrial potential. Compared to free Ga compounds, cytotoxicity of NP-loaded Ga (5-150 microg/ml) was less dependent on concentration and incubation time (exposure) with A549 cells. NP-mediated delivery (5-150 microg Ga/ml) enhanced antitumor effects of Ga compounds and the effect was pronounced at: (i) shorter incubation times; and (ii) at low concentrations of gallium (approximately 50 microg/ml) (p < 0.0006). Additional studies showed that NP-mediated Ga delivery was not dependent on transferrin receptor uptake mechanism (p > 0.13) suggesting the potential in overcoming gallium resistance in some tumors. In general, preparation of stable and biocompatible NPs that facilitated Ga tumor uptake and antitumor effects could be effective in gallium-based cancer therapy.

The mediating effect of caregiver burden on the caregivers' quality of life.

PubMed

Jeong, Yeon-Gyu; Jeong, Yeon-Jae; Kim, Won-Cheol; Kim, Jeong-Soo

2015-05-01

[Purpose] Quality of life (QoL) can be closely related to caregiver burden, which may be a potential mediating effect on the relationships among stroke patient caregivers. This study investigated the predictors of caregiver's QoL based on patient and caregiver characteristics, with caregiver burden as a mediator. [Methods] This study was conducted using surveys, a literature review, and interviews. Survey data were collected from 238 subjects, who were diagnosed with stroke, and their family caregivers from October 2013 to April 2014. [Results] Caregiver health status, income, spouses caring for patients, and duration of hospitalization were identified as significant predictors of caregivers' QoL with a mediating effect of caregiver burden. The time spent on caregiving per day and patient education level were the only direct predictors of caregivers' QoL. [Conclusion] The responsibility of caring for patients with stroke, in particular for a spouse, must be administered by means of a holistic family-centered rehabilitation program. In addition, financial support and availability of various health and social service programs must be comprehensively provided in order to maintain caregivers' well-being.

Business cycles, hypertension and cardiovascular disease: evidence from the Icelandic economic collapse.

PubMed

Asgeirsdottir, Tinna Laufey; Olafsdottir, Thorhildur; Ragnarsdottir, Dagny Osk

2014-08-01

Business cycles affect people's lives. A growing literature examines their effect on health outcomes. The available studies on the relationship between ambient economic conditions and cardiovascular health show mixed results. They are furthermore limited in their outcome measures, focusing mostly on mortality. We examined the relationship between economic conditions and cardiovascular disease and hypertension, using the Icelandic economic collapse of 2008. Logit regression analyses are used to examine the relationship between economic conditions and the probability of reporting a cardiovascular disease or hypertension. We furthermore investigated potential mediators of this relationship. The data used come from a health and lifestyle survey carried out by the Public Health Institute of Iceland in 2007 and 2009. The crisis was positively related to hypertension in males but no statistically significant relationship was found for females. The mediation analyses indicated partial mediation through changes in working hours and stress level, but negligible mediation through changes in income. The male hypertension was, however, suppressed by concurrent changes in smoking and body weight. Only examining mortality effects of society-wide economic conditions may understate the overall effect on cardiovascular health.

Potassium iodide potentiates antimicrobial photodynamic inactivation mediated by Rose Bengal: in vitro and in vivo studies

NASA Astrophysics Data System (ADS)

Wen, Xiang; Zhang, Xiaoshen; Szewczyk, Grzegorz; ElHussien, Ahmed; Huang, Ying-Ying; Sarna, Tadeusz; Hamblin, Michael R.

2018-02-01

Rose Bengal (RB) is a halogenated xanthene dye that has been used to mediate antimicrobial photodynamic inactivation. While highly active against Gram-positive bacteria, RB is largely inactive in killing Gram-negative bacteria. We have discovered that addition of the non-toxic salt potassium iodide (100mM) potentiates green light (540nm)-mediated killing by up to six extra logs with Gramnegative bacteria Escherichia coli and Pseudomonas aeruginosa,Gram-positive methicillin resistant Staphylococcus aureus, and fungal yeast Candida albicans. The mechanism is proposed to be singlet oxygen addition to iodide anion to form peroxyiodide, which decomposes into radicals, finally forms hydrogen peroxide and molecular iodine. The effects of these different bactericidal species can be teased apart by comparing killing in three different scenarios: (1) cells+RB+KI are mixed together then illuminated with green light; (2) cells+RB are centrifuged then KI added then green light; (3) RB+KI+green light then cells added after light. We showed that KI could potentiate RBPDT in a mouse model of skin abrasions infected with bioluminescent P.aeruginosa.

Using structural equation modeling to investigate relationships among ecological variables

USGS Publications Warehouse

Malaeb, Z.A.; Kevin, Summers J.; Pugesek, B.H.

2000-01-01

Structural equation modeling is an advanced multivariate statistical process with which a researcher can construct theoretical concepts, test their measurement reliability, hypothesize and test a theory about their relationships, take into account measurement errors, and consider both direct and indirect effects of variables on one another. Latent variables are theoretical concepts that unite phenomena under a single term, e.g., ecosystem health, environmental condition, and pollution (Bollen, 1989). Latent variables are not measured directly but can be expressed in terms of one or more directly measurable variables called indicators. For some researchers, defining, constructing, and examining the validity of latent variables may be the end task of itself. For others, testing hypothesized relationships of latent variables may be of interest. We analyzed the correlation matrix of eleven environmental variables from the U.S. Environmental Protection Agency's (USEPA) Environmental Monitoring and Assessment Program for Estuaries (EMAP-E) using methods of structural equation modeling. We hypothesized and tested a conceptual model to characterize the interdependencies between four latent variables-sediment contamination, natural variability, biodiversity, and growth potential. In particular, we were interested in measuring the direct, indirect, and total effects of sediment contamination and natural variability on biodiversity and growth potential. The model fit the data well and accounted for 81% of the variability in biodiversity and 69% of the variability in growth potential. It revealed a positive total effect of natural variability on growth potential that otherwise would have been judged negative had we not considered indirect effects. That is, natural variability had a negative direct effect on growth potential of magnitude -0.3251 and a positive indirect effect mediated through biodiversity of magnitude 0.4509, yielding a net positive total effect of 0.1258. Natural variability had a positive direct effect on biodiversity of magnitude 0.5347 and a negative indirect effect mediated through growth potential of magnitude -0.1105 yielding a positive total effects of magnitude 0.4242. Sediment contamination had a negative direct effect on biodiversity of magnitude -0.1956 and a negative indirect effect on growth potential via biodiversity of magnitude -0.067. Biodiversity had a positive effect on growth potential of magnitude 0.8432, and growth potential had a positive effect on biodiversity of magnitude 0.3398. The correlation between biodiversity and growth potential was estimated at 0.7658 and that between sediment contamination and natural variability at -0.3769.

Microbial mitigation-exacerbation continuum: a novel framework for microbiome effects on hosts in the face of stress.

PubMed

David, Aaron S; Thapa-Magar, Khum B; Afkhami, Michelle E

2018-03-01

A key challenge to understanding microbiomes and their role in ecological processes is contextualizing their effects on host organisms, particularly when faced with environmental stress. One influential theory, the Stress Gradient Hypothesis, might predict that the frequency of positive interactions increases with stressful conditions such that microbial taxa would mitigate harmful effects on host performance. Yet, equally plausible is that microbial taxa could exacerbate these effects. Here, we introduce the Mitigation-Exacerbation Continuum as a novel framework to conceptualize microbial mediation of stress. We (1) use this continuum to quantify microbial mediation of stress for six plant species and (2) test the association between these continuum values and natural species' abundance. We factorially manipulated a common stress (allelopathy) and the presence of soil microbes to quantify microbial effects in benign and stressed environments for two critical early life-history metrics, seed germination and seedling biomass. Although we found evidence of both mitigation and exacerbation among the six species, exacerbation was more common. Across species, the degree of microbial-mediated effects on germination explained >80% of the variation of natural field abundances. Our results suggest a critical role of soil microbes in mediating plant stress responses, and a potential microbial mechanism underlying species abundance. © 2018 by the Ecological Society of America.

Does Anger Regulation Mediate the Discrimination-Mental Health Link among Mexican-Origin Adolescents? A Longitudinal Mediation Analysis Using Multilevel Modeling

PubMed Central

Park, Irene J. K.; Wang, Lijuan; Williams, David R.; Alegría, Margarita

2016-01-01

Although prior research has consistently documented the association between racial/ethnic discrimination and poor mental health outcomes, the mechanisms that underlie this link are still unclear. The present three-wave longitudinal study tested the mediating role of anger regulation in the discrimination—mental health link among 269 Mexican-origin adolescents (Mage = 14.1 years, SD = 1.6; 57% girls), 12 – 17 years old. Three competing anger regulation variables were tested as potential mediators: outward anger expression, anger suppression, and anger control. Longitudinal mediation analyses were conducted using multilevel modeling that disaggregated within-person effects from between-person effects. Results indicated that outward anger expression was a significant mediator; anger suppression and anger control were not significant mediators. Within a given individual, greater racial/ethnic discrimination was associated with more frequent outward anger expression. In turn, more frequent outward anger expression was associated with higher levels of anxiety and depression at a given time point. Gender, age, and nativity status were not significant moderators of the hypothesized mediation models. By identifying outward anger expression as an explanatory mechanism in the discrimination-distress link among Latino youths, this study points to a malleable target for prevention and intervention efforts aimed at mitigating the detrimental impact of racism on Latino youths’ mental health during the developmentally critical period of adolescence. PMID:27893238

Bystander Effect Induced by Electroporation is Possibly Mediated by Microvesicles and Dependent on Pulse Amplitude, Repetition Frequency and Cell Type.

PubMed

Prevc, Ajda; Bedina Zavec, Apolonija; Cemazar, Maja; Kloboves-Prevodnik, Veronika; Stimac, Monika; Todorovic, Vesna; Strojan, Primoz; Sersa, Gregor

2016-10-01

Bystander effect, a known phenomenon in radiation biology, where irradiated cells release signals which cause damage to nearby, unirradiated cells, has not been explored in electroporated cells yet. Therefore, our aim was to determine whether bystander effect is present in electroporated melanoma cells in vitro, by determining viability of non-electroporated cells exposed to medium from electroporated cells and by the release of microvesicles as potential indicators of the bystander effect. Here, we demonstrated that electroporation of cells induces bystander effect: Cells exposed to electric pulses mediated their damage to the non-electroporated cells, thus decreasing cell viability. We have shown that shedding microvesicles may be one of the ways used by the cells to mediate the death signals to the neighboring cells. The murine melanoma B16F1 cell line was found to be more electrosensitive and thus more prone to bystander effect than the canine melanoma CMeC-1 cell line. In B16F1 cell line, bystander effect was present above the level of electropermeabilization of the cells, with the threshold at 800 V/cm. Furthermore, with increasing electric field intensities and the number of pulses, the bystander effect also increased. In conclusion, electroporation can induce bystander effect which may be mediated by microvesicles, and depends on pulse amplitude, repetition frequency and cell type.

Autophagy-mediated degradation of IAPs and c-FLIP L potentiates apoptosis induced by combination of TRAIL and Chal-24

DOE PAGES

Xu, Jennings; Xu, Xiuling; Shi, Shaoqing; ...

2015-11-02

Combination chemotherapy is an effective strategy for increasing anticancer efficacy, reducing side effects and alleviating drug resistance. In this paper, we report that combination of the recently identified novel chalcone derivative, chalcone-24 (Chal-24), and TNF-related apoptosis-inducing ligand (TRAIL) significantly increases cytotoxicity in lung cancer cells. Chal-24 treatment significantly enhanced TRAIL-induced activation of caspase-8 and caspase-3, and the cytotoxicity induced by combination of these agents was effectively suppressed by the pan-caspase inhibitor z-VAD-fmk. Chal-24 and TRAIL combination suppressed expression of cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein large (c-FLIPL) and cellular inhibitor of apoptosis proteins (c-IAPs), and ectopic expression of c-FLIPL andmore » c-IAPs inhibited the potentiated cytotoxicity. In addition, TRAIL and Chal-24 cooperatively activated autophagy. Suppression of autophagy effectively attenuated cytotoxicity induced by Chal-24 and TRAIL combination, which was associated with attenuation of c-FLIPL and c-IAPs degradation. In conclusion, these results suggest that Chal-24 potentiates the anticancer activity of TRAIL through autophagy-mediated degradation of c-FLIPL and c-IAPs, and that combination of Chal-24 and TRAIL could be an effective approach in improving chemotherapy efficacy.« less

Health effects of unemployment in Europe (2008-2011): a longitudinal analysis of income and financial strain as mediating factors.

PubMed

Tøge, Anne Grete

2016-05-06

Unemployment has a number of negative consequences, such as decreased income and poor self-rated health. However, the relationships between unemployment, income, and health are not fully understood. Longitudinal studies have investigated the health effect of unemployment and income separately, but the mediating role of income remains to be scrutinized. Using longitudinal data and methods, this paper investigates whether the effect of unemployment on self-rated health (SRH) is mediated by income, financial strain and unemployment benefits. The analyses use data from the longitudinal panel of European Union Statistics on Income and Living Conditions (EU-SILC) over the 4 years of 2008 to 2011. Individual fixed effects models are applied, estimating the longitudinal change in SRH as people move from employment to unemployment, and investigating whether this change is reduced after controlling for possible mediating mechanisms, absolute income change, relative income change, relative income rank, income deprivation, financial strain, and unemployment benefits. Becoming unemployed is associated with decreased SRH (-0.048, SE 0.012). This decrease is 19 % weaker (-0.039, SE 0.010) after controlling for change in financial strain. Absolute and relative changes in household equalized income, as well as changes in relative rank and transitions into income deprivation, are not found to be associated with change in SRH. Financial strain is found to be a potential mediator of the individual health effect of unemployment, while neither absolute income, relative income, relative rank, income deprivation nor unemployment benefits are found to be mediators of this relationship.

Mechanistic studies of cancer cell mitochondria- and NQO1-mediated redox activation of beta-lapachone, a potentially novel anticancer agent

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Jason Z.; Ke, Yuebin; Misra, Hara P.

Beta-lapachone (beta-Lp) derived from the Lapacho tree is a potentially novel anticancer agent currently under clinical trials. Previous studies suggested that redox activation of beta-Lp catalyzed by NAD(P)H:quinone oxidoreductase 1 (NQO1) accounted for its killing of cancer cells. However, the exact mechanisms of this effect remain largely unknown. Using chemiluminescence and electron paramagnetic resonance (EPR) spin-trapping techniques, this study for the first time demonstrated the real-time formation of ROS in the redox activation of beta-lapachone from cancer cells mediated by mitochondria and NQO1 in melanoma B16–F10 and hepatocellular carcinoma HepG2 cancer cells. ES936, a highly selective NQO1 inhibitor, and rotenone,more » a selective inhibitor of mitochondrial electron transport chain (METC) complex I were found to significantly block beta-Lp meditated redox activation in B16–F10 cells. In HepG2 cells ES936 inhibited beta-Lp-mediated oxygen radical formation by ∼ 80% while rotenone exerted no significant effect. These results revealed the differential contribution of METC and NQO1 to beta-lapachone-induced ROS formation and cancer cell killing. In melanoma B16–F10 cells that do not express high NQO1 activity, both NOQ1 and METC play a critical role in beta-Lp redox activation. In contrast, in hepatocellular carcinoma HepG2 cells expressing extremely high NQO1 activity, redox activation of beta-Lp is primarily mediated by NQO1 (METC plays a minor role). These findings will contribute to our understanding of how cancer cells are selectively killed by beta-lapachone and increase our ability to devise strategies to enhance the anticancer efficacy of this potentially novel drug while minimizing its possible adverse effects on normal cells. - Highlights: • Both isolated mitochondria and purified NQO1 are able to generate ROS by beta-Lp. • The differential roles of mitochondria and NQO1 in mediating redox activation of beta-Lp • In cancer cells with low NQO1 expression, mitochondria play a critical role in beta-Lp redox activation. • In cancer cells with high NQO1 activity, redox activation of beta-Lp is primarily mediated by NQO1.« less

Design of organic dyes and cobalt polypyridine redox mediators for high-efficiency dye-sensitized solar cells.

PubMed

Feldt, Sandra M; Gibson, Elizabeth A; Gabrielsson, Erik; Sun, Licheng; Boschloo, Gerrit; Hagfeldt, Anders

2010-11-24

Dye-sensitized solar cells (DSCs) with cobalt-based mediators with efficiencies surpassing the record for DSCs with iodide-free electrolytes were developed by selecting a suitable combination of a cobalt polypyridine complex and an organic sensitizer. The effect of the steric properties of two triphenylamine-based organic sensitizers and a series of cobalt polypyridine redox mediators on the overall device performance in DSCs as well as on transport and recombination processes in these devices was compared. The recombination and mass-transport limitations that, previously, have been found to limit the performance of these mediators were avoided by matching the properties of the dye and the cobalt redox mediator. Organic dyes with higher extinction coefficients than the standard ruthenium sensitizers were employed in DSCs in combination with outer-sphere redox mediators, enabling thinner TiO(2) films to be used. Recombination was reduced further by introducing insulating butoxyl chains on the dye rather than on the cobalt redox mediator, enabling redox couples with higher diffusion coefficients and more suitable redox potential to be used, simultaneously improving the photocurrent and photovoltage of the device. Optimization of DSCs sensitized with a triphenylamine-based organic dye in combination with tris(2,2'-bipyridyl)cobalt(II/III) yielded solar cells with overall conversion efficiencies of 6.7% and open-circuit potentials of more than 0.9 V under 1000 W m(-2) AM1.5 G illumination. Excellent performance was also found under low light intensity indoor conditions.

Prosociality and negative emotionality mediate the association of serotonin transporter genotype with childhood ADHD and ODD.

PubMed

Brammer, Whitney A; Lee, Steve S

2013-01-01

Although there is evidence that the promoter polymorphism of the serotonin transporter (5-HTTLPR) gene is associated with attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD), the pathways underlying these associations are largely unknown. Given their theoretical and biological plausibility, we tested whether individual differences in key temperament dimensions (i.e., prosociality, negative emotionality, daring) constituted potential pathways from 5-HTTLPR to ADHD and ODD. Using a well-characterized sample of 194 six to nine-year-old children with and without ADHD, we utilized multiple mediation procedures with bootstrapping to evaluate prosociality, negative emotionality, and daring as independent mediators of 5-HTTLPR with separate parent and teacher ratings of ADHD and ODD. Controlling for ODD, prosociality and negative emotionality significantly mediated the association of 5-HTTLPR and parent-reported ADHD. Similarly, controlling for ADHD, prosociality and negative emotionality each uniquely mediated the association of 5-HTTLPR and parent-reported ODD. For teacher-reported ADHD, prosociality significantly mediated the association of 5-HTTLPR (controlling for ODD) whereas controlling for ODD, negative emotionality significantly mediated the prediction of teacher-reported ODD from 5-HTTLPR. Specifically, the number of 5-HTTLPR long alleles was inversely associated with prosociality and positively associated with negative emotionality; prosociality was inversely associated and negative emotionality was positively associated with ADHD and ODD. We consider the role of temperament in genetically sensitive designs as well as its potential value in the development and delivery of effective interventions.

Interacting effects of sunlight, agriculturally derived dissolved organic matter and reactive oxygen species on fecal indicator bacteria growth dynamics

EPA Science Inventory

Bacterial survival in agriculturally impacted surface waters is dependent on resource availability and also on potential resource transformations, mediated by biotic and abiotic processes. In this study, we focused on the effect of sunlight irradiated cattle fecal extract (CFE) a...

Isolation, Synthesis, and Antisepsis Effects of a C-Methylcoumarinochromone Isolated from Abronia nana Cell Culture.

PubMed

Lee, Wonhwa; Lee, Doohyun; Lee, Yuri; Lee, Taeho; Song, Kyung-Sik; Yang, Eun-Ju; Bae, Jong-Sup

2018-05-25

Only a few isoflavones have been isolated from plants of the genus Abronia. The biological properties of compounds isolated from Abronia species have not been well established, and their antisepsis effects have not been reported yet. In the present study, a new C-methylcoumarinochromone, was isolated from Abronia nana suspension cultures. Its structure was deduced as 9,11-dihydroxy-10-methylcoumarinochromone (boeravinone Y, 1) by spectroscopic data analysis and verified by chemical synthesis. The potential inhibitory effects of 1 against high mobility group box 1 (HMGB1)-mediated septic responses were investigated. Results showed that 1 effectively inhibited lipopolysaccharide-induced release of HMGB1 and suppressed HMGB1-mediated septic responses, in terms of reduction of hyperpermeability, leukocyte adhesion and migration, and cell adhesion molecule expression. In addition, 1 increased the phagocytic activity of macrophages and exhibited bacterial clearance effects in the peritoneal fluid and blood of mice with cecal ligation and puncture-induced sepsis. Collectively, these results suggested that 1 might have potential therapeutic activity against various severe vascular inflammatory diseases via inhibition of the HMGB1 signaling pathway.

Understanding the Relationship between Rainstorm-Related Experiences and PTSD among Chinese Adolescents after Rainstorm Disaster: The Roles of Rumination and Social Support.

PubMed

Zhen, Rui; Quan, Lijuan; Yao, Benxian; Zhou, Xiao

2016-01-01

Posttraumatic stress disorder (PTSD) is prevalent among adolescents following natural disasters, and the trauma experiences represent a critical risk factor for PTSD. Nevertheless, the underlying mechanism of adolescents' PTSD following trauma experiences remains unclear. Rumination appears to be a mediating factor between trauma experiences and PTSD, and social support may moderate this mediating relationship between trauma experiences, rumination, and PTSD, but few studies have examined these assumptions. Thus, this study aimed to assess the mediating role of rumination and the moderating role of social support in the relationship between rainstorm-related experiences and PTSD among adolescents, following a rainstorm in China. Nine hundred and fifty-one middle school students completed self-report questionnaires, and structural equation modeling was conducted to examine the potential moderated mediation effect. Rainstorm-related experiences had a direct and positive effect on PTSD, and also indirectly influenced PTSD via rumination. Moreover, social support work to buffer the direct effect of rainstorm-related experiences on PTSD, but not the effect of rumination on PTSD. Implications for clinical practice and research are discussed along with study limitations.

Understanding the Relationship between Rainstorm-Related Experiences and PTSD among Chinese Adolescents after Rainstorm Disaster: The Roles of Rumination and Social Support

PubMed Central

Zhen, Rui; Quan, Lijuan; Yao, Benxian; Zhou, Xiao

2016-01-01

Posttraumatic stress disorder (PTSD) is prevalent among adolescents following natural disasters, and the trauma experiences represent a critical risk factor for PTSD. Nevertheless, the underlying mechanism of adolescents’ PTSD following trauma experiences remains unclear. Rumination appears to be a mediating factor between trauma experiences and PTSD, and social support may moderate this mediating relationship between trauma experiences, rumination, and PTSD, but few studies have examined these assumptions. Thus, this study aimed to assess the mediating role of rumination and the moderating role of social support in the relationship between rainstorm-related experiences and PTSD among adolescents, following a rainstorm in China. Nine hundred and fifty-one middle school students completed self-report questionnaires, and structural equation modeling was conducted to examine the potential moderated mediation effect. Rainstorm-related experiences had a direct and positive effect on PTSD, and also indirectly influenced PTSD via rumination. Moreover, social support work to buffer the direct effect of rainstorm-related experiences on PTSD, but not the effect of rumination on PTSD. Implications for clinical practice and research are discussed along with study limitations. PMID:27695436

Suppressive Effects of Pelargonidin on Endothelial Protein C Receptor Shedding via the Inhibition of TACE Activity and MAP Kinases.

PubMed

Kang, Hyejin; Lee, Taeho; Bae, Jong-Sup

2016-01-01

Beyond its role in the activation of protein C, the endothelial cell protein C receptor (EPCR) plays an important role in the cytoprotective pathway. EPCR can be shed from the cell surface, which is mediated by tumor necrosis factor-[Formula: see text] converting enzyme (TACE). Pelargonidin is a well-known red pigment found in plants, and has been reported to have important biological activities that are potentially beneficial to human health. However, little is known about the effects of pelargonidin on EPCR shedding. We investigated this issue by monitoring the effects of pelargonidin on phorbol-12-myristate 13-acetate (PMA)-, tumor necrosis factor (TNF)-[Formula: see text]-, interleukin (IL)-1β-, and cecal ligation and puncture (CLP)-mediated EPCR shedding and by investigating the underlying mechanism of pelargonidin action. Data demonstrate that pelargonidin induced potent inhibition of PMA-, TNF-[Formula: see text]-, IL-1β-, and CLP-induced EPCR shedding by inhibiting the phosphorylation of mitogen-activated protein kinases (MAPKs) such as p38, janus kinase (JNK), and extracellular signal-regulated kinase (ERK) 1/2. Pelargonidin also inhibited the expression and activity of PMA-induced TACE in endothelial cells. These results demonstrate the potential of pelargonidin as an anti-EPCR shedding reagent against PMA- and CLP-mediated EPCR shedding.

The potential role of meaning in life in the relationship between bullying victimization and suicidal ideation.

PubMed

Henry, Kimberly L; Lovegrove, Peter J; Steger, Michael F; Chen, Peter Y; Cigularov, Konstantin P; Tomazic, Rocco G

2014-02-01

Adolescent bullying is a common problem in schools across America. The consequences of bullying are significant, and can include severe psychological trauma and suicide. A better understanding of the mechanisms that link bullying and suicidal ideation is needed in order to develop effective prevention and intervention initiatives. Meaning in life is a potential mechanism that has not been studied in this context. It was hypothesized that meaning in life could serve as both a mediator and a moderator of the relationship between bullying victimization and suicidal ideation. As a mediator, meaning in life is considered to explain why bullying victimization leads to suicidal ideation. As a moderator, meaning in life is considered to buffer the ill effect of bullying victimization on suicidal ideation. Data collected from an ethnically diverse sample of 2,936 (50% female), 6th-12th grade students from one urban school district in the Northeastern US were used to examine the hypotheses. The model for girls was consistent with mediation (i.e., meaning in life may explain how victimization leads to suicidal ideation). The model for boys was consistent with moderation (i.e., the ill effect of victimization on suicidal ideation was attenuated as meaning in life increased). Implications for prevention are discussed.

Valproic Acid Induces Endocytosis-Mediated Doxorubicin Internalization and Shows Synergistic Cytotoxic Effects in Hepatocellular Carcinoma Cells

PubMed Central

Saha, Subbroto Kumar; Yin, Yingfu; Kim, Kyeongseok; Yang, Gwang-Mo; Abdal Dayem, Ahmed; Choi, Hye Yeon; Cho, Ssang-Goo

2017-01-01

Valproic acid (VPA), a well-known histone deacetylase (HDAC) inhibitor, is used as an anti-cancer drug for various cancers, but the synergistic anti-cancer effect of VPA and doxorubicin (DOX) combination treatment and its potential underlying mechanism in hepatocellular carcinoma (HCC) remain to be elucidated. Here, we evaluate the mono- and combination-therapy effects of VPA and DOX in HCC and identify a specific and efficient, synergistic anti-proliferative effect of the VPA and DOX combination in HCC cells, especially HepG2 cells; this effect was not apparent in MIHA cells, a normal hepatocyte cell line. The calculation of the coefficient of drug interaction confirmed the significant synergistic effect of the combination treatment. Concurrently, the synergistic apoptotic cell death caused by the VPA and DOX combination treatment was confirmed by Hoechst nuclear staining and Western blot analysis of caspase-3 and poly (ADP-ribose) polymerase (PARP) activation. Co-treatment with VPA and DOX enhanced reactive oxygen species (ROS) generation and autophagy, which were clearly attenuated by ROS and autophagy inhibitors, respectively. Furthermore, as an indication of the mechanism underlying the synergistic effect, we observed that DOX internalization, which was induced in the VPA and DOX combination-treated group, occurred via by the caveolae-mediated endocytosis pathway. Taken together, our study uncovered the potential effect of the VPA and DOX combination treatment with regard to cell death, including induction of cellular ROS, autophagy, and the caveolae-mediated endocytosis pathway. Therefore, these results present novel implications in drug delivery research for the treatment of HCC. PMID:28498322

I say a little prayer for you: praying for partner increases commitment in romantic relationships.

PubMed

Fincham, Frank D; Beach, Steven R H

2014-10-01

Partner-focused petitionary prayer (PFPP) has received little attention in the prayer literature. In two studies, we examine PFPP to see whether it is uniquely important in conveying relationship benefits, whether its benefits are transmitted through an effect on relationship satisfaction, and whether one's own or the partner's PFPP is central to beneficial effects. In Study 1, we examined PFPP in a sample of 316 undergraduate students who were in an "exclusive" romantic relationship, finding that PFPP was related to later level of commitment and that this relationship was partially mediated through enhanced relationship satisfaction. Study 2 examined PFPP in a sample of 205, married African American couples, finding that both partners' PFPP was consequential for commitment, with actor effects partially mediated through relationship quality, and partner effects fully mediated. Together the studies suggest the value of continued investigation of PFPP as a potentially important vehicle for enhancing relationship outcomes. (PsycINFO Database Record (c) 2014 APA, all rights reserved).

Yeast Model Uncovers Dual Roles of Mitochondria in the Action of Artemisinin

PubMed Central

Li, Wei; Mo, Weike; Shen, Dan; Sun, Libo; Wang, Juan; Lu, Shan; Gitschier, Jane M; Zhou, Bing

2005-01-01

Artemisinins, derived from the wormwood herb Artemisia annua, are the most potent antimalarial drugs currently available. Despite extensive research, the exact mode of action of artemisinins has not been established. Here we use yeast, Saccharamyces cerevisiae, to probe the core working mechanism of this class of antimalarial agents. We demonstrate that artemisinin's inhibitory effect is mediated by disrupting the normal function of mitochondria through depolarizing their membrane potential. Moreover, in a genetic study, we identify the electron transport chain as an important player in artemisinin's action: Deletion of NDE1 or NDI1, which encode mitochondrial NADH dehydrogenases, confers resistance to artemisinin, whereas overexpression of NDE1 or NDI1 dramatically increases sensitivity to artemisinin. Mutations or environmental conditions that affect electron transport also alter host's sensitivity to artemisinin. Sensitivity is partially restored when the Plasmodium falciparum NDI1 ortholog is expressed in yeast ndi1 strain. Finally, we showed that artemisinin's inhibitory effect is mediated by reactive oxygen species. Our results demonstrate that artemisinin's effect is primarily mediated through disruption of membrane potential by its interaction with the electron transport chain, resulting in dysfunctional mitochondria. We propose a dual role of mitochondria played during the action of artemisinin: the electron transport chain stimulates artemisinin's effect, most likely by activating it, and the mitochondria are subsequently damaged by the locally generated free radicals. PMID:16170412

Dopaminergic Modulation of Excitatory Transmission in the Anterior Cingulate Cortex of Adult Mice

PubMed Central

Darvish-Ghane, Soroush; Yamanaka, Manabu

2016-01-01

Dopamine (DA) possesses potent neuromodulatory properties in the central nervous system. In the anterior cingulate cortex, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPAR) are key ion channels in mediating nerve injury induced long-term potentiation (LTP) and chronic pain phenotype. In the present study, we reported the effects of DA on glutamate mediated excitatory post-synaptic currents (EPSCs) in pyramidal neurons of layer II/III of the ACC in adult mice. Bath application of DA (50 μM) caused a significant, rapid and reversible inhibition of evoked EPSCs (eEPSC). This inhibitory effect is dose-related and was absent in lower concentration of DA (5 μM). Furthermore, selective postsynaptic application of GDP-β-S (1.6 mM) in the internal solution completely abolished the inhibitory effects of DA (50 μM). We also investigated modulation of spontaneous EPSCs (sEPSCs) and TTX sensitive, miniature EPSCs (mEPSCs) by DA. Our results indicated mixed effects of potentiation and inhibition of frequency and amplitude for sEPSCs and mEPSCs. Furthermore, high doses of SCH23390 (100 μM) and sulpiride (100 μM) revealed that, inhibition of eEPSCs is mediated by postsynaptic D2-receptors (D2R). Our finding posits a pre- and postsynaptic mode of pyramidal neuron EPSC modulation in mice ACC by DA. PMID:27317578

Zinc oxide nanoparticles mediated cytotoxicity, mitochondrial membrane potential and level of antioxidants in presence of melatonin.

