Psychedelics as Medicines: An Emerging New Paradigm.

PubMed

Nichols, D E; Johnson, M W; Nichols, C D

2017-02-01

Scientific interest in serotonergic psychedelics (e.g., psilocybin and LSD; 5-HT 2A receptor agonists) has dramatically increased within the last decade. Clinical studies administering psychedelics with psychotherapy have shown preliminary evidence of robust efficacy in treating anxiety and depression, as well as addiction to tobacco and alcohol. Moreover, recent research has suggested that these compounds have potential efficacy against inflammatory diseases through novel mechanisms, with potential advantages over existing antiinflammatory agents. We propose that psychedelics exert therapeutic effects for psychiatric disorders by acutely destabilizing local brain network hubs and global network connectivity via amplification of neuronal avalanches, providing the occasion for brain network "resetting" after the acute effects have resolved. Antiinflammatory effects may hold promise for efficacy in treatment of inflammation-related nonpsychiatric as well as potentially for psychiatric disorders. Serotonergic psychedelics operate through unique mechanisms that show promising effects for a variety of intractable, debilitating, and lethal disorders, and should be rigorously researched. © 2016 American Society for Clinical Pharmacology and Therapeutics.

Analyzing phorbol ester effects on gap junctional communication: a dramatic inhibition of assembly

PubMed Central

1994-01-01

The effect of 12-O-tetradeconylphorbol-13-acetate (TPA) on gap junction assembly between Novikoff hepatoma cells was examined. Cells were dissociated with EDTA to single cells and then reaggregated to form new junctions. When TPA (25 nM) was added to the cells at the onset of the 60-min reaggregation, dye transfer was detected at only 0.6% of the cell-cell interfaces compared to 72% for the untreated control and 74% for 4-alpha TPA, an inactive isomer of TPA. Freeze-fracture electron microscopy of reaggregated control cells showed interfaces containing an average of more than 600 aggregated intramembranous gap junction particles, while TPA-treated cells had no gap junctions. However, Lucifer yellow dye transfer between nondissociated cells via gap junctions was unaffected by 60 min of TPA treatment. Therefore, TPA dramatically inhibited gap junction assembly but did not alter channel gating nor enhance disassembly of preexisting gap junction structures. Short term TPA treatment (< 30 min) increased phosphorylation of the gap junction protein molecular weight of 43,000 (Cx43), but did not change the cellular level of Cx43. Cell surface biotinylation experiments suggested that TPA did not substantially reduce the plasma membrane concentration of Cx43. Therefore, the simple presence of Cx43 in the plasma membrane is not sufficient for gap junction assembly, and protein kinase C probably exerts an effect on assembly of gap junctions at the plasma membrane level. PMID:7806568

Low-molecular-weight fucoidan and high-stability fucoxanthin from brown seaweed exert prebiotics and anti-inflammatory activities in Caco-2 cells.

PubMed

Hwang, Pai-An; Phan, Nam Nhut; Lu, Wen-Jung; Ngoc Hieu, Bui Thi; Lin, Yen-Chang

2016-01-01

The aim of this study is to investigate the anti-inflammatory effects of low-molecular-weight fucoidan (LMF) and high-stability fucoxanthin (HS-Fucox) in a lipopolysaccharide-induced inflammatory Caco-2 cell line co-culture with B. lactis. We used various methods such as transepithelial resistance (TER) assay, cytokine secretion assay, and tight junction protein mRNA expression assay to examine LMF and HS-Fucox anti-inflammatory properties. LMF and HS-Fucox activated probiotic growth and reduced the inflammation of the intestinal epithelial cells. Moreover, the combination of LMFHS-Fucox dramatically enhanced the intestinal epithelial barrier and immune function against the lipopolysaccharide effect by inhibiting IL-1β and TNF-α and promoting IL-10 and IFN-γ. These findings suggested that LMF and HS-Fucox, alone or in combination, could be the potential natural compounds to enhance the immune system and have an anti-inflammatory effect on the intestinal cells.

Estradiol is a protective factor in the adult and aging brain: understanding of mechanisms derived from in vivo and in vitro studies.

PubMed

Wise, P M; Dubal, D B; Wilson, M E; Rau, S W; Böttner, M; Rosewell, K L

2001-11-01

We have shown that 17beta-estradiol exerts profound protective effects against stroke-like ischemic injury in female rats. These effects are evident using physiological levels of estradiol replacement in ovariectomized rats and require hormone treatment prior to the time of injury. The protective actions of estradiol appear to be most prominent in the cerebral cortex, where cell death is not apparent until at least 4 h after the initiation of ischemic injury and where cell death is thought to be apoptotic in nature. Middle-aged rats remain equally responsive to the protective actions of estradiol. The maintenance of responsiveness of the cerebral cortex to the neuroprotective actions of estradiol was unexpected since responsiveness of the hypothalamus to estradiol decreases dramatically by the time animals are middle-aged. We believe that the protective actions of estradiol require the estrogen receptor-alpha, since estradiol does not protect in estrogen receptor-alpha knockout mice. We have also implemented a method of culturing cerebral cortical explants to assess the protective effects of estradiol in vitro. This model exhibits remarkable parallelisms with our in vivo model of brain injury. We have found that 17beta-estradiol decreases the extent of cell death and that this protective effect requires hormone pretreatment. Finally, 17alpha-estradiol, which does not interact effectively with the estrogen receptor, does not protect; and addition of ICI 182,780, an estrogen receptor antagonist, blocks the protective actions of estradiol. We have begun to explore the molecular and cellular mechanisms of estradiol-mediated protection. In summary, our findings demonstrate that estradiol exerts powerful protective effects both in vivo and in vitro and suggest that these actions are mediated by estrogen receptors.

Anti-neuroinflammatory Effect of Emodin in LPS-Stimulated Microglia: Involvement of AMPK/Nrf2 Activation.

PubMed

Park, Sun Young; Jin, Mei Ling; Ko, Min Jung; Park, Geuntae; Choi, Young-Whan

2016-11-01

AMPK/Nrf2 signaling regulates multiple antioxidative factors and exerts neuroprotective effects. Emodin is one of the main bioactive components extracted from Polygonum multiflorum, a plant possessing important activities for human health and for treating a variety of diseases. This study examined whether emodin can activate AMPK/Nrf2 signaling and induce the expression of genes targeted by this pathway. In addition, the anti-neuroinflammatory properties of emodin in lipopolysaccharide (LPS)-stimulated microglia were examined. In microglia, the emodin treatment increased the levels of LKB1, CaMKII, and AMPK phosphorylation. Emodin increased the translocation and transactivity of Nrf2 and enhanced the levels of HO-1 and NQO1. In addition, the emodin-mediated expression of HO-1 and NQO1 was attenuated completely by an AMPK inhibitor (compound C). Moreover, emodin decreased dramatically the LPS-induced production of NO and PGE 2 as well as the protein expression and promoter activity of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). In addition, emodin effectively inhibited the production of pro-inflammatory cytokines, TNF-α and IL-6, and reduced the level of IκBα phosphorylation, leading to the suppression of the nuclear translocation, phosphorylation, and transactivity of NF-κB. Emodin also suppressed the LPS-stimulated activation of STATs, JNK, and p38 MAPK. The anti-inflammatory effects of emodin were reversed by transfection with Nrf-2 and HO-1 siRNA and by a co-treatment with an AMPK inhibitor. These results suggest that emodin isolated from P. multiflorum can be used as a natural anti-neuroinflammatory agent that exerts its effects by inducing HO-1 and NQO1 via AMPK/Nrf2 signaling in microglia.

[Inflammatory rheumatism flare-up after surgical treatment of Cushing's disease: two cases].

PubMed

Raccah, D; Zeitoun, C; Lafforgue, P; Lassmann-Vague, V; Mallet, B; Vialettes, B; Weiller, P J; Vague, P

1992-01-01

The anti-inflammatory effect of natural glucocorticoids is often overlooked, as shown by these two cases of inflammatory rheumatism flare-up which occurred after surgical treatment of Cushing's syndrome. The disorder in the first case was exacerbation of a probable rheumatoid arthritis; in the second case an unlabelled inflammatory rheumatism appeared in a context of postoperative corticotropic deficiency. In both cases a purely substitutive hydrocortisone therapy resulted in dramatic regression of the articular symptoms. It is well known that rheumatismal manifestations may occur in patients with slow adrenal failure. The determinant factor seems to be a glucocorticoid deficiency, either isolated or associated with others, since cortisol exerts and anti-inflammatory activity. In patients with corticotropic deficiency following surgical treatment of Cushing's disease, the endogenous corticosteroid therapy of hypercortisolism is interrupted, allowing the aggravation or emergence of inflammatory rheumatism.

Final Scientific/Technical Report

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

Liang, Yanna

To increase our understanding of coal biogasification and move this technology closer toward field scale demonstration, we have thoroughly investigated coal bioconversion both ex situ and in situ. Specifically, we have screened a total of 12 parameters and identified those that exert statistically positive influence on coal biogasification. Based on these evaluations, a recipe for a nutrient solution was developed. With the addition of this nutrient solution, methane yield from Illinois coal was enhanced dramatically. In addition, we have demonstrated that coal bioconversion can be sustained over a long period of time as long as suitable conditions were maintained. Furthermore,more » biogasification of coal was tested under pressure simulating in situ conditions. Surprisingly, pressure was found to have no negative effects on microbial activities. Thus, the same recipe developed for ex situ may be used in situ as well.« less

Nurr1 overexpression exerts neuroprotective and anti-inflammatory roles via down-regulating CCL2 expression in both in vivo and in vitro Parkinson's disease models

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

Liu, Wei; Gao, Yang; Chang, Na

The abnormality of nuclear receptor-related protein 1 (Nurr1) in expression and function can contribute to neurodegeneration of dopaminergic neurons and occurrence of Parkinson's disease (PD). However, its related mechanism in PD is still unknown. In this study, we found that Nurr1 was down-regulated and CCL2 was up-regulated in PD patients and PD mice. CCL2 promoted apoptosis and secretion of TNF-α and IL-1β in SH-SY5Y cells and inhibited cell viability while knockdown of CCL2 exerted the opposite effects. Nurr1 overexpression inhibited apoptosis, the release of TNF-α and IL-1β and promoted viability in α-Syn-treated SH-SY5Y cells, which was markedly promoted by CCL2more » antibody and dramatically reversed by CCL2. Nurr1 overexpression negatively regulated CCL2 expression in vivo and in vitro. Furthermore, Nurr1 overexpression remarkably relieved MPTP-induced movement disorder and spatial memory deficits and played neuroprotective and anti-inflammatory roles in MPTP-induced PD mice by down-regulating CCL2 in vivo. In conclusion, Nurr1 overexpression exerts neuroprotective and anti-inflammatory roles via down-regulating CCL2 in both in vivo and in vitro PD models, contributing to developing mechanism-based and neuroprotective strategies against PD. - Highlights: • Nurr1 was down-regulated and CCL2 was up-regulated in PD patients and PD mice. • Nurr1 overexpression inhibited apoptosis, release of TNF-α and IL-1β and promoted viability in α-Syn-treated SH-SY5Y cells. • CCL2 reversed the effect of Nurr1 overexpression on apoptosis, inflammatory cytokines secretion and viability. • Nurr1 overexpression negatively regulated CCL2 expression in vivo and in vitro. • Nurr1 overexpression remarkably relieved MPTP-induced movement disorder and spatial memory deficits.« less

Prospects for cannabinoid therapies in basal ganglia disorders.

PubMed

Fernández-Ruiz, Javier; Moreno-Martet, Miguel; Rodríguez-Cueto, Carmen; Palomo-Garo, Cristina; Gómez-Cañas, María; Valdeolivas, Sara; Guaza, Carmen; Romero, Julián; Guzmán, Manuel; Mechoulam, Raphael; Ramos, José A

2011-08-01

Cannabinoids are promising medicines to slow down disease progression in neurodegenerative disorders including Parkinson's disease (PD) and Huntington's disease (HD), two of the most important disorders affecting the basal ganglia. Two pharmacological profiles have been proposed for cannabinoids being effective in these disorders. On the one hand, cannabinoids like Δ(9) -tetrahydrocannabinol or cannabidiol protect nigral or striatal neurons in experimental models of both disorders, in which oxidative injury is a prominent cytotoxic mechanism. This effect could be exerted, at least in part, through mechanisms independent of CB(1) and CB(2) receptors and involving the control of endogenous antioxidant defences. On the other hand, the activation of CB(2) receptors leads to a slower progression of neurodegeneration in both disorders. This effect would be exerted by limiting the toxicity of microglial cells for neurons and, in particular, by reducing the generation of proinflammatory factors. It is important to mention that CB(2) receptors have been identified in the healthy brain, mainly in glial elements and, to a lesser extent, in certain subpopulations of neurons, and that they are dramatically up-regulated in response to damaging stimuli, which supports the idea that the cannabinoid system behaves as an endogenous neuroprotective system. This CB(2) receptor up-regulation has been found in many neurodegenerative disorders including HD and PD, which supports the beneficial effects found for CB(2) receptor agonists in both disorders. In conclusion, the evidence reported so far supports that those cannabinoids having antioxidant properties and/or capability to activate CB(2) receptors may represent promising therapeutic agents in HD and PD, thus deserving a prompt clinical evaluation. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

The mitochondrially targeted antioxidant MitoQ protects the intestinal barrier by ameliorating mitochondrial DNA damage via the Nrf2/ARE signaling pathway.

PubMed

Hu, Qiongyuan; Ren, Jianan; Li, Guanwei; Wu, Jie; Wu, Xiuwen; Wang, Gefei; Gu, Guosheng; Ren, Huajian; Hong, Zhiwu; Li, Jieshou

2018-03-14

Disruption of the mucosal barrier following intestinal ischemia reperfusion (I/R) is life threatening in clinical practice. Mitochondrial dysfunction and oxidative stress significantly contribute to the early phase of I/R injury and amplify the inflammatory response. MitoQ is a mitochondrially targeted antioxidant that exerts protective effects following I/R injury. In the present study, we aimed to determine whether and how MitoQ protects intestinal epithelial cells (IECs) from I/R injury. In both in vivo and in vitro studies, we found that MitoQ pretreatment downregulated I/R-induced oxidative stress and stabilized the intestinal barrier, as evidenced by MitoQ-treated I/R mice exhibiting attenuated intestinal hyperpermeability, inflammatory response, epithelial apoptosis, and tight junction damage compared to controls. Mechanistically, I/R elevated mitochondrial 8-hydroxyguanine content, reduced mitochondrial DNA (mtDNA) copy number and mRNA transcription levels, and induced mitochondrial disruption in IECs. However, MitoQ pretreatment dramatically inhibited these deleterious effects. mtDNA depletion alone was sufficient to induce apoptosis and mitochondrial dysfunction of IECs. Mitochondrial transcription factor A (TFAM), a key activator of mitochondrial transcription, was significantly reduced during I/R injury, a phenomenon that was prevented by MitoQ treatment. Furthermore, we observed that thee protective properties of MitoQ were affected by upregulation of cellular antioxidant genes, including HO-1, NQO-1, and γ-GCLC. Transfection with Nrf2 siRNA in IECs exposed to hypoxia/reperfusion conditions partially blocked the effects of MitoQ on mtDNA damage and mitochondrial oxidative stress. In conclusion, our data suggest that MitoQ exerts protective effect on I/R-induced intestinal barrier dysfunction.

Evodiamine, a Novel NOTCH3 Methylation Stimulator, Significantly Suppresses Lung Carcinogenesis in Vitro and in Vivo.

PubMed

Su, Tao; Yang, Xia; Deng, Jian-Hua; Huang, Qiu-Ju; Huang, Su-Chao; Zhang, Yan-Min; Zheng, Hong-Ming; Wang, Ying; Lu, Lin-Lin; Liu, Zhong-Qiu

2018-01-01

Lung cancer is a leading cause of cancer-related deaths worldwide. NOTCH3 signaling is mainly expressed in non-small cell lung carcinoma (NSCLC), and has been proposed as a therapeutic target of NSCLC. While, few agents for preventing or treating NSCLC via targeting NOTCH3 signaling are used in modern clinical practice. Evodiamine (EVO), an alkaloid derived from Euodiae Fructus, possesses low toxicity and has long been shown to exert anti-lung cancer activity. However, the underlying anti-lung cancer mechanisms of EVO are not yet fully understood. In this study, we explored the involvement of NOTCH3 signaling in the anti-lung cancer effects of EVO. Urethane-induced lung cancer mouse model and two NSCLC cell models, A549 and H1299, were used to evaluate the in vivo and in vitro anti-lung cancer action of EVO. A DNA methyltransferase inhibitor was employed to investigate the role of NOTCH3 signaling in the anti-lung cancer effects of EVO. Results showed that EVO potently reduced tumor size and tumor numbers in mice, and inhibited NOTCH3 in the tumors. EVO also dramatically reduced cell viability, induced G2/M cell cycle arrest, inhibited cell migration and reduced stemness in cultured NSCLC cells. Mechanistic studies showed that EVO potently inhibited NOTCH3 signaling by activation of DNMTs-induced NOTCH3 methylation. Importantly, inhibition of NOTCH3 methylation in NSCLC cells diminished EVO's anti-NSCLC effects. Collectively, EVO, a novel NOTCH3 methylation stimulator, exerted potent anti-lung cancer effects partially by inhibiting NOTCH3 signaling. These findings provide new insight into the EVO's anti-NSCLC action, and suggest a potential role of EVO in lung cancer prevention and treatment.

Evodiamine, a Novel NOTCH3 Methylation Stimulator, Significantly Suppresses Lung Carcinogenesis in Vitro and in Vivo

PubMed Central

Su, Tao; Yang, Xia; Deng, Jian-Hua; Huang, Qiu-Ju; Huang, Su-Chao; Zhang, Yan-Min; Zheng, Hong-Ming; Wang, Ying; Lu, Lin-Lin; Liu, Zhong-Qiu

2018-01-01

Lung cancer is a leading cause of cancer-related deaths worldwide. NOTCH3 signaling is mainly expressed in non-small cell lung carcinoma (NSCLC), and has been proposed as a therapeutic target of NSCLC. While, few agents for preventing or treating NSCLC via targeting NOTCH3 signaling are used in modern clinical practice. Evodiamine (EVO), an alkaloid derived from Euodiae Fructus, possesses low toxicity and has long been shown to exert anti-lung cancer activity. However, the underlying anti-lung cancer mechanisms of EVO are not yet fully understood. In this study, we explored the involvement of NOTCH3 signaling in the anti-lung cancer effects of EVO. Urethane-induced lung cancer mouse model and two NSCLC cell models, A549 and H1299, were used to evaluate the in vivo and in vitro anti-lung cancer action of EVO. A DNA methyltransferase inhibitor was employed to investigate the role of NOTCH3 signaling in the anti-lung cancer effects of EVO. Results showed that EVO potently reduced tumor size and tumor numbers in mice, and inhibited NOTCH3 in the tumors. EVO also dramatically reduced cell viability, induced G2/M cell cycle arrest, inhibited cell migration and reduced stemness in cultured NSCLC cells. Mechanistic studies showed that EVO potently inhibited NOTCH3 signaling by activation of DNMTs-induced NOTCH3 methylation. Importantly, inhibition of NOTCH3 methylation in NSCLC cells diminished EVO’s anti-NSCLC effects. Collectively, EVO, a novel NOTCH3 methylation stimulator, exerted potent anti-lung cancer effects partially by inhibiting NOTCH3 signaling. These findings provide new insight into the EVO’s anti-NSCLC action, and suggest a potential role of EVO in lung cancer prevention and treatment. PMID:29765324

Acute effects of alemtuzumab infusion in patients with active relapsing-remitting MS

PubMed Central

Thomas, Katja; Eisele, Judith; Rodriguez-Leal, Francisco Alejandro; Hainke, Undine

2016-01-01

Objective: Alemtuzumab exerts its clinical efficacy by its specific pattern of depletion and repopulation of different immune cells. Beyond long-term immunologic and clinical data, little is known about acute changes in immunologic and routine laboratory parameters and their clinical relevance during the initial alemtuzumab infusion. Methods: Fifteen patients with highly active MS were recruited. In addition to parameters including heart rate, blood pressure, body temperature, and monitoring of adverse events, complete blood cell count, liver enzymes, kidney function, acute-phase proteins, serum cytokine profile, complement activation, peripheral immune cell distribution, and their potential of cytokine release were investigated prior to and after methylprednisolone and after alemtuzumab on each day of alemtuzumab infusion. Results: After the first alemtuzumab infusion, both the total leukocyte and granulocyte counts markedly increased, whereas lymphocyte counts dramatically decreased. In addition to lymphocyte depletion, cell subtypes important for innate immunity also decreased within the first week after alemtuzumab infusion. Although patients reported feeling well, C-reactive protein and procalcitonin peaked at serum levels consistent with septic conditions. Increases in liver enzymes were detected, although kidney function remained stable. Proinflammatory serum cytokine levels clearly rose after the first alemtuzumab infusion. Alemtuzumab led to impaired cytokine release ex vivo in nondepleted cells. Normal clinical parameters and mild adverse events were presented. Conclusions: Dramatic immunologic effects were observed. Standardized infusion procedure and pretreatment management attenuated infusion-related reactions. Alemtuzumab-mediated effects led to artificially altered parameters in standard blood testing. We recommend clinical decision-making based on primarily clinical symptoms within the first alemtuzumab treatment week. PMID:27213173

Dysfunctional HDL as a therapeutic target for atherosclerosis prevention.

PubMed

Ossoli, Alice; Pavanello, Chiara; Giorgio, Eleonora; Calabresi, Laura; Gomaraschi, Monica

2018-03-15

Hypercholesterolemia is one of the main risk factors for the development of atherosclerosis. Among the various lipoprotein classes, however, high density lipoproteins (HDL) are inversely associated with the incidence of atherosclerosis, since they are able to exert a series of atheroprotective functions. The central role of HDL within the reverse cholesterol transport, their antioxidant and anti-inflammatory properties and their ability to preserve endothelial homeostasis are likely responsible for HDL-mediated atheroprotection. However, drugs that effectively raise HDL-C failed to result in a decreased incidence of cardiovascular event, suggesting that plasma levels of HDL-C and HDL function are not always related. Several evidences are showing that different pathologic conditions, especially those associated with an inflammatory response, can cause dramatic alterations of HDL protein and lipid cargo resulting in HDL dysfunction. Established and investigational drugs designed to affect lipid metabolism and to increase HDL-C are only partly effective in correcting HDL dysfunction. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The Potential of Leptin for Treating Diabetes and Its Mechanism of Action

PubMed Central

Coppari, Roberto; Bjørbæk, Christian

2014-01-01

Following the discovery of leptin in 1994, major research efforts have brought us much closer to a fuller understanding of the cellular and molecular mechanisms underlying the biological effects of the hormone. Interestingly, leptin exerts potent anti-diabetic actions that are independent of its effects on body weight and food intake. In particular, leptin can correct diabetes in animal models of either diabetes mellitus type 1 (T1DM) or type 2 (T2DM). In addition, long-term leptin-replacement therapy is well tolerated and dramatically improves glycemic control, insulin sensitivity, and plasma triglycerides in patients with severe insulin resistance due to lipodystrophy. Together, these results have spurred enthusiasm for the use of leptin therapy to treat humans suffering from diabetes mellitus. Here, we review current understandings of these glucoregulatory functions of leptin, with particular emphasis on its central mechanisms of action, lessons from clinical studies and discuss possible therapeutic applications of leptin in the treatment of T1DM and T2DM. PMID:22935803

Population trends of grassland birds in North America are linked to the prevalence of an agricultural epizootic in Europe

PubMed Central

Nocera, Joseph J.; Koslowsky, Hannah M.

2011-01-01

Globalization of trade has dramatic socioeconomic effects, and, intuitively, significant ecological effects should follow. However, few quantitative examples exist of the interrelationship of globalization, socioeconomics, and ecological patterns. We present a striking illustration of a cascade in which bovine spongiform encephalopathy (BSE; “mad cow disease”) outbreaks in Europe exerted pressure on global beef markets, subsequently affecting North American hayfields and grassland bird populations. We examined competing models, which linked the prevalence of BSE in five focal countries, volume of beef exports to those countries from North America, and the amount of hayfield harvested and the abundance of grassland birds in North America. We found that (i) imports from North America increased 1 y after BSE outbreaks; (ii) probably because fewer cattle remained, the hay harvest in North America was reduced 2 y after the outbreak; (iii) the reduced hay harvest yielded a positive response in grassland bird populations 3 y after the outbreak. PMID:21383197

Arms Transfer and Security Assistance to the Korean Peninsula, 1945-1980: Impact and Implications.

DTIC Science & Technology

1980-06-01

Centuries of Warfare, (London: Octopus Books Ltd., 1978), pp. 450-452. 31. Ibid., p. 460. Alert to the possibilities that the Americans might resort...1973, in reality, found it could exert little control over 134 ii .4 Pyongyang’s actions. The commando raid on the " Blue House" and the axe-slayings...dramatic use of North Korean guerrilla raids, the armed clashes along the DMZ, and the 1968 commando raid on the " Blue House" obviously did nothing to belay

Decrease of contact resistance at the interface of carbon nanotube/electrode by nanowelding

NASA Astrophysics Data System (ADS)

Zhao, Bo; Wang, Yanfang; Zhang, Yafei

2017-03-01

Reliable interconnection between carbon nanotubes (CNTs) and external circuit is one of the prerequisite in CNT electronics. In this work, ultrasonic nanowelding was used to bond CNTs with metal electrodes. By exerting ultrasonic energy at the interface of CNT/electrode, a reliable joint with negligible contact resistance was obtained between CNTs and electrodes. The performance of welding is susceptible to the ultrasonic parameters such as ultrasonic power and clamping force, as well as the metal type. It is found that the metals with good ductility or low melting point are easier to achieve effective joints. Moreover, interfacial compounds are formed at the welded surface of metal Al and Fe, which is resulted from the interacting and chemical bonding of carbon and metal atoms. After nanowelding, the contact resistance between CNTs and electrode is decreased dramatically, and the two-terminal resistance of the sample approximates to the intrinsic resistance of the CNT itself.

Food Intake and Eating Behavior After Bariatric Surgery.

PubMed

Al-Najim, Werd; Docherty, Neil G; le Roux, Carel W

2018-07-01

Obesity is an escalating global chronic disease. Bariatric surgery is a very efficacious treatment for obesity and its comorbidities. Alterations to gastrointestinal anatomy during bariatric surgery result in neurological and physiological changes affecting hypothalamic signaling, gut hormones, bile acids, and gut microbiota, which coalesce to exert a profound influence on eating behavior. A thorough understanding of the mechanisms underlying eating behavior is essential in the management of patients after bariatric surgery. Studies investigating candidate mechanisms have expanded dramatically in the last decade. Herein we review the proposed mechanisms governing changes in eating behavior, food intake, and body weight after bariatric surgery. Additive or synergistic effects of both conditioned and unconditioned factors likely account for the complete picture of changes in eating behavior. Considered application of strategies designed to support the underlying principles governing changes in eating behavior holds promise as a means of optimizing responses to surgery and long-term outcomes.

Mindfulness treatment for substance misuse: A systematic review and meta-analysis.

PubMed

Li, Wen; Howard, Matthew O; Garland, Eric L; McGovern, Patricia; Lazar, Michael

2017-04-01

High rates of relapse following substance misuse treatment highlight an urgent need for effective therapies. Although the number of empirical studies investigating effects of mindfulness treatment for substance misuse has increased dramatically in recent years, few reviews have examined findings of mindfulness studies. Thus, this systematic review examined methodological characteristics and substantive findings of studies evaluating mindfulness treatments for substance misuse published by 2015. The review also includes the first meta-analysis of randomized controlled trials of mindfulness treatments for substance misuse. Comprehensive bibliographic searches in PubMed, PsycInfo, and Web of Science, identified 42 pertinent studies. Meta-analytic results revealed significant small-to-large effects of mindfulness treatments in reducing the frequency and severity of substance misuse, intensity of craving for psychoactive substances, and severity of stress. Mindfulness treatments were also effective in increasing rates of posttreatment abstinence from cigarette smoking compared to alternative treatments. Mindfulness treatment for substance misuse is a promising intervention for substance misuse, although more research is needed examining the mechanisms by which mindfulness interventions exert their effects and the effectiveness of mindfulness treatments in diverse treatment settings. Copyright © 2017 Elsevier Inc. All rights reserved.

Genomewide Association Study Identifies Novel Genetic Loci That Modify Antiplatelet Effects and Pharmacokinetics of Clopidogrel

PubMed Central

Zhong, W‐P; Wu, H; Chen, J‐Y; Li, X‐X; Lin, H‐M; Zhang, B; Zhang, Z‐W; Ma, D‐L; Sun, S; Li, H‐P; Mai, L‐P; He, G‐D; Wang, X‐P; Lei, H‐P; Zhou, H‐K; Tang, L; Liu, S‐W

2017-01-01

Genetic variants in the pharmacokinetic (PK) mechanism are the main underlying factors affecting the antiplatelet response to clopidogrel. Using a genomewide association study (GWAS) to identify new genetic loci that modify antiplatelet effects in Chinese patients with coronary heart disease, we identified novel variants in two transporter genes (SLC14A2 rs12456693, ATP‐binding cassette [ABC]A1 rs2487032) and in N6AMT1 (rs2254638) associated with P2Y12 reaction unit (PRU) and plasma active metabolite (H4) concentration. These new variants dramatically improved the predictability of PRU variability to 37.7%. The associations between these loci and PK parameters of clopidogrel and H4 were observed in additional patients, and its function on the activation of clopidogrel was validated in liver S9 fractions (P < 0.05). Rs2254638 was further identified to exert a marginal risk effect for major adverse cardiac events in an independent cohort. In conclusion, new genetic variants were systematically identified as risk factors for the reduced efficacy of clopidogrel treatment. PMID:27981573

An 8-Week Ketogenic Low Carbohydrate, High Fat Diet Enhanced Exhaustive Exercise Capacity in Mice.

PubMed

Ma, Sihui; Huang, Qingyi; Yada, Koichi; Liu, Chunhong; Suzuki, Katsuhiko

2018-05-25

Current fueling tactics for endurance exercise encourage athletes to ingest a high carbohydrate diet. However, athletes are not generally encouraged to use fat, the largest energy reserve in the human body. A low carbohydrate, high fat ketogenic diet (KD) is a nutritional approach ensuring that the body utilizes lipids. Although KD has been associated with weight-loss, enhanced fat utilization in muscle and other beneficial effects, there is currently no clear proof whether it could lead to performance advantage. To evaluate the effects of KD on endurance exercise capacity, we studied the performance of mice subjected to a running model after consuming KD for eight weeks. Weight dropped dramatically in KD-feeding mice, even though they ate more calories. KD-feeding mice showed enhanced running time without aggravated muscle injury. Blood biochemistry and correlation analysis indicated the potential mechanism is likely to be a keto-adaptation enhanced capacity to transport and metabolize fat. KD also showed a potential preventive effect on organ injury caused by acute exercise, although KD failed to exert protection from muscle injury. Ultimately, KD may contribute to prolonged exercise capacity.

Deep-brain magnetic stimulation promotes adult hippocampal neurogenesis and alleviates stress-related behaviors in mouse models for neuropsychiatric disorders

PubMed Central

2014-01-01

Background Repetitive Transcranial Magnetic Stimulation (rTMS)/ Deep-brain Magnetic Stimulation (DMS) is an effective therapy for various neuropsychiatric disorders including major depression disorder. The molecular and cellular mechanisms underlying the impacts of rTMS/DMS on the brain are not yet fully understood. Results Here we studied the effects of deep-brain magnetic stimulation to brain on the molecular and cellular level. We examined the adult hippocampal neurogenesis and hippocampal synaptic plasticity of rodent under stress conditions with deep-brain magnetic stimulation treatment. We found that DMS promotes adult hippocampal neurogenesis significantly and facilitates the development of adult new-born neurons. Remarkably, DMS exerts anti-depression effects in the learned helplessness mouse model and rescues hippocampal long-term plasticity impaired by restraint stress in rats. Moreover, DMS alleviates the stress response in a mouse model for Rett syndrome and prolongs the life span of these animals dramatically. Conclusions Deep-brain magnetic stimulation greatly facilitates adult hippocampal neurogenesis and maturation, also alleviates depression and stress-related responses in animal models. PMID:24512669

17 beta-estradiol modifies nitric oxide-sensitive guanylyl cyclase expression and down-regulates its activity in rat anterior pituitary gland.

PubMed

Cabilla, Jimena P; Díaz, María del Carmen; Machiavelli, Leticia I; Poliandri, Ariel H; Quinteros, Fernanda A; Lasaga, Mercedes; Duvilanski, Beatriz H

2006-09-01

Previous studies showed that 17 beta-estradiol (17 beta-E2) regulates the nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cGMP pathway in many tissues. Evidence from our laboratory indicates that 17 beta-E2 disrupts the inhibitory effect of NO on prolactin release, decreasing sGC activity and affecting the cGMP pathway in anterior pituitary gland of adult ovariectomized and estrogenized rats. To ascertain the mechanisms by which 17 beta-E2 affects sGC activity, we investigated the in vivo and in vitro effects of 17 beta-E2 on sGC protein and mRNA expression in anterior pituitary gland from immature female rats. In the present work, we showed that 17 beta-E2 acute treatment exerted opposite effects on the two sGC subunits, increasing alpha1 and decreasing beta1 subunit protein and mRNA expression. This action on sGC protein expression was maximal 6-9 h after 17 beta-E2 administration. 17beta-E2 also caused the same effect on mRNA expression at earlier times. Concomitantly, 17 beta-E2 dramatically decreased sGC activity 6 and 9 h after injection. These effects were specific of 17 beta-E2, because they were not observed with the administration of other steroids such as progesterone and 17 alpha-estradiol. This inhibitory action of 17beta-E2 on sGC also required the activation of estrogen receptor (ER), because treatment with the pure ER antagonist ICI 182,780 completely blocked 17 beta-E2 action. 17 beta-E2 acute treatment caused the same effects on pituitary cells in culture. These results suggest that 17 beta-E2 exerts an acute inhibitory effect on sGC in anterior pituitary gland by down-regulating sGC beta 1 subunit and sGC activity in a specific, ER-dependent manner.

Edaravone Protects against Methylglyoxal-Induced Barrier Damage in Human Brain Endothelial Cells

PubMed Central

Tóth, Andrea E.; Walter, Fruzsina R.; Bocsik, Alexandra; Sántha, Petra; Veszelka, Szilvia; Nagy, Lajos; Puskás, László G.; Couraud, Pierre-Olivier; Takata, Fuyuko; Dohgu, Shinya; Kataoka, Yasufumi; Deli, Mária A.

2014-01-01

Background Elevated level of reactive carbonyl species, such as methylglyoxal, triggers carbonyl stress and activates a series of inflammatory responses leading to accelerated vascular damage. Edaravone is the active substance of a Japanese medicine, which aids neurological recovery following acute brain ischemia and subsequent cerebral infarction. Our aim was to test whether edaravone can exert a protective effect on the barrier properties of human brain endothelial cells (hCMEC/D3 cell line) treated with methylglyoxal. Methodology Cell viability was monitored in real-time by impedance-based cell electronic sensing. The barrier function of the monolayer was characterized by measurement of resistance and flux of permeability markers, and visualized by immunohistochemistry for claudin-5 and β-catenin. Cell morphology was also examined by holographic phase imaging. Principal Findings Methylglyoxal exerted a time- and dose-dependent toxicity on cultured human brain endothelial cells: a concentration of 600 µM resulted in about 50% toxicity, significantly reduced the integrity and increased the permeability of the barrier. The cell morphology also changed dramatically: the area of cells decreased, their optical height significantly increased. Edaravone (3 mM) provided a complete protection against the toxic effect of methylglyoxal. Co-administration of edaravone restored cell viability, barrier integrity and functions of brain endothelial cells. Similar protection was obtained by the well-known antiglycating molecule, aminoguanidine, our reference compound. Conclusion These results indicate for the first time that edaravone is protective in carbonyl stress induced barrier damage. Our data may contribute to the development of compounds to treat brain endothelial dysfunction in carbonyl stress related diseases. PMID:25033388

Retigeric acid B exerts antifungal effect through enhanced reactive oxygen species and decreased cAMP.

PubMed

Chang, Wen-Qiang; Wu, Xiu-Zhen; Cheng, Ai-Xia; Zhang, Li; Ji, Mei; Lou, Hong-Xiang

2011-05-01

Retigeric acid B (RAB), a triterpene acid isolated from Lobaria kurokawae exerts antifungal effect. The present study was designed to elucidate the underlying mechanisms by which RAB regulates the proliferation and cell death of Candida albicans. We measured the metabolic activity of C. albicans with WST1 Cell Proliferation and Cytotoxicity Assay Kit, analyzed the cell cycle by flow cytometry, visualized the ultrastructure by transmission electron microscopy (TEM) and investigated the apoptosis and necrosis induced by RAB using confocal microscopy. The reactive oxygen species (ROS) accumulation was determined by spectrophotometry, flow cytometry and fluorescent microscopy. The mtΔψ was detected using flow cytometry. And the levels of intracellular cAMP and ATP were measured with cAMP ELISA and ATP Assay Kits, respectively. The proliferation of the yeasts was blocked in G(2)/M phase by a low dose of RAB treatment and in G(1) phase at high concentration. When cultured in phosphate buffered saline (PBS) deprived of energy source, yeasts displayed the phenotype of death caused by accumulated ROS, mtΔψ hyperpolarization and dramatic decrease in ATP level in the presence of high dose of RAB. RAB inhibits the growth of C. albicans by stimulating ROS production and reducing intracellular cAMP. The ROS accumulation, mtΔψ hyperpolarization, ATP depletion and damaged plasma membrane integrity together mediate cell death of C. albicans induced by RAB. Our findings provide a novel molecular mechanism for exploring possible applications of lichen derived metabolites in fighting fungal infection in humans. Copyright © 2011 Elsevier B.V. All rights reserved.

Musical agency reduces perceived exertion during strenuous physical performance

PubMed Central

Fritz, Thomas Hans; Hardikar, Samyogita; Demoucron, Matthias; Niessen, Margot; Demey, Michiel; Giot, Olivier; Li, Yongming; Haynes, John-Dylan; Villringer, Arno; Leman, Marc

2013-01-01

Music is known to be capable of reducing perceived exertion during strenuous physical activity. The current interpretation of this modulating effect of music is that music may be perceived as a diversion from unpleasant proprioceptive sensations that go along with exhaustion. Here we investigated the effects of music on perceived exertion during a physically strenuous task, varying musical agency, a task that relies on the experience of body proprioception, rather than simply diverting from it. For this we measured psychologically indicated exertion during physical workout with and without musical agency while simultaneously acquiring metabolic values with spirometry. Results showed that musical agency significantly decreased perceived exertion during workout, indicating that musical agency may actually facilitate physically strenuous activities. This indicates that the positive effect of music on perceived exertion cannot always be explained by an effect of diversion from proprioceptive feedback. Furthermore, this finding suggests that the down-modulating effect of musical agency on perceived exertion may be a previously unacknowledged driving force for the development of music in humans: making music makes strenuous physical activities less exhausting. PMID:24127588

Musical agency reduces perceived exertion during strenuous physical performance.

PubMed

Fritz, Thomas Hans; Hardikar, Samyogita; Demoucron, Matthias; Niessen, Margot; Demey, Michiel; Giot, Olivier; Li, Yongming; Haynes, John-Dylan; Villringer, Arno; Leman, Marc

2013-10-29

Music is known to be capable of reducing perceived exertion during strenuous physical activity. The current interpretation of this modulating effect of music is that music may be perceived as a diversion from unpleasant proprioceptive sensations that go along with exhaustion. Here we investigated the effects of music on perceived exertion during a physically strenuous task, varying musical agency, a task that relies on the experience of body proprioception, rather than simply diverting from it. For this we measured psychologically indicated exertion during physical workout with and without musical agency while simultaneously acquiring metabolic values with spirometry. Results showed that musical agency significantly decreased perceived exertion during workout, indicating that musical agency may actually facilitate physically strenuous activities. This indicates that the positive effect of music on perceived exertion cannot always be explained by an effect of diversion from proprioceptive feedback. Furthermore, this finding suggests that the down-modulating effect of musical agency on perceived exertion may be a previously unacknowledged driving force for the development of music in humans: making music makes strenuous physical activities less exhausting.

Management of reproduction and pregnancy complications in maternal obesity: which role for dietary polyphenols?

PubMed

Santangelo, Carmela; Varì, Rosaria; Scazzocchio, Beatrice; Filesi, Carmelina; Masella, Roberta

2014-01-01

Obesity is a global and dramatic public health problem; maternal obesity represents one of the main risk factors of infertility and pregnancy complications as it is associated with adverse maternal and offspring outcomes. In the last few years, adipose tissue dysfunction associated with altered adipocytokine secretion has been suggested to play a critical role in all the phases of reproductive process. Obesity is a nutrition-related disorder. In this regard, dietary intervention strategies, such as high intake of fruit and vegetables, have shown significant effects in both preserving health and counteracting obesity-associated diseases. Evidence has been provided that polyphenols, important constituents of plant-derived food, can influence developmental program of oocyte and embryo, as well as pregnancy progression by modulating several cellular pathways. This review will examine the controversial results so far obtained on adipocytokine involvement in fertility impairment and pregnancy complications. Furthermore, the different effects exerted by polyphenols on oocyte, embryo, and pregnancy development will be also taken in account. © 2013 International Union of Biochemistry and Molecular Biology.

Resveratrol induces growth inhibition and apoptosis in metastatic breast cancer cells via de novo ceramide signaling.

PubMed

Scarlatti, Francesca; Sala, Giusy; Somenzi, Giulia; Signorelli, Paola; Sacchi, Nicoletta; Ghidoni, Riccardo

2003-12-01

Resveratrol (3,4',5-trans-trihydroxystilbene), a phytoalexin present in grapes and red wine, is emerging as a natural compound with potential anticancer properties. Here we show that resveratrol can induce growth inhibition and apoptosis in MDA-MB-231, a highly invasive and metastatic breast cancer cell line, in concomitance with a dramatic endogenous increase of growth inhibitory/proapoptotic ceramide. We found that accumulation of ceramide derives from both de novo ceramide synthesis and sphingomyelin hydrolysis. More specifically we demonstrated that ceramide accumulation induced by resveratrol can be traced to the activation of serine palmitoyltransferase (SPT), the key enzyme of de novo ceramide biosynthetic pathway, and neutral sphingomyelinase (nSMase), a main enzyme involved in the sphingomyelin/ceramide pathway. However, by using specific inhibitors of SPT, myriocin and L-cycloserine, and nSMase, gluthatione and manumycin, we found that only the SPT inhibitors could counteract the biological effects induced by resveratrol. Thus, resveratrol seems to exert its growth inhibitory/apoptotic effect on the metastatic breast cancer cell line MDA-MB-231 by activating the de novo ceramide synthesis pathway.

Human mesenchymal stromal cell transplantation modulates neuroinflammatory milieu in a mouse model of amyotrophic lateral sclerosis.

PubMed

Boido, Marina; Piras, Antonio; Valsecchi, Valeria; Spigolon, Giada; Mareschi, Katia; Ferrero, Ivana; Vizzini, Andrea; Temi, Santa; Mazzini, Letizia; Fagioli, Franca; Vercelli, Alessandro

2014-08-01

Mesenchymal stromal cells (MSCs), after intraparenchymal, intrathecal and endovenous administration, have been previously tested for cell therapy in amyotrophic lateral sclerosis in the SOD1 (superoxide dismutase 1) mouse. However, every administration route has specific pros and cons. We administrated human MSCs (hMSCs) in the cisterna lumbaris, which is easily accessible and could be used in outpatient surgery, in the SOD1 G93A mouse, at the earliest onset of symptoms. Control animals received saline injections. Motor behavior was checked starting from 2 months of age until the mice were killed. Animals were killed 2 weeks after transplantation; lumbar motoneurons were stereologically counted, astrocytes and microglia were analyzed and quantified after immunohistochemistry and cytokine expression was assayed by means of real-time polymerase chain reaction. We provide evidence that this route of administration can exert strongly positive effects. Motoneuron death and motor decay were delayed, astrogliosis was reduced and microglial activation was modulated. In addition, hMSC transplantation prevented the downregulation of the anti-inflammatory interleukin-10, as well as that of vascular endothelial growth factor observed in saline-treated transgenic mice compared with wild type, and resulted in a dramatic increase in the expression of the anti-inflammatory interleukin-13. Our results suggest that hMSCs, when intracisternally administered, can exert their paracrine potential, influencing the inflammatory response of the host. Copyright © 2014 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Comparison of Ionomic and Metabolites Response under Alkali Stress in Old and Young Leaves of Cotton (Gossypium hirsutum L.) Seedlings

PubMed Central

Guo, Rui; Shi, LianXuan; Yang, ChunWu; Yan, ChangRong; Zhong, XiuLi; Liu, Qi; Xia, Xu; Li, HaoRu

2016-01-01

Soil salinization is an important agriculture-related environmental problem. Alkali stress and salt stress strongly influence the metabolic balance in plants. Salt and alkali stresses exert varied effects on old and young tissues, which display different adaptive strategies. In this study, we used cotton (Gossypium hirsutum L.) plants as experimental material to investigate whether alkali stress induces ionic and metabolism changes in old and young leaves of cotton plants exposed to alkali stress. Results showed that alkali stress exerted a considerably stronger growth inhibition on old leaves than on young leaves. Under alkali stress, young leaves can maintain low Na and high K contents and retain relatively stable tricarboxylic acid cycle, resulting in greater accumulation of photosynthetic metabolites. In terms of metabolic response, the young and old leaves clearly displayed different mechanisms of osmotic regulation. The amounts of inositol and mannose significantly increased in both old and young leaves of cotton exposed to alkali stress, and the extent of increase was higher in young leaves than in old leaves. In old leaves, synthesis of amino acids, such as GABA, valine, and serine, was dramatically enhanced, and this phenomenon is favorable for osmotic adjustment and membrane stability. Organs at different developmental stages possibly display different mechanisms of metabolic regulation under stress condition. Thus, we propose that future investigations on alkali stress should use more organs obtained at different developmental stages. PMID:27933088

Prospects for cannabinoid therapies in basal ganglia disorders

PubMed Central

Fernández-Ruiz, Javier; Moreno-Martet, Miguel; Rodríguez-Cueto, Carmen; Palomo-Garo, Cristina; Gómez-Cañas, María; Valdeolivas, Sara; Guaza, Carmen; Romero, Julián; Guzmán, Manuel; Mechoulam, Raphael; Ramos, José A

2011-01-01

Cannabinoids are promising medicines to slow down disease progression in neurodegenerative disorders including Parkinson's disease (PD) and Huntington's disease (HD), two of the most important disorders affecting the basal ganglia. Two pharmacological profiles have been proposed for cannabinoids being effective in these disorders. On the one hand, cannabinoids like Δ9-tetrahydrocannabinol or cannabidiol protect nigral or striatal neurons in experimental models of both disorders, in which oxidative injury is a prominent cytotoxic mechanism. This effect could be exerted, at least in part, through mechanisms independent of CB1 and CB2 receptors and involving the control of endogenous antioxidant defences. On the other hand, the activation of CB2 receptors leads to a slower progression of neurodegeneration in both disorders. This effect would be exerted by limiting the toxicity of microglial cells for neurons and, in particular, by reducing the generation of proinflammatory factors. It is important to mention that CB2 receptors have been identified in the healthy brain, mainly in glial elements and, to a lesser extent, in certain subpopulations of neurons, and that they are dramatically up-regulated in response to damaging stimuli, which supports the idea that the cannabinoid system behaves as an endogenous neuroprotective system. This CB2 receptor up-regulation has been found in many neurodegenerative disorders including HD and PD, which supports the beneficial effects found for CB2 receptor agonists in both disorders. In conclusion, the evidence reported so far supports that those cannabinoids having antioxidant properties and/or capability to activate CB2 receptors may represent promising therapeutic agents in HD and PD, thus deserving a prompt clinical evaluation. LINKED ARTICLES This article is part of a themed issue on Cannabinoids in Biology and Medicine. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue-7 PMID:21545415

Negative feedback exerted by cAMP-dependent protein kinase and cAMP phosphodiesterase on subsarcolemmal cAMP signals in intact cardiac myocytes: an in vivo study using adenovirus-mediated expression of CNG channels.