PubMed

Sruthi, S; Millot, N; Mohanan, P V

2017-10-01

Zinc oxide nanoparticles (ZnO NPs) are widely used in a variety of products and are currently being investigated for biomedical applications. However, they have the potential to interact with macromolecules like proteins, lipids and DNA within the cells which makes the safe biomedical application difficult. The toxicity of the ZnO NP is mainly attributed reactive oxygen species (ROS) generation. Different strategies like iron doping, polymer coating and external supply of antioxidants have been evaluated to minimize the toxic potential of ZnO NPs. Melatonin is a hormone secreted by the pineal gland with great antioxidant properties. The melatonin is known to protect cells from ROS inducing external agents like lipopolysaccharides. In the present study, the protective effect of melatonin on ZnO NPs mediated toxicity was evaluated using C6 glial cells. The Cytotoxicity, mitochondrial membrane potential and free radical formation were measured to study the effect of melatonin. Antioxidant assays were done on mice brain slices, incubated with melatonin and ZnO NPs. The results of the study reveal that, instead of imparting a protective effect, the melatonin pre-treatment enhanced the toxicity of ZnO NPs. Melatonin increased antioxidant enzymes in brain slices. Copyright © 2017 Elsevier B.V. All rights reserved.

Chondro-Protective and Antiarthritic Effects of Sulfonamido-Based Gallate-ZXHA-TC in Vitro and in Vivo.

PubMed

Lu, Zhenhui; Wu, Huayu; Lin, Xiao; Liu, Buming; Lin, Cuiwu; Zheng, Li; Zhao, Jinmin

2016-06-17

The effects of gallic acid (GA) on arthritis are limited by weak antioxidant effects and inferior biological properties of GA. We recently described a new series of synthesized GA derivatives by coupling with sulfonamides. Among these analogs, a novel compound synthesized from GA and sulfadimoxine (SDM) named ZXHA-TC exhibited the most robust anti-inflammatory potential. In this current study, the chondro-protective and antiarthritic effects of ZXHA-TC were investigated both in vitro and in vivo. In the in vitro study, ZXHA-TC exerted chondro-protective effects as evidenced by promoting cell proliferation and the maintaining of the phenotype of articular chondrocytes treated with interleukin-1-beta (IL-1β). The potential of ZXHA-TC to slow the progress of osteoarthritis (OA) was suggested by a reduction in matrix metalloproteinases (MMPs) and the up-regulation of the tissue inhibitor of metalloproteinase-1 (TIMP-1). In a rabbit anterior cruciate ligament transaction (ACLT) model of OA, ZXHA-TC exerted a protective effect on arthritis as assessed by macroscopic scores, histological, qRT-PCR, and immunohistochemical analyses. The effects of ZXHA-TC on inhibiting the production of inflammatory mediators in OA may be mediated partly by the suppression of the PI3K/AKT pathway or MAPK cascades, leading to NF-κB inactivation. Thus, this study indicates that ZXHA-TC may be developed as a potential therapeutic agent for OA.

Cocoa and cardiovascular health.

PubMed

Corti, Roberto; Flammer, Andreas J; Hollenberg, Norman K; Lüscher, Thomas F

2009-03-17

Epidemiological data demonstrate that regular dietary intake of plant-derived foods and beverages reduces the risk of coronary heart disease and stroke. Among many ingredients, cocoa might be an important mediator. Indeed, recent research demonstrates a beneficial effect of cocoa on blood pressure, insulin resistance, and vascular and platelet function. Although still debated, a range of potential mechanisms through which cocoa might exert its benefits on cardiovascular health have been proposed, including activation of nitric oxide and antioxidant and antiinflammatory effects. This review summarizes the available data on the cardiovascular effects of cocoa, outlines potential mechanisms involved in the response to cocoa, and highlights the potential clinical implications associated with its consumption.

Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders

PubMed Central

Campos, Alline Cristina; Moreira, Fabricio Araújo; Gomes, Felipe Villela; Del Bel, Elaine Aparecida; Guimarães, Francisco Silveira

2012-01-01

Cannabidiol (CBD) is a major phytocannabinoid present in the Cannabis sativa plant. It lacks the psychotomimetic and other psychotropic effects that the main plant compound Δ9-tetrahydrocannabinol (THC) being able, on the contrary, to antagonize these effects. This property, together with its safety profile, was an initial stimulus for the investigation of CBD pharmacological properties. It is now clear that CBD has therapeutic potential over a wide range of non-psychiatric and psychiatric disorders such as anxiety, depression and psychosis. Although the pharmacological effects of CBD in different biological systems have been extensively investigated by in vitro studies, the mechanisms responsible for its therapeutic potential are still not clear. Here, we review recent in vivo studies indicating that these mechanisms are not unitary but rather depend on the behavioural response being measured. Acute anxiolytic and antidepressant-like effects seem to rely mainly on facilitation of 5-HT1A-mediated neurotransmission in key brain areas related to defensive responses, including the dorsal periaqueductal grey, bed nucleus of the stria terminalis and medial prefrontal cortex. Other effects, such as anti-compulsive, increased extinction and impaired reconsolidation of aversive memories, and facilitation of adult hippocampal neurogenesis could depend on potentiation of anandamide-mediated neurotransmission. Finally, activation of TRPV1 channels may help us to explain the antipsychotic effect and the bell-shaped dose-response curves commonly observed with CBD. Considering its safety profile and wide range of therapeutic potential, however, further studies are needed to investigate the involvement of other possible mechanisms (e.g. inhibition of adenosine uptake, inverse agonism at CB2 receptor, CB1 receptor antagonism, GPR55 antagonism, PPARγ receptors agonism, intracellular (Ca2+) increase, etc.), on CBD behavioural effects. PMID:23108553

Specific Jak3 Downregulation in Lymphocytes Impairs γc Cytokine Signal Transduction and Alleviates Antigen-driven Inflammation In Vivo

PubMed Central

Gómez-Valadés, Alicia G; Llamas, María; Blanch, Sílvia; Perales, José C; Román, Juan; Gómez-Casajús, Lluís; Mascaró, Cristina

2012-01-01

Jak3, one of the four members comprising the Jak family of cytosolic tyrosine kinases, has emerged as a promising target for nontoxic immunotherapies. Although a number of Jak inhibitors has already demonstrated efficacy, they suffer from secondary effects apparently associated to their pan-Jak activity. However, whether selective Jak3 inhibition would afford therapeutic efficacy remains unclear. To address this question we have investigated the immunosuppressive potential of selective Jak3 intervention in lymphocytes using RNA interference (RNAi) technology in vitro and in vivo. Using synthetic small interference RNA (siRNA) sequences we achieved successful transfections into human and mouse primary T lymphocytes. We found that Jak3 knockdown was sufficient to impair not only interleukin-2 (IL-2) and T cell receptor (TCR)-mediated cell activation in vitro, but also antigen-triggereds welling, inflammatory cell infiltration, and proinflammatory cytokine raise in vivo. Furthermore, Jak1 (which mediates γc cytokine signaling in conjunction with Jak3) cosilencing did not provide higher potency to the aforementioned immunosuppressant effects. Our data provides direct evidences indicating that Jak3 protein plays an important role in γc cytokine and antigen-mediated T cell activation and modulates Th1-mediated inflammatory disorders, all in all highlighting its potential as a target in immunosuppressive therapies. PMID:23344234

Myelin-mediated inhibition of oligodendrocyte precursor differentiation can be overcome by pharmacological modulation of Fyn-RhoA and protein kinase C signalling

PubMed Central

Baer, Alexandra S.; Syed, Yasir A.; Kang, Sung Ung; Mitteregger, Dieter; Vig, Raluca; ffrench-Constant, Charles; Franklin, Robin J. M.; Altmann, Friedrich; Lubec, Gert

2009-01-01

Failure of oligodendrocyte precursor cell (OPC) differentiation contributes significantly to failed myelin sheath regeneration (remyelination) in chronic demyelinating diseases. Although the reasons for this failure are not completely understood, several lines of evidence point to factors present following demyelination that specifically inhibit differentiation of cells capable of generating remyelinating oligodendrocytes. We have previously demonstrated that myelin debris generated by demyelination inhibits remyelination by inhibiting OPC differentiation and that the inhibitory effects are associated with myelin proteins. In the present study, we narrow down the spectrum of potential protein candidates by proteomic analysis of inhibitory protein fractions prepared by CM and HighQ column chromatography followed by BN/SDS/SDS–PAGE gel separation using Nano-HPLC-ESI-Q-TOF mass spectrometry. We show that the inhibitory effects on OPC differentiation mediated by myelin are regulated by Fyn-RhoA-ROCK signalling as well as by modulation of protein kinase C (PKC) signalling. We demonstrate that pharmacological or siRNA-mediated inhibition of RhoA-ROCK-II and/or PKC signalling can induce OPC differentiation in the presence of myelin. Our results, which provide a mechanistic link between myelin, a mediator of OPC differentiation inhibition associated with demyelinating pathologies and specific signalling pathways amenable to pharmacological manipulation, are therefore of significant potential value for future strategies aimed at enhancing CNS remyelination. PMID:19208690

Illegitimate Tasks as an Impediment to Job Satisfaction and Intrinsic Motivation: Moderated Mediation Effects of Gender and Effort-Reward Imbalance

PubMed Central

Omansky, Rachel; Eatough, Erin M.; Fila, Marcus J.

2016-01-01

The current work examines a contemporary workplace stressor that has only recently been introduced into the literature: illegitimate tasks. Illegitimate tasks are work tasks that violate identity role norms about what can reasonably be expected from an employee in a given position. Although illegitimate tasks have been linked to employee well-being in past work, we know little about the potential explanatory mechanisms linking illegitimate tasks to work-relevant negative psychological states. Using a sample of 213 US-based employees of mixed occupations and a cross-sectional design, the present study examines job satisfaction and intrinsic motivation as outcomes of illegitimate tasks. Additionally, we examine perception of effort-reward imbalance (ERI) as a potential mediating mechanism through which illegitimate tasks relate to job satisfaction and intrinsic motivation, highlighting a possible pathway by which these relationships are functioning. Finally, we explore gender as a socially constructed variable that could contribute to variation in responses to illegitimate tasks and moderate the mediated link between illegitimate tasks and outcomes. Results indicated that illegitimate tasks were significantly related to job satisfaction and intrinsic motivation both directly and indirectly through perceptions of ERI in the predicted directions. Moreover, a moderated-mediation effect was found such that male workers reacted more than female workers to illegitimate tasks through the mechanism of perceived ERI. PMID:27917145

Illegitimate Tasks as an Impediment to Job Satisfaction and Intrinsic Motivation: Moderated Mediation Effects of Gender and Effort-Reward Imbalance.

PubMed

Omansky, Rachel; Eatough, Erin M; Fila, Marcus J

2016-01-01

The current work examines a contemporary workplace stressor that has only recently been introduced into the literature: illegitimate tasks. Illegitimate tasks are work tasks that violate identity role norms about what can reasonably be expected from an employee in a given position. Although illegitimate tasks have been linked to employee well-being in past work, we know little about the potential explanatory mechanisms linking illegitimate tasks to work-relevant negative psychological states. Using a sample of 213 US-based employees of mixed occupations and a cross-sectional design, the present study examines job satisfaction and intrinsic motivation as outcomes of illegitimate tasks. Additionally, we examine perception of effort-reward imbalance (ERI) as a potential mediating mechanism through which illegitimate tasks relate to job satisfaction and intrinsic motivation, highlighting a possible pathway by which these relationships are functioning. Finally, we explore gender as a socially constructed variable that could contribute to variation in responses to illegitimate tasks and moderate the mediated link between illegitimate tasks and outcomes. Results indicated that illegitimate tasks were significantly related to job satisfaction and intrinsic motivation both directly and indirectly through perceptions of ERI in the predicted directions. Moreover, a moderated-mediation effect was found such that male workers reacted more than female workers to illegitimate tasks through the mechanism of perceived ERI.

An investigation of vago-regulatory and health-behavior accounts for increased inflammation in posttraumatic stress disorder.

PubMed

Dennis, Paul A; Weinberg, J Brice; Calhoun, Patrick S; Watkins, Lana L; Sherwood, Andrew; Dennis, Michelle F; Beckham, Jean C

2016-04-01

Posttraumatic stress disorder (PTSD) has been linked to chronic inflammation, a condition that poses a risk for cardiovascular disease. Attenuated vagal activity has been proposed as a potential mediator of PTSD and inflammation, although associated behavioral health risks-namely cigarette smoking and alcohol dependence-might also account for that link. Inflammation was quantified by fasting serum concentrations of C-reactive protein (CRP), tumor necrosis factor (TNF)-α, interleukin (IL)-10, and thymus- and activation-regulated chemokine (TARC)/CCL17 collected from 85 participants with PTSD and 82 without PTSD. Latent variable modeling was used to assess the relationship between PTSD symptom severity and inflammation along with potential mediators vagal activity (respiratory sinus arrhythmia; RSA), smoking status, and lifetime alcohol dependence. PTSD symptom severity was associated with increased inflammation (β=.18, p=.02). However, this association was reduced in models that adjusted for RSA, smoking status, and lifetime alcohol dependence. Independent mediation effects were deemed significant via bootstrapping analyses. Together, RSA, smoking status, and lifetime alcohol dependence accounted for 95% of the effect of PTSD symptom severity on inflammation. Although RSA accounted for a modest proportion of the association between posttraumatic stress and pro-inflammatory responses, behavioral factors-specifically cigarette smoking and alcohol dependence-proved to be larger mediators. The benefits of PTSD treatment may be enhanced by additional interventions aimed at modifying these health behaviors. Published by Elsevier Inc.

Menthol enhances phasic and tonic GABAA receptor-mediated currents in midbrain periaqueductal grey neurons

PubMed Central

Lau, Benjamin K; Karim, Shafinaz; Goodchild, Ann K; Vaughan, Christopher W; Drew, Geoffrey M

2014-01-01

Background and Purpose Menthol, a naturally occurring compound in the essential oil of mint leaves, is used for its medicinal, sensory and fragrant properties. Menthol acts via transient receptor potential (TRPM8 and TRPA1) channels and as a positive allosteric modulator of recombinant GABAA receptors. Here, we examined the actions of menthol on GABAA receptor-mediated currents in intact midbrain slices. Experimental Approach Whole-cell voltage-clamp recordings were made from periaqueductal grey (PAG) neurons in midbrain slices from rats to determine the effects of menthol on GABAA receptor-mediated phasic IPSCs and tonic currents. Key Results Menthol (150–750 μM) produced a concentration-dependent prolongation of spontaneous GABAA receptor-mediated IPSCs, but not non-NMDA receptor-mediated EPSCs throughout the PAG. Menthol actions were unaffected by TRPM8 and TRPA1 antagonists, tetrodotoxin and the benzodiazepine antagonist, flumazenil. Menthol also enhanced a tonic current, which was sensitive to the GABAA receptor antagonists, picrotoxin (100 μM), bicuculline (30 μM) and Zn2+ (100 μM), but unaffected by gabazine (10 μM) and a GABAC receptor antagonist, 1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid hydrate (TPMPA; 50 μM). In addition, menthol potentiated currents induced by the extrasynaptic GABAA receptor agonist THIP/gaboxadol (10 μM). Conclusions and Implications These results suggest that menthol positively modulates both synaptic and extrasynaptic populations of GABAA receptors in native PAG neurons. The development of agents that potentiate GABAA-mediated tonic currents and phasic IPSCs in a manner similar to menthol could provide a basis for novel GABAA-related pharmacotherapies. PMID:24460753

Potential of acetylacetone as a mediator for Trametes versicolor laccase in enzymatic transformation of organic pollutants.

PubMed

Yang, Hua; Sun, Hongfei; Zhang, Shujuan; Wu, Bingdang; Pan, Bingcai

2015-07-01

Low-cost and environmentally friendly mediators could facilitate the application of laccase (EC 1.10.3.2) in variant biotechnological processes. Acetylacetone (AA) represents an inexpensive and low toxic small molecular diketone that has been proven as an effective mediator for laccase in free radical polymerization. However, the potential of AA as a mediator for laccase in pollutant detoxification and/or degradation is still unknown. In this work, the roles of AA in laccase-induced polymerization and transformation were investigated. AA was demonstrated to be a highly efficient mediator in the laccase-induced grafting copolymerization of acrylamide and chitosan. The efficacy of AA in the laccase-induced decoloration of malachite green (MG) was compared with that of the widely used 1-hydroxybenzotriazole (HBT). The laccase-AA system had the highest turnover number (TON, 39.1 μmol/U), followed by the laccase-only system (28.5 μmol/U), while the TON of the laccase-HBT system was the lowest (14.9 μmol/U). The pseudo-first-order transformation rate constant (k 1) of MG in the laccase-AA system was up to 0.283 h(-1) under the given conditions, while the k 1 of AA caused by laccase was only 0.008 h(-1). In the five-cycle run, the concentration of AA remained stable. The larger TON of the laccase-AA system and the stability of AA in the cycling runs demonstrate that AA was more recyclable than HBT in the LMS, leading to a prolonged serving life of laccase. These results suggest that AA might be a potential redox mediator for laccase.

Radio frequency-mediated local thermotherapy for destruction of pancreatic tumors using Ni-Au core-shell nanowires

NASA Astrophysics Data System (ADS)

Hopkins, Xiaoping; Gill, Waqas Amin; Kringel, Rosemarie; Wang, Guankui; Hass, Jamie; Acharya, Suresh; Park, Jungrae; Tak Jeon, In; An, Boo Hyun; Lee, Ji Sung; Ryu, Jong Eun; Hill, Rod; McIlroy, David; Kim, Young Keun; Choi, Daniel S.

2017-01-01

We present a novel method of radio frequency (RF)-mediated thermotherapy in tumors by remotely heating nickel (Ni)-gold (Au) core-shell nanowires (CSNWs). Ectopic pancreatic tumors were developed in nude mice to evaluate the thermotherapeutic effects on tumor progression. Tumor ablation was produced by RF-mediated thermotherapy via activation of the paramagnetic properties of the Ni-Au CSNWs. Histopathology demonstrated that heat generated by RF irradiation caused significant cellular death with pyknotic nuclei and nuclear fragmentation dispersed throughout the tumors. These preliminary results suggest that thermotherapy ablation induced via RF activation of nanowires provides a potential alternative therapy for cancer treatment.

Evaluating the truth brand.

PubMed

Evans, W Douglas; Price, Simani; Blahut, Steven

2005-03-01

The American Legacy Foundation developed the truth campaign, an aspirational antismoking brand for adolescents. This study tested whether a multidimensional scale, brand equity in truth, mediates the relationship between campaign exposure and youth smoking. We collected brand equity responses from 2,306 youth on a nationally representative telephone survey. Factor analysis indicates that the scale has excellent psychometric properties and effectively measures brand equity. We developed a structural equation model to test the mediation hypothesis. Results show that brand equity mediates the relationship between truth and smoking. Analyses of potential cofounders show this relationship is robust. Behavioral branding (brands about a behavior or a lifestyle) is an important public health strategy.

Lotka-Volterra pairwise modeling fails to capture diverse pairwise microbial interactions

PubMed Central

Momeni, Babak; Xie, Li; Shou, Wenying

2017-01-01

Pairwise models are commonly used to describe many-species communities. In these models, an individual receives additive fitness effects from pairwise interactions with each species in the community ('additivity assumption'). All pairwise interactions are typically represented by a single equation where parameters reflect signs and strengths of fitness effects ('universality assumption'). Here, we show that a single equation fails to qualitatively capture diverse pairwise microbial interactions. We build mechanistic reference models for two microbial species engaging in commonly-found chemical-mediated interactions, and attempt to derive pairwise models. Different equations are appropriate depending on whether a mediator is consumable or reusable, whether an interaction is mediated by one or more mediators, and sometimes even on quantitative details of the community (e.g. relative fitness of the two species, initial conditions). Our results, combined with potential violation of the additivity assumption in many-species communities, suggest that pairwise modeling will often fail to predict microbial dynamics. DOI: http://dx.doi.org/10.7554/eLife.25051.001 PMID:28350295

Computer-mediated communication and interpersonal attraction: an experimental test of two explanatory hypotheses.

PubMed

Antheunis, Marjolijn L; Valkenburg, Patti M; Peter, Jochen

2007-12-01

The aims of this study were (a) to investigate the influence of computer-mediated communication (CMC) on interpersonal attraction and (b) to examine two underlying processes in the CMC-interpersonal attraction relationship. We identified two variables that may mediate the influence of CMC on interpersonal attraction: self-disclosure and direct questioning. Focusing on these potential mediating variables, we tested two explanatory hypotheses: the CMC-induced direct questioning hypothesis and the CMC-induced self-disclosure hypothesis. Eighty-one cross-sex dyads were randomly assigned to one of three experimental conditions: text-only CMC, visual CMC, and face-to-face communication. We did not find a direct effect of CMC on interpersonal attraction. However, we did find two positive indirect effects of text-only CMC on interpersonal attraction: text-only CMC stimulated both self-disclosure and direct questioning, both of which in turn enhanced interpersonal attraction. Results are discussed in light of uncertainty reduction theory and CMC theories.

PAXIP1 potentiates the combination of WEE1 inhibitor AZD1775 and platinum agents in lung cancer

PubMed Central

Jhuraney, Ankita; Woods, Nicholas T.; Wright, Gabriela; Rix, Lily; Kinose, Fumi; Kroeger, Jodi L.; Remily-Wood, Elizabeth; Cress, W. Douglas; Koomen, John M.; Brantley, Stephen G.; Gray, Jhanelle E.; Haura, Eric B.; Rix, Uwe; Monteiro, Alvaro N.

2016-01-01

The DNA damage response (DDR) involves a complex network of signaling events mediated by modular protein domains such as the BRCT (BRCA1 C-terminal) domain. Thus, proteins that interact with BRCT domains and are a part of the DDR constitute potential targets for sensitization to DNA damaging chemotherapy agents. We performed a pharmacological screen to evaluate seventeen kinases, identified in a BRCT-mediated interaction network as targets to enhance platinum-based chemotherapy in lung cancer. Inhibition of mitotic kinase WEE1 was found to have the most effective response in combination with platinum compounds in lung cancer cell lines. In the BRCT-mediated interaction network, WEE1 was found in complex with PAXIP1, a protein containing six BRCT domains involved in transcription and in the cellular response to DNA damage. We show that PAXIP1 BRCT domains regulate WEE1-mediated phosphorylation of CDK1. Further, ectopic expression of PAXIP1 promotes enhanced caspase 3-mediated apoptosis in cells treated with WEE1 inhibitor AZD1775 (formerly, MK-1775) and cisplatin compared with cells treated with AZD1775 alone. Cell lines and patient-derived xenograft models expressing both PAXIP1 and WEE1 exhibited synergistic effects of AZD1775 and cisplatin. In summary, PAXIP1 is involved in sensitizing lung cancer cells to the WEE1 inhibitor AZD1775 in combination with platinum-based treatment. We propose that WEE1 and PAXIP1 levels may be used as mechanism-based biomarkers of response when WEE1 inhibitor AZD1775 is combined with DNA damaging agents. PMID:27196765

Effective mRNA Inhibition in PANC-1 Cells in Vitro Mediated via an mPEG-SeSe-PEI Delivery System.

PubMed

Zhang, Yuefeng; Yang, Bin; Liu, Yajie; Qin, Wenjie; Li, Chao; Wang, Lantian; Zheng, Wen; Wu, Yulian

2016-05-01

RNA interference (RNAi)-mediated gene therapy is a promising approach to cure various diseases. However, developing an effective, safe, specific RNAi delivery system remains a major challenge. In this study, a novel redox-responsive polyetherimide (PEI)-based nanovector, mPEG-SeSe-PEI, was developed and its efficacy evaluated. We prepared three mPEG-SeSe-PEI vector candidates for small interfering glyceraldehyde-3-phosphate dehydrogenase (siGADPH) and determined their physiochemical properties and transfection efficiency using flow cytometry and PEG11.6-SeSe-PEI polymer. We investigated the silencing efficacy of GADPH mRNA expression in PANC-1 cells and observed that PEG11.6-SeSe-PEI/siGADPH (N/P ratio=10) polyplexes possessed the appropriate size and zeta-potential and exhibited excellent in vitro gene silencing effects with the least cytotoxicity in PANC-1 cells. In conclusion, we present PEG11.6-SeSe-PEI as a potential therapeutic gene delivery system for small interfering RNA (siRNA).

Effect of agmatine on the development of morphine dependence in rats: potential role of cAMP system

PubMed Central

Aricioglu, Feyza; Means, Andrea; Regunathan, Soundar

2010-01-01

Agmatine is an endogenous amine derived from arginine that potentiates morphine analgesia and blocks symptoms of naloxone-precipitated morphine withdrawal in rats. In this study, we sought to determine whether treatment with agmatine during the development of morphine dependence inhibits the withdrawal symptoms and that the effect is mediated by cAMP system. Exposure of rats to morphine for 7 days resulted in marked naloxone-induced withdrawal symptoms and agmatine treatment along with morphine significantly decreasing the withdrawal symptoms. The levels of cAMP were markedly increased in morphine-treated rat brain slices when incubated with naloxone and this increase was significantly reduced in rats treated with morphine and agmatine. The induction of tyrosine hydroxylase after morphine exposure was also reduced in locus coeruleus when agmatine was administered along with morphine. We conclude that agmatine reduces the development of dependence to morphine and that this effect is probably mediated by the inhibition of cAMP signaling pathway during chronic morphine exposure. PMID:15541421

The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate

PubMed Central

Gergely, P; Nuesslein-Hildesheim, B; Guerini, D; Brinkmann, V; Traebert, M; Bruns, C; Pan, S; Gray, NS; Hinterding, K; Cooke, NG; Groenewegen, A; Vitaliti, A; Sing, T; Luttringer, O; Yang, J; Gardin, A; Wang, N; Crumb, WJ; Saltzman, M; Rosenberg, M; Wallström, E

2012-01-01

BACKGROUND AND PURPOSE BAF312 is a next-generation sphingosine 1-phosphate (S1P) receptor modulator, selective for S1P1 and S1P5 receptors. S1P1 receptors are essential for lymphocyte egress from lymph nodes and a drug target in immune-mediated diseases. Here, we have characterized the immunomodulatory potential of BAF312 and the S1P receptor-mediated effects on heart rate using preclinical and human data. EXPERIMENTAL APPROACH BAF312 was tested in a rat experimental autoimmune encephalomyelitis (EAE) model. Electrophysiological recordings of G-protein-coupled inwardly rectifying potassium (GIRK) channels were carried out in human atrial myocytes. A Phase I multiple-dose trial studied the pharmacokinetics, pharmacodynamics and safety of BAF312 in 48 healthy subjects. KEY RESULTS BAF312 effectively suppressed EAE in rats by internalizing S1P1 receptors, rendering them insensitive to the egress signal from lymph nodes. In healthy volunteers, BAF312 caused preferential decreases in CD4+ T cells, Tnaïve, Tcentral memory and B cells within 4–6 h. Cell counts returned to normal ranges within a week after stopping treatment, in line with the elimination half-life of BAF312. Despite sparing S1P3 receptors (associated with bradycardia in mice), BAF312 induced rapid, transient (day 1 only) bradycardia in humans. BAF312-mediated activation of GIRK channels in human atrial myocytes can fully explain the bradycardia. CONCLUSION AND IMPLICATIONS This study illustrates species-specific differences in S1P receptor specificity for first-dose cardiac effects. Based on its profound but rapidly reversible inhibition of lymphocyte trafficking, BAF312 may have potential as a treatment for immune-mediated diseases. PMID:22646698

Life on the line: the therapeutic potentials of computer-mediated conversation.

PubMed

Miller, J K; Gergen, K J

1998-04-01

In what ways are computer networking practices comparable to face-to-face therapy? With the exponential increase in computer-mediated communication and the increasing numbers of people joining topically based computer networks, the potential for grass-roots therapeutic (or antitherapeutic) interchange is greatly augmented. Here we report the results of research into exchanges on an electronic bulletin board devoted to the topic of suicide. Over an 11-month period participants offered each other valuable resources in terms of validation of experience, sympathy, acceptance, and encouragement. They also asked provocative questions and furnished broad-ranging advice. Hostile entries were rare. However, there were few communiques that parallel the change-inducing practices more frequent within many therapeutic settings. In effect, on-line dialogues seemed more sustaining than transforming. Further limits and potentials of on-line communication are explored.

Febuxostat, an Inhibitor of Xanthine Oxidase, Suppresses Lipopolysaccharide-Induced MCP-1 Production via MAPK Phosphatase-1-Mediated Inactivation of JNK

PubMed Central

Nomura, Johji; Busso, Nathalie; Ives, Annette; Tsujimoto, Syunsuke; Tamura, Mizuho; So, Alexander; Yamanaka, Yoshihiro

2013-01-01

Excess reactive oxygen species (ROS) formation can trigger various pathological conditions such as inflammation, in which xanthine oxidase (XO) is one major enzymatic source of ROS. Although XO has been reported to play essential roles in inflammatory conditions, the molecular mechanisms underlying the involvement of XO in inflammatory pathways remain unclear. Febuxostat, a selective and potent inhibitor of XO, effectively inhibits not only the generation of uric acid but also the formation of ROS. In this study, therefore, we examined the effects of febuxostat on lipopolysaccharide (LPS)-mediated inflammatory responses. Here we show that febuxostat suppresses LPS-induced MCP-1 production and mRNA expression via activating MAPK phosphatase-1 (MKP-1) which, in turn, leads to dephosphorylation and inactivation of JNK in macrophages. Moreover, these effects of febuxostat are mediated by inhibiting XO-mediated intracellular ROS production. Taken together, our data suggest that XO mediates LPS-induced phosphorylation of JNK through ROS production and MKP-1 inactivation, leading to MCP-1 production in macrophages. These studies may bring new insights into the novel role of XO in regulating inflammatory process through MAPK phosphatase, and demonstrate the potential use of XO inhibitor in modulating the inflammatory processes. PMID:24086554

Growth Inhibition by Bupivacaine Is Associated with Inactivation of Ribosomal Protein S6 Kinase 1

PubMed Central

Beigh, Mushtaq Ahmad; Showkat, Mehvish; Bashir, Basharat; Bashir, Asma; Hussain, Mahboob ul; Andrabi, Khurshid Iqbal

2014-01-01

Bupivacaine is an amide type long acting local anesthetic used for epidural anesthesia and nerve blockade in patients. Use of bupivacaine is associated with severe cytotoxicity and apoptosis along with inhibition of cell growth and proliferation. Although inhibition of Erk, Akt, and AMPK seemingly appears to mediate some of the bupivacaine effects, potential downstream targets that mediate its effect remain unknown. S6 kinase 1 is a common downstream effector of several growth regulatory pathways involved in cell growth and proliferation known to be affected by bupivacaine. We have accordingly attempted to relate the growth inhibitory effects of bupivacaine with the status of S6K1 activity and we present evidence that decrease in cell growth and proliferation by bupivacaine is mediated through inactivation of S6 kinase 1 in a concentration and time dependent manner. We also show that ectopic expression of constitutively active S6 kinase 1 imparts substantial protection from bupivacaine induced cytotoxicity. Inactivation of S6K1 though associated with loss of putative mTOR mediated phosphorylation did not correspond with loss of similar phosphorylations in 4EBP1 indicating that S6K1 inhibition was not mediated through inactivation of mTORC1 signaling pathway or its down regulation. PMID:24605337

The Mediating Effect of Self-Efficacy in the Connections between Strength-Based Parenting, Happiness and Psychological Distress in Teens

PubMed Central

Loton, Daniel J.; Waters, Lea E.