PubMed

Rochais, Francesca; Vandecasteele, Grégoire; Lefebvre, Florence; Lugnier, Claire; Lum, Hazel; Mazet, Jean-Luc; Cooper, Dermot M F; Fischmeister, Rodolphe

2004-12-10

Intracardiac cAMP levels are modulated by hormones and neuromediators with specific effects on contractility and metabolism. To understand how the same second messenger conveys different information, mutants of the rat olfactory cyclic nucleotide-gated (CNG) channel alpha-subunit CNGA2, encoded into adenoviruses, were used to monitor cAMP in adult rat ventricular myocytes. CNGA2 was not found in native myocytes but was strongly expressed in infected cells. In whole cell patch-clamp experiments, the forskolin analogue L-858051 (L-85) elicited a non-selective, Mg2+ -sensitive current observed only in infected cells, which was thus identified as the CNG current (ICNG). The beta-adrenergic agonist isoprenaline (ISO) also activated ICNG, although the maximal efficiency was approximately 5 times lower than with L-85. However, ISO and L-85 exerted a similar maximal increase of the L-type Ca2+ current. The use of a CNGA2 mutant with a higher sensitivity for cAMP indicated that this difference is caused by the activation of a localized fraction of CNG channels by ISO. cAMP-dependent protein kinase (PKA) blockade with H89 or PKI, or phosphodiesterase (PDE) inhibition with IBMX, dramatically potentiated ISO- and L-85-stimulated ICNG. A similar potentiation of beta-adrenergic stimulation occurred when PDE4 was blocked, whereas PDE3 inhibition had a smaller effect (by 2-fold). ISO and L-85 increased total PDE3 and PDE4 activities in cardiomyocytes, although this effect was insensitive to H89. However, in the presence of IBMX, H89 had no effect on ISO stimulation of ICNG. This study demonstrates that subsarcolemmal cAMP levels are dynamically regulated by a negative feedback involving PKA stimulation of subsarcolemmal cAMP-PDE.

Arctigenin exerts anti-colitis efficacy through inhibiting the differentiation of Th1 and Th17 cells via an mTORC1-dependent pathway.

PubMed

Wu, Xin; Dou, Yannong; Yang, Yan; Bian, Difei; Luo, Jinque; Tong, Bei; Xia, Yufeng; Dai, Yue

2015-08-15

Arctigenin, the main effective constituent of Arctium lappa L. fruit, has previously been proven to dramatically attenuate dextran sulfate sodium (DSS)-induced colitis in mice, a frequently used animal model of inflammatory bowel disease (IBD). As Th1 and Th17 cells play a crucial role in the pathogenesis of IBD, the present study addressed whether and how arctigenin exerted anti-colitis efficacy by interfering with the differentiation and activation of Th1/Th17 cells. In vitro, arctigenin was shown to markedly inhibit the differentiation of Th17 cells from naïve T cells, and moderately inhibit the differentiation of Th1 cells, which was accompanied by lowered phosphorylation of STAT3 and STAT4, respectively. In contrast, arctigenin was lack of marked effect on the differentiation of either Th2 or regulatory T cells. Furthermore, arctigenin was shown to suppress the mammalian target of rapamycin complex 1 (mTORC1) pathway in T cells as demonstrated by down-regulated phosphorylation of the downstream target genes p70S6K and RPS6, and it functioned independent of two well-known upstream kinases PI3K/AKT and ERK. Arctigenin was also able to inhibit the activity of mTORC1 by dissociating raptor from mTOR. Interestingly, the inhibitory effect of arctigenin on T cell differentiation disappeared under a status of mTORC1 overactivation via knockdown of tuberous sclerosis complex 2 (TSC2, a negative regulator of mTORC1) or pretreatment of leucine (an agonist of mTOR). In DSS-induced mice, the inhibition of Th1/Th17 responses and anti-colitis effect of arctigenin were abrogated by leucine treatment. In conclusion, arctigenin ameliorates colitis through down-regulating the differentiation of Th1 and Th17 cells via mTORC1 pathway. Copyright © 2015 Elsevier Inc. All rights reserved.

Enhancement of synaptic transmission induced by BDNF in cultured cortical neurons

NASA Astrophysics Data System (ADS)

He, Jun; Gong, Hui; Zeng, Shaoqun; Li, Yanling; Luo, Qingming

2005-03-01

Brain-derived neurotrophic factor (BDNF), like other neurotrophins, has long-term effects on neuronal survival and differentiation; furthermore, BDNF has been reported to exert an acute potentiation of synaptic activity and are critically involved in long-term potentiation (LTP). We found that BDNF rapidly induced potentiation of synaptic activity and an increase in the intracellular Ca2+ concentration in cultured cortical neurons. Within minutes of BDNF application to cultured cortical neurons, spontaneous firing rate was dramatically increased as were the frequency and amplitude of excitatory spontaneous postsynaptic currents (EPSCs). Fura-2 recordings showed that BDNF acutely elicited an increase in intracellular calcium concentration ([Ca2+]c). This effect was partially dependent on [Ca2+]o; The BDNF-induced increase in [Ca2+]c can not be completely blocked by Ca2+-free solution. It was completely blocked by K252a and partially blocked by Cd2+ and TTX. The results demonstrate that BDNF can enhances synaptic transmission and that this effect is accompanied by a rise in [Ca2+]c that requires two route: the release of Ca2+ from intracellular calcium stores and influx of extracellular Ca2+ through voltage-dependent Ca2+ channels in cultured cortical neurons.

Peroxisome proliferator-activated receptors: bridging metabolic syndrome with molecular nutrition.

PubMed

Guri, Amir J; Hontecillas, Raquel; Bassaganya-Riera, Josep

2006-12-01

Over recent years, obesity rates and the onset of obesity-induced chronic diseases have risen dramatically. The more we learn about the physiological and morphological changes that occur during obesity, the more it is becoming clear that obesity-related disorders can be traced back to adipocyte hypertrophy and inflammation at white adipose tissue (WAT). To combat this problem, the body has developed a regulatory system specifically designed at mediating the systemic response to obesity, utilizing free fatty acids (FFAs) and their metabolites as nutrient messengers to signal adaptations from peripheral tissues. These messages are predominantly interceded through the peroxisome proliferator-activated receptors (PPARs), a family of ligand-induced transcription factors that serve as a net of lipid sensors throughout the body. Understanding how and why nutrients, nutrient derivatives and metabolites exert their physiological effects are the key goals in the study of molecular nutrition. By learning about the mechanisms and tissue-specific effects of endogenous PPAR ligands and expanding our knowledge of the body's integrated homeostatic system, we will significantly increase our odds of designing safe and effective preventive and therapeutic interventions that keep us one step ahead of obesity-related diseases.

Microcirculatory effects of sildenafil in experimental testicular torsion in rats.

PubMed

Oroszi, Márton; Szabó, Andrea; Fehér, Ádám Miklós; Deák, Gábor; Bajory, Zoltán

2018-05-21

Investigate the short-term effect of sildenafil on microcirculation, especially the velocity, the pattern of the flow and the recruitment of the leukocyte in postcapillaries. In male Sprague-Dawley rats, the microcirculatory consequences of 60 min experimental testicular torsion, followed by 240 min of reperfusion, were examined. Using fluorescence intravital microscopy, changes in red blood cell velocity in post-capillary venules and rolling as well as adhesion of leukocytes in the postcapillary venules were examined before the torsion and every hour during the reperfusion period. Sildenafil was given 10 min prior to reperfusion (iv 0.7 mg/kg, n = 6), while control animals received saline vehicle (n = 5). The characteristic flow motion disappeared in the affected testicular during the torsion. Red blood cell velocity values were dramatically decreased (by > 50%) and both rolling and adhesion of leukocytes increased during the reperfusion phase. Sildenafil treatment resulted in significantly higher red blood cell velocity values during the entire reperfusion period, but exerted only a temporary positive effect on the plost-ischaemic leukocyte-endothelial interactions. Intraoperative administration of sildenafil during surgical detorsion may provide marked testicular microperfusion benefits, but failed to influence the overall leukocyte-driven microcirculatory inflammatory reactions.

Sonication-Induced Modification of Carbon Nanotubes: Effect on the Rheological and Thermo-Oxidative Behaviour of Polymer-Based Nanocomposites.

PubMed

Arrigo, Rossella; Teresi, Rosalia; Gambarotti, Cristian; Parisi, Filippo; Lazzara, Giuseppe; Dintcheva, Nadka Tzankova

2018-03-05

The aim of this work is the investigation of the effect of ultrasound treatment on the structural characteristics of carbon nanotubes (CNTs) and the consequent influence that the shortening induced by sonication exerts on the morphology, rheological behaviour and thermo-oxidative resistance of ultra-high molecular weight polyethylene (UHMWPE)-based nanocomposites. First, CNTs have been subjected to sonication for different time intervals and the performed spectroscopic and morphological analyses reveal that a dramatic decrease of the CNT's original length occurs with increased sonication time. The reduction of the initial length of CNTs strongly affects the nanocomposite rheological behaviour, which progressively changes from solid-like to liquid-like as the CNT sonication time increases. The study of the thermo-oxidative behaviour of the investigated nanocomposites reveals that the CNT sonication has a detrimental effect on the thermo-oxidative stability of nanocomposites, especially for long exposure times. The worsening of the thermo-oxidative resistance of sonicated CNT-containing nanocomposites could be attributed to the lower thermal conductivity of low-aspect-ratio CNTs, which causes the increase of the local temperature at the polymer/nanofillers interphase, with the consequent acceleration of the degradative phenomena.

Asialoglycoprotein receptor 1 mediates productive uptake of N-acetylgalactosamine-conjugated and unconjugated phosphorothioate antisense oligonucleotides into liver hepatocytes

PubMed Central

Hettrick, Lisa; Revenko, Alexey; Kinberger, Garth A.; Prakash, Thazha P.; Seth, Punit P.

2017-01-01

Abstract Antisense oligonucleotide (ASO) therapeutics show tremendous promise for the treatment of previously intractable human diseases but to exert their effects on cellular RNA processing they must first cross the plasma membrane by endocytosis. The conjugation of ASOs to a receptor ligand can dramatically increase their entry into certain cells and tissues, as demonstrated by the implementation of N-acetylgalactosamine (GalNAc)-conjugated ASOs for Asialoglycoprotein Receptor (ASGR)-mediated uptake into liver hepatocytes. We compared the internalization and activity of GalNAc-conjugated ASOs and their parents in endogenous ASGR-expressing cells and were able to recapitulate hepatocyte ASO uptake and activity in cells engineered to heterologously express the receptor. We found that the minor receptor subunit, ASGR2, is not required for effective in vitro or in vivo uptake of GalNAc-conjugated ASO and that the major subunit, ASGR1, plays a small but significant role in the uptake of unconjugated phosphorothioate ASOs into hepatocytes. Moreover, our data demonstrates there is a large excess capacity of liver ASGR for the effective uptake of GalNAc–ASO conjugates, suggesting broad opportunities to exploit receptors with relatively moderate levels of expression. PMID:29069408

Sonication-Induced Modification of Carbon Nanotubes: Effect on the Rheological and Thermo-Oxidative Behaviour of Polymer-Based Nanocomposites

PubMed Central

Teresi, Rosalia; Gambarotti, Cristian; Dintcheva, Nadka Tzankova

2018-01-01

The aim of this work is the investigation of the effect of ultrasound treatment on the structural characteristics of carbon nanotubes (CNTs) and the consequent influence that the shortening induced by sonication exerts on the morphology, rheological behaviour and thermo-oxidative resistance of ultra-high molecular weight polyethylene (UHMWPE)-based nanocomposites. First, CNTs have been subjected to sonication for different time intervals and the performed spectroscopic and morphological analyses reveal that a dramatic decrease of the CNT’s original length occurs with increased sonication time. The reduction of the initial length of CNTs strongly affects the nanocomposite rheological behaviour, which progressively changes from solid-like to liquid-like as the CNT sonication time increases. The study of the thermo-oxidative behaviour of the investigated nanocomposites reveals that the CNT sonication has a detrimental effect on the thermo-oxidative stability of nanocomposites, especially for long exposure times. The worsening of the thermo-oxidative resistance of sonicated CNT-containing nanocomposites could be attributed to the lower thermal conductivity of low-aspect-ratio CNTs, which causes the increase of the local temperature at the polymer/nanofillers interphase, with the consequent acceleration of the degradative phenomena. PMID:29510595

Anomalous thermodynamics at the microscale.

PubMed

Celani, Antonio; Bo, Stefano; Eichhorn, Ralf; Aurell, Erik

2012-12-28

Particle motion at the microscale is an incessant tug-of-war between thermal fluctuations and applied forces on one side and the strong resistance exerted by fluid viscosity on the other. Friction is so strong that completely neglecting inertia--the overdamped approximation--gives an excellent effective description of the actual particle mechanics. In sharp contrast to this result, here we show that the overdamped approximation dramatically fails when thermodynamic quantities such as the entropy production in the environment are considered, in the presence of temperature gradients. In the limit of vanishingly small, yet finite, inertia, we find that the entropy production is dominated by a contribution that is anomalous, i.e., has no counterpart in the overdamped approximation. This phenomenon, which we call an entropic anomaly, is due to a symmetry breaking that occurs when moving to the small, finite inertia limit. Anomalous entropy production is traced back to futile phase-space cyclic trajectories displaying a fast downgradient sweep followed by a slow upgradient return to the original position.

Dietary Clostridium butyricum Induces a Phased Shift in Fecal Microbiota Structure and Increases the Acetic Acid-Producing Bacteria in a Weaned Piglet Model.

PubMed

Zhang, Jie; Chen, Xiyue; Liu, Ping; Zhao, Jinbiao; Sun, Jian; Guan, Wenyi; Johnston, Lee J; Levesque, Crystal L; Fan, Peixin; He, Ting; Zhang, Guolong; Ma, Xi

2018-05-23

Clostridium butyricum is known as a butyrate producer and a regulator of gut health, but whether it exerts a beneficial effect as a dietary supplement via modulating the intestinal microbiota remains elusive. This study investigated the impact of C. butyricum on the fecal microbiota composition and their metabolites 14 and 28 days after weaning with 10 g/kg dietary supplementation of C. butyricum. Dynamic changes of microbial compositions showed dramatically increasing Selenomonadales and decreasing Clostridiales on days 14 and 28. Within Selenomonadales, Megasphaera became the main responder by increasing from 3.79 to 11.31%. Following the prevalence of some acetate producers ( Magasphaera) and utilizers ( Eubacterium_hallii) at the genus level and even with a significant decrease in fecal acetate on day 28, the present data suggested that C. butyricum influenced microbial metabolism by optimizing the structure of microbiota and enhancing acetate production and utilization for butyrate production.

[Screening specific recognition motif of RNA-binding proteins by SELEX in combination with next-generation sequencing technique].

PubMed

Zhang, Lu; Xu, Jinhao; Ma, Jinbiao

2016-07-25

RNA-binding protein exerts important biological function by specifically recognizing RNA motif. SELEX (Systematic evolution of ligands by exponential enrichment), an in vitro selection method, can obtain consensus motif with high-affinity and specificity for many target molecules from DNA or RNA libraries. Here, we combined SELEX with next-generation sequencing to study the protein-RNA interaction in vitro. A pool of RNAs with 20 bp random sequences were transcribed by T7 promoter, and target protein was inserted into plasmid containing SBP-tag, which can be captured by streptavidin beads. Through only one cycle, the specific RNA motif can be obtained, which dramatically improved the selection efficiency. Using this method, we found that human hnRNP A1 RRMs domain (UP1 domain) bound RNA motifs containing AGG and AG sequences. The EMSA experiment indicated that hnRNP A1 RRMs could bind the obtained RNA motif. Taken together, this method provides a rapid and effective method to study the RNA binding specificity of proteins.

Sheet on a deformable sphere: Wrinkle patterns suppress curvature-induced delamination

NASA Astrophysics Data System (ADS)

Hohlfeld, Evan; Davidovitch, Benny

2015-01-01

The adhesion of a stiff film onto a curved substrate often generates elastic stresses in the film that eventually give rise to its delamination. Here we predict that delamination of very thin films can be dramatically suppressed through tiny, smooth deformations of the substrate, dubbed here "wrinklogami," that barely affect the macro-scale topography. This "prolamination" effect reflects a surprising capability of smooth wrinkles to suppress compression in elastic films even when spherical or other doubly curved topography is imposed, in a similar fashion to origami folds that enable construction of curved structures from an unstretchable paper. We show that the emergence of a wrinklogami pattern signals a nontrivial isometry of the sheet to its planar, undeformed state, in the doubly asymptotic limit of small thickness and weak tensile load exerted by the adhesive substrate. We explain how such an "asymptotic isometry" concept broadens the standard usage of isometries for describing the response of elastic sheets to geometric constraints and mechanical loads.

Anomalous Thermodynamics at the Microscale

NASA Astrophysics Data System (ADS)

Celani, Antonio; Bo, Stefano; Eichhorn, Ralf; Aurell, Erik

2012-12-01

Particle motion at the microscale is an incessant tug-of-war between thermal fluctuations and applied forces on one side and the strong resistance exerted by fluid viscosity on the other. Friction is so strong that completely neglecting inertia—the overdamped approximation—gives an excellent effective description of the actual particle mechanics. In sharp contrast to this result, here we show that the overdamped approximation dramatically fails when thermodynamic quantities such as the entropy production in the environment are considered, in the presence of temperature gradients. In the limit of vanishingly small, yet finite, inertia, we find that the entropy production is dominated by a contribution that is anomalous, i.e., has no counterpart in the overdamped approximation. This phenomenon, which we call an entropic anomaly, is due to a symmetry breaking that occurs when moving to the small, finite inertia limit. Anomalous entropy production is traced back to futile phase-space cyclic trajectories displaying a fast downgradient sweep followed by a slow upgradient return to the original position.

Effect of physical workload and modality of information presentation on pattern recognition and navigation task performance by high-fit young males.

PubMed

Zahabi, Maryam; Zhang, Wenjuan; Pankok, Carl; Lau, Mei Ying; Shirley, James; Kaber, David

2017-11-01

Many occupations require both physical exertion and cognitive task performance. Knowledge of any interaction between physical demands and modalities of cognitive task information presentation can provide a basis for optimising performance. This study examined the effect of physical exertion and modality of information presentation on pattern recognition and navigation-related information processing. Results indicated males of equivalent high fitness, between the ages of 18 and 34, rely more on visual cues vs auditory or haptic for pattern recognition when exertion level is high. We found that navigation response time was shorter under low and medium exertion levels as compared to high intensity. Navigation accuracy was lower under high level exertion compared to medium and low levels. In general, findings indicated that use of the haptic modality for cognitive task cueing decreased accuracy in pattern recognition responses. Practitioner Summary: An examination was conducted on the effect of physical exertion and information presentation modality in pattern recognition and navigation. In occupations requiring information presentation to workers, who are simultaneously performing a physical task, the visual modality appears most effective under high level exertion while haptic cueing degrades performance.

Delay of T cell senescence by caloric restriction in aged long-lived nonhuman primates

PubMed Central

Messaoudi, Ilhem; Warner, Jessica; Fischer, Miranda; Park, Buyng; Hill, Brenna; Mattison, Julie; Lane, Mark A.; Roth, George S.; Ingram, Donald K.; Picker, Louis J.; Douek, Daniel C.; Mori, Motomi; Nikolich-Žugich, Janko

2006-01-01

Caloric restriction (CR) has long been known to increase median and maximal lifespans and to decreases mortality and morbidity in short-lived animal models, likely by altering fundamental biological processes that regulate aging and longevity. In rodents, CR was reported to delay the aging of the immune system (immune senescence), which is believed to be largely responsible for a dramatic increase in age-related susceptibility to infectious diseases. However, it is unclear whether CR can exert similar effects in long-lived organisms. Previous studies involving 2- to 4-year CR treatment of long-lived primates failed to find a CR effect or reported effects on the immune system opposite to those seen in CR-treated rodents. Here we show that long-term CR delays the adverse effects of aging on nonhuman primate T cells. CR effected a marked improvement in the maintenance and/or production of naïve T cells and the consequent preservation of T cell receptor repertoire diversity. Furthermore, CR also improved T cell function and reduced production of inflammatory cytokines by memory T cells. Our results provide evidence that CR can delay immune senescence in nonhuman primates, potentially contributing to an extended lifespan by reducing susceptibility to infectious disease. PMID:17159149

Regulation of 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase expression and activity in the hypophysectomized rat ovary: Interactions between the stimulatory effect of human chorionic gonadotropin and the luteolytic effect of prolactin

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

Martel, C.; Labrie, C.; Dupont, E.

1990-12-01

The enzyme 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) catalyzes an obligatory step in the conversion of pregnenolone and other 5-ene-3 beta-hydroxysteroids into progesterone as well as precursors of all androgens and estrogens in the ovary. Since 3 beta-HSD is likely to be an important target for regulation by pituitary hormones, we have studied the effect of chronic treatment with LH (hCG), FSH, and PRL on ovarian 3 beta-HSD expression and activity in hypophysectomized adult female rats. Human CG (hCG) (10 IU, twice a day (bid)), ovine FSH (0.5 microgram, bid), and ovine PRL (1 mg, bid) were administered,more » singly or in combination, for a period of 10 days starting 15 days after hypophysectomy. In hypophysectomized rats, PRL exerted a potent inhibitory effect on all the parameters studied. In fact, PRL caused a 81% decrease in ovarian 3 beta-HSD mRNA content accompanied by a similar decrease in 3 beta-HSD activity and protein levels. In addition, ovarian weight decreased by 40% whereas serum progesterone fell dramatically from 1.92 nmol/liter to undetectable levels after treatment with PRL. Whereas hCG alone had only slight stimulatory effects on 3 beta-HSD mRNA, protein content and activity levels, treatment with the gonadotropin partially or completely reversed the potent inhibitory effects of oPRL on all the parameters measured. FSH, on the other hand, had no significant effect on 3 beta-HSD expression and activity. In situ hybridization experiments using the 35S-labeled rat ovary 3 beta-HSD cDNA probe show that the inhibitory effect of PRL is exerted primarily on luteal cell 3 beta-HSD expression and activity. On the other hand, it can be seen that hCG stimulates 3 beta-HSD mRNA accumulation in interstitial cells.« less

Prior Acute Mental Exertion in Exercise and Sport

PubMed Central

Silva-Júnior, Fernando Lopes e; Emanuel, Patrick; Sousa, Jordan; Silva, Matheus; Teixeira, Silmar; Pires, Flávio Oliveira; Machado, Sérgio; Arias-Carrion, Oscar

2016-01-01

Introduction: Mental exertion is a psychophysiological state caused by sustained and prolonged cognitive activity. The understanding of the possible effects of acute mental exertion on physical performance, and their physiological and psychological responses are of great importance for the performance of different occupations, such as military, construction workers, athletes (professional or recreational) or simply practicing regular exercise, since these occupations often combine physical and mental tasks while performing their activities. However, the effects of implementation of a cognitive task on responses to aerobic exercise and sports are poorly understood. Our narrative review aims to provide information on the current research related to the effects of prior acute mental fatigue on physical performance and their physiological and psychological responses associated with exercise and sports. Methods: The literature search was conducted using the databases PubMed, ISI Web of Knowledge and PsycInfo using the following terms and their combinations: “mental exertion”, “mental fatigue”, “mental fatigue and performance”, “mental exertion and sports” “mental exertion and exercise”. Results: We concluded that prior acute mental exertion affects effectively the physiological and psychophysiological responses during the cognitive task, and performance in exercise. Conclusion: Additional studies involving prior acute mental exertion, exercise/sports and physical performance still need to be carried out in order to analyze the physiological, psychophysiological and neurophysiological responses subsequently to acute mental exertion in order to identify cardiovascular factors, psychological, neuropsychological associates. PMID:27867415

The effects of therapeutic instrumental music performance on endurance level, self-perceived fatigue level, and self-perceived exertion of inpatients in physical rehabilitation.

PubMed

Lim, Hayoung A; Miller, Karen; Fabian, Chuck

2011-01-01

The present study investigated the effects of a Neurologic Music Therapy (NMT) sensory-motor rehabilitation technique, Therapeutic Instrumental Music Performance (TIMP) as compared to Traditional Occupational Therapy (TOT), on endurance, self-perceived fatigue, and self-perceived exertion of 35 hospitalized patients in physical rehabilitation. The present study attempted to examine whether an active musical experience such as TIMP with musical cueing (i.e., rhythmic auditory cueing) during physical exercises influences one's perception of pain, fatigue, and exertion. All participants were diagnosed with a neurologic disorder or had recently undergone orthopedic surgery. Investigators measured the effects of TOT and TIMP during upper extremity exercise of the less affected or stronger upper extremity. Results showed no significant difference on endurance measures between the 2 treatment conditions (TIMP and TOT). Statistically significant differences were found between TIMP and TOT when measuring their effects on perceived exertion and perceived fatigue. TIMP resulted in significantly less perception of fatigue and exertion levels than TOT. TIMP can be used foran effective sensory-motor rehabilitation technique to decrease perceived exertion and fatigue level of inpatients in physical rehabilitation.

Role of n-3 Polyunsaturated Fatty Acids in Ameliorating the Obesity-Induced Metabolic Syndrome in Animal Models and Humans

PubMed Central

Huang, Chao-Wei; Chien, Yi-Shan; Chen, Yu-Jen; Ajuwon, Kolapo M.; Mersmann, Harry M.; Ding, Shih-Torng

2016-01-01

The incidence of obesity and its comorbidities, such as insulin resistance and type II diabetes, are increasing dramatically, perhaps caused by the change in the fatty acid composition of common human diets. Adipose tissue plays a role as the major energy reservoir in the body. An excess of adipose mass accumulation caused by chronic positive energy balance results in obesity. The n-3 polyunsaturated fatty acids (n-3 PUFA), DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid) exert numerous beneficial effects to maintain physiological homeostasis. In the current review, the physiology of n-3 PUFA effects in the body is delineated from studies conducted in both human and animal experiments. Although mechanistic studies in human are limited, numerous studies conducted in animals and models in vitro provide potential molecular mechanisms of the effects of these fatty acids. Three aspects of n-3 PUFA in adipocyte regulation are discussed: (1) lipid metabolism, including adipocyte differentiation, lipolysis and lipogenesis; (2) energy expenditure, such as mitochondrial and peroxisomal fatty acid β-oxidation; and (3) inflammation, including adipokines and specialized pro-resolving lipid mediators. Additionally, the mechanisms by which n-3 PUFA regulate gene expression are highlighted. The beneficial effects of n-3 PUFA may help to reduce the incidence of obesity and its comorbidities. PMID:27735847

A Novel Nitronyl Nitroxide with Salicylic Acid Framework Attenuates Pain Hypersensitivity and Ectopic Neuronal Discharges in Radicular Low Back Pain.

PubMed

Han, Wen-Juan; Chen, Lei; Wang, Hai-Bo; Liu, Xiang-Zeng; Hu, San-Jue; Sun, Xiao-Li; Luo, Ceng

2015-01-01

Evidence has accumulated that reactive oxygen species and inflammation play crucial roles in the development of chronic pain, including radicular low back pain. Nonsteroid anti-inflammatory drugs (NSAIDs), for example, salicylic acid, aspirin, provided analgesic effects in various types of pain. However, long-term use of these drugs causes unwanted side effects, which limits their implication. Stable nitronyl (NIT) nitroxide radicals have been extensively studied as a unique and interesting class of new antioxidants for protection against oxidative damage. The present study synthesized a novel NIT nitroxide radical with salicylic acid framework (SANR) to provide synergistic effect of both antioxidation and antiinflammation. We demonstrated for the first time that both acute and repeated SANR treatment exerted dramatic analgesic effect in radicular low back pain mimicked by chronic compression of dorsal root ganglion in rats. This analgesic potency was more potent than that produced by classical NSAIDs aspirin and traditional nitroxide radical Tempol alone. Furthermore, SANR-induced behavioral analgesia is found to be mediated, at least in partial, by a reduction of ectopic spontaneous discharges in injured DRG neurons. Therefore, the synthesized NIT nitroxide radical coupling with salicylic acid framework may represent a novel potential therapeutic candidate for treatment of chronic pain, including radicular low back pain.

Synchrony and exertion during dance independently raise pain threshold and encourage social bonding

PubMed Central

Tarr, Bronwyn; Launay, Jacques; Cohen, Emma; Dunbar, Robin

2015-01-01

Group dancing is a ubiquitous human activity that involves exertive synchronized movement to music. It is hypothesized to play a role in social bonding, potentially via the release of endorphins, which are analgesic and reward-inducing, and have been implicated in primate social bonding. We used a 2 × 2 experimental design to examine effects of exertion and synchrony on bonding. Both demonstrated significant independent positive effects on pain threshold (a proxy for endorphin activation) and in-group bonding. This suggests that dance which involves both exertive and synchronized movement may be an effective group bonding activity. PMID:26510676

Analysis of Oxidative Stress and Wound-Inducible Dinor Isoprostanes F1 (Phytoprostanes F1) in Plants1

PubMed Central

Imbusch, Ruth; Mueller, Martin J.

2000-01-01

Isoprostanes F2 are arachidonate autoxidation products in mammals that have been shown to be induced during several human disorders associated with enhanced free-radical generation. Isoprostanes F2 represent not only extremely reliable markers of oxidative stress in vivo, but they also exert potent biological effects. Therefore, it has been postulated that isoprostanoids are mediators of oxidant injury in vivo. Higher plants, however, do not synthesize arachidonic acid or isoprostanes. Here we show that a series of isoprostane F2 analogs termed phytoprostanes F1 (previously dinor isoprostanes F1) are formed by an analogous pathway from α-linolenate in plants. High-performance liquid chromatography and gas chromatography-mass spectrometry methods using [18O]3phytoprostanes F1 as internal standard have been developed to quantify phytoprostanes F1. In fresh peppermint (Mentha piperita) leaves, phytoprostanes F1 were found in free form (76 ng/g of dry weight) and at about 150-fold higher levels esterified in lipids. It is notable that these levels of phytoprostanes F1 are more than two orders of magnitude higher than the basal levels of isoprostanes F2 in mammalian tissues. Furthermore, wounding, as well as butyl hydroperoxide or cupric acetate stress triggered a dramatic increase of free and esterified phytoprostanes F1. Thus phytoprostanes F1 may represent a sensitive measure of oxidative damage in plants similar to isoprostanes in mammals. However, one of the most exciting issues to be clarified is the possibility that linolenate-derived phytoprostanes F1 exert biological activities in plants and/or animals. PMID:11080305

Quantitative analysis of immune cell subset infiltration of supraspinatus muscle after severe rotator cuff injury.

PubMed

Krieger, J R; Tellier, L E; Ollukaren, M T; Temenoff, J S; Botchwey, E A

2017-06-01

Rotator cuff tears cause muscle degeneration that is characterized by myofiber atrophy, fatty infiltration, and fibrosis and is minimally responsive to current treatment options. The underlying pathogenesis of rotator cuff muscle degeneration remains to be elucidated, and increasing evidence implicates immune cell infiltration as a significant factor. Because immune cells are comprised of highly heterogeneous subpopulations that exert divergent effects on injured tissue, understanding trafficking and accumulation of immune subpopulations may hold the key to more effective therapies. The present study quantifies subpopulations of immune cells infiltrating the murine supraspinatus muscle after severe rotator cuff injury that includes tenotomy and denervation. Rotator cuff injury stimulates dramatic infiltration of mononuclear phagocytes, enriches mononuclear phagocytes in non-classical subpopulations, and enriches T lymphocytes in T H and T reg subpopulations. The combination of tenotomy plus denervation significantly increases mononuclear phagocyte infiltration, enriches macrophages in the non-classical subpopulation, and decreases T lymphocyte enrichment in T H cells compared to tenotomy alone. Depletion of circulating monocytes via liposomal clodronate accelerates supraspinatus atrophy after tenotomy and denervation. The study may aid rational design of immunologically smart therapies that harness immune cells to enhance outcomes after rotator cuff tears.

Essential role for RGS9 in opiate action.

PubMed

Zachariou, Venetia; Georgescu, Dan; Sanchez, Nick; Rahman, Zia; DiLeone, Ralph; Berton, Olivier; Neve, Rachael L; Sim-Selley, Laura J; Selley, Dana E; Gold, Stephen J; Nestler, Eric J

2003-11-11

Regulators of G protein signaling (RGS) are a family of proteins known to accelerate termination of effector stimulation after G protein receptor activation. RGS9-2, a brain-specific splice variant of the RGS9 gene, is highly enriched in striatum and also expressed at much lower levels in periaqueductal gray and spinal cord, structures known to mediate various actions of morphine and other opiates. Morphine exerts its acute rewarding and analgesic effects by activation of inhibitory guanine nucleotide-binding regulatory protein-coupled opioid receptors, whereas chronic morphine causes addiction, tolerance to its acute analgesic effects, and profound physical dependence by sustained activation of these receptors. We show here that acute morphine administration increases expression of RGS9-2 in NAc and the other CNS regions, whereas chronic exposure decreases RGS9-2 levels. Mice lacking RGS9 show enhanced behavioral responses to acute and chronic morphine, including a dramatic increase in morphine reward, increased morphine analgesia with delayed tolerance, and exacerbated morphine physical dependence and withdrawal. These findings establish RGS9 as a potent negative modulator of opiate action in vivo, and suggest that opiate-induced changes in RGS9 levels contribute to the behavioral and neural plasticity associated with chronic opiate administration.

Caffeic acid ameliorates colitis in association with increased Akkermansia population in the gut microbiota of mice

PubMed Central

Zhang, Zhan; Wu, Xinyue; Cao, Shuyuan; Wang, Li; Wang, Di; Yang, Hui; Feng, Yiming; Wang, Shoulin; Li, Lei

2016-01-01

Emerging evidence shows that dietary agents and phytochemicals contribute to the prevention and treatment of ulcerative colitis (UC). We first reported the effects of dietary caffeic acid (CaA) on murine experimental colitis and on fecal microbiota. Colitis was induced in C57BL/6 mice by administration of 2.5% dextran sulfate sodium (DSS). Mice were fed a control diet or diet with CaA (1 mM). Our results showed that dietary CaA exerted anti-inflammatory effects in DSS colitis mice. Moreover, CaA could significantly suppress the secretion of IL-6, TNFα, and IFNγ and the colonic infiltration of CD3+ T cells, CD177+ neutrophils and F4/80+ macrophages via inhibition of the activation of NF-κB signaling pathway. Analysis of fecal microbiota showed that CaA could restore the reduction of richness and inhibit the increase of the ratio of Firmicute to Bacteroidetes in DSS colitis mice. And CaA could dramatically increase the proportion of the mucin-degrading bacterium Akkermansia in DSS colitis mice. Thus, CaA could ameliorate colonic pathology and inflammation in DSS colitis mice, and it might be associated with a proportional increase in Akkermansia. PMID:27177331

Biosafe inertization of municipal solid waste incinerator residues by COSMOS technology.

PubMed

Guarienti, Michela; Gianoncelli, Alessandra; Bontempi, Elza; Moscoso Cardozo, Sdenka; Borgese, Laura; Zizioli, Daniela; Mitola, Stefania; Depero, Laura E; Presta, Marco

2014-08-30

Municipal solid waste incinerator (MSWI) residues can generate negative environmental impacts when improperly handled. The COlloidal Silica Medium to Obtain Safe inert (COSMOS) technology represents a new method to stabilize MSWI residues and to produce inert safe material. Here we report the results about aquatic biotoxicity of lixiviated MSWI fly ash and the corresponding inertized COSMOS material using a zebrafish (Danio rerio) embryo toxicity test. Quantitative assessment of waste biotoxicity included evaluation of mortality rate and of different morphological and teratogenous endpoints in zebrafish embryos exposed to tested materials from 3 to 72h post-fertilization. The results demonstrate that lixiviated MSWI fly ash exerts a dose-dependent lethal effect paralleled by dramatic morphological/teratogenous alterations and apoptotic events in the whole embryo body. Similar effects were observed following MSWI fly ash stabilization in classical concrete matrices, demonstrating that the obtained materials are not biologically safe. On the contrary, no significant mortality and developmental defects were observed in zebrafish embryos exposed to COSMOS inert solution. Our results provide the first experimental in vivo evidence that, in contrast with concrete stabilization procedure, COSMOS technology provides a biologically safe inert. Copyright © 2014 Elsevier B.V. All rights reserved.

The Mediating Role of Self-Exertion on the Effects of Effort on Learning Virtues and Emotional Distress in Academic Failure in a Confucian Context

PubMed Central

Fwu, Bih-Jen; Chen, Shun-Wen; Wei, Chih-Fen; Wang, Hsiou-Huai

2017-01-01

Previous studies have found that in East Asian Confucian societies, hardworking students are often trapped in a dilemma of enjoying a positive moral image while suffering from emotional distress due to academic failure. This study intends to further explore whether the cultural-specific belief in self-exertion acts as a psychological mechanism to lessen these students’ negative emotions. A group of 288 college students in Taiwan were administered a questionnaire to record their responses to past academic failures. The results from structural equation modeling showed that self-exertion functioned as a mediator between the effects of effort on learning virtues and emotional distress. Self-exertion to fulfill one’s duty to oneself positively mediated the effect of effort on learning virtues, whereas self-exertion to fulfill one’s duty to one’s parents negatively mediated the effect of effort on emotional distress. Theoretical and cultural implications are further discussed. PMID:28119648

Sulfiredoxin-1 protects against simulated ischaemia/reperfusion injury in cardiomyocyte by inhibiting PI3K/AKT-regulated mitochondrial apoptotic pathways.

PubMed

Zhang, Jiankai; He, Zhangyou; Guo, Jinhua; Li, Zhe; Wang, Xiaohong; Yang, Chun; Cui, Xiaojun

2016-01-01

Reactive oxygen species (ROS)-triggered cardiac cell injury is recognized as the major contributor for the pathogenesis progression of ischaemic cardiovascular diseases. Sulfiredoxin-1 (Srx-1) is an endogenous antioxidant and exerts the crucial neuroprotective effects in cerebral ischaemia. However, its function and the underlying mechanism in ischaemic heart diseases remain poorly defined. Here, a dramatical decrease in Srx-1 was validated in H9c2 cardiomyocytes upon simulated ischaemia-reperfusion (SI/R) injury. Moreover, Srx-1 protected H9c2 cells from SI/R-injured injury as the evidences that Srx-1 up-regulation attenuated the inhibitory effects on cell viability, lactate dehydrogenase (LDH) and cell apoptosis upon SI/R treatment. Knockdown of Srx-1 accelerated cell injury upon SI/R. Mechanism assay corroborated that SI/R treatment noticeably aggravated the loss of mitochondrial membrane potential (Δψm), which was remarkably abated in Ad-Srx-1 groups. Importantly, Srx-1 elevation substantially reduced cytochrome c release, the activity of caspase-9 and caspase-3, accompany with the subsequent decrease in the cleavage of poly (ADP ribose) polymerase (PARP). Concomitantly, overexpression of Srx-1 also decreased the expression of pro-apoptosis protein Bax and increased anti-apoptotic Bcl-2 expression. Further analysis substantiated that Srx-1 treatment remarkably induced the activation of PI3K/AKT signalling. Preconditioning with LY294002 dramatically decreased Srx-1-enhanced cell resistance to SI/R injury. Importantly, LY294002 mitigated the inhibitory effects of Srx-1 on Δψm loss, cytochrome c release, caspase-9/3 activity, and the expression of Bcl-2 family. Together, these results suggested that Srx-1 might protect cardiomyocyte injury upon SI/R by suppressing PI3K/AKT-mediated mitochondria dependent apoptosis, revealing a promising therapeutic agent against ischaemic cardiovascular diseases. © 2016 The Author(s).

Economic and Health Predictors of National Postpartum Depression Prevalence: A Systematic Review, Meta-analysis, and Meta-Regression of 291 Studies from 56 Countries.

PubMed

Hahn-Holbrook, Jennifer; Cornwell-Hinrichs, Taylor; Anaya, Itzel

2017-01-01

Postpartum depression (PPD) poses a major global public health challenge. PPD is the most common complication associated with childbirth and exerts harmful effects on children. Although hundreds of PPD studies have been published, we lack accurate global or national PPD prevalence estimates and have no clear account of why PPD appears to vary so dramatically between nations. Accordingly, we conducted a meta-analysis to estimate the global and national prevalence of PPD and a meta-regression to identify economic, health, social, or policy factors associated with national PPD prevalence. We conducted a systematic review of all papers reporting PPD prevalence using the Edinburgh Postnatal Depression Scale. PPD prevalence and methods were extracted from each study. Random effects meta-analysis was used to estimate global and national PPD prevalence. To test for country level predictors, we drew on data from UNICEF, WHO, and the World Bank. Random effects meta-regression was used to test national predictors of PPD prevalence. 291 studies of 296284 women from 56 countries were identified. The global pooled prevalence of PPD was 17.7% (95% confidence interval: 16.6-18.8%), with significant heterogeneity across nations ( Q  = 16,823, p  = 0.000, I 2  = 98%), ranging from 3% (2-5%) in Singapore to 38% (35-41%) in Chile. Nations with significantly higher rates of income inequality ( R 2  = 41%), maternal mortality ( R 2  = 19%), infant mortality ( R 2  = 16%), or women of childbearing age working ≥40 h a week ( R 2  = 31%) have higher rates of PPD. Together, these factors explain 73% of the national variation in PPD prevalence. The global prevalence of PPD is greater than previously thought and varies dramatically by nation. Disparities in wealth inequality and maternal-child-health factors explain much of the national variation in PPD prevalence.

Continuous 1.3-million-year record of East African hydroclimate, and implications for patterns of evolution and biodiversity

NASA Astrophysics Data System (ADS)

Lyons, Robert P.; Scholz, Christopher A.; Cohen, Andrew S.; King, John W.; Brown, Erik T.; Ivory, Sarah J.; Johnson, Thomas C.; Deino, Alan L.; Reinthal, Peter N.; McGlue, Michael M.; Blome, Margaret W.

2015-12-01

The transport of moisture in the tropics is a critical process for the global energy budget and on geologic timescales, has markedly influenced continental landscapes, migratory pathways, and biological evolution. Here we present a continuous, first-of-its-kind 1.3-My record of continental hydroclimate and lake-level variability derived from drill core data from Lake Malawi, East Africa (9-15° S). Over the Quaternary, we observe dramatic shifts in effective moisture, resulting in large-scale changes in one of the world's largest lakes and most diverse freshwater ecosystems. Results show evidence for 24 lake level drops of more than 200 m during the Late Quaternary, including 15 lowstands when water levels were more than 400 m lower than modern. A dramatic shift is observed at the Mid-Pleistocene Transition (MPT), consistent with far-field climate forcing, which separates vastly different hydroclimate regimes before and after ∼800,000 years ago. Before 800 ka, lake levels were lower, indicating a climate drier than today, and water levels changed frequently. Following the MPT high-amplitude lake level variations dominate the record. From 800 to 100 ka, a deep, often overfilled lake occupied the basin, indicating a wetter climate, but these highstands were interrupted by prolonged intervals of extreme drought. Periods of high lake level are observed during times of high eccentricity. The extreme hydroclimate variability exerted a profound influence on the Lake Malawi endemic cichlid fish species flock; the geographically extensive habitat reconfiguration provided novel ecological opportunities, enabling new populations to differentiate rapidly to distinct species.

Continuous 1.3-million-year record of East African hydroclimate, and implications for patterns of evolution and biodiversity

PubMed Central

Lyons, Robert P.; Scholz, Christopher A.; Cohen, Andrew S.; King, John W.; Brown, Erik T.; Ivory, Sarah J.; Johnson, Thomas C.; Deino, Alan L.; Reinthal, Peter N.; McGlue, Michael M.; Blome, Margaret W.

2015-01-01

The transport of moisture in the tropics is a critical process for the global energy budget and on geologic timescales, has markedly influenced continental landscapes, migratory pathways, and biological evolution. Here we present a continuous, first-of-its-kind 1.3-My record of continental hydroclimate and lake-level variability derived from drill core data from Lake Malawi, East Africa (9–15° S). Over the Quaternary, we observe dramatic shifts in effective moisture, resulting in large-scale changes in one of the world’s largest lakes and most diverse freshwater ecosystems. Results show evidence for 24 lake level drops of more than 200 m during the Late Quaternary, including 15 lowstands when water levels were more than 400 m lower than modern. A dramatic shift is observed at the Mid-Pleistocene Transition (MPT), consistent with far-field climate forcing, which separates vastly different hydroclimate regimes before and after ∼800,000 years ago. Before 800 ka, lake levels were lower, indicating a climate drier than today, and water levels changed frequently. Following the MPT high-amplitude lake level variations dominate the record. From 800 to 100 ka, a deep, often overfilled lake occupied the basin, indicating a wetter climate, but these highstands were interrupted by prolonged intervals of extreme drought. Periods of high lake level are observed during times of high eccentricity. The extreme hydroclimate variability exerted a profound influence on the Lake Malawi endemic cichlid fish species flock; the geographically extensive habitat reconfiguration provided novel ecological opportunities, enabling new populations to differentiate rapidly to distinct species. PMID:26644580

Continuous 1.3-million-year record of East African hydroclimate, and implications for patterns of evolution and biodiversity.

PubMed

Lyons, Robert P; Scholz, Christopher A; Cohen, Andrew S; King, John W; Brown, Erik T; Ivory, Sarah J; Johnson, Thomas C; Deino, Alan L; Reinthal, Peter N; McGlue, Michael M; Blome, Margaret W

2015-12-22

The transport of moisture in the tropics is a critical process for the global energy budget and on geologic timescales, has markedly influenced continental landscapes, migratory pathways, and biological evolution. Here we present a continuous, first-of-its-kind 1.3-My record of continental hydroclimate and lake-level variability derived from drill core data from Lake Malawi, East Africa (9-15° S). Over the Quaternary, we observe dramatic shifts in effective moisture, resulting in large-scale changes in one of the world's largest lakes and most diverse freshwater ecosystems. Results show evidence for 24 lake level drops of more than 200 m during the Late Quaternary, including 15 lowstands when water levels were more than 400 m lower than modern. A dramatic shift is observed at the Mid-Pleistocene Transition (MPT), consistent with far-field climate forcing, which separates vastly different hydroclimate regimes before and after ∼800,000 years ago. Before 800 ka, lake levels were lower, indicating a climate drier than today, and water levels changed frequently. Following the MPT high-amplitude lake level variations dominate the record. From 800 to 100 ka, a deep, often overfilled lake occupied the basin, indicating a wetter climate, but these highstands were interrupted by prolonged intervals of extreme drought. Periods of high lake level are observed during times of high eccentricity. The extreme hydroclimate variability exerted a profound influence on the Lake Malawi endemic cichlid fish species flock; the geographically extensive habitat reconfiguration provided novel ecological opportunities, enabling new populations to differentiate rapidly to distinct species.

Pressure garment design tool to monitor exerted pressures.