2017-01-01

Preliminary studies of strength-based parenting (SBP), a style of parenting that seeks to build strengths knowledge and strengths use in one’s child, have reported benefits such as higher life satisfaction, subjective wellbeing, and positive emotions together with lower stress in children and teens. Two proximal mediators conveying these effects have been identified: teen’s own use of strengths and strength-based coping, along with a small moderating effect of growth mindsets relating to strengths. The current study tests the potential mediating effect of self-efficacy, a sense of agency in life, in the relationship between SBP and mental health (wellbeing and illbeing) in teens. Self efficacy has been linked to wellbeing and strengths processes in past studies and is classed as a basic human need and form of eudaimonic happiness. This study reconfirmed the adaptive benefits of SBP in a large sample of Australian adolescents (N = 11,368; 59% male; Mage = 14.04, SDage = 1.99) sourced from 28 schools. Using structural equation modeling, SBP significantly and directly predicted higher happiness and lower depression, with direct effects falling into the 85th and 95th percentile of meta-analytically derived individual differences effect sizes. In addition, self-efficacy was a significant partial mediator, accounting for 40.0% of the total effect on happiness and 52.7% of the total effect on distress. Self-efficacy was also a full mediator in the case of anxiety, with a strong indirect effect. Results suggest that building strengths in teens can also build self-efficacy, and given the large effect sizes, that SBP is a promising leverage point for increasing teen wellbeing. PMID:29066986

The Mediating Effect of Self-Efficacy in the Connections between Strength-Based Parenting, Happiness and Psychological Distress in Teens.

PubMed

Loton, Daniel J; Waters, Lea E

2017-01-01

Preliminary studies of s trength-based parenting (SBP), a style of parenting that seeks to build strengths knowledge and strengths use in one's child, have reported benefits such as higher life satisfaction, subjective wellbeing, and positive emotions together with lower stress in children and teens. Two proximal mediators conveying these effects have been identified: teen's own use of strengths and strength-based coping, along with a small moderating effect of growth mindsets relating to strengths. The current study tests the potential mediating effect of self-efficacy, a sense of agency in life, in the relationship between SBP and mental health (wellbeing and illbeing) in teens. Self efficacy has been linked to wellbeing and strengths processes in past studies and is classed as a basic human need and form of eudaimonic happiness. This study reconfirmed the adaptive benefits of SBP in a large sample of Australian adolescents ( N = 11,368; 59% male; M age = 14.04, SD age = 1.99) sourced from 28 schools. Using structural equation modeling, SBP significantly and directly predicted higher happiness and lower depression, with direct effects falling into the 85th and 95th percentile of meta-analytically derived individual differences effect sizes. In addition, self-efficacy was a significant partial mediator, accounting for 40.0% of the total effect on happiness and 52.7% of the total effect on distress. Self-efficacy was also a full mediator in the case of anxiety, with a strong indirect effect. Results suggest that building strengths in teens can also build self-efficacy, and given the large effect sizes, that SBP is a promising leverage point for increasing teen wellbeing.

Sonodynamic action of pyropheophorbide-a methyl ester induces mitochondrial damage in liver cancer cells.

PubMed

Xu, Jing; Xia, Xinshu; Leung, Albert Wingnang; Xiang, Junyan; Jiang, Yuan; Yu, Heping; Bai, Dingqun; Li, Xiaohong; Xu, Chuanshan

2011-05-01

Sonodynamic therapy with pyropheophorbide-a methyl ester (MPPa) presents a promising aspect in treating liver cancer. The present study aims to investigate the mitochondrial damage of liver cancer cells induced by MPPa-mediated sonodynamic action. Mouse hepatoma cell line H(22) cells were incubated with MPPa (2 μM) for 20 h and then exposed to ultrasound with an intensity of 0.97 W/cm(2) for 8 s. Cytotoxicity was investigated 24h after sonodynamic action using MTT assay and light microscopy. Mitochondrial membrane potential (ΔΨm) was analyzed using flow cytometry with rhodamine 123 staining and ultrastructural changes were observed using transmission electron microscopy (TEM). The cytotoxicity of MPPa-mediated SDT on H(22) cell line was 73.00±3.42%, greater than ultrasound treatment alone (28.12±5.19%) significantly while MPPa treatment alone had no significant effect on H(22) cells. Moreover, after MPPa-mediated SDT cancer cells showed swollen mitochondria under TEM and a significant collapse of mitochondrial membrane potential. Our findings demonstrated that MPPa-mediated SDT could remarkably induce cell death of H(22) cells, and highlighted that mitochondrial damage might be an important cause of cell death induced by MPPa-mediated SDT. Copyright © 2010 Elsevier B.V. All rights reserved.

Bioelectrochemical ethanol production through mediated acetate reduction by mixed cultures.

PubMed

Steinbusch, Kirsten J J; Hamelers, Hubertus V M; Schaap, Joris D; Kampman, Christel; Buisman, Cees J N

2010-01-01

Biological acetate reduction with hydrogen is a potential method to convert wet biomass waste into ethanol. Since the ethanol concentration and reaction rates are low, this research studies the feasibility of using an electrode, in stead of hydrogen, as an electron donor for biological acetate reduction in conjunction of an electron mediator. Initially, the effect of three selected mediators on metabolic flows during acetate reduction with hydrogen was explored; subsequently, the best performing mediator was used in a bioelectrochemical system to stimulate acetate reduction at the cathode with mixed cultures at an applied cathode potential of -550 mV. In the batch test, methyl viologen (MV) was found to accelerate ethanol production 6-fold and increased ethanol concentration 2-fold to 13.5 +/- 0.7 mM compared to the control. Additionally, MV inhibited n-butyrate and methane formation, resulting in high ethanol production efficiency (74.6 +/- 6%). In the bioelectrochemical system, MV addition to an inoculated cathode led directly to ethanol production (1.82 mM). Hydrogen was coproduced at the cathode (0.0035 Nm(3) hydrogen m(-2) d(-1)), so it remained unclear whether acetate was reduced to ethanol by electrons supplied by the mediator or by hydrogen. As MV reacted irreversibly at the cathode, ethanol production stopped after 5 days.

Effects of Olive Oil on TNF-α and IL-6 in Humans: Implication in Obesity and Frailty.

PubMed

Yarla, Nagendra S; Polito, Angela; Peluso, Ilaria

2018-01-01

Tumor necrosis factor-alpha (TNF)-α and interleukin (IL)-6 are important mediators of chronic low-grade systemic inflammation. The latter plays a central role in several obesity-related pathologies, such as diabetes, metabolic syndrome and cardiovascular diseases. Besides, these cytokines have been also implicated in geriatric and cancer-induced anorexia, cachexia, sarcopenia and frailty. Potential interventions for both obesity and frailty include dietary advice and nutraceuticals. In this context, the consumption of olive oil (OO) has been associated with the health effects of the Mediterranean diet (Med-diet). This review is aimed to discuss the OO-mediated modulation of TNF- α and IL-6 in human studies and the potential implication in obesity and frailty. The reviewed studies suggest that the improvement of postprandial TNF-α and IL-6 observed with OO consumption is affected by body mass index (BMI). The effects on TNF-α and IL-6 after medium and long-term consumptions involved many factors and the cross-talk between adipose tissue, liver, skeletal muscle and brain. Major anti-inflammatory effects were observed when OO was consumed with Med-diet, which is associated with healthy behaviors. In this context, the role of microbioma- polyphenols, diet-gene and exercise-gene interactions in the effects of OO on immune-mediated inflammatory responses involved in obesity and frailty deserves further investigation. Further studies are needed to clarify the effect of OO net of possible synergistic effects with other dietary and lifestyle factors of Mediterranean area. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

G-protein coupled receptor 30 (GPR30): a novel regulator of endothelial inflammation.

PubMed

Chakrabarti, Subhadeep; Davidge, Sandra T

2012-01-01

Estrogen, the female sex hormone, is known to exert anti-inflammatory and anti-atherogenic effects. Traditionally, estrogen effects were believed to be largely mediated through the classical estrogen receptors (ERs). However, there is increasing evidence that G-protein coupled receptor 30 (GPR30), a novel estrogen receptor, can mediate many estrogenic effects on the vasculature. Despite this, the localization and functional significance of GPR30 in the human vascular endothelium remains poorly understood. Given this background, we examined the subcellular location and potential anti-inflammatory roles of GPR30 using human umbilical vein endothelial cells as a model system. Inflammatory changes were induced by treatment with tumor necrosis factor (TNF), a pro-inflammatory cytokine involved in atherogenesis and many other inflammatory conditions. We found that GPR30 was located predominantly in the endothelial cell nuclei. Treatment with the selective GPR30 agonist G-1 partially attenuated the TNF induced upregulation of pro-inflammatory proteins such as intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). This effect was completely abolished by the selective GPR30 antagonist G-15, suggesting that it was indeed mediated in a GPR30 dependent manner. Interestingly, estrogen alone had no effects on TNF-treated endothelium. Concomitant activation of the classical ERs blocked the anti-inflammatory effects of G-1, indicating opposing effects of GPR30 and the classical ERs. Our findings demonstrate that endothelial GPR30 is a novel regulator of the inflammatory response which could be a potential therapeutic target against atherosclerosis and other inflammatory diseases.

The Influence of Background Music on Learning in the Light of Different Theoretical Perspectives and the Role of Working Memory Capacity.

PubMed

Lehmann, Janina A M; Seufert, Tina

2017-01-01

This study investigates how background music influences learning with respect to three different theoretical approaches. Both the Mozart effect as well as the arousal-mood-hypothesis indicate that background music can potentially benefit learning outcomes. While the Mozart effect assumes a direct influence of background music on cognitive abilities, the arousal-mood-hypothesis assumes a mediation effect over arousal and mood. However, the seductive detail effect indicates that seductive details such as background music worsen learning. Moreover, as working memory capacity has a crucial influence on learning with seductive details, we also included the learner's working memory capacity as a factor in our study. We tested 81 college students using a between-subject design with half of the sample listening to two pop songs while learning a visual text and the other half learning in silence. We included working memory capacity in the design as a continuous organism variable. Arousal and mood scores before and after learning were collected as potential mediating variables. To measure learning outcomes we tested recall and comprehension. We did not find a mediation effect between background music and arousal or mood on learning outcomes. In addition, for recall performance there were no main effects of background music or working memory capacity, nor an interaction effect of these factors. However, when considering comprehension we did find an interaction between background music and working memory capacity: the higher the learners' working memory capacity, the better they learned with background music. This is in line with the seductive detail assumption.

The Influence of Background Music on Learning in the Light of Different Theoretical Perspectives and the Role of Working Memory Capacity

PubMed Central

Lehmann, Janina A. M.; Seufert, Tina

2017-01-01

This study investigates how background music influences learning with respect to three different theoretical approaches. Both the Mozart effect as well as the arousal-mood-hypothesis indicate that background music can potentially benefit learning outcomes. While the Mozart effect assumes a direct influence of background music on cognitive abilities, the arousal-mood-hypothesis assumes a mediation effect over arousal and mood. However, the seductive detail effect indicates that seductive details such as background music worsen learning. Moreover, as working memory capacity has a crucial influence on learning with seductive details, we also included the learner’s working memory capacity as a factor in our study. We tested 81 college students using a between-subject design with half of the sample listening to two pop songs while learning a visual text and the other half learning in silence. We included working memory capacity in the design as a continuous organism variable. Arousal and mood scores before and after learning were collected as potential mediating variables. To measure learning outcomes we tested recall and comprehension. We did not find a mediation effect between background music and arousal or mood on learning outcomes. In addition, for recall performance there were no main effects of background music or working memory capacity, nor an interaction effect of these factors. However, when considering comprehension we did find an interaction between background music and working memory capacity: the higher the learners’ working memory capacity, the better they learned with background music. This is in line with the seductive detail assumption. PMID:29163283

Mucuna pruriens (L.) DC chemo sensitize human breast cancer cells via downregulation of prolactin-mediated JAK2/STAT5A signaling.

PubMed

Sinha, Sonam; Sharma, Sonal; Vora, Jaykant; Shah, Heta; Srivastava, Anshu; Shrivastava, Neeta

2018-05-10

Mucuna pruriens (L.) DC (MP) is an ancient Indian medicinal plant traditionally used to treat Parkinson's disease. L-Dopa (LD), precursor of dopamine is abundantly found in the seeds of MP. L-dopa is a natural inhibitor of prolactin (PRL) hormone which is required to maintain lactation in women but it's over production (hyperprolactinemia) plays critical role in advancement of breast cancer. We aim to examine the pharmacological effect of LD and MP on this hyperprolactinemia associated breast cancer and related signaling for effective management of the disease. We also investigated chemo-sensitizing effect of MP on hyperprolactinemia-mediated cisplatin resistance. Methanolic seed extract of MP were prepared and analysed using HPLC. Effect of LD and MP on the cellular viability of breast cancer cells (T47D, MCF-7, MDA-MB-468 and MDA-MB-231) were evaluated using MTT assay. Further, effect of LD and MP on colony forming potential, DNA damage, cell cycle distribution and apoptosis was determined using agar/agarose method, comet assay and annexin and PI method followed by FACS analysis. To reveal the molecular mechanism involved in the anti-cancer activity of MP, transcriptional and translational level analysis of the key proteins involved in the PRL-mediated signaling, was performed using RT-PCR and western blot analysis. The effect of MP extract on PRL-mediated signaling was validated using dopaminergic agonist bromocriptine. MP extract and cisplatin was given in different combination with appropriate controls to check their effect on chemo-resistivity of breast cancer cells. Our results demonstrated that MP seed extract has the potential to inhibit cellular proliferation of PRL expressing T47D and MCF-7 breast cancer cells via induction of DNA damage, G1 phase of cell cycle arrest and apoptosis more effectively as compare to LD. Further, MP-mediated anti-cancerous effect was associated with the downregulation of PRL expression, further suppressing the JAK2/STAT5A/Cyclin D1 signaling pathway which has been validated using dopaminergic agonist bromocriptine. Cancer-related hyperprolactinemia confers cisplatin resistance, we observed that MP via PRL inhibition, enhances cisplatin efficacy after their combinatorial treatment in breast cancer cells. Collectively, our study suggests that MP could be recommended as dietary supplement along with the chemotherapeutic agents against breast cancer. Copyright © 2018 Elsevier B.V. All rights reserved.

Anxiety symptoms mediate the relationship between exposure to stressful negative life events and depressive symptoms: A conditional process modelling of the protective effects of resilience.

PubMed

Anyan, Frederick; Worsley, Lyn; Hjemdal, Odin

2017-10-01

Resilience has provided a useful framework that elucidates the effects of protective factors to overcome psychological adversities but studies that address the potential contingencies of resilience to protect against direct and indirect negative effects are lacking. These obvious gaps have also resulted in oversimplification of complex processes that can be clarified by moderated mediation associations. This study examines a conditional process modelling of the protective effects of resilience against indirect effects. Two separate samples were recruited in a cross-sectional survey from Australia and Norway to complete the Patient Health Questionnaire -9, Generalized Anxiety Disorder, Stressful Negative Life Events Questionnaire and the Resilience Scale for Adults. The final sample sizes were 206 (females=114; males=91; other=1) and 210 (females=155; males=55) for Australia and Norway respectively. Moderated mediation analyses were conducted across the samples. Anxiety symptoms mediated the relationship between exposure to stressful negative life events and depressive symptoms in both samples. Conditional indirect effects of exposure to stressful negative life events on depressive symptoms mediated by anxiety symptoms showed that high subgroup of resilience was associated with less effect of exposure to stressful negative life events through anxiety symptoms on depressive symptoms than the low subgroup of resilience. As a cross-sectional survey, the present study does not answer questions about causal processes despite the use of a conditional process modelling. These findings support that, resilience protective resources can protect against both direct and indirect - through other channels - psychological adversities. Copyright © 2017 Elsevier B.V. All rights reserved.

Au@Pt nanoparticles as catalase mimics to attenuate tumor hypoxia and enhance immune cell-mediated cytotoxicity

NASA Astrophysics Data System (ADS)

Liang, Hong; Wu, Ying; Ou, Xiang-Yu; Li, Jing-Ying; Li, Juan

2017-11-01

Hypoxic tumor microenvironment (TME) is closely linked to tumor progression, heterogeneity and immune suppression. Therefore, the development of effective methods to overcome hypoxia and substantially enhance the immunotherapy efficacy remains a desirable goal. Herein, we engineered a biocompatible Au core/Pt shell nanoparticles (Au@Pt NPs) to reoxygenate the TME by reacting with endogenous H2O2. Treatment with Au@Pt NPs appeared to improve oxygen in intracellular environments and decrease hypoxia-inducible factor-1α expression. Furthermore, the integration of high catalytic efficiency of Au@Pt NPs with cytokine-induced killer (CIK) cell immunotherapy, could lead to significantly improve the effect of CIK cell-mediated cytotoxicity. These results suggest great potential of Au@Pt NPs for regulation of the hypoxic TME and enhance immune cell mediated anti-tumor immunity.

Apoptosis triggered by pyropheophorbide-α methyl ester-mediated photodynamic therapy in a giant cell tumor in bone

NASA Astrophysics Data System (ADS)

Li, K.-T.; Zhang, J.; Duan, Q.-Q.; Bi, Y.; Bai, D.-Q.; Ou, Y.-S.

2014-06-01

A giant cell tumor in bone is the common primary bone tumor with aggressive features, occurring mainly in young adults. Photodynamic therapy is a new therapeutic technique for tumors. In this study, we investigated the effects of Pyropheophorbide-α methyl ester (MPPa)-mediated photodynamic therapy on the proliferation of giant cell tumor cells and its mechanism of action. Cell proliferation was evaluated using an MTT assay. Cellular apoptosis was detected by Hoechst nuclear staining, and flow cytometric assay. Mitochondrial membrane potential changes and cytochrome c, caspase-9, caspase-3, and Bcl-2 expression was assessed. Finally, we found that MPPa-mediated photodynamic therapy could effectively suppress the proliferation of human giant cell tumor cells and induce apoptosis. The mitochondrial pathway was involved in the MPPa-photodynamic therapy-induced apoptosis.

Smoking abstinence-related expectancies among American Indians, African Americans, and women: potential mechanisms of tobacco-related disparities.

PubMed

Hendricks, Peter S; Westmaas, J Lee; Ta Park, Van M; Thorne, Christopher B; Wood, Sabrina B; Baker, Majel R; Lawler, R Marsh; Webb Hooper, Monica; Delucchi, Kevin L; Hall, Sharon M

2014-03-01

Research has documented tobacco-related health disparities by race and gender. Prior research, however, has not examined expectancies about the smoking cessation process (i.e., abstinence-related expectancies) as potential contributors to tobacco-related disparities in special populations. This cross-sectional study compared abstinence-related expectancies between American Indian (n = 87), African American (n = 151), and White (n = 185) smokers, and between women (n = 231) and men (n = 270) smokers. Abstinence-related expectancies also were examined as mediators of race and gender relationships with motivation to quit and abstinence self efficacy. Results indicated that American Indians and African Americans were less likely than Whites to expect withdrawal effects, and more likely to expect that quitting would be unproblematic. African Americans also were less likely than Whites to expect smoking cessation interventions to be effective. Compared with men, women were more likely to expect withdrawal effects and weight gain. These expectancy differences mediated race and gender relationships with motivation to quit and abstinence self-efficacy. Findings emphasize potential mechanisms underlying tobacco-related health disparities among American Indians, African Americans, and women and suggest a number of specific approaches for targeting tobacco dependence interventions to these populations.

Smoking Abstinence-related Expectancies among American Indians, African Americans, and Women: Potential Mechanisms of Tobacco-related Disparities

PubMed Central

Hendricks, Peter S.; Westmaas, J. Lee; Park, Van M. Ta; Thorne, Christopher B.; Wood, Sabrina B.; Baker, Majel R.; Lawler, R. Marsh; Hooper, Monica Webb; Delucchi, Kevin L.; Hall, Sharon M.

2014-01-01

Research has documented tobacco-related health disparities by race and gender. Prior research, however, has not examined expectancies about the smoking cessation process (i.e., abstinence-related expectancies) as potential contributors to tobacco-related disparities in special populations. This cross-sectional study compared abstinence-related expectancies between American Indian (n = 87), African American (n = 151), and White (n = 185) smokers, and between women (n = 231) and men (n = 270) smokers. Abstinence-related expectancies also were examined as mediators of race and gender relationships with motivation to quit and abstinence self-efficacy. Results indicated that American Indians and African Americans were less likely than Whites to expect withdrawal effects, and more likely to expect that quitting would be unproblematic. African Americans also were less likely than Whites to expect smoking cessation interventions to be effective. Compared to men, women were more likely to expect withdrawal effects and weight gain.These expectancy differences mediated race and gender relationships with motivation to quit and abstinence self-efficacy. Findings emphasize potential mechanisms underlying tobacco-related health disparities among American Indians, African Americans, and women, and suggest a number of specific approaches for targeting tobacco dependence interventions to these populations. PMID:23528192

Attitude similarity and familiarity and their links to mental health: An examination of potential interpersonal mediators.

PubMed

Moore, Shannon M; Uchino, Bert N; Baucom, Brian R W; Behrends, Arwen A; Sanbonmatsu, David

2017-01-01

Similarity and familiarity with partner's attitudes are linked to positive relationship outcomes, while interpersonal variables have been linked to mental health. Using multilevel models (MLMs), we modeled the associations between these attitudinal variables and mental health outcomes in 74 married couples. We found that higher levels of attitude similarity in couples were linked to lower depression, while higher levels of attitude familiarity in couples were associated with greater satisfaction with life. Mediational analyses indicated marital satisfaction and interpersonal stress mediated the link between attitude similarity and depression. Marital satisfaction also mediated the link between familiarity and satisfaction with life. This study is the first linking attitude familiarity to mental health and provides evidence that familiarity and similarity have mental health effects partly due to their interpersonal consequences.

Curcumin as a potential candidate for treating hyperlipidemia: A review of cellular and metabolic mechanisms.

PubMed

Panahi, Yunes; Ahmadi, Yasin; Teymouri, Manouchehr; Johnston, Thomas P; Sahebkar, Amirhossein

2018-01-01

Curcumin is an herbal polyphenol extensively investigated for antioxidant, anti-inflammatory, and hypolipidaemic properties. In the present review, the efficacy of curcumin for improving a plasma lipid profile has been evaluated and compared with statins, a well-known class of medicines for treating hypercholesterolemia and hyperlipidaemia. Curcumin is presumably most effective in reducing triglyceride (TG), while statins are most efficient in lowering low-density lipoproteins-cholesterol (LDL-C). Additionally, various molecular and metabolic mediators of cholesterol and plasma lipid homeostasis are discussed in relation to how they are modulated by curcumin or statins. Overall, curcumin influences the same mediators of plasma lipid alteration as statins do. Almost all the pathways through which cholesterol trafficking takes place are affected by these agents. These include gastrointestinal absorption of dietary cholesterol, hepatocellular removal of plasma cholesterol, the mediators of reverse cholesterol transport, and removal of cholesterol from peripheral tissues. Moreover, the reactive oxygen species (ROS) scavenging potential of curcumin limits the risk of lipid peroxidation that triggers inflammatory responses causing cardiovascular diseases (CVD) and atherosclerosis. Taken together, curcumin could be used as a safe and well-tolerated adjunct to statins to control hyperlipidaemia more effectively than statins alone. © 2017 Wiley Periodicals, Inc.

Cannabidiol enhances microglial phagocytosis via transient receptor potential (TRP) channel activation

PubMed Central

Hassan, Samia; Eldeeb, Khalil; Millns, Paul J; Bennett, Andrew J; Alexander, Stephen P H; Kendall, David A

2014-01-01

Background and Purpose Microglial cells are important mediators of the immune response in the CNS. The phytocannabinoid, cannabidiol (CBD), has been shown to have central anti-inflammatory properties, and the purpose of the present study was to investigate the effects of CBD and other phytocannabinoids on microglial phagocytosis. Experimental Approach Phagocytosis was assessed by measuring ingestion of fluorescently labelled latex beads by cultured microglial cells. Drug effects were probed using single-cell Ca2+ imaging and expression of mediator proteins by immunoblotting and immunocytochemistry. Key Results CBD (10 μM) enhanced bead phagocytosis to 175 ± 7% control. Other phytocannabinoids, synthetic and endogenous cannabinoids were without effect. The enhancement was dependent upon Ca2+ influx and was abolished in the presence of EGTA, the Ca2+ channel inhibitor SKF96365, the transient receptor potential (TRP) channel blocker ruthenium red, and the TRPV1 antagonists capsazepine and AMG9810. CBD produced a sustained increase in intracellular Ca2+ concentration in BV-2 microglia and this was abolished by ruthenium red. CBD rapidly increased the expression of TRPV2 and TRPV1 proteins and caused a translocation of TRPV2 to the cell membrane. Wortmannin blocked CBD enhancement of BV-2 cell phagocytosis, suggesting that it is mediated by PI3K signalling downstream of the Ca2+ influx. Conclusions and Implications The TRPV-dependent phagocytosis-enhancing effect of CBD suggests that pharmacological modification of TRPV channel activity could be a rational approach to treating neuroinflammatory disorders involving changes in microglial function and that CBD is a potential starting point for future development of novel therapeutics acting on the TRPV receptor family. PMID:24641282

Zyflamend Sensitizes Tumor Cells to TRAIL-Induced Apoptosis Through Up-Regulation of Death Receptors and Down-Regulation of Survival Proteins: Role of ROS-Dependent CCAAT/Enhancer-Binding Protein-Homologous Protein Pathway

PubMed Central

Kim, Ji Hye; Park, Byoungduck; Gupta, Subash C.; Kannappan, Ramaswamy; Sung, Bokyung

2012-01-01

Abstract Aim: TNF (tumor necrosis factor)-related apoptosis-inducing ligand (TRAIL), is a selective killer of tumor cells, although its potential is limited by the development of resistance. In this article, we investigated whether the polyherbal preparation Zyflamend® can sensitize tumor cells to TRAIL. Results: We found that Zyflamend potentiated TRAIL-induced apoptosis in human cancer cells. Zyflamend manifested its effects through several mechanisms. First, it down-regulated the expression of cell survival proteins known to be linked to resistance to TRAIL. Second, Zyflamend up-regulated the expression of pro-apoptotic protein, Bax. Third, Zyflamend up-regulated the expression of death receptors (DRs) for TRAIL. Up-regulation of DRs was critical as gene-silencing of these receptors significantly reduced the effect of Zyflamend on TRAIL-induced apoptosis. The up-regulation of DRs was dependent on CCAAT/enhancer-binding protein-homologous protein (CHOP), as Zyflamend induced CHOP, its gene-silencing abolished the induction of receptors, and mutation of the CHOP binding site on DR5 promoter abolished Zyflamend-mediated DR5 transactivation. Zyflamend mediated its effects through reactive oxygen species (ROS), as ROS quenching reduced its effect. Further, Zyflamend induced DR5 and CHOP and down-regulated the expression of cell survival proteins in nude mice bearing human pancreatic cancer cells. Innovation: Zyflamend can sensitize tumor cells to TRAIL through modulation of multiple cell signaling mechanisms that are linked to ROS. Conclusion: Zyflamend potentiates TRAIL-induced apoptosis through the ROS-CHOP-mediated up-regulation of DRs, increase in pro-apoptotic protein and down-regulation of cell survival proteins. Antioxid. Redox Signal. 16, 413–427. PMID:22004570

A Multiyear Assessment of Public Response to a Statewide Drug Take-Back and Disposal Campaign, 2010 to 2012.

PubMed

Yanovitzky, Itzhak

2017-08-01

This study is the first to analyze public response to a drug take-back program, the American Medicine Chest Challenge, in a single state over a period of 3 years (2010-2012). The study utilized a three-wave repeated cross-sectional design and an annual phone survey conducted with a representative sample of adults ( N = 906 in 2010, N = 907 in 2011, and N = 906 in 2012), which assessed exposure to the campaign, drug disposal behaviors, possible mediators of campaign effects (risk appraisal, personal agency, normative influence, and interpersonal talk), and potential confounders. Logistic regression and causal mediation analysis were employed to estimate confounder-adjusted direct and mediated effects of the campaign. Results showed that the campaign reached a sizable portion (50% to 60%) of state adults and that campaign exposure was associated with increased likelihood of having conversations with others about this topic. About 55% of all adults in the state reported taking at least one of the actions recommended by the campaign, and campaign exposure was associated with increased likelihood of disposing of prescription drugs at a drug collection day event (adjusted odds ratio = 4) and of talking to a child about the risks associated with prescription drug abuse (adjusted odds ratio = 2). The causal mediation analysis demonstrated that the campaign influenced audiences by reinforcing their efficacy to safely dispose of prescription drugs, but also potentially by stimulating conversations among community members about this topic. Drug take-back campaigns can be an effective mechanism to decrease the availability of prescription drugs in communities.

Cell type specificity of GABA(A) receptor mediated signaling in the hippocampus.

PubMed

Semyanov, A

2003-08-01

Inhibitory signaling mediated by ionotropic GABA(1) receptors generally acts as a major brake against excessive excitability in the brain. This is especially relevant in epilepsy-prone structures such as the hippocampus, in which GABA(A) receptor mediated inhibition is critical in suppressing epileptiform activity. Indeed, potentiating GABA(A) receptor mediated signaling is an important target for antiepileptic drug therapy. GABA(A) receptor mediated inhibition has different roles in the network dependent on the target neuron. Inhibiting principal cells will thus reduce network excitability, whilst inhibiting interneurons will increase network excitability; GABAergic therapeutic agents do not distinguish between these two alternatives, which may explain why, on occasion, GABAergic antiepileptic drugs can be proconvulsant. The importance of the target-cell for the effect of neuroactive drugs has emerged from a number of recent studies. Immunocytochemical data have suggested non-uniform distribution of GABA(A) receptor subunits among hippocampal interneurons and pyramidal cells. This has been confirmed by subsequent electropharmacological data. These have demonstrated that compounds which act on GABA(A) receptors or the extracellular GABA concentration can have distinct effects in different neuronal populations. Recently, it has also been discovered that presynaptic glutamate heteroreceptors can modulate GABA release in the hippocampus in a postsynaptic cell-specific manner. Since systemically administrated drugs may act on different neuronal subtypes, they can exhibit paradoxical effects. Distinguishing compounds that have target specific effects on GABAergic signaling may lead to novel and more effective treatments against epilepsy.