PubMed

Macintyre, Lisa; Ferguson, Rhona

2013-09-01

Pressure garments are used in the treatment of hypertrophic scarring following serious burns. The use of pressure garments is believed to hasten the maturation process, reduce pruritus associated with immature hypertrophic scars and prevent the formation of contractures over flexor joints. Pressure garments are normally made to measure for individual patients from elastic fabrics and are worn continuously for up to 2 years or until scar maturation. There are 2 methods of constructing pressure garments. The most common method, called the Reduction Factor method, involves reducing the patient's circumferential measurements by a certain percentage. The second method uses the Laplace Law to calculate the dimensions of pressure garments based on the circumferential measurements of the patient and the tension profile of the fabric. The Laplace Law method is complicated to utilise manually and no design tool is currently available to aid this process. This paper presents the development and suggested use of 2 new pressure garment design tools that will aid pressure garment design using the Reduction Factor and Laplace Law methods. Both tools calculate the pressure garment dimensions and the mean pressure that will be exerted around the body at each measurement point. Monitoring the pressures exerted by pressure garments and noting the clinical outcome would enable clinicians to build an understanding of the implications of particular pressures on scar outcome, maturation times and patient compliance rates. Once the optimum pressure for particular treatments is known, the Laplace Law method described in this paper can be used to deliver those average pressures to all patients. This paper also presents the results of a small scale audit of measurements taken for the fabrication of pressure garments in two UK hospitals. This audit highlights the wide range of pressures that are exerted using the Reduction Factor method and that manual pattern 'smoothing' can dramatically change the actual Reduction Factors used. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.

Effect of fibrillation conditions on the anti-amyloidogenic properties of polyphenols and their involved mechanisms.

PubMed

Mahdavimehr, Mohsen; Katebi, Bentolhoda; Meratan, Ali Akbar

2018-06-24

In the present study, we have investigated the effects of protein concentration and stirring on the in vitro assembly of Hen Egg White Lysozyme (HEWL), particularly with regard to the aggregate morphology and anti-amyloidogenic properties of two naturally occurring polyphenols, taxifolin and silibinin. The results obtained clearly demonstrated that applying stirring and concentration enhancement alter the amount as well as morphology of amyloid fibrils formed. Additionally, latter aggregates exhibited higher affinity for amyloid-specific dyes. The second part of the present investigation was devoted to studies involving anti-amyloidogenic properties of selected polyphenols. Importantly, we found that the potency of polyphenols to inhibit HEWL amyloid fibrillation and related toxicity is strongly dependent on the amyloidogenic conditions in which amyloid fibrils are produced. Based on obtained data, under condition where the rate of protein assembly is high (higher protein concentration and stirring), the capacity of polyphenols to inhibit HEWL fibrillogenesis and related cytotoxicity may dramatically decrease. Similar results were obtained when we used taxifolin to inhibit bovine insulin amyloid fibrillation. Additionally, amyloidogenic conditions may also affect the mechanism by which these molecules inhibit HEWL fibrillation. The possible mechanism by which selected polyphenols exert their inhibitory effects, under various experimental conditions, is also discussed. Copyright © 2018. Published by Elsevier B.V.

Gossypium herbaceam extracts inhibited NF-kappaB activation to attenuate spatial memory impairment and hippocampal neurodegeneration induced by amyloid-beta in rats.

PubMed

Ji, Chao; Aisa, Haji Akber; Yang, Nan; Li, Qing; Wang, Tao; Zhang, Ling; Qu, Kai; Zhu, Hai-Bo; Zuo, Ping-Ping

2008-07-01

Amyloid-beta (Abeta) is considered to be responsible for the pathogenesis of Alzheimer's disease. In the present study, the protective effect of Gossypium herbaceam extracts (GHE) on learning and memory impairment induced by Abeta were examined in vivo using Morris water maze and step through task. Furthermore, the antioxidant activity and neuroprotective effect of GHE was investigated with methods of histochemistry and biochemistry. These data showed that oral administration with GHE at the doses of 35, 70 and 140 mg/kg exerted an improved effect on the learning and memory impairment in rats induced by intracerebroventricular (i.c.v.) injection of 10 microg of Abeta(25-35). Subsequently, the GHE afforded a beneficial action on promotion on the activity of glutathione peroxidase and catalase, as well as inhibition on the NF-kappaB activation in the hippocampus followed by the presence of Abeta(25-35). Meanwhile, the number of degenerating neurons with an apoptotic feature was dramatically decreased in hippocampus after treatment with GHE, implicating that its antioxidant stress and inhibition of NF-kappaB activation could be involved in the mechanism underlying neuroprotection of GHE against Abeta-induced cell death. These findings suggested that GHE might be a potential agent for treatment of Alzheimer's disease.

Silymarin attenuated paraquat-induced cytotoxicity in macrophage by regulating Trx/TXNIP complex, inhibiting NLRP3 inflammasome activation and apoptosis.

PubMed

Liu, Zhenning; Sun, Mingli; Wang, Yu; Zhang, Lichun; Zhao, Hang; Zhao, Min

2018-02-01

Oxidative stress and inflammation are involved in paraquat-induced cytotoxicity. Silymarin can exert a potent antioxidative and anti-inflammatory effect in various pathophysiological processes. The aim of this current study is to explore the protective effect and potential mechanism of silymarin in paraquat-induced macrophage injury. Cells were pretreated with different doses of silymarin for 3h before exposure to paraquat. At 24h after exposure to paraquat, the paraquat-induced cytotoxicity to macrophage was measured via the MTT assay and LDH release. The levels of intracellular reactive oxygen species, GSH-Px, SOD, and lipid peroxidation product malondialdehyde were measured to evaluate the oxidative effect of paraquat. NLRP3 inflammasome and cytokines secretion in macrophage exposed to paraquat at 24h were measured via immunofluorescence microscopy, western blot or Elisa. Our results revealed that paraquat could dramatically cause cytotoxicity and reactive oxygen species generation, enhance TXNIP expression, and induce NLRP3 inflammasome activation and cytokines secretion. The pretreatment with silymarin could remarkably reduce the cytotoxicity, promote the expression of Trx and antioxidant enzymes, and suppress the TXNIP and NLRP3 inflammasome activation. In conclusion, silymarin attenuated paraquat-induced cytotoxicity in macrophage by inhibiting oxidative stress, NLRP3 inflammasome activation, cytokines secretion and apoptosis. Copyright © 2017 Elsevier Ltd. All rights reserved.

Toxic effects of X-linked adrenoleukodystrophy-associated, very long chain fatty acids on glial cells and neurons from rat hippocampus in culture.

PubMed

Hein, Sabine; Schönfeld, Peter; Kahlert, Stefan; Reiser, Georg

2008-06-15

Saturated very long chain fatty acids (VLCFAs; > or =C22:0) accumulate in X-linked adrenoleukodystrophy (X-ALD, OMIM 300100), a severe hereditary neurodegenerative disease, due to peroxisomal impairment. Previous studies analysed the development of X-ALD in humans and gene knockout animal models. However, the toxic effect of VLCFA leading to severe symptoms with progressive and multifocal demyelination, adrenal insufficiency and inflammation still remains unclear. To understand the toxic effects of VLCFA in the brain, here we exposed neural cells to VLCFA and analysed the cellular consequences. We found that oligodendrocytes and astrocytes challenged with docosanoic- (C22:0), tetracosanoic- (C24:0) and hexacosanoic acids (C24:0) die within 24 h. VLCFA-induced depolarization of mitochondria in situ and increased intracellular Ca2+ level in all three brain cell types provides indications about the mechanism of toxicity of VLCFA. Interestingly, VLCFAs affect to the largest degree the myelin-producing oligodendrocytes. In isolated mitochondria, VLCFAs exert a detrimental effect by affecting the inner mitochondrial membrane and promoting the permeability transition. In conclusion, we suggest that there is a potent toxic activity of VLCFA due to dramatic cell physiological effects with mitochondrial dysfunction and Ca2+ deregulation. This provides the first evidence for mitochondrial-based cell death mechanisms in neurodegenerative disease with peroxisomal defects and subsequent VLCFA accumulation.

Do placebo expectations influence perceived exertion during physical exercise?

PubMed

Mothes, Hendrik; Leukel, Christian; Seelig, Harald; Fuchs, Reinhard

2017-01-01

This study investigates the role of placebo expectations in individuals' perception of exertion during acute physical exercise. Building upon findings from placebo and marketing research, we examined how perceived exertion is affected by expectations regarding a) the effects of exercise and b) the effects of the exercise product worn during the exercise. We also investigated whether these effects are moderated by physical self-concept. Seventy-eight participants conducted a moderate 30 min cycling exercise on an ergometer, with perceived exertion (RPE) measured every 5 minutes. Beforehand, each participant was randomly assigned to 1 of 4 conditions and watched a corresponding film clip presenting "scientific evidence" that the exercise would or would not result in health benefits and that the exercise product they were wearing (compression garment) would additionally enhance exercise benefits or would only be worn for control purposes. Participants' physical self-concept was assessed via questionnaire. Results partially demonstrated that participants with more positive expectations experienced reduced perceived exertion during the exercise. Furthermore, our results indicate a moderator effect of physical self-concept: Individuals with a high physical self-concept benefited (in terms of reduced perceived exertion levels) in particular from an induction of generally positive expectations. In contrast, individuals with a low physical self-concept benefited when positive expectations were related to the exercise product they were wearing. In sum, these results suggest that placebo expectations may be a further, previously neglected class of psychological factors that influence the perception of exertion.

Do placebo expectations influence perceived exertion during physical exercise?

PubMed Central

Leukel, Christian; Seelig, Harald; Fuchs, Reinhard

2017-01-01

This study investigates the role of placebo expectations in individuals’ perception of exertion during acute physical exercise. Building upon findings from placebo and marketing research, we examined how perceived exertion is affected by expectations regarding a) the effects of exercise and b) the effects of the exercise product worn during the exercise. We also investigated whether these effects are moderated by physical self-concept. Seventy-eight participants conducted a moderate 30 min cycling exercise on an ergometer, with perceived exertion (RPE) measured every 5 minutes. Beforehand, each participant was randomly assigned to 1 of 4 conditions and watched a corresponding film clip presenting “scientific evidence” that the exercise would or would not result in health benefits and that the exercise product they were wearing (compression garment) would additionally enhance exercise benefits or would only be worn for control purposes. Participants’ physical self-concept was assessed via questionnaire. Results partially demonstrated that participants with more positive expectations experienced reduced perceived exertion during the exercise. Furthermore, our results indicate a moderator effect of physical self-concept: Individuals with a high physical self-concept benefited (in terms of reduced perceived exertion levels) in particular from an induction of generally positive expectations. In contrast, individuals with a low physical self-concept benefited when positive expectations were related to the exercise product they were wearing. In sum, these results suggest that placebo expectations may be a further, previously neglected class of psychological factors that influence the perception of exertion. PMID:28662168

Epigenetic mechanisms in cerebral ischemia

PubMed Central

Schweizer, Sophie; Meisel, Andreas; Märschenz, Stefanie

2013-01-01

Treatment efficacy for ischemic stroke represents a major challenge. Despite fundamental advances in the understanding of stroke etiology, therapeutic options to improve functional recovery remain limited. However, growing knowledge in the field of epigenetics has dramatically changed our understanding of gene regulation in the last few decades. According to the knowledge gained from animal models, the manipulation of epigenetic players emerges as a highly promising possibility to target diverse neurologic pathologies, including ischemia. By altering transcriptional regulation, epigenetic modifiers can exert influence on all known pathways involved in the complex course of ischemic disease development. Beneficial transcriptional effects range from attenuation of cell death, suppression of inflammatory processes, and enhanced blood flow, to the stimulation of repair mechanisms and increased plasticity. Most striking are the results obtained from pharmacological inhibition of histone deacetylation in animal models of stroke. Multiple studies suggest high remedial qualities even upon late administration of histone deacetylase inhibitors (HDACi). In this review, the role of epigenetic mechanisms, including histone modifications as well as DNA methylation, is discussed in the context of known ischemic pathways of damage, protection, and regeneration. PMID:23756691

[Obstacles and perspectives of new antimicrobial concepts within research and development].

PubMed

Kloß, Florian; Gerbach, Sina

2018-05-01

Antimicrobial resistance (AMR) has developed into a serious problem for the healthcare sector worldwide. Research on fundamentally novel antibiotics has been insufficient for decades and only a few new compounds have reached the market. Thus, the pressure to implement novel and effective concepts for the reduction of infections through problematic pathogens has dramatically increased. This demand has been recognized by politicians and comprehensive national and international funding programs have been launched. A major role of many funding lines is the investigation and development of therapeutics exerting a novel mechanism of action and/or minimizing the frequency of resistance. In addition to the actual clinical pipeline, this article lists selected examples from research and early development with a special focus on antibiotics. Moreover, alternative approaches like antivirulence and phage therapy as well as immunomodulation are summarized. AMR is no longer solely a healthcare policy, but is of societal significance as a whole. A consolidation of infrastructures and public-private partnerships, a reduction of regulatory obstacles and a continuous pursuit of innovations for antimicrobial therapy are urgently needed.

Systems vaccinology: Probing humanity’s diverse immune systems with vaccines

PubMed Central

Pulendran, Bali

2014-01-01

Homo sapiens are genetically diverse, but dramatic demographic and socioeconomic changes during the past century have created further diversification with respect to age, nutritional status, and the incidence of associated chronic inflammatory disorders and chronic infections. These shifting demographics pose new challenges for vaccination, as emerging evidence suggests that age, the metabolic state, and chronic infections can exert major influences on the immune system. Thus, a key public health challenge is learning how to reprogram suboptimal immune systems to induce effective vaccine immunity. Recent advances have applied systems biological analysis to define molecular signatures induced early after vaccination that correlate with and predict the later adaptive immune responses in humans. Such “systems vaccinology” approaches offer an integrated picture of the molecular networks driving vaccine immunity, and are beginning to yield novel insights about the immune system. Here we discuss the promise of systems vaccinology in probing humanity’s diverse immune systems, and in delineating the impact of genes, the environment, and the microbiome on protective immunity induced by vaccination. Such insights will be critical in reengineering suboptimal immune systems in immunocompromised populations. PMID:25136102

Development of a low noise induction magnetic sensor using magnetic flux negative feedback in the time domain.

PubMed

Wang, X G; Shang, X L; Lin, J

2016-05-01

Time-domain electromagnetic system can implement great depth detection. As for the electromagnetic system, the receiver utilized an air coil sensor, and the matching mode of the sensor employed the resistance matching method. By using the resistance matching method, the vibration of the coil in the time domain can be effectively controlled. However, the noise of the sensor, especially the noise at the resonance frequency, will be increased as well. In this paper, a novel design of a low noise induction coil sensor is proposed, and the experimental data and noise characteristics are provided. The sensor is designed based on the principle that the amplified voltage will be converted to current under the influence of the feedback resistance of the coil. The feedback loop around the induction coil exerts a magnetic field and sends the negative feedback signal to the sensor. The paper analyses the influence of the closed magnetic feedback loop on both the bandwidth and the noise of the sensor. The signal-to-noise ratio is improved dramatically.

Acromegaly and Cushing's syndrome associated with a foregut carcinoid tumor.

PubMed

Leveston, S A; McKeel, D W; Buckley, P J; Deschryver, K; Greider, M H; Jaffe, B M; Daughaday, W H

1981-10-01

We report an 18-yr-old youth with a metastatic foregut carcinoid tumor, Cushing's syndrome, and hypersomatotropic gigantism. Administration of cyproheptadine caused a dramatic fall in urinary cortisol excretion and plasma ACTH levels associated with clinical remission of the Cushing's syndrome. GH secretion was not affected by cyproheptadine administration. Ectopic ACTH secretion was confirmed by RIA of tumor extracts and immunohistochemical demonstration of ACTH-containing cells in hepatic metastases. There were two sources of GH production demonstrated in this patient. Ectopic secretion of GH by the carcinoid hepatic metastases was documented by both RIA and immunohistochemical techniques. A somatotrophic pituitary tumor was also present. The histological characteristics of this tumor suggest adenomatous hyperplasia rather than de novo neoplastic change as the likely mechanism of its pathogenesis. GH releasing factor-like activity was demonstrated in extracts of plasma and in extracts of the carcinoid tumor. We conclude that cyproheptadine exerted an effect on the ectopic ACTH-producing cells but not on the ectopic GH-producing cells or on adenohypophyseal GH secretion. Production of a GH releasing factor-like activity by the carcinoid tumor may have caused the pituitary somatotrophic tumor.

Systems vaccinology: probing humanity's diverse immune systems with vaccines.

PubMed

Pulendran, Bali

2014-08-26

Homo sapiens are genetically diverse, but dramatic demographic and socioeconomic changes during the past century have created further diversification with respect to age, nutritional status, and the incidence of associated chronic inflammatory disorders and chronic infections. These shifting demographics pose new challenges for vaccination, as emerging evidence suggests that age, the metabolic state, and chronic infections can exert major influences on the immune system. Thus, a key public health challenge is learning how to reprogram suboptimal immune systems to induce effective vaccine immunity. Recent advances have applied systems biological analysis to define molecular signatures induced early after vaccination that correlate with and predict the later adaptive immune responses in humans. Such "systems vaccinology" approaches offer an integrated picture of the molecular networks driving vaccine immunity, and are beginning to yield novel insights about the immune system. Here we discuss the promise of systems vaccinology in probing humanity's diverse immune systems, and in delineating the impact of genes, the environment, and the microbiome on protective immunity induced by vaccination. Such insights will be critical in reengineering suboptimal immune systems in immunocompromised populations.

The Effectiveness of Creative Dramatics and Storytelling in a Library Setting

ERIC Educational Resources Information Center

Amato, Anthony; And Others

1973-01-01

This 2-year study involving 298 grade school pupils investigates the comparative effectiveness of creative dramatics and storytelling. While the results indicate neither had an effect on children's interests and reading achievement, there is indication that storytelling may have more influence than creative dramatics on self-image and empathy.…

Drag and lift forces in granular media

NASA Astrophysics Data System (ADS)

Guillard, F.; Forterre, Y.; Pouliquen, O.

2013-09-01

Forces exerted on obstacles moving in granular media are studied. The experiment consists in a horizontal cylinder rotating around the vertical axis in a granular medium. Both drag forces and lift forces experienced by the cylinder are measured. The first striking result is obtained during the first half rotation, before the cylinder crosses its wake. Despite the symmetry of the object, a strong lift force is measured, about 20 times the buoyancy. The scaling of this force is studied experimentally. The second remarkable observation is made after several rotations. The drag force dramatically drops and becomes independent of depth, showing that it no longer scales with the hydrostatic pressure. The rotation of the cylinder induces a structure in the packing, which screens the weight of the grains above

Long pentraxin-3 as an epithelial-stromal fibroblast growth factor-targeting inhibitor in prostate cancer.

PubMed

Ronca, Roberto; Alessi, Patrizia; Coltrini, Daniela; Di Salle, Emanuela; Giacomini, Arianna; Leali, Daria; Corsini, Michela; Belleri, Mirella; Tobia, Chiara; Garlanda, Cecilia; Bonomi, Elisa; Tardanico, Regina; Vermi, William; Presta, Marco

2013-06-01

Fibroblast growth factors (FGFs) exert autocrine/paracrine functions in prostate cancer by stimulating angiogenesis and tumour growth. Here dihydrotestosterone (DHT) up-regulates FGF2 and FGF8b production in murine TRAMP-C2 prostate cancer cells, activating a FGF-dependent autocrine loop of stimulation. The soluble pattern recognition receptor long pentraxin-3 (PTX3) acts as a natural FGF antagonist that binds FGF2 and FGF8b via its N-terminal domain. We demonstrate that recombinant PTX3 protein and the PTX3-derived pentapeptide Ac-ARPCA-NH2 abolish the mitogenic response of murine TRAMP-C2 cells and human LNCaP prostate cancer cells to DHT and FGFs. Also, PTX3 hampers the angiogenic activity of DHT-activated TRAMP-C2 cells on the chick embryo chorioallantoic membrane (CAM). Accordingly, human PTX3 overexpression inhibits the mitogenic activity exerted by DHT or FGFs on hPTX3_TRAMP-C2 cell transfectants and their angiogenic activity. Also, hPTX3_TRAMP-C2 cells show a dramatic decrease of their angiogenic and tumourigenic potential when grafted in syngeneic or immunodeficient athymic male mice. A similar inhibitory effect is observed when TRAMP-C2 cells overexpress only the FGF-binding N-terminal PTX3 domain. In keeping with the anti-tumour activity of PTX3 in experimental prostate cancer, immunohistochemical analysis of prostate needle biopsies from primary prostate adenocarcinoma patients shows that parenchymal PTX3 expression, abundant in basal cells of normal glands, is lost in high-grade prostatic intraepithelial neoplasia and in invasive tumour areas. These results identify PTX3 as a potent FGF antagonist endowed with anti-angiogenic and anti-neoplastic activity in prostate cancer. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Magnolol, a Natural Polyphenol, Attenuates Dextran Sulfate Sodium-Induced Colitis in Mice.

PubMed

Zhao, Ling; Xiao, Hai-Tao; Mu, Huai-Xue; Huang, Tao; Lin, Ze-Si; Zhong, Linda L D; Zeng, Guang-Zhi; Fan, Bao-Min; Lin, Cheng-Yuan; Bian, Zhao-Xiang

2017-07-20

Magnolol is a lignan with anti-inflammatory activity identified in Magnolia officinalis . Ulcerative colitis (UC), one of the types of inflammatory bowel disease (IBD), is a disease that causes inflammation and ulcers in the colon. To investigate the effect of magnolol in dextran sulfate sodium (DSS)-induced experimental UC model, male C57 mice were treated with 2% DSS drinking water for 5 consecutive days followed by intragastric administration with magnolol (5, 10 and 15 mg/kg) daily for 7 days. The results showed that magnolol significantly attenuated disease activity index, inhibited colonic shortening, reduced colonic lesions and suppressed myeloperoxidase (MPO) activity. Moreover, colonic pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) induced by colitis were dramatically decreased by magnolol. To further unveil the metabolic signatures upon magnolol treatment, mass spectrometry-based metabolomic analysis of the small molecular metabolites in mice serum were performed. Compared with controls, abnormality of serum metabolic phenotypes in DSS-treated mice were effectively reversed by different doses of magnolol. In particular, magnolol treatment effectively elevated the serum levels of tryptophan metabolites including kynurenic acid (KA), 5-hydroxyindoleacetic acid, indoleacetic acid (IAA), indolelactic acid and indoxylsulfuric acid, which are potential aryl hydrocarbon receptor (AHR) ligands to impact colitis. These findings suggest that magnolol exerts anti-inflammatory effect on DSS-induced colitis and its underlying mechanisms are associated with the restoring of tryptophan metabolites that inhibit the colonic inflammation.

Human migration activities drive the fluctuation of ARGs: Case study of landfills in Nanjing, eastern China.

PubMed

Sun, Mingming; Ye, Mao; Schwab, Arthur P; Li, Xu; Wan, Jinzhong; Wei, Zhong; Wu, Jun; Friman, Ville-Petri; Liu, Kuan; Tian, Da; Liu, Manqiang; Li, Huixin; Hu, Feng; Jiang, Xin

2016-09-05

Landfills are perfect sites to study the effect of human migration on fluctuation of antibiotic resistance genes (ARGs) as they are the final destination of municipal waste. For example, large-scale human migration during the holidays is often accompanied by changes in waste dumping having potential effects on ARG abundance. Three landfills were selected to examine fluctuation in the abundance of fifteen ARGs and Intl1 genes for 14 months in Nanjing, eastern China. Mass human migration, the amount of dumped waste and temperature exerted the most significant effects on bimonthly fluctuations of ARG levels in landfill sites. As a middle-sized cosmopolitan city in China, millions of college students and workers migrate during holidays, contributing to the dramatic increases in waste production and fluctuation in ARG abundances. In line with this, mass migration explained most of the variation in waste dumping. The waste dumping also affected the bioaccessibility of mixed-compound pollutants that further positively impacted the level of ARGs. The influence of various bioaccessible compounds on ARG abundance followed the order: antibiotics>nutrients>metals>organic pollutants. Concentrations of bioaccessible compounds were more strongly correlated with ARG levels compared to total compound concentrations. Improved waste classification and management strategies could thus help to decrease the amount of bioaccessible pollutants leading to more effective control for urban ARG dissemination. Copyright © 2016 Elsevier B.V. All rights reserved.

Effects of prior physical exertion on tolerance to hypoxia, orthostatic stress, and physical fatigue.

DOT National Transportation Integrated Search

1982-03-01

Ten healthy men, 20-35 years old, were tested for tolerance to hypoxia, orthostatic stress, and physical fatigue after a period of rest, and, on another occasion, after a period of physical exertion. Exertion consisted of four 10-min periods of pedal...

Basolateral amygdalar D2 receptor activation is required for the companions-exerted suppressive effect on the cocaine conditioning.

PubMed

Tzeng, Wen-Yu; Cherng, Chian-Fang G; Yu, Lung; Wang, Ching-Yi

2017-01-01

The presence of companions renders decreases in cocaine-stimulated dopamine release in the nucleus accumbens and cocaine-induced conditioned place preference (CPP) magnitude. Limbic systems are widely believed to underlie the modulation of accumbal dopamine release and cocaine conditioning. Thus, this study aimed to assess whether intact basolateral nucleus of amygdala (BLA), dorsal hippocampus (DH), and dorsolateral striatum (DLS) is required for the companions-exerted suppressive effect on the cocaine-induced CPP. Three cage mates, serving as companions, were arranged to house with the experimental mice in the cocaine conditioning compartment throughout the cocaine conditioning sessions. Approximately 1week before the conditioning procedure, intracranial ibotenic acid infusions were done in an attempt to cause excitotoxic lesions targeting bilateral BLA, DH and DLS. Albeit their BLA, DH, and DLS lesions, the lesioned mice exhibited comparable cocaine-induced CPP magnitudes compared to the intact and sham lesion controls. Bilateral BLA, but not DH or DLS, lesions abolished the companions-exerted suppressive effect on the cocaine-induced CPP. Intact mice receiving intra-BLA infusion of raclopride, a selective D2 antagonist, 30min prior to the cocaine conditioning did not exhibit the companions-exerted suppressive effect on the cocaine-induced CPP. Intra-BLA infusion of Sch23390, a selective D1 antagonist, did not affect the companions-exerted suppressive effect on the CPP. These results, taken together, prompt us to conclude that the intactness of BLA is required for the companions-exerted suppressive effect on the cocaine-induced CPP. Importantly, activation of D2 receptor in the BLA is required for such suppressive effect on the CPP. Copyright © 2016 Elsevier Inc. All rights reserved.

The effect of grip force, stroke rotation and frequency on discomfort for a torqueing tasks.

PubMed

Bano, Farheen; Mallick, Zulqernian; Khan, Abid Ali

2015-08-08

Occupational tasks involve awkward upper limb postures, especially movement of forearm with repetitive combined gripping and torqueing exertions, which may lead to development of WMSDs. From the literature survey it was observed that there was a lack of studies focussed on the combined effect of torque and grip exertions on forearm discomfort. The present study was to investigate the effects of grip force, stroke rotation and frequency of exertions on discomfort and Electromyography (EMG) activities of the forearm muscles in a repetitive torqueing task. Twenty-seven male participants volunteered in this study. The participants performed repetitive exertions for a 5 minutes duration for each combination of the different levels of stroke rotation, grip force and frequency of exertions. Three levels of stroke rotation, three levels of grip force and three levels of frequency of exertion were chosen as independent variables. Therefore a 3 × 3 customized factorial design was used for the experiment for each level of grip force. Hence, the study was divided into three groups on the basis of grip force (50N, 70N and 90N). The ANOVA showed that stroke rotation and frequency of exertion were significant on discomfort. Further Students Newmann test (SNK) revealed that discomfort was increased with increasing stroke rotation and frequency of exertion. The multivariate analysis of variances (MANOVA) performed on EMG data instead of ANOVA because EMG activities of five muscles simultaneously were recorded. The Results found that extensor muscles were more fatigued in torqueing with gripping task. It was found that stroke rotation for the torqueing tasks must be kept below 45°. It was concluded that it is important to control stroke rotation to improve performance of repetitive torqueing activity.

Distinct Mechanisms of the ORANGE Protein in Controlling Carotenoid Flux1[OPEN

PubMed Central

Ohali, Shachar; Meir, Ayala; Sa’ar, Uzi; Mazourek, Michael; Lewinsohn, Efraim; Schaffer, Arthur A.; Burger, Joseph

2017-01-01

β-Carotene adds nutritious value and determines the color of many fruits, including melon (Cucumis melo). In melon mesocarp, β-carotene accumulation is governed by the Orange gene (CmOr) golden single-nucleotide polymorphism (SNP) through a yet to be discovered mechanism. In Arabidopsis (Arabidopsis thaliana), OR increases carotenoid levels by posttranscriptionally regulating phytoene synthase (PSY). Here, we identified a CmOr nonsense mutation (Cmor-lowβ) that lowered fruit β-carotene levels with impaired chromoplast biogenesis. Cmor-lowβ exerted a minimal effect on PSY transcripts but dramatically decreased PSY protein levels and enzymatic activity, leading to reduced carotenoid metabolic flux and accumulation. However, the golden SNP was discovered to not affect PSY protein levels and carotenoid metabolic flux in melon fruit, as shown by carotenoid and immunoblot analyses of selected melon genotypes and by using chemical pathway inhibitors. The high β-carotene accumulation in golden SNP melons was found to be due to a reduced further metabolism of β-carotene. This was revealed by genetic studies with double mutants including carotenoid isomerase (yofi), a carotenoid-isomerase nonsense mutant, which arrests the turnover of prolycopene. The yofi F2 segregants accumulated prolycopene independently of the golden SNP. Moreover, Cmor-lowβ was found to inhibit chromoplast formation and chloroplast disintegration in fruits from 30 d after anthesis until ripening, suggesting that CmOr regulates the chloroplast-to-chromoplast transition. Taken together, our results demonstrate that CmOr is required to achieve PSY protein levels to maintain carotenoid biosynthesis metabolic flux but that the mechanism of the CmOr golden SNP involves an inhibited metabolism downstream of β-carotene to dramatically affect both carotenoid content and plastid fate. PMID:27837090

Phenylbutyrate ameliorates cognitive deficit and reduces tau pathology in an Alzheimer's disease mouse model.

PubMed

Ricobaraza, Ana; Cuadrado-Tejedor, Mar; Pérez-Mediavilla, Alberto; Frechilla, Diana; Del Río, Joaquin; García-Osta, Ana

2009-06-01

Chromatin modification through histone acetylation is a molecular pathway involved in the regulation of transcription underlying memory storage. Sodium 4-phenylbutyrate (4-PBA) is a well-known histone deacetylase inhibitor, which increases gene transcription of a number of genes, and also exerts neuroprotective effects. In this study, we report that administration of 4-PBA reversed spatial learning and memory deficits in an established mouse model of Alzheimer's disease (AD) without altering beta-amyloid burden. We also observed that the phosphorylated form of tau was decreased in the AD mouse brain after 4-PBA treatment, an effect probably due to an increase in the inactive form of the glycogen synthase kinase 3beta (GSK3beta). Interestingly, we found a dramatic decrease in brain histone acetylation in the transgenic mice that may reflect an indirect transcriptional repression underlying memory impairment. The administration of 4-PBA restored brain histone acetylation levels and, as a most likely consequence, activated the transcription of synaptic plasticity markers such as the GluR1 subunit of the AMPA receptor, PSD95, and microtubule-associated protein-2. The results suggest that 4-PBA, a drug already approved for clinical use, may provide a novel approach for the treatment of AD.

Calcium Phosphate Cement with Antimicrobial Properties and Radiopacity as an Endodontic Material

PubMed Central

Shieh, Tzong-Ming; Hsu, Shih-Ming; Chang, Kai-Chi; Lin, Dan-Jae

2017-01-01

Calcium phosphate cements (CPCs) have several advantages for use as endodontic materials, and such advantages include ease of use, biocompatibility, potential hydroxyapatite-forming ability, and bond creation between the dentin and appropriate filling materials. However, unlike tricalcium silicate (CS)-based materials, CPCs do not have antibacterial properties. The present study doped a nonwashable CPC with 0.25–1.0 wt % hinokitiol and added 0, 5, and 10 wt % CS. The CPCs with 0.25–0.5 wt % hinokitiol showed appreciable antimicrobial properties without alterations in their working or setting times, mechanical properties, or cytocompatibility. Addition of CS slightly retarded the apatite formation of CPC and the working and setting time was obviously reduced. Moreover, addition of CS dramatically increased the compressive strength of CPC. Doping CS with 5 wt % ZnO provided additional antibacterial effects to the present CPC system. CS and hinokitiol exerted a synergic antibacterial effect, and the CPC with 0.25 wt % hinokitiol and 10 wt % CS (doped with 5 wt % ZnO) had higher antibacterial properties than that of pure CS. The addition of 10 wt % bismuth subgallate doubled the CPC radiopacity. The results demonstrate that hinokitiol and CS can improve the antibacterial properties of CPCs, and they can thus be considered for endodontic applications. PMID:29088119

The effect of vocal and instrumental music on cardio respiratory variables, energy expenditure and exertion levels during sub maximal treadmill exercise.

PubMed

Savitha, D; Sejil, T V; Rao, Shwetha; Roshan, C J; Roshan, C J

2013-01-01

The purpose of the study was to investigate the effect of vocal and instrumental music on various physiological parameters during submaximal exercise. Each subject underwent three sessions of exercise protocol without music, with vocal music, and instrumental versions of same piece of music. The protocol consisted of 10 min treadmill exercise at 70% HR(max) and 20 min of recovery. Minute to minute heart rate and breath by breath recording of respiratory parameters, rate of energy expenditure and perceived exertion levels were measured. Music, irrespective of the presence or absence of lyrics, enabled the subjects to exercise at a significantly lower heart rate and oxygen consumption, reduced the metabolic cost and perceived exertion levels of exercise (P < 0.05). There was faster recovery of systolic and diastolic blood pressures and exertion levels during the post exercise period. Music having a relaxant effect could have probably increased the parasympathetic activation leading to these effects.

Performance evaluation of two protective treatments on salt-laden limestones and marble after natural and artificial weathering.

PubMed

Salvadori, Barbara; Pinna, Daniela; Porcinai, Simone

2014-02-01

Salt crystallization is a major damage factor in stone weathering, and the application of inappropriate protective products may amplify its effects. This research focuses on the evaluation of two protective products' performance (organic polydimethylsiloxane and inorganic ammonium oxalate (NH4)2(COO)2·H2O) in the case of a salt load from behind. Experimental laboratory simulations based on salt crystallization cycles and natural weathering in an urban area were carried out. The effects were monitored over time, applying different methods: weight loss evaluation, colorimetric and water absorption by capillarity measurements, stereomicroscope observations, FTIR and SEM-EDS analyses. The results showed minor impact exerted on the short term on stones, particularly those treated with the water repellent, by atmospheric agents compared to salt crystallization. Lithotypes with low salt load (Gioia marble) underwent minor changes than the heavily salt-laden limestones (Lecce and Ançã stones), which were dramatically damaged when treated with polysiloxane. The results suggest that the ammonium oxalate treatment should be preferred to polysiloxane in the presence of soluble salts, even after desalination procedures which might not completely remove them. In addition, the neo-formed calcium oxalate seemed to effectively protect the stone, improving its resistance against salt crystallization without occluding the pores and limiting the superficial erosion caused by atmospheric agents.

The tumor suppressor miR-138-5p targets PD-L1 in colorectal cancer

PubMed Central

Zhao, Lian; Yu, Haibo; Yi, Shuijing; Peng, Xiaowei; Su, Peng; Xiao, Zhiming; Liu, Rui; Tang, Anliu; Li, Xiayu; Liu, Fen; Shen, Shourong

2016-01-01

microRNAs (miRNAs) play critical roles in cancer development and progression. This study investigated the effects of miR-138-5p in human colorectal cancer (CRC) development. miR-138-5p was frequently downregulated in CRC tissues and was associated with advanced clinical stage, lymph node metastasis and poor overall survival. We found that miR-138-5p decreased expression of programmed cell death ligand 1 (PD-L1) through interaction with its PD-L1 3′ untranslated region. miR-138-5p also dramatically suppressed CRC cell growth in vitro and inhibited tumorigenesis in vivo. PD-L1 and miR-138-5p levels were inversely correlated in human CRC tumors, and miR-138-5p inhibited PD-L1 expression in tumor models. These results suggest that miR-138-5p is a tumor suppressor in CRC, and its effects are exerted at least partially through PD-L1 downregulation. Low miR-138-5p and high PD-L1 levels correlated with shorter overall CRC patient survival, indicating that miR-138-5p and PD-L1 may serve as CRC biomarkers for risk group assignment, optimal therapy selection and clinical outcome prediction. Targeting PD-L1, possibly by administering miR-138-5p mimics, might be a clinically effective anti-CRC therapeutic strategy. PMID:27248318

The tumor suppressor miR-138-5p targets PD-L1 in colorectal cancer.

PubMed

Zhao, Lian; Yu, Haibo; Yi, Shuijing; Peng, Xiaowei; Su, Peng; Xiao, Zhiming; Liu, Rui; Tang, Anliu; Li, Xiayu; Liu, Fen; Shen, Shourong

2016-07-19

microRNAs (miRNAs) play critical roles in cancer development and progression. This study investigated the effects of miR-138-5p in human colorectal cancer (CRC) development. miR-138-5p was frequently downregulated in CRC tissues and was associated with advanced clinical stage, lymph node metastasis and poor overall survival. We found that miR-138-5p decreased expression of programmed cell death ligand 1 (PD-L1) through interaction with its PD-L1 3' untranslated region. miR-138-5p also dramatically suppressed CRC cell growth in vitro and inhibited tumorigenesis in vivo. PD-L1 and miR-138-5p levels were inversely correlated in human CRC tumors, and miR-138-5p inhibited PD-L1 expression in tumor models. These results suggest that miR-138-5p is a tumor suppressor in CRC, and its effects are exerted at least partially through PD-L1 downregulation. Low miR-138-5p and high PD-L1 levels correlated with shorter overall CRC patient survival, indicating that miR-138-5p and PD-L1 may serve as CRC biomarkers for risk group assignment, optimal therapy selection and clinical outcome prediction. Targeting PD-L1, possibly by administering miR-138-5p mimics, might be a clinically effective anti-CRC therapeutic strategy.

Exertion Testing in Youth with Mild Traumatic Brain Injury/Concussion.

PubMed

Dematteo, Carol; Volterman, Kimberly A; Breithaupt, Peter G; Claridge, Everett A; Adamich, John; Timmons, Brian W

2015-11-01

The decision regarding return to activity (RTA) after mild traumatic brain injuries/concussion is one of the most difficult and controversial areas in concussion management, particularly for youth. This study investigated how youth with postconcussion syndrome (PCS) are affected by exertion and whether standardized exertion testing using the McMaster All-Out Progressive Continuous Cycling Test can contribute to clinical decision making for safe RTA. Fifty-four youth (8.5-18.3 yr) with a previously confirmed concussion participated in the study. Each participant performed exertion testing on a cycle ergometer and completed a Postconcussion Symptom scale at the following time points: before exertion (baseline), 5 and 30 min, and 24 h after exertion. A modified Postconcussion Symptom scale was administered at 2-min intervals during exertion. Participants had a mean ± SD symptom duration of 6.3 ± 6.9 months after the most recent concussive injury, with a median of 4.1 months (range, 0.7-35 months). Sixty-three percent of participants had symptoms during exertion testing. Symptom profile (number and severity) significantly affected perception of exertion at 50% peak mechanical power. During acute assessment of symptoms (30-min after exertion), headache (P = 0.39), nausea (P = 0.63), and dizziness (P = 0.35) did not change. However, both the number and severity of symptoms significantly improved over 24 h, with 56.8% of youth showing improvements. The time from the most recent injury had a significant effect on the symptom score at baseline, 30 min after exertion, and 24 h after exertion. Exertion testing has an important role in the evaluation of symptoms and readiness to RTA, particularly in youth who are slow to recover. Overall, controlled exertion seemed to lesson symptoms for most youth.

Interaction Potency of Single-Walled Carbon Nanotubes with DNAs: A Novel Assay for Assessment of Hazard Risk

PubMed Central

Yao, Chunhe; Carlisi, Cristina; Li, Yuning; Chen, Da; Ding, Jianfu; Feng, Yong-Lai

2016-01-01

Increasing use of single-walled carbon nanotubes (SWCNTs) necessitates a novel method for hazard risk assessment. In this work, we investigated the interaction of several types of commercial SWCNTs with single-stranded (ss) and double-stranded (ds) DNA oligonucleotides (20-mer and 20 bp). Based on the results achieved, we proposed a novel assay that employed the DNA interaction potency to assess the hazard risk of SWCNTs. It was found that SWCNTs in different sizes or different batches of the same product number of SWCNTs showed dramatically different potency of interaction with DNAs. In addition, the same SWCNTs also exerted strikingly different interaction potency with ss- versus ds- DNAs. The interaction rates of SWCNTs with DNAs were investigated, which could be utilized as the indicator of potential hazard for acute exposure. Compared to solid SWCNTs, the SWCNTs dispersed in liquid medium (2% sodium cholate solution) exhibited dramatically different interaction potency with DNAs. This indicates that the exposure medium may greatly influence the subsequent toxicity and hazard risk produced by SWCNTs. Based on the findings of dose-dependences and time-dependences from the interactions between SWCNTs and DNAs, a new chemistry based assay for hazard risk assessment of nanomaterials including SWCNTs has been presented. PMID:27936089

Interaction Potency of Single-Walled Carbon Nanotubes with DNAs: A Novel Assay for Assessment of Hazard Risk.

PubMed

Yao, Chunhe; Carlisi, Cristina; Li, Yuning; Chen, Da; Ding, Jianfu; Feng, Yong-Lai

2016-01-01

Increasing use of single-walled carbon nanotubes (SWCNTs) necessitates a novel method for hazard risk assessment. In this work, we investigated the interaction of several types of commercial SWCNTs with single-stranded (ss) and double-stranded (ds) DNA oligonucleotides (20-mer and 20 bp). Based on the results achieved, we proposed a novel assay that employed the DNA interaction potency to assess the hazard risk of SWCNTs. It was found that SWCNTs in different sizes or different batches of the same product number of SWCNTs showed dramatically different potency of interaction with DNAs. In addition, the same SWCNTs also exerted strikingly different interaction potency with ss- versus ds- DNAs. The interaction rates of SWCNTs with DNAs were investigated, which could be utilized as the indicator of potential hazard for acute exposure. Compared to solid SWCNTs, the SWCNTs dispersed in liquid medium (2% sodium cholate solution) exhibited dramatically different interaction potency with DNAs. This indicates that the exposure medium may greatly influence the subsequent toxicity and hazard risk produced by SWCNTs. Based on the findings of dose-dependences and time-dependences from the interactions between SWCNTs and DNAs, a new chemistry based assay for hazard risk assessment of nanomaterials including SWCNTs has been presented.

Hydrocortisone Infusion Exerts Dose- and Sex-Dependent Effects on Attention to Emotional Stimuli

ERIC Educational Resources Information Center

Breitberg, Alaina; Drevets, Wayne C.; Wood, Suzanne E.; Mah, Linda; Schulkin, Jay; Sahakian, Barbara J.; Erickson, Kristine

2013-01-01

Glucocorticoid administration has been shown to exert complex effects on cognitive and emotional processing. In the current study we investigated the effects of glucocorticoid administration on attention towards emotional words, using an Affective Go/No-go task on which healthy humans have shown an attentional bias towards positive as compared to…

The Effectiveness of the Dramatic Activities in the Development of the Oral Performance Skills of Prep Students in English

ERIC Educational Resources Information Center

Zayed, Jihan El-Sayed Ahmed

2003-01-01

The goal of this study was to determine the effect of using some dramatic activities on developing the oral performance skills of second year prep school students in English. The dramatic activities included storytelling, story-acting, pantomime, puppetry, role-playing, reader's theater and choral reading. The oral performance skills were…

Natural Antioxidants: Multiple Mechanisms to Protect Skin From Solar Radiation

PubMed Central

Dunaway, Spencer; Odin, Rachel; Zhou, Linli; Ji, Liyuan; Zhang, Yuhang; Kadekaro, Ana L.

2018-01-01

Human skin exposed to solar ultraviolet radiation (UVR) results in a dramatic increase in the production of reactive oxygen species (ROS). The sudden increase in ROS shifts the natural balance toward a pro-oxidative state, resulting in oxidative stress. The detrimental effects of oxidative stress occur through multiple mechanisms that involve alterations to proteins and lipids, induction of inflammation, immunosuppression, DNA damage, and activation of signaling pathways that affect gene transcription, cell cycle, proliferation, and apoptosis. All of these alterations promote carcinogenesis and therefore, regulation of ROS levels is critical to the maintenance of normal skin homeostasis. Several botanical products have been found to exhibit potent antioxidant capacity and the ability to counteract UV-induced insults to the skin. These natural products exert their beneficial effects through multiple pathways, including some known to be negatively affected by solar UVR. Aging of the skin is also accelerated by UVR exposure, in particular UVA rays that penetrate deep into the epidermis and the dermis where it causes the degradation of collagen and elastin fibers via oxidative stress and activation of matrix metalloproteinases (MMPs). Because natural compounds are capable of attenuating some of the UV-induced aging effects in the skin, increased attention has been generated in the area of cosmetic sciences. The focus of this review is to cover the most prominent phytoproducts with potential to mitigate the deleterious effects of solar UVR and suitability for use in topical application. PMID:29740318

Quantification of transcription factor-DNA binding affinity in a living cell

PubMed Central

Belikov, Sergey; Berg, Otto G.; Wrange, Örjan

2016-01-01

The apparent dissociation constant (Kd) for specific binding of glucocorticoid receptor (GR) and androgen receptor (AR) to DNA was determined in vivo in Xenopus oocytes. The total nuclear receptor concentration was quantified as specifically retained [3H]-hormone in manually isolated oocyte nuclei. DNA was introduced by nuclear microinjection of single stranded phagemid DNA, chromatin is then formed during second strand synthesis. The fraction of DNA sites occupied by the expressed receptor was determined by dimethylsulphate in vivo footprinting and used for calculation of the receptor-DNA binding affinity. The forkhead transcription factor FoxA1 enhanced the DNA binding by GR with an apparent Kd of ∼1 μM and dramatically stimulated DNA binding by AR with an apparent Kd of ∼0.13 μM at a composite androgen responsive DNA element containing one FoxA1 binding site and one palindromic hormone receptor binding site known to bind one receptor homodimer. FoxA1 exerted a weak constitutive- and strongly cooperative DNA binding together with AR but had a less prominent effect with GR, the difference reflecting the licensing function of FoxA1 at this androgen responsive DNA element. PMID:26657626

Sex and the shifting biodiversity dynamics of marine animals in deep time

NASA Astrophysics Data System (ADS)

Bush, Andrew M.; Hunt, Gene; Bambach, Richard K.

2016-12-01

The fossil record of marine animals suggests that diversity-dependent processes exerted strong control on biodiversification: after the Ordovician Radiation, genus richness did not trend for hundreds of millions of years. However, diversity subsequently rose dramatically in the Cretaceous and Cenozoic (145 million years ago-present), indicating that limits on diversification can be overcome by ecological or evolutionary change. Here, we show that the Cretaceous-Cenozoic radiation was driven by increased diversification in animals that transfer sperm between adults during fertilization, whereas animals that broadcast sperm into the water column have not changed significantly in richness since the Late Ordovician (˜450 million years ago). We argue that the former group radiated in part because directed sperm transfer permits smaller population sizes and additional modes of prezygotic isolation, as has been argued previously for the coincident radiation of angiosperms. Directed sperm transfer tends to co-occur with many ecological traits, such as a predatory lifestyle. Ecological specialization likely operated synergistically with mode of fertilization in driving the diversification that began during the Mesozoic marine revolution. Plausibly, the ultimate driver of diversification was an increase in food availability, but its effects on the fauna were regulated by fundamental reproductive and ecological traits.