Polyoxometalate active charge-transfer material for mediated redox flow battery

DOEpatents

Anderson, Travis Mark; Hudak, Nicholas; Staiger, Chad; Pratt, Harry

2017-01-17

Redox flow batteries including a half-cell electrode chamber coupled to a current collecting electrode are disclosed herein. In a general embodiment, a separator is coupled to the half-cell electrode chamber. The half-cell electrode chamber comprises a first redox-active mediator and a second redox-active mediator. The first redox-active mediator and the second redox-active mediator are circulated through the half-cell electrode chamber into an external container. The container includes an active charge-transfer material. The active charge-transfer material has a redox potential between a redox potential of the first redox-active mediator and a redox potential of the second redox-active mediator. The active charge-transfer material is a polyoxometalate or derivative thereof. The redox flow battery may be particularly useful in energy storage solutions for renewable energy sources and for providing sustained power to an electrical grid.

Mechanisms and mediation in survival analysis: towards an integrated analytical framework.

PubMed

Pratschke, Jonathan; Haase, Trutz; Comber, Harry; Sharp, Linda; de Camargo Cancela, Marianna; Johnson, Howard

2016-02-29

A wide-ranging debate has taken place in recent years on mediation analysis and causal modelling, raising profound theoretical, philosophical and methodological questions. The authors build on the results of these discussions to work towards an integrated approach to the analysis of research questions that situate survival outcomes in relation to complex causal pathways with multiple mediators. The background to this contribution is the increasingly urgent need for policy-relevant research on the nature of inequalities in health and healthcare. The authors begin by summarising debates on causal inference, mediated effects and statistical models, showing that these three strands of research have powerful synergies. They review a range of approaches which seek to extend existing survival models to obtain valid estimates of mediation effects. They then argue for an alternative strategy, which involves integrating survival outcomes within Structural Equation Models via the discrete-time survival model. This approach can provide an integrated framework for studying mediation effects in relation to survival outcomes, an issue of great relevance in applied health research. The authors provide an example of how these techniques can be used to explore whether the social class position of patients has a significant indirect effect on the hazard of death from colon cancer. The results suggest that the indirect effects of social class on survival are substantial and negative (-0.23 overall). In addition to the substantial direct effect of this variable (-0.60), its indirect effects account for more than one quarter of the total effect. The two main pathways for this indirect effect, via emergency admission (-0.12), on the one hand, and hospital caseload, on the other, (-0.10) are of similar size. The discrete-time survival model provides an attractive way of integrating time-to-event data within the field of Structural Equation Modelling. The authors demonstrate the efficacy of this approach in identifying complex causal pathways that mediate the effects of a socio-economic baseline covariate on the hazard of death from colon cancer. The results show that this approach has the potential to shed light on a class of research questions which is of particular relevance in health research.

Staurosporine synergistically potentiates the deoxycholate-mediated induction of COX-2 expression.

PubMed

Saeki, Tohru; Inui, Haruka; Fujioka, Saya; Fukuda, Suguru; Nomura, Ayumi; Nakamura, Yasushi; Park, Eun Young; Sato, Kenji; Kanamoto, Ryuhei

2014-08-01

Colorectal cancer is a major cause of cancer-related death in western countries, and thus there is an urgent need to elucidate the mechanism of colorectal tumorigenesis. A diet that is rich in fat increases the risk of colorectal tumorigenesis. Bile acids, which are secreted in response to the ingestion of fat, have been shown to increase the risk of colorectal tumors. The expression of cyclooxygenase (COX)-2, an inducible isozyme of cyclooxygenase, is induced by bile acids and correlates with the incidence and progression of cancers. In this study, we investigated the signal transduction pathways involved in the bile-acid-mediated induction of COX-2 expression. We found that staurosporine (sts), a potent protein kinase C (PKC) inhibitor, synergistically potentiated the deoxycholate-mediated induction of COX-2 expression. Sts did not increase the stabilization of COX-2 mRNA. The sts- and deoxycholate-mediated synergistic induction of COX-2 expression was suppressed by a membrane-permeable Ca(2+) chelator, a phosphoinositide 3-kinase inhibitor, a nuclear factor-κB pathway inhibitor, and inhibitors of canonical and stress-inducible mitogen-activated protein kinase pathways. Inhibition was also observed using PKC inhibitors, suggesting the involvement of certain PKC isozymes (η, θ, ι, ζ, or μ). Our results indicate that sts exerts its potentiating effects via the phosphorylation of p38. However, the effects of anisomycin did not mimic those of sts, indicating that although p38 activation is required, it does not enhance deoxycholate-induced COX-2 expression. We conclude that staurosporine synergistically enhances deoxycholate-induced COX-2 expression in RCM-1 colon cancer cells. © 2014 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Electrochemically mediated polymerization for highly sensitive detection of protein kinase activity.

PubMed

Hu, Qiong; Wang, Qiangwei; Jiang, Cuihua; Zhang, Jian; Kong, Jinming; Zhang, Xueji

2018-07-01

Protein kinases play a pivotal role in cellular regulation and signal transduction, the detection of protein kinase activity and inhibition is therefore of great importance to clinical diagnosis and drug discovery. In this work, a novel electrochemical platform using the electrochemically mediated polymerization as an efficient and cost-effective signal amplification strategy is described for the highly sensitive detection of protein kinase activity. This platform involves 1) the phosphorylation of substrate peptide by protein kinase, 2) the attachment of alkyl halide to the phosphorylated sites via the carboxylate-Zr 4+ -phosphate chemistry, and 3) the in situ grafting of electroactive polymers from the phosphorylated sites through the electrochemically mediated atom transfer radical polymerization (eATRP) at a negative potential, in the presence of the surface-attached alkyl halide as the initiator and the electroactive tag-conjugated acrylate as the monomer, respectively. Due to the electrochemically mediated polymerization, a large number of electroactive tags can be linked to each phosphorylated site, thereby greatly improving the detection sensitivity. This platform has been successfully applied to detect the activity of cAMP-dependent protein kinase (PKA) with a detection limit down to 1.63 mU mL -1 . Results also demonstrate that it is highly selective and can be used for the screening of protein kinase inhibitors. The potential application of our platform for protein kinase activity detection in complex biological samples has been further verified using normal human serum and HepG2 cell lysate. Moreover, our platform is operationally simple, highly efficient and cost-effective, thus holding great potential in protein kinase detection and inhibitor screening. Copyright © 2018 Elsevier B.V. All rights reserved.

Traumatic symptomatology in children who witness marital violence.

PubMed

Finkelstein, J; Yates, J K

2001-01-01

For many years, research has demonstrated the devastating effects of violence upon children, particularly in the form of direct physical and sexual abuse. What has only recently come to into focus are the potential effects of witnessing violence upon children. This area of vicarious victimization seems of particular import given the fact that so many youngsters are known to witness violent acts within their own households. This paper shall review the psychological effects which may be effected upon children as a result of witnessing marital violence. Relevant research issues concerning the potential roles of moderating and mediating variables will also be discussed.

Discovery of a Positive Allosteric Modulator of the Thyrotropin Receptor: Potentiation of Thyrotropin-Mediated Preosteoblast Differentiation In Vitro

PubMed Central

Eliseeva, Elena; Boutin, Alisa; Barnaeva, Elena; Ferrer, Marc; Southall, Noel; Kim, David; Hu, Xin; Morgan, Sarah J.; Marugan, Juan J.; Gershengorn, Marvin C.

2018-01-01

Recently, we showed that TSH-enhanced differentiation of a human preosteoblast-like cell model involved a β-arrestin 1 (β-Arr 1)-mediated pathway. To study this pathway in more detail, we sought to discover a small molecule ligand that was functionally selective toward human TSH receptor (TSHR) activation of β-Arr 1. High-throughput screening using a cell line stably expressing mutated TSHRs and mutated β-Arr 1 (DiscoverX1 cells) led to the discovery of agonists that stimulated translocation of β-Arr 1 to the TSHR, but did not activate Gs-mediated signaling pathways, i.e., cAMP production. D3-βArr (NCGC00379308) was selected. In DiscoverX1 cells, D3-βArr stimulated β-Arr 1 translocation with a 5.1-fold greater efficacy than TSH and therefore potentiated the effect of TSH in stimulating β-Arr 1 translocation. In human U2OS-TSHR cells expressing wild-type TSHRs, which is a model of human preosteoblast-like cells, TSH upregulated the osteoblast-specific genes osteopontin (OPN) and alkaline phosphatase (ALPL). D3-βArr alone had only a weak effect to upregulate these bone markers, but D3-βArr potentiated TSH-induced upregulation of ALPL and OPN mRNA levels 1.6-fold and 5.5-fold, respectively, at the maximum dose of ligands. Furthermore, the positive allosteric modulator effect of D3-βArr resulted in an increase of TSH-induced secretion of OPN protein. In summary, we have discovered the first small molecule positive allosteric modulator of TSHR. As D3-βArr potentiates the effect of TSH to enhance differentiation of a human preosteoblast in an in vitro model, it will allow a novel experimental approach for probing the role of TSH-induced β-Arr 1 signaling in osteoblast differentiation. PMID:29089368

Discovery of a Positive Allosteric Modulator of the Thyrotropin Receptor: Potentiation of Thyrotropin-Mediated Preosteoblast Differentiation In Vitro.

PubMed

Neumann, Susanne; Eliseeva, Elena; Boutin, Alisa; Barnaeva, Elena; Ferrer, Marc; Southall, Noel; Kim, David; Hu, Xin; Morgan, Sarah J; Marugan, Juan J; Gershengorn, Marvin C

2018-01-01

Recently, we showed that TSH-enhanced differentiation of a human preosteoblast-like cell model involved a β -arrestin 1 ( β -Arr 1)-mediated pathway. To study this pathway in more detail, we sought to discover a small molecule ligand that was functionally selective toward human TSH receptor (TSHR) activation of β -Arr 1. High-throughput screening using a cell line stably expressing mutated TSHRs and mutated β -Arr 1 (DiscoverX1 cells) led to the discovery of agonists that stimulated translocation of β -Arr 1 to the TSHR, but did not activate G s -mediated signaling pathways, i.e., cAMP production. D3- β Arr (NCGC00379308) was selected. In DiscoverX1 cells, D3- β Arr stimulated β -Arr 1 translocation with a 5.1-fold greater efficacy than TSH and therefore potentiated the effect of TSH in stimulating β -Arr 1 translocation. In human U2OS-TSHR cells expressing wild-type TSHRs, which is a model of human preosteoblast-like cells, TSH upregulated the osteoblast-specific genes osteopontin (OPN) and alkaline phosphatase (ALPL). D3- β Arr alone had only a weak effect to upregulate these bone markers, but D3- β Arr potentiated TSH-induced upregulation of ALPL and OPN mRNA levels 1.6-fold and 5.5-fold, respectively, at the maximum dose of ligands. Furthermore, the positive allosteric modulator effect of D3- β Arr resulted in an increase of TSH-induced secretion of OPN protein. In summary, we have discovered the first small molecule positive allosteric modulator of TSHR. As D3- β Arr potentiates the effect of TSH to enhance differentiation of a human preosteoblast in an in vitro model, it will allow a novel experimental approach for probing the role of TSH-induced β -Arr 1 signaling in osteoblast differentiation. U.S. Government work not protected by U.S. copyright.

Zinc and Autophagy

PubMed Central

Liuzzi, Juan P.; Guo, Liang; Yoo, Changwon; Stewart, Tiffanie S

2014-01-01

Autophagy is a highly conserved degradative process through which cells overcome stressful conditions. Inasmuch as faulty autophagy has been associated with aging, neuronal degeneration disorders, diabetes, and fatty liver, autophagy is regarded as a potential therapeutic target. This review summarizes the present state of knowledge concerning the role of zinc in the regulation of autophagy, the role of autophagy in zinc metabolism, and the potential role of autophagy as a mediator of the protective effects of zinc. Data from in vitro studies consistently support the notion that zinc is critical for early and late autophagy. Studies have shown inhibition of early and late autophagy in cells cultured in medium treated with zinc chelators. Conversely, excess zinc added to the medium has shown to potentiate the stimulation of autophagy by tamoxifen, H2O2, ethanol and dopamine. The potential role of autophagy in zinc homeostasis has just begun to be investigated.Increasing evidence indicates that autophagy dysregulation causes significant changes in cellular zinc homeostasis. Autophagy may mediate the protective effect of zinc against lipid accumulation, apoptosis and inflammation by promoting degradation of lipid droplets, inflammasomes, p62/SQSTM1 and damaged mitochondria.Studies with humans and animal models are necessary to determine whether autophagy is influenced by zinc intake. PMID:25012760

A neuronal mechanism of propofol-induced central respiratory depression in newborn rats.

PubMed

Kashiwagi, Masanori; Okada, Yasumasa; Kuwana, Shun-Ichi; Sakuraba, Shigeki; Ochiai, Ryoichi; Takeda, Junzo

2004-07-01

The neural mechanisms of propofol-induced central respiratory depression remain poorly understood. In the present study, we studied these mechanisms and the involvement of gamma-aminobutyric acid (GABA)A receptors in propofol-induced central respiratory depression. The brainstem and the cervical spinal cord of 1- to 4-day-old rats were isolated, and preparations were maintained in vitro with oxygenated artificial cerebrospinal fluid. Rhythmic inspiratory burst activity was recorded from the C4 spinal ventral root. The activity of respiratory neurons in the ventrolateral medulla was recorded using a perforated patch-clamp technique. We found that bath-applied propofol decreased C4 inspiratory burst rate, which could be reversed by the administration of a GABAA antagonist, bicuculline. Propofol caused resting membrane potentials to hyperpolarize and suppressed the firing of action potentials in preinspiratory and expiratory neurons. In contrast, propofol had little effect on resting membrane potentials and action potential firing in inspiratory neurons. Our findings suggest that the depressive effects of propofol are, at least in part, mediated by the agonistic action of propofol on GABAA receptors. It is likely that the GABAA receptor-mediated hyperpolarization of preinspiratory neurons serves as the neuronal basis of propofol-induced respiratory depression in the newborn rat.

Curcumin as a potential therapeutic candidate for Helicobacter pylori associated diseases

PubMed Central

Sarkar, Avijit; De, Ronita; Mukhopadhyay, Asish K

2016-01-01

Curcumin, a yellow pigment and principal polyphenolic Curcuminoid obtained from the turmeric rhizome Curcuma longa, is commonly used as a food-coloring agent. Studies suggest that curcumin has a wide range of beneficial properties e.g., anti-inflammatory, anti-oxidant, anti-cancer, anti-proliferative, anti-fungal and anti-microbial. These pleiotropic activities prompted several research groups to elucidate the role of curcumin in Helicobacter pylori (H. pylori) infection. This is the first review with this heading where we discussed regarding the role of curcumin as an anti-H. pylori agent along with its potential in other gastrointestinal diseases. Based on several in vitro, early cell culture, animal research and few pre-clinical trials, curcumin projected as a potential therapeutic candidate against H. pylori mediated gastric pathogenesis. This review sheds light on the anti-H. pylori effects of curcumin in different models with meticulous emphasis on its anti-oxidant, anti-inflammatory and anti-carcinogenic effects as well as some critical signaling and effecter molecules. Remarkably, non-toxic molecule curcumin fulfills the characteristics for an ideal chemopreventive agent against H. pylori mediated gastric carcinogenesis but the foremost challenge is to obtain the optimum therapeutic levels of curcumin, due to its low solubility and poor bioavailability. Further, we have discussed about the possibilities for improving its efficacy and bioavailability. Lastly, we concluded with the anticipation that in near future curcumin may be used to develop a therapeutic drug against H. pylori mediated gastric ailments through improved formulation or delivery systems, facilitating its enhanced absorption and cellular uptake. PMID:26973412

Identifying cis-mediators for trans-eQTLs across many human tissues using genomic mediation analysis.

PubMed

Yang, Fan; Wang, Jiebiao; Pierce, Brandon L; Chen, Lin S

2017-11-01

The impact of inherited genetic variation on gene expression in humans is well-established. The majority of known expression quantitative trait loci (eQTLs) impact expression of local genes ( cis -eQTLs). More research is needed to identify effects of genetic variation on distant genes ( trans -eQTLs) and understand their biological mechanisms. One common trans -eQTLs mechanism is "mediation" by a local ( cis ) transcript. Thus, mediation analysis can be applied to genome-wide SNP and expression data in order to identify transcripts that are " cis -mediators" of trans -eQTLs, including those " cis -hubs" involved in regulation of many trans -genes. Identifying such mediators helps us understand regulatory networks and suggests biological mechanisms underlying trans -eQTLs, both of which are relevant for understanding susceptibility to complex diseases. The multitissue expression data from the Genotype-Tissue Expression (GTEx) program provides a unique opportunity to study cis -mediation across human tissue types. However, the presence of complex hidden confounding effects in biological systems can make mediation analyses challenging and prone to confounding bias, particularly when conducted among diverse samples. To address this problem, we propose a new method: Genomic Mediation analysis with Adaptive Confounding adjustment (GMAC). It enables the search of a very large pool of variables, and adaptively selects potential confounding variables for each mediation test. Analyses of simulated data and GTEx data demonstrate that the adaptive selection of confounders by GMAC improves the power and precision of mediation analysis. Application of GMAC to GTEx data provides new insights into the observed patterns of cis -hubs and trans -eQTL regulation across tissue types. © 2017 Yang et al.; Published by Cold Spring Harbor Laboratory Press.

NMDA receptor-mediated long term modulation of electrically evoked field potentials in the rat medial vestibular nuclei.

PubMed

Capocchi, G; Della Torre, G; Grassi, S; Pettorossi, V E; Zampolini, M

1992-01-01

The effect of high frequency stimulation (HFS) of the primary vestibular afferents on field potentials recorded in the ipsilateral Medial Vestibular Nuclei (MVN) was studied. Our results show that potentiation and depression can be induced in different portions of MVN, which are distinguishable by their anatomical organization. HFS induces potentiation of the monosynaptic component in the ventral portion of the MVN, whereas it provokes depression of the polysynaptic component in the dorsal portion of the same nucleus. The induction of both potentiation and depression was blocked under AP5 perfusion, thus demonstrating that NMDA receptor activation mediates both phenomena. Furthermore, the finding that the field potentials were not modified during perfusion with DL-AP5, as previously reported, supports the hypothesis that NMDA receptors are not involved in the normal synaptic transmission from the primary vestibular afferent fibres, but are only activated following hyperstimulation of this afferent system. Our results suggest that the mechanisms of long term modification of synaptic efficacy observed in MVN may underlie the plasticity phenomena occurring in vestibular nuclei.

The effect of Cree traditional medicinal teas on the activity of human cytochrome P450-mediated metabolism.

PubMed

Tam, Teresa W; Liu, Rui; Saleem, Ammar; Arnason, John T; Krantis, Anthony; Haddad, Pierre S; Foster, Brian C

2014-08-08

Rhododendron groenlandicum (Bog Labrador tea), Rhododendron tomentosum (Marsh Labrador tea) and Juniperus communis (Juniper) are used in medicinal teas by Canadian aboriginal cultures alone and in combination with conventional drug products. The safety of this combination had not been previously examined and this study was initiated to examine the potential of medicinal teas to inhibit the major human drug metabolizing enzyme, cytochrome P450 3A4 (CYP3A4). The decoctions of Rhododendron groenlandicum and Rhododendron tomentosum leaves and Juniperus communis berries were examined in a microtiter fluorometric assay to examine their potential to inhibit CYP-mediated metabolism. The decoctions showed progressive inhibition towards CYP3A4 the longer the leaves or berries were brewed. R. Rhododendron groenlandicum and Juniperus communis may have the potential to inhibit CYP3A4-mediated metabolism. The findings of this study with these traditional medicines are significant in that they provide mechanistic support that these products have the potential to affect the safety and efficacy of other health and medicinal products. As this study only examined CYP3A4, it is possible that these medicinals contain substances that could also affect other metabolic enzymes. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Effective Stress Management: A Model of Emotional Intelligence, Self-Leadership, and Student Stress Coping

ERIC Educational Resources Information Center

Houghton, Jeffery D.; Wu, Jinpei; Godwin, Jeffrey L.; Neck, Christopher P.; Manz, Charles C.

2012-01-01

This article develops and presents a model of the relationships among emotional intelligence, self-leadership, and stress coping among management students. In short, the authors' model suggests that effective emotion regulation and self-leadership, as mediated through positive affect and self-efficacy, has the potential to facilitate stress coping…

Statistical Power for Causally Defined Indirect Effects in Group-Randomized Trials with Individual-Level Mediators

ERIC Educational Resources Information Center

Kelcey, Benjamin; Dong, Nianbo; Spybrook, Jessaca; Cox, Kyle

2017-01-01

Designs that facilitate inferences concerning both the total and indirect effects of a treatment potentially offer a more holistic description of interventions because they can complement "what works" questions with the comprehensive study of the causal connections implied by substantive theories. Mapping the sensitivity of designs to…

Influence of Human Factor Issues on Patient-Centered mHealth Apps' Impact; Where Do We Stand?

PubMed

Wildenbos, G A; Peute, L W; Jaspers, M W M

2016-01-01

This paper discusses the preliminary results of a literature review on studies published in 2014-2015 concerning patient-centered mHealth applications' (apps) impact. Abstracts were included when they described a mHealth app targeted at patients and reported on the effects of this app on patient care. From a total of 559 potentially relevant articles, 17 papers were finally included. Nine studies reported a positive impact of the patient-centered mHealth app on patient care; 4 of these studies were randomized controlled trials. Measured impacts in the 17 studies focused on improving patients' physical activity, self-efficacy and medication adherence. Human factors issues potentially mediating these effects were discussed in all studies. Transitions in the interaction between healthcare providers and their patients were most often discussed as influencing the impact of the mHealth app. More research is needed, focussing on human issues mediating the effect of patient-centered mHealth apps to precipitate knowledge on the effectiveness of mHealth. This research should preferably be guided by socio-technical models.

Sodium channel γENaC mediates IL-17 synergized high salt induced inflammatory stress in breast cancer cells

PubMed Central

Amara, Suneetha; Ivy, Michael T; Myles, Elbert L; Tiriveedhi, Venkataswarup

2015-01-01

Chronic inflammation is known to play a critical role in the development of cancer. Recent evidence suggests that high salt in the tissue microenvironment induces chronic inflammatory milieu. In this report, using three breast cancer-related cell lines, we determined the molecular basis of the potential synergistic inflammatory effect of sodium chloride (NaCl) with interleukin-17 (IL-17). Combined treatment of high NaCl (0.15 M) with sub-effective IL-17 (0.1 nM) induced enhanced growth in breast cancer cells along with activation of reactive nitrogen and oxygen (RNS/ROS) species known to promote cancer. Similar effect was not observed with equi-molar mannitol. This enhanced of ROS/RNS activity correlates with upregulation of γENaC an inflammatiory sodium channel. The similar culture conditions have also induced expression of pro-inflammatory cytokines such as IL-6, TNFα etc. Taken together, these data suggest that high NaCl in the cellular microenvironment induces a γENaC mediated chronic inflammatory response with a potential pro-carcinogenic effect. PMID:26723502

Effects of an online alcohol education course among college freshmen: an investigation of potential mediators.

PubMed

Paschall, Mallie J; Ringwalt, Chris; Wyatt, Todd; Dejong, William

2014-04-01

The authors investigated possible mediating effects of psychosocial variables (perceived drinking norms, positive and negative alcohol expectancies, personal approval of alcohol use, protective behavioral strategies) targeted by an online alcohol education course (AlcoholEdu for College) as part of a 30-campus randomized trial with 2,400 first-year students. Previous multilevel analyses have found significant effects of the AlcoholEdu course on the frequency of past-30-day alcohol use and binge drinking during the fall semester, and the most common types of alcohol-related problems. Exposure to the online AlcoholEdu course was inversely related to perceived drinking norms but was not related to any of the other psychosocial variables. Multilevel analyses indicated at least partial mediating effects of perceived drinking norms on behavioral outcomes. Findings of this study suggest that AlcoholEdu for College affects alcohol use and related consequences indirectly through its effect on student perceptions of drinking norms. Further research is needed to better understand why this online course did not appear to affect other targeted psychosocial variables.

Heart rate variability and the relationship between trauma exposure age, and psychopathology in a post-conflict setting.

PubMed

Liddell, Belinda J; Kemp, Andrew H; Steel, Zachary; Nickerson, Angela; Bryant, Richard A; Tam, Natalino; Tay, Alvin Kuowei; Silove, Derrick

2016-05-10

Cumulative exposure to potentially traumatic events (PTEs) increases risk for mental distress in conflict-affected settings, but the psychophysiological mechanisms that mediate this dose-response relationship are unknown. We investigated diminished heart rate variability (HRV) - an index of vagus nerve function and a robust predictor of emotion regulation capacity - as a vulnerability marker that potentially mediates the association between PTE exposure, age and symptoms of posttraumatic stress disorder (PTSD), psychological distress and aggressive behavior, in a community sample from Timor-Leste - a post-conflict country with a history of mass violence. Resting state heart rate data was recorded from 45 cases of PTSD, depression and intermittent explosive disorder (IED); and 29 non-case controls. Resting HRV was significantly reduced in the combined case group compared with non-cases (p = .021; Cohen's d = 0.5). A significant mediation effect was also observed, whereby a sequence of increased age, reduced HRV and elevated PTSD symptoms mediated the association between PTE exposure and distress (B = .06, SE = .05, 95% CI = [.00-.217]) and aggression (B = .02, SE = .02, 95% CI = [.0003-.069])). The findings demonstrate an association between diminished resting HRV and psychopathology. Moreover, age-related HRV reductions emerged as a potential psychophysiological mechanism that underlies enhanced vulnerability to distress and aggression following cumulative PTE exposure.

Elucidating the relation between childhood emotional abuse and depressive symptoms in adulthood: The mediating role of maladaptive interpersonal processes

PubMed Central

Massing-Schaffer, Maya; Liu, Richard T.; Kraines, Morganne A.; Choi, Jimmy Y.; Alloy, Lauren B.

2015-01-01

Objective The purpose of this study is to assess the potential unique and relative mediating effects of three interpersonal risk factors (i.e., excessive reassurance-seeking [ERS], negative feedback seeking [NFS], and rejection sensitivity [RS]) in the relationship between childhood emotional abuse (CEA) and depressive symptoms. Method One hundred eighty-five undergraduates were followed over a four-month interval. Participants completed assessments of childhood abuse history, ERS, NFS, and RS, and depressive symptoms at baseline, as well as depressive symptoms at four-month followup. Results Findings from single-mediator analyses indicated that RS and NFS, but not ERS, mediated the relationship between CEA and prospective depressive symptoms, after accounting for childhood sexual and physical abuse, as well as baseline depressive symptoms. In our multi-mediator model, only RS remained a significant mediator of the relationship between CEA and prospective depressive symptoms. Conclusions The current study provides preliminary evidence that negative behavioral styles may function as a mechanism linking prior experiences of CEA to subsequent depressive symptoms. Clinical implications of these findings suggest that targeting maladaptive behavioral tendencies, particularly RS, may be an effective adjunct in behavioral modification treatments of CEA victims at risk for depression. PMID:26246650

Mediating pathways in the socio-economic gradient of child development

PubMed Central

Attanasio, Orazio; Grantham-McGregor, Sally

2016-01-01

Research has previously shown a gap of near 0.5 of a standard deviation (SD) in cognition and language development between the top and bottom household wealth quartile in children aged 6–42 months in a large representative sample of low- and middle-income families in Bogota, using the Bayley Scales of Infant and Toddler Development. The gaps in fine motor and socio-emotional development were about half that size. Developmental deficits increased with age. The current study explored the associations amongst child development, household socio-economic status (SES), and a set of potential mediating variables—parental characteristics, child biomedical factors, and the quality of the home environment—in this sample. We ran mediation tests to quantify the contribution of these variables to the SES gap, and explored the role of age as a moderator. Parental education, particularly maternal education, and the quality of the home environment mediated the SES gap in all outcomes examined. Height-for-age mediated a small amount of the deficit in language scales only. More educated mothers provided better home stimulation than less educated mothers and the home environment partly mediated the effect of maternal education. These results suggested that in interventions aimed at promoting child development, those focusing on the quality of the home environment should be effective. PMID:27885311

Negative evaluations of self and others, and peer victimization as mediators of the relationship between childhood adversity and psychotic experiences in adolescence: the moderating role of loneliness.

PubMed

Murphy, Siobhan; Murphy, Jamie; Shevlin, Mark

2015-09-01

Previous research has identified an association between traumatic experiences and psychotic symptoms. Few studies, however, have explored the underlying mechanisms and contingent nature of these associations in an integrated model. This study aimed to test a moderated mediation model of negative childhood experiences, associated cognitive processes, and psychotic experiences within a context of adolescent loneliness. Cross-sectional survey. A total of 785 Northern Irish secondary school adolescents completed the survey. A moderated mediation model was specified and tested. Childhood experiences of threat and subordination were directly associated with psychotic experiences. Analyses indicated that peer victimization was a mediator of this effect and that loneliness moderated this mediated effect. A new model is proposed to provide an alternative framework for assessing the association between trauma and psychotic experience in adolescence that recognizes loneliness as a significant contextual moderator that can potentially strengthen the trauma-psychosis relationship. Moderated mediation analyses poses an alternative framework to the understanding of trauma-psychosis associations Adolescent loneliness is a vulnerability factor within this association Data are based on a Northern Irish sample with relatively low levels of loneliness Cross-sectional data cannot explore the developmental course of these experiences in adolescence. © 2015 The British Psychological Society.

[The role of VEGF, HSP-70 and protein S-100B in the potentiation effect of the neuroprotective effect of hypercapnic hypoxia].

PubMed

Bespalov, A G; Tregub, P P; Kulikov, V P; Pijanzin, A I; Belousov, A A

2014-01-01

Studied the role of VEGF, HSP-70 and S-100B in potentiating hypercapnia neuroprotective effect of hypoxia. Demonstrated that neuroprotective effects when exposed hypercapnic hypoxia-mediated protein synthesis increased S-100B, mainly due to the action of carbon dioxide, and not oxygen deficiency. Neuroprotective effects of HSP-70 due to hypoxia, but the combined effect of hypoxia and hypercapnia gives a significant increase in the synthesis of HSP-70 in comparison with the isolated effect of hypoxia. Vascularization activated equally as hypoxia and hypercapnia, without adding significant effects in combination. This suggests dominant effect hypercapnia, hypoxia compared in neuroprotection mechanisms related to protein S-100B, but not the protein VEGF, hypercapnia and potentiate the neuroprotective efficacy of hypoxia-related protein HSP-70.

Molecular mechanisms of hypolipidemic effects of curcumin

USDA-ARS?s Scientific Manuscript database

Recent evidence suggests potential benefits from phytochemicals and micronutrients in reducing the elevated oxidative- and lipid-mediated stress present during inflammation, obesity and atherosclerosis. These compounds may either directly scavenge reactive oxygen or nitrogen species or they may modu...

Ascomycin macrolactam derivative SDZ ASM 981 inhibits the release of granule-associated mediators and of newly synthesized cytokines in RBL 2H3 mast cells in an immunophilin-dependent manner.