Effects of restructuring of international trade on changing energy use patterns and CO{sub 2} emissions in Taiwan: 1981-1991

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

Chia-Yon Chen; Rong-Hwa Wu

1995-12-31

Over the past two decades, as a result of the increasing complexity of world-wide economic developments, many countries have experienced dramatical changes in energy use patterns which in turn have affected the associated CO{sub 2} emission patterns. This is especially true with the major economic restructuring now underway in Taiwan. The Taiwan economy is highly export-oriented and trade-dependent. However, owing to the persistent trade surplus with its trading partners over the past years, The Taiwan economy was confronted with two phenomenon, namely, escalating excess savings and mounting trade surpluses. The latter exerted a great degree of upward pressure on themore » New Taiwan dollar. Furthermore, since the turn of the 80s, Taiwan is no longer a labor-surplus economy and wages have been on the rise, thereby blunting the competitive edge of its exports. Taiwan lost its comparative advantage in low-cost labor-intensive products to other emerging developing countries. To cope with the problems, the government has dedicated itself to a program of reorientation of trade policy, economic restructuring, and expansion of domestic demand.« less

Oxytocin, Motivation and the Role of Dopamine

PubMed Central

Love, Tiffany M.

2013-01-01

The hypothalamic neuropeptide oxytocin has drawn the attention of scientists for more than a century. The understanding of the function of oxytocin has expanded dramatically over the years from a simple peptide adept at inducing uterine contractions and milk ejection to a complex neuromodulator with a capacity to shape human social behavior. Decades of research have outlined oxytocin’s ability to enhance intricate social activities ranging from pair bonding, sexual activity, affiliative preferences, and parental behaviors. The precise neural mechanisms underlying oxytocin’s influence on such behaviors have just begun to be understood. Research suggests that oxytocin interacts closely with the neural pathways responsible for processing motivationally relevant stimuli. In particular, oxytocin appears to impact dopaminergic activity within the mesocorticolimbic dopamine system, which is crucial not only for reward and motivated behavior but also for the expression of affiliative behaviors. Though most of the work performed in this area has been done using animal models, several neuroimaging studies suggest similar relationships may be observed in humans. In order to introduce this topic further, this paper will review the recent evidence that oxytocin may exert some of its social-behavioral effects through its impact on motivational networks. PMID:23850525

Overturn of the proposed alcohol advertising ban in Lithuania.

PubMed

Paukštė, Ernesta; Liutkutė, Vaida; Stelemėkas, Mindaugas; Goštautaitė Midttun, Nijolė; Veryga, Aurelijus

2014-05-01

In response to the dramatic increase in alcohol-related problems in Lithuania, policy measures, including alcohol advertising and availability restrictions combined with taxation increase, were implemented in 2007-08. Simultaneously, a full alcohol advertising ban was adopted to take effect from 1 January 2012. Therefore, the alcohol industry responded with extensive lobbying aiming to revoke this ban, and ultimately they succeeded at the end of December 2011. To document and analyse actions of stakeholders and events during the alcohol advertising ban cancellation process in Lithuania. Policy analysis includes a development of event time-line, description of key stakeholders' actions and a review of policy context. The alcohol industry in Lithuania used similar tactics as the tobacco industry globally, such as creating strong and diverse opposing groups. The industry successfully exerted pressure to change alcohol control legislation, while non-governmental organizations had the important role of a watchdog, blunting industry's efforts. Unequal power distribution made it difficult to withstand combined local and international lobbying to cancel the ban. Given the global nature of the alcohol industry, there is a need for international regulation to limit the influence of vested interests on national lawmaking. © 2014 Society for the Study of Addiction.

The up-regulation of miR-300 in gastric cancer and its effects on cells malignancy

PubMed Central

Shen, Zhen; Li, Chunsheng; Zhang, Kai; Yu, Wei; Xiao, Huijie; Li, Bo; Liu, Tongjun

2015-01-01

Objective: In this study, we investigated the role of miR-300 in regulating cell proliferation and invasion of gastric cancer cells. Methods: MicroRNA and protein expression patterns were compared between gastric cancer tissue and normal tissue and between two different prognostic groups. The up-regulation of miR-300 was confirmed by real-time reverse transcription polymerase chain reaction and its expression was analyzed in AGS gastric cancer cells. Results: We observed that miR-300 expression was frequently and dramatically up-regulated in human gastric cancer tissues and cell lines compared with the matched adjacent normal tissues and cells. We further showed that transient and stable over-expression of miR-300 could promote cell proliferation and cell cycle progression. Moreover, p53, a key inhibitor of cell cycle, was verified as a direct target of miR-300, suggesting that miR-300 might promote gastric cancer cell proliferation and invasion by increasing p53 expression. Conclusion: Our findings indicated that miR-300 up-regulation might exert some sort of antagonistic function by targeting p53 in gastric cancer cell proliferation during gastric tumorigenesis. PMID:26221215

The up-regulation of miR-300 in gastric cancer and its effects on cells malignancy.

PubMed

Shen, Zhen; Li, Chunsheng; Zhang, Kai; Yu, Wei; Xiao, Huijie; Li, Bo; Liu, Tongjun

2015-01-01

In this study, we investigated the role of miR-300 in regulating cell proliferation and invasion of gastric cancer cells. MicroRNA and protein expression patterns were compared between gastric cancer tissue and normal tissue and between two different prognostic groups. The up-regulation of miR-300 was confirmed by real-time reverse transcription polymerase chain reaction and its expression was analyzed in AGS gastric cancer cells. We observed that miR-300 expression was frequently and dramatically up-regulated in human gastric cancer tissues and cell lines compared with the matched adjacent normal tissues and cells. We further showed that transient and stable over-expression of miR-300 could promote cell proliferation and cell cycle progression. Moreover, p53, a key inhibitor of cell cycle, was verified as a direct target of miR-300, suggesting that miR-300 might promote gastric cancer cell proliferation and invasion by increasing p53 expression. Our findings indicated that miR-300 up-regulation might exert some sort of antagonistic function by targeting p53 in gastric cancer cell proliferation during gastric tumorigenesis.

Sex and the shifting biodiversity dynamics of marine animals in deep time

PubMed Central

Bush, Andrew M.; Hunt, Gene; Bambach, Richard K.

2016-01-01

The fossil record of marine animals suggests that diversity-dependent processes exerted strong control on biodiversification: after the Ordovician Radiation, genus richness did not trend for hundreds of millions of years. However, diversity subsequently rose dramatically in the Cretaceous and Cenozoic (145 million years ago–present), indicating that limits on diversification can be overcome by ecological or evolutionary change. Here, we show that the Cretaceous–Cenozoic radiation was driven by increased diversification in animals that transfer sperm between adults during fertilization, whereas animals that broadcast sperm into the water column have not changed significantly in richness since the Late Ordovician (∼450 million years ago). We argue that the former group radiated in part because directed sperm transfer permits smaller population sizes and additional modes of prezygotic isolation, as has been argued previously for the coincident radiation of angiosperms. Directed sperm transfer tends to co-occur with many ecological traits, such as a predatory lifestyle. Ecological specialization likely operated synergistically with mode of fertilization in driving the diversification that began during the Mesozoic marine revolution. Plausibly, the ultimate driver of diversification was an increase in food availability, but its effects on the fauna were regulated by fundamental reproductive and ecological traits. PMID:27821755

Houttuynia cordata Facilitates Metformin on Ameliorating Insulin Resistance Associated with Gut Microbiota Alteration in OLETF Rats.

PubMed

Wang, Jing-Hua; Bose, Shambhunath; Lim, Soo-Kyoung; Ansari, AbuZar; Chin, Young-Won; Choi, Han Seok; Kim, Hojun

2017-09-22

Metformin and Houttuynia cordata are representative anti-diabetic therapeutics in western and oriental medicine, respectively. The current study examined the synergistic anti-diabetic effect of Houttuynia cordata extraction (HCE) and metformin combination in Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Fecal microbiota were analyzed by denaturing gradient gel electrophoresis (DGGE) and real-time PCR. Combining HCE + metformin resulted in significantly ameliorated glucose tolerance (oral glucose tolerance test (OGTT))-the same as metformin alone. Particularly, results of the insulin tolerance test (ITT) showed that combining HCE + metformin dramatically improved insulin sensitivity as compared to metformin treatment alone. Both fecal and serum endotoxin, as well as cytokines (tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6)) were significantly ameliorated by HCE + metformin compared to metformin alone. Meanwhile, the activation of AMPK (adenosine monophosphate-activated protein kinase) by metformin was distinctly enhanced by HCE. Both of HCE and metformin evidently changed the gut microbiota composition, causing the alteration of bacterial metabolite, like short-chain fatty acids. H. cordata , together with metformin, exerts intensive sensibilization to insulin; the corresponding mechanisms are associated with alleviation of endotoxemia via regulation of gut microbiota, particularly Roseburia , Akkermansia , and Gram-negative bacterium.

Houttuynia cordata Facilitates Metformin on Ameliorating Insulin Resistance Associated with Gut Microbiota Alteration in OLETF Rats

PubMed Central

Bose, Shambhunath; Lim, Soo-Kyoung; Ansari, AbuZar; Chin, Young-Won; Choi, Han Seok; Kim, Hojun

2017-01-01

Metformin and Houttuynia cordata are representative anti-diabetic therapeutics in western and oriental medicine, respectively. The current study examined the synergistic anti-diabetic effect of Houttuynia cordata extraction (HCE) and metformin combination in Otsuka Long–Evans Tokushima Fatty (OLETF) rats. Fecal microbiota were analyzed by denaturing gradient gel electrophoresis (DGGE) and real-time PCR. Combining HCE + metformin resulted in significantly ameliorated glucose tolerance (oral glucose tolerance test (OGTT))—the same as metformin alone. Particularly, results of the insulin tolerance test (ITT) showed that combining HCE + metformin dramatically improved insulin sensitivity as compared to metformin treatment alone. Both fecal and serum endotoxin, as well as cytokines (tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6)) were significantly ameliorated by HCE + metformin compared to metformin alone. Meanwhile, the activation of AMPK (adenosine monophosphate-activated protein kinase) by metformin was distinctly enhanced by HCE. Both of HCE and metformin evidently changed the gut microbiota composition, causing the alteration of bacterial metabolite, like short-chain fatty acids. H. cordata, together with metformin, exerts intensive sensibilization to insulin; the corresponding mechanisms are associated with alleviation of endotoxemia via regulation of gut microbiota, particularly Roseburia, Akkermansia, and Gram-negative bacterium. PMID:28937612

Alkylating chemotherapy may exert a uniquely deleterious effect upon neo-antigen-targeting anticancer vaccination

PubMed Central

Litterman, Adam J; Dudek, Arkadiusz Z; Largaespada, David A

2013-01-01

Alkylating chemotherapy exerts both antineoplastic and immunostimulatory effects. However, in addition to depleting regulatory T cells (Treg), alkylating agents also mediate a long lasting antiproliferative effect on responder lymphocytes. Our recent findings indicate that this antiproliferative effect profoundly impairs vaccination-induced immune responses, especially in the case of vaccines that target specific tumor-associated neo-antigens that do not require Treg depletion. PMID:24251080

Effect of Carbohydrate Ingestion on Ratings of Perceived Exertion during a Marathon.

ERIC Educational Resources Information Center

Utter, Alan C.; Kang, Jie; Robertson, Robert J.; Nieman, David C.; Chaloupka, Edward C.; Suminski, Richard R.; Piccinni, Cristiana R.

2002-01-01

Investigated the effects of carbohydrate substrate availability on ratings of perceived exertion (RPE) and hormonal regulation during a competitive marathon. Data on marathon runners randomly assigned to receive carbohydrate or placebo indicated that those who ingested carbohydrate rather than placebo beverages were able to run at a higher…

Immunomodulatory effects of endogenous and synthetic peptides activating opioid receptors.

PubMed

Pomorska, Dorota K; Gach, Katarzyna; Janecka, Anna

2014-01-01

The main role of endogenous opioid peptides is the modulation of pain. Opioid peptides exert their analgesic activity by binding to the opioid receptors distributed widely in the central nervous system (CNS). However, opioid receptors are also found on tissues and organs outside the CNS, including the cells of the immune system, indicating that opioids are capable of exerting additional effects in periphery. Morphine, which is a gold standard in the treatment of chronic pain, is well-known for its immunosuppressive effects. Much less is known about the immunomodulatory effects exerted by endogenous (enkephalins, endorphins, dynorphins and endomorphins) and synthetic peptides activating opioid receptors. In this review we tried to summarize opioid peptide-mediated modulation of immune cell functions which can be stimulatory as well as inhibitory.

Ecological effects of particulate matter.

PubMed

Grantz, D A; Garner, J H B; Johnson, D W

2003-06-01

Atmospheric particulate matter (PM) is a heterogeneous material. Though regulated as un-speciated mass, it exerts most effects on vegetation and ecosystems by virtue of the mass loading of its chemical constituents. As this varies temporally and spatially, prediction of regional impacts remains difficult. Deposition of PM to vegetated surfaces depends on the size distribution of the particles and, to a lesser extent, on the chemistry. However, chemical loading of an ecosystem may be determined by the size distribution as different constituents dominate different size fractions. Coating with dust may cause abrasion and radiative heating, and may reduce the photosynthetically active photon flux reaching the photosynthetic tissues. Acidic and alkaline materials may cause leaf surface injury while other materials may be taken up across the cuticle. A more likely route for metabolic uptake and impact on vegetation and ecosystems is through the rhizosphere. PM deposited directly to the soil can influence nutrient cycling, especially that of nitrogen, through its effects on the rhizosphere bacteria and fungi. Alkaline cation and aluminum availability are dependent upon the pH of the soil that may be altered dramatically by deposition of various classes of PM. A regional effect of PM on ecosystems is linked to climate change. Increased PM may reduce radiation interception by plant canopies and may reduce precipitation through a variety of physical effects. At the present time, evidence does not support large regional threats due to un-speciated PM, though site-specific and constituent-specific effects can be readily identified. Interactions of PM with other pollutants and with components of climate change remain important areas of research in assessment of challenges to ecosystem stability.

Invited review: heat stress effects during late gestation on dry cows and their calves.

PubMed

Tao, S; Dahl, G E

2013-07-01

In dairy cattle, late gestation is a critical period for fetal growth and physiological transition into the next lactation. Environmental factors, such as temperature and light, exert dramatic effects on the production, health, and well-being of animals during this period and after parturition. The aim of this review was to introduce effects of heat stress during late gestation on dairy cattle, and discuss the biological mechanisms that underlie the observed production and health responses in the dam and her fetus. Relative to cooled cows, cows that are heat stressed during late gestation have impaired mammary growth before parturition and decreased milk production in the subsequent lactation. In response to higher milk yield, cows cooled prepartum undergo a series of homeorhetic adaptations in early lactation to meet higher demand for milk synthesis compared with heat-stressed cows, but no direct effect of environmental heat stress on metabolism exists during the dry period. Prepartum cooling improves immune status of transition cows and evidence suggests that altered prolactin signaling in immune cells mediates the effects of heat stress on immune function. Late-gestation heat stress compromises placental development, which results in fetal hypoxia, malnutrition, and eventually fetal growth retardation. Maternal heat stress may also have carryover effects on the postnatal growth of offspring, but direct evidence is still lacking. Emerging evidence suggests that offspring from prepartum heat-stressed cows have compromised passive immunity and impaired cell-mediated immune function compared with those from cooled cows. Copyright © 2013 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Habitual exercise program protects murine intestinal, skeletal, and cardiac muscles against aging.

PubMed

Rosa, Eloi F; Silva, Antonio C; Ihara, Silvia S M; Mora, Oswaldo A; Aboulafia, Jeannine; Nouailhetas, Viviane L A

2005-10-01

Aging and aerobic exercise are two conditions known to interfere with health and quality of life, most likely by inducing oxidative stress to the organism. We studied the effects of aging on the morphological and functional properties of skeletal, cardiac, and intestinal muscles and their corresponding oxidative status in C57BL/6 mice and investigated whether a lifelong moderate exercise program would exert a protective effect against some deleterious effects of aging. As expected, aged animals presented a significant reduction of physical performance, accompanied by a decrease of gastrocnemius cross-sectional area and cardiac hypertrophy. However, most interesting was that aging dramatically interfered with the intestinal structure, causing a significant thickening of the ileum muscular layer. Senescent intestinal myocytes displayed many mitochondria with disorganized cristae and the presence of cytosolic lamellar corpuscles. Lipid peroxidation of ileum and gastrocnemius muscle, but not of the heart, increased in aged mice, thus suggesting enhanced oxidative stress. With exception of the intestinal muscle responsiveness, animals submitted to a daily session of 60 min, 5 days/wk, at 13 up to 21 m/min of moderate running in treadmill during animal life span exhibited a reversion of all the observed aging effects on intestinal, skeletal, and heart muscles. The introduction of this lifelong exercise protocol prevented the enhancement of lipid peroxidation and sarcopenia and also preserved cellular and ultracellular structures of the ileum. This is the first time that the protective effect of a lifelong regular aerobic physical activity against the deleterious effects of aging on intestinal muscle was demonstrated.

Exertional heat illness: emerging concepts and advances in prehospital care.

PubMed

Pryor, Riana R; Roth, Ronald N; Suyama, Joe; Hostler, David

2015-06-01

Exertional heat illness is a classification of disease with clinical presentations that are not always diagnosed easily. Exertional heat stroke is a significant cause of death in competitive sports, and the increasing popularity of marathons races and ultra-endurance competitions will make treating many heat illnesses more common for Emergency Medical Services (EMS) providers. Although evidence is available primarily from case series and healthy volunteer studies, the consensus for treating exertional heat illness, coupled with altered mental status, is whole body rapid cooling. Cold or ice water immersion remains the most effective treatment to achieve this goal. External thermometry is unreliable in the context of heat stress and direct internal temperature measurement by rectal or esophageal probes must be used when diagnosing heat illness and during cooling. With rapid recognition and implementation of effective cooling, most patients suffering from exertional heat stroke will recover quickly and can be discharged home with instructions to rest and to avoid heat stress and exercise for a minimum of 48 hours; although, further research pertaining to return to activity is warranted.

Influence of ambient music on perceived exertion during a pulmonary rehabilitation session: a randomized crossover study.

PubMed

Reychler, Gregory; Mottart, Florian; Boland, Maelle; Wasterlain, Emmanuelle; Pieters, Thierry; Caty, Gilles; Liistro, Giuseppe

2015-05-01

Pulmonary rehabilitation is a key element in the treatment of COPD. Music has been shown to have a positive effect on parameters related to a decrease in exercise tolerance. The aim of this study was to evaluate the effect of listening to ambient music on perceived exertion during a pulmonary rehabilitation session for COPD subjects. COPD subjects randomly performed a session of pulmonary rehabilitation with or without ambient music. Perceived exertion (Borg scales), anxiety (Hospital Anxiety and Depression Scale-Anxiety Subscale), dyspnea (visual analog scale), and cardiorespiratory parameters were compared at the end of both sessions. Forty-one subjects were analyzed. The characteristics of the COPD subjects were as follows: age, 70.5 ± 8.4 y; body mass index, 22.7 ± 3.9 kg/m(2); and FEV1, 38.6 ± 12.5 % predicted. Perceived exertion was not modified by ambient music, but anxiety was improved (P = .02). Dyspnea, fatigue and cardiorespiratory parameters were not influenced by music during a typical session of the pulmonary rehabilitation program. This study demonstrates that perceived exertion during one pulmonary rehabilitation session was not influenced by ambient music. However, a positive effect on anxiety was observed. (ClinicalTrials.gov registration NCT01833260.). Copyright © 2015 by Daedalus Enterprises.

The effect of bracing availability on one-hand isometric force exertion capability.

PubMed

Jones, Monica L H; Reed, Matthew P; Chaffin, Don B

2013-01-01

Environmental obstructions that workers encounter can kinematically limit the postures that they can achieve. However, such obstructions can also provide an opportunity for additional support by bracing with the hand, thigh or other body part. The reaction forces on bracing surfaces, which are in addition to those acting at the feet and task hand, are hypothesised to improve force exertion capability, and become required inputs to biomechanical analysis of tasks with bracing. The effects of kinematic constraints and associated bracing opportunities on isometric hand force were quantified in a laboratory study of 22 men and women. Analyses of one-hand maximal push, pull and lift tasks demonstrated that bracing surfaces available at the thighs and non-task hand enabled participants to exert an average of 43% more force at the task hand. Task hand force direction deviated significantly from the nominal direction for exertions performed with bracing at both medium and low task hand locations. This study quantifies the effect of bracing on kinematically constrained force exertions. Knowledge that appropriate bracing surfaces can substantially increase hand force is critical to the evaluation of task-oriented strength capability. Force estimates may also involve large off-axis components, which have clear implications for ergonomic analyses of manual tasks.

Microbial bioreporters of trace explosives.

PubMed

Shemer, Benjamin; Koshet, Ori; Yagur-Kroll, Sharon; Belkin, Shimshon

2017-06-01

Since its introduction as an explosive in the late 19th century, 2,4,6-trinitrotoluene (TNT), along with other explosive compounds, has left numerous environmental marks. One of these is widespread soil and water pollution by trace explosives in military proving grounds, manufacturing facilities, or actual battlefields. Another dramatic impact is that exerted by the millions of landmines and other explosive devices buried in large parts of the world, causing extensive loss of life, injuries, and economical damage. In this review we highlight recent advances in the design and construction of microbial bioreporters, molecularly engineered to generate a quantifiable dose-dependent signal in the presence of trace amounts of explosives. Such sensor strains may be employed for monitoring environmental pollution as well as for the remote detection of buried landmines. Copyright © 2017 Elsevier Ltd. All rights reserved.

The impact of transposable elements on mammalian development

PubMed Central

Garcia-Perez, Jose L.; Widmann, Thomas J.; Adams, Ian R.

2018-01-01

Summary Despite often being classified as selfish or junk DNA, transposable elements (TEs) are a group of abundant genetic sequences that significantly impact on mammalian development and genome regulation. In recent years, our understanding of how pre-existing TEs affect genome architecture, gene regulatory networks and protein function during mammalian embryogenesis has dramatically expanded. In addition, the mobilization of active TEs in selected cell types has been shown to generate genetic variation during development and in fully differentiated tissues. Importantly, the ongoing domestication and evolution of TEs appears to provide a rich source of regulatory elements, functional modules and genetic variation that fuels the evolution of mammalian developmental processes. Here, we review the functional impact that TEs exert on mammalian developmental processes and how the somatic activity of TEs can influence gene regulatory networks. PMID:27875251

First demonstration of gold nanorods-mediated photodynamic therapeutic destruction of tumors via near infra-red light activation.

PubMed

Vankayala, Raviraj; Huang, Yu-Kuan; Kalluru, Poliraju; Chiang, Chi-Shiun; Hwang, Kuo Chu

2014-04-24

Previously, a large volume of papers reports that gold nanorods (Au NRs) are able to effectively kill cancer cells upon high laser doses (usually 808 nm, 1-48 W/cm²) irradiation, leading to hyperthermia-induced destruction of cancer cells, i.e, photothermal therapy (PTT) effects. Combination of Au NRs-mediated PTT and organic photosensitizers-mediated photodynamic therapy (PDT) were also reported to achieve synergistic PTT and PDT effects on killing cancer cells. Herein, we demonstrate for the first time that Au NRs alone can sensitize formation of singlet oxygen (¹O₂) and exert dramatic PDT effects on complete destrcution of tumors in mice under very low LED/laser doses of single photon NIR (915 nm, <130 mW/cm²) light excitation. By changing the NIR light excitation wavelengths, Au NRs-mediated phototherapeutic effects can be switched from PDT to PTT or combination of both. Both PDT and PTT effects were confirmed by measurements of reactive oxygen species (ROS) and heat shock protein (HSP 70), singlet oxygen sensor green (SOSG) sensing, and sodium azide quenching in cellular experiments. In vivo mice experiments further show that the PDT effect via irradiation of Au NRs by 915 nm can destruct the B16F0 melanoma tumor in mice far more effectively than doxorubicin (a clinically used anti-cancer drug) as well as the PTT effect (via irradiation of Au NRs by 780 nm light). In addition, we show that Au NRs can emit single photon-induced fluorescence to illustrate their in vivo locations/distribution. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Amino acids as central synaptic transmitters or modulators in mammalian thermoregulation

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

Bligh, J.

1981-11-01

Of the amino acids that affect the activity of central neurons, aspartate and glutamate (which exert generally excitatory influences) and glycine, taurine, and ..gamma..-aminobutyric acid (GABA) (which generally exert inhibitory influences) are the strongest neurotransmitter candidates. As with other putative transmitter substances, their effects on body temperature when injected into the cerebral ventricles or the preoptic hypothalamus tend to vary within and between species. These effects are uninterpretable without accompanying information regarding effector activity changes and the influences of dose and ambient temperature. Observations necessary for analysis of apparent action have been made in studies of the effects of intracerebroventricularmore » injections of these amino acids into sheep. Aspartate and glutamate have similar excitatory effects on the pathway from cold sensors, whereas taurine and GABA exert inhibitory influences on the neural pathways that activate both heat production and heat loss effectors. Glycine appears to be without effect.« less

Diverse effects of crop distribution and climate change on crop production in the agro-pastoral transitional zone of China

NASA Astrophysics Data System (ADS)

Qiao, Jianmin; Yu, Deyong; Wang, Qianfeng; Liu, Yupeng

2018-06-01

Both crop distribution and climate change are important drivers for crop production and can affect food security, which is an important requirement for sustainable development. However, their effects on crop production are confounded and warrant detailed investigation. As a key area for food production that is sensitive to climate change, the agro-pastoral transitional zone (APTZ) plays a significant role in regional food security. To investigate the respective effects of crop distribution and climate change on crop production, the well-established GIS-based Environmental Policy Integrated Climate (EPIC) model was adopted with different scenario designs in this study. From 1980 to 2010, the crop distribution for wheat, maize, and rice witnessed a dramatic change due to agricultural policy adjustments and ecological engineering-related construction in the APTZ. At the same time, notable climate change was observed. The simulation results indicated that the climate change had a positive impact on the crop production of wheat, maize, and rice, while the crop distribution change led to an increase in the production of maize and rice, but a decrease in the wheat production. Comparatively, crop distribution change had a larger impact on wheat (-1.71 × 106 t) and maize (8.53 × 106 t) production, whereas climate change exerted a greater effect on rice production (0.58 × 106 t), during the period from 1980 to 2010 in the APTZ. This study is helpful to understand the mechanism of the effects of crop distribution and climate change on crop production, and aid policy makers in reducing the threat of future food insecurity.

Diverse effects of crop distribution and climate change on crop production in the agro-pastoral transitional zone of China

NASA Astrophysics Data System (ADS)

Qiao, Jianmin; Yu, Deyong; Wang, Qianfeng; Liu, Yupeng

2017-07-01

Both crop distribution and climate change are important drivers for crop production and can affect food security, which is an important requirement for sustainable development. However, their effects on crop production are confounded and warrant detailed investigation. As a key area for food production that is sensitive to climate change, the agro-pastoral transitional zone (APTZ) plays a significant role in regional food security. To investigate the respective effects of crop distribution and climate change on crop production, the well-established GIS-based Environmental Policy Integrated Climate (EPIC) model was adopted with different scenario designs in this study. From 1980 to 2010, the crop distribution for wheat, maize, and rice witnessed a dramatic change due to agricultural policy adjustments and ecological engineering-related construction in the APTZ. At the same time, notable climate change was observed. The simulation results indicated that the climate change had a positive impact on the crop production of wheat, maize, and rice, while the crop distribution change led to an increase in the production of maize and rice, but a decrease in the wheat production. Comparatively, crop distribution change had a larger impact on wheat (-1.71 × 106 t) and maize (8.53 × 106 t) production, whereas climate change exerted a greater effect on rice production (0.58 × 106 t), during the period from 1980 to 2010 in the APTZ. This study is helpful to understand the mechanism of the effects of crop distribution and climate change on crop production, and aid policy makers in reducing the threat of future food insecurity.

Thiamet G mediates neuroprotection in experimental stroke by modulating microglia/macrophage polarization and inhibiting NF-κB p65 signaling.

PubMed

He, Yating; Ma, Xiaofeng; Li, Daojing; Hao, Junwei

2017-08-01

Inflammatory responses are accountable for secondary injury induced by acute ischemic stroke (AIS). Previous studies indicated that O-GlcNAc modification (O-GlcNAcylation) is involved in the pathology of AIS, and increase of O-GlcNAcylation by glucosamine attenuated the brain damage after ischemia/reperfusion. Inhibition of β-N-acetylglucosaminidase (OGA) with thiamet G (TMG) is an alternative option for accumulating O-GlcNAcylated proteins. In this study, we investigate the neuroprotective effect of TMG in a mouse model of experimental stroke. Our results indicate that TMG administration either before or after middle cerebral artery occlusion (MCAO) surgery dramatically reduced infarct volume compared with that in untreated controls. TMG treatment ameliorated the neurological deficits and improved clinical outcomes in neurobehavioral tests by modulating the expression of pro-inflammatory and anti-inflammatory cytokines. Additionally, TMG administration reduced the number of Iba1 + cells in MCAO mice, decreased expression of the M1 markers, and increased expression of the M2 markers in vivo. In vitro, M1 polarization of BV2 cells was inhibited by TMG treatment. Moreover, TMG decreased the expression of iNOS and COX2 mainly by suppressing NF-κB p65 signaling. These results suggest that TMG exerts a neuroprotective effect and could be useful as an anti-inflammatory agent for ischemic stroke therapy.

Physiotherapy intervention as a complementary treatment for people living with HIV/AIDS

PubMed Central

Pullen, Sara D; Chigbo, Nnenna Nina; Nwigwe, Emmanuel Chukwudi; Chukwuka, Chinwe J; Amah, Christopher Chim; Idu, Stanley C

2014-01-01

Background The advent of highly active antiretroviral therapy has dramatically extended the life expectancy of people living with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome. Despite this increased longevity, HIV disease and its pharmacological treatment can cause long-term and acute health complications, many of which can be treated successfully by physiotherapy. The purpose of this paper is to report the effect of a 12-week rehabilitation program on several health-related markers in a 43-year-old woman living with HIV. Methods This case study examined the effect of a 12-week exercise and manual therapy intervention on morphology, pain, cardiopulmonary fitness, strength, neurological balance, immune markers (CD4 cell count), and quality of life in a 43-year-old woman living with HIV. Results The results showed complete elimination of pain and shortness of breath on exertion. There was also a reduction in resting heart rate, waist circumference, exercise duration, muscle strength, and endurance. The patient showed an increase in peak expiratory flow rate, maximal heart rate attained, upper arm, forearm, and thigh circumference, and CD4+ cell count. The patient also showed improvements in the quality of life domains of general health, pain, energy/fatigue, social and physical functioning, and emotional well-being. Conclusion Physiotherapy interventions consisting of exercise and manual therapy appear beneficial in several areas as an adjunct therapy in HIV management. PMID:24936132

Adsorption/desorption of linear alkylbenzenesulfonate (LAS) and azoproteins by/from activated sludge flocs.

PubMed

Conrad, A; Cadoret, A; Corteel, P; Leroy, P; Block, J-C

2006-01-01

Our study investigated the adsorption/desorption by/from activated sludge flocs, dispersed in river water or in diluted wastewater, of organic compounds (C(11)-LAS, azoalbumin and azocasein) at concentrations relevant to environmental conditions. Activated sludge flocs, used as a model of biological aggregates, are characterized by a very heterogeneous matrix able to sorb the three organic compounds tested at 4 degrees C. The adsorbed amount of C(11)-LAS by activated sludge flocs was higher than that of azocasein or azoalbumin, as shown by the Freundlich parameters (K(ads)=8.6+/-1.7, 1.6+/-0.3 and 0.3+/-0.1 micromol(1-1/n)g(-1)l(1/n) for C(11)-LAS, azocasein and azoalbumin, respectively; n=3 sludges). C(11)-LAS sorption from activated sludge appeared to be partially reversible in river water, while a marked hysteresis phenomenon was observed for azocasein and azoalbumin, implying a low degree of reversibility in their exchange between activated sludge and river water. It has also been displayed that the conductivity variation of bulk water (comprised between 214 and 838 microS cm(-1)) exerted no dramatic effect on the C(11)-LAS desorption from activated sludge flocs, while a little effect of it on azocasein desorption was observed. Thus, biological aggregates as activated sludge flocs can serve as an intermediate carrier for C(11)-LAS, while it represents a sink for proteins.

Arachidonic Acid Stress Impacts Pneumococcal Fatty Acid Homeostasis

PubMed Central

Eijkelkamp, Bart A.; Begg, Stephanie L.; Pederick, Victoria G.; Trapetti, Claudia; Gregory, Melissa K.; Whittall, Jonathan J.; Paton, James C.; McDevitt, Christopher A.

2018-01-01

Free fatty acids hold dual roles during infection, serving to modulate the host immune response while also functioning directly as antimicrobials. Of particular importance are the long chain polyunsaturated fatty acids, which are not commonly found in bacterial organisms, that have been proposed to have antibacterial roles. Arachidonic acid (AA) is a highly abundant long chain polyunsaturated fatty acid and we examined its effect upon Streptococcus pneumoniae. Here, we observed that in a murine model of S. pneumoniae infection the concentration of AA significantly increases in the blood. The impact of AA stress upon the pathogen was then assessed by a combination of biochemical, biophysical and microbiological assays. In vitro bacterial growth and intra-macrophage survival assays revealed that AA has detrimental effects on pneumococcal fitness. Subsequent analyses demonstrated that AA exerts antimicrobial activity via insertion into the pneumococcal membrane, although this did not increase the susceptibility of the bacterium to antibiotic, oxidative or metal ion stress. Transcriptomic profiling showed that AA treatment also resulted in a dramatic down-regulation of the genes involved in fatty acid biosynthesis, in addition to impacts on other metabolic processes, such as carbon-source utilization. Hence, these data reveal that AA has two distinct mechanisms of perturbing the pneumococcal membrane composition. Collectively, this work provides a molecular basis for the antimicrobial contribution of AA to combat pneumococcal infections. PMID:29867785

The Effectiveness of a 6-Week Intervention Program Aimed at Modifying Running Style in Patients With Chronic Exertional Compartment Syndrome: Results From a Series of Case Studies.

PubMed

Helmhout, Pieter H; Diebal, Angela R; van der Kaaden, Lisanne; Harts, Chris C; Beutler, Anthony; Zimmermann, Wes O

2015-03-01

Previous studies have reported on the promising effects of changing running style in patients with chronic exertional compartment syndrome (CECS) using a 6-week training program aimed at adopting a forefoot strike technique. This study expands that work by comparing a 6-week in-house, center-based run training program with a less extensive, supervised, home-based run training program (50% home training). An alteration in running technique will lead to improvements in CECS complaints and running performance, with the less supervised program producing less dramatic results. Cohort study; Level of evidence, 3. Nineteen patients with CECS were prospectively enrolled. Postrunning intracompartmental pressure (ICP), run performance, and self-reported questionnaires were taken for all patients at baseline and after 6 weeks of running intervention. Questionnaires were also taken from 14 patients (7 center-based, 6 home-based) 4 months posttreatment. Significant improvement between preintervention and postintervention rates was found for running distance (43%), ICP values (36%), and scores on the questionnaires Single Assessment Numeric Evaluation (SANE; 36%), Lower Leg Outcome Survey (LLOS; 18%), and Patient Specific Complaints (PSC; 60%). The mean posttreatment score on the Global Rating of Change (GROC) was between +4 and +5 ("somewhat better" to "moderately better"). In 14 participants (74%), no elevation of pain was reported posttreatment, compared with 3 participants (16%) at baseline; in all these cases, the running test was aborted because of a lack of cardiorespiratory fitness. Self-reported scores continued to improve 4 months after the end of the intervention program, with mean improvement rates of 48% (SANE), 26% (LLOS), and 81% (PSC). The mean GROC score improved to +6 points ("a great deal better"). In 19 patients diagnosed with CECS, a 6-week forefoot running intervention performed in both a center-based and home-based training setting led to decreased postrunning lower leg ICP values, improved running performances, and self-assessed leg condition. The influence of training group was not statistically significant. Overall, this is a promising finding, taking into consideration the significantly reduced investments in time and resources needed for the home-based program.

Adenosine monophosphate-activated protein kinase attenuates cardiomyocyte hypertrophy through regulation of FOXO3a/MAFbx signaling pathway.

PubMed

Chen, Baolin; Wu, Qiang; Xiong, Zhaojun; Ma, Yuedong; Yu, Sha; Chen, Dandan; Huang, Shengwen; Dong, Yugang

2016-09-01

Control of cardiac muscle mass is thought to be determined by a dynamic balance of protein synthesis and degradation. Recent studies have demonstrated that atrophy-related forkhead box O 3a (FOXO3a)/muscle atrophy F-box (MAFbx) signaling pathway plays a central role in the modulation of proteolysis and exert inhibitory effect on cardiomyocyte hypertrophy. In this study, we tested the hypothesis that adenosine monophosphate-activated protein kinase (AMPK) activation attenuates cardiomyocyte hypertrophy by regulating FOXO3a/MAFbx signaling pathway and its downstream protein degradation. The results showed that activation of AMPK with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) attenuated cardiomyocyte hypertrophy induced by angiotensin II (Ang II). The antihypertrophic effects of AICAR were blunted by AMPK inhibitor Compound C. In addition, AMPK dramatically increased the activity of transcription factor FOXO3a, up-regulated the expression of its downstream ubiquitin ligase MAFbx, and enhanced cardiomyocyte proteolysis. Meanwhile, the effects of AMPK on protein degradation and cardiomyocyte hypertrophy were blocked after MAFbx was silenced by transfection of cardiomyocytes with MAFbx-siRNA. These results indicate that AMPK plays an important role in the inhibition of cardiomyocyte hypertrophy by activating protein degradation via FOXO3a/MAFbx signaling pathway. © The Author 2016. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Evaluating the biological risk of functionalized multiwalled carbon nanotubes and functionalized oxygen-doped multiwalled carbon nanotubes as possible toxic, carcinogenic, and embryotoxic agents

PubMed Central

Lara-Martínez, Luis A; Massó, Felipe; Palacios González, Eduardo; García-Peláez, Isabel; Contreras–Ramos, Alejandra; Valverde, Mahara; Rojas, Emilio; Cervantes-Sodi, Felipe; Hernández-Gutiérrez, Salomón

2017-01-01

Carbon nanotubes (CNTs) have been a focus of attention due to their possible applications in medicine, by serving as scaffolds for cell growth and proliferation and improving mesenchymal cell transplantation and engraftment. The emphasis on the benefits of CNTs has been offset by the ample debate on the safety of nanotechnologies. In this study, we determine whether functionalized multiwalled CNTs (fMWCNTs) and functionalized oxygen-doped multiwalled CNTs (fCOxs) have toxic effects on rat mesenchymal stem cells (MSCs) in vitro by analyzing morphology and cell proliferation and, using in vivo models, whether they are able to transform MSCs in cancer cells or induce embryotoxicity. Our results demonstrate that there are statistically significant differences in cell proliferation and the cell cycle of MSCs in culture. We identified dramatic changes in cells that were treated with fMWCNTs. Our evaluation of the transformation to cancer cells and cytotoxicity process showed little effect. However, we found a severe embryotoxicity in chicken embryos that were treated with fMWCNTs, while fCOxs seem to exert cardioembryotoxicity and a discrete teratogenicity. Furthermore, it seems that the time of contact plays an important role during cell transformation and embryotoxicity. A single contact with fMWCNTs is not sufficient to transform cells in a short time; an exposure of fMWCNTs for 2 weeks led to cell transformation risk and cardioembryotoxicity effects. PMID:29089764

The effect of sulforaphane on histone deacetylase activity in keratinocytes: differences between in vitro and in vivo analyses

PubMed Central

Dickinson, Sally E.; Rusche, Jadrian J.; Bec, Sergiu L.; Horn, David J.; Janda, Jaroslav; Rim, So Hyun; Smith, Catharine L.; Bowden, G. Timothy

2015-01-01

Sulforaphane is a natural product found in broccoli which is known to exert many different molecular effects in the cell, including inhibition of histone deacetylase (HDAC) enzymes. Here we examine for the first time the potential for sulforaphane to inhibit HDACs in HaCaT keratinocytes and compare our results with those found using HCT116 colon cancer cells. Significant inhibition of HDAC activity in HCT116 nuclear extracts required prolonged exposure to sulforaphane in the presence of serum. Under the same conditions HaCaT nuclear extracts did not exhibit reduced HDAC activity with sulforaphane treatment. Both cell types displayed down-regulation of HDAC protein levels by sulforaphane treatment. Despite these reductions in HDAC family member protein levels, acetylation of marker proteins (acetylated Histone H3, H4 and tubulin) was decreased by sulforaphane treatment. Timecourse analysis revealed that HDAC6, HDAC3 and acetylated histone H3 protein levels are significantly inhibited as early as 6hr into sulforaphane treatment. Transcript levels of HDAC6 are also suppressed after 48hr of treatment. These results suggest that HDAC activity noted in nuclear extracts is not always translated as expected to target protein acetylation patterns, despite dramatic inhibition of some HDAC protein levels. In addition, our data suggest that keratinocytes are at least partially resistant to the nuclear HDAC inhibitory effects of sulforaphane which is exhibited in HCT116 and other cells. PMID:25307283

Evaluating the biological risk of functionalized multiwalled carbon nanotubes and functionalized oxygen-doped multiwalled carbon nanotubes as possible toxic, carcinogenic, and embryotoxic agents.

PubMed

Lara-Martínez, Luis A; Massó, Felipe; Palacios González, Eduardo; García-Peláez, Isabel; Contreras-Ramos, Alejandra; Valverde, Mahara; Rojas, Emilio; Cervantes-Sodi, Felipe; Hernández-Gutiérrez, Salomón

2017-01-01

Carbon nanotubes (CNTs) have been a focus of attention due to their possible applications in medicine, by serving as scaffolds for cell growth and proliferation and improving mesenchymal cell transplantation and engraftment. The emphasis on the benefits of CNTs has been offset by the ample debate on the safety of nanotechnologies. In this study, we determine whether functionalized multiwalled CNTs (fMWCNTs) and functionalized oxygen-doped multiwalled CNTs (fCOxs) have toxic effects on rat mesenchymal stem cells (MSCs) in vitro by analyzing morphology and cell proliferation and, using in vivo models, whether they are able to transform MSCs in cancer cells or induce embryotoxicity. Our results demonstrate that there are statistically significant differences in cell proliferation and the cell cycle of MSCs in culture. We identified dramatic changes in cells that were treated with fMWCNTs. Our evaluation of the transformation to cancer cells and cytotoxicity process showed little effect. However, we found a severe embryotoxicity in chicken embryos that were treated with fMWCNTs, while fCOxs seem to exert cardioembryotoxicity and a discrete teratogenicity. Furthermore, it seems that the time of contact plays an important role during cell transformation and embryotoxicity. A single contact with fMWCNTs is not sufficient to transform cells in a short time; an exposure of fMWCNTs for 2 weeks led to cell transformation risk and cardioembryotoxicity effects.

Anti-biofouling property studies on carboxyl-modified multi-walled carbon nanotubes filled PDMS nanocomposites.

PubMed

Sun, Yuan; Zhang, Zhizhou

2016-09-01

Polydimethylsiloxane (PDMS) with exceptional fouling-release properties is extremely susceptible to the microfouling resulted from the colonization of the pioneer microorganisms in the marine environment. In this study, six carboxyl-modified multi-walled carbon nanotubes (cMWNTs) nanoparticles were incorporated into the PDMS matrix, respectively, in order to produce the cMWNTs-filled PDMS nanocomposites (CPs) with improved antifouling (AF) properties. The AF properties of the six CPs were examined via the field assays conducted in Weihai, China. The effects of the anti-biofouling potential of the CPs (i.e. the P3 surface) on the colonization of the pioneer prokaryotic and eukaryotic microbes were investigated using the single-stranded conformation polymorphism technique via the comparison of the diversity indices. Different CPs have displayed differential and better AF properties as compared to that of the unfilled PDMS (P0). The P3 surface has exhibited exceptional anti-biofouling capacity compared with the other CPs surfaces, which can effectively prevent biofouling for more than 14 weeks in the field. The SSCP analysis revealed that the P3 surface may have significant modulating effect on the pioneer microbial communities. The pioneer eukaryotic microbes seemed more susceptible than the pioneer prokaryotic microbes to be subjected to the major perturbations exerted by the P3 surface. The dramatically reduced eukaryotic-microbial diversity may contribute to the impeding and weakening of the development and growth of the biofilm. The P3 surface has the potential to be used for future maritime applications.

[Analysis on occupational exposure levels and control effectiveness of dust in cement production line of new dry method].

PubMed

Wang, De-jun; Sui, Shao-feng; Kong, Fan-ling; Huang, Dong-hai

2012-11-01

To investigate the occupational exposure levels of dust in new suspension preheated dry process (NSP) cement production line and put forward rectification measures for dust-exposed posts, and to provide ideas for the modern cement production enterprises in dust control and occupational health management. Occupational health field investigation combined with field test were used to measure the time-weighted average concentration (C(TWA)) of the dust in the workplace. Rectification measures were taken for the dust-exposed posts with unqualified dust concentration, and the protective effects of dustproof facilities in the rectified workplace were evaluated. The field investigation revealed incompletely closed dustproof facilities, improperly set dust hoods, excess of dust leakage points, and other problems in the dust-exposed posts of an NSP cement production line before rectification, and the dustproof facilities could hardly exert dust removal effect. The field test showed that the vast majority of dust-exposed posts had the dust concentrations exceeding the occupational exposure limits (OELs), with a qualified rate as low as 31.8%. A series of rectification measures were taken for these posts. After the rectification, the dust-exposed posts demonstrated dramatically dropped C(TWA), and the qualified rate of dust concentration in the dust-exposed posts rose to 90.9%. The dust hazards in NSP cement production line cannot be ignored. Taking appropriate protective measures are critical for curbing dust hazards in modern cement production.

Severe mammal declines coincide with proliferation of invasive Burmese pythons in Everglades National Park

USGS Publications Warehouse

Dorcas, Michael E.; Wilson, John D.; Reed, Robert N.; Snow, Ray W.; Rochford, Michael R.; Miller, Melissa A.; Meshaka, Walter E.; Andreadis, Paul T.; Mazzotti, Frank J.; Romagosa, Christina M.; Hart, Kristen M.

2012-01-01

Invasive species represent a significant threat to global biodiversity and a substantial economic burden. Burmese pythons, giant constricting snakes native to Asia, now are found throughout much of southern Florida, including all of Everglades National Park (ENP). Pythons have increased dramatically in both abundance and geographic range since 2000 and consume a wide variety of mammals and birds. Here we report severe apparent declines in mammal populations that coincide temporally and spatially with the proliferation of pythons in ENP. Before 2000, mammals were encountered frequently during nocturnal road surveys within ENP. In contrast, road surveys totaling 56,971 km from 2003–2011 documented a 99.3% decrease in the frequency of raccoon observations, decreases of 98.9% and 87.5% for opossum and bobcat observations, respectively, and failed to detect rabbits. Road surveys also revealed that these species are more common in areas where pythons have been discovered only recently and are most abundant outside the python's current introduced range. These findings suggest that predation by pythons has resulted in dramatic declines in mammals within ENP and that introduced apex predators, such as giant constrictors, can exert significant top-down pressure on prey populations. Severe declines in easily observed and/or common mammals, such as raccoons and bobcats, bode poorly for species of conservation concern, which often are more difficult to sample and occur at lower densities.

Dramatic Developments in the Neurosciences Challenge Educators.

ERIC Educational Resources Information Center

Sylwester, Robert

1986-01-01

Recent dramatic developments in brain research and technology suggest that a comprehensive understanding of how the human brain works may soon be within reach. Just as the ability of the medical profession to treat patients improved dramatically with the advent of effective research skills and technology concerning the structure, biochemistry, and…

Effect of aspirin on acute changes in peripheral arterial stiffness and endothelial function following exertional heat stress in firefighters: The factorial group results of the Enhanced Firefighter Rehab Trial.