PubMed

Hultsch, T; Müller, K D; Meingassner, J G; Grassberger, M; Schopf, R E; Knop, J

1998-09-01

Mast cells play an important role in the pathological development of many inflammatory and allergic diseases and inhibition of mast cell activation is a potential target for therapeutic intervention. Therefore, the effect of the novel ascomycin macrolactam derivative SDZ ASM 981 on Fc epsilonRI-mediated activation of rat basophilic leukemia (RBL) cells, as a model for mast cell activation, was investigated. First, the ability to inhibit different mast cell immunophilins in vitro was tested. Using recombinant macrophilin-12 (FKBP-12), inhibition of rotamase activity with an IC50 of approximately 6 nM was observed. The rotamase activity of cyclophilin A (18 kDa) was not affected. Secondly, the effect of SDZ ASM 981 on Fc epsilonRI-mediated mast cell activation was investigated in the RBL cell model. SDZ ASM 981 inhibited exocytosis of preformed mediators (e.g. serotonin) with an IC50 of approximately 30 nM. Transcription and release of newly synthesized mediators (e.g. TNF-alpha) was inhibited with an IC50 of approximately 100 nM. The inhibitory effect of SDZ ASM 981 was antagonized by rapamycin. We conclude that SDZ ASM 981 is a potent inhibitor of Fc epsilonRI-mediated activation of mast cells in vitro. The mechanism of action involves formation of (calcineurin) inhibitory complexes with macrophilins. We suggest that this inhibitory action on mast cells might contribute to the antiinflammatory effect of SDZ ASM 981 observed in vivo (e.g. in aptopic dermatitis and psoriasis).

Effects of Child Psychopathology on Maternal Depression: The Mediating Role of Child-Related Acute and Chronic Stressors

ERIC Educational Resources Information Center

Raposa, Elizabeth B.; Hammen, Constance L.; Brennan, Patricia A.

2011-01-01

In light of recent research highlighting the potential effects of children's behavior on mothers' mental health, the current study examined 679 mothers and their adolescent children from a community-based sample to determine the effects of youth psychopathology on maternal depression and levels of child-related stress in mothers' lives. It was…

The effects of gender discrimination on refugee torture survivors: a cross-cultural traumatology perspective.

PubMed

Kira, Ibrahim A; Smith, Iris; Lewandowski, Linda; Templin, Thomas

2010-09-01

Trauma developmental theory identifies gender discrimination (GD) as a type of persistent, ongoing trauma that has the potential for serious, negative effects on mental health. This study was conducted to examine the potential role of GD in the development of cumulative trauma disorders (CTD) and symptoms of posttraumatic stress disorder (PTSD) as well as the role of GD in mediating the effects of other traumas on these disorders. The sample included 160 female torture survivors from more than 30 countries. Measures of PTSD, CTD, and types of trauma exposure were acquired as part of a larger study on refugee torture survivors. Structural equation modeling was used to test several plausible models for the direct and indirect effects of GD on PTSD and CTD, within the context of other trauma exposure. Results suggest that GD mediates the effects of identity traumas on CTD and PTSD. GD also had direct effects on CTD, including relationships with dissociation, suicidality, and deficits in executive function. GD did not appear to directly influence the development of PTSD. The implications of these results for assessment and treatment of women's trauma-related disorders as well as strategies for their prevention are discussed.

Evidence that theory of planned behaviour variables mediate the effects of socio-demographic variables on homeless people's participation in service programmes.

PubMed

Christian, Julie; Armitage, Christopher J; Abrams, Dominic

2007-09-01

This article reports findings from two studies (N = 88, N = 100) using Ajzen's theory of planned behaviour (TPB) to predict homeless people's uptake of service programmes. Study 1 was conducted with an opportunity sample whereas Study 2 employed a representative sample. Both studies provide support for the application of the TPB, and demonstrate that the effects of demographic characteristics on behaviour were mediated by TPB variables. The discussion focuses on the role of attitudinal and normative components in actual behaviour, and on the potential role of social normative processes and stigmatization in homeless people's uptake of services.

Testing the Causal Direction of Mediation Effects in Randomized Intervention Studies.

PubMed

Wiedermann, Wolfgang; Li, Xintong; von Eye, Alexander

2018-05-21

In a recent update of the standards for evidence in research on prevention interventions, the Society of Prevention Research emphasizes the importance of evaluating and testing the causal mechanism through which an intervention is expected to have an effect on an outcome. Mediation analysis is commonly applied to study such causal processes. However, these analytic tools are limited in their potential to fully understand the role of theorized mediators. For example, in a design where the treatment x is randomized and the mediator (m) and the outcome (y) are measured cross-sectionally, the causal direction of the hypothesized mediator-outcome relation is not uniquely identified. That is, both mediation models, x → m → y or x → y → m, may be plausible candidates to describe the underlying intervention theory. As a third explanation, unobserved confounders can still be responsible for the mediator-outcome association. The present study introduces principles of direction dependence which can be used to empirically evaluate these competing explanatory theories. We show that, under certain conditions, third higher moments of variables (i.e., skewness and co-skewness) can be used to uniquely identify the direction of a mediator-outcome relation. Significance procedures compatible with direction dependence are introduced and results of a simulation study are reported that demonstrate the performance of the tests. An empirical example is given for illustrative purposes and a software implementation of the proposed method is provided in SPSS.

The Association Between Obesity and Cognitive Function in Older Persons: How Much Is Mediated by Inflammation, Fasting Plasma Glucose, and Hypertriglyceridemia?

PubMed

Gunathilake, Roshan; Oldmeadow, Christopher; McEvoy, Mark; Inder, Kerry J; Schofield, Peter W; Nair, Balakrishnan R; Attia, John

2016-12-01

The aim of the study was to determine how much of the association between obesity, measured by body mass index (BMI), and cognition in older persons is mediated through inflammation, fasting plasma glucose, and hypertriglyceridemia. Anthropometrics, high-sensitivity C-reactive protein (CRP), fasting plasma glucose, and serum triglycerides were measured in 3,256 community-dwelling individuals aged 55-85 years residing in Newcastle, New South Wales, Australia. Audio recorded cognitive screen (ARCS) was used to assess multiple cognitive domains. Mediation analyses showed very modest but significant direct mediation effects, whereby obesity was associated with better cognitive function after adjusting for potential confounders (controlled direct effect ≈ 1/500 point increase in the total ARCS score per 1.0-kg/m 2 increase in BMI). There were significant indirect negative mediation effects from BMI to cognition mediated through CRP, that is, increased BMI was associated with increased CRP which was associated with decreased cognition (natural indirect effect -0.20 unit; 95% confidence interval [CI] -0.39, -0.02), and through fasting plasma glucose, that is, increased BMI was associated with increased fasting plasma glucose which was associated with decreased cognition (natural indirect effect -0.12 unit; 95% CI -0.24, -0.01], but not through serum triglycerides. There is a weak positive association between obesity and cognitive performance in older persons, which is partially antagonized by inflammation and elevated fasting plasma glucose, but not hypertriglyceridemia. Further studies are needed to elucidate whether this is due to selection bias, or truly reflects biologically complex and counter balancing pathways involved in obesity. © The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Transancestral fine-mapping of four type 2 diabetes susceptibility loci highlights potential causal regulatory mechanisms

PubMed Central

Horikoshi, Momoko; Pasquali, Lorenzo; Wiltshire, Steven; Huyghe, Jeroen R.; Mahajan, Anubha; Asimit, Jennifer L.; Ferreira, Teresa; Locke, Adam E.; Robertson, Neil R.; Wang, Xu; Sim, Xueling; Fujita, Hayato; Hara, Kazuo; Young, Robin; Zhang, Weihua; Choi, Sungkyoung; Chen, Han; Kaur, Ismeet; Takeuchi, Fumihiko; Fontanillas, Pierre; Thuillier, Dorothée; Yengo, Loic; Below, Jennifer E.; Tam, Claudia H.T.; Wu, Ying; Abecasis, Gonçalo; Altshuler, David; Bell, Graeme I.; Blangero, John; Burtt, Noél P.; Duggirala, Ravindranath; Florez, Jose C.; Hanis, Craig L.; Seielstad, Mark; Atzmon, Gil; Chan, Juliana C.N.; Ma, Ronald C.W.; Froguel, Philippe; Wilson, James G.; Bharadwaj, Dwaipayan; Dupuis, Josee; Meigs, James B.; Cho, Yoon Shin; Park, Taesung; Kooner, Jaspal S.; Chambers, John C.; Saleheen, Danish; Kadowaki, Takashi; Tai, E. Shyong; Mohlke, Karen L.; Cox, Nancy J.; Ferrer, Jorge; Zeggini, Eleftheria; Kato, Norihiro; Teo, Yik Ying; Boehnke, Michael; McCarthy, Mark I.; Morris, Andrew P.

2016-01-01

To gain insight into potential regulatory mechanisms through which the effects of variants at four established type 2 diabetes (T2D) susceptibility loci (CDKAL1, CDKN2A-B, IGF2BP2 and KCNQ1) are mediated, we undertook transancestral fine-mapping in 22 086 cases and 42 539 controls of East Asian, European, South Asian, African American and Mexican American descent. Through high-density imputation and conditional analyses, we identified seven distinct association signals at these four loci, each with allelic effects on T2D susceptibility that were homogenous across ancestry groups. By leveraging differences in the structure of linkage disequilibrium between diverse populations, and increased sample size, we localised the variants most likely to drive each distinct association signal. We demonstrated that integration of these genetic fine-mapping data with genomic annotation can highlight potential causal regulatory elements in T2D-relevant tissues. These analyses provide insight into the mechanisms through which T2D association signals are mediated, and suggest future routes to understanding the biology of specific disease susceptibility loci. PMID:26911676

The effect of prenatal maternal cigarette smoking on children's BMI z-score with SGA as a mediator.

PubMed

Salahuddin, Meliha; Pérez, Adriana; Ranjit, Nalini; Hoelscher, Deanna M; Kelder, Steven H

2018-02-21

The goal of this study was to assess the effect of prenatal maternal cigarette smoking on children's BMI z-score trajectories, and to evaluate whether small-for-gestational-age (SGA) acts as a potential mediator between prenatal maternal cigarette smoking and child's BMI z-score at 4 years of age. Group-based trajectory modeling (GBTM) methods were employed to describe and classify developmental BMI z-score trajectories (the outcome of interest) in children from 9 months to 4 years of age (n = 5221) in the Early Childhood Longitudinal Study, Birth Cohort (ECLS-B) study (2001-2005). Further analysis examined whether the identified BMI z-score trajectories varied with the exposure, prenatal maternal cigarette smoking. Mediation analyses were utilized to examine whether being SGA (binary measure) acted as a potential mediator in the relationship between prenatal maternal cigarette smoking and BMI z-score among 4-year-old children. Using GBTM, two BMI z-score trajectory groups were identified: normal BMI z-score (57.8%); and high BMI z-score (42.2%). Children of mothers who smoked cigarettes during pregnancy were 2.1 times (RR 95% CI: 1.1-4.0, P value = 0.023) more at risk of being in the high BMI z-score trajectory group. Prenatal cigarette smoking was positively related to SGA at birth, but SGA was inversely related to BMI z-score at 4 years. The direct effect (0.19, 95% CI: 0.18, 0.19; P value < 0.001) of maternal cigarette smoking status during pregnancy on BMI z-score among 4-year-old children was stronger and in the opposite direction of the indirect effect (-0.04, 95% CI: -0.04, -0.04; P value < 0.001) mediated through SGA. In this study, prenatal maternal cigarette smoking was positively associated with the high BMI z-score group, as well with SGA. The effects of prenatal smoking on BMI z-score at 4 years appears to act through pathways other than SGA.

A novel histone deacetylase inhibitor prevents IL‐1β induced metabolic dysfunction in pancreatic β‐cells

PubMed Central

Susick, Laura; Senanayake, Thulani; Veluthakal, Rajakrishnan; Woster, Patrick M.

2009-01-01

Abstract The histone deacetylase (HDAC) inhibitor trichostatin A (TSA) has recently been shown to inhibit deleterious effects of cytokines on β‐cells, but it is unable to protect β‐cells from death due to its own cytotoxicity. Herein, we investigated novel HDAC inhibitors for their cytoprotective effects against IL‐1β‐induced damage to isolated β‐cells. We report that three novel compounds (THS‐73–44, THS‐72–5 and THS‐78–5) significantly inhibited HDAC activity and increased the acetylation of histone H4 in isolated β‐cells. Further, these compounds exerted no toxic effects on metabolic cell viability in these cells. However, among the three compounds tested, only THS‐78–5 protected against IL‐1β‐mediated loss in β‐cell viability. THS‐78–5 was also able to attenuate IL‐1β‐induced inducible nitric oxide synthase expression and subsequent NO release. Our data also indicate that the cytoprotective properties of THS‐78–5 against IL‐1β‐mediated effects may, in part, be due to inhibition of IL‐1β‐induced transactivation of nuclear factor κB (NF‐κB) in these cells. Together, we provide evidence for a novel HDAC inhibitor with a significant potential to prevent IL‐1β‐mediated effects on isolated β‐cells. Potential implications of these findings in the development of novel therapeutics to prevent deleterious effects of cytokines and the onset of autoimmune diabetes are discussed. PMID:20141611

β-adrenergic Receptor Blocker ICI 118,551 Selectively Increases Intermediate-Conductance Calcium-Activated Potassium Channel (IKCa )-Mediated Relaxations in Rat Main Mesenteric Artery.

PubMed

Ozkan, Melike Hacer; Uma, Serdar

2018-06-01

Endothelial IK C a and/or SK C a channels play an important role in the control of vascular tone by participating in endothelium-dependent relaxation. Whether β-AR antagonists, mainly used in hypertension, affect endothelial K C a channel function is unknown. In this study, we examined the effect of the β2-AR antagonist and inverse agonist ICI 118,551 on the IK C a /SK C a channel activity by assessing functional relaxation responses to several agonists that stimulate these channels. Mesenteric arterial rings isolated from male Sprague Dawley mounted to organ baths. Acetylcholine elicited IK C a - and SK C a -mediated relaxations that were abolished by TRAM-34 and apamin, respectively. ICI 118,551, which did not dilate the arteries per se, increased the IK C a -mediated relaxations, whereas SK C a -mediated relaxations remained unaltered. Same potentiating effect was also detected on the IK C a -mediated relaxations to carbachol and A23187, but not to NS309. Neither acetylcholine-induced nitric oxide-mediated relaxations nor SNP relaxations changed with ICI 118,551. The PKA inhibitor KT-5720, the selective β2-AR agonist salbutamol, the selective β2-AR antagonist butoxamine, the non-selective β-AR antagonist propranolol, and the inverse agonists carvedilol or nadolol failed to affect the IK C a -mediated relaxations. ICI 118,551-induced increase was not reversed by salbutamol or propranolol as well. Besides, low potassium-induced relaxations in endothelium-removed arteries remained the same in the presence of ICI 118,551. These data demonstrate a previously unrecognized action of ICI 118,551, the ability to potentiate endothelial IK C a channel-mediated vasodilation, through a mechanism independent of β2-AR antagonistic or inverse agonistic action. Instead, the enhancement of acetylcholine relaxation seems likely to occur by a mechanism secondary to endothelial calcium increase. © 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Mediators and moderators of long-term effects of violent video games on aggressive behavior: practice, thinking, and action.

PubMed

Gentile, Douglas A; Li, Dongdong; Khoo, Angeline; Prot, Sara; Anderson, Craig A

2014-05-01

Although several longitudinal studies have demonstrated an effect of violent video game play on later aggressive behavior, little is known about the psychological mediators and moderators of the effect. To determine whether cognitive and/or emotional variables mediate the effect of violent video game play on aggression and whether the effect is moderated by age, sex, prior aggressiveness, or parental monitoring. Three-year longitudinal panel study. A total of 3034 children and adolescents from 6 primary and 6 secondary schools in Singapore (73% male) were surveyed annually. Children were eligible for inclusion if they attended one of the 12 selected schools, 3 of which were boys' schools. At the beginning of the study, participants were in third, fourth, seventh, and eighth grades, with a mean (SD) age of 11.2 (2.1) years (range, 8-17 years). Study participation was 99% in year 1. The final outcome measure was aggressive behavior, with aggressive cognitions (normative beliefs about aggression, hostile attribution bias, aggressive fantasizing) and empathy as potential mediators. Longitudinal latent growth curve modeling demonstrated that the effects of violent video game play are mediated primarily by aggressive cognitions. This effect is not moderated by sex, prior aggressiveness, or parental monitoring and is only slightly moderated by age, as younger children had a larger increase in initial aggressive cognition related to initial violent game play at the beginning of the study than older children. Model fit was excellent for all models. Given that more than 90% of youths play video games, understanding the psychological mechanisms by which they can influence behaviors is important for parents and pediatricians and for designing interventions to enhance or mitigate the effects.

New method for characterizing electron mediators in microbial systems using a thin-layer twin-working electrode cell.

PubMed

Hassan, Md Mahamudul; Cheng, Ka Yu; Ho, Goen; Cord-Ruwisch, Ralf

2017-01-15

Microbial biofilms are significant ecosystems where the existence of redox gradients drive electron transfer often via soluble electron mediators. This study describes the use of two interfacing working electrodes (WEs) to simulate redox gradients within close proximity (250µm) for the detection and quantification of electron mediators. By using a common counter and reference electrode, the potentials of the two WEs were independently controlled to maintain a suitable "voltage window", which enabled simultaneous oxidation and reduction of electron mediators as evidenced by the concurrent anodic and cathodic currents, respectively. To validate the method, the electrochemical properties of different mediators (hexacyanoferrate, HCF, riboflavin, RF) were characterized by stepwise shifting the "voltage window" (ranging between 25 and 200mV) within a range of potentials after steady equilibrium current of both WEs was established. The resulting differences in electrical currents between the two WEs were recorded across a defined potential spectrum (between -1V and +0.5V vs. Ag/AgCl). Results indicated that the technique enabled identification (by the distinct peak locations at the potential scale) and quantification (by the peak of current) of the mediators for individual species as well as in an aqueous mixture. It enabled a precise determination of mid-potentials of the externally added mediators (HCF, RF) and mediators produced by pyocyanin-producing Pseudomonas aeruginosa (WACC 91) culture. The twin working electrode described is particularly suitable for studying mediator-dependent microbial electron transfer processes or simulating redox gradients as they exist in microbial biofilms. Copyright © 2016 Elsevier B.V. All rights reserved.

Are effort-reward imbalance and social isolation mediating the association between education and depressiveness? Baseline findings from the lidA(§)-study.

PubMed

du Prel, Jean-Baptist; Iskenius, Mario; Peter, Richard

2014-12-01

To investigate multiple mediations of the association between education and depressive symptoms (BDI-V) by work-related stress (ERI) and social isolation, the regional variation of the first mediation and a potential moderating effect of regional unemployment rate. 6339 employees born in 1959 and 1965 were randomly recruited from 222 sample points in a German cohort study on work, age, health and work participation. A multilevel model of moderated lower-level mediation was used to investigate the confirmatory research question. Multiple mediations were tested corresponding to Baron and Kenny. These analyses were stratified for age and adjusted for sex, negative affectivity and overcommitment. In the association between education and depressive symptoms, indirect effects of work-related stress and social isolation were significant in both age cohorts whereas a direct association was observable in the younger cohort, only. The significant regional variation in the association between work-related stress and depressive symptoms was not statistically explained by regional unemployment rate. Our findings point out that work-related stress and social isolation play an intermediary role between education and depressive symptoms in middle-aged employees.

Acculturation, Social Self-Control, and Substance Use Among Hispanic Adolescents

PubMed Central

Pokhrel, Pallav; Herzog, Thaddeus A.; Sun, Ping; Rohrbach, Louise A.; Sussman, Steve

2014-01-01

It is unclear how acculturation is related to self-control characteristics and whether part of the effect of acculturation on Hispanic adolescents’ substance use behavior is mediated through lower self-control. We tested social self-control, peer substance use, and baseline substance use as mediators of the effect of Hispanic (predominantly Mexican or Mexican American) adolescents’ level of U.S. acculturation on their substance use behavior 1 year later. In addition, we tested gender as a possible moderator of the pathways involved in the mediation model. Participants included 1,040 self-identified Hispanic/Latino adolescents (M = 14.7; SD = 0.90; 89% Mexican/Mexican American) recruited from nine public high schools. Acculturation was measured in terms of adolescents’ extent of English language use in general, at home, with friends, and their use of the English-language entertainment media. Analyses were conducted using structural equation modeling and controlled for potential confounders such as age and parental education. Results indicated a statistically significant three-path mediation in which poor social self-control and peer substance use mediated the effects of acculturation on prospective substance use. Paths in the mediation model were not found to differ by gender. Our findings suggest that acculturation may influence adolescents’ self-control characteristics related to interpersonal functioning, which may in turn influence their affiliation with substance-using friends and substance use behavior. Implications of the findings are discussed in terms of future research and prevention programming. PMID:23772765

Childhood Maltreatment Predicts Allostatic Load in Adulthood

PubMed Central

Widom, Cathy Spatz; Horan, Jacqueline; Brzustowicz, Linda

2015-01-01

Childhood maltreatment has been linked to numerous negative health outcomes. However, few studies have examined mediating processes using longitudinal designs or objectively measured biological data. This study sought to determine whether child abuse and neglect predicts allostatic load (a composite indicator of accumulated stress-induced biological risk) and to examine potential mediators. Using a prospective cohort design, children (ages 0-11) with documented cases of abuse and neglect were matched with non-maltreated children and followed up into adulthood with in-person interviews and a medical status exam (mean age 41). Allostatic load was assessed with nine physical health indicators. Child abuse and neglect predicted allostatic load, controlling for age, sex, and race. The direct effect of child abuse and neglect persisted despite the introduction of potential mediators of internalizing and externalizing problems in adolescence and social support and risky lifestyle in middle adulthood. These findings reveal the long-term impact of childhood abuse and neglect on physical health over 30 years later. PMID:25700779

Maternal childhood trauma, postpartum depression, and infant outcomes: Avoidant affective processing as a potential mechanism.

PubMed

Choi, Karmel W; Sikkema, Kathleen J; Vythilingum, Bavi; Geerts, Lut; Faure, Sheila C; Watt, Melissa H; Roos, Annerine; Stein, Dan J

2017-03-15

Women who have experienced childhood trauma may be at risk for postpartum depression, increasing the likelihood of negative outcomes among their children. Predictive pathways from maternal childhood trauma to child outcomes, as mediated by postpartum depression, require investigation. A longitudinal sample of South African women (N=150) was followed through pregnancy and postpartum. Measures included maternal trauma history reported during pregnancy; postpartum depression through six months; and maternal-infant bonding, infant development, and infant physical growth at one year. Structural equation models tested postpartum depression as a mediator between maternal experiences of childhood trauma and children's outcomes. A subset of women (N=33) also participated in a lab-based emotional Stroop paradigm, and their responses to fearful stimuli at six weeks were explored as a potential mechanism linking maternal childhood trauma, postpartum depression, and child outcomes. Women with childhood trauma experienced greater depressive symptoms through six months postpartum, which then predicted negative child outcomes at one year. Mediating effects of postpartum depression were significant, and persisted for maternal-infant bonding and infant growth after controlling for covariates and antenatal distress. Maternal avoidance of fearful stimuli emerged as a potential affective mechanism. Limitations included modest sample size, self-report measures, and unmeasured potential confounders. Findings suggest a mediating role of postpartum depression in the intergenerational transmission of negative outcomes. Perinatal interventions that address maternal trauma histories and depression, as well as underlying affective mechanisms, may help interrupt cycles of disadvantage, particularly in high-trauma settings such as South Africa. Copyright © 2017. Published by Elsevier B.V.

Mechanisms of potentiation of mossy fiber EPSCs in the cerebellar nuclei by coincident synaptic excitation and inhibition

PubMed Central

Pugh, Jason R.; Raman, Indira M.

2008-01-01

Neurons of the cerebellar nuclei receive synaptic excitation from cerebellar mossy fibers. Unlike in many principal neurons, coincident presynaptic activity and postsynaptic depolarization do not generate long-term potentiation at these synapses. Instead, EPSCs are potentiated by high-frequency trains of presynaptic activity applied with postsynaptic hyperpolarization, in patterns resembling the mossy fiber-mediated excitation and Purkinje cell-mediated inhibition predicted to occur during delay eyelid conditioning. Here, we have used electrophysiology and Ca imaging to test how synaptic excitation and inhibition interact to generate long-lasting synaptic plasticity in nuclear cells in cerebellar slices. We find that the extent of plasticity varies with the relative timing of synaptic excitation and hyperpolarization. Potentiation is most effective when synaptic stimuli precede the post-inhibitory rebound by ~400 ms, whereas with longer intervals, or with a reverse sequence, EPSCs tend to depress. When basal intracellular Ca is raised by spontaneous firing or reduced by voltage-clamping at subthreshold potentials, potentiation is induced as long as the synaptic-rebound temporal sequence is maintained, suggesting that plasticity does not require Ca levels to exceed a threshold or attain a specific concentration. Although rebound and spike-dependent Ca influx are global, potentiation is synapse-specific, and is disrupted by inhibitors of calcineurin or CaMKII, but not PKC. When IPSPs replace the hyperpolarizing step in the induction protocol, potentiation proceeds normally. These results lead us to propose that synaptic and inhibitory/rebound stimuli initiate separate processes, with local NMDA-receptor-mediated Ca influx “priming” synapses, and Ca changes from the inhibition and rebound “triggering” potentiation at recently activated synapses. PMID:18923031

mTOR activation is required for the anti-alcohol effect of ketamine, but not memantine, in alcohol-preferring rats

PubMed Central

Sabino, Valentina; Narayan, Aditi R.; Zeric, Tamara; Steardo, Luca; Cottone, Pietro

2013-01-01

Glutamate NMDA receptors mediate many molecular and behavioral effects of alcohol, and they play a key role in the development of excessive drinking. Uncompetitive NMDA receptor antagonists may, therefore, have therapeutic potential for alcoholism. The first aim was to compare the effects of the NMDA antagonists memantine and ketamine on ethanol and saccharin drinking in alcohol-preferring rats. The second aim was to determine whether the effects of the two NMDA receptor antagonists were mediated by the mammalian target of rapamycin (mTOR). TSRI Sardinian alcohol-preferring rats were allowed to self-administer either 10% w/v ethanol or 0.08% w/v saccharin, and water. Operant responding and motor activity were assessed following administration of either memantine (0–10 mg/kg) or ketamine (0–20 mg/kg). Finally, ethanol self-administration was assessed in rats administered with either memantine or ketamine but pretreated with the mTOR inhibitor rapamycin (2.5 mg/kg). The uncompetitive NMDA receptor antagonists memantine and ketamine dose-dependently reduced ethanol drinking in alcohol-preferring rats; while memantine had a preferential effect on alcohol over saccharin, ketamine reduced responding for both solutions. Neither antagonist induced malaise, as shown by the lack of effect on water intake and motor activity. The mTOR inhibitor rapamycin blocked the effects of ketamine, but not those of memantine. Memantine and ketamine both reduce alcohol drinking in alcohol-preferring rats, but only memantine is selective for alcohol. The effects of ketamine, but not memantine, are mediated by mTOR. The results support the therapeutic potential of uncompetitive NMDA receptor antagonists, especially memantine, in alcohol addiction. PMID:23466691

Potentiation of transient receptor potential V1 functions by the activation of metabotropic 5-HT receptors in rat primary sensory neurons

PubMed Central

Ohta, Toshio; Ikemi, Yuki; Murakami, Matsuka; Imagawa, Toshiaki; Otsuguro, Ken-ichi; Ito, Shigeo

2006-01-01

5-Hydroxytryptamine (5-HT) is one of the major chemical mediators released in injured and inflamed tissue and is capable of inducing hyperalgesia in vivo. However, the cellular mechanisms of 5-HT-induced hyperalgesia remain unclear. Transient receptor potential V1 (TRPV1) plays a pivotal role in nociceptive receptors. In the present study, we determined whether 5-HT changes TRPV1 functions in cultured dorsal root ganglion (DRG) neurons isolated from neonatal rats, using Ca2+ imaging and whole-cell patch-clamp techniques. In more than 70% of DRG neurons, 5-HT potentiated the increases of [Ca2+]i induced by capsaicin, protons and noxious heat. Capsaicin-induced current and depolarizing responses, and proton-induced currents were also augmented by 5-HT. RT-PCR analysis revealed the expression of 5-HT2A and 5-HT7 receptors in rat DRG neurons. Agonists for 5-HT2A and 5-HT7 receptors mimicked the potentiating effect of 5-HT, and their antagonists decreased it. In DRG ipsilateral to the complete Freund's adjuvant-injected inflammation side, expression levels of 5-HT2A and 5-HT7 mRNAs increased, and the potentiating effect of 5-HT was more prominent than in the contralateral control side. These results suggest that the PKC- and PKA-mediated signalling pathways are involved in the potentiating effect of 5-HT on TRPV1 functions through the activation of 5-HT2A and 5-HT7 receptors, respectively. Under inflammatory conditions, the increases of the biosynthesis of these 5-HT receptors may lead to further potentiation of TRPV1 functions, resulting in the generation of inflammatory hyperalgesia in vivo. PMID:16901936

Corticosterone Potentiation of Cocaine-Induced Reinstatement of Conditioned Place Preference in Mice is Mediated by Blockade of the Organic Cation Transporter 3

PubMed Central

McReynolds, Jayme R; Taylor, Analisa; Vranjkovic, Oliver; Ambrosius, Terra; Derricks, Olivia; Nino, Brittany; Kurtoglu, Beliz; Wheeler, Robert A; Baker, David A; Gasser, Paul J; Mantsch, John R

2017-01-01

The mechanisms by which stressful life events increase the risk of relapse in recovering cocaine addicts are not well understood. We previously reported that stress, via elevated corticosterone, potentiates cocaine-primed reinstatement of cocaine seeking following self-administration in rats and that this potentiation appears to involve corticosterone-induced blockade of dopamine clearance via the organic cation transporter 3 (OCT3). In the present study, we use a conditioned place preference/reinstatement paradigm in mice to directly test the hypothesis that corticosterone potentiates cocaine-primed reinstatement by blockade of OCT3. Consistent with our findings following self-administration in rats, pretreatment of male C57/BL6 mice with corticosterone (using a dose that reproduced stress-level plasma concentrations) potentiated cocaine-primed reinstatement of extinguished cocaine-induced conditioned place preference. Corticosterone failed to re-establish extinguished preference alone but produced a leftward shift in the dose–response curve for cocaine-primed reinstatement. A similar potentiating effect was observed upon pretreatment of mice with the non-glucocorticoid OCT3 blocker, normetanephrine. To determine the role of OCT3 blockade in these effects, we examined the abilities of corticosterone and normetanephrine to potentiate cocaine-primed reinstatement in OCT3-deficient and wild-type mice. Conditioned place preference, extinction and reinstatement of extinguished preference in response to low-dose cocaine administration did not differ between genotypes. However, corticosterone and normetanephrine failed to potentiate cocaine-primed reinstatement in OCT3-deficient mice. Together, these data provide the first direct evidence that the interaction of corticosterone with OCT3 mediates corticosterone effects on drug-seeking behavior and establish OCT3 function as an important determinant of susceptibility to cocaine use. PMID:27604564

Q-balls in flat potentials

DOE Office of Scientific and Technical Information (OSTI.GOV)

Copeland, Edmund J.; Tsumagari, Mitsuo I.

2009-07-15

We study the classical and absolute stability of Q-balls in scalar field theories with flat potentials arising in both gravity-mediated and gauge-mediated models. We show that the associated Q-matter formed in gravity-mediated potentials can be stable against decay into their own free particles as long as the coupling constant of the nonrenormalizable term is small, and that all of the possible three-dimensional Q-ball configurations are classically stable against linear fluctuations. Three-dimensional gauge-mediated Q-balls can be absolutely stable in the thin-wall limit, but are completely unstable in the thick-wall limit.

Underpotential deposition-mediated layer-by-layer growth of thin films

DOEpatents

Wang, Jia Xu; Adzic, Radoslav R.

2017-06-27

A method of depositing contiguous, conformal submonolayer-to-multilayer thin films with atomic-level control is described. The process involves electrochemically exchanging a mediating element on a substrate with a noble metal film by alternatingly sweeping potential in forward and reverse directions for a predetermined number of times in an electrochemical cell. By cycling the applied voltage between the bulk deposition potential for the mediating element and the material to be deposited, repeated desorption/adsorption of the mediating element during each potential cycle can be used to precisely control film growth on a layer-by-layer basis.

Investigating the Effects of Mass Media Exposure on the Uptake of Preventive Measures by Hong Kong Residents during the 2015 MERS Outbreak: The Mediating Role of Interpersonal Communication and the Perception of Concern.

PubMed

Ludolph, Ramona; Schulz, Peter J; Chen, Ling

2018-01-01

In 2015, South Korea experienced the largest outbreak to date of the Middle East Respiratory Syndrome (MERS-CoV) outside the Middle East. Fears related to a potential spread of the disease led to an increased alert level as well as heightened media coverage in the neighboring Hong Kong. A cross-sectional survey (N = 533) among residents of Hong Kong was conducted to assess the relationships between the effects of outbreak-related mass media coverage, interpersonal communication, the perceived level of concern in one's close environment, and the uptake of preventive measures. A serial multiple mediator model finds that interpersonal communication and higher perceived concern indirectly influence the effects of media coverage on the engagement in preventive actions. These results expand previous research on the mediating role of interpersonal communication and support assumptions about a modified two-step flow of communication in the context of a public health emergency.

Being bullied as an environmentally mediated contributing factor to children's internalizing problems: a study of twins discordant for victimization.

PubMed

Arseneault, Louise; Milne, Barry J; Taylor, Alan; Adams, Felicity; Delgado, Kira; Caspi, Avshalom; Moffitt, Terrie E

2008-02-01

To test whether the experience of being bullied has an environmentally mediated effect on internalizing symptoms in young children. A genetically informative, longitudinal 1994-1995 birth cohort. A nationally representative sample from the United Kingdom. We examined 1116 twin pairs who are participants in the Environmental Risk Longitudinal Twin Study. Main Exposure The experience of being bullied between the ages of 7 and 9 years. Mothers' and teachers' reports of children's internalizing problems at 7 and 10 years of age. Monozygotic twins who had been bullied had more internalizing symptoms (mean, 0.23; SD, 1.00) compared with their co-twin who had not been bullied (mean, -0.13; SD, 0.86), indicating that being bullied has an environmentally mediated effect on children's internalizing problems (beta, 0.36 [95% confidence interval (CI), 0.18-0.54]). This effect remained significant after controlling for preexisting internalizing problems (beta, 0.26 [95% CI, 0.09-0.44]). Being bullied at a young age is an environmentally mediated contributing factor to children's internalizing problems. Intervention programs aimed at reducing bullying behavior in schools and in the community have the potential to influence children's early symptoms of mental health problems.

Improvements in maternal depression as a mediator of intervention effects on early childhood problem behavior

PubMed Central

Shaw, Daniel S.; Connell, Arin; Dishion, Thomas J.; Wilson, Melvin N.; Gardner, Frances

2009-01-01

Maternal depression has been consistently linked to the development of child problem behavior, particularly in early childhood, but few studies have examined whether reductions in maternal depression serve as a mediator in relation to changes associated with a family-based intervention. The current study addressed this issue with a sample of 731 families receiving services from a national food supplement and nutrition program. Families with toddlers between ages 2 and 3 were sereened and then randomized to a brief family intervention, the Family Check-Up, which included linked interventions that were tailored and adapted to the families needs. Follow-up intervention services were provided at age 3 and follow-up of child outcomes oecurred at ages 3 and 4. Latent growth models revealed intervention effects for early externalizing and internalizing problems from 2 to 4, and reductions in maternal depression from ages 2 to 3. In addition, reductions in maternal depression mediated improvements in both child externalizing and internalizing problem behavior after accounting for the potential mediating effects of improvements in positive parenting. The results are discussed with respect to targeting maternal depression in future intervention studies aimed at improving early child problem behavior. PMID:19338691

Tumor Necrosis Factor-α, a Regulator and Therapeutic Agent on Breast Cancer.

PubMed

Liu, Dongwu; Wang, Xiaoqian; Chen, Zhiwei

2016-01-01

The cell-mediated immunity and cytotoxic agents play a significant role on tumor cell apoptosis. Tumor necrosis factor-α (TNF-α) is an intricate linker between inflammation and cancer through mediating the process of apoptosis and cell-mediated immunity. A variety of evidences have confirmed the critical role of TNF-α on tumor migration, proliferation, matrix degradation, tumor metastasis, invasion, and angiogenesis. Through binding to receptors, TNF-α participates in activating multiple cell signaling cascades that link inflammation, survival and evolution towards breast cancer. TNF-α is an important agent for tumor biotherapy, but its clinical application is limited for its severe fatal systemic toxicity. The poly-lactic acid microspheres (PLAM) with intratumoral cytokine release hold tremendous potential for the immunotherapy of breast cancer, and TNF-α antagonists may offer therapeutic potential in solid tumors. In addition, TNF-α is related with the blockage of estrogen and progesterone receptors. For breast cancer treatment, it is necessary to understand the molecular signaling pathways that mediate TNF-α and the aggressive behavior of negative breast cancer. The aim of present review is to summarize the effect of TNF-α on breast cancer cells.

Potentiation of T-cell mediated immunity by levamisole.

PubMed Central

Renoux, G; Renoux, M; Teller, M N; McMahon, S; Guillaumin, J M

1976-01-01

Cell-mediated immunity is a requirement for recognition and elimination of cells and for prevention or treatment of a variety of diseases. Therefore, the development of a product potentially active in increasing immunity involves its testing in assays specific for cell-mediated immunity. The effectiveness of a single administration of levamisole was demonstrated in the rejection of isografts in a male to female C57BL/6 system, and on the enhancement of levels of the delayed type hypersensitivity (DTH) to sheep red cells (SRBC). Indeed, in five on nine tests, an injection of 25 mg/kg of levamisole to female recipients either on the day of grafting or 7 days after grafting resulted in a RT50% rejection time of 25 days, compared with 46 days in untreated controls. Levamisole administered at the time of immunization with various doses of SRBC elicited earlier, higher and more sustained DTH levels than in untreated controls. Such induction of T-cell activation was accompanied by a switch on anti-SRBC antibodies from IgM to IgG. These findings confirm and extend data evidencing the ability of levamisole to recruit and activate T cells for an increased or restored cell-mediated immunity. PMID:782749

Deployment cycle stressors and post-traumatic stress symptoms in Army National Guard women: the mediating effect of resilience.

PubMed

Wooten, Nikki R

2012-01-01

This study examined the associations between deployment cycle stressors, post-traumatic stress symptoms (PTSS), and resilience in Army National Guard (ARNG) women deployed to Operations Enduring Freedom and Iraqi Freedom. Resilience was also tested as a mediator. Hierarchical linear regression indicated that deployment and post-deployment stressors were positively associated, and resilience was negatively associated with PTSS. Resilience fully mediated the association between post-deployment stressors and PTSS. Findings suggest assessing deployment and post-deployment stressors in ARNG women may be helpful in identifying those at risk for severe PTSS; and highlight the potential of individual-level resilient characteristics in mitigating the adverse impact of post-deployment stressors.

Increasing verbal knowledge mediates development of multidimensional emotion representations

PubMed Central

Nook, Erik C.; Sasse, Stephanie F.; Lambert, Hilary K.; McLaughlin, Katie A.; Somerville, Leah H.

2017-01-01

How do people represent their own and others’ emotional experiences? Contemporary emotion theories and growing evidence suggest that the conceptual representation of emotion plays a central role in how people understand the emotions both they and other people feel.1–6 Although decades of research indicate that adults typically represent emotion concepts as multidimensional, with valence (positive—negative) and arousal (activating—deactivating) as two primary dimensions,7–10 little is known about how this bidimensional (or circumplex) representation arises.11 Here we show that emotion representations develop from a monodimensional focus on valence to a bidimensional focus on both valence and arousal from age 6 to age 25. We investigated potential mechanisms underlying this effect and found that increasing verbal knowledge mediated emotion representation development over and above three other potential mediators: (i) fluid reasoning, (ii) the general ability to represent non-emotional stimuli bidimensionally, and (iii) task-related behaviors (e.g., using extreme ends of rating scales). These results suggest that verbal development facilitates the expansion of emotion concept representations (and potentially emotional experiences) from a “positive or negative” dichotomy in childhood to a multidimensional organization in adulthood. PMID:29399639

Little SUSY hierarchy in mixed modulus-anomaly mediation

NASA Astrophysics Data System (ADS)

Choi, Kiwoon; Jeong, Kwang Sik; Kobayashi, Tatsuo; Okumura, Ken-ichi

2006-02-01

Motivated by the KKLT string compactification involving a supersymmetry-breaking uplifting potential, we examine 4D effective supergravity with a generic form of uplifting potential, focusing on the possibility that the resulting mixed modulus-anomaly mediated soft terms realize the little hierarchy between the Higgs boson masses mH and the sparticle masses mSUSY. It is noted that for some type of uplifting potential, the anomaly-mediated contribution to mH2 at MGUT can cancel the subsequent renormalization group evolution of mH2 down to TeV scale, thereby the model can naturally realize the little hierarchy mH2 ∼mSUSY2 / 8π2 which is desirable for the lightest Higgs boson mass to satisfy the experimental bound. In such models, the other Higgs mass parameters μ and B can have the desirable size μ ∼ B ∼mH without severe fine-tuning of parameters, although the gravitino is much heavier than the Higgs boson. Those models for the little hierarchy avoid naturally the dangerous SUSY flavor and CP violations, and predict nearly degenerate low energy gaugino masses, pure Higgsino LSP, and also a specific relation between the stop and gaugino masses.

Food cravings mediate the relationship between chronic stress and body mass index.

PubMed

Chao, Ariana; Grilo, Carlos M; White, Marney A; Sinha, Rajita

2015-06-01

This study examined the relationships between chronic stress, food cravings, and body mass index. A community-based sample of adults (N = 619) completed a comprehensive assessment battery and heights and weights were measured. Chronic stress had a significant direct effect on food cravings, and food cravings had a significant direct effect on body mass index. The total effect of chronic stress on body mass index was significant. Food cravings partially mediated the relationship between chronic stress and body mass index. These findings are consistent with research that chronic stress may potentiate motivation for rewarding substances and behaviors and indicate that high food cravings may contribute to stress-related weight gain. © The Author(s) 2015.

Prevention System Mediation of Communities That Care Effects on Youth Outcomes

PubMed Central

Hawkins, J. David; Rhew, Isaac C.; Shapiro, Valerie B.; Abbott, Robert D.; Oesterle, Sabrina; Arthur, Michael W.; Briney, John S.; Catalano, Richard F.

2013-01-01

This study examined whether the significant intervention effects of the Communities That Care (CTC) prevention system on youth problem behaviors observed in a panel of eighth-grade students (Hawkins et al. Archives of Pediatrics and Adolescent Medicine 163:789–798 2009) were mediated by community-level prevention system constructs posited in the CTC theory of change. Potential prevention system constructs included the community’s degree of (a) adoption of a science-based approach to prevention, (b) collaboration on prevention activities, (c) support for prevention, and (d) norms against adolescent drug use as reported by key community leaders in 24 communities. Higher levels of community adoption of a science-based approach to prevention and support for prevention in 2004 predicted significantly lower levels of youth problem behaviors in 2007, and higher levels of community norms against adolescent drug use predicted lower levels of youth drug use in 2007. Effects of the CTC intervention on youth problem behaviors by the end of eighth grade were mediated fully by community adoption of a science-based approach to prevention. No other significant mediated effects were found. Results support CTC’s theory of change that encourages communities to adopt a science- based approach to prevention as a primary mechanism for improving youth outcomes. PMID:23828448

Prenatal methyl-donor supplementation augments colitis in young adult mice

USDA-ARS?s Scientific Manuscript database

Inflammatory bowel diseases have become highly prevalent in developed countries. Environmentally triggered exaggerated immune responses against the intestinal microbiome are thought to mediate the disorders. The potential dietary origins of the disease group have been implicated. However, the effect...

Interactive effects of fire and large herbivores on web-building spiders.

PubMed

Foster, C N; Barton, P S; Wood, J T; Lindenmayer, D B

2015-09-01

Altered disturbance regimes are a major driver of biodiversity loss worldwide. Maintaining or re-creating natural disturbance regimes is therefore the focus of many conservation programmes. A key challenge, however, is to understand how co-occurring disturbances interact to affect biodiversity. We experimentally tested for the interactive effects of prescribed fire and large macropod herbivores on the web-building spider assemblage of a eucalypt forest understorey and investigated the role of vegetation in mediating these effects using path analysis. Fire had strong negative effects on the density of web-building spiders, which were partly mediated by effects on vegetation structure, while negative effects of large herbivores on web density were not related to changes in vegetation. Fire amplified the effects of large herbivores on spiders, both via vegetation-mediated pathways and by increasing herbivore activity. The importance of vegetation-mediated pathways and fire-herbivore interactions differed for web density and richness and also differed between web types. Our results demonstrate that for some groups of web-building spiders, the effects of co-occurring disturbance drivers may be mostly additive, whereas for other groups, interactions between drivers can amplify disturbance effects. In our study system, the use of prescribed fire in the presence of high densities of herbivores could lead to reduced densities and altered composition of web-building spiders, with potential cascading effects through the arthropod food web. Our study highlights the importance of considering both the independent and interactive effects of disturbances, as well as the mechanisms driving their effects, in the management of disturbance regimes.

Effects of 810 nm laser on mouse primary cortical neurons

NASA Astrophysics Data System (ADS)

Kharkwal, Gitika B.; Sharma, Sulbha K.; Huang, Ying-Ying; De Taboada, Luis; McCarthy, Thomas; Hamblin, Michael R.

2011-03-01

In the past four decades numerous studies have reported the efficacy of low level light (laser) therapy (LLLT) as a treatment for diverse diseases and injuries. Recent studies have shown that LLLT can biomodulate processes in the central nervous system and has been extensively studied as a stroke treatment. However there is still a lack of knowledge on the effects of LLLT at the cellular level in neurons. The present study aimed to study the effect of 810 nm laser on several cellular processes in primary cortical neurons cultured from mouse embryonic brains. Neurons were irradiated with light dose of 0.03, 0.3, 3, 10 and 30 J/cm2 and intracellular levels of reactive oxygen species, nitric oxide and calcium were measured. The changes in mitochondrial function in response to light were studied in terms of adenosine triphosphate (ATP) and mitochondrial membrane potential (MMP). Light induced a significant increase in calcium, ATP and MMP at lower fluences and a decrease at higher fluence. ROS was induced significantly by light at all light doses. Nitric oxide levels also showed an increase on treatment with light. The results of the present study suggest that LLLT at lower fluences is capable of inducing mediators of cell signaling process which in turn may be responsible for the biomodulatory effects of the low level laser. At higher fluences beneficial mediators are reduced but potentially harmful mediators are increased thus offering an explanation for the biphasic dose response.

Silibinin strongly inhibits the growth kinetics of colon cancer stem cell-enriched spheroids by modulating interleukin 4/6-mediated survival signals

PubMed Central

Agarwal, Chapla; Agarwal, Rajesh

2014-01-01

Involvement of cancer stem cells (CSC) in initiation, progression, relapse, and therapy-resistance of colorectal cancer (CRC) warrants search for small molecules as ‘adjunct-therapy’ to target both colon CSC and bulk tumor population. Herein, we assessed the potential of silibinin to eradicate colon CSC together with associated molecular mechanisms. In studies examining how silibinin modulates dynamics of CSC spheroids in terms of its effect on kinetics of CSC spheroids generated in presence of mitogenic and interleukin (IL)-mediated signaling which provides an autocrine/paracrine amplification loop in CRC, silibinin strongly decreased colon CSC pool together with cell survival of bulk tumor cells. Silibinin effect on colon CSC was mediated via blocking of pro-tumorigenic signaling, notably IL-4/-6 signaling that affects CSC population. These silibinin effects were associated with decreased mRNA and protein levels of various CSC-associated transcription factors, signaling molecules and markers. Furthermore, 2D and 3D differentiation assays indicated formation of more differentiated clones by silibinin. These results highlight silibinin potential to interfere with kinetics of CSC pool by shifting CSC cell division to asymmetric type via targeting various signals associated with the survival and multiplication of colon CSC pool. Together, our findings further support clinical usefulness of silibinin in CRC intervention and therapy. PMID:24970802

Species-specific effects of soil fauna on fungal foraging and decomposition.

PubMed

Crowther, Thomas W; Boddy, Lynne; Jones, T Hefin

2011-10-01

Decomposer fungi are primary decomposing agents in terrestrial soils. Their mycelial networks play an important role in nutrient mineralisation and distribution, but are also nutritious resources for various soil invertebrates. Global climate change is predicted to alter the diversity and community composition of these soil fauna. To understand whether changes in invertebrate species diversity are likely to affect fungal-mediated decomposition, this study compared the grazing potentials of different invertebrate taxa and functional groups. Specifically, the grazing impacts of seven invertebrate taxa on the growth and spatial distribution of six basidiomycete fungi growing from beech wood blocks in soil microcosms were explored. Wood decay rates by fungi were also compared. The consequences of grazing were both taxon- and species-specific. Generally, macro-invertebrates caused the greatest damage, while meso- and micro-invertebrates often stimulated mycelial growth. Invertebrate size, preferences and population dynamics are likely to influence grazing potentials. Effects of grazing varied between fungi, with mycelial morphology and biochemistry possibly influencing susceptibility. Heavy grazing indirectly increased fungal-mediated wood decomposition. Changes in invertebrate community composition are predicted to have consequences for fungal growth, activity and community structure in woodland soils. Abiotic climate change factors including CO(2) and temperature affect mycelial productivity directly, but the indirect effects, mediated through changes in the soil invertebrate community, may be equally important in controlling ecosystem functioning.

Polymeric mechanical amplifiers of immune cytokine-mediated apoptosis

NASA Astrophysics Data System (ADS)

Mitchell, Michael J.; Webster, Jamie; Chung, Amanda; Guimarães, Pedro P. G.; Khan, Omar F.; Langer, Robert

2017-03-01

Physical forces affect tumour growth, progression and metastasis. Here, we develop polymeric mechanical amplifiers that exploit in vitro and in vivo physical forces to increase immune cytokine-mediated tumour cell apoptosis. Mechanical amplifiers, consisting of biodegradable polymeric particles tethered to the tumour cell surface via polyethylene glycol linkers, increase the apoptotic effect of an immune cytokine on tumour cells under fluid shear exposure by as much as 50% compared with treatment under static conditions. We show that targeted polymeric particles delivered to tumour cells in vivo amplify the apoptotic effect of a subsequent treatment of immune cytokine, reduce circulating tumour cells in blood and overall tumour cell burden by over 90% and reduce solid tumour growth in combination with the antioxidant resveratrol. The work introduces a potentially new application for a broad range of micro- and nanoparticles to maximize receptor-mediated signalling and function in the presence of physical forces.

Leptin: a potential mediator for protective effects of fat mass on bone tissue.

PubMed

Thomas, Thierry

2003-02-01

Body weight is among the most powerful predictors of bone status, and adipose tissue plays a substantial role in weight-related protective effects on bone. An understanding of the mechanisms underlying the relation between adipose tissue and bone may open up new perspectives for treatment. Leptin, which is known to regulate appetite and energy expenditures, may also contribute to mediate the effects of fat mass on bone. Although reported data are somewhat conflicting, there is some evidence that leptin may decrease bone formation via a central nervous effect and may stimulate both bone formation and bone resorption via direct peripheral effects on stromal precursor cells. The net result of these central and peripheral effects may depend on serum leptin levels and blood-brain barrier permeability, of which the first increase and the second decrease as obesity develops. Further work is needed to improve our understanding of these effects.

Cognitive and family therapies for adolescent depression: treatment specificity, mediation, and moderation.

PubMed

Kolko, D J; Brent, D A; Baugher, M; Bridge, J; Birmaher, B

2000-08-01

The specificity of cognitive and family therapies, and potential treatment mediators and moderators, was examined in a randomized clinical trial for adolescent depression. After acute treatment, cognitive-behavioral therapy (CBT) exerted specific effects on cognitive distortions relative to either systemic-behavioral family therapy (SBFT) or nondirective supportive therapy (NST). At 2-year follow-up, SBFT was found to impact family conflict and parent-child relationship problems more than CBT; NST and CBT tended to show a greater reduction in anxiety symptoms than SBFT. Nonspecific therapist variables qualified few outcome analyses. No measures of cognitive distortion or family dysfunction mediated or moderated treatment outcome. As in adult studies, relatively few areas of treatment specificity or mediation were identified. The implications of these findings for clinical treatment and research in adolescent depression are discussed.

Attributional style as a mediator between parental abuse risk and child internalizing symptomatology.

PubMed

Rodriguez, Christina M

2006-05-01

This study examined a model wherein children's attributional style mediates the relationship between parental physical child-abuse risk and children's internalizing problems. Using structural equation modeling, three indices of abuse risk were selected (child abuse potential, physical discipline use, and dysfunctional parenting style) and two indices of children's internalizing problems (depression and anxiety). The sample included 75 parent-child dyads, in which parents reported on their abuse risk and children independently completed measures of depressive and anxious symptomatology and a measure on their attributional style. Findings supported the model that children's attributional style for positive events (but not negative events) partially mediated the relationship between abuse risk and internalizing symptoms, with significant direct and indirect effects of abuse risk on internalizing symptomatology. Future directions to continue evaluating additional mediators and other possible contextual variables are discussed.

Evaluation of hyperpolarized [1-¹³C]-pyruvate by magnetic resonance to detect ionizing radiation effects in real time.

PubMed

Sandulache, Vlad C; Chen, Yunyun; Lee, Jaehyuk; Rubinstein, Ashley; Ramirez, Marc S; Skinner, Heath D; Walker, Christopher M; Williams, Michelle D; Tailor, Ramesh; Court, Laurence E; Bankson, James A; Lai, Stephen Y

2014-01-01

Ionizing radiation (IR) cytotoxicity is primarily mediated through reactive oxygen species (ROS). Since tumor cells neutralize ROS by utilizing reducing equivalents, we hypothesized that measurements of reducing potential using real-time hyperpolarized (HP) magnetic resonance spectroscopy (MRS) and spectroscopic imaging (MRSI) can serve as a surrogate marker of IR induced ROS. This hypothesis was tested in a pre-clinical model of anaplastic thyroid carcinoma (ATC), an aggressive head and neck malignancy. Human ATC cell lines were utilized to test IR effects on ROS and reducing potential in vitro and [1-¹³C] pyruvate HP-MRS/MRSI imaging of ATC orthotopic xenografts was used to study in vivo effects of IR. IR increased ATC intra-cellular ROS levels resulting in a corresponding decrease in reducing equivalent levels. Exogenous manipulation of cellular ROS and reducing equivalent levels altered ATC radiosensitivity in a predictable manner. Irradiation of ATC xenografts resulted in an acute drop in reducing potential measured using HP-MRS, reflecting the shunting of reducing equivalents towards ROS neutralization. Residual tumor tissue post irradiation demonstrated heterogeneous viability. We have adapted HP-MRS/MRSI to non-invasively measure IR mediated changes in tumor reducing potential in real time. Continued development of this technology could facilitate the development of an adaptive clinical algorithm based on real-time adjustments in IR dose and dose mapping.

A Drug-Repositioning Screening Identifies Pentetic Acid as a Potential Therapeutic Agent for Suppressing the Elastase-Mediated Virulence of Pseudomonas aeruginosa

PubMed Central

Gi, Mia; Jeong, Junhui; Lee, Keehoon; Lee, Kang-Mu; Toyofuku, Masanori; Yong, Dong Eun

2014-01-01

Pseudomonas aeruginosa, a Gram-negative bacterium of clinical significance, produces elastase as a predominant exoprotease. Here, we screened a library of chemical compounds currently used for human medication and identified diethylene triamine penta-acetic acid (DTPA, pentetic acid) as an agent that suppresses the production of elastase. Elastase activity found in the prototype P. aeruginosa strain PAO1 was significantly decreased when grown with a concentration as low as 20 μM DTPA. Supplementation with Zn2+ or Mn2+ ions restored the suppressive effect of DTPA, suggesting that the DTPA-mediated decrease in elastase activity is associated with ion-chelating activity. In DTPA-treated PAO1 cells, transcription of the elastase-encoding lasB gene and levels of the Pseudomonas quinolone signal (PQS), a molecule that mediates P. aeruginosa quorum sensing (QS), were significantly downregulated, reflecting the potential involvement of the PQS QS system in DTPA-mediated elastase suppression. Biofilm formation was also decreased by DTPA treatment. When A549 alveolar type II-like adenocarcinoma cells were infected with PAO1 cells in the presence of DTPA, A549 cell viability was substantially increased. Furthermore, the intranasal delivery of DTPA to PAO1-infected mice alleviated the pathogenic effects of PAO1 cells in the animals. Together, our results revealed a novel function for a known molecule that may help treat P. aeruginosa airway infection. PMID:25246397

Vitamin K3 (menadione) redox cycling inhibits cytochrome P450-mediated metabolism and inhibits parathion intoxication.

PubMed

Jan, Yi-Hua; Richardson, Jason R; Baker, Angela A; Mishin, Vladimir; Heck, Diane E; Laskin, Debra L; Laskin, Jeffrey D

2015-10-01

Parathion, a widely used organophosphate insecticide, is considered a high priority chemical threat. Parathion toxicity is dependent on its metabolism by the cytochrome P450 system to paraoxon (diethyl 4-nitrophenyl phosphate), a cytotoxic metabolite. As an effective inhibitor of cholinesterases, paraoxon causes the accumulation of acetylcholine in synapses and overstimulation of nicotinic and muscarinic cholinergic receptors, leading to characteristic signs of organophosphate poisoning. Inhibition of parathion metabolism to paraoxon represents a potential approach to counter parathion toxicity. Herein, we demonstrate that menadione (methyl-1,4-naphthoquinone, vitamin K3) is a potent inhibitor of cytochrome P450-mediated metabolism of parathion. Menadione is active in redox cycling, a reaction mediated by NADPH-cytochrome P450 reductase that preferentially uses electrons from NADPH at the expense of their supply to the P450s. Using human recombinant CYP 1A2, 2B6, 3A4 and human liver microsomes, menadione was found to inhibit the formation of paraoxon from parathion. Administration of menadione bisulfite (40mg/kg, ip) to rats also reduced parathion-induced inhibition of brain cholinesterase activity, as well as parathion-induced tremors and the progression of other signs and symptoms of parathion poisoning. These data suggest that redox cycling compounds, such as menadione, have the potential to effectively mitigate the toxicity of organophosphorus pesticides including parathion which require cytochrome P450-mediated activation. Copyright © 2015 Elsevier Inc. All rights reserved.

Major role of HSP70 as a paracrine inducer of cytokine production in human oxidized LDL treated macrophages.

PubMed

Svensson, Per-Arne; Asea, Alexzander; Englund, Mikael C O; Bausero, Maria A; Jernås, Margareta; Wiklund, Olov; Ohlsson, Bertil G; Carlsson, Lena M S; Carlsson, Björn

2006-03-01

Lipid accumulation and inflammation are key hallmarks of the atherosclerotic plaque and macrophage uptake of oxidized low-density lipoprotein (oxLDL) is believed to drive these processes. Initial experiments show that supernatants from oxLDL treated macrophages could induce IL-1beta production in naïve macrophages. To search for potential paracrine mediators that could mediate this effect a DNA microarray scan of oxLDL treated human macrophages was performed. This analysis revealed that oxLDL induced activation of heat shock protein (HSP) expression. HSPs have been implicated in the development of atherosclerosis, but the exact mechanisms for this is unclear. Extracellular heat shock protein 70 (HSP70) has been shown to elicit a pro-inflammatory cytokine response in monocytes and could therefore be a potential paracrine pro-inflammatory mediator. After 24 h of oxLDL treatment there was a significant increase of HSP70 concentrations in supernatants from oxLDL treated macrophages (oxLDLsup) compared to untreated controls (P<0.05). OxLDLsup could induce both interleukin (IL)-1beta and IL-12 secretion in naïve macrophages. We also demonstrate that the effect of oxLDLsup on cytokine production and release could be blocked by inhibition of HSP70 transcription or secretion or by the use of HSP70 neutralizing antibodies. This suggests that extracellular HSP70 can mediate pro-inflammatory changes in macrophages in response to oxLDL.

Major role of HSP70 as a paracrine inducer of cytokine production in human oxidized LDL treated macrophages

PubMed Central

Svensson, Per-Arne; Asea, Alexzander; Englund, Mikael C.O.; Bausero, Maria A.; Jernås, Margareta; Wiklund, Olov; Ohlsson, Bertil G.; Carlsson, Lena M.S.; Carlsson, Björn

2006-01-01

Lipid accumulation and inflammation are key hallmarks of the atherosclerotic plaque and macrophage uptake of oxidized low-density lipoprotein (oxLDL) is believed to drive these processes. Initial experiments show that supernatants from oxLDL treated macrophages could induce IL-1β production in naïve macrophages. To search for potential paracrine mediators that could mediate this effect a DNA microarray scan of oxLDL treated human macrophages was performed. This analysis revealed that oxLDL induced activation of heat shock protein (HSP) expression. HSPs have been implicated in the development of atherosclerosis, but the exact mechanisms for this is unclear. Extracellular heat shock protein 70 (HSP70) has been shown to elicit a pro-inflammatory cytokine response in monocytes and could therefore be a potential paracrine pro-inflammatory mediator. After 24 h of oxLDL treatment there was a significant increase of HSP70 concentrations in supernatants from oxLDL treated macrophages (oxLDLsup) compared to untreated controls (P < 0.05). OxLDLsup could induce both interleukin (IL)-1β and IL-12 secretion in naïve macrophages. We also demonstrate that the effect of oxLDLsup on cytokine production and release could be blocked by inhibition of HSP70 transcription or secretion or by the use of HSP70 neutralizing antibodies. This suggests that extracellular HSP70 can mediate pro-inflammatory changes in macrophages in response to oxLDL. PMID:15993884

Personality subtypes and chest pain in patients with nonobstructive coronary artery disease from the TweeSteden Mild Stenosis study: mediating effect of anxiety and depression.