PubMed

Olafiranye, Oladipupo; Hostler, David; Winger, Daniel G; Wang, Li; Reis, Steven E

2015-06-01

Peripheral arterial stiffness and endothelial function, which are independent predictors of cardiac events, are abnormal in firefighters. We examined the effects of aspirin on peripheral arterial stiffness and endothelial function in firefighters. Fifty-two firefighters were randomized to receive daily 81 mg aspirin or placebo for 14 days before treadmill exercise in thermal protection clothing, and a single dose of 325 mg aspirin or placebo immediately following exertion. Peripheral arterial augmentation index adjusted for a heart rate of 75 (AI75) and reactive hyperemia index (RHI) were determined immediately before, and 30, 60, and 90 minutes after exertion. Low-dose aspirin was associated with lower AI75 (-15.25±9.25 vs -8.08±10.70, p=0.014) but not RHI. On repeated measures analysis, treatment with low-dose aspirin before, but not single-dose aspirin after exertion, was associated with lower AI75 following exertional heat stress (p=0.018). Low-dose aspirin improved peripheral arterial stiffness and wave reflection but not endothelial function in firefighters. © The Author(s) 2015.

Caffeine and theanine exert opposite effects on attention under emotional arousal.

PubMed

Giles, Grace E; Mahoney, Caroline R; Brunyé, Tad T; Taylor, Holly A; Kanarek, Robin B

2017-01-01

Tea is perceived as more relaxing than coffee, even though both contain caffeine. L-theanine in tea may account for the difference. Consumed together, caffeine and theanine exert similar cognitive effects to that of caffeine alone, but exert opposite effects on arousal, in that caffeine accentuates and theanine mitigates physiological and felt stress responses. We evaluated whether caffeine and theanine influenced cognition under emotional arousal. Using a double-blind, repeated-measures design, 36 participants received 4 treatments (200 mg caffeine + 0 mg theanine, 0 mg caffeine + 200 mg theanine, 200 mg caffeine + 200 mg theanine, 0 mg caffeine + 0 mg theanine) on separate days. Emotional arousal was induced by highly arousing negative film clips and pictures. Mood, salivary cortisol, and visual attention were evaluated. Caffeine accentuated global processing of visual attention on the hierarchical shape task (p < 0.05), theanine accentuated local processing (p < 0.05), and the combination did not differ from placebo. Caffeine reduced flanker conflict difference scores on the Attention Network Test (p < 0.05), theanine increased difference scores (p < 0.05), and the combination did not differ from placebo. Thus, under emotional arousal, caffeine and theanine exert opposite effects on certain attentional processes, but when consumed together, they counteract the effects of each other.

Enhancement of arachidonic acid signaling pathway by nicotinic acid receptor HM74A

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

Tang, Yuting; Zhou, Lubing; Gunnet, Joseph W.

2006-06-23

HM74A is a G protein-coupled receptor for nicotinic acid (niacin), which has been used clinically to treat dyslipidemia for decades. The molecular mechanisms whereby niacin exerts its pleiotropic effects on lipid metabolism remain largely unknown. In addition, the most common side effect in niacin therapy is skin flushing that is caused by prostaglandin release, suggesting that the phospholipase A{sub 2} (PLA{sub 2})/arachidonic acid (AA) pathway is involved. Various eicosanoids have been shown to activate peroxisome-proliferator activated receptors (PPAR) that play a diverse array of roles in lipid metabolism. To further elucidate the potential roles of HM74A in mediating the therapeuticmore » effects and/or side effects of niacin, we sought to explore the signaling events upon HM74A activation. Here we demonstrated that HM74A synergistically enhanced UTP- and bradykinin-mediated AA release in a pertussis toxin-sensitive manner in A431 cells. Activation of HM74A also led to Ca{sup 2+}-mobilization and enhanced bradykinin-promoted Ca{sup 2+}-mobilization through Gi protein. While HM74A increased ERK1/2 activation by the bradykinin receptor, it had no effects on UTP-promoted ERK1/2 activation.Furthermore, UTP- and bradykinin-mediated AA release was significantly decreased in the presence of both MAPK kinase inhibitor PD 098059 and PKC inhibitor GF 109203X. However, the synergistic effects of HM74A were not dramatically affected by co-treatment with both inhibitors, indicating the cross-talk occurred at the receptor level. Finally, stimulation of A431 cells transiently transfected with PPRE-luciferase with AA significantly induced luciferase activity, mimicking the effects of PPAR{gamma} agonist rosiglitazone, suggesting that alteration of AA signaling pathway can regulate gene expression via endogenous PPARs.« less

The effects of a picosecond pulsed electric field on angiogenesis in the cervical cancer xenograft models.

PubMed

Wu, Limei; Yao, Chenguo; Xiong, Zhengai; Zhang, Ruizhe; Wang, Zhiliang; Wu, Yutong; Qin, Qin; Hua, Yuanyuan

2016-04-01

The application of picosecond pulsed electric field (psPEF) is a new biomedical engineering technique used in cancer therapy. However, its effects on cervical cancer angiogenesis are not clear. Therefore, the aim of the present study is to investigate the effects of psPEF on angiogenesis in cervical cancer xenograft models. Xenograft tumors were created by subcutaneously inoculating nude mice (athymic BALB/c nu/nu mice) with HeLa cells, then were placed closely between tweezer-type plate electrodes and subjected to psPEF with a gradually increased electric field intensity (0kV/cm, 50kV/cm, 60kV/cm, 70kV/cm). The direct effect on tumor tissue was observed by hematoxylin and eosin (H&E) staining and transmission electron microscopy (TEM). The changes of blood vessels and oxygen saturation (sO2) of tumors were monitored in vivo by photoacoustic tomography (PAT). The microvessel density (MVD), vascular endothelial growth factor (VEGF) and hypoxia-inducible transcription factors (HIF-1α and HIF-2α) were detected by immunohistochemical technique (IHC). Their protein expressions and gene transcription levels were evaluated using western blot (WB) and quantitative reverse transcription and polymerase chain reaction (RT-PCR). PsPEF induced obvious necrosis of cervical cancer tissue; with the increasing of electric field intensity, the MVD, vascular PA signal and sO2 values declined significantly. The protein expression and gene transcription levels of VEGF, HIF1α and HIF2α were significantly decreased at the same time. PsPEF exhibited dramatic anti-tumor and anti-angiogenesis effects in cervical cancer xenograft models by exerting direct effect on cancer cells and vascular endothelial cells and indirect effect on tumor angiogenesis-related factors. Copyright © 2016 Elsevier Inc. All rights reserved.

Effect of Stimulant Medication Use by Children with ADHD on Heart Rate and Perceived Exertion

ERIC Educational Resources Information Center

Mahon, Anthony D.; Woodruff, Megan E.; Horn, Mary P.; Marjerrison, Andrea D.; Cole, Andrew S.

2012-01-01

The effect of stimulant medication use by children with attention deficit/hyperactivity disorder (ADHD) on the rating of perceived exertion (RPE)--heart rate (HR) relationship was examined. Children with ADHD (n = 20; 11.3 [plus or minus] 1.8 yrs) and children without ADHD (n = 25; 11.2 [plus or minus] 2.1 yrs) were studied. Children with ADHD…

Self-selected music-induced reduction of perceived exertion during moderate-intensity exercise does not interfere with post-exercise improvements in inhibitory control.

PubMed

Tanaka, Daichi; Tsukamoto, Hayato; Suga, Tadashi; Takenaka, Saki; Hamaoka, Takafumi; Hashimoto, Takeshi; Isaka, Tadao

2018-05-26

Acute aerobic exercise improves inhibitory control (IC). This improvement is often associated with increases in perceived exertion during exercise. However, listening to music during aerobic exercise mitigates an exercise-induced increase in perceived exertion. Thus, it is hypothesized that such effects of music may interfere with exercise-induced improvements in IC. To test this hypothesis, we examined the effect of music on post-exercise IC improvements that were induced by moderate-intensity exercise. Fifteen healthy young men performed cycle ergometer exercise with music or non-music. The exercise was performed using a moderate-intensity of 60% of VO 2 peak for 30 min. The music condition was performed while listening to self-selected music. The non-music condition involved no music. To evaluate IC, the Stroop task was administered before exercise, immediately after exercise, and during the 30-min post-exercise recovery period. The rate of perceived exertion immediately before moderate-intensity exercise completed was significantly lower in music condition than in non-music condition. The IC significantly improved immediately after exercise and during the post-exercise recovery period compared to before exercise in both music and non-music conditions. The post-exercise IC improvements did not significantly differ between the two conditions. These findings indicate that self-selected music-induced mitigation of the increase in perceived exertion during moderate-intensity exercise dose not interfere with exercise-induced improvements in IC. Therefore, we suggest that listening to music may be a beneficial strategy in mitigating the increase in perceived exertion during aerobic exercise without decreasing the positive effects on IC. Copyright © 2018 Elsevier Inc. All rights reserved.

Dramatics in the Classroom: Making Lessons Come Alive. Fastback 70.

ERIC Educational Resources Information Center

Kelly, Elizabeth Flory

The contents of this booklet focus on effective techniques for using dramatics in the classroom and are based on the premise that drama can integrate all skills and help to avoid fragmentation in learning. Chapters discuss motivating the dreamers in the classroom, curriculum dramatics--eclectic teaching, training the teacher, transforming the…

Allosteric control in a metalloprotein dramatically alters function

PubMed Central

Baxter, Elizabeth Leigh; Zuris, John A.; Wang, Charles; Vo, Phu Luong T.; Axelrod, Herbert L.; Cohen, Aina E.; Paddock, Mark L.; Nechushtai, Rachel; Onuchic, Jose N.; Jennings, Patricia A.

2013-01-01

Metalloproteins (MPs) comprise one-third of all known protein structures. This diverse set of proteins contain a plethora of unique inorganic moieties capable of performing chemistry that would otherwise be impossible using only the amino acids found in nature. Most of the well-studied MPs are generally viewed as being very rigid in structure, and it is widely thought that the properties of the metal centers are primarily determined by the small fraction of amino acids that make up the local environment. Here we examine both theoretically and experimentally whether distal regions can influence the metal center in the diabetes drug target mitoNEET. We demonstrate that a loop (L2) 20 Å away from the metal center exerts allosteric control over the cluster binding domain and regulates multiple properties of the metal center. Mutagenesis of L2 results in significant shifts in the redox potential of the [2Fe-2S] cluster and orders of magnitude effects on the rate of [2Fe-2S] cluster transfer to an apo-acceptor protein. These surprising effects occur in the absence of any structural changes. An examination of the native basin dynamics of the protein using all-atom simulations shows that twisting in L2 controls scissoring in the cluster binding domain and results in perturbations to one of the cluster-coordinating histidines. These allosteric effects are in agreement with previous folding simulations that predicted L2 could communicate with residues surrounding the metal center. Our findings suggest that long-range dynamical changes in the protein backbone can have a significant effect on the functional properties of MPs. PMID:23271805

Differential anti-inflammatory and anti-oxidative effects of dexamethasone and N-acetylcysteine in endotoxin-induced lung inflammation

PubMed Central

Rocksén, D; Lilliehöök, B; Larsson, R; Johansson, T; Bucht, A

2000-01-01

Inhalation of bacterial endotoxin induces an acute inflammation in the lower respiratory tract. In this study, the anti-inflammatory effects of the anti-oxidant N-acetylcysteine (NAC) and the glucocorticoid dexamethasone were investigated in mice exposed to aerosolized endotoxin (lipopolysaccharide (LPS)). Powerful reduction of neutrophils in bronchoalveolar lavage fluid (BALF) was obtained by a single i.p. injection of dexamethasone (10 mg/kg), whereas treatment with NAC only resulted in reduction of neutrophils when administered at a high dose (500 mg/kg). Measurement of cytokine and chemokine expression in lung tissue revealed a significant decrease of tumour necrosis factor-alpha, IL-1α, IL-1β, IL-6, IL-12p40, and MIP-1α mRNA when mice where treated with dexamethasone but not when treated with NAC. Analysis of oxidative burst demonstrated a remarkable reduction of oxygen radicals in BALF neutrophils after treatment with dexamethasone, whereas the effect of NAC was not significantly different from that in untreated animals. In conclusion, dexamethasone exerted both anti-inflammatory and anti-oxidative effects in acute airway inflammation, probably by blocking early events in the inflammatory cascade. In contrast, treatment with NAC resulted in a weak reduction of the inflammatory response but no inhibition of proinflammatory cytokines or reduction of oxidative burst in neutrophils. These results demonstrate dramatic differences in efficiency and also indicate that the two drugs have different actions. Combined treatment with NAC and dexamethasone revealed an additive action but no synergy was observed. PMID:11091282

Low-Dose Curcumin Stimulates Proliferation, Migration and Phagocytic Activity of Olfactory Ensheathing Cells

PubMed Central

Tello Velasquez, Johana; Watts, Michelle E.; Todorovic, Michael; Nazareth, Lynnmaria; Pastrana, Erika; Diaz-Nido, Javier; Lim, Filip; Ekberg, Jenny A. K.; Quinn, Ronald J.; John, James A. St

2014-01-01

One of the promising strategies for neural repair therapies is the transplantation of olfactory ensheathing cells (OECs) which are the glial cells of the olfactory system. We evaluated the effects of curcumin on the behaviour of mouse OECs to determine if it could be of use to further enhance the therapeutic potential of OECs. Curcumin, a natural polyphenol compound found in the spice turmeric, is known for its anti-cancer properties at doses over 10 µM, and often at 50 µM, and it exerts its effects on cancer cells in part by activation of MAP kinases. In contrast, we found that low-dose curcumin (0.5 µM) applied to OECs strikingly modulated the dynamic morphology, increased the rate of migration by up to 4-fold, and promoted significant proliferation of the OECs. Most dramatically, low-dose curcumin stimulated a 10-fold increase in the phagocytic activity of OECs. All of these potently stimulated behavioural characteristics of OECs are favourable for neural repair therapies. Importantly, low-dose curcumin gave a transient activation of p38 kinases, which is in contrast to the high dose curcumin effects on cancer cells in which these MAP kinases tend to undergo prolonged activation. Low-dose curcumin mediated effects on OECs demonstrate cell-type specific stimulation of p38 and ERK kinases. These results constitute the first evidence that low-dose curcumin can modulate the behaviour of olfactory glia into a phenotype potentially more favourable for neural repair and thereby improve the therapeutic use of OECs for neural repair therapies. PMID:25360677

Strength capability while kneeling.

PubMed

Haslegrave, C M; Tracy, M F; Corlett, E N

1997-12-01

Work sometimes has to be carried out kneeling, particularly where jobs are performed in confined spaces as is common for miners, aircraft baggage handlers and maintenance workers. In order to assess the risks in performing forceful tasks under such conditions, data is needed on strength capabilities of kneeling subjects. A study was undertaken to measure isometric strength in single-handed exertions for male subjects and to investigate the effects on this of task layout factors (direction of force exertion, reach distance, height of the workpiece and orientation relative to the subject's sagittal plane). The data has been tabulated to show the degree to which strength may be reduced in different situations and analysis of the task factors showed their influence to be complex with direction of exertion and reach distance having the greatest effect. The results also suggest that exertions are weaker when subjects are kneeling on two knees than when kneeling on one knee, although this needs to be confirmed by direct experimental comparison.

The impact of transposable elements on mammalian development.

PubMed

Garcia-Perez, Jose L; Widmann, Thomas J; Adams, Ian R

2016-11-15

Despite often being classified as selfish or junk DNA, transposable elements (TEs) are a group of abundant genetic sequences that have a significant impact on mammalian development and genome regulation. In recent years, our understanding of how pre-existing TEs affect genome architecture, gene regulatory networks and protein function during mammalian embryogenesis has dramatically expanded. In addition, the mobilization of active TEs in selected cell types has been shown to generate genetic variation during development and in fully differentiated tissues. Importantly, the ongoing domestication and evolution of TEs appears to provide a rich source of regulatory elements, functional modules and genetic variation that fuels the evolution of mammalian developmental processes. Here, we review the functional impact that TEs exert on mammalian developmental processes and discuss how the somatic activity of TEs can influence gene regulatory networks. © 2016. Published by The Company of Biologists Ltd.

The need to increase awareness of the risk factors of COPD.

PubMed

Roche, Nicolas

2016-07-01

COPD is a heterogeneous disease responsible for a major burden on public and individual health. A wide variety of intrinsic and environmental risk factors are involved, and exert their influence at various time points during the life span of individuals. Knowledge of these factors is of utmost importance to develop appropriate screening and prevention programs, and may help improving the pathophysiological knowledge of the disease. Accordingly, there are multiple targets of information and education on risk factors for COPD, including the general population and patients, workers and employers, doctors and other healthcare professionals, researchers, policy-makers, payers, etc. Gender and socioeconomic factors need to be specifically considered. Importantly, it is likely that increasing the specific knowledge of COPD risk factors among the above-mentioned targets cannot not be obtained without increasing the general knowledge of COPD in the population, which at present is dramatically low.

Tumor morphology and phenotypic evolution driven by selective pressure from the microenvironment.

PubMed

Anderson, Alexander R A; Weaver, Alissa M; Cummings, Peter T; Quaranta, Vito

2006-12-01

Emergence of invasive behavior in cancer is life-threatening, yet ill-defined due to its multifactorial nature. We present a multiscale mathematical model of cancer invasion, which considers cellular and microenvironmental factors simultaneously and interactively. Unexpectedly, the model simulations predict that harsh tumor microenvironment conditions (e.g., hypoxia, heterogenous extracellular matrix) exert a dramatic selective force on the tumor, which grows as an invasive mass with fingering margins, dominated by a few clones with aggressive traits. In contrast, mild microenvironment conditions (e.g., normoxia, homogeneous matrix) allow clones with similar aggressive traits to coexist with less aggressive phenotypes in a heterogeneous tumor mass with smooth, noninvasive margins. Thus, the genetic make-up of a cancer cell may realize its invasive potential through a clonal evolution process driven by definable microenvironmental selective forces. Our mathematical model provides a theoretical/experimental framework to quantitatively characterize this selective pressure for invasion and test ways to eliminate it.

Ubiquitin-specific protease 11 (USP11) functions as a tumor suppressor through deubiquitinating and stabilizing VGLL4 protein

PubMed Central

Zhang, Encheng; Shen, Bing; Mu, Xingyu; Qin, Yan; Zhang, Fang; Liu, Yong; Xiao, Jiantao; Zhang, Pingzhao; Wang, Chenji; Tan, Mingyue; Fan, Yu

2016-01-01

VGLL4 is a transcriptional repressor that interacts with transcription factors TEADs and inhibits YAP-induced overgrowth and tumorigenesis. VGLL4 protein was dramatically reduced in various types of human cancers. But how VGLL4 protein is post-transcriptional regulated is poorly understood. In this study, we identify deubiquitinating enzyme USP11 as a novel VGLL4 interactor. We reveal that the USP domain of USP11 and the N-terminal region of VGLL4 are required for mutual binding. USP11 controls VGLL4 protein stability by promoting its deubiquitination. Furthermore, our results show that knockdown of USP11 promotes cell growth, migration, and invasion in a YAP-dependent manner. Together, our results suggest that USP11 may exert its tumor suppressor role by modulating VGLL4/YAP-TEADs regulatory loop. PMID:28042509

The Medicinal Rod: Slave Health and Redhibition Law in George Washington Cable's The Grandissimes.

PubMed

Chacón, Heather

The economic transactions and litigation necessary for slavery to function, coupled with the South's honor culture, meant skepticism and posturing frequently attended the buying and selling of enslaved people. This atmosphere provided opportunities for enslaved individuals familiar with the symbiotic ways their health and value intertwined to manipulate owners by feigning illness or adopting behaviors contrary to those of a "sound and sane" captive under Louisiana's redhibitory (slave warranty) law. Such actions offered a chance at preserving that which slavery denied its victims: proximity to family, a reduced chance of being sold, and an opportunity to exert agency within a strictly oppressive system. In dramatizing these paradoxes, George Washington Cable's The Grandissimes illustrates the vile hollowness of owners' paternalistic attitudes towards the enslaved, acknowledges the subjectivity and will of enslaved individuals, and castigates the return of slavery-like conditions in the form of the convict lease system.

Phase 9 Fiber Optic Cable Microbending and Temperature Cycling Tests

NASA Technical Reports Server (NTRS)

Abushagur, Mustafa A.G.; Huang, Po T.; Hand, Larry

1996-01-01

Optical fibers represent the back bone of the current communications networks. Their performance in the field lacks long term testing data because of the continuous evolution of the manufacturing of fibers and cables. An optical fiber cable that is installed in NASA's KSC has experienced a dramatic increase in attenuation after three years of use from 0.7 dB/km to 7 dB/km in some fibers. A thorough study is presented to assess the causes of such an attenuation increase. Material and chemical decomposition testing showed that there are no changes in the composition of the fiber which might have caused the increase in attenuation. Microbending and heat cycling tests were performed on the cable and individual fibers. It was found that the increase in attenuation is due to microbending caused by excessive stress exerted on the fibers. This was the result of manufacturing and installation irregularities.

Disrupting effects of polychlorinated biphenyls on gonadal development and reproductive functions in chickens.

PubMed

Zhang, Caiqiao; Fang, Changge; Liu, Li; Xia, Guoliang; Qiao, Huili

2002-01-01

Polychlorinated biphenyls (PCBs) are worldwide persistent pollutants that have produced detrimental effects on endocrine function and reproduction in a variety of species. The present study revealed effects of PCBs on gonadal development and functions in chickens of different ages. Aroclor 1254 (0-100 microg/egg) was injected into Hyline chicken eggs before incubation. The adult chickens received Aroclor 1254 by gavage (50 mg/kg BW). It was observed that in day 5 embryos, PCBs resulted in a dose-dependent decrease of primordial germ cell (PGC) numbers, and caused PGCs pyknosis and vacuolation. Clomiphen failed to block the effects of PCBs. In the newly hatched chicken, PCBs induced a marked decrease in area of the transverse sections, diameter and relative area of the testicular tubules. The differentiation of germ cells was retarded after PCB treatment. In contrast, the area of the left ovarian transverse sections, the thickness of ovarian cortex and the number of oocytes increased dramatically in the female chickens after PCB exposure. In the adult chickens, PCBs caused no significant changes in body weight, respiration, heart rate, body temperature, red and white blood cell number, but induced a marked decrease in the testicular weight, and severe damage of the seminiferous tubules. The number of the spermatogenic cells and serum testosterone level were decreased significantly by PCBs. On the contrary, in the laying hens there was no significant effect of PCB on egg quality except a slight decrease in egg weight. These results indicated that PCBs exerted its disrupting effects on chicken reproduction with a sex and stage-related pattern, and in vivo disruption of gonadal development represents a possible model for risk assessment of environmental endocrine disrupters by in ovo treatment.

Cylindrical effects on Richtmyer-Meshkov instability for arbitrary Atwood numbers in weakly nonlinear regime

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

Liu, W. H.; He, X. T.; LCP, Institute of Applied Physics and Computational Mathematics, Beijing 100088

2012-07-15

When an incident shock collides with a corrugated interface separating two fluids of different densities, the interface is prone to Richtmyer-Meshkov instability (RMI). Based on the formal perturbation expansion method as well as the potential flow theory, we present a simple method to investigate the cylindrical effects in weakly nonlinear RMI with the transmitted and reflected cylindrical shocks by considering the nonlinear corrections up to fourth order. The cylindrical results associated with the material interface show that the interface expression consists of two parts: the result in the planar system and that from the cylindrical effects. In the limit ofmore » the cylindrical radius tending to infinity, the cylindrical results can be reduced to those in the planar system. Our explicit results show that the cylindrical effects exert an inward velocity on the whole perturbed interface, regardless of bubbles or spikes of the interface. On the one hand, outgoing bubbles are constrained and ingoing spikes are accelerated for different Atwood numbers (A) and mode numbers k'. On the other hand, for ingoing bubbles, when |A|k'{sup 3/2} Less-Than-Or-Equivalent-To 1, bubbles are considerably accelerated especially at the small |A| and k'; otherwise, bubbles are decelerated. For outgoing spikes, when |A|k' Greater-Than-Or-Equivalent-To 1, spikes are dramatically accelerated especially at large |A| and k'; otherwise, spikes are decelerated. Furthermore, the cylindrical effects have a significant influence on the amplitudes of the ingoing spike and bubble for large k'. Thus, it should be included in applications where the cylindrical effects play a role, such as inertial confinement fusion ignition target design.« less

Influence of Layer Thickness, Raster Angle, Deformation Temperature and Recovery Temperature on the Shape-Memory Effect of 3D-Printed Polylactic Acid Samples

PubMed Central

Wu, Wenzheng; Ye, Wenli; Wu, Zichao; Geng, Peng; Wang, Yulei; Zhao, Ji

2017-01-01

The success of the 3D-printing process depends upon the proper selection of process parameters. However, the majority of current related studies focus on the influence of process parameters on the mechanical properties of the parts. The influence of process parameters on the shape-memory effect has been little studied. This study used the orthogonal experimental design method to evaluate the influence of the layer thickness H, raster angle θ, deformation temperature Td and recovery temperature Tr on the shape-recovery ratio Rr and maximum shape-recovery rate Vm of 3D-printed polylactic acid (PLA). The order and contribution of every experimental factor on the target index were determined by range analysis and ANOVA, respectively. The experimental results indicated that the recovery temperature exerted the greatest effect with a variance ratio of 416.10, whereas the layer thickness exerted the smallest effect on the shape-recovery ratio with a variance ratio of 4.902. The recovery temperature exerted the most significant effect on the maximum shape-recovery rate with the highest variance ratio of 1049.50, whereas the raster angle exerted the minimum effect with a variance ratio of 27.163. The results showed that the shape-memory effect of 3D-printed PLA parts depended strongly on recovery temperature, and depended more weakly on the deformation temperature and 3D-printing parameters. PMID:28825617

Pharmacodynamic studies of vancomycin, metronidazole and fusidic acid against Clostridium difficile.

PubMed

Odenholt, Inga; Walder, Mats; Wullt, Marlene

2007-01-01

Pharmacodynamic studies of antibiotics have attracted great interest in recent years. However, studies on the pharmacodynamics of different antibiotics against Clostridium difficile are scarce. The postantibiotic effects (PAE) and the postantibiotic sub-minimum inhibitory concentration (MIC) effects (PA SME) of vancomycin, metronidazole and fusidic acid were investigated by viable counts against three different strains of C. difficile. The killing rate and extent of the three antibiotics against the same strains were also studied by adding 2, 4, 8, 16 and 32x MIC of the three antibiotics, respectively. Metronidazole exerted a very rapid bactericidal effect at concentrations of 8x MIC and above against all three strains investigated. Vancomycin gave overall less kill in comparison to metronidazole and was bacteriostatic against two of the three strains. Fusidic acid exerted a concentration-dependent killing against two of the strains. Vancomycin exerted short PAEs and PA SMEs against all three strains. Significantly longer PAEs and PA SMEs were noted for fusidic acid. Metronidazole gave similar short PAEs like vancomycin but longer PA SMEs were noted against two of the investigated strains. Metronidazole exerted the most prominent bactericidal effect greater than fusidic acid and greater than vancomycin. Fusidic acid gave overall the longest PAEs and PA SMEs greater than metronidazole and greater than vancomycin. Copyright 2007 S. Karger AG, Basel.

Defining the Focus of Attention: Effects of Attention on Perceived Exertion and Fatigue

PubMed Central

Lohse, Keith R.; Sherwood, David E.

2011-01-01

This manuscript presents two experiments designed to explore the effects of attention on perceived exertion and time to failure in a fatiguing athletic task. There were two major motivating factors for these experiments. First, there are few studies evaluating attentional focus effects in endurance tasks and, second, there is a lack of integration between studies of attentional focus as external/internal (e.g., Wulf, 2007a) compared to associative/dissociative (e.g., Stevinson and Biddle, 1998). In Experiment 1, we used a fatiguing wall-sit posture (essentially a complex, isometric task) to compare two different types of external attention with an internal focus on the position of the legs. An external focus (regardless of type) increased the time taken to failure and reduced perceived exertion. In Experiment 2, we manipulated subjects’ expectancy of fatigue to test the interaction of attention and expectancy (both top-down factors) in this highly fatiguing task. Previous theories of attention during endurance tasks have suggested that as fatigue/pain increase, bottom-up factors begin to dominate subjects’ attention. While this may be true, Experiment 2 showed that even in a highly fatiguing task, attentional strategies, and expectancies affected the time to failure and perceived exertion. PMID:22102843

Reverse ego-depletion: Acts of self-control can improve subsequent performance in Indian cultural contexts.

PubMed

Savani, Krishna; Job, Veronika

2017-10-01

The strength model of self-control has been predominantly tested with people from Western cultures. The present research asks whether the phenomenon of ego-depletion generalizes to a culture emphasizing the virtues of exerting mental self-control in everyday life. A pilot study found that whereas Americans tended to believe that exerting willpower on mental tasks is depleting, Indians tended to believe that exerting willpower is energizing. Using dual task ego-depletion paradigms, Studies 1a, 1b, and 1c found reverse ego-depletion among Indian participants, such that participants exhibited better mental self-control on a subsequent task after initially working on strenuous rather than nonstrenuous cognitive tasks. Studies 2 and 3 found that Westerners exhibited the ego-depletion effect whereas Indians exhibited the reverse ego-depletion effect on the same set of tasks. Study 4 documented the causal effect of lay beliefs about whether exerting willpower is depleting versus energizing on reverse ego-depletion with both Indian and Western participants. Together, these studies reveal the underlying basis of the ego-depletion phenomenon in culturally shaped lay theories about willpower. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Design considerations for liposomal vaccines: Influence of formulation parameters on antibody and cell-mediated immune responses to liposome associated antigens

PubMed Central

Watson, Douglas S.; Endsley, Aaron N.; Huang, Leaf

2012-01-01

Liposomes (phospholipid bilayer vesicles) are versatile and robust delivery systems for induction of antibody and T lymphocyte responses to associated subunit antigens. In the last 15 years, liposome vaccine technology has matured and now several vaccines containing liposome-based adjuvants have been approved for human use or have reached late stages of clinical evaluation. Given the intensifying interest in liposome-based vaccines, it is important to understand precisely how liposomes interact with the immune system and stimulate immunity. It has become clear that the physicochemical properties of liposomal vaccines – method of antigen attachment, lipid composition, bilayer fluidity, particle charge, and other properties – exert dramatic effects on the resulting immune response. Here, we present a comprehensive review of the physicochemical properties of liposomal vaccines and how they influence immune responses. A discussion of novel and emerging immunomodulators that are suitable for inclusion in liposomal vaccines is also presented. Through a comprehensive analysis of the body of liposomal vaccine literature, we enumerate a series of principles that can guide the rational design of liposomal vaccines to elicit immune responses of a desired magnitude and quality. We also identify major unanswered questions in the field, pointing the direction for future study. PMID:22306376

BMI-1 Promotes Self-Renewal of Radio- and Temozolomide (TMZ)-Resistant Breast Cancer Cells.

PubMed

Yan, Yanfang; Wang, Ying; Zhao, Pengxin; Ma, Weiyuan; Hu, Zhigang; Zhang, Kaili

2017-12-01

Breast cancer is a hormone-dependent malignancy and is the most prevalent cause of cancer-related mortality among females. Radiation therapy and chemotherapy are common treatments of breast cancer. However, tumor relapse and metastasis following therapy are major clinical challenges. The importance of B-lymphoma Moloney murine leukemia virus insertion region-1 (BMI-1) was implicated in cell proliferation, stem cell maintenance, and tumor initiation. We established radio- and temozolomide (TMZ)-resistant (IRC-R) MCF-7 and MDA-MB-231 cell lines to investigate the mechanism involved in therapeutic resistance. Cell proliferation and sphere number were dramatically elevated, and BMI-1 was remarkably upregulated, in IRC-R cells compared to parental cells. Silencing BMI-1 by RNA interference only affected the cell proliferation of IRC-R but not parental cells, suggesting the critical role of BMI-1 in radio- and TMZ resistance. We used a xenograft mice model to elucidate that BMI-1 was necessary in tumor development by assessing tumor volume and Ki67 expression. We found that Hedgehog (Hhg) signaling exerted synergized functions together with BMI-1, implicating the importance of BMI-1 in Hhg signaling. Downregulation of BMI-1 could be an effective strategy to suppress tumor growth, which supports the potential clinical use of targeting BMI-1 in breast cancer treatment.

Response of rocky reef top predators (Serranidae: Epinephelinae) in and around marine protected areas in the Western Mediterranean Sea.

PubMed

Hackradt, Carlos Werner; García-Charton, José Antonio; Harmelin-Vivien, Mireille; Pérez-Ruzafa, Ángel; Le Diréach, Laurence; Bayle-Sempere, Just; Charbonnel, Eric; Ody, Denis; Reñones, Olga; Sanchez-Jerez, Pablo; Valle, Carlos

2014-01-01

Groupers species are extremely vulnerable to overfishing and many species are threatened worldwide. In recent decades, Mediterranean groupers experienced dramatic population declines. Marine protected areas (MPAs) can protect populations inside their boundaries and provide individuals to adjacent fishing areas through the process of spillover and larval export. This study aims to evaluate the effectiveness of six marine reserves in the Western Mediterranean Sea to protect the populations of three species of grouper, Epinephelus marginatus, Epinephelus costae and Mycteroperca rubra, and to understand in which circumstances MPAs are able to export biomass to neighbouring areas. All the studied MPAs, except one where no grouper was observed, were able to maintain high abundance, biomass and mean weight of groupers. Size classes were more evenly distributed inside than outside MPAs. In two reserves, biomass gradients could be detected through the boundaries of the reserve as an indication of spillover. In some cases, habitat structure appeared to exert a great influence on grouper abundance, biomass and mean individual weight, influencing the gradient shape. Because groupers are generally sedentary animals with a small home range, we suggest that biomass gradients could only occur where groupers attain sufficient abundance inside MPA limits, indicating a strongly density-dependent process.

Insulin protects against hepatic damage postburn.

PubMed

Jeschke, Marc G; Kraft, Robert; Song, Juquan; Gauglitz, Gerd G; Cox, Robert A; Brooks, Natasha C; Finnerty, Celeste C; Kulp, Gabriela A; Herndon, David N; Boehning, Darren

2011-01-01

Burn injury causes hepatic dysfunction associated with endoplasmic reticulum (ER) stress and induction of the unfolded protein response (UPR). ER stress/UPR leads to hepatic apoptosis and activation of the Jun-N-terminal kinase (JNK) signaling pathway, leading to vast metabolic alterations. Insulin has been shown to attenuate hepatic damage and to improve liver function. We therefore hypothesized that insulin administration exerts its effects by attenuating postburn hepatic ER stress and subsequent apoptosis. Male Sprague Dawley rats received a 60% total body surface area (TBSA) burn injury. Animals were randomized to receive saline (controls) or insulin (2.5 IU/kg q. 24 h) and euthanized at 24 and 48 h postburn. Burn injury induced dramatic changes in liver structure and function, including induction of the ER stress response, mitochondrial dysfunction, hepatocyte apoptosis, and up-regulation of inflammatory mediators. Insulin decreased hepatocyte caspase-3 activation and apoptosis significantly at 24 and 48 h postburn. Furthermore, insulin administration decreased ER stress significantly and reversed structural and functional changes in hepatocyte mitochondria. Finally, insulin attenuated the expression of inflammatory mediators IL-6, MCP-1, and CINC-1. Insulin alleviates burn-induced ER stress, hepatocyte apoptosis, mitochondrial abnormalities, and inflammation leading to improved hepatic structure and function significantly. These results support the use of insulin therapy after traumatic injury to improve patient outcomes.

Insulin Protects against Hepatic Damage Postburn

PubMed Central

Jeschke, Marc G; Kraft, Robert; Song, Juquan; Gauglitz, Gerd G; Cox, Robert A; Brooks, Natasha C; Finnerty, Celeste C; Kulp, Gabriela A; Herndon, David N; Boehning, Darren

2011-01-01

Burn injury causes hepatic dysfunction associated with endoplasmic reticulum (ER) stress and induction of the unfolded protein response (UPR). ER stress/UPR leads to hepatic apoptosis and activation of the Jun-N-terminal kinase (JNK) signaling pathway, leading to vast metabolic alterations. Insulin has been shown to attenuate hepatic damage and to improve liver function. We therefore hypothesized that insulin administration exerts its effects by attenuating postburn hepatic ER stress and subsequent apoptosis. Male Sprague Dawley rats received a 60% total body surface area (TBSA) burn injury. Animals were randomized to receive saline (controls) or insulin (2.5 IU/kg q. 24 h) and euthanized at 24 and 48 h postburn. Burn injury induced dramatic changes in liver structure and function, including induction of the ER stress response, mitochondrial dysfunction, hepatocyte apoptosis, and up-regulation of inflammatory mediators. Insulin decreased hepatocyte caspase-3 activation and apoptosis significantly at 24 and 48 h postburn. Furthermore, insulin administration decreased ER stress significantly and reversed structural and functional changes in hepatocyte mitochondria. Finally, insulin attenuated the expression of inflammatory mediators IL-6, MCP-1, and CINC-1. Insulin alleviates burn-induced ER stress, hepatocyte apoptosis, mitochondrial abnormalities, and inflammation leading to improved hepatic structure and function significantly. These results support the use of insulin therapy after traumatic injury to improve patient outcomes. PMID:21267509

The flavonoid fisetin promotes osteoblasts differentiation through Runx2 transcriptional activity.

PubMed

Léotoing, Laurent; Davicco, Marie-Jeanne; Lebecque, Patrice; Wittrant, Yohann; Coxam, Véronique

2014-06-01

Flavonoids represent a group of polyphenolic compounds commonly found in daily nutrition with proven health benefits. Among this group, the flavonol fisetin has been previously shown to protect bone by repressing osteoclast differentiation. In the present study, we investigated the role of fisetin in regulating osteoblasts physiology. In vivo mice treated with LPSs exhibited osteoporosis features associated with a dramatic repression of osteoblast marker expression. In this model, inhibition of osteocalcin and type I collagen alpha 1 transcription was partially countered by a daily consumption of fisetin. Interestingly, in vitro, fisetin promoted both osteoblast alkaline phosphatase activity and mineralization process. To decipher how fisetin may exert its positive effect on osteoblastogenesis, we analyzed its ability to control the runt-related transcription factor 2 (Runx2), a key organizer in developing and maturing osteoblasts. While fisetin did not impact Runx2 mRNA and protein levels, it upregulated its transcriptional activity. Actually, fisetin stimulated the luciferase activity of a reporter plasmid driven by the osteocalcin gene promoter that contains Runx2 binding sites and promoted the mRNA expression of osteocalcin and type I collagen alpha 1 targets. Bone sparing properties of fisetin also rely on its positive influence on osteoblast differentiation and activity. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Circular RNA circZFR contributes to papillary thyroid cancer cell proliferation and invasion by sponging miR-1261 and facilitating C8orf4 expression.

PubMed

Wei, Hong; Pan, Lin; Tao, Deyou; Li, Rongguo

2018-06-08

In recent years, more and more circular RNAs (circRNAs) have been identified in multiple tissues and cells. Increasing evidences show circRNAs play important roles in human cancers. However, the role of circRNAs in papillary thyroid carcinoma (PTC) remains largely unknown. In this study, we identified a new circRNA circZFR that was significantly upregulated in PTC tissues compared to adjacent normal tissues. Furthermore, circZFR expression level was negatively correlated with clinical severity. We found that circZFR knockdown dramatically inhibited the proliferation, migration and invasion of PTC cells in vitro. Mechanistically, we found circZFR could promote C8orf4 expression via serving as a competing endogenous RNA (ceRNA) of miR-1261 in PTC cells. Rescue assays indicated that restoration of C8orf4 significantly attenuated the inhibitory effects of circZFR knockdown on PTC cell proliferation, migration and invasion. In summary, our findings demonstrated that circRNA circZFR exerted oncogenic roles via regulating miR-1261/C8orf4 axis in PTC, which suggested circZFR might be a potential therapeutic target. Copyright © 2018 Elsevier Inc. All rights reserved.

A novel hydroxyapatite film coated with ionic silver via inositol hexaphosphate chelation prevents implant-associated infection

NASA Astrophysics Data System (ADS)

Funao, Haruki; Nagai, Shigenori; Sasaki, Aya; Hoshikawa, Tomoyuki; Tsuji, Takashi; Okada, Yasunori; Koyasu, Shigeo; Toyama, Yoshiaki; Nakamura, Masaya; Aizawa, Mamoru; Matsumoto, Morio; Ishii, Ken

2016-03-01

Various silver-coated implants have been developed to prevent implant-associated infections, and have shown dramatic effects in vitro. However, the in vivo results have been inconsistent. Recent in vitro studies showed that silver exerts antibacterial activity by mediating the generation of reactive oxygen species in the presence of oxygen. To maintain its antibacterial activity in vivo, the silver should remain in an ionic state and be stably bound to the implant surface. Here, we developed a novel bacteria-resistant hydroxyapatite film in which ionic silver is immobilized via inositol hexaphosphate chelation using a low-heat immersion process. This bacteria-resistant coating demonstrated significant antibacterial activity both in vitro and in vivo. In a murine bioluminescent osteomyelitis model, no bacteria were detectable 21 days after inoculation with S. aureus and placement of this implant. Serum interleukin-6 was elevated in the acute phase in this model, but it was significantly lower in the ionic-silver group than the control group on day 2. Serum C-reactive protein remained significantly higher in the control group than the ionic-silver group on day 14. Because this coating is produced by a low-heat immersion process, it can be applied to complex structures of various materials, to provide significant protection against implant-associated infections.

Formation and Structure of Calcium Carbonate Thin Films and Nanofibers Precipitated in the Presence of Poly(Allylamine Hydrochloride) and Magnesium Ions

PubMed Central

2013-01-01

That the cationic polyelectrolyte poly(allylamine hydrochloride) (PAH) exerts a significant influence on CaCO3 precipitation challenges the idea that only anionic additives have this effect. Here, we show that in common with anionic polyelectrolytes such as poly(aspartic acid), PAH supports the growth of calcite thin films and abundant nanofibers. While investigating the formation of these structures, we also perform the first detailed structural analysis of the nanofibers by transmission electron microscopy (TEM) and selected area electron diffraction. The nanofibers are shown to be principally single crystal, with isolated domains of polycrystallinity, and the single crystal structure is even preserved in regions where the nanofibers dramatically change direction. The formation mechanism of the fibers, which are often hundreds of micrometers long, has been the subject of intense speculation. Our results suggest that they form by aggregation of amorphous particles, which are incorporated into the fibers uniquely at their tips, before crystallizing. Extrusion of polymer during crystallization may inhibit particle addition at the fiber walls and result in local variations in the fiber nanostructure. Finally, we investigate the influence of Mg2+ on CaCO3 precipitation in the presence of PAH, which gives thinner and smoother films, together with fibers with more polycrystalline, granular structures. PMID:24489438

Formation and Structure of Calcium Carbonate Thin Films and Nanofibers Precipitated in the Presence of Poly(Allylamine Hydrochloride) and Magnesium Ions.

PubMed

Cantaert, Bram; Verch, Andreas; Kim, Yi-Yeoun; Ludwig, Henning; Paunov, Vesselin N; Kröger, Roland; Meldrum, Fiona C

2013-12-23

That the cationic polyelectrolyte poly(allylamine hydrochloride) (PAH) exerts a significant influence on CaCO 3 precipitation challenges the idea that only anionic additives have this effect. Here, we show that in common with anionic polyelectrolytes such as poly(aspartic acid), PAH supports the growth of calcite thin films and abundant nanofibers. While investigating the formation of these structures, we also perform the first detailed structural analysis of the nanofibers by transmission electron microscopy (TEM) and selected area electron diffraction. The nanofibers are shown to be principally single crystal, with isolated domains of polycrystallinity, and the single crystal structure is even preserved in regions where the nanofibers dramatically change direction. The formation mechanism of the fibers, which are often hundreds of micrometers long, has been the subject of intense speculation. Our results suggest that they form by aggregation of amorphous particles, which are incorporated into the fibers uniquely at their tips, before crystallizing. Extrusion of polymer during crystallization may inhibit particle addition at the fiber walls and result in local variations in the fiber nanostructure. Finally, we investigate the influence of Mg 2+ on CaCO 3 precipitation in the presence of PAH, which gives thinner and smoother films, together with fibers with more polycrystalline, granular structures.

Antitumor effects and persistence of a novel HER2 CAR T cells directed to gastric cancer in preclinical models

PubMed Central

Han, Yali; Liu, Chuanyong; Li, Guanhua; Li, Juan; Lv, Xingyan; Shi, Huan; Liu, Jie; Liu, Shuai; Yan, Peng; Wang, Shuyun; Sun, Yuping; Sun, Meili

2018-01-01

New immunotherapeutic approaches are urgently needed for gastric cancer due to its poor survival and unsatisfactory treatment. Here we applied the humanized chA21 scfv based chimeric antigen receptor (CAR) modified T cells approach to the HER2 overexpressing gastric cancer treatment. The chA21-4-1BBz CAR T cells specifically exerted Th1 skewed cytokine response and efficient cytolysis of HER2 overexpressing human gastric cancer cells in vitro. Both the cytokine production and cytotoxicity levels were correlated with the level of HER2 surface expression by tumor cells. In established subcutaneous xenograft and peritoneal metastasis models, chA21-4-1BBz CAR T cells dramatically facilitated regression of HER2 overexpressing tumor and prolonged survival of tumor-bearing mice, whereas spared the progression of HER2 low-expressing tumor. Additionally, the capability of these CAR T cells to persist in circulation, as well as specifically home to, and accumulate in tumor sites were identified. Taken together, these results provide the basis for the future clinical investigation of the humanized chA21 scFv based, 4-1BB costimulated CAR T cells for the treatment of gastric cancer, and other HER2-expressing solid tumors. PMID:29416924

Response of Rocky Reef Top Predators (Serranidae: Epinephelinae) in and Around Marine Protected Areas in the Western Mediterranean Sea

PubMed Central

Hackradt, Carlos Werner; García-Charton, José Antonio; Harmelin-Vivien, Mireille; Pérez-Ruzafa, Ángel; Le Diréach, Laurence; Bayle-Sempere, Just; Charbonnel, Eric; Ody, Denis; Reñones, Olga; Sanchez-Jerez, Pablo; Valle, Carlos

2014-01-01

Groupers species are extremely vulnerable to overfishing and many species are threatened worldwide. In recent decades, Mediterranean groupers experienced dramatic population declines. Marine protected areas (MPAs) can protect populations inside their boundaries and provide individuals to adjacent fishing areas through the process of spillover and larval export. This study aims to evaluate the effectiveness of six marine reserves in the Western Mediterranean Sea to protect the populations of three species of grouper, Epinephelus marginatus, Epinephelus costae and Mycteroperca rubra, and to understand in which circumstances MPAs are able to export biomass to neighbouring areas. All the studied MPAs, except one where no grouper was observed, were able to maintain high abundance, biomass and mean weight of groupers. Size classes were more evenly distributed inside than outside MPAs. In two reserves, biomass gradients could be detected through the boundaries of the reserve as an indication of spillover. In some cases, habitat structure appeared to exert a great influence on grouper abundance, biomass and mean individual weight, influencing the gradient shape. Because groupers are generally sedentary animals with a small home range, we suggest that biomass gradients could only occur where groupers attain sufficient abundance inside MPA limits, indicating a strongly density-dependent process. PMID:24905331

Water, plants, and early human habitats in eastern Africa

PubMed Central

Magill, Clayton R.; Ashley, Gail M.; Freeman, Katherine H.