PubMed

Mommersteeg, P M C; Widdershoven, J W; Aarnoudse, W; Denollet, J

2016-03-01

Patients presenting with chest pain in nonobstructive coronary artery disease (CAD, luminal narrowing <60%) are at risk for emotional distress and future events. We aimed to examine the association of personality subtypes with persistent chest pain, and investigated the potential mediating effects of negative mood states. Any chest pain in the past month was the primary outcome measure reported by 523 patients with nonobstructive CAD (mean age 61.4 years, SD = 9.4; 48% men), who participate in the TweeSteden Mild Stenosis (TWIST) observational cohort. Personality was categorized into a 'reference group', a high social inhibition ('SI only'), a high negative affectivity ('NA only') and a 'Type D' (NA and SI) group. Negative mood states included symptoms of depression and anxiety (Hospital Anxiety and Depression Scale) and cognitive and somatic depression (Beck Depression Inventory). The PROCESS macro was used to examine the relation between personality subtypes and chest pain presence, with the negative mood states as potential mediators. Persistent chest pain was present in 44% of the patients with nonobstructive CAD. Type D personality (OR = 1.91, 95% CI 1.24-2.95), but not the 'NA only' (OR = 1.48, 95% CI 0.89-2.44) or the 'SI only' (OR = 0.93, 95% CI 0.53-1.64) group was associated with chest pain, adjusted for age and sex. Negative mood states mediated the association between personality and chest pain. Type D personality, but not negative affectivity or social inhibition, was related to chest pain in nonobstructive CAD, which was mediated by negative mood states. © 2015 European Pain Federation - EFIC®

Vitamin K3 (menadione) redox cycling inhibits cytochrome P450-mediated metabolism and inhibits parathion intoxication

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jan, Yi-Hua; Richardson, Jason R., E-mail: jricha3@eohsi.rutgers.edu; Baker, Angela A.

Parathion, a widely used organophosphate insecticide, is considered a high priority chemical threat. Parathion toxicity is dependent on its metabolism by the cytochrome P450 system to paraoxon (diethyl 4-nitrophenyl phosphate), a cytotoxic metabolite. As an effective inhibitor of cholinesterases, paraoxon causes the accumulation of acetylcholine in synapses and overstimulation of nicotinic and muscarinic cholinergic receptors, leading to characteristic signs of organophosphate poisoning. Inhibition of parathion metabolism to paraoxon represents a potential approach to counter parathion toxicity. Herein, we demonstrate that menadione (methyl-1,4-naphthoquinone, vitamin K3) is a potent inhibitor of cytochrome P450-mediated metabolism of parathion. Menadione is active in redox cycling,more » a reaction mediated by NADPH-cytochrome P450 reductase that preferentially uses electrons from NADPH at the expense of their supply to the P450s. Using human recombinant CYP 1A2, 2B6, 3A4 and human liver microsomes, menadione was found to inhibit the formation of paraoxon from parathion. Administration of menadione bisulfite (40 mg/kg, ip) to rats also reduced parathion-induced inhibition of brain cholinesterase activity, as well as parathion-induced tremors and the progression of other signs and symptoms of parathion poisoning. These data suggest that redox cycling compounds, such as menadione, have the potential to effectively mitigate the toxicity of organophosphorus pesticides including parathion which require cytochrome P450-mediated activation. - Highlights: • Menadione redox cycles with cytochrome P450 reductase and generates reactive oxygen species. • Redox cycling inhibits cytochrome P450-mediated parathion metabolism. • Short term administration of menadione inhibits parathion toxicity by inhibiting paraoxon formation.« less

Components of the CCR4-NOT complex function as nuclear hormone receptor coactivators via association with the NRC-interacting Factor NIF-1.

PubMed

Garapaty, Shivani; Mahajan, Muktar A; Samuels, Herbert H

2008-03-14

CCR4-NOT is an evolutionarily conserved, multicomponent complex known to be involved in transcription as well as mRNA degradation. Various subunits (e.g. CNOT1 and CNOT7/CAF1) have been reported to be involved in influencing nuclear hormone receptor activities. Here, we show that CCR4/CNOT6 and RCD1/CNOT9, members of the CCR4-NOT complex, potentiate nuclear receptor activity. RCD1 interacts in vivo and in vitro with NIF-1 (NRC-interacting factor), a previously characterized nuclear receptor cotransducer that activates nuclear receptors via its interaction with NRC. As with NIF-1, RCD1 and CCR4 do not directly associate with nuclear receptors; however, they enhance ligand-dependent transcriptional activation by nuclear hormone receptors. CCR4 mediates its effect through the ligand binding domain of nuclear receptors and small interference RNA-mediated silencing of endogenous CCR4 results in a marked decrease in nuclear receptor activation. Furthermore, knockdown of CCR4 results in an attenuated stimulation of RARalpha target genes (e.g. Sox9 and HoxA1) as shown by quantitative PCR assays. The silencing of endogenous NIF-1 also resulted in a comparable decrease in the RAR-mediated induction of both Sox9 and HoxA1. Furthermore, CCR4 associates in vivo with NIF-1. In addition, the CCR4-enhanced transcriptional activation by nuclear receptors is dependent on NIF-1. The small interference RNA-mediated knockdown of NIF-1 blocks the ligand-dependent potentiating effect of CCR4. Our results suggest that CCR4 plays a role in the regulation of certain endogenous RARalpha target genes and that RCD1 and CCR4 might mediate their function through their interaction with NIF-1.

Enhancing the electron transfer capacity and subsequent color removal in bioreactors by applying thermophilic anaerobic treatment and redox mediators.

PubMed

dos Santos, A B; Traverse, J; Cervantes, F J; van Lier, J B

2005-01-05

The effect of temperature, hydraulic retention time (HRT) and the redox mediator anthraquinone-2,6-disulfonate (AQDS), on electron transfer and subsequent color removal from textile wastewater was assessed in mesophilic and thermophilic anaerobic bioreactors. The results clearly show that compared with mesophilic anaerobic treatment, thermophilic treatment at 55 degrees C is an effective approach for increasing the electron transfer capacity in bioreactors, and thus improving the decolorization rates. Furthermore, similar color removals were found at 55 degrees C between the AQDS-free and AQDS-supplemented reactors, whereas a significant difference (up to 3.6-fold) on decolorization rates occurred at 30 degrees C. For instance, at an HRT of 2.5 h and in the absence of AQDS, the color removal was 5.3-fold higher at 55 degrees C compared with 30 degrees C. The impact of a mix of mediators with different redox potentials on the decolorization rate was investigated with both industrial textile wastewater and the azo dye Reactive Red 2 (RR2). Color removal of RR2 in the presence of anthraquinone-2-sulfonate (AQS) (standard redox potential E(0)' of -225 mV) was 3.8-fold and 2.3-fold higher at 30 degrees C and 55 degrees C, respectively, than the values found in the absence of AQS. Furthermore, when the mediators 1,4-benzoquinone (BQ) (E(0)' of +280 mV), and AQS were incubated together, there was no improvement on the decolorization rates compared with the bottles solely supplemented with AQS. Results imply that the use of mixed redox mediators with positive and negative E(0)' under anaerobic conditions is not an efficient approach to improve color removal in textile wastewaters. (c) 2004 Wiley Periodicals, Inc.

The mediating roles of cancer-related rumination in the relationship between dispositional hope and psychological outcomes among childhood cancer survivors.

PubMed

Yuen, Ada N Y; Ho, Samuel M Y; Chan, Calais K Y

2014-04-01

This study aimed to examine the effects of dispositional hope on psychopathology as well as self-perceived positive change in childhood cancer survivors through the potential mediation of cancer-related ruminations. A cross-sectional design was used, and a group of childhood cancer survivors (N = 89; mean age = 23.2 years; age range = 17.2-31.3 years) were studied. Dispositional hope level was measured by the Hope Scale; positive and negative cancer-related ruminations were assessed by the Chinese Cancer-related Rumination Scale; depression symptoms were measured by Beck Depression Inventory; and anxiety symptoms were measured by Beck Anxiety Inventory. Positive adjustment outcome of posttraumatic growth (PTG) was assessed by the Chinese Post-traumatic Growth Inventory. Multiple regressions were used to analyze the relationship between dispositional hope and the outcome variables of PTG, anxiety and depression and the potential mediators of positive and negative cancer-related rumination. Dispositional hope was positively related to PTG, and the correlation was specifically mediated by positive cancer-related rumination. Dispositional hope also correlated with lower levels of depression and anxiety, specifically mediated by negative cancer-related rumination. The present finding supported hope as a significant positive factor for childhood cancer survivors, which was associated with PTG and better psychological adjustment. The findings may inform development of therapeutic intervention programs aimed at increasing childhood cancer patients' hope levels, which may be correlated with more positive cancer-related thoughts and better adjustment. The present study, which examined survivors diagnosed at young age, may enrich existing studies on the effect of onset age and adjustment outcomes. Copyright © 2013 John Wiley & Sons, Ltd.

Socioeconomic status and executive function: developmental trajectories and mediation.

PubMed

Hackman, Daniel A; Gallop, Robert; Evans, Gary W; Farah, Martha J

2015-09-01

Childhood socioeconomic status (SES) predicts executive function (EF), but fundamental aspects of this relation remain unknown: the developmental course of the SES disparity, its continued sensitivity to SES changes during that course, and the features of childhood experience responsible for the SES-EF relation. Regarding course, early disparities would be expected to grow during development if caused by accumulating stressors at a given constant level of SES. Alternatively, they would narrow if schooling partly compensates for the effects of earlier deprivation, allowing lower-SES children to 'catch up'. The potential for later childhood SES change to affect EF is also unknown. Regarding mediating factors, previous analyses produced mixed answers, possibly due to correlation amongst candidate mediators. We address these issues with measures of SES, working memory and planning, along with multiple candidate mediators, from the NICHD Study of Early Childcare (n = 1009). Early family income-to-needs and maternal education predicted planning by first grade, and income-to-needs predicted working memory performance at 54 months. Effects of early SES remained consistent through middle childhood, indicating that the relation between early indicators of SES and EF emerges in childhood and persists without narrowing or widening across early and middle childhood. Changes in family income-to-needs were associated with significant changes in planning and trend-level changes in working memory. Mediation analyses supported the role of early childhood home characteristics in explaining the association between SES and EF, while early childhood maternal sensitivity was specifically implicated in the association between maternal education and planning. Early emerging and persistent SES-related differences in EF, partially explained by characteristics of the home and family environment, are thus a potential source of socioeconomic disparities in achievement and health across development. © 2015 John Wiley & Sons Ltd.

Optical Fluorescent Imaging to Monitor Temporal Effects of Microbubble-Mediated Ultrasound Therapy

PubMed Central

Sorace, Anna G.; Saini, Reshu; Rosenthal, Eben; Warram, Jason M.; Zinn, Kurt R.; Hoyt, Kenneth

2013-01-01

Microbubble-mediated ultrasound therapy can noninvasively enhance drug delivery to localized regions in the body. This technique can be beneficial in cancer therapy, but currently there are limitations to tracking the therapeutic effects. The purpose of this experiment was to investigate the potential of fluorescent imaging for monitoring the temporal effects of microbubble-mediated ultrasound therapy. Mice were implanted with 2LMP breast cancer cells. The animals underwent microbubble-mediated ultrasound therapy in the presence of Cy5.5 fluorescent-labeled IgG antibody (large molecule) or Cy5.5 dye (small molecule) and microbubble contrast agents. Control animals were administered fluorescent molecules only. Animals were transiently imaged in vivo at 1, 10, 30, and 60 min post therapy using a small animal optical imaging system. Tumors were excised and analyzed ex vivo. Tumors were homogenized and emulsion imaged for Cy5.5 fluorescence. Monitoring in vivo results showed significant influx of dye into the tumor (p < 0.05) using the small molecule, but not in the large molecule group (p > 0.05). However, after tumor emulsion, significantly higher dye concentration was detected in therapy group tumors for both small and large molecule groups in comparison to their control counterparts (p < 0.01). This paper explores a noninvasive optical imaging method for monitoring the effects of microbubble-mediated ultrasound therapy in a cancer model. It provides temporal information following the process of increasing extravasation of molecules into target tumors. PMID:23357902

Optical fluorescent imaging to monitor temporal effects of microbubble-mediated ultrasound therapy.

PubMed

Sorace, Anna G; Saini, Reshu; Rosenthal, Eben; Warram, Jason M; Zinn, Kurt R; Hoyt, Kenneth

2013-02-01

Microbubble-mediated ultrasound therapy can noninvasively enhance drug delivery to localized regions in the body. This technique can be beneficial in cancer therapy, but currently there are limitations to tracking the therapeutic effects. The purpose of this experiment was to investigate the potential of fluorescent imaging for monitoring the temporal effects of microbubble-mediated ultrasound therapy. Mice were implanted with 2LMP breast cancer cells. The animals underwent microbubble-mediated ultrasound therapy in the presence of Cy5.5 fluorescent-labeled IgG antibody (large molecule) or Cy5.5 dye (small molecule) and microbubble contrast agents. Control animals were administered fluorescent molecules only. Animals were transiently imaged in vivo at 1, 10, 30, and 60 min post therapy using a small animal optical imaging system. Tumors were excised and analyzed ex vivo. Tumors were homogenized and emulsion imaged for Cy5.5 fluorescence. Monitoring in vivo results showed significant influx of dye into the tumor (p < 0.05) using the small molecule, but not in the large molecule group (p > 0.05). However, after tumor emulsion, significantly higher dye concentration was detected in therapy group tumors for both small and large molecule groups in comparison to their control counterparts (p <0.01). This paper explores a noninvasive optical imaging method for monitoring the effects of microbubble-mediated ultrasound therapy in a cancer model. It provides temporal information following the process of increasing extravasation of molecules into target tumors.

Isoliquiritigenin protects against sepsis-induced lung and liver injury by reducing inflammatory responses.

PubMed

Chen, Xiong; Cai, Xueding; Le, Rongrong; Zhang, Man; Gu, Xuemei; Shen, Feixia; Hong, Guangliang; Chen, Zimiao

2018-02-05

Sepsis, one of the most fatal diseases worldwide, often leads to multiple organ failure, mainly due to uncontrolled inflammatory responses. Despite accumulating knowledge obtained in recent years, effective drugs to treat sepsis in the clinic are still urgently needed. Isoliquiritigenin (ISL), a chalcone compound, has been reported to exert anti-inflammatory properties. However, little is known about the effects of ISL on sepsis and its related complications. In this study, we investigated the potential protective effects of ISL on lipopolysaccharide (LPS)-induced injuries and identified the mechanisms underlying these effects. ISL inhibited inflammatory cytokine expression in mouse primary peritoneal macrophages (MPMs) exposed to LPS. In an acute lung injury (ALI) mouse model, ISL prevented LPS-induced structural damage and inflammatory cell infiltration. Additionally, pretreatment with ISL attenuated sepsis-induced lung and liver injury, accompanied by a reduction in inflammatory responses. Moreover, these protective effects were mediated by the nuclear factor kappa B (NF-κB) pathway-mediated inhibition of inflammatory responses in vitro and in vivo. Our study suggests that ISL may be a potential therapeutic agent for sepsis-induced injuries. Copyright © 2017. Published by Elsevier Inc.

Effects of Germinated Brown Rice and Its Bioactive Compounds on the Expression of the Peroxisome Proliferator-Activated Receptor Gamma Gene

PubMed Central

Imam, Mustapha Umar; Ismail, Maznah; Ithnin, Hairuszah; Tubesha, Zaki; Omar, Abdul Rahman

2013-01-01

Dysregulated metabolism is implicated in obesity and other disease conditions like type 2 diabetes mellitus and cardiovascular diseases, which are linked to abnormalities of peroxisome proliferator-activated receptor gamma (PPARγ). PPARγ has been the focus of much research aimed at managing these diseases. Also, germinated brown rice (GBR) is known to possess antidiabetic, antiobesity and hypocholesterolemic effects. We hypothesized that GBR bioactive compounds may mediate some of the improvements in metabolic indices through PPARγ modulation. Cultured HEP-G2 cells were treated with 50 ppm and 100 ppm of extracts from GBR (GABA, ASG and oryzanol) after determination of cell viabilities using MTT assays. Results showed that all extracts upregulated the expression of the PPARγ. However, combination of all three extracts showed downregulation of the gene, suggesting that, in combination, the effects of these bioactives differ from their individual effects likely mediated through competitive inhibition of the gene. Upregulation of the gene may have therapeutic potential in diabetes mellitus and cardiovascular diseases, while its downregulation likely contributes to GBR’s antiobesity effects. These potentials are worth studying further. PMID:23389305

Large-scale controls on potential respiration and denitrification in riverine floodplains

PubMed Central

Welti, Nina; Bondar-Kunze, Elisabeth; Singer, Gabriel; Tritthart, Michael; Zechmeister-Boltenstern, Sophie; Hein, Thomas; Pinay, Gilles

2012-01-01

Restoration measures of deteriorated river ecosystems generally aim at increasing the spatial heterogeneity and connectivity of these systems in order to increase biodiversity and ecosystem stability. While this is believed to benefit overall ecological integrity, consequences of such restoration projects on biogeochemical processes per se (i.e. ecosystem functioning) in fluvial systems are rarely considered. We address these issues by evaluating the characteristics of surface water connection between side arms and the main river channel in a former braided river section and the role and degree of connectivity (i.e. duration of surface water connection) on the sediment biogeochemistry. We hypothesized that potential respiration and denitrification would be controlled by the degree of hydrological connectivity, which was increased after floodplain restoration. We measured potential microbial respiration (SIR) and denitrification (DEA) and compared a degraded floodplain section of the Danube River with a reconnected and restored floodplain in the same river section. Re-establishing surface water connection altered the controls on sediment microbial respiration and denitrification ultimately impacting potential microbial activities. Meta-variables were created to characterize the effects of hydrology, morphology, and the available carbon and nutrient pools on potential microbial processing. Mantel statistics and path analysis were performed and demonstrate a hierarchy where the effects of hydrology on the available substrates and microbial processing are mediated by the morphology of the floodplain. In addition, these processes are highest in the least connected sites. Surface water connection, mediated by morphology regulates the potential denitrification rate and the ratio of N2O to N2 emissions, demonstrating the effects of restoration in floodplain systems. PMID:23565037

The effects of hyperventilation on postural control mechanisms.

PubMed

Sakellari, V; Bronstein, A M; Corna, S; Hammon, C A; Jones, S; Wolsley, C J

1997-09-01

The effect of hyperventilation on postural balance was investigated. Voluntary hyperventilation increased body sway in normal subjects, particularly in the sagittal plane. The possibility that this hyperventilation-induced unsteadiness is due to interference with lower limb somatosensory input, vestibular reflexes or cerebellar function was assessed. (i) The effect of hyperventilation on peripheral compound sensory action potentials (SAPs) and somatosensory evoked potentials (SEPs) (recorded centrally, from the scalp) elicited by electrical stimulation of the sural nerve was measured in six normal adults. A reduction in the scalp SEP amplitude and an increase in the peripheral SAP amplitude were observed during hyperventilation, which reversed during the recovery period. These changes indicate increased peripheral neural excitability which could lead to a higher level of ectopic activity; the latter would interfere with central reception of peripheral input. (ii) The click-evoked vestibulo-collic reflex was recorded to study the effect of hyperventilation on vestibulo-spinal activity. EMG recordings from both sternocleidomastoid muscles of six healthy subjects were made in response to loud clicks presented to either ear. Neither the amplitude nor the latency of the response were altered significantly by hyperventilation. (iii) Eye-movement recordings were obtained in the six normal subjects to assess the effect of hyperventilation on the vestibulo-ocular reflex and its visual suppression, the latter being a function largely mediated by the cerebellum; no changes were detected. (iv) Three-dimensional eye-movement recordings and body-sway measurements were obtained in six patients with longstanding unilateral vestibular loss in order to evaluate if hyperventilation disrupts vestibular compensation. In all patients, a horizontal nystagmus either appeared or was significantly enhanced for > or = 60 s after voluntary hyperventilation. Sway was also enhanced by hyperventilation in these patients, particularly in the frontal plane. This study suggests that hyperventilation disrupts mechanisms mediating vestibular compensation. The increase in sway may be, at least partly, mediated by deranged peripheral and central somatosensory signals from the lower limbs. Hyperventilation seems to spare vestibular reflex activity and cerebellar-mediated eye movements.

Effortful Control Mediates Associations of Fetal Growth with Hyperactivity and Behavioural Problems in 7- to 9-Year-Old Children

ERIC Educational Resources Information Center

Schlotz, Wolff; Jones, Alexander; Godfrey, Keith M.; Phillips, David I. W.

2008-01-01

Background: Inverse associations of fetal growth with behavioural problems in childhood have been repeatedly reported, suggesting long-term effects of the prenatal developmental environment on behaviour later in life. However, no study so far has examined effects on temperament and potential developmental pathways. Temperamental traits may be…

Adult Social Behavioral Effects of Heavy Adolescent Marijuana Use among African Americans

ERIC Educational Resources Information Center

Green, Kerry M.; Ensminger, Margaret E.

2006-01-01

The authors examined the effects of heavy adolescent marijuana use on employment, marriage, and family formation and tested both dropping out of high school and adult marijuana use as potential mediators of these associations among a community sample of African Americans followed longitudinally from age 6 to age 32-33. They used propensity …

Potentiation of a functional autoantibody in narcolepsy by a cholinesterase inhibitor.

PubMed

Jackson, Michael W; Spencer, Nicolas J; Reed, Joanne H; Smith, Anthony J F; Gordon, Tom P

2009-12-01

We have recently reported the presence of an immunoglobulin G (IgG) autoantibody (Ab) in patients with narcolepsy with cataplexy that abolishes spontaneous colonic migrating motor complexes (CMMCs) and increases smooth muscle tension and atropine-sensitive phasic contractions in a physiological assay of an isolated colon. In this study, we used the cholinesterase inhibitor, neostigmine, to explore the mechanism of the narcoleptic IgG-mediated disruption of enteric motor function in four patients with narcolepsy with cataplexy and to identify a pharmacological mimic of the Ab. Neostigmine potentiated the narcoleptic IgG-mediated increase in smooth muscle resting tension and phasic smooth muscle contractions by an atropine-sensitive mechanism but exerted no effect on resting tension in the presence of control IgG. Decreased frequency of CMMCs mediated by IgG with anti-M3R activity was reversed by neostigmine. Therefore, a challenge with a cholinesterase inhibitor improves the specificity of the CMMC assay for narcoleptic IgG. Tetrodotoxin (TTX), a neuronal sodium channel blocker, also abolished CMMCs and increased resting tone, and a similar potentiation was observed with neostigmine; thus, TTX is a mimic of the functional effects of the narcoleptic IgG in this bioassay. These findings provide a link to pharmacological studies of canine narcolepsy and are consistent with a functional blockade of both excitatory and inhibitory motor neurons by the narcoleptic Ab, similar to the TTX mimic, presumably by binding to an autoantigenic target expressed in both populations of neurons.

Dimensions of Perceived Racism and Self-Reported Health: Examination of Racial/Ethnic Differences and Potential Mediators

PubMed Central

Hausmann, Leslie R. M.; Jhalani, Juhee; Pencille, Melissa; Atencio-Bacayon, Jennifer; Kumar, Asha; Kwok, Jasmin; Ullah, Jahanara; Roth, Alan; Chen, Daniel; Crupi, Robert; Schwartz, Joseph

2016-01-01

Background Many details of the negative relationship between perceived racial/ethnic discrimination and health are poorly understood. Purpose The purpose of this study was to examine racial/ ethnic differences in the relationship between perceived discrimination and self-reported health, identify dimensions of discrimination that drive this relationship, and explore psychological mediators. Methods Asian, Black, and Latino(a) adults (N=734) completed measures of perceived racial/ethnic discrimination, self-reported health, depression, anxiety, and cynical hostility. Results The association between perceived discrimination and poor self-reported health was significant and did not differ across racial/ethnic subgroups. Race-related social exclusion and threat/harassment uniquely contributed to poor health for all groups. Depression, anxiety, and cynical hostility fully mediated the effect of social exclusion on health, but did not fully explain the effect of threat. Conclusions Our results suggest that noxious effects of race-related exclusion and threat transcend between-group differences in discriminatory experiences. The effects of race-related exclusion and threat on health, however, may operate through different mechanisms. PMID:21374099

Organ-Protective Effects of Red Wine Extract, Resveratrol, in Oxidative Stress-Mediated Reperfusion Injury

PubMed Central

Liu, Fu-Chao; Tsai, Hsin-I; Yu, Huang-Ping

2015-01-01

Resveratrol, a polyphenol extracted from red wine, possesses potential antioxidative and anti-inflammatory effects, including the reduction of free radicals and proinflammatory mediators overproduction, the alteration of the expression of adhesion molecules, and the inhibition of neutrophil function. A growing body of evidence indicates that resveratrol plays an important role in reducing organ damage following ischemia- and hemorrhage-induced reperfusion injury. Such protective phenomenon is reported to be implicated in decreasing the formation and reaction of reactive oxygen species and pro-nflammatory cytokines, as well as the mediation of a variety of intracellular signaling pathways, including the nitric oxide synthase, nicotinamide adenine dinucleotide phosphate oxidase, deacetylase sirtuin 1, mitogen-activated protein kinase, peroxisome proliferator-activated receptor-gamma coactivator 1 alpha, hemeoxygenase-1, and estrogen receptor-related pathways. Reperfusion injury is a complex pathophysiological process that involves multiple factors and pathways. The resveratrol is an effective reactive oxygen species scavenger that exhibits an antioxidative property. In this review, the organ-protective effects of resveratrol in oxidative stress-related reperfusion injury will be discussed. PMID:26161238

Rosiglitazone Suppresses In Vitro Seizures in Hippocampal Slice by Inhibiting Presynaptic Glutamate Release in a Model of Temporal Lobe Epilepsy.

PubMed

Wong, Shi-Bing; Cheng, Sin-Jhong; Hung, Wei-Chen; Lee, Wang-Tso; Min, Ming-Yuan

2015-01-01

Peroxisomal proliferator-activated receptor gamma (PPARγ) is a nuclear hormone receptor whose agonist, rosiglitazone has a neuroprotective effect to hippocampal neurons in pilocarpine-induced seizures. Hippocampal slice preparations treated in Mg2+ free medium can induce ictal and interictal-like epileptiform discharges, which is regarded as an in vitro model of N-methyl-D-aspartate (NMDA) receptor-mediated temporal lobe epilepsy (TLE). We applied rosiglitazone in hippocampal slices treated in Mg2+ free medium. The effects of rosiglitazone on hippocampal CA1-Schaffer collateral synaptic transmission were tested. We also examined the neuroprotective effect of rosiglitazone toward NMDA excitotoxicity on cultured hippocampal slices. Application of 10 μM rosiglitazone significantly suppressed amplitude and frequency of epileptiform discharges in CA1 neurons. Pretreatment with the PPARγ antagonist GW9662 did not block the effect of rosiglitazone on suppressing discharge frequency, but reverse the effect on suppressing discharge amplitude. Application of rosiglitazone suppressed synaptic transmission in the CA1-Schaffer collateral pathway. By miniature excitatory-potential synaptic current (mEPSC) analysis, rosiglitazone significantly suppressed presynaptic neurotransmitter release. This phenomenon can be reversed by pretreating PPARγ antagonist GW9662. Also, rosiglitazone protected cultured hippocampal slices from NMDA-induced excitotoxicity. The protective effect of 10 μM rosiglitazone was partially antagonized by concomitant high dose GW9662 treatment, indicating that this effect is partially mediated by PPARγ receptors. In conclusion, rosiglitazone suppressed NMDA receptor-mediated epileptiform discharges by inhibition of presynaptic neurotransmitter release. Rosiglitazone protected hippocampal slice from NMDA excitotoxicity partially by PPARγ activation. We suggest that rosiglitazone could be a potential agent to treat patients with TLE.

Metabotropic GABAB receptors mediate GABA inhibition of acetylcholine release in the rat neuromuscular junction.

PubMed

Malomouzh, Artem I; Petrov, Konstantin A; Nurullin, Leniz F; Nikolsky, Evgeny E

2015-12-01

Gamma-aminobutyric acid (GABA) is an amino acid which acts as a neurotransmitter in the central nervous system. Here, we studied the effects of GABA on non-quantal, spontaneous, and evoked quantal acetylcholine (ACh) release from motor nerve endings. We found that while the application of 10 μM of GABA had no effect on spontaneous quantal ACh release, as detected by the frequency of miniature endplate potentials, GABA reduced the non-quantal ACh release by 57%, as determined by the H-effect value. Finally, the evoked quantal ACh release, estimated by calculating the quantal content of full-sized endplate potentials (EPPs), was reduced by 34%. GABA's inhibitory effect remained unchanged after pre-incubation with picrotoxin, an ionotropic GABAA receptor blocker, but was attenuated following application of the GABAB receptor blocker CGP 55845, which itself had no effect on ACh release. An inhibitor of phospholipase C, U73122, completely prevented the GABA-induced decrease in ACh release. Immunofluorescence demonstrated the presence of both subunits of the GABAB receptor (GABAB R1 and GABAB R2) in the neuromuscular junction. These findings suggest that metabotropic GABAB receptors are expressed in the mammalian neuromuscular synapse and their activation results in a phospholipase C-mediated reduction in the intensity of non-quantal and evoked quantal ACh release. We investigated the effect of gamma-aminobutyric acid (GABA) on neuromuscular transmission. GABA reduced the non-quantal and evoked quantal release of acetylcholine. These effects are mediated by GABAB receptors and are implemented via phospholipase C (PLC) activation. Our findings suggest that in the mammalian neuromuscular synapse, metabotropic GABAB receptors are expressed and their activation results in a reduction in the intensity of acetylcholine release. © 2015 International Society for Neurochemistry.

Culture in Psychiatric Epidemiology: Using Ethnography and Multiple Mediator Models to Assess the Relationship of Caste with Depression and Anxiety in Nepal

PubMed Central

Kohrt, Brandon A.; Speckman, Rebecca A.; Kunz, Richard D.; Baldwin, Jennifer L.; Upadhaya, Nawaraj; Acharya, Nanda Raj; Sharma, Vidya Dev; Nepal, Mahendra K.; Worthman, Carol M.

2013-01-01

Background The causes of ethnic and caste-based disparities in mental health are poorly understood. Aim To identify mediators underlying caste-based disparities in mental health in Nepal. Subjects and methods A mixed methods ethnographic and epidemiological study of 307 adults (Dalit/Nepali, n=75; high caste Brahman and Chhetri, n=232) assessed with Nepali versions of Beck Depression (BDI) and Anxiety (BAI) Inventories. Results One third (33.7%) of participants were classified as depressed: Dalit/Nepali 50.0%, high caste 28.4%. One quarter (27.7%) of participants were classified as anxious: Dalit/Nepali 50.7%, high caste 20.3%. Ethnographic research identified four potential mediators: stressful life events, owning few livestock, no household income, and lack of social support. The direct effect of caste was 1.08 (95% CI -1.10—3.27) on depression score and 4.76 (95% CI 2.33—7.19) on anxiety score. All four variables had significant indirect (mediation) effects on anxiety, and all but social support had significant indirect effects on depression. Conclusion Caste-based disparities in mental health in rural Nepal are statistically mediated by poverty, lack of social support, and stressful life events. Interventions should target these areas to alleviate the excess mental health burden born by Dalit/Nepali women and men. PMID:19381985

Culture in psychiatric epidemiology: using ethnography and multiple mediator models to assess the relationship of caste with depression and anxiety in Nepal.

PubMed

Kohrt, Brandon A; Speckman, Rebecca A; Kunz, Richard D; Baldwin, Jennifer L; Upadhaya, Nawaraj; Acharya, Nanda Raj; Sharma, Vidya Dev; Nepal, Mahendra K; Worthman, Carol M

2009-01-01

The causes of ethnic and caste-based disparities in mental health are poorly understood. The study aimed to identify mediators underlying caste-based disparities in mental health in Nepal. A mixed methods ethnographic and epidemiological study of 307 adults (Dalit/Nepali, n=75; high caste Brahman and Chhetri, n=232) was assessed with Nepali versions of Beck Depression (BDI) and Anxiety (BAI) Inventories. One-third (33.7%) of participants were classified as depressed: Dalit/Nepali 50.0%, high caste 28.4%. One quarter (27.7%) of participants were classified as anxious: Dalit/Nepali 50.7%, high caste 20.3%. Ethnographic research identified four potential mediators: Stressful life events, owning few livestock, no household income, and lack of social support. The direct effect of caste was 1.08 (95% CI -1.10-3.27) on depression score and 4.76 (95% CI 2.33-7.19) on anxiety score. All four variables had significant indirect (mediation) effects on anxiety, and all but social support had significant indirect effects on depression. Caste-based disparities in mental health in rural Nepal are statistically mediated by poverty, lack of social support, and stressful life events. Interventions should target these areas to alleviate the excess mental health burden born by Dalit/Nepali women and men.