2013-01-01

Water and its influence on plants likely exerted strong adaptive pressures in human evolution. Understanding relationships among water, plants, and early humans is limited both by incomplete terrestrial records of environmental change and by indirect proxy data for water availability. Here we present a continuous record of stable hydrogen-isotope compositions (expressed as δD values) for lipid biomarkers preserved in lake sediments from an early Pleistocene archaeological site in eastern Africa—Olduvai Gorge. We convert sedimentary leaf- and algal-lipid δD values into estimates for ancient source-water δD values by accounting for biochemical, physiological, and environmental influences on isotopic fractionation via published water–lipid enrichment factors for living plants, algae, and recent sediments. Reconstructed precipitation and lake-water δD values, respectively, are consistent with modern isotopic hydrology and reveal that dramatic fluctuations in water availability accompanied ecosystem changes. Drier conditions, indicated by less negative δD values, occur in association with stable carbon-isotopic evidence for open, C4-dominated grassland ecosystems. Wetter conditions, indicated by lower δD values, are associated with expanded woody cover across the ancient landscape. Estimates for ancient precipitation amounts, based on reconstructed precipitation δD values, range between approximately 250 and 700 mm·y−1 and are consistent with modern precipitation data for eastern Africa. We conclude that freshwater availability exerted a substantial influence on eastern African ecosystems and, by extension, was central to early human proliferation during periods of rapid climate change. PMID:23267102

Water, plants, and early human habitats in eastern Africa.

PubMed

Magill, Clayton R; Ashley, Gail M; Freeman, Katherine H

2013-01-22

Water and its influence on plants likely exerted strong adaptive pressures in human evolution. Understanding relationships among water, plants, and early humans is limited both by incomplete terrestrial records of environmental change and by indirect proxy data for water availability. Here we present a continuous record of stable hydrogen-isotope compositions (expressed as δD values) for lipid biomarkers preserved in lake sediments from an early Pleistocene archaeological site in eastern Africa--Olduvai Gorge. We convert sedimentary leaf- and algal-lipid δD values into estimates for ancient source-water δD values by accounting for biochemical, physiological, and environmental influences on isotopic fractionation via published water-lipid enrichment factors for living plants, algae, and recent sediments. Reconstructed precipitation and lake-water δD values, respectively, are consistent with modern isotopic hydrology and reveal that dramatic fluctuations in water availability accompanied ecosystem changes. Drier conditions, indicated by less negative δD values, occur in association with stable carbon-isotopic evidence for open, C(4)-dominated grassland ecosystems. Wetter conditions, indicated by lower δD values, are associated with expanded woody cover across the ancient landscape. Estimates for ancient precipitation amounts, based on reconstructed precipitation δD values, range between approximately 250 and 700 mm · y(-1) and are consistent with modern precipitation data for eastern Africa. We conclude that freshwater availability exerted a substantial influence on eastern African ecosystems and, by extension, was central to early human proliferation during periods of rapid climate change.

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

Ogawa, E.; Suzuki, S.; Tsuzuki, H.

Mice were subcutaneoulsy injected with Sr/sup 90/ or Sr/sup 85/, and effects of various drugs on their 3-day excretion and retention on the 4th day were investigated. Among chelating agents, NaCa citrate, NaMg citrate, NaSr citrate, Achromycin (or tetracycline), and aspartic MgK (alone or in combination with NH/sub 4/Cl) displayed Sr-eliminating effects. ATP increased only the excretion without diminishing the retention in bone. EDTA, DTPA, BADE, tricarballylate, Na citrate and NaPb citrate were not effective. Among salts, Mg salt, sulfite, and thiosulfate were effective in eliminating Sr. The last exerted a greater effect when given concurrently with Mg, Ca, ormore » Sr salt. Ca and Sr salt exerted no effect, and ammonium chloride promoted only urinary secretion, not extending to local or total excretion. Such salts as induce alkalosis conversely exerted inhibitory effects. Among hormones, glucocorticoids had Sreliminating effects. TSH was effective, and antithyroidal drugs conversely seemed to have excretion-diminishing effects. Among vitamins, cocarboxylase increased Sr excretion, but did not decrease the retention in bone. Also metabolic inhibitors were ineffective, and NaF conversely increased bone deposition of Sr. Among diuretics, SHdrugs, and weak chelating agents, there were no effective drugs. (JAIF)« less

Easy-to-Make Cryophoruses

ERIC Educational Resources Information Center

Battino, Rubin; Letcher, Trevor M.

2008-01-01

The cryophorus dramatically demonstrates the cooling effect of evaporation. This article describes some simple and easy-to-make cryophoruses, ideal for demonstrating evaporative cooling to students at all levels. The most dramatic effects occurred with cyclohexane and benzene, with water generally freezing more slowly. (Contains 4 notes, 2 tables,…

Independent effects of relevance and arousal on deductive reasoning.

PubMed

Caparos, Serge; Blanchette, Isabelle

2017-08-01

Emotional content can have either a deleterious or a beneficial impact on logicality. Using standard deductive-reasoning tasks, we tested the hypothesis that the interplay of two factors - personal relevance and arousal - determines the nature of the effect of emotional content on logicality. Arousal was assessed using measures of skin conductance. Personal relevance was manipulated by asking participants to reason about semantic contents linked to an emotional event that they had experienced or not. Findings showed that (1) personal relevance exerts a positive effect on logicality while arousal exerts a negative effect, and that (2) these effects are independent of each other.

Melatonin mediated antidepressant-like effect in the hippocampus of chronic stress-induced depression rats: Regulating vesicular monoamine transporter 2 and monoamine oxidase A levels.

PubMed

Stefanovic, Bojana; Spasojevic, Natasa; Jovanovic, Predrag; Jasnic, Nebojsa; Djordjevic, Jelena; Dronjak, Sladjana

2016-10-01

The hippocampus is sensitive to stress which activates norepinephrine terminals deriving from the locus coeruleus. Melatonin exerts positive effects on the hippocampal neurogenic process and on depressive-like behaviour. Thus, in the present study, an examination was made of the effect of chronic melatonin treatment on norepinephrine content, synthesis, uptake, vesicular transport and degradation in the hippocampus of rats exposed to CUMS. This entailed quantifying the norephinephrine, mRNA and protein levels of DBH, NET, VMAT 2, MAO-A and COMT. The results show that CUMS evoked prolonged immobility. Melatonin treatment decreased immobility in comparison with the placebo group, reflecting an antidepressant-like effect. Compared with the placebo group, a dramatic decrease in norepinephrine content, decreased VMAT2 mRNA and protein and increased MAO-A protein levels in the hippocampus of the CUMS rats were observed. However, no significant differences in the levels of DBH, NET, COMT mRNA and protein and MAO-A mRNA levels between the placebo and the stressed groups were found. The results showed the restorative effects of melatonin on the stress-induced decline in the norepinephrine content of the hippocampus. It was observed that melatonin treatment in the CUMS rats prevented the stress-induced decrease in VMAT2 mRNA and protein levels, whereas it reduced the increase of the mRNA of COMT and protein levels of MAO-A. Chronic treatment with melatonin failed to alter the gene expression of DBH or NET in the hippocampus of the CUMS rats. Additionally, the results show that melatonin enhances VMAT2 expression and norepinephrine storage, whilst it reduces norepinephrine degrading enzymes. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

The influence of allosteric modulators and transmembrane mutations on desensitisation and activation of α7 nicotinic acetylcholine receptors

PubMed Central

Chatzidaki, Anna; D'Oyley, Jarryl M.; Gill-Thind, JasKiran K.; Sheppard, Tom D.; Millar, Neil S.

2015-01-01

Acetylcholine activates nicotinic acetylcholine receptors (nAChRs) by binding at an extracellular orthosteric site. Previous studies have described several positive allosteric modulators (PAMs) that are selective for homomeric α7 nAChRs. These include type I PAMs, which exert little or no effect on the rate of receptor desensitisation, and type II PAMs, which cause a dramatic loss of agonist-induced desensitisation. Here we report evidence that transmembrane mutations in α7 nAChRs have diverse effects on receptor activation and desensitisation by allosteric ligands. It has been reported previously that the L247T mutation, located toward the middle of the second transmembrane domain (at the 9′ position), confers reduced levels of desensitisation. In contrast, the M260L mutation, located higher up in the TM2 domain (at the 22′ position), does not show any difference in desensitisation compared to wild-type receptors. We have found that in receptors containing the L247T mutation, both type I PAMs and type II PAMs are converted into non-desensitising agonists. In contrast, in receptors containing the M260L mutation, this effect is seen only with type II PAMs. These findings, indicating that the M260L mutation has a selective effect on type II PAMs, have been confirmed both with previously described PAMs and also with a series of novel α7-selective PAMs. The novel PAMs examined in this study have close chemical similarity but diverse pharmacological properties. For example, they include compounds displaying effects on receptor desensitisation that are typical of classical type I and type II PAMs but, in addition, they include compounds with intermediate properties. PMID:25998276

The influence of allosteric modulators and transmembrane mutations on desensitisation and activation of α7 nicotinic acetylcholine receptors.

PubMed

Chatzidaki, Anna; D'Oyley, Jarryl M; Gill-Thind, JasKiran K; Sheppard, Tom D; Millar, Neil S

2015-10-01

Acetylcholine activates nicotinic acetylcholine receptors (nAChRs) by binding at an extracellular orthosteric site. Previous studies have described several positive allosteric modulators (PAMs) that are selective for homomeric α7 nAChRs. These include type I PAMs, which exert little or no effect on the rate of receptor desensitisation, and type II PAMs, which cause a dramatic loss of agonist-induced desensitisation. Here we report evidence that transmembrane mutations in α7 nAChRs have diverse effects on receptor activation and desensitisation by allosteric ligands. It has been reported previously that the L247T mutation, located toward the middle of the second transmembrane domain (at the 9' position), confers reduced levels of desensitisation. In contrast, the M260L mutation, located higher up in the TM2 domain (at the 22' position), does not show any difference in desensitisation compared to wild-type receptors. We have found that in receptors containing the L247T mutation, both type I PAMs and type II PAMs are converted into non-desensitising agonists. In contrast, in receptors containing the M260L mutation, this effect is seen only with type II PAMs. These findings, indicating that the M260L mutation has a selective effect on type II PAMs, have been confirmed both with previously described PAMs and also with a series of novel α7-selective PAMs. The novel PAMs examined in this study have close chemical similarity but diverse pharmacological properties. For example, they include compounds displaying effects on receptor desensitisation that are typical of classical type I and type II PAMs but, in addition, they include compounds with intermediate properties. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

LL-37 attenuates inflammatory impairment via mTOR signaling-dependent mitochondrial protection.

PubMed

Sun, Wenyan; Zheng, Yan; Lu, Zhuoyang; Wang, Hui; Feng, Zhihui; Wang, Juan; Xiao, Shengxiang; Liu, Feng; Liu, Jiankang

2014-09-01

The human cationic antimicrobial protein LL-37 is a multifunctional host defense peptide with a wide range of immunomodulatory activities. Previous work has shown that LL-37 exerts both pro- and anti-inflammatory effects. The role of mitochondria in the skin inflammatory effects of LL-37 has not been well studied. Therefore, our aim was to investigate the immunomodulatory effect of LL-37 in HaCaT cells and to delineate the underlying mechanisms related to mitochondrial function. Immunohistochemistry results from tissue microarrays showed strong cytoplasmic LL-37 staining in inflammatory cells in chronic dermatic inflammation. Using exogenous LL-37 stimulation and LL-37 knockdown and overexpression, LL-37 was demonstrated to dramatically reduce the mRNA levels and protein secretion of inflammatory cytokines including IL-6, IL-8, IL-1α and tumor necrosis factor-α (TNF-α), which are induced by lipopolysaccharides (LPS). The anti-inflammatory effects of LL-37 are dependent upon its ability to increase mitochondrial biogenesis and to maintain mitochondrial homeostasis. Furthermore, we observed that LL-37 enhances the LPS-induced phosphorylation of extracellular signal-regulated kinase (ERK1/2) and mammalian target of rapamycin (mTOR). The mTOR inhibitor rapamycin can neutralize the protective effects of LL-37 on mitochondria. In conclusion, these results suggest that high LL-37 expression levels correlate with chronic skin inflammation; mitochondrial dysfunction occurs in HaCaT cells during inflammation; and LL-37 attenuates inflammatory impairment by stimulating mitochondrial biogenesis and protecting mitochondrial function, which are dependent upon mTOR signaling. These findings provide new insights into targeting mitochondria with LL-37 to prevent skin inflammatory reactions. Copyright © 2014 Elsevier Ltd. All rights reserved.

Progesterone attenuates airway remodeling and glucocorticoid resistance in a murine model of exposing to ozone.

PubMed

Zhang, Xue; Bao, Wuping; Fei, Xia; Zhang, Yingying; Zhang, Guoqing; Zhou, Xin; Zhang, Min

2018-04-01

Airway remodeling is a vital component of chronic obstructive pulmonary disease (COPD). Despite the broad anti-inflammation effects of glucocorticoids, they exhibit relatively little therapeutic benefit in COPD, indicating the accelerating demands of new agents for COPD. We aim to explore the effect of progesterone on airway remodeling in a murine modeling of exposing to ozone and to further examine the potential effect of progesterone on glucocorticoid insensitivity. C57/BL6 mice were exposed to ozone for 12 times over 6 weeks, and were administered with progesterone alone or combined with budesonide (BUD) after each exposure until the 10th week. The peribronchial collagen deposition was measured. The protein levels of MMP8 and MMP9 in bronchoalveolar lavage fluid (BALF) and lungs were assessed. Western blot analysis was used to detect the levels of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), a-smooth muscle actin (α-SMA), glycogen synthase kinase-3β (GSK-3β). The expression of VEGF and histone deacetylase 2 (HDAC2) in the lung were determined by Immunohistochemical analyses. We observe that progesterone attenuates the peribronchial collagen deposition, as well as the expression of MMP8, MMP9, HIF-1α, VEGF, α-SMA, and GSK-3β in BALF or lung tissues. Progesterone or BUD monotherapy has no effect on HDAC2 production. Progesterone combines with BUD induce dramatically enhanced effects. Thus, these results demonstrate novel roles of progesterone for the pathogenesis and airway remodeling in COPD. Progesterone plus BUD administration exerts more significant inhibition on airway remodeling with dose-independent. Additionally, progesterone may, to some extent, improve the glucocorticoid insensitivity. Copyright © 2018. Published by Elsevier Ltd.

Genomic and post-genomic effects of anti-glaucoma drugs preservatives in trabecular meshwork.

PubMed

Izzotti, Alberto; La Maestra, Sebastiano; Micale, Rosanna Tindara; Longobardi, Maria Grazia; Saccà, Sergio Claudio

2015-02-01

Oxidative stress plays an important role in glaucoma. Some preservatives of anti-glaucoma drugs, commonly used in glaucoma therapy, can prevent or induce oxidative stress in the trabecular meshwork. The aim of this study is to evaluate cellular and molecular damage induced in trabecular meshwork by preservatives contained in anti-glaucoma drugs. Cell viability (MTT test), DNA fragmentation (Comet test), oxidative DNA damage (8-oxo-dG), and gene expression (cDNA microarray) have been evaluated in trabecular meshwork specimens and in human trabecular meshwork cells treated with benzalkonium chloride, polyQuad, purite, and sofzia-like mixture. Moreover, antimicrobial effectiveness and safety of preservative contents in drugs was tested. In ex vivo experiments, benzalkonium chloride and polyQuad induced high level of DNA damage in trabecular meshwork specimens, while the effect of purite and sofzia were more attenuated. The level of DNA fragmentation induced by benzalkonium chloride was 2.4-fold higher in subjects older than 50 years than in younger subjects. Benzalkonium chloride, and polyQuad significantly increased oxidative DNA damage as compared to sham-treated specimens. Gene expression was altered by benzalkonium chloride, polyQuad, and purite but not by sofzia. In in vitro experiments, benzalkonium chloride and polyQuad dramatically decreased trabecular meshwork cell viability, increased DNA fragmentation, and altered gene expression. A lesser effect was also exerted by purite and sofzia. Genes targeted by these alterations included Fas and effector caspase-3. The efficacy of the preservatives in inhibiting bacterial growth increased the adverse effects in trabecular meshwork in terms of DNA damage and alteration of gene expression. Presented data indicates the delicate balance between efficacy and safety of drug preservatives as not yet optimized. Copyright © 2014 Elsevier B.V. All rights reserved.

Growth Stimulation by Catecholamines in Plant Tissue/Organ Cultures 1

PubMed Central

Protacio, Calixto M.; Dai, Yao-ren; Lewis, Eldrin F.; Flores, Hector E.

1992-01-01

Addition of catecholamines at micromolar concentrations caused a dramatic stimulation of growth of tobacco (Nicotiana tabacum) thin cell layers (TCLs) and Acmella oppositifolia “hairy” root cultures. A threefold increase in the rate of ethylene evolution was observed in the catecholamine-treated explants. Aminooxyacetic acid and silver thiosulfate, inhibitors of ethylene biosynthesis and action, respectively, reduced the growth-promoting effect of dopamine. However, these compounds alone could also inhibit the growth of the TCL explants. When ethylene in the culture vessel was depleted by trapping with mercuric perchlorate, dopamine-stimulated growth was still obtained, suggesting that ethylene does not mediate the dopamine effect. Dopamine potentiated the growth of TCLs grown in Murashige and Skoog medium supplemented with indoleacetic acid (IAA) and kinetin. When IAA was replaced by 2,4-dichlorophenoxyacetic acid, dopamine addition showed no growth-promoting effect. Instead, 2,4-dichlorophenoxyacetic acid stimulated the growth of TCL explants to the same extent as that obtained with IAA plus dopamine. Because synthetic auxins do not appear to be substrates for IAA oxidizing enzymes, we hypothesized that catecholamines exert their effect by preventing IAA oxidation. Consistent with this explanation, dopamine (25 micromolar) inhibited IAA oxidase activity by 60 to 100% in crude enzyme extracts from tobacco roots and etiolated corn coleoptiles, but had no effect on peroxidase activity in the same extracts. Furthermore, addition of dopamine to TCL cultures resulted in a fourfold reduction in the oxidative degradation of [1-14C]IAA fed to the explants. Because the growth enhancement by catecholamines is observed in both IAA-requiring and IAA-independent cultures, we suggest that these aromatic amines may have a role in the regulation of IAA levels in vivo. ImagesFigure 2 PMID:16668653

Ways of increasing muscular activity by means of isometric muscular exertion

NASA Technical Reports Server (NTRS)

Kovalik, A. V.

1980-01-01

The effect of isometric muscular exertion on the human body was investigated by having subjects perform basic movements in a sitting position in the conventional manner with additional muscle tension at 50% maximum force and at maximum force. The pulse, arterial pressure, skin temperature, respiratory rate, minute respiratory volume and electrical activity of the muscles involved were all measured. Performance of the exercises with maximum muscular exertion for 20 sec and without movement resulted in the greatest shifts in these indices; in the conventional manner substantial changes did not occur; and with isometric muscular exertion with 50% maximum force with and without movement, optimal functional shifts resulted. The latter is recommended for use in industrial exercises for the prevention of hypodynamia. Ten exercises are suggested.

Examining Effects of Physical Exertion on the Dynamic Visual Acuity Test in Collegiate Athletes.

PubMed

Patterson, Jessie N; Murphy, Anna M; Honaker, Julie A

2017-01-01

Acute symptoms of dizziness and/or imbalance commonly experienced in athletes postconcussion are speculated to arise from dysfunction at multiple levels (i.e., inner ear or central vestibular system) to appropriately integrate afferent sensory information. Disruption along any pathway of the balance system can result in symptoms of dizziness, decreased postural control function (vestibulospinal reflex), and reduced vestibulo-ocular reflex function. This may also lead to decreased gaze stability with movements of the head and may account for symptoms of blurred vision or diplopia reported in almost half of athletes sustaining a concussion. Current concussion position statements include measures of postural control to examine changes to the balance system postconcussion. The Balance Error Scoring System (BESS) is a commonly used low-cost postural control measure for concussion assessment. Although this is a widely used measure for documenting balance function on both immediate (sideline) and recovery monitoring, the BESS has been shown to be affected by physical exertion. Therefore, the BESS may not be the most efficient means of examining functional changes to the balance system immediately after head injury. Dynamic Visual Acuity Test (DVAT) has been found to effectively evaluate and monitor changes to the gaze stability system postinjury. Thus, DVAT may be an additional measure in the concussion assessment battery, as well as an alternative for more immediate sideline assessment to help make objective return-to-play decisions. The aim of the study was to determine the effects of physical exertion on a clinical vestibular assessment, the DVAT, in collegiate athletes, as a first step in defining the role of this measure in the concussion assessment battery. Cross-sectional, repeated-measures design. Twenty-eight healthy collegiate athletes (20 males, 8 females; age = 20.25 ± 1.46 yr, range = 18-25 yr) volunteered to participate in the study. Participants were randomly assigned to complete a 20-min protocol of physical exertion or rest. DVAT was completed pre-exertion or rest (pre-DVAT), immediately following the 20-min protocol (post-DVAT I), and again 10 min after the completion of the 20-min protocol (post-DVAT II). Ratings of perceived exertion (RPE) and heart rate (HR) were monitored throughout testing. Repeated-measures analysis of the variance were used to examine the effects of exertion on DVAT. Additionally, intraclass correlation coefficients were used to examine test reliability. No significant main effect was observed for right and left DVAT logarithm of the minimal angle of resolution loss between groups or across time points (p > 0.05). A significant main effect was observed for RPE and HR for groups and time points (p < 0.001), indicating adequate physical exertion and rest. Fair to good reliability (intraclass correlation coefficient values between 0.4 and 0.74) was observed for both rightward and leftward movements of the head across the three time points. Findings from this study suggest that DVAT is not affected by physical exertion and may provide a more immediate assessment of the balance system that may be of use for the sideline concussion assessment. Future studies will be performed to examine additional factors (e.g., background noise, complex visual backgrounds) that may affect DVAT performance in the sideline environment. American Academy of Audiology

Effects of Physical Activity on Mathematical Computation among Young Children.

ERIC Educational Resources Information Center

Gabbard, Carl; Barton, Joel

1979-01-01

When 106 second-grade children were tested for simple computation ability in various conditions of induced physical exertion (no exertion v 20, 30, 40, or 50 minutes of activity), significantly higher scores were observed after the 50-minute treatment, and no significant differences were noted between male and female scores. (Author/RL)

Professional Preparation regarding the Recognition and Treatment of Exertional Heat Stroke: The Student Perspective

ERIC Educational Resources Information Center

Mazerolle, Stephanie M.; Pagnotta, Kelly D.; Casa, Douglas J.; Armstrong, Lawrence; Maresh, Carl

2011-01-01

Context: Current evidence suggests rectal temperature(T[subscript re] and cold-water immersion (CWI) are the most effective means to diagnose and treat exertional heat stroke (EHS), respectively. Educators, clinicians, and students should be apprised of this evidence to guide their practice. Objective: Investigate what athletic training students…

The novel HDAC inhibitor AR-42-induced anti-colon cancer cell activity is associated with ceramide production

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

Xu, Weihong; Xu, Bin; Yao, Yiting

In the current study, we investigated the potential activity of AR-42, a novel histone deacetylase (HDAC) inhibitor, against colon cancer cells. Our in vitro results showed that AR-42 induced ceramide production, exerted potent anti-proliferative and pro-apoptotic activities in established (SW-620 and HCT-116 lines) and primary human colon cancer cells. Exogenously-added sphingosine 1-phosphate (S1P) suppressed AR-42-induced activity, yet a cell-permeable ceramide (C4) facilitated AR-42-induced cytotoxicity against colon cancer cells. In addition, AR-42-induced ceramide production and anti-colon cancer cell activity were inhibited by the ceramide synthase inhibitor fumonisin B1, but were exacerbated by PDMP, which is a ceramide glucosylation inhibitor. In vivo, oral administrationmore » of a single dose of AR-42 dramatically inhibited SW-620 xenograft growth in severe combined immunodeficient (SCID) mice, without inducing overt toxicities. Together, these results show that AR-42 dramatically inhibits colon cancer cell proliferation in vitro and in vivo, and ceramide production might be the key mechanism responsible for its actions. - Highlights: • AR-42 is anti-proliferative against primary/established colon cancer cells. • AR-42 induces significant apoptotic death in primary/established colon cancer cells. • Ceramide production mediates AR-42-induced cytotoxicity in colon cancer cells. • AR-42 oral administration potently inhibits SW-620 xenograft growth in SCID mice.« less

The effect of personality dimensions on functional outcomes in mood disorders.

PubMed

Leen, Jessica; Soczynska, Joanna K; Gallaugher, Laura Ashley; Woldeyohannes, Hanna O; Alsuwaidan, Mohammad T; Cha, Danielle S; Dale, Roman M; Muzina, David J; Kennedy, Sidney H; McIntyre, Roger S

2013-07-01

Functional impairment associated with mood disorders may be related to a characteristic "profile" of normative personality dimensions. Individuals (age ≥ 18 years) with MDD (n = 400) or BD (n = 317), as defined by the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR), were enrolled in the IMDCP. Personality was evaluated with the Neuroticism-Extraversion-Openness Five-Factor Inventory (NEO-FFI), and functionality with the Sheehan Disability Scale and Endicott Work Productivity Scale. Path analysis using linear multiple regressions was performed to identify direct and indirect effects of personality on functional impairment. Lower conscientiousness exerted a significant direct effect on global (p = 0.017) and family life dysfunction in individuals with MDD (p = 0.002), as well as lower work productivity in both MDD (p = 0.020) and BD (p = 0.018). Lower extraversion exerted a significant direct effect on social impairment in individuals with BD (p = 0.017). Higher neuroticism and agreeableness as well as lower extraversion exerted indirect effects on global and social dysfunction in individuals with MDD via their effects on depression severity. In BD, higher neuroticism and openness indirectly affected global dysfunction. Family dysfunction was indirectly affected by higher neuroticism and openness as well as lower extraversion in MDD and BD. The results suggest that discrete personality dimensions may exert direct and indirect effects on functional outcomes in individuals with mood disorders. Personalizing disease management approaches in mood disorders with emphasis on vocational rehabilitation may benefit from measurement and intervention targeting personality.

The concomitant effects of phrase length and informational content in sentence comprehension.

PubMed

Thornton, R; MacDonald, M C; Arnold, J E

2000-03-01

Recent evidence suggests that phrase length plays a crucial role in modification ambiguities. Using a self-paced reading task, we extended these results by examining the additional pragmatic effects that length manipulations may exert. The results demonstrate that length not only modulates modification preferences directly, but that it also necessarily changes the informational content of a sentence, which itself affects modification preferences. Our findings suggest that the same length manipulation affects multiple sources of constraints, both structural and pragmatic, which can each exert differing effects on processing.

Galectin-3 Negatively Regulates Hippocampus-Dependent Memory Formation through Inhibition of Integrin Signaling and Galectin-3 Phosphorylation

PubMed Central

Chen, Yan-Chu; Ma, Yun-Li; Lin, Cheng-Hsiung; Cheng, Sin-Jhong; Hsu, Wei-Lun; Lee, Eminy H.-Y.

2017-01-01

Galectin-3, a member of the galectin protein family, has been found to regulate cell proliferation, inhibit apoptosis and promote inflammatory responses. Galectin-3 is also expressed in the adult rat hippocampus, but its role in learning and memory function is not known. Here, we found that contextual fear-conditioning training, spatial training or injection of NMDA into the rat CA1 area each dramatically decreased the level of endogenous galectin-3 expression. Overexpression of galectin-3 impaired fear memory, whereas galectin-3 knockout (KO) enhanced fear retention, spatial memory and hippocampal long-term potentiation. Galectin-3 was further found to associate with integrin α3, an association that was decreased after fear-conditioning training. Transfection of the rat CA1 area with small interfering RNA against galectin-3 facilitated fear memory and increased phosphorylated focal adhesion kinase (FAK) levels, effects that were blocked by co-transfection of the FAK phosphorylation-defective mutant Flag-FAKY397F. Notably, levels of serine-phosphorylated galectin-3 were decreased by fear conditioning training. In addition, blockade of galectin-3 phosphorylation at Ser-6 facilitated fear memory, whereas constitutive activation of galectin-3 at Ser-6 impaired fear memory. Interestingly galectin-1 plays a role in fear-memory formation similar to that of galectin-3. Collectively, our data provide the first demonstration that galectin-3 is a novel negative regulator of memory formation that exerts its effects through both extracellular and intracellular mechanisms. PMID:28744198

Circulating cortisol levels after exogenous cortisol administration are higher in women using hormonal contraceptives: Data from two preliminary studies

PubMed Central

Gaffey, Allison E.; Wirth, Michelle M.; Hoks, Roxanne M.; Jahn, Allison L.; Abercrombie, Heather C.

2014-01-01

Exogenous cortisol administration has been used to test the influence of glucocorticoids on a variety of outcomes, including memory and affect. Careful control of factors known to influence cortisol and other endogenous hormone levels is central to the success of this research. While use of hormonal birth control (HBC) is known to exert many physiological effects, including decreasing the salivary cortisol response to stress, it is unknown how HBC influences circulating cortisol levels after exogenous cortisol administration. To determine those effects, we examined the role of HBC on participants’ cortisol levels after receiving synthetic cortisol (hydrocortisone) in two separate studies. In Study 1, 24 healthy women taking HBC and 26 healthy men were administered a 0.1 mg/kg body weight intravenous dose of hydrocortisone, and plasma cortisol levels were measured over 3 hours. In Study 2, 61 participants (34 women; 16 were on HBC) received a 15 mg hydrocortisone pill, and salivary cortisol levels were measured over 6 hours. Taken together, results from these studies suggest that HBC use is associated with a greater cortisol increase following cortisol administration. These data have important methodological implications: (1) when given a controlled dose of hydrocortisone, cortisol levels may increase more dramatically in women taking HBC vs. women not on HBC or men; and (2) in studies manipulating cortisol levels, women on hormonal contraceptives should be investigated as a separate group. PMID:24773147

Transcriptional Inhibition of the Human Papilloma Virus Reactivates Tumor Suppressor p53 in Cervical Carcinoma Cells

PubMed Central

Kochetkov, D. V.; Ilyinskaya, G. V.; Komarov, P. G.; Strom, E.; Agapova, L. S.; Ivanov, A. V.; Budanov, A. V.; Frolova, E. I.; Chumakov, P. M.

2009-01-01

Inactivation of tumor suppressor p53 accompanies the majority of human malignancies. Restoration of p53 function causes death of tumor cells and is potentially suitable for gene therapy of cancer. In cervical carcinoma, human papilloma virus (HPV) E6 facilitates proteasomal degradation of p53. Hence, a possible approach to p53 reactivation is the use of small molecules suppressing the function of viral proteins. HeLa cervical carcinoma cells (HPV-18) with a reporter construct containing the b-galactosidase gene under the control of a p53-responsive promoter were used as a test system to screen a library of small molecules for restoration of the transcriptional activity of p53. The effect of the two most active compounds was studied with cell lines differing in the state of p53-dependent signaling pathways. The compounds each specifically activated p53 in cells expressing HPV-18 and, to a lesser extent, HPV-16 and exerted no effect on control p53-negative cells or cells with the intact p53-dependent pathways. Activation of p53 in cervical carcinoma cells was accompanied by induction of p53-dependent CDKN1 (p21), inhibition of cell proliferation, and induction of apoptosis. In addition, the two compounds dramatically decreased transcription of the HPV genome, which was assumed to cause p53 reactivation. The compounds were low-toxic for normal cells and can be considered as prototypes of new anticancer drugs. PMID:17685229

Circulating cortisol levels after exogenous cortisol administration are higher in women using hormonal contraceptives: data from two preliminary studies.

PubMed

Gaffey, Allison E; Wirth, Michelle M; Hoks, Roxanne M; Jahn, Allison L; Abercrombie, Heather C

2014-07-01

Exogenous cortisol administration has been used to test the influence of glucocorticoids on a variety of outcomes, including memory and affect. Careful control of factors known to influence cortisol and other endogenous hormone levels is central to the success of this research. While the use of hormonal birth control (HBC) is known to exert many physiological effects, including decreasing the salivary cortisol response to stress, it is unknown how HBC influences circulating cortisol levels after exogenous cortisol administration. To determine those effects, we examined the role of HBC on participants' cortisol levels after receiving synthetic cortisol (hydrocortisone) in two separate studies. In Study 1, 24 healthy women taking HBC and 26 healthy men were administered a 0.1 mg/kg body weight intravenous dose of hydrocortisone, and plasma cortisol levels were measured over 3 h. In Study 2, 61 participants (34 women; 16 were on HBC) received a 15 mg hydrocortisone pill, and salivary cortisol levels were measured over 6 h. Taken together, results from these studies suggest that HBC use is associated with a greater cortisol increase following cortisol administration. These data have important methodological implications: (1) when given a controlled dose of hydrocortisone, cortisol levels may increase more dramatically in women taking HBC versus women not on HBC or men; and (2) in studies manipulating cortisol levels, women on hormonal contraceptives should be investigated as a separate group.

FXR induces SOCS3 and suppresses hepatocellular carcinoma

PubMed Central

Zhang, Yan; Jiang, Peng; Huang, Gang; Chen, Shan; Lyu, Xilin; Zheng, Ping; Zhao, Xin; Zeng, Yijun; Wang, Shuguang; He, Fengtian

2015-01-01

Suppressor of cytokine signaling 3 (SOCS3) is regarded as a vital repressor in the liver carcinogenesis mainly by inhibiting signal transducer and activator of transcription 3 (STAT3) activity. Farnesoid X Receptor (FXR), highly expressed in liver, has an important role in protecting against hepatocellular carcinoma (HCC). However, it is unclear whether the tumor suppressive activity of FXR involves the regulation of SOCS3. In the present study, we found that activation of FXR by its specific agonist GW4064 in HCC cells inhibited cell growth, induced cell cycle arrest at G1 phase, elevated p21 expression and repressed STAT3 activity. The above anti-tumor effects of FXR were dramatically alleviated by knockdown of SOCS3 with siRNA. Reporter assay revealed that FXR activation enhanced the transcriptional activity of SOCS3 promoter. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay displayed that FXR directly bound to IR9 DNA motif within SOCS3 promoter region. The in vivo study in nude mice showed that treatment with FXR ligand GW4064 could decelerate the growth of HCC xenografts, up-regulate SOCS3 and p21 expression and inhibit STAT3 phosphorylation in the xenografts. These results suggest that induction of SOCS3 may be a novel mechanism by which FXR exerts its anti-HCC effects, and the FXR-SOCS3 signaling may serve as a new potential target for the prevention/treatment of HCC. PMID:26416445

Toxicity of N-substituted aromatics to acetoclastic methanogenic activity in granular sludge

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

Donlon, B.A.; Razo-Flores, E.; Field, J.A.

1995-11-01

N-substituted aromatics are important priority pollutants entering the environment primarily through anthropogenic activities associated associated with the industrial production of dyes, explosives, pestides, and pharmaceuticals. Anaerobic treatment of wastewaters discharged by these industries could potentially be problematical as a result of the high toxicity of N-substituted aromatics. The objective of this study was to examine the structure-toxicity relationship of N-substituted aromatic compounds to acetoclastic methanogenic bacteria. The toxicity was assayed to serum flasks by measuring methane production in granular sludge. Unacclimated cultures were used to minimize the biotransformation of the toxic organic chemicals during the test. The nature and themore » degree of the aromatic substitution were observed to have a profound effect on the toxicity of the test compound. Nitroaromatic compounds were, on the average, over 500-fold more toxic than their corresponding aromatic amines. Considering the facile reduction of nitro groups by anerobic microorganisms, a dramatic detoxification of nitroaromatics towards methanogens can be expected to occur during anaerobic wastewater treatment. While the toxicity exerted by the N-substituted aromatic compounds was closely correlated with compound apolarity (log P), it was observed that at any given log P, N-substituted phenols had a toxicity that was 2 orders of magnitude higher than that of chlorophenols and alkylphenols. This indicates that toxicity due to the chemical reactivity of nitroaromatics is much more important than partitioning effects in bacterial membranes. 41 refs., 3 figs., 1 tab.« less

Obatoclax and LY3009120 Efficiently Overcome Vemurafenib Resistance in Differentiated Thyroid Cancer.

PubMed

Wei, Wei-Jun; Sun, Zhen-Kui; Shen, Chen-Tian; Song, Hong-Jun; Zhang, Xin-Yun; Qiu, Zhong-Ling; Luo, Quan-Yong

2017-01-01

Although the prognosis of differentiated thyroid cancer (DTC) is relatively good, 30-40% of patients with distant metastases develop resistance to radioactive iodine therapy due to tumor dedifferentiation. For DTC patients harboring BRAF V600E mutation, Vemurafenib, a BRAF kinase inhibitor, has dramatically changed the therapeutic landscape, but side effects and drug resistance often lead to termination of the single agent treatment. In the present study, we showed that either LY3009120 or Obatoclax (GX15-070) efficiently inhibited cell cycle progression and induced massive death of DTC cells. We established that BRAF/CRAF dimerization was an underlying mechanism for Vemurafenib resistance. LY3009120, the newly discovered pan-RAF inhibitor, successfully overcame Vemurafenib resistance and suppressed the growth of DTC cells in vitro and in vivo. We also observed that expression of anti-apoptotic Bcl-2 increased substantially following BRAF inhibitor treatment in Vemurafenib-resistant K1 cells, and both Obatoclax and LY3009120 efficiently induced apoptosis of these resistant cells. Specifically, Obatoclax exerted its anti-cancer activity by inducing loss of mitochondrial membrane potential (ΔΨm), dysfunction of mitochondrial respiration, reduction of cellular glycolysis, autophagy, neutralization of lysosomes, and caspase-related apoptosis. Furthermore, the cancer killing effects of LY3009120 and Obatoclax extended to two more Vemurafenib-resistant DTC cell lines, KTC-1 and BCPAP. Taken together, our results highlighted the potential value of LY3009120 for both Vemurafenib-sensitive and -resistant DTC and provided evidence for the combination therapy using Vemurafenib and Obatoclax for radioiodine-refractory DTC.

The effect of sulforaphane on histone deacetylase activity in keratinocytes: Differences between in vitro and in vivo analyses.

PubMed

Dickinson, Sally E; Rusche, Jadrian J; Bec, Sergiu L; Horn, David J; Janda, Jaroslav; Rim, So Hyun; Smith, Catharine L; Bowden, G Timothy

2015-11-01

Sulforaphane is a natural product found in broccoli, which is known to exert many different molecular effects in the cell, including inhibition of histone deacetylase (HDAC) enzymes. Here, we examine for the first time the potential for sulforaphane to inhibit HDACs in HaCaT keratinocytes and compare our results with those found using HCT116 colon cancer cells. Significant inhibition of HDAC activity in HCT116 nuclear extracts required prolonged exposure to sulforaphane in the presence of serum. Under the same conditions HaCaT nuclear extracts did not exhibit reduced HDAC activity with sulforaphane treatment. Both cell types displayed down-regulation of HDAC protein levels by sulforaphane treatment. Despite these reductions in HDAC family member protein levels, acetylation of marker proteins (acetylated Histone H3, H4, and tubulin) was decreased by sulforaphane treatment. Time-course analysis revealed that HDAC6, HDAC3, and acetylated histone H3 protein levels are significantly inhibited as early as 6 h into sulforaphane treatment. Transcript levels of HDAC6 are also suppressed after 48 h of treatment. These results suggest that HDAC activity noted in nuclear extracts is not always translated as expected to target protein acetylation patterns, despite dramatic inhibition of some HDAC protein levels. In addition, our data suggest that keratinocytes are at least partially resistant to the nuclear HDAC inhibitory effects of sulforaphane, which is exhibited in HCT116 and other cells. © 2014 The Authors. Molecular Carcinogenesis published by Wiley Periodicals, Inc.

Thiazide diuretics directly induce osteoblast differentiation and mineralized nodule formation by targeting a NaCl cotransporter in bone

PubMed Central

Dvorak, Melita M; De Joussineau, Cyrille; Carter, D Howard; Pisitkun, Trairak; Knepper, Mark A; Gamba, Gerardo; Kemp, Paul J; Riccardi, Daniela

2008-01-01

Thiazide diuretics are used, worldwide, as the first-choice drug for patients with uncomplicated hypertension. In addition to their anti-hypertensive actions, they increase bone mineral density and reduce the prevalence of fractures, indicating that thiazides may have a role in the management of postmenopausal osteoporosis. Traditionally, the bone-protective effects of thiazides have been attributed to an increase in renal calcium reabsorption, secondary to the inhibition of the sodium chloride cotransporter, NCC, expressed in the kidney distal tubule. Whether thiazides exert a direct osteoanabolic effect independently of their renal action is controversial. Here we demonstrate that freshly frozen sections of human and rat bone express NCC, principally in bone-forming cells, the osteoblasts. In primary and established culture models of osteoblasts, fetal rat calvarial (FRC) and human MG63 cells, NCC protein is virtually absent in proliferating cells while its expression is dramatically increased during differentiation. Thiazides directly stimulate the production of osteoblast markers, runt-related transcription factor 2 (runx2) and osteopontin, in the absence of a proliferative effect. Using overexpression/knockdown studies in FRC cells, we show that thiazides, but not loop diuretics, increase mineralized nodule formation acting on NCC. Overall, our study demonstrates that thiazides stimulate osteoblast differentiation and bone mineral formation independently of their renal actions. In addition to their use as part of a therapeutic treatment plan for elderly, hypertensive individuals, our discovery opens up the possibility that bone-specific drug targeting by thiazides may be developed for the prevention and treatment of osteoporosis in the patient population as a whole. PMID:17656470

The role of the microbiome for human health: from basic science to clinical applications.

PubMed

Mohajeri, M Hasan; Brummer, Robert J M; Rastall, Robert A; Weersma, Rinse K; Harmsen, Hermie J M; Faas, Marijke; Eggersdorfer, Manfred

2018-05-10

The 2017 annual symposium organized by the University Medical Center Groningen in The Netherlands focused on the role of the gut microbiome in human health and disease. Experts from academia and industry examined interactions of prebiotics, probiotics, or vitamins with the gut microbiome in health and disease, the development of the microbiome in early-life and the role of the microbiome on the gut-brain axis. The gut microbiota changes dramatically during pregnancy and intrinsic factors (such as stress), in addition to extrinsic factors (such as diet, and drugs) influence the composition and activity of the gut microbiome throughout life. Microbial metabolites, e.g. short-chain fatty acids affect gut-brain signaling and the immune response. The gut microbiota has a regulatory role on anxiety, mood, cognition and pain which is exerted via the gut-brain axis. Ingestion of prebiotics or probiotics has been used to treat a range of conditions including constipation, allergic reactions and infections in infancy, and IBS. Fecal microbiota transplantation (FMT) highly effective for treating recurrent Clostridium difficile infections. The gut microbiome affects virtually all aspects of human health, but the degree of scientific evidence, the models and technologies and the understanding of mechanisms of action vary considerably from one benefit area to the other. For a clinical practice to be broadly accepted, the mode of action, the therapeutic window, and potential side effects need to thoroughly be investigated. This calls for further coordinated state-of-the art research to better understand and document the human gut microbiome's effects on human health.

Funding the new biologics--public policy issues in drug formulary decision making.

PubMed

Lewis, Steven

2002-12-01

One function of drug formularies is to allow health care providers to exert some control over spending. Decisions about whether to include a given medication in a formulary are based on estimates of its costs and effectiveness, relative to other treatment strategies. These decisions are made from a societal perspective, as opposed to that of individual patients, which sometimes results in conflicts. The clinical response to a medication often varies widely among subjects, which means that a small subgroup of patients might benefit dramatically, while others with the same disease do not. The result would be that a drug might appear not to be cost effective in an economic analysis, even though it is of proven value for some patients. New and innovative medications are assessed according to high standards of cost effectiveness, even though established treatments are wasteful of valuable health care resources. Moreover, quality-adjusted life-years (QALYs) discriminate against certain patient groups, including those with diseases that are associated with a high morbidity but a low mortality. Such patients often incur high indirect costs, including loss of employment income and costs incurred by family caregivers that QALYs do not reflect. Therefore, even though QALYs are transparent and widely applicable, they are not necessarily appropriate in the evaluation of a particular therapeutic intervention. A new paradigm should be developed for evaluating emerging therapies. An example would be a risk-sharing approach, whereby the pharmaceutical industry and public insurers share in the costs and rewards of introducing new treatments. This would have implications for the prices charged for new medications.

Flavanol monomer-induced changes to the human faecal microflora.

PubMed

Tzounis, Xenofon; Vulevic, Jelena; Kuhnle, Gunter G C; George, Trevor; Leonczak, Jadwiga; Gibson, Glenn R; Kwik-Uribe, Catherine; Spencer, Jeremy P E

2008-04-01

We have investigated the bacterial-dependent metabolism of ( - )-epicatechin and (+)-catechin using a pH-controlled, stirred, batch-culture fermentation system reflective of the distal region of the human large intestine. Incubation of ( - )-epicatechin or (+)-catechin (150 mg/l or 1000 mg/l) with faecal bacteria, led to the generation of 5-(3',4'-dihydroxyphenyl)-gamma-valerolactone, 5-phenyl-gamma-valerolactone and phenylpropionic acid. However, the formation of these metabolites from (+)-catechin required its initial conversion to (+)-epicatechin. The metabolism of both flavanols occurred in the presence of favourable carbon sources, notably sucrose and the prebiotic fructo-oligosaccharides, indicating that bacterial utilisation of flavanols also occurs when preferential energy sources are available. (+)-Catechin incubation affected the growth of select microflora, resulting in a statistically significant increase in the growth of the Clostridium coccoides-Eubacterium rectale group, Bifidobacterium spp. and Escherichia coli, as well as a significant inhibitory effect on the growth of the C. histolyticum group. In contrast, the effect of ( - )-epicatechin was less profound, only significantly increasing the growth of the C. coccoides-Eubacterium rectale group. These potential prebiotic effects for both (+)-catechin and ( - )-epicatechin were most notable at the lower concentration of 150 mg/l. As both ( - )-epicatechin and (+)-catechin were converted to the same metabolites, the more dramatic change in the growth of distinct microfloral populations produced by (+)-catechin incubation may be linked to the bacterial conversion of (+)-catechin to (+)-epicatechin. Together these data suggest that the consumption of flavanol-rich foods may support gut health through their ability to exert prebiotic actions.

Neuroprotective Mechanisms of Calycosin Against Focal Cerebral Ischemia and Reperfusion Injury in Rats.

PubMed

Wang, Yong; Ren, Qianyao; Zhang, Xing; Lu, Huiling; Chen, Jian

2018-01-01

Emerging evidence suggests that autophagy plays important roles in the pathophysiological processes of cerebral ischemia and reperfusion injury. Calycosin, an isoflavone phytoestrogen, possesses neuroprotective effects in cerebral ischemia and reperfusion in rats. Here, we investigated the neuroprotective effects of calycosin against ischemia and reperfusion injury, as well as related probable mechanisms behind autophagy pathways. A cerebral ischemic and reperfusion injury model was established by middle cerebral artery occlusion in male Sprague-Dawley rats. Neurological scores, infarct volumes, and brain water content were assessed after 24 h reperfusion following 2 h ischemia. Additionally, the expression of the autophagy-related protein p62 and NBR1 (neighbor of BRCA1 gene 1), as well as Bcl-2, and TNF-α in rat brain tissues was measured by RT-PCR, western blotting and immunohistochemical analyses. The results showed that calycosin pretreatment for 14 days markedly decreased infarct volume and brain edema, and ameliorated neurological scores in rats with focal cerebral ischemia and reperfusion. It was observed that levels of p62, NBR1 and Bcl-2 were greatly decreased, and levels of TNF-α significantly increased after ischemia and reperfusion injury. However, calycosin administration dramatically upregulated the expression of p62, NBR1 and Bcl-2, and downregulated the level of TNF-α. All data reveal that calycosin exerts a neuroprotective effect on cerebral ischemia and reperfusion injury, and the mechanisms maybe associated with its anti-autophagic, anti-apoptotic and anti-inflammatory action. © 2018 The Author(s). Published by S. Karger AG, Basel.

"I Did Not Wash My Feet with that Woman": Using Dramatic Performance to Teach Biblical Studies

ERIC Educational Resources Information Center

Torbett, David

2010-01-01

The student dramatic performance is an effective way for undergraduates to learn biblical studies. In this article I will give an example of a dramatic performance assignment that I developed over a number of courses and used most recently and most successfully in an undergraduate course in the Hebrew Bible at a small liberal arts college in the…

Exercise, physical activity, and exertion over the business cycle.

PubMed

Colman, Gregory; Dave, Dhaval

2013-09-01

Shifts in time and income constraints over economic expansions and contractions would be expected to affect individuals' behaviors. We explore the impact of the business cycle on individuals' exercise, time use, and total physical exertion, utilizing information on 112,000 individual records from the 2003-2010 American Time Use Surveys. In doing so, we test a key causal link that has been hypothesized in the relation between unemployment and health, but not heretofore assessed. Using more precise measures of exercise (and other activities) than previous studies, we find that as work-time decreases during a recession, recreational exercise, TV-watching, sleeping, childcare, and housework increase. This, however, does not compensate for the decrease in work-related exertion due to job-loss, and total physical exertion declines. These effects are strongest among low-educated men, which is validating given that employment in the Great Recession has declined most within manufacturing, mining, and construction. We also find evidence of intra-household spillover effects, wherein individuals respond to shifts in spousal employment conditional on their own labor supply. The decrease in total physical activity during recessions is especially problematic for vulnerable populations concentrated in boom-and-bust industries, and may have longer-term effects on obesity and related health outcomes. Copyright © 2013 Elsevier Ltd. All rights reserved.

A Negative Allosteric Modulator for α5 Subunit-Containing GABA Receptors Exerts a Rapid and Persistent Antidepressant-Like Action without the Side Effects of the NMDA Receptor Antagonist Ketamine in Mice

PubMed Central

Nelson, Mackenzie E.; Krimmel, Samuel R.; Georgiou, Polymnia; Gould, Todd D.

2017-01-01

Abstract New antidepressant pharmacotherapies that provide rapid relief of depressive symptoms are needed. The NMDA receptor antagonist ketamine exerts rapid antidepressant actions in depressed patients but also side effects that complicate its clinical utility. Ketamine promotes excitatory synaptic strength, likely by producing high-frequency correlated activity in mood-relevant regions of the forebrain. Negative allosteric modulators of GABA-A receptors containing α5 subunits (α5 GABA-NAMs) should also promote high-frequency correlated electroencephalogram (EEG) activity and should therefore exert rapid antidepressant responses. Because α5 subunits display a restricted expression in the forebrain, we predicted that α5 GABA-NAMs would produce activation of principle neurons but exert fewer side effects than ketamine. We tested this hypothesis in male mice and observed that the α5 GABA-NAM MRK-016 exerted an antidepressant-like response in the forced swim test at 1 and 24 h after administration and an anti-anhedonic response after chronic stress in the female urine sniffing test (FUST). Like ketamine, MRK-016 produced a transient increase in EEG γ power, and both the increase in γ power and its antidepressant effects in the forced swim test were blocked by prior administration of the AMPA-type glutamate receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX). Unlike ketamine, however, MRK-016 produced no impairment of rota-rod performance, no reduction of prepulse inhibition (PPI), no conditioned-place preference (CPP), and no change in locomotion. α5 GABA-NAMs, thus reproduce the rapid antidepressant-like actions of ketamine, perhaps via an AMPA receptor (AMPAR)-dependent increase in coherent neuronal activity, but display fewer potential negative side effects. These compounds thus demonstrate promise as clinically useful fast-acting antidepressants. PMID:28275719

Do 'mind over muscle' strategies work? Examining the effects of attentional association and dissociation on exertional, affective and physiological responses to exercise.

PubMed

Lind, Erik; Welch, Amy S; Ekkekakis, Panteleimon

2009-01-01

Despite the well established physical and psychological benefits derived from leading a physically active life, rates of sedentary behaviour remain high. Dropout and non-compliance are major contributors to the problem of physical inactivity. Perceptions of exertion, affective responses (e.g. displeasure or discomfort), and physiological stress could make the exercise experience aversive, particularly for beginners. Shifting one's attentional focus towards environmental stimuli (dissociation) instead of one's body (association) has been theorized to enhance psychological responses and attenuate physiological stress. Research evidence on the effectiveness of attentional focus strategies, however, has been perplexing, covering the entire gamut of possible outcomes (association and dissociation having been shown to be both effective and ineffective). This article examines the effects of manipulations of attentional focus on exertional and affective responses, as well as on exercise economy and tolerance. The possible roles of the characteristics of the exercise stimulus (intensity, duration) and the exercise participants, methodological issues, and limitations of experimental designs are discussed. In particular, the critical role of exercise intensity is emphasized. Dissociative strategies may be more effective in reducing perceptions of exertion and enhancing affective responses at low to moderate exercise intensities, but their effectiveness may be diminished at higher and near-maximal levels, at which physiological cues dominate. Conversely, associative strategies could enable the exerciser to regulate intensity to avoid injury or overexertion. Thus, depending on intensity, both strategies have a place in the 'toolbox' of the public health or exercise practitioner as methods of enhancing the exercise experience and promoting long-term compliance.

Usefulness of a Perceived Exertion Scale for Monitoring Exercise Intensity in Adults with Intellectual Disabilities

ERIC Educational Resources Information Center

Stanish, Heidi I.; Aucoin, Michael

2007-01-01

In order to gain physical fitness and health, exercise must be performed at a sufficient level of intensity. Exercise intensity can be monitored with rated perceived exertion (RPE) scales to promote safe and effective programming. The usefulness of the Children's OMNI Scale as a subjective measure of intensity for adults with intellectual…

A novel role for an RCAN3-derived peptide as a tumor suppressor in breast cancer.

PubMed

Martínez-Høyer, Sergio; Solé-Sánchez, Sònia; Aguado, Fernando; Martínez-Martínez, Sara; Serrano-Candelas, Eva; Hernández, José Luis; Iglesias, Mar; Redondo, Juan Miguel; Casanovas, Oriol; Messeguer, Ramon; Pérez-Riba, Mercè

2015-07-01

The members of the human regulators of calcineurin (RCAN) protein family are endogenous regulators of the calcineurin (CN)-cytosolic nuclear factor of activated T-cells (NFATc) pathway activation. This function is explained by the presence of a highly conserved calcipressin inhibitor of calcineurin (CIC) motif in RCAN proteins, which has been shown to compete with NFATc for the binding to CN and therefore are able to inhibit NFATc dephosphorylation and activation by CN. Very recently, emerging roles for NFATc proteins in transformation, tumor angiogenesis and metastasis have been described in different cancer cell types. In this work, we report that the overexpression of RCAN3 dramatically inhibits tumor growth and tumor angiogenesis in an orthotopic human breast cancer model. We suggest that RCAN3 exerts these effects in a CN-dependent manner, as mutation of the CIC motif in RCAN3 abolishes the tumor suppressor effect. Moreover, the expression of the EGFP-R3(178-210) peptide, spanning the CIC motif of RCAN3, is able to reproduce all the antitumor effects of RCAN3 full-length protein. Finally, we show that RCAN3 and the EGFP-R3(178-210) peptide inhibit the CN-NFATc signaling pathway and the induction of the NFATc-dependent gene cyclooxygenase-2. Our work suggests that the EGFP-R3(178-210) peptide possess potent tumor suppressor properties and therefore constitutes a novel lead for the development of potent and specific antitumoral agents. Moreover, we propose the targeting of the CN-NFATc pathway in the tumor cells constitutes an effective way to hamper tumor progression by impairing the paracrine network among tumor, endothelial and polymorphonucleated cells. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Plantaricin A, a cationic peptide produced by Lactobacillus plantarum, permeabilizes eukaryotic cell membranes by a mechanism dependent on negative surface charge linked to glycosylated membrane proteins.

PubMed

Sand, Sverre L; Nissen-Meyer, Jon; Sand, Olav; Haug, Trude M

2013-02-01

Lactobacillus plantarum C11 releases plantaricin A (PlnA), a cationic peptide pheromone that has a membrane-permeabilizing, antimicrobial effect. We have previously shown that PlnA may also permeabilize eukaryotic cells, with a potency that differs between cell types. It is generally assumed that cationic antimicrobial peptides exert their effects through electrostatic attraction to negatively charged phospholipids in the membrane. The aim of the present study was to investigate if removal of the negative charge linked to glycosylated proteins at the cell surface reduces the permeabilizing potency of PlnA. The effects of PlnA were tested on clonal rat anterior pituitary cells (GH(4) cells) using patch clamp and microfluorometric techniques. In physiological extracellular solution, GH(4) cells are highly sensitive to PlnA, but the sensitivity was dramatically reduced in solutions that partly neutralize the negative surface charge of the cells, in agreement with the notion that electrostatic interactions are probably important for the PlnA effects. Trypsination of cells prior to PlnA exposure also rendered the cells less sensitive to the peptide, suggesting that negative charges linked to membrane proteins are involved in the permeabilizing action. Finally, pre-exposure of cells to a mixture of enzymes that split carbohydrate residues from the backbone of glycosylated proteins also impeded the PlnA-induced membrane permeabilization. We conclude that electrostatic attraction between PlnA and glycosylated membrane proteins is probably an essential first step before PlnA can interact with membrane phospholipids. Deviating glycosylation patterns may contribute to the variation in PlnA sensitivity of different cell types, including cancerous cells and their normal counterparts. Copyright © 2012 Elsevier B.V. All rights reserved.

In vivo interactions between α7 nicotinic acetylcholine receptor and nuclear peroxisome proliferator-activated receptor-α: Implication for nicotine dependence.

PubMed

Jackson, Asti; Bagdas, Deniz; Muldoon, Pretal P; Lichtman, Aron H; Carroll, F Ivy; Greenwald, Mark; Miles, Michael F; Damaj, M Imad

2017-05-15

Chronic tobacco use dramatically increases health burdens and financial costs. Limitations of current smoking cessation therapies indicate the need for improved molecular targets. The main addictive component of tobacco, nicotine, exerts its dependency effects via nicotinic acetylcholine receptors (nAChRs). Activation of the homomeric α7 nAChR reduces nicotine's rewarding properties in conditioned place preference (CPP) test and i.v. self-administration models, but the mechanism underlying these effects is unknown. Recently, the nuclear receptor peroxisome proliferator-activated receptor type-α (PPARα) has been implicated as a downstream signaling target of the α7 nAChR in ventral tegmental area dopamine cells. The present study investigated PPARα as a possible mediator of the effect of α7 nAChR activation in nicotine dependence. Our results demonstrate the PPARα antagonist GW6471 blocks actions of the α7 nAChR agonist PNU282987 on nicotine reward in an unbiased CPP test in male ICR adult mice. These findings suggests that α7 nAChR activation attenuates nicotine CPP in a PPARα-dependent manner. To evaluate PPARα activation in nicotine dependence we used the selective and potent PPARα agonist, WY-14643 and the clinically used PPARα activator, fenofibrate, in nicotine CPP and we observed attenuation of nicotine preference, but fenofibrate was less potent. We also studied PPARα in nicotine dependence by evaluating its activation in nicotine withdrawal. WY-14643 reversed nicotine withdrawal signs whereas fenofibrate had modest efficacy. This suggests that PPARα plays a role in nicotine reward and withdrawal and that further studies are warranted to elucidate its function in mediating the effects of α7 nAChRs in nicotine dependence. Copyright © 2017 Elsevier Ltd. All rights reserved.

In vivo Interactions between α7 Nicotinic Acetylcholine Receptor and Nuclear Peroxisome Proliferator-Activated Receptor-α: Implication for Nicotine Dependence

PubMed Central

Jackson, Asti; Bagdas, Deniz; Muldoon, Pretal P.; Lichtman, Aron H.; Carroll, F. Ivy; Greenwald, Mark; Miles, Michael F.; Damaj, M. Imad

2017-01-01

Chronic tobacco use dramatically increases health burdens and financial costs. Limitations of current smoking cessation therapies indicate the need for improved molecular targets. The main addictive component of tobacco, nicotine, exerts its dependency effects via nicotinic acetylcholine receptors (nAChRs). Activation of the homomeric α7 nAChR reduces nicotine's rewarding properties in conditioned place preference (CPP) test and i.v. self-administration models, but the mechanism underlying these effects is unknown. Recently, the nuclear receptor peroxisome proliferator-activated receptor type-α (PPARα) has been implicated as a downstream signaling target of the α7 nAChR in ventral tegmental area dopamine cells. The present study investigated PPARα as a possible mediator of the effect of α7 nAChR activation in nicotine dependence. Our results demonstrate the PPARα antagonist GW6471 blocks actions of the α7 nAChR agonist PNU282987 on nicotine reward in an unbiased CPP test in male ICR adult mice. These findings suggests that α7 nAChR activation attenuates nicotine CPP in a PPARα-dependent manner. To evaluate PPARα activation in nicotine dependence we used the selective and potent PPARα agonist, WY-14643 and the clinically used PPARα activator, fenofibrate, in nicotine CPP and we observed attenuation of nicotine preference, but fenofibrate was less potent. We also studied PPARα in nicotine dependence by evaluating its activation in nicotine withdrawal. WY-14643 reversed nicotine withdrawal signs whereas fenofibrate had modest efficacy. This suggests that PPARα plays a role in nicotine reward and withdrawal and that further studies are warranted to elucidate its function in mediating the effects of α7 nAChRs in nicotine dependence. PMID:28279662

Protective effect of astaxanthin against multiple organ injury in a rat model of sepsis.

PubMed

Zhou, Liping; Gao, Min; Xiao, Zhiming; Zhang, Juan; Li, Xiangmin; Wang, Aimin

2015-05-15

Astaxanthin, a xanthophyll carotenoid, holds exceptional promise as an antioxidant, anti-inflammatory, and anticancer agent. No evidence has been published whether it has protective effects on sepsis. The study aimed to investigate the potential effects of astaxanthin on sepsis and multiple organ dysfunctions. Sepsis was induced by cecal ligation and puncture (CLP) in Sprague-Dawley rats. Animals subjected to CLP and sham-operated control rats were given vehicle or astaxanthin 100 mg/kg/d by oral gavage for 7 d before the operation. The rats were killed at the indicated time points, and the specimen was collected. Cytokines and multiorgan injury-associated enzymatic and oxidative stress indicators were investigated. Multiorgan tissues were assessed histologically, the peritoneal bacterial load and the 72-h survival was observed too. Sepsis resulted in a significant increase in serum tumor necrosis factor-α, interleukin-1β, and interleukin-6 levels showing systemic inflammatory response; it also caused a remarkable decrease in the superoxide dismutase activity and a significant increase in the malondialdehyde content showing oxidative damage; sepsis caused a great increase in organ injury-associated indicators, including blood urea nitrogen, creatinine, lactate dehydrogenase, creatine kinase isoenzyme-MB isotype, alanine aminotransferase, and aspartate aminotransferase, which was confirmed by histologic examination. And there was a dramatical increase of colony-forming units in the peritoneal cavity in septic rats. Astaxanthin reversed these inflammatory and oxidant response, alleviated the organ injury, reduced the peritoneal bacterial load, and improved the survival of septic rats induced by CLP. Astaxanthin exerts impressively protective effects on CLP-induced multiple organ injury. It might be used as a potential treatment for clinical sepsis. Copyright © 2015 Elsevier Inc. All rights reserved.

Role of Endogenous Microbiota, Probiotics and Their Biological Products in Human Health

PubMed Central

Howarth, Gordon S.; Wang, Hanru

2013-01-01

Although gut diseases such as inflammatory bowel disease, mucositis and the alimentary cancers share similar pathogenetic features, further investigation is required into new treatment modalities. An imbalance in the gut microbiota, breached gut integrity, bacterial invasion, increased cell apoptosis to proliferation ratio, inflammation and impaired immunity may all contribute to their pathogenesis. Probiotics are defined as live bacteria, which when administered in sufficient amounts, exert beneficial effects to the gastrointestinal tract. More recently, probiotic-derived factors including proteins and other molecules released from living probiotics, have also been shown to exert beneficial properties. In this review we address the potential for probiotics, with an emphasis on probiotic-derived factors, to reduce the severity of digestive diseases and further discuss the known mechanisms by which probiotics and probiotic-derived factors exert their physiological effects. PMID:23306189

Prunus mume extract exerts antioxidant activities and suppressive effect of melanogenesis under the stimulation by alpha-melanocyte stimulating hormone in B16-F10 melanoma cells.

PubMed

Pi, KyungBae; Lee, KiBeom

2017-10-01

In the current study, we examined the antioxidant and skin-whitening properties of Prunus mume extract (PME). The ability of PME to scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals was investigated in vitro. At a concentration of 1000 μg/mL, PME neutralized >45% free radical activity. Cell viability assessment with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed that at concentrations <1500 μg/mL, PME does not exert cytotoxic effects on murine B16 melanoma (B16) cells. Morphological analysis disclosed that melanin production is inhibited in B16 cells treated with 250 nM α-melanocyte-stimulating hormone (α-MSH) and PME. We conclude that fruit extracts of P. mume exert a skin-whitening effect by inhibiting melanin production via regulation of melanogenesis-associated protein expression in melanocytes.

Melatonin potentiates the anticonvulsant action of phenobarbital in neonatal rats.

PubMed

Forcelli, Patrick A; Soper, Colin; Duckles, Anne; Gale, Karen; Kondratyev, Alexei

2013-12-01

Phenobarbital is the most commonly utilized drug for neonatal seizures. However, questions regarding safety and efficacy of this drug make it particularly compelling to identify adjunct therapies that could boost therapeutic benefit. One potential adjunct therapy is melatonin. Melatonin is used clinically in neonatal and pediatric populations, and moreover, it exerts anticonvulsant actions in adult rats. However, it has not been previously evaluated for anticonvulsant effects in neonatal rats. Here, we tested the hypothesis that melatonin would exert anticonvulsant effects, either alone, or in combination with phenobarbital. Postnatal day (P)7 rats were treated with phenobarbital (0-40mg/kg) and/or melatonin (0-80mg/kg) prior to chemoconvulsant challenge with pentylenetetrazole (100mg/kg). We found that melatonin significantly potentiated the anticonvulsant efficacy of phenobarbital, but did not exert anticonvulsant effects on its own. These data provide additional evidence for the further examination of melatonin as an adjunct therapy in neonatal/pediatric epilepsy. Copyright © 2013 Elsevier B.V. All rights reserved.

Melatonin potentiates the anticonvulsant action of phenobarbital in neonatal rats

PubMed Central

Forcelli, Patrick A.; Soper, Colin; Duckles, Anne; Gale, Karen; Kondratyev, Alexei

2013-01-01

Phenobarbital is the most commonly utilized drug for neonatal seizures. However, questions regarding safety and efficacy of this drug make it particularly compelling to identify adjunct therapies that could boost therapeutic benefit. One potential adjunct therapy is melatonin. Melatonin is used clinically in neonatal and pediatric populations, and moreover, it exerts anticonvulsant actions in adult rats. However, it has not been previously evaluated for anticonvulsant effects in neonatal rats. Here, we tested the hypothesis that melatonin would exert anticonvulsant effects, either alone, or in combination with phenobarbital, the most commonly utilized anticonvulsant in neonatal medicine. Postnatal day (P)7 rats were treated with phenobarbital (0–40 mg/kg) and/or melatonin (0–80 mg/kg) prior to chemoconvulsant challenge with pentylenetetrazole (100 mg/kg). We found that melatonin significantly potentiated the anticonvulsant efficacy of phenobarbital, but did not exert anticonvulsant effects on its own. These data provide additional evidence for the further examination of melatonin as an adjunct therapy in neonatal/pediatric epilepsy. PMID:24206906

Interest Group Conflict Over Medicaid Expansion: The Surprising Impact of Public Advocates.

PubMed

Callaghan, Timothy; Jacobs, Lawrence R

2016-02-01

We examined the potential economic, policy, and political influences on the decisions of the 50 US states to expand Medicaid under the Affordable Care Act. We related a measure of relative state progress toward Medicaid expansion updated to 2015 to each state's economic circumstances, established policy frameworks in states, partisan control of state government, and lobbyists for businesses, medical professionals, unions, and public interest organizations. The 9201 lobbyists working on health care reform in state capitols exerted a strong and significant impact on Medicaid expansion. Controlling for confounding factors (including partisanship and existing policy frameworks), we found that business and professional lobbyists exerted a negative effect on state Medicaid expansion and, unexpectedly, that public interest advocates exerted a positive effect. There are 3.1 million adults who lack coverage because they live in the 20 states that refused to expand Medicaid. Although political party and lobbyists for private interests present significant barriers in these states, legislative lobbying on behalf of the uninsured appears likely to be effective.

New weight factor for Brownian force exerted on micro/nano-particles in air flow

NASA Astrophysics Data System (ADS)

Zhang, Peijie; Lin, Jianzhong; Ku, Xiaoke

2018-05-01

In order to effectively describe the effect of Brownian force exerted on the micro/nano-particles in air flow, a new weight factor, which is defined as the ratio of the characteristic velocity of the Brownian motion to the macroscopic velocity, is proposed and applied to the particle settlement under gravity. Results show that the weight factor can quantitatively evaluate the effect of Brownian force on the particle motion. Moreover, the value of the weight factor can also be used to judge the particle motion pattern and determine whether the Brownian force should be taken into account.

N-ω-chloroacetyl-L-ornithine has in-vitro activity against cancer cell lines and in-vivo activity against ascitic and solid tumors.

PubMed

Vargas-Ramírez, Alba L; Medina-Enríquez, Miriam M; Cordero-Rodríguez, Neira I; Ruiz-Cuello, Tatiana; Aguilar-Faisal, Leopoldo; Trujillo-Ferrara, José G; Alcántara-Farfán, Verónica; Rodríguez-Páez, Lorena

2016-07-01

N-ω-chloroacetyl-L-ornithine (NCAO) is an ornithine decarboxylase (ODC) inhibitor that is known to exert cytotoxic and antiproliferative effects on three neoplastic human cancer cell lines (HeLa, MCF-7, and HepG2). Here, we show that NCAO has antiproliferative activity in 13 cancer cell lines, of diverse tissue origin from human and mice, and in a mouse cancer model in vivo. All cell lines were sensitive to NCAO after 72 h of treatment (the EC50 ranged from 1 to 50.6 µmol/l). The Ca Ski cell line was the most sensitive (EC50=1.18±0.07 µmol/l) and MDA-MB-231 was the least sensitive (EC50=50.6±0.3 µmol/l). This ODC inhibitor showed selectivity for cancer cells, exerting almost no cytotoxic effect on the normal Vero cell line (EC50>1000 µmol/l). NCAO induced apoptosis and inhibited tumor cell migration in vitro. Furthermore, in vivo, this compound (at 50 and 100 mg/kg, daily intraperitoneal injection for 7 days) exerted potent antitumor activity against both solid and ascitic tumors in a mouse model using the myeloma (Ag8) cell line. At these same two doses, the toxicological evaluation showed that NCAO has no obvious systemic toxicity. The current results suggest that the antitumor activity is exerted by apoptosis related not only to a local but also a systemic cytotoxic effect exerted by NCAO on tumor cells. The applications for NCAO as an antitumor agent may be extensive; however, further studies are needed to ascertain the antitumor activity on other types of tumor in vivo and to determine the precise molecular mechanism of its activity.

Dynamic interactions between coastal storms and salt marshes: A review

NASA Astrophysics Data System (ADS)

Leonardi, Nicoletta; Carnacina, Iacopo; Donatelli, Carmine; Ganju, Neil Kamal; Plater, Andrew James; Schuerch, Mark; Temmerman, Stijn

2018-01-01

This manuscript reviews the progresses made in the understanding of the dynamic interactions between coastal storms and salt marshes, including the dissipation of extreme water levels and wind waves across marsh surfaces, the geomorphic impact of storms on salt marshes, the preservation of hurricanes signals and deposits into the sedimentary records, and the importance of storms for the long term survival of salt marshes to sea level rise. A review of weaknesses, and strengths of coastal defences incorporating the use of salt marshes including natural, and hybrid infrastructures in comparison to standard built solutions is then presented. Salt marshes are effective in dissipating wave energy, and storm surges, especially when the marsh is highly elevated, and continuous. This buffering action reduces for storms lasting more than one day. Storm surge attenuation rates range from 1.7 to 25 cm/km depending on marsh and storms characteristics. In terms of vegetation properties, the more flexible stems tend to flatten during powerful storms, and to dissipate less energy but they are also more resilient to structural damage, and their flattening helps to protect the marsh surface from erosion, while stiff plants tend to break, and could increase the turbulence level and the scour. From a morphological point of view, salt marshes are generally able to withstand violent storms without collapsing, and violent storms are responsible for only a small portion of the long term marsh erosion. Our considerations highlight the necessity to focus on the indirect long term impact that large storms exerts on the whole marsh complex rather than on sole after-storm periods. The morphological consequences of storms, even if not dramatic, might in fact influence the response of the system to normal weather conditions during following inter-storm periods. For instance, storms can cause tidal flats deepening which in turn promotes wave energy propagation, and exerts a long term detrimental effect for marsh boundaries even during calm weather. On the other hand, when a violent storm causes substantial erosion but sediments are redistributed across nearby areas, the long term impact might not be as severe as if sediments were permanently lost from the system, and the salt marsh could easily recover to the initial state.

Dynamic interactions between coastal storms and salt marshes: A review

USGS Publications Warehouse

Leonardi, Nicoletta; Carnacina, Iacopo; Donatelli, Carmine; Ganju, Neil K.; Plater, Andrew James; Schuerch, Mark; Temmerman, Stijn

2018-01-01

This manuscript reviews the progresses made in the understanding of the dynamic interactions between coastal storms and salt marshes, including the dissipation of extreme water levels and wind waves across marsh surfaces, the geomorphic impact of storms on salt marshes, the preservation of hurricanes signals and deposits into the sedimentary records, and the importance of storms for the long term survival of salt marshes to sea level rise. A review of weaknesses, and strengths of coastal defences incorporating the use of salt marshes including natural, and hybrid infrastructures in comparison to standard built solutions is then presented.Salt marshes are effective in dissipating wave energy, and storm surges, especially when the marsh is highly elevated, and continuous. This buffering action reduces for storms lasting more than one day. Storm surge attenuation rates range from 1.7 to 25 cm/km depending on marsh and storms characteristics. In terms of vegetation properties, the more flexible stems tend to flatten during powerful storms, and to dissipate less energy but they are also more resilient to structural damage, and their flattening helps to protect the marsh surface from erosion, while stiff plants tend to break, and could increase the turbulence level and the scour. From a morphological point of view, salt marshes are generally able to withstand violent storms without collapsing, and violent storms are responsible for only a small portion of the long term marsh erosion.Our considerations highlight the necessity to focus on the indirect long term impact that large storms exerts on the whole marsh complex rather than on sole after-storm periods. The morphological consequences of storms, even if not dramatic, might in fact influence the response of the system to normal weather conditions during following inter-storm periods. For instance, storms can cause tidal flats deepening which in turn promotes wave energy propagation, and exerts a long term detrimental effect for marsh boundaries even during calm weather. On the other hand, when a violent storm causes substantial erosion but sediments are redistributed across nearby areas, the long term impact might not be as severe as if sediments were permanently lost from the system, and the salt marsh could easily recover to the initial state.

Dewetting and Segregation of Zn-Doped InSb in Microgravity Experiments

NASA Technical Reports Server (NTRS)

Ostrogorsky, A. G.; Marin, C.; Duffar, T.; Volz, M.

2009-01-01

In directional solidification, dewetting is characterized by the lack of contact between the crystal and the crucible walls, due to the existence of a liquid meniscus at the level of the solid-liquid interface. This creates a gap of a few tens of micrometers between the crystal and the crucible. One of the immediate consequences of this phenomenon is the dramatic improvement of the quality of the crystal. This improvement is partly due to the modification of the solid-liquid interface curvature and partly to the absence of sticking and spurious nucleation at the crystal-crucible interface. Dewetting has been, commonly observed during the growth of semiconductors in crucibles under microgravity conditions where it appears to be very stable: the gap between the crystal and the crucible remains constant along several centimetres of growth. The physical models of the phenomenon are well established and they predict that dewetting should not occur in microgravity, if sufficient static pressure is imposed on the melt, pushing it towards the crucible. We present the results of InSb(Zn) solidification experiments conducted at the International Space Station (ISS) where, in spite of a spring exerting a pressure on the liquid, partial dewetting did occur. This surprising result is discussed in terms of force exerted .by the spring on the liquid and of possibility that the spring did not work properly. Furthermore, it appears that the segregation of the Zn was not affected by the occurrence of the dewetting. The data suggest that there was no significant interference of convection with segregation of Zn in InSb.

Inhibition of p38/CREB phosphorylation and COX-2 expression by olive oil polyphenols underlies their anti-proliferative effects

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

Corona, Giulia; Dipartimento di Biologia Sperimentale, Sez. Patologia Sperimentale, Universita degli Studi di Cagliari, 09042 Monserrato; Deiana, Monica

2007-10-26

We investigated the anti-proliferative effects of an olive oil polyphenolic extract on human colon adenocarcinoma cells. Analysis indicated that the extract contained hydroxytyrosol, tyrosol and the various secoiridoid derivatives, including oleuropein. This extract exerted a strong inhibitory effect on cancer cell proliferation, which was linked to the induction of a G2/M phase cell cycle block. Following treatment with the extract (50 {mu}g/ml) the number of cells in the G2/M phase increased to 51.82 {+-} 2.69% relative to control cells (15.1 {+-} 2.5%). This G2/M block was mediated by the ability of olive oil polyphenols (50 {mu}g/ml) to exert rapid inhibitionmore » of p38 (38.7 {+-} 4.7%) and CREB (28.6 {+-} 5.5%) phosphorylation which led to a downstream reduction in COX-2 expression (56.9 {+-} 9.3%). Our data suggest that olive oil polyphenols may exert chemopreventative effects in the large intestine by interacting with signalling pathways responsible for colorectal cancer development.« less

Policy statement—Climatic heat stress and exercising children and adolescents.

PubMed

Bergeron, Michael F; Devore, Cynthia; Rice, Stephen G

2011-09-01

Results of new research indicate that, contrary to previous thinking, youth do not have less effective thermoregulatory ability, insufficient cardiovascular capacity, or lower physical exertion tolerance compared with adults during exercise in the heat when adequate hydration is maintained. Accordingly, besides poor hydration status, the primary determinants of reduced performance and exertional heat-illness risk in youth during sports and other physical activities in a hot environment include undue physical exertion, insufficient recovery between repeated exercise bouts or closely scheduled same-day training sessions or rounds of sports competition, and inappropriately wearing clothing, uniforms, and protective equipment that play a role in excessive heat retention. Because these known contributing risk factors are modifiable, exertional heat illness is usually preventable. With appropriate preparation, modifications, and monitoring, most healthy children and adolescents can safely participate in outdoor sports and other physical activities through a wide range of challenging warm to hot climatic conditions.

Parent-Child Attunement Moderates the Prospective Link between Parental Overcontrol and Adolescent Adjustment.

PubMed

Miller, Kelly F; Borelli, Jessica L; Margolin, Gayla

2017-10-22

Parental overcontrol (OC), behavior that intrusively or dominantly restricts child autonomy, has been identified as a transdiagnostic risk factor for youth. However, it is as yet unknown whether the association between parental OC and child maladjustment remains even when OC is exerted infrequently or by attuned parents. Rather, the selective use of OC might steer children away from danger. Taking a developmental psychopathology approach, this study focuses on the larger parent-child relationship context, testing whether either the dose at which parents demonstrate OC or the degree to which children perceive their parents as attuned determines whether OC is risky or protective for adolescents' adjustment. Among a community sample of 114 families of children followed from the ages of 12-18, we examine whether OC, behaviorally coded from triadic mother-father-child discussions in middle childhood, is associated with later risky behavior and anxiety symptoms in adolescence. Overcontrol exerted by either mothers or fathers had a curvilinear effect on adolescent risky behaviors, and this effect was moderated by children's perceived attunement. Although OC generally was associated with increased risky behaviors, low doses of OC or OC exerted by highly attuned parents protected against engagement in risky behaviors. No main effect of OC was observed on adolescent anxiety; however, mothers' OC interacted with perceived parental attunement, such that OC exerted by less attuned parents predicted greater anxiety. Results underscore that the effect of parenting behaviors depends on the larger parent-child relationship context. © 2017 Family Process Institute.

Modeling Local Item Dependence Due to Common Test Format with a Multidimensional Rasch Model

ERIC Educational Resources Information Center

Baghaei, Purya; Aryadoust, Vahid

2015-01-01

Research shows that test method can exert a significant impact on test takers' performance and thereby contaminate test scores. We argue that common test method can exert the same effect as common stimuli and violate the conditional independence assumption of item response theory models because, in general, subsets of items which have a shared…

Baseline Intraocular Pressure Is Associated with Subjective Sensitivity to Physical Exertion in Young Males

ERIC Educational Resources Information Center

Vera, Jesús; Jiménez, Raimundo; García, José Antonio; Perales, José Cesar; Cárdenas, David

2018-01-01

Purpose: The purposes of this study were to (a) investigate the effect of physical effort (cycling for 60 min at 60 ± 5% of individually computed reserve heart-rate capacity), combined with 2 different levels of cognitive demand (2-back, oddball), on intraocular pressure (IOP) and subjective judgments of perceived exertion (ratings of perceived…

THE EFFECTS OF DIFFERENT TRUNK INCLINATIONS ON BILATERAL TRUNK MUSCULAR ACTIVITIES, CENTRE OF PRESSURE AND FORCE EXERTIONS IN STATIC PUSHING POSTURES.

PubMed

Sanjaya, Kadek Heri; Lee, Soomin; Sriwarno, Andar Bagus; Shimomura, Yoshihito; Katsuura, Tetsuo

2014-06-01

In order to reconcile contradictory results from previous studies on manual pushing, a study was conducted to examine the effect of trunk inclination on muscular activities, centre of pressure (COP) and force exertion during static pushing. Ten subjects pushed at 0 degrees, 15 degrees, 30 degrees, and 45 degrees body inclinations in parallel and staggered feet stances. Wall and ground force plates measured pushing force, wall COP, vertical ground reaction force (GRF) and ground COP. Electromyogram data were recorded at 10 trunk muscle sites. Pushing force was found to increase with body inclination. GRF peaked at 15 degrees and reached its lowest level at the 45 degrees inclination. The lowest wall force plate standard deviation of COP displacement was found at the 30 degrees inclination. The lowest low back muscular activity was found at the 15 degrees and 30 degrees inclinations. Based on force exertion, muscular load, and stability, the 30 degrees body inclination was found to be the best posture for static pushing. This study also showed asymmetry in muscular activity and force exertion which has been received less attention in manual pushing studies. These findings will require further study.

Implicit theories about willpower predict the activation of a rest goal following self-control exertion.

PubMed

Job, Veronika; Bernecker, Katharina; Miketta, Stefanie; Friese, Malte

2015-10-01

Past research indicates that peoples' implicit theories about the nature of willpower moderate the ego-depletion effect. Only people who believe or were led to believe that willpower is a limited resource (limited-resource theory) showed lower self-control performance after an initial demanding task. As of yet, the underlying processes explaining this moderating effect by theories about willpower remain unknown. Here, we propose that the exertion of self-control activates the goal to preserve and replenish mental resources (rest goal) in people with a limited-resource theory. Five studies tested this hypothesis. In Study 1, individual differences in implicit theories about willpower predicted increased accessibility of a rest goal after self-control exertion. Furthermore, measured (Study 2) and manipulated (Study 3) willpower theories predicted an increased preference for rest-conducive objects. Finally, Studies 4 and 5 provide evidence that theories about willpower predict actual resting behavior: In Study 4, participants who held a limited-resource theory took a longer break following self-control exertion than participants with a nonlimited-resource theory. Longer resting time predicted decreased rest goal accessibility afterward. In Study 5, participants with an induced limited-resource theory sat longer on chairs in an ostensible product-testing task when they had engaged in a task requiring self-control beforehand. This research provides consistent support for a motivational shift toward rest after self-control exertion in people holding a limited-resource theory about willpower. (c) 2015 APA, all rights reserved).

Performing History: The Effects of a Dramatic Art-Based History Program on Student Achievement and Enjoyment

ERIC Educational Resources Information Center

Otten, Mark; Stigler, James W.; Woodward, J. Arthur; Staley, Lisle

2004-01-01

This study examines the influence of a dramatic art-based history program for fifth-grade students on both their learning and enjoyment of history. The program, called "Performing History," reflects theories of effective use of drama in the classroom as well as successful ways to teach history. The program presents historical information as part…

Do Props Matter in the Dramatic Play Center? The Effects of Prop Realism on Children's Play.

ERIC Educational Resources Information Center

Hogan, Claudia; Howe, Nina

2001-01-01

This study investigated the effects of prop realism on the play of 24 preschoolers. Observations of play sessions revealed that highly realistic props and low-realism props elicited equal amounts of group dramatic play. However, low- realism props generated greater diversity of play themes, more fantasy role enactments, and more nonintended use of…

An Investigation Into the Effects of Background Music in a Dramatic Television Presentation on University Students' Perception and Retention of Cognitive Content.

ERIC Educational Resources Information Center

Rink, Otho P.

To investigate the effects of background music on perception and retention of a dramatic television presentation's cognitive content, 107 English literature students were randomly assigned to one of five background treatments for a play. Four of the videotaped presentations included background music; Shostakovich's Symphony No. 6; Japanese jazz;…

The War Film: Historical Perspective or Simple Entertainment

DTIC Science & Technology

2001-06-01

published in 1978, the effect of the image repair campaign was not evident.25 Dr. Suid is an extremely helpful source of DOD assistance and filmmaker ...single speech at any one particular venue.32 The filmmakers merged several snippets of Patton speeches into dialogue to provide dramatic effect and a... filmmakers could support it and that the historical 135 accurate scene was still a good story. If the story faltered, dramatic effect was inserted to

Effects of the Visual Exercise Environments on Cognitive Directed Attention, Energy Expenditure and Perceived Exertion

PubMed Central

Rogerson, Mike; Barton, Jo

2015-01-01

Green exercise research often reports psychological health outcomes without rigorously controlling exercise. This study examines effects of visual exercise environments on directed attention, perceived exertion and time to exhaustion, whilst measuring and controlling the exercise component. Participants completed three experimental conditions in a randomized counterbalanced order. Conditions varied by video content viewed (nature; built; control) during two consistently-ordered exercise bouts (Exercise 1: 60% VO2peakInt for 15-mins; Exercise 2: 85% VO2peakInt to voluntary exhaustion). In each condition, participants completed modified Backwards Digit Span tests (a measure of directed attention) pre- and post-Exercise 1. Energy expenditure, respiratory exchange ratio and perceived exertion were measured during both exercise bouts. Time to exhaustion in Exercise 2 was also recorded. There was a significant time by condition interaction for Backwards Digit Span scores (F2,22 = 6.267, p = 0.007). Scores significantly improved in the nature condition (p < 0.001) but did not in the built or control conditions. There were no significant differences between conditions for either perceived exertion or physiological measures during either Exercise 1 or Exercise 2, or for time to exhaustion in Exercise 2. This was the first study to demonstrate effects of controlled exercise conducted in different visual environments on post-exercise directed attention. Via psychological mechanisms alone, visual nature facilitates attention restoration during moderate-intensity exercise. PMID:26133125

Effects of the Visual Exercise Environments on Cognitive Directed Attention, Energy Expenditure and Perceived Exertion.

PubMed

Rogerson, Mike; Barton, Jo

2015-06-30

Green exercise research often reports psychological health outcomes without rigorously controlling exercise. This study examines effects of visual exercise environments on directed attention, perceived exertion and time to exhaustion, whilst measuring and controlling the exercise component. Participants completed three experimental conditions in a randomized counterbalanced order. Conditions varied by video content viewed (nature; built; control) during two consistently-ordered exercise bouts (Exercise 1: 60% VO2peakInt for 15-mins; Exercise 2: 85% VO2peakInt to voluntary exhaustion). In each condition, participants completed modified Backwards Digit Span tests (a measure of directed attention) pre- and post-Exercise 1. Energy expenditure, respiratory exchange ratio and perceived exertion were measured during both exercise bouts. Time to exhaustion in Exercise 2 was also recorded. There was a significant time by condition interaction for Backwards Digit Span scores (F2,22 = 6.267, p = 0.007). Scores significantly improved in the nature condition (p < 0.001) but did not in the built or control conditions. There were no significant differences between conditions for either perceived exertion or physiological measures during either Exercise 1 or Exercise 2, or for time to exhaustion in Exercise 2. This was the first study to demonstrate effects of controlled exercise conducted in different visual environments on post-exercise directed attention. Via psychological mechanisms alone, visual nature facilitates attention restoration during moderate-intensity exercise.

The Role of Motivation, Glucose and Self-Control in the Antisaccade Task

PubMed Central

Kelly, Claire L.; Sünram-Lea, Sandra I.; Crawford, Trevor J.

2015-01-01

Research shows that self-control is resource limited and there is a gradual weakening in consecutive self-control task performance akin to muscle fatigue. A body of evidence suggests that the resource is glucose and consuming glucose reduces this effect. This study examined the effect of glucose on performance in the antisaccade task - which requires self-control through generating a voluntary eye movement away from a target - following self-control exertion in the Stroop task. The effects of motivation and individual differences in self-control were also explored. In a double-blind design, 67 young healthy adults received a 25g glucose or inert placebo drink. Glucose did not enhance antisaccade performance following self-control exertion in the Stroop task. Motivation however, predicted performance on the antisaccade task; more specifically high motivation ameliorated performance decrements observed after initial self-control exertion. In addition, individuals with high levels of self-control performed better on certain aspects of the antisaccade task after administration of a glucose drink. The results of this study suggest that the antisaccade task might be a powerful paradigm, which could be used as a more objective measure of self-control. Moreover, the results indicate that level of motivation and individual differences in self-control should be taken into account when investigating deficiencies in self-control following prior exertion. PMID:25826334

Semipurified Ethyl Acetate Partition of Methanolic Extract of Melastoma malabathricum Leaves Exerts Gastroprotective Activity Partly via Its Antioxidant-Antisecretory-Anti-Inflammatory Action and Synergistic Action of Several Flavonoid-Based Compounds

PubMed Central

Ismail Suhaimy, Noor Wahida; Noor Azmi, Ahmad Khusairi; Mohtarrudin, Norhafizah; Cheema, Manraj Singh

2017-01-01

Recent study has demonstrated the gastroprotective activity of crude methanolic extract of M. malabathricum leaves. The present study evaluated the gastroprotective potential of semipurified extracts (partitions): petroleum ether, ethyl acetate (EAMM), and aqueous obtained from the methanolic extract followed by the elucidation of the gastroprotective mechanisms of the most effective partition. Using the ethanol-induced gastric ulcer assay, all partitions exerted significant gastroprotection, with EAMM being the most effective partition. EAMM significantly (i) reduced the volume and acidity (free and total) while increasing the pH of gastric juice and enhanced the gastric wall mucus secretion when assessed using the pylorus ligation assay, (ii) increased the enzymatic and nonenzymatic antioxidant activity of the stomach tissue, (iii) lost its gastroprotective activity following pretreatment with N-omega-nitro-L-arginine methyl ester (L-NAME; NO blocker) or carbenoxolone (CBXN; NP-SH blocker), (iv) exerted antioxidant activity against various in vitro oxidation assays, and (v) showed moderate in vitro anti-inflammatory activity via the LOX-modulated pathway. In conclusion, EAMM exerts a remarkable NO/NP-SH-dependent gastroprotective effect that is attributed to its antisecretory and antioxidant activities, ability to stimulate the gastric mucus production and endogenous antioxidant system, and synergistic action of several gastroprotective-induced flavonoids. PMID:28168011

Ergonomics and patient handling.

PubMed

McCoskey, Kelsey L

2007-11-01

This study aimed to describe patient-handling demands in inpatient units during a 24-hour period at a military health care facility. A 1-day total population survey described the diverse nature and impact of patient-handling tasks relative to a variety of nursing care units, patient characteristics, and transfer equipment. Productivity baselines were established based on patient dependency, physical exertion, type of transfer, and time spent performing the transfer. Descriptions of the physiological effect of transfers on staff based on patient, transfer, and staff characteristics were developed. Nursing staff response to surveys demonstrated how patient-handling demands are impacted by the staff's physical exertion and level of patient dependency. The findings of this study describe the types of transfers occurring in these inpatient units and the physical exertion and time requirements for these transfers. This description may guide selection of the most appropriate and cost-effective patient-handling equipment required for specific units and patients.

Influence of Protein-Phenolic Complex on the Antioxidant Capacity of Flaxseed (Linum usitatissimum L.) Products.

PubMed

Guimarães Drummond E Silva, Fernanda; Miralles, Beatriz; Hernández-Ledesma, Blanca; Amigo, Lourdes; Iglesias, Amadeu Hoshi; Reyes Reyes, Felix Guillermo; Netto, Flavia Maria

2017-02-01

The impact of the naturally present phenolic compounds and/or proteins on the antioxidant capacity of flaxseed products (phenolic fraction, protein concentrates, and hydrolysates) before and after simulated gastrointestinal digestion was studied. For that, whole and phenolic reduced products were assessed. Four glycosylated phenolic compounds (secoisolariciresinol and ferulic, p-coumaric, and caffeic acids) were identified in flaxseed products. Phenolic fraction exerts the highest antioxidant capacity that increased by alkaline hydrolysis and by simulated gastrointestinal digestion. The action of Alcalase and digestive enzymes resulted in an increase of the antioxidant capacity of whole and phenolic reduced products. Principal component analysis showed that proteinaceous samples act as antioxidant is by H + transfer, while those samples containing phenolic compounds exert their effects by both electron donation and H + transfer mechanisms. Protein/peptide-phenolic complexation, confirmed by fluorescence spectra, exerted a positive effect on the antioxidant capacity, mainly in protein concentrates.

Beneficial effect of prolonged heme oxygenase 1 activation in a rat model of chronic heart failure.

PubMed

Collino, Massimo; Pini, Alessandro; Mugelli, Niccolò; Mastroianni, Rosanna; Bani, Daniele; Fantozzi, Roberto; Papucci, Laura; Fazi, Marilena; Masini, Emanuela

2013-07-01

We and others have previously demonstrated that heme oxygenase 1 (HO-1) induction by acute hemin administration exerts cardioprotective effects. Here, we developed a rat model of heart failure to investigate whether a long-term induction of HO-1 by chronic hemin administration exerted protective effects. Sprague Dawley rats that underwent permanent ligation of the left coronary artery were closely monitored for survival rate analysis and sacrificed on day 28 post-operation. Administration of hemin (4 mg/kg body weight) every other day for 4 weeks induced a massive increase in HO-1 expression and activity, as shown by the increased levels of the two main metabolic products of heme degradation, bilirubin and carbon monoxide (CO). These effects were associated with significant improvement in survival and reduced the extension of myocardial damage. The ischemic hearts of the hemin-treated animals displayed reduced oxidative stress and apoptosis in comparison with the non-treated rats, as shown by the decreased levels of lipid peroxidation, free-radical-induced DNA damage, caspase-3 activity and Bax expression. Besides, chronic HO-1 activation suppressed the elevated levels of myeloperoxidase (MPO) activity, interleukin 1β (IL-1β) production and tumor necrosis factor-α (TNFα) production that were evoked by the ischemic injury, and increased the plasma level of the anti-inflammatory cytokine IL-10. Interestingly, HO-1 inhibitor zinc protoporphyrin IX (ZnPP-IX; 1 mg/kg) lowered bilirubin and CO concentrations to control values, thus abolishing all the cardioprotective effects of hemin. In conclusion, the results demonstrate that chronic HO-1 activation by prolonged administration of hemin improves survival and exerts protective effects in a rat model of myocardial ischemia by exerting a potent antioxidant activity and disrupting multiple levels of the apoptotic and inflammatory cascade.

Overexpression of GDNF in the uninjured DRG exerts analgesic effects on neuropathic pain following segmental spinal nerve ligation in mice.

PubMed

Takasu, Kumiko; Sakai, Atsushi; Hanawa, Hideki; Shimada, Takashi; Suzuki, Hidenori

2011-11-01

Glial cell line-derived neurotrophic factor (GDNF), a survival-promoting factor for a subset of nociceptive small-diameter neurons, has been shown to exert analgesic effects on neuropathic pain. However, its detailed mechanisms of action are still unknown. In the present study, we investigated the site-specific analgesic effects of GDNF in the neuropathic pain state using lentiviral vector-mediated GDNF overexpression in mice with left fifth lumbar (L5) spinal nerve ligation (SNL) as a neuropathic pain model. A lentiviral vector expressing both GDNF and enhanced green fluorescent protein (EGFP) was constructed and injected into the left dorsal spinal cord, uninjured fourth lumbar (L4) dorsal root ganglion (DRG), injured L5 DRG, or plantar skin of mice. In SNL mice, injection of the GDNF-EGFP-expressing lentivirus into the dorsal spinal cord or uninjured L4 DRG partially but significantly reduced the mechanical allodynia in association with an increase in GDNF protein expression in each virus injection site, whereas injection into the injured L5 DRG or plantar skin had no effects. These results suggest that GDNF exerts its analgesic effects in the neuropathic pain state by acting on the central terminals of uninjured DRG neurons and/or on the spinal cells targeted by the uninjured DRG neurons. This article shows that GDNF exerts its analgesic effects on neuropathic pain by acting on the central terminals of uninjured DRG neurons and/or on the spinal cells targeted by these neurons. Therefore, research focusing on these GDNF-dependent neurons in the uninjured DRG would provide a new strategy for treating neuropathic pain. Copyright © 2011 American Pain Society. Published by Elsevier Inc. All rights reserved.

Delta-9-tetrahydrocannabinol (THC) affects forelimb motor map expression but has little effect on skilled and unskilled behavior.

PubMed

Scullion, K; Guy, A R; Singleton, A; Spanswick, S C; Hill, M N; Teskey, G C

2016-04-05

It has previously been shown in rats that acute administration of delta-9-tetrahydrocannabinol (THC) exerts a dose-dependent effect on simple locomotor activity, with low doses of THC causing hyper-locomotion and high doses causing hypo-locomotion. However the effect of acute THC administration on cortical movement representations (motor maps) and skilled learned movements is completely unknown. It is important to determine the effects of THC on motor maps and skilled learned behaviors because behaviors like driving place people at a heightened risk. Three doses of THC were used in the current study: 0.2mg/kg, 1.0mg/kg and 2.5mg/kg representing the approximate range of the low to high levels of available THC one would consume from recreational use of cannabis. Acute peripheral administration of THC to drug naïve rats resulted in dose-dependent alterations in motor map expression using high resolution short duration intracortical microstimulation (SD-ICMS). THC at 0.2mg/kg decreased movement thresholds and increased motor map size, while 1.0mg/kg had the opposite effect, and 2.5mg/kg had an even more dramatic effect. Deriving complex movement maps using long duration (LD)-ICMS at 1.0mg/kg resulted in fewer complex movements. Dosages of 1.0mg/kg and 2.5mg/kg THC reduced the number of reach attempts but did not affect percentage of success or the kinetics of reaching on the single pellet skilled reaching task. Rats that received 2.5mg/kg THC did show an increase in latency of forelimb removal on the bar task, while dose-dependent effects of THC on unskilled locomotor activity using the rotorod and horizontal ladder tasks were not observed. Rats may be employing compensatory strategies after receiving THC, which may account for the robust changes in motor map expression but moderate effects on behavior. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

A Study of the Effects of Creative Dramatics on the Progress in Use of the Library, Reading Interests, Reading Achievement, Self-Concept, Creativity, and Empathy of Fourth and Fifth Grade Children.

ERIC Educational Resources Information Center

Ziegler, Elsie Mae

To appraise the value of a creative dramatics program in a public library setting was the purpose of this study. Nine public library branches comprised the setting for the experiment. At each branch there were three units: (1) creative dramatics, (2) storytelling, and (3) library usage. Storytelling and library usage were the control group. Pre…

Comprehensive and Holistic Analysis of HT-29 Colorectal Cancer Cells and Tumor-Bearing Nude Mouse Model: Interactions Among Fractions Derived From the Chinese Medicine Formula Tian Xian Liquid in Effects on Human Colorectal Carcinoma.

PubMed

Leigh, Annballaw Bridget; Cheung, Ho Pan; Lin, Li-Zhu; Ng, Tzi Bun; Lao, Lixing; Zhang, Yanbo; Zhang, Zhang-Jin; Tong, Yao; Sze, Stephen Cho Wing

2017-09-01

The Chinese medicine formula Tian Xian Liquid (TXL) has been used clinically for cancer therapy in China for more than 25 years. However, the comprehensive and holistic effects of its bioactive fractions for various antitumor therapeutic effects have not been unraveled. This is the first study to scientifically elucidate the holistic effect of Chinese medicine formula for treating colon cancer, hence allowing a better understanding of the essence of Chinese medicine formula, through the comparison of the actions of TXL and its functional constituent fractions, including ethyl acetate (EA), butanol (BU), and aqueous (WA) fractions. Tissue-specific proliferative/antiproliferative effects of these fractions on human colorectal carcinoma HT-29 cells and splenocytes were studied by using the MTT assay. Their modulations on the expression of markers of antiproliferation, antimetastasis, reversion of multidrug resistance in treated HT-29 cells were examined with real-time polymerase chain reaction and Western blot analysis, and their modulations in a xenografted nude mouse model were examined by Western blot analysis. Results revealed that EA fraction slightly inhibited the proliferation of HT-29 cells, but tissue-specifically exerted the most potent antiproliferative effect on splenocytes. On the contrary, only TXL and BU fraction tissue-specifically contributed to the proliferation of splenocytes, but inhibited the proliferation of HT-29 cells. WA fraction exerted the most potent antiproliferative effect on HT-29 cells and also the strongest inhibitory action on tumor size in the nude mouse model in our previous study. In the HT-29 model, TXL and WA fraction exerted the most pronounced effect on upregulation of p21 mRNA and protein; TXL, and EA and WA fractions exerted the effect on downregulation of G1 phase cell cycle protein, cyclin D1 mRNA and protein; EA and BU fractions exerted the most prominent anti-invasive effect on anti-invasion via downregulation of MMP-1 mRNA; TXL potently reversed most multidrug resistance via downregulation of MDR-1 protein. In conclusion, the comprehensive and holistic effects of TXL were demonstrated with ( a) mutual accentuation and mutual enhancement, ( b) mutual counteraction and mutual suppression, and ( c) mutual antagonism among the 3 constituent fractions. Moreover, the design of the present study may lead to further development of more tissue-specific effective drugs with minimal side effects for clinical use in combating carcinoma.

The effects of vinblastine on endothelial cells.

PubMed

Gallagher, H; Carroll, W M; Dowd, M; Rochev, Y

2008-01-01

The development of drug-eluting stents to combat the problem of in-stent restenosis has revolutionized interventional cardiology. However, concerns have emerged about the risk of late angiographic stent thromboses associated with drug-eluting stents. It has been shown that noncytotoxic concentrations of paclitaxel exert an antiangiogenic effect, suggesting that paclitaxel and similar agents may inhibit key cellular functions in a threshold-independent manner. In this study, the effect of vinblastine, an antimitotic drug, on endothelial cells is analyzed. It is investigated whether noncytotoxic concentrations of the drug could exert an antirestenotic effect. The change in levels of cell proliferation, activity, and viability in human umbilical vein endothelial cells was measured at a range of concentrations and over a number of time points. Also, the level of apoptotic activity in response to vinblastine was analyzed. This study shows that the concentration of vinblastine most appropriate in restenosis treatment would be between 0.1 and 1 nM. At this concentration, vinblastine exerts a distinct biological effect without causing an increase in apoptotic activity. These results emphasize the importance of finding an appropriate concentration window in order to minimize the risk of delayed endothelialization and thrombosis.

Effects of retinoic acids on the dendritic morphology of cultured hippocampal neurons.

PubMed

Liu, Ying; Kagechika, Hiroyuki; Ishikawa, Junko; Hirano, Hitoshi; Matsukuma, Satoshi; Tanaka, Kazuko; Nakamura, Shoji

2008-08-01

Vitamin A-derived retinoic acids (RAs) are known to exert a variety of biological actions, including modulatory effects on cell differentiation and apoptosis. A recent study has demonstrated that 13-cis-RA and all-trans-RA suppressed neurogenesis in the dentate gyrus of the hippocampus in adult mice. The present experiments were performed to see whether 13-cis-RA and all-trans-RA could alter the dendritic morphology of cultured hippocampal neurons via RA receptors: retinoic acid receptor (RAR) and retinoid X receptor (RXR). High doses of 13-cis-RA and all-trans-RA exerted a negative effect on the cultured hippocampal neurons, while a low dose of 13-cis-RA but not all-trans-RA caused a positive effect. The negative changes induced by 13-cis-RA and all-trans-RA were antagonized by RXR antagonists and RAR antagonists, respectively. The positive changes induced by a low dose of 13-cis-RA were blocked by both RXR antagonists and RAR antagonists. These results suggest that RAs at high concentrations cause a negative effect on the dendritic morphology of cultured hippocampal neurons through RA receptors, while RAs at low concentrations exert a positive influence on cultured hippocampal neurons.

Mirtazapine exerts an anxiolytic-like effect through activation of the median raphe nucleus-dorsal hippocampal 5-HT pathway in contextual fear conditioning in rats.

PubMed

An, Yan; Chen, Chong; Inoue, Takeshi; Nakagawa, Shin; Kitaichi, Yuji; Wang, Ce; Izumi, Takeshi; Kusumi, Ichiro

2016-10-03

The functional role of serotonergic projections from the median raphe nucleus (MRN) to the dorsal hippocampus (DH) in anxiety remains understood poorly. The purpose of the present research was to examine the functional role of this pathway, using the contextual fear conditioning (CFC) model of anxiety. We show that intra-MRN microinjection of mirtazapine, a noradrenergic and specific serotonergic antidepressant, reduced freezing in CFC without affecting general motor activity dose-dependently, suggesting an anxiolytic-like effect. In addition, intra-MRN microinjection of mirtazapine dose-dependently increased extracellular concentrations of serotonin (5-HT) but not dopamine in the DH. Importantly, intra-DH pre-microinjection of WAY-100635, a 5-HT1A antagonist, significantly attenuated the effect of mirtazapine on freezing. These results, for the first time, suggest that activation of the MRN-DH 5-HT1A pathway exerts an anxiolytic-like effect in CFC. This is consistent with the literature that the hippocampus is essential for retrieval of contextual memory and that 5-HT1A receptor activation in the hippocampus primarily exerts an inhibitory effect on the neuronal activity. Copyright © 2016 Elsevier Inc. All rights reserved.

ASP6537, a novel highly selective cyclooxygenase-1 inhibitor, exerts potent antithrombotic effect without "aspirin dilemma".

PubMed

Sakata, Chinatsu; Kawasaki, Tomihisa; Kato, Yasuko; Abe, Masaki; Suzuki, Ken-ichi; Ohmiya, Makoto; Funatsu, Toshiyuki; Morita, Yoshiaki; Okada, Masamichi

2013-07-01

Aspirin inhibits both the cyclooxygenase (COX)-1-dependent production of thromboxane A2 (TXA2) in platelets and COX-2-dependent production of anti-aggregatory prostaglandin I2 (PGI2) in vessel walls, resulting in "aspirin dilemma." Our objective is to investigate whether ASP6537 can overcome aspirin dilemma and exert a potent antithrombotic effect without a concurrent ulcerogenic effect. We evaluated the inhibitory effects of ASP6537 on recombinant human COX-1 (rhCOX-1) and rhCOX-2 activities using a COX-1/2 selectivity test. To determine whether ASP6537 induces aspirin dilemma, we examined the effects of ASP6537 on in vitro TXA2 and PGI2 metabolite production from platelets and isolated aorta of guinea pigs, and on plasma concentrations of TXA2 and PGI2 metabolites in aged rats. Finally, we evaluated the antithrombotic effects and ulcerogenic activity of ASP6537 using an electrically induced carotid arterial thrombosis model and a gastric ulcer model in guinea pigs. The IC50 ratios of rhCOX-2 to rhCOX-1 for ASP6537 and aspirin were >142,000 and 1.63 fold, respectively. ASP6537 inhibited TXA2 production more selectively than aspirin in in vitro and in vivo TXA2/PGI2 production studies. ASP6537 exerted a significant antithrombotic effect at ≥3 mg/kg, while aspirin tended to inhibit thrombosis at 300 mg/kg but it was not statistically significant. Further, ASP6537 did not induce ulcer formation at 100 mg/kg, whereas aspirin exhibited an ulcerogenic effect at doses of ≥100 mg/kg. ASP6537 functions as a highly selective COX-1 inhibitor with a superior ability to aspirin for normalizing TXA2/PGI2 balance, and exerts antithrombotic effect without ulcerogenic effect. Copyright © 2013 Elsevier Ltd. All rights reserved.

The Effect of Environmental Chemicals on Human Health -- CJA

EPA Science Inventory

Humans and animals have always been exposed to chemicals in our environment - natural products in foods, smoke from cooking fires, sewage in drinking water, pesticides from plants. However, the dramatic increases in industrialization over the past three centuries have dramatical...

THE EFFECT OF ENVIRONMENTAL CHEMICALS ON HUMAN HEALTH -- USCF

EPA Science Inventory

Humans and animals have always been exposed to chemicals in our environment - natural products in foods, smoke from cooking fires, sewage in drinking water, pesticides from plants. However, the dramatic increases in industrialization over the past three centuries have dramatical...

Curcumin phytosomal softgel formulation: Development, optimization and physicochemical characterization.

PubMed

Allam, Ahmed N; Komeil, Ibrahim A; Abdallah, Ossama Y

2015-09-01

Curcumin, a naturally occurring lipophilic molecule can exert multiple and diverse bioactivities. However, its limited aqueous solubility and extensive presystemic metabolism restrict its bioavailability. Curcumin phytosomes were prepared by a simple solvent evaporation method where free flowing powder was obtained in addition to a newly developed semisolid formulation to increase curcumin content in softgels. Phytosomal powder was characterized in terms of drug content and zeta potential. Thirteen different softgel formulations were developed using oils such as Miglyol 812, castor oil and oleic acid, a hydrophilic vehicle such as PEG 400 and bioactive surfactants such as Cremophor EL and KLS P 124. Selected formulations were characterized in terms of curcumin in vitro dissolution. TEM analysis revealed good stability and a spherical, self-closed structure of curcumin phytosomes in complex formulations. Stability studies of chosen formulations prepared using the hydrophilic vehicle revealed a stable curcumin dissolution pattern. In contrast, a dramatic decrease in curcumin dissolution was observed in case of phytosomes formulated in oily vehicles.

Fire and vegetation shifts in the Americas at the vanguard of Paleoindian migration

USGS Publications Warehouse

Pinter, N.; Fiedel, S.; Keeley, J.E.

2011-01-01

Across North and South America, the final millennia of the Pleistocene saw dramatic changes in climate, vegetation, fauna, fire regime, and other local and regional paleo-environmental characteristics. Rapid climate shifts following the Last Glacial Maximum (LGM) exerted a first-order influence, but abrupt postglacial shifts in vegetation composition, vegetation structure, and fire regime also coincided with human arrival and transformative faunal extinctions in the Americas. We propose a model of post-glacial vegetation change in response to climatic drivers, punctuated by local fire regime shifts in response to megaherbivore-driven fuel changes and anthropogenic ignitions. The abrupt appearance of humans, disappearance of megaherbivores, and resulting changes in New World fire systems were transformative events that should not be dismissed in favor of climate-only interpretations of post-glacial paleo-environmental shifts in the Americas. Fire is a mechanism by which small human populations can have broad impacts, and growing evidence suggests that early anthropogenic influences on regional, even global, paleo-environments should be tested alongside other potential causal mechanisms.

The functional role for condensin in the regulation of chromosomal organization during the cell cycle.

PubMed

Kagami, Yuya; Yoshida, Kiyotsugu

2016-12-01

In all organisms, the control of cell cycle progression is a fundamental process that is essential for cell growth, development, and survival. Through each cell cycle phase, the regulation of chromatin organization is essential for natural cell proliferation and maintaining cellular homeostasis. During mitosis, the chromatin morphology is dramatically changed to have a "thread-like" shape and the condensed chromosomes are segregated equally into two daughter cells. Disruption of the mitotic chromosome architecture physically impedes chromosomal behaviors, such as chromosome alignment and chromosome segregation; therefore, the proper mitotic chromosome structure is required to maintain chromosomal stability. Accumulating evidence has demonstrated that mitotic chromosome condensation is induced by condensin complexes. Moreover, recent studies have shown that condensin also modulates interphase chromatin and regulates gene expression. This review mainly focuses on the molecular mechanisms that condensin uses to exert its functions during the cell cycle progression. Moreover, we discuss the condensin-mediated chromosomal organization in cancer cells.

Aging of the T cell compartment in mice and humans: from no naïve expectations to foggy memories

PubMed Central

Nikolich-Žugich, Janko

2014-01-01

Until the mid-20th century, infectious diseases were the major cause of morbidity and mortality in humans. Massive vaccination campaigns, antibiotics, antivirals and advanced public health measures drastically reduced sickness and death of infections in children and younger adults. Older adults (>65yr of age), however, remain vulnerable to infections, and to date infectious diseases remain amongst the top 5–10 causes of death in this population. The aging of the immune system, often referred to as immune senescence, is the key phenomenon underlying this vulnerability. This review centers on age-related changes in T cells, which are dramatically and reproducibly altered with aging. I will discuss changes in T cell production, maintenance, function and response to latent persistent infection, particularly against the cytomegalovirus (CMV), that exerts profound influence on the aging T cell pool, concluding with a brief list of measures to improve immune function in older adults. PMID:25193936

Translating Mechanism-Based Strategies to Break the Obesity-Cancer Link: A Narrative Review.

PubMed

Smith, Laura A; O'Flanagan, Ciara H; Bowers, Laura W; Allott, Emma H; Hursting, Stephen D

2018-04-01

Prevalence of obesity, an established risk factor for many cancers, has increased dramatically over the past 50 years in the United States and across the globe. Relative to normoweight cancer patients, obese cancer patients often have poorer prognoses, resistance to chemotherapies, and are more likely to develop distant metastases. Recent progress on elucidating the mechanisms underlying the obesity-cancer connection suggests that obesity exerts pleomorphic effects on pathways related to tumor development and progression and, thus, there are multiple opportunities for primary prevention and treatment of obesity-related cancers. Obesity-associated alterations, including systemic metabolism, adipose inflammation, growth factor signaling, and angiogenesis, are emerging as primary drivers of obesity-associated cancer development and progression. These obesity-associated host factors interact with the intrinsic molecular characteristics of cancer cells, facilitating several of the hallmarks of cancer. Each is considered in the context of potential preventive and therapeutic strategies to reduce the burden of obesity-related cancers. In addition, this review focuses on emerging mechanisms behind the obesity-cancer link, as well as relevant dietary interventions, including calorie restriction, intermittent fasting, low-fat diet, and ketogenic diet, that are being implemented in preclinical and clinical trials, with the ultimate goal of reducing incidence and progression of obesity-related cancers. Copyright © 2018 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.

Determining Suction Feeding Efficiency in the Bowfin fish (Amia) using Particle Image Velocimery and Computaional Fluid Dynamics

NASA Astrophysics Data System (ADS)

Rua, Yenny; Kharbouch, Karim; Sanford, Christopher; Reckinger, Shanon

2014-11-01

Suction feeding is the most common form of prey capture in aquatic vertebrates. During the early evolution of fishes there was a major change in shape of the mouth, from a wedge shaped mouth opening in more primitive fishes to a more circular and planar mouth. This change in shape resulted from increased mobility of a key upper jaw bone, the maxilla. It has been suggested that this change in shape dramatically increased suction feeding efficiency. This study examines the hydrodynamic effects of these two mouth shapes in the same animal, the bowfin fish (Amia calva). 2D Particle Image Velocimetry (PIV) is used to analyze suction feeding events. Post-processing algorithms have been developed to determine the flow rate of water into the mouth of the fish; the area of fluid, the velocity of fluid and the volume of fluid affected by the fish; the velocity of the fluid at the mouth, as well as the velocity of the fluid as a function of the distance from the mouth, finally the force exerted on the fluid by the fish is also determined. Lastly, a numerical model has been developed for comparison using a non-uniform mesh, which adapts dynamically in space and time to the fish feeding event. The realistic geometry of the fish's head is modeled in CAD.

Exploration into Uric and Cardiovascular Disease: Uric Acid Right for heArt Health (URRAH) Project, A Study Protocol for a Retrospective Observational Study.

PubMed

Desideri, Giovambattista; Virdis, Agostino; Casiglia, Edoardo; Borghi, Claudio

2018-06-01

The relevance of cardiovascular role played by levels of serum uric acid is dramatically growing, especially as cardiovascular risk factor potentially able to exert either a direct deleterious impact or a synergic effect with other cardiovascular risk factors. At the present time, it still remains undefined the threshold level of serum uric acid able to contribute to the cardiovascular risk. Indeed, the available epidemiological case studies are not homogeneous, and some preliminary data suggest that the so-called "cardiovascular threshold limit" may substantially differ from that identified as a cut-off able to trigger the acute gout attack. In such scenario, there is the necessity to clarify and quantify this threshold value, to insert it in the stratification of risk algorithm scores and, in turn, to adopt proper prevention and correction strategies. The clarification of the relationship between circulating levels of uric acid and cardio-nephro-metabolic disorders in a broad sample representative of general population is critical to identify the threshold value of serum uric acid better discriminating the increased risk associated with uric acid. The Uric acid Right for heArt Health (URRAH) project has been designed to define, as primary objective, the level of uricemia above which the independent risk of cardiovascular disease may increase in a significantly manner in a general Italian population.

Scale-dependent variation in nitrogen cycling and soil fungal communities along gradients of forest composition and age in regenerating tropical dry forests.

PubMed

Waring, Bonnie G; Adams, Rachel; Branco, Sara; Powers, Jennifer S

2016-01-01

Rates of ecosystem nitrogen (N) cycling may be mediated by the presence of ectomycorrhizal fungi, which compete directly with free-living microbes for N. In the regenerating tropical dry forests of Central America, the distribution of ectomycorrhizal trees is affected by succession and soil parent material, both of which may exert independent influence over soil N fluxes. In order to quantify these interacting controls, we used a scale-explicit sampling strategy to examine soil N cycling at scales ranging from the microsite to ecosystem level. We measured fungal community composition, total and inorganic N pools, gross proteolytic rate, net N mineralization and microbial extracellular enzyme activity at multiple locations within 18 permanent plots that span dramatic gradients of soil N concentration, stand age and forest composition. The ratio of inorganic to organic N cycling was correlated with variation in fungal community structure, consistent with a strong influence of ectomycorrhiza on ecosystem-scale N cycling. However, on average, > 61% of the variation in soil biogeochemistry occurred within plots, and the effects of forest composition were mediated by this local-scale heterogeneity in total soil N concentrations. These cross-scale interactions demonstrate the importance of a spatially explicit approach towards an understanding of controls on element cycling. © 2015 The Authors. New Phytologist © 2015 New Phytologist Trust.

Constant light affects retinal dopamine levels and blocks deprivation myopia but not lens-induced refractive errors in chickens.

PubMed

Bartmann, M; Schaeffel, F; Hagel, G; Zrenner, E

1994-01-01

Chickens were raised with either translucent occluders or lenses, both under normal light cycles (12-h light/12-h dark) and in constant light (CL). Under normal light cycles, eyes with occluders became very myopic, and eyes with lenses became either relatively hyperopic (positive lenses) or myopic (negative lenses). After the treatment, retinal dopamine (DA), DOPAC, and serotonin levels were measured by high-pressure liquid chromatography (HPLC-EC). A significant drop in daytime retinal DOPAC (-20%) was observed after 1 week of deprivation, and in both DOPAC (-40%) and DA (-30%) after 2 weeks of deprivation. No changes in retinal serotonin levels were found. Retinal DA or DOPAC content remained unchanged after 2 or 4 days of lens wearing even though the lenses had already exerted their maximal effect on axial eye growth. When the chickens were raised in CL, development of deprivation myopia was reduced (8 days CL) or entirely blocked (13 days CL). Lens-induced changes in eye growth were not different after either 6 or 11 days in CL, compared to animals raised in a normal light cycle. Thirteen days of CL resulted in a dramatic reduction of DA and DOPAC levels, but serotonin levels were also lowered. The results suggest that lens-induced changes in refraction may not be dependent on dopaminergic pathways whereas deprivation myopia requires normal diurnal DA rhythms to develop.

A stapled peptide antagonist of MDM2 carried by polymeric micelles sensitizes glioblastoma to temozolomide treatment through p53 activation

PubMed Central

Chen, Xishan; Tai, Lingyu; Gao, Jie; Qian, Jianchang; Zhang, Mingfei; Li, Beibei; Xie, Cao; Lu, Linwei; Lu, Wuyuan; Lu, Weiyue

2017-01-01

Antagonizing MDM2 and MDMX to activate the tumor suppressor protein p53 is an attractive therapeutic paradigm for the treatment of glioblastoma multiforme (GBM). However, challenges remain with respect to the poor ability of p53 activators to efficiently cross the blood–brain barrier and/or blood–brain tumor barrier and to specifically target tumor cells. To circumvent these problems, we developed a cyclic RGD peptide-conjugated poly(-ethylene glycol)-co-poly(lactic acid) polymeric micelle (RGD-M) that carried a stapled peptide antagonist of both MDM2 and MDMX (sPMI). The peptide-carrying micelle RGD-M/sPMI was prepared via film-hydration method with high encapsulation efficiency and loading capacity as well as ideal size distribution. Micelle encapsulation dramatically increased the solubility of sPMI, thus alleviating its serum sequestration. In vitro studies showed that RGD-M/sPMI efficiently inhibited the proliferation of glioma cells in the presence of serum by activating the p53 signaling pathway. Further, RGD-M/sPMI exerted potent tumor growth inhibitory activity against human glioblastoma in nude mouse xenograft models. Importantly, the combination of RGD-M/sPMI and temozolomide — a standard chemotherapy drug for GBM increased antitumor efficacy against glioblastoma in experimental animals. Our results validate a combination therapy using p53 activators with temozolomide as a more effective treatment for GBM. PMID:26428461

Retropharyngeal cerebrospinal fluid collection as a cause of postoperative dysphagia after anterior cervical discectomy.

PubMed

Spennato, Pietro; Rapanà, Armando; Sannino, Ettore; Iaccarino, Corrado; Tedeschi, Enrico; Massarelli, Ilario; Bellotti, Alfredo; Schönauer, Massimo

2007-05-01

Transient dysphagia after anterior cervical discectomy is not uncommon. It is usually related to esophageal edema secondary to retraction, mechanical adhesions of the esophagus to the anterior spine, and stretch injuries to nerves involved in the swallowing mechanism. Structurally induced dysphagia, secondary to laceration of the neck viscera or to the presence of retropharyngeal masses, is by far less frequent, and it does not usually improve over time. The authors present the case of a 36-year-old woman who complained of severe dysphagia both for solids and liquids after C4 through C5 anterior discectomy and fusion, complicated by a millimetric dural tear of the anterior thecal sac. Postoperative neuroimaging revealed retropharyngeal fluid collection, extending in front of the vertebral bodies of C3, C4, and C5, exerting a mass effect on the posterior wall of the pharynx. Taking into account both the MRI aspect of the collection and the dramatic improvement of symptoms after lumbar punctures, we conducted a diagnosis of CSF collection in continuity with the subarachnoid space. The dysphagia and the CSF collection resolved with conservative therapy (bed rest and 3 lumbar punctures). To the best of our knowledge, such a complication has never been described before in the literature. It should be included in the differential diagnosis of patients with postoperative dysphagia lasting more than 48 hours.

Apple Polysaccharide inhibits microbial dysbiosis and chronic inflammation and modulates gut permeability in HFD-fed rats.

PubMed

Wang, Sheng; Li, Qian; Zang, Yue; Zhao, Yang; Liu, Nan; Wang, Yifei; Xu, Xiaotao; Liu, Li; Mei, Qibing

2017-06-01

The saying "An apple a day keeps the doctor away" has been known for over 150 years, and numerous studies have shown that apple consumption is closely associated with reduced risks of chronic diseases. It has been well accepted that dysbiosis is the reflection of various chronic diseases. Therefore, this study investigates the effects of apple polysaccharides (AP) on gut dysbiosis. High-fat diet (HFD) fed rats were treated for 14 weeks with AP. The microbiota composition, microbiota-generated short chain fatty acids (SCFAs), gut permeability and chronic inflammation were analyzed. AP treatment showed higher abundance of Bacteroidetes and Lactobacillus while lower Firmicutes and Fusobacteium. AP significantly increased total SCFAs level that contributed by acetic acid and isobutyric acid. Moreover, AP dramatically alleviated dysbiosis-associated gut permeability and chronic inflammation with decreased plasma LBP, up-regulation of Occludin, down-regulation of tumor necrosis factor a (TNF-a), monocyte chemotactic protein 1 (MCP-1), chemokine ligand 1 (CXCL-1) and interleukin 1 beta (IL-1β). The potential mechanism is due to the fact that AP reduces gut permeability, which involves the induction of autophagy in goblet cells. Therefore, AP exerts health benefits through inhibiting gut dysbiosis and chronic inflammation and modulating gut permeability in HFD-induced dysbiosis rats. Copyright © 2017 Elsevier B.V. All rights reserved.

USP22 knockdown enhanced chemosensitivity of hepatocellular carcinoma cells to 5-Fu by up-regulation of Smad4 and suppression of Akt

PubMed Central

Li, Jiazhi; Yang, Xiaozhou; Yin, Huimin; Xiao, Congshu; Sheng, Jie; Li, Yang; Tang, Bo; Li, Rongkuan

2017-01-01

USP22, a member of the deubiquitinases (DUBs) family, is known to be a key subunit of the human Spt-Ada-Gcn5 acetyltransferase (hSAGA) transcriptional cofactor complex. Within hSAGA, USP22 removes ubiquitin from histone proteins, thus regulating the transcription and expression of downstream genes. USP22 plays important roles in many cancers; however, its effect and the mechanism underlying HCC chemoresistance remain unclear. In the present study, we found that USP22 was highly expressed in chemoresistant HCC tissues and cells and was correlated with the prognosis of HCC patients who received chemotherapy. Silencing USP22 in chemoresistant HCC Bel/Fu cells dramatically inhibited proliferation, migration, invasion and epithelial-mesenchymal transition in vitro; suppressed tumorigenic and metastatic capacities in vivo; and inhibited drug resistance-related proteins (MDR1, LRP, MRP1). Mechanistically, we found that USP22 knockdown exerts its function through down-regulating PI3K and activating Smad4, which inhibited phosphorylation of Akt. Silencing Smad4 blocked USP22 knockdown-induced Akt inhibition in Bel/Fu cells. Our results, for the first time, provide evidence that USP22 plays a critical role in the development of chemoresistant HCC cells and that high USP22 expression serves as a molecular marker for the prognosis of HCC patients who undergo chemotherapy. PMID:28445968

USP22 knockdown enhanced chemosensitivity of hepatocellular carcinoma cells to 5-Fu by up-regulation of Smad4 and suppression of Akt.

PubMed

Zhang, Jing; Luo, Nan; Tian, Yu; Li, Jiazhi; Yang, Xiaozhou; Yin, Huimin; Xiao, Congshu; Sheng, Jie; Li, Yang; Tang, Bo; Li, Rongkuan

2017-04-11

USP22, a member of the deubiquitinases (DUBs) family, is known to be a key subunit of the human Spt-Ada-Gcn5 acetyltransferase (hSAGA) transcriptional cofactor complex. Within hSAGA, USP22 removes ubiquitin from histone proteins, thus regulating the transcription and expression of downstream genes. USP22 plays important roles in many cancers; however, its effect and the mechanism underlying HCC chemoresistance remain unclear. In the present study, we found that USP22 was highly expressed in chemoresistant HCC tissues and cells and was correlated with the prognosis of HCC patients who received chemotherapy. Silencing USP22 in chemoresistant HCC Bel/Fu cells dramatically inhibited proliferation, migration, invasion and epithelial-mesenchymal transition in vitro; suppressed tumorigenic and metastatic capacities in vivo; and inhibited drug resistance-related proteins (MDR1, LRP, MRP1). Mechanistically, we found that USP22 knockdown exerts its function through down-regulating PI3K and activating Smad4, which inhibited phosphorylation of Akt. Silencing Smad4 blocked USP22 knockdown-induced Akt inhibition in Bel/Fu cells. Our results, for the first time, provide evidence that USP22 plays a critical role in the development of chemoresistant HCC cells and that high USP22 expression serves as a molecular marker for the prognosis of HCC patients who undergo chemotherapy.

Organization of cytoskeleton controls the changes in cytosolic calcium of cold-shocked Nicotiana plumbaginifolia protoplasts.

PubMed

Mazars, C; Thion, L; Thuleau, P; Graziana, A; Knight, M R; Moreau, M; Ranjeva, R

1997-11-01

Using Nicotiana plumbaginifolia constitutively expressing the recombinant bioluminescent calcium indicator, aequorin, it has been previously demonstrated that plant cells react to cold-shock by an immediate rise in cytosolic calcium. Such an opportune system has been exploited to address the regulatory pathway involved in the calcium response. For this purpose, we have used protoplasts derived from N. plumbaginifolia leaves that behave as the whole plant but with a better reproducibility. By both immunodetecting cytoskeletal components on membrane ghosts and measuring the relative change in cytosolic calcium, we demonstrate that the organization of the cytoskeleton has profound influences on the calcium response. The disruption of the microtubule meshwork by various active drugs, such as colchicin, oryzalin and vinblastin, leads to an important increase in the cytosolic calcium (up to 400 nM) in cold-shocked protoplasts over control. beta-Lumicolchicin, an inactive analogue of colchicin, is ineffective either on cytoplasmic calcium increase or on microtubule organization. A microfilament disrupting drug, cytochalasin D, exerts a slight stimulatory effect, whereas the simultaneous disruption of microtubule and microfilament meshworks results in a dramatic increase in the calcium response to cold-shock. The results described in the present paper illustrate the role of the intracellular organization and, more specifically, the role of cytoskeleton in controlling the intensity of calcium response to an extracellular stimulus.

Comparison of the bioavailability of quercetin and catechin in rats.

PubMed

Manach, C; Texier, O; Morand, C; Crespy, V; Régérat, F; Demigné, C; Rémésy, C

1999-12-01

Quercetin and catechin are present in noticeable amounts in human diet and these polyphenolic compounds are supposed to exert beneficial effects on human health. However, their metabolic fates in the organism have never been compared. In the present study, rats were fed a 0.25% quercetin or a 0.25% catechin diet. Quercetin and catechin metabolites were analyzed in plasma and liver samples by high-performance liquid chromatography coupled to an ultraviolet or a multielectrode coulometric detection. All plasma metabolites were present as conjugated forms, but catechin metabolites were mainly constituted by glucuronidated derivatives, whereas quercetin metabolites were sulfo- and glucurono-sulfo conjugates. Quercetin was more intensively methylated than catechin in plasma. The plasma quercetin metabolites are well maintained during the postabsorptive period (approximately 50 microM), whereas the concentration of catechin metabolites dropped dramatically between 12- and 24-h after an experimental meal (from 38.0 to 4.5 microM). In the liver, the concentrations of quercetin and catechin derivatives were lower than in plasma, and no accumulation was observed when the rats were adapted for 14 d to the supplemented diets. The hepatic metabolites were intensively methylated (90-95%), but in contrast to plasma, some free aglycones could be detected. Thus, it clearly appears that studies dealing with the biological impact of these polyphenols should take into account the feature of their bioavailability, particularly the fact that their circulating metabolites are conjugated derivatives.

Low-levels of fluoride in plaque and saliva and their effects on the demineralisation and remineralisation of enamel; role of fluoride toothpastes.

PubMed

Lynch, R J M; Navada, R; Walia, R

2004-01-01

To summarise support for current consensus on the likely means by which fluoride toothpastes reduce caries and review some relevant studies of the effect of low levels of fluoride on the demineralisation and remineralisation of enamel. The major anti-caries effect of fluoride toothpastes is thought to result from small but protracted elevations in levels of fluoride in plaque and saliva. Fluoride incorporated into enamel systemically does not reduce enamel solubility sufficiently to exert an anti-caries effect. Fluoride has the potential to exert an anti-caries benefit largely through three mechanisms; inhibition of demineralisation, promotion of remineralisation and interference with bacterial growth and metabolism. However, the low levels of fluoride thought to influence caries are insufficient to have a significant effect via the latter mechanism. Thus reductions in caries resulting from the use of fluoride toothpastes can be linked to modification of the demineralisation/remineralisation balance by direct effects on dental mineral exerted topically by low levels of fluoride. Numerous in vitro studies have shown that low levels of fluoride, typical of those found after many hours in resting plaque and saliva, and resulting from the regular use of fluoride toothpastes, can have a profound effect on enamel demineralisation and remineralisation.

Cardiac and Vascular Synergic Protective Effect of Olea europea L. Leaves and Hibiscus sabdariffa L. Flower Extracts.

PubMed

Micucci, Matteo; Malaguti, Marco; Toschi, Tullia Gallina; Di Lecce, Giuseppe; Aldini, Rita; Angeletti, Andrea; Chiarini, Alberto; Budriesi, Roberta; Hrelia, Silvana

2015-01-01

This study was aimed at investigating the cardiovascular effects of an Olea europea L. leaf extract (OEE), of a Hibiscus sabdariffa L. flower extract (HSE), and of their 13 : 2 w/w mixture in order to assess their cardiac and vascular activity. Both extracts were fully characterized in their bioactive compounds by HPLC-MS/MS analysis. The study was performed using primary vascular endothelial cells (HUVECs) to investigate the antioxidant and cytoprotective effect of the extracts and their mixture and isolated guinea-pig left and right atria and aorta to evaluate the inotropic and chronotropic activities and vasorelaxant properties. In cultured HUVECs, OEE and HSE reduced intracellular reactive oxygen species formation and improved cell viability, following oxidative stress in dose-dependent manner. OEE and HSE exerted negative inotropic and vasorelaxant effects without any chronotropic property. Interestingly, the mixture exerted higher cytoprotective effects and antioxidant activities. Moreover, the mixture exerted an inotropic effect similar to each single extract, while it revealed an intrinsic negative chronotropic activity different from the single extract; its relaxant activity was higher than that of each single extract. In conclusion OEE and HSE mixture has a good potential for pharmaceutical and nutraceutical application, thanks to the synergistic effects of the single phytochemicals.

Cardiac and Vascular Synergic Protective Effect of Olea europea L. Leaves and Hibiscus sabdariffa L. Flower Extracts

PubMed Central

Micucci, Matteo; Gallina Toschi, Tullia; Di Lecce, Giuseppe; Aldini, Rita; Angeletti, Andrea; Chiarini, Alberto

2015-01-01

This study was aimed at investigating the cardiovascular effects of an Olea europea L. leaf extract (OEE), of a Hibiscus sabdariffa L. flower extract (HSE), and of their 13 : 2 w/w mixture in order to assess their cardiac and vascular activity. Both extracts were fully characterized in their bioactive compounds by HPLC-MS/MS analysis. The study was performed using primary vascular endothelial cells (HUVECs) to investigate the antioxidant and cytoprotective effect of the extracts and their mixture and isolated guinea-pig left and right atria and aorta to evaluate the inotropic and chronotropic activities and vasorelaxant properties. In cultured HUVECs, OEE and HSE reduced intracellular reactive oxygen species formation and improved cell viability, following oxidative stress in dose-dependent manner. OEE and HSE exerted negative inotropic and vasorelaxant effects without any chronotropic property. Interestingly, the mixture exerted higher cytoprotective effects and antioxidant activities. Moreover, the mixture exerted an inotropic effect similar to each single extract, while it revealed an intrinsic negative chronotropic activity different from the single extract; its relaxant activity was higher than that of each single extract. In conclusion OEE and HSE mixture has a good potential for pharmaceutical and nutraceutical application, thanks to the synergistic effects of the single phytochemicals. PMID:26180582

Silibinin (Milk Thistle) potentiates ethanol-dependent hepatocellular carcinoma progression in male mice

PubMed Central

Brandon-Warner, Elizabeth; Eheim, Ashley L; Foureau, David M; Walling, Tracy L; Schrum, Laura W; McKillop, Iain H

2012-01-01

Hepatocellular carcinoma (HCC) is a global health burden with limited treatment options and poor prognosis. Silibinin, an antioxidant derived from the Milk Thistle plant (Silybum marianum), is reported to exert hepatoprotective and antitumorigenic effects in vitro and in vivo by suppressing oxidative stress and proliferation. Using a DEN-initiated mouse model of HCC, this study examined the effects of dietary silibinin supplementation alone, or in combination with chronic ethanol consumption on HCC progression. Our data demonstrate silibinin exerted marginal hepatoprotective effects in early stages of hepatocarcinogenesis but, when co-administered with ethanol, exacerbated the promotional effects of ethanol in HCC bearing mice, but only in males. PMID:22863537

Silibinin (Milk Thistle) potentiates ethanol-dependent hepatocellular carcinoma progression in male mice.

PubMed

Brandon-Warner, Elizabeth; Eheim, Ashley L; Foureau, David M; Walling, Tracy L; Schrum, Laura W; McKillop, Iain H

2012-12-29

Hepatocellular carcinoma (HCC) is a global health burden with limited treatment options and poor prognosis. Silibinin, an antioxidant derived from the Milk Thistle plant (Silybum marianum), is reported to exert hepatoprotective and antitumorigenic effects in vitro and in vivo by suppressing oxidative stress and proliferation. Using a DEN-initiated mouse model of HCC, this study examined the effects of dietary silibinin supplementation alone, or in combination with chronic ethanol consumption on HCC progression. Our data demonstrate silibinin exerted marginal hepatoprotective effects in early stages of hepatocarcinogenesis but, when co-administered with ethanol, exacerbated the promotional effects of ethanol in HCC bearing mice, but only in males. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Determinants and magnitudes of manual force strengths and joint moments during two-handed standing maximal horizontal pushing and pulling.

PubMed

Chow, Amy Y; Dickerson, Clark R

2016-04-01

Pushing and pulling are common occupational exertions that are increasingly associated with musculoskeletal complaints. This study focuses on the sensitivity of shoulder capacity to gender, handle height, exertion type (push or pull) and handle orientation for these tasks. All factors except for handle orientation influenced unilateral and total manual force strength (p < 0.01), with exertion type being the most influential. Interaction effects also existed between handle height and exertion type. Additionally, joint moments at the shoulders and low back were influenced by all factors studied (p < 0.01), with exertion type again being most influential. Knowledge of the relative influence of multiple factors on shoulder capacity can provide guidance regarding these factors when designing or evaluating occupational pushing and pulling tasks for a diverse population. Practitioner Summary: pushing and pulling comprise nearly half of all manual materials handling tasks. Practitioners often assess, design or modify these tasks while incorporating constraints, including manual force direction and handle interface. This study provides guidance to aid design of pushing and pulling tasks in the context of shoulder physical capacity.

Osthole improves acute lung injury in mice by up-regulating Nrf-2/thioredoxin 1.

PubMed

Chen, Xiang-Jun; Zhang, Bo; Hou, Shao-Jie; Shi, Yun; Xu, Dun-Quan; Wang, Yan-Xia; Liu, Man-Ling; Dong, Hai-Ying; Sun, Ri-He; Bao, Nan-Di; Jin, Fa-Guang; Li, Zhi-Chao

2013-08-15

Inhibiting reactive oxygen species (ROS) has been viewed as a therapeutic target for the treatment of acute lung injury (ALI). Osthole, an active component in Chinese herbal medicine, has drawn increasing attention because of its various pharmacological functions, including anti-inflammatory and anti-oxidative activities. The aim of the present study was to examine the effects of osthole on ALI induced by lipopolysaccharide (LPS) through intratracheal instillation. The mRNA and protein expression levels of thioredoxin 1 (Trx1) and the nuclear factor erythroid-2 related factor 2 (Nrf2) were detected by real-time PCR, reverse transcription PCR (RT-PCR) and Western blot, respectively. ROS production was measured by flow cytometry. Our results showed that osthole treatment improved the mice survival rates in the middle and high dosage groups, compared with the untreated LPS group. Moreover, osthole treatment significantly improved LPS-induced lung pathological damage, and it decreased the lung injury scores, lung wet/dry ratios and the total protein level in Bronchoalveolar lavage fluid (BALF). Osthole treatment dramatically reduced the H2O2, MDA and OH levels in the lung homogenates. LDH and ROS were markedly reduced in the osthole+LPS group in vitro. Furthermore, osthole increased Nrf2 and Trx1 expression in terms of mRNA and protein in vivo and in vitro. Nrf2 siRNA (siNrf2) could suppress the beneficial effects of osthole on ALI. In conclusion, the current study demonstrates that osthole exerted protective effects on LPS-induced ALI by up-regulating the Nrf-2/Trx-1 pathway. Copyright © 2013 Elsevier B.V. All rights reserved.

Diet‐induced obesity alters skeletal muscle fiber types of male but not female mice

PubMed Central

DeNies, Maxwell S.; Johnson, Jordan; Maliphol, Amanda B.; Bruno, Michael; Kim, Annabelle; Rizvi, Abbas; Rustici, Kevyn; Medler, Scott

2014-01-01

Abstract Skeletal muscles are highly plastic tissues capable dramatic remodeling in response to use, disuse, disease, and other factors. Growing evidence suggests that adipose tissues exert significant effects on the basic fiber‐type composition of skeletal muscles. In the current study, we investigated the long‐term effects of a high‐fat diet and subsequent obesity on the muscle fiber types in C57 BLK/6J mice. Litters of mice were randomly assigned to either a high‐fat diet or a control group at the time of weaning, and were maintained on this diet for approximately 1 year. Single fibers were harvested from the soleus and plantaris muscles, and fiber types were determined using SDS‐PAGE. The high‐fat diet mice were significantly heavier than the control mice (39.17 ± 2.7 g vs. 56.87 ± 3.4 g; P < 0.0003), but muscle masses were not different. In male mice, the high‐fat diet was associated with a significantly lower proportion of slow, type I fibers in the soleus muscle (40.4 ± 3.5% vs. 29.33 ± 2.6%; P < 0.0165). Moreover, the proportion of type I fibers in the soleus of male mice was inversely proportional to the relative fatness of the male mice (P < 0.003; r2 = 0.65), but no association was observed in female mice. In male mice, the decline in type I fibers was correlated with an increase in type I/IIA hybrid fibers, suggesting that the type I fibers were transformed primarily into these hybrids. The reported trends indicate that type I fibers are most susceptible to the effects of obesity, and that these fiber‐type changes can be sex specific. PMID:24744883

Linking canopy reflectance to crop structure and photosynthesis to capture and interpret spatiotemporal dimensions of per-field photosynthetic productivity

NASA Astrophysics Data System (ADS)

Xue, Wei; Jeong, Seungtaek; Ko, Jonghan; Tenhunen, John

2017-03-01

Nitrogen and water availability alter canopy structure and physiology, and