Cerebral microhemorrhages due to traumatic brain injury and their effects on the aging human brain.

PubMed

Irimia, Andrei; Van Horn, John D; Vespa, Paul M

2018-06-01

Although cerebral microbleeds (CMBs) are frequently associated with traumatic brain injury (TBI), their effects on clinical outcome after TBI remain controversial and poorly understood, particularly in older adults. Here we (1) highlight major challenges and opportunities associated with studying the effects of TBI-mediated CMBs; (2) review the evidence on their potential effects on cognitive and neural outcome as a function of age at injury; and (3) suggest priorities for future research on understanding the clinical implications of CMBs. Although TBI-mediated CMBs are likely distinct from those due to cerebral amyloid angiopathy or other neurodegenerative diseases, the effects of these 2 CMB types on brain function may share common features. Furthermore, in older TBI victims, the incidence of TBI-mediated CMBs may approximate that of cerebral amyloid angiopathy-related CMBs, and thus warrants detailed study. Because the alterations effected by CMBs on brain structure and function are both unique and age-dependent, it seems likely that novel, age-tailored therapeutic approaches are necessary for the adequate clinical interpretation and treatment of these ubiquitous and underappreciated TBI sequelae. Copyright © 2018 Elsevier Inc. All rights reserved.

The Presence of a Calling and Academic Satisfaction: Examining Potential Mediators

ERIC Educational Resources Information Center

Duffy, Ryan D.; Allan, Blake A.; Dik, Bryan J.

2011-01-01

The present study examined the relation of calling and academic satisfaction with a diverse sample of 312 undergraduate students. The presence of a calling was moderately correlated with academic satisfaction, and a multiple mediation model was utilized to test three potential mediators to this relation: career decision self-efficacy, work hope,…

Emerging Mechanistic Targets in Lung Injury Induced by Combustion-Generated Particles

PubMed Central

Fariss, Marc W.; Gilmour, M. Ian; Reilly, Christopher A.; Liedtke, Wolfgang; Ghio, Andrew J.

2013-01-01

The mechanism for biological effect following exposure to combustion-generated particles is incompletely defined. The identification of pathways regulating the acute toxicological effects of these particles provides specific targets for therapeutic manipulation in an attempt to impact disease following exposures. Transient receptor potential (TRP) cation channels were identified as “particle sensors” in that their activation was coupled with the initiation of protective responses limiting airway deposition and inflammatory responses, which promote degradation and clearance of the particles. TRPA1, V1, V4, and M8 have a capacity to mediate adverse effects after exposure to combustion-generated particulate matter (PM); relative contributions of each depend upon particle composition, dose, and deposition. Exposure of human bronchial epithelial cells to an organic extract of diesel exhaust particle was followed by TRPV4 mediating Ca++ influx, increased RAS expression, mitogen-activated protein kinase signaling, and matrix metalloproteinase-1 activation. These novel pathways of biological effect can be targeted by compounds that specifically inhibit critical signaling reactions. In addition to TRPs and calcium biochemistry, humic-like substances (HLS) and cell/tissue iron equilibrium were identified as potential mechanistic targets in lung injury after particle exposure. In respiratory epithelial cells, iron sequestration by HLS in wood smoke particle (WSP) was associated with oxidant generation, cell signaling, transcription factor activation, and release of inflammatory mediators. Similar to WSP, cytotoxic insoluble nanosized spherical particles composed of HLS were isolated from cigarette smoke condensate. Therapies that promote bioelimination of HLS and prevent the disruption of iron homeostasis could function to reduce the harmful effects of combustion-generated PM exposure. PMID:23322347

Karanjin interferes with ABCB1, ABCC1, and ABCG2.

PubMed

Michaelis, Martin; Rothweiler, Florian; Nerreter, Thomas; Sharifi, Mohsen; Ghafourian, Taravat; Cinatl, Jindrich

2014-01-01

The prominent ATP-binding cassette (ABC) transporters ABCB1, ABCC1, and ABCG2 are involved in substance transport across physiological barriers and therefore in drug absorption, distribution, and elimination. They also mediate multi-drug resistance in cancer cells. Different flavonoids are known to interfere with different ABC transporters. Here, the effect of the furanoflavonol karanjin, a potential drug with antiglycaemic, gastroprotective, antifungal, and antibacterial effects, was investigated on ABCB1, ABCC1, and ABCG2-mediated drug transport in comparison to the flavonoids apigenin, genistein, and naringenin. Cells expressing the relevant transporters (ABCB1: UKF-NB-3(ABCB1), UKF-NB-3(r)VCR¹⁰; ABCC1: G62, PC-3(r)VCR²⁰; ABCG2: UKF-NB-3(ABCG2)) were used in combination with specific fluorescent and cytotoxic ABC transporter substrates and ABC transporter inhibitors to study ABC transporter function. Moreover, the effects of the investigated flavonoids were determined on the ABC transporter ATPase activities. Karanjin interfered with drug efflux mediated by ABCB1, ABCC1, and ABCG2 and enhanced the ATPase activity of all three transporters. Moreover, karanjin exerted more pronounced effects than the control flavonoids apigenin, genistein, and naringenin on all three transporters. Most notably, karanjin interfered with ABCB1 at low concentrations being about 1 µM. Taken together, these findings should be taken into account during further consideration of karanjin as a potential drug for different therapeutic indications. The effects on ABCB1, ABCC1, and ABCG2 may affect the pharmacokinetics of co-administered drugs.

Exploration of Nanoparticle-Mediated Photothermal Effect of TMB-H2O2 Colorimetric System and Its Application in a Visual Quantitative Photothermal Immunoassay.

PubMed

Fu, Guanglei; Sanjay, Sharma T; Zhou, Wan; Brekken, Rolf A; Kirken, Robert A; Li, XiuJun

2018-05-01

The exploration of new physical and chemical properties of materials and their innovative application in different fields are of great importance to advance analytical chemistry, material science, and other important fields. Herein, we, for the first time, discovered the photothermal effect of an iron oxide nanoparticles (NPs)-mediated TMB (3,3',5,5'-tetramethylbenzidine)-H 2 O 2 colorimetric system, and applied it toward the development of a new NP-mediated photothermal immunoassay platform for visual quantitative biomolecule detection using a thermometer as the signal reader. Using a sandwich-type proof-of-concept immunoassay, we found that the charge transfer complex of the iron oxide NPs-mediated one-electron oxidation product of TMB (oxidized TMB) exhibited not only color changes, but also a strong near-infrared (NIR) laser-driven photothermal effect. Hence, oxidized TMB was explored as a new sensitive photothermal probe to convert the immunoassay signal into heat through the near-infrared laser-driven photothermal effect, enabling simple photothermal immunoassay using a thermometer. Based on the new iron oxide NPs-mediated TMB-H 2 O 2 photothermal immunoassay platform, prostate-specific antigen (PSA) as a model biomarker can be detected at a concentration as low as 1.0 ng·mL -1 in normal human serum. The discovered photothermal effect of the colorimetric system and the developed new photothermal immunoassay platform open up a new horizon for affordable detection of disease biomarkers and have great potential for other important material and biomedical applications of interest.

Role of receptor-mediated endocytosis in the antiangiogenic effects of human T lymphoblastic cell-derived microparticles.

PubMed

Yang, Chun; Xiong, Wei; Qiu, Qian; Shao, Zhuo; Shao, Zuo; Hamel, David; Tahiri, Houda; Leclair, Grégoire; Lachapelle, Pierre; Chemtob, Sylvain; Hardy, Pierre

2012-04-15

Microparticles possess therapeutic potential regarding angiogenesis. We have demonstrated the contribution of apoptotic human CEM T lymphocyte-derived microparticles (LMPs) as inhibitors of angiogenic responses in animal models of inflammation and tumor growth. In the present study, we characterized the antivascular endothelial growth factor (VEGF) effects of LMPs on pathological angiogenesis in an animal model of oxygen-induced retinopathy and explored the role of receptor-mediated endocytosis in the effects of LMPs on human retinal endothelial cells (HRECs). LMPs dramatically inhibited cell growth of HRECs, suppressed VEGF-induced cell migration in vitro experiments, and attenuated VEGF-induced retinal vascular leakage in vivo. Intravitreal injections of fluorescently labeled LMPs revealed accumulation of LMPs in retinal tissue, with more than 60% reductions of the vascular density in retinas of rats with oxygen-induced neovascularization. LMP uptake experiments demonstrated that the interaction between LMPs and HRECs is dependent on temperature. In addition, endocytosis is partially dependent on extracellular calcium. RNAi-mediated knockdown of low-density lipoprotein receptor (LDLR) reduced the uptake of LMPs and attenuated the inhibitory effects of LMPs on VEGF-A protein expression and HRECs cell growth. Intravitreal injection of lentivirus-mediated RNA interference reduced LDLR protein expression in retina by 53% and significantly blocked the antiangiogenic effects of LMPs on pathological vascularization. In summary, the potent antiangiogenic LMPs lead to a significant reduction of pathological retinal angiogenesis through modulation of VEGF signaling, whereas LDLR-mediated endocytosis plays a partial, but pivotal, role in the uptake of LMPs in HRECs.

Mediating toxic emotions in the workplace--the impact of abusive supervision.

PubMed

Chu, Li-Chuan

2014-11-01

This study explores whether abusive supervision can effectively predict employees' counterproductive work behaviour (CWB) and organisational citizenship behaviour (OCB) and the role of toxic emotions at work as a potential mediator of these relationships in nursing settings. Workplace bullying is widespread in nursing. Despite the growing literature on abusive supervision and employees' counterproductive work behaviour and organisational citizenship behaviour, few studies have examined the relationships between abusive supervision and these work behaviours from the viewpoint of the victimed employee's emotion process. This study adopted a two-stage survey of 212 nurses, all of whom were employed by hospitals in Taiwan. Hypotheses were tested through the use of hierarchical multiple regression. The results showed that abusive supervision was positively associated with toxic emotions. Moreover, toxic emotions could effectively predict nurses' counterproductive work behaviour and organisational citizenship behaviour. Finally, it was found that toxic emotions partially mediated the negative effects of abusive supervision on both work behaviours. Toxic emotions at work are a critical mediating variable between abusive supervision and both counterproductive work behaviour and organisational citizenship behaviour. Hospital administrators can implement policies designed to manage events effectively that can spark toxic emotions in their employees. Work empowerment may be an effective way to reduce counterproductive work behaviour and to enhance organisational citizenship behaviour among nurses when supervisors do not promote a healthy work environment for them. © 2013 John Wiley & Sons Ltd.

Cognitive Activity Mediates the Association between Social Activity and Cognitive Performance: A Longitudinal Study

PubMed Central

Brown, Cassandra L.; Robitaille, Annie; Zelinski, Elizabeth M.; Dixon, Roger A.; Hofer, Scott M.; Piccinin, Andrea M.

2016-01-01

Social activity is one aspect of an active lifestyle and some evidence indicates it is related to preserved cognitive function in older adulthood. However, the potential mechanisms underlying this association remain unclear. We investigate four potential mediational pathways through which social activity may relate to cognitive performance. A multilevel structural equation modeling approach to mediation was used to investigate whether cognitive activity, physical activity, depressive symptoms, and vascular health conditions mediate the association between social activity and cognitive function in older adults. Using data from the Victoria Longitudinal Study (VLS), we tested four cognitive outcomes: fluency, episodic memory, reasoning, and vocabulary. Three important findings emerged. First, the association between social activity and all four domains of cognitive function was significantly mediated by cognitive activity at the within-person level. Second, we observed a significant indirect effect of social activity on all domains of cognitive function through cognitive activity at the between-person level. Third, we found a within-person indirect relationship of social activity with episodic memory performance through physical activity. For these older adults, engagement in social activities was related to participation in everyday cognitive activities and in turn to better cognitive performance. This pattern is consistent with the interpretation that a lifestyle of social engagement may benefit cognitive performance by providing opportunities or motivation to participate in supportive cognitively stimulating activities. PMID:27929339

Cognitive activity mediates the association between social activity and cognitive performance: A longitudinal study.

PubMed

Brown, Cassandra L; Robitaille, Annie; Zelinski, Elizabeth M; Dixon, Roger A; Hofer, Scott M; Piccinin, Andrea M

2016-12-01

Social activity is 1 aspect of an active lifestyle and some evidence indicates it is related to preserved cognitive function in older adulthood. However, the potential mechanisms underlying this association remain unclear. We investigate 4 potential mediational pathways through which social activity may relate to cognitive performance. A multilevel structural equation modeling approach to mediation was used to investigate whether cognitive activity, physical activity, depressive symptoms, and vascular health conditions mediate the association between social activity and cognitive function in older adults. Using data from the Victoria Longitudinal Study, we tested 4 cognitive outcomes: fluency, episodic memory, reasoning, and vocabulary. Three important findings emerged. First, the association between social activity and all 4 domains of cognitive function was significantly mediated by cognitive activity at the within-person level. Second, we observed a significant indirect effect of social activity on all domains of cognitive function through cognitive activity at the between-person level. Third, we found a within-person indirect relationship of social activity with episodic memory performance through physical activity. For these older adults, engagement in social activities was related to participation in everyday cognitive activities and in turn to better cognitive performance. This pattern is consistent with the interpretation that a lifestyle of social engagement may benefit cognitive performance by providing opportunities or motivation to participate in supportive cognitively stimulating activities. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Restless Legs Syndrome and Depression: Effect Mediation by Disturbed Sleep and Periodic Limb Movements.

PubMed

Koo, Brian B; Blackwell, Terri; Lee, Hochang B; Stone, Katie L; Louis, Elan D; Redline, Susan

2016-11-01

To investigate an association between restless legs syndrome (RLS) and depression and to what extent sleep disturbance, periodic limb movements during sleep (PLMS), and antidepressant medication mediate this relationship. A cross-sectional analysis was conducted of the Osteoporotic Fractures in Older Men Study data in 982 men assessed for RLS (International RLS Study Group scale [IRLSS]) and depression (Geriatric Depression Scale [GDS]), who underwent actigraphy (for sleep latency/efficiency) and polysomnography (for PLMS). Men were split into three groups: no RLS (N = 815), mild RLS (IRLSS ≤ 12, N = 85), moderate-to-severe RLS (IRLSS > 12, N = 82). Depression was defined as GDS score ≥ 6. Logistic and linear regression assessed associations of RLS and depression or number depressive symptoms, respectively. Models were adjusted for age, site, race, education, body mass index, personal habits, benzodiazepine/dopaminergic medication, physical activity, cardiovascular risk factors, and apnea-hypopnea index. Of 982 men, 167 (17.0%) had RLS. Depression was significantly associated with moderate-to-severe RLS after adjustment (versus no RLS: OR [95% CI] 2.85 [1.23, 6.64]). Further adjustment for potential mediators attenuated effect size modestly, most for sleep efficiency (OR: 2.85-2.55). Compared with no RLS, moderate-to-severe RLS was associated with the number of depressive symptoms after adjustment (adjusted means [95% CI]; no RLS: 1.14 [1.05, 1.24] versus IRLSS > 12: 1.69 [1.32, 2.11]). Further adjustment for potential mediators did not alter effect size. For men with PLMS index at least median, number of depressive symptoms significantly increased as RLS category became more severe. Depression is more common as RLS severity worsens. The RLS-depression relationship is modestly explained by sleep disturbance and PLMS. Published by Elsevier Inc.

Study on the effect of reactive oxygen species-mediated oxidative stress on the activation of mitochondrial apoptosis and the tenderness of yak meat.

PubMed

Wang, Lin-Lin; Yu, Qun-Li; Han, Ling; Ma, Xiu-Li; Song, Ren-De; Zhao, Suo-Nan; Zhang, Wen-Hua

2018-04-01

This study investigated the effect of reactive oxygen species-mediated oxidative stress on activation of mitochondrial apoptosis and tenderness of yak meat during postmortem ageing. Oxidative stress degree, Ca 2+ levels, membrane permeability transition pore opening, mitochondrial membrane potential, apoptotic factors and the shear force were examined. Results showed that the ROS generated by H 2 O 2 significantly increased mitochondrial oxidative stress by decreasing the activities of superoxide dismutase, catalase and glutathione peroxidase, and increasing lipid peroxidation. Furthermore, oxidative stress enhanced Ca 2+ production and cytochrome c release, changed the levels of Bcl-2 family proteins and activated caspase-9 and -3 activities. Ultimately, oxidative stress increased the apoptosis rate and tenderness of yak meat. These observations confirmed that ROS-mediated oxidative stress participates in the activation of the apoptotic cascade reaction involving Ca 2+ and Bcl-2 family proteins. The results further suggested that ROS-mediated oxidative stress plays a significant role in meat tenderization through the mitochondrial apoptotic pathway. Copyright © 2017. Published by Elsevier Ltd.

Particle-size-dependent cytokine responses and cell damage induced by silica particles and macrophages-derived mediators in endothelial cell.

PubMed

Rong, Yi; Zhou, Ting; Cheng, Wenjuan; Guo, Jiali; Cui, Xiuqing; Liu, Yuewei; Chen, Weihong

2013-11-01

Epidemiological evidence reports silica dust exposure has been associated with increased risk of cardiovascular diseases, but the mechanisms are largely unknown. In this study, endothelial cells were exposed to increasing concentrations of two sizes silica particles and the soluble mediators released by macrophages treated with the same particles for 24 h. Expression and release of cytokines (IL-1β, TNF-α and IL-6) were measured by using ELISA. Cytotoxicity was measured by MTT assay and LDH release. We show that both ways induced increases in cell toxicity and cytokines in a dose-dependent manner. For smaller particles, the soluble mediators are more capable of increasing cytokines compared with the effect of particles directly. For larger particles, evaluating results of these two ways are similar. Either way, smaller particles make the increasing action of cell toxicity and cytokines more remarkable. Our results indicate both silica particle and macrophage-derived mediators can induce endothelial cell injury and inflammation and demonstrate the potential importance of the particle sizes in this effect. Copyright © 2013. Published by Elsevier B.V.

Burnout and Engagement as Mediators in the Relationship between Work Characteristics and Turnover Intentions across Two Ibero-American Nations.

PubMed

Gabel Shemueli, Rachel; Dolan, Simon L; Suárez Ceretti, Adriana; Nuñez Del Prado, Pamela

2016-12-01

This study examines the mediating effects of burnout and engagement on the relationships between work characteristics (work overload and social support) and turnover intentions in the nursing community of two Ibero-American countries within the job demands-resources model. The sample consists of 316 registered nurses employed in Uruguay and 502 employed in Spain. We used multiple structural equation modelling analyses. The proposed model fit the data for both nursing samples. Burnout was found to fully mediate the relationship between work overload and turnover intention, whereas work engagement partially mediates the relationship between social support and turnover intention. The results contribute to our understanding of the potential applicability of two leading empirical models and of the dynamic relationship between work characteristics and turnover intentions through work engagement and burnout. Researchers should continue to focus on gaining a broader understanding of the effects of work characteristics in healthcare facilities and the associated organizational outcomes. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Regulatory effects of curcumin on lipid accumulation in monocytes/macrophages

USDA-ARS?s Scientific Manuscript database

Recent evidence suggests potential benefits from phytochemicals and micronutrients in protecting against oxidative and lipid-mediated damage, but the molecular mechanisms of these actions are still unclear. Here we investigated whether the dietary polyphenol curcumin can modulate the accumulation of...

Treatment of Social Phobia: Potential Mediators and Moderators

PubMed Central

Hofmann, Stefan G.

2006-01-01

Although the efficacy of numerous psychosocial interventions for social phobia has been clearly demonstrated, little is known about the mediators and moderators of treatment change. Three potential mediators are discussed that are derived from prominent psychological theories: negative cognitive appraisal (estimated social costs), perceived self-efficacy (perceived social skills), and perceived emotional control. Furthermore, the generalized subtype of social phobia and the additional diagnosis of avoidant personality disorder are considered as potential treatment moderators. PMID:16799697

Quantifying the Role of Circulating Unconjugated Estradiol in Mediating the Body Mass Index-Breast Cancer Association.

PubMed

Schairer, Catherine; Fuhrman, Barbara J; Boyd-Morin, Jennifer; Genkinger, Jeanine M; Gail, Mitchell H; Hoover, Robert N; Ziegler, Regina G

2016-01-01

Higher body mass index (BMI) and circulating estrogen levels each increase postmenopausal breast cancer risk, particularly estrogen receptor-positive (ER(+)) tumors. Higher BMI also increases estrogen production. We estimated the proportion of the BMI-ER(+) breast cancer association mediated through estrogen in a case-control study nested within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Participants included 143 women with invasive ER(+) breast cancer and 268 matched controls, all postmenopausal and never having used hormone therapy at baseline. We used liquid chromatography-tandem mass spectrometry to measure 15 estrogens and estrogen metabolites in baseline serum. We calculated BMI from self-reported height and weight at baseline. We estimated the mediating effect of unconjugated estradiol on the BMI-ER(+) breast cancer association using Aalen additive hazards and Cox regression models. All estrogens and estrogen metabolites were statistically significantly correlated with BMI, with unconjugated estradiol most strongly correlated [Pearson correlation (r) = 0.45]. Approximately 7% to 10% of the effect of overweight, 12% to 15% of the effect of obesity, and 19% to 20% of the effect of a 5 kg/m(2) BMI increase on ER(+) breast cancer risk was mediated through unconjugated estradiol. The BMI-breast cancer association, once adjusted for unconjugated estradiol, was not modified by further adjustment for two metabolic ratios statistically significantly associated with both breast cancer and BMI. Circulating unconjugated estradiol levels partially mediate the BMI-breast cancer association, but other potentially important estrogen mediators (e.g., bioavailable estradiol) were not evaluated. Further research is required to identify mechanisms underlying the BMI-breast cancer association. ©2015 American Association for Cancer Research.

The impact of early parenting bonding on young adults' internet addiction, through the mediation effects of negative relating to others and sadness.

PubMed

Kalaitzaki, Argyroula E; Birtchnell, John

2014-03-01

The aim of the present study is the investigation of the potential role of negative relating to others, perceived loneliness, sadness, and anxiety, as mediators of the association between early parental bonding and adult Internet Addiction (IA). The factorial structure of the Internet Addiction Test (IAT) and the prevalence rates of it in a Greek sample will also be investigated. A total of 774 participants were recruited from a Technological Education Institute (mean age=20.2, SD=2.8) and from high school technical schools (mean age=19.9, SD=7.4). The IAT was used to measure the degree of problematic Internet use behaviors; the Parental Bonding Instrument was used to assess one's recalled parenting experiences during the first 16years of life; the shortened Person's Relating to Others Questionnaire was used to assess one's negative (i.e. maladaptive) relating to others (NRO). Both exploratory and confirmatory factor analyses confirmed the three-factor structure of the IAT. Only 1.0% of the sample was severely addicted to the Internet. The mediated effects of only the NRO and sadness were confirmed. Negative relating to others was found to fully mediate the effect of both the father's optimal parenting and affectionless control on IA, whereas sadness was found to fully mediate the effect of the mother's optimal parenting on IA. Overall, the results suggest that parenting style has an indirect impact on IA, through the mediating role of negative relating to others or sadness in later life. Both family-based and individual-based prevention and intervention efforts may reduce the incidence of IA. Copyright © 2013 Elsevier Ltd. All rights reserved.

Specificity in mediated pathways by anxiety symptoms linking adolescent stress profiles to depressive symptoms: Results of a moderated mediation approach.

PubMed

Anyan, Frederick; Bizumic, Boris; Hjemdal, Odin

2018-03-01

We investigated the specificity in mediated pathways that separately link specific stress dimensions through anxiety to depressive symptoms and the protective utility of resilience. Thus, this study goes beyond lumping together potential mediating and moderating processes that can explain the relations between stress and (symptoms of) psychopathology and the buffering effect of resilience. Ghanaian adolescents between 13 and 17 years (female = 285; male = 244) completed the Adolescent Stress Questionnaire (ASQ), Spielberger State Anxiety Inventory (STAI), Short Mood Feeling Questionnaire (SMFQ) and the Resilience Scale for Adolescents (READ). Independent samples t-test, multivariate analysis of covariance with follow-up tests and moderated mediation analyses were performed. Evidences were found for specificity in the associations between dimensions of adolescent stressors and depressive symptoms independent of transient anxiety. Transient anxiety partly accounted for the indirect effects of eight stress dimensions on depressive symptoms. Except stress of school attendance and school/leisure conflict, resilience moderated the indirect effects of specific stress dimensions on depressive symptoms. Results suggested differences in how Ghanaian adolescents view the various stress dimensions, and mediated pathways associated with anxiety and depressive symptoms. Use of cross-sectional data does not show causal process and temporal changes over time. Findings support and clarify the specificity in the interrelations and mediated pathways among dimensions of adolescent stress, transient anxiety, and depressive symptoms. Conditional process analyses shows that resilience does not only buffer direct, but also indirect psychological adversities. Interventions for good mental health may focus on low resilience subgroups in specific stress dimensions while minimizing transient anxiety. Copyright © 2017 Elsevier B.V. All rights reserved.

In vivo suppression of plasma IL-12 levels by acute and chronic stress paradigms: potential mediating mechanisms and sex differences

PubMed Central

Shaashua, L.; Sominsky, L.; Levi, B.; Sorski, L.; Reznick, M.; Page, G.; Ben-Eliyahu, S.

2012-01-01

Interleukin-12 (IL-12) is a major pro-inflammatory cytokine, which promotes cell-mediated immunity and TH1 differentiation. In vitro studies indicated suppression of IL-12 production by several stress-related factors, but no effects of behavioral stress were shown on plasma IL-12 levels. Therefore, in the current study we (i) examined the in vivo effects of various behavioral and pharmacological stress paradigms on baseline plasma IL-12 levels; (ii) compared these in vivo findings to those obtained following in vitro stimulation of leukocytes from the same rats; and (iii) assessed potential sexual dimorphism in these outcomes. The findings indicated that plasma IL-12 levels were significantly reduced by social confrontation, wet-cage exposure, surgery, and the administration of corticosterone, epinephrine, or prostaglandin-E2. Notably, most in vivo impacts on plasma levels were not evident when assessed in vitro. The IL-12-reducing effects of wet-cage exposure, and of corticosterone and epinephrine administration, were significantly greater in males than in females, although females exhibited greater total corticosterone levels following stress. The duration of acute stressors predicted the degree of IL-12 reduction, but more prolonged stressors did not. Furthermore, seven days of alternating behavioral stressors reduced plasma IL-12 levels more than fourteen days. These findings suggest animals’ behavioral habituation to stress conditions, or a specific immune mechanism restricting the duration of IL-12 reduction. Overall, our findings indicate a generic and robust stress-induced reduction in plasma IL-12 levels, and suggest epinephrine, corticosterone, and prostaglandin-E2, as potential mediators that should be scrutinized in vivo in the context of natural physiological stress responses. PMID:22659252

Assessment of potential biological activities and distributions of endocrine-disrupting chemicals in sediments of the west coast of South Korea.

PubMed

Jeon, Seungyeon; Hong, Seongjin; Kwon, Bong-Oh; Park, Jinsoon; Song, Sung Joon; Giesy, John P; Khim, Jong Seong

2017-02-01

The west coast of Korea has experienced environmental deterioration for more than half a century. In the present study, we specifically aimed to: i) evaluate potential toxicities of contaminants in sediments that cause effects mediated through the aryl hydrocarbon receptor (AhR) and estrogen receptor (ER); ii) determine spatio-temporal distributions of polycyclic aromatic hydrocarbons (PAHs) and alkylphenols (APs); and iii) identify causes of greater potencies of samples. From 2010 to 2014, sediments were collected from 12 major estuarine and coastal regions along the west coast of South Korea. In vitro cell bioassays were performed to determine AhR- and ER-mediated potencies using H4IIE-luc and MVLN cells, respectively. Fifteen PAHs and six APs in sediments were identified by GC/MSD. Results of bioassays generally showed a low-to-moderate degree of contamination, however, greater AhR- and ER-mediated potencies were measured at some locations. Concentrations of PAHs and APs varied among locations, which indicated that sources were independently affected by the surrounding environment (e.g., industrial complex and cities). Results of bioassays were generally well correlated with concentrations of putative causative chemicals. Benzo[k]fluoranthene, dibenz[a,h]anthracene, and benzo[b]fluoranthene were the major AhR agonists, explaining approximately 30% of the bioassay-derived benzo[a]pyrene equivalent concentration (BaP-EQ). Unknown AhR and ER agonists and potential mixture effects remain in question. Overall, the present study provides baseline information on chemical contaminations and potential toxicity of sediments in a fairly wide geographical region of the west coast of South Korea. Copyright © 2016 Elsevier Ltd. All rights reserved.

The pro-angiogenic cytokine pleiotrophin potentiates cardiomyocyte apoptosis through inhibition of endogenous AKT/PKB activity.

PubMed

Li, Jinliang; Wei, Hong; Chesley, Alan; Moon, Chanil; Krawczyk, Melissa; Volkova, Maria; Ziman, Bruce; Margulies, Kenneth B; Talan, Mark; Crow, Michael T; Boheler, Kenneth R

2007-11-30

Pleiotrophin is a development-regulated cytokine and growth factor that can promote angiogenesis, cell proliferation, or differentiation, and it has been reported to have neovasculogenic effects in damaged heart. Developmentally, it is prominently expressed in fetal and neonatal hearts, but it is minimally expressed in normal adult heart. Conversely, we show in a rat model of myocardial infarction and in human dilated cardiomyopathy that pleiotrophin is markedly up-regulated. To elucidate the effects of pleiotrophin on cardiac contractile cells, we employed primary cultures of rat neonatal and adult cardiomyocytes. We show that pleiotrophin is released from cardiomyocytes in vitro in response to hypoxia and that the addition of recombinant pleiotrophin promotes caspase-mediated genomic DNA fragmentation in a dose- and time-dependent manner. Functionally, it potentiates the apoptotic response of neonatal cardiomyocytes to hypoxic stress and to ultraviolet irradiation and of adult cardiomyocytes to hypoxia-reoxygenation. Moreover, UV-induced apoptosis in neonatal cardiomyocytes can be partially inhibited by small interfering RNA-mediated knockdown of endogenous pleiotrophin. Mechanistically, pleiotrophin antagonizes IGF-1 associated Ser-473 phosphorylation of AKT/PKB, and it concomitantly decreases both BAD and GSK3beta phosphorylation. Adenoviral expression of constitutively active AKT and lithium chloride-mediated inhibition of GSK3beta reduce the potentiated programmed cell death elicited by pleiotrophin. These latter data indicate that pleiotrophin potentiates cardiomyocyte cell death, at least partially, through inhibition of AKT signaling. In conclusion, we have uncovered a novel function for pleiotrophin on heart cells following injury. It fosters cardiomyocyte programmed cell death in response to pro-apoptotic stress, which may be critical to myocardial injury repair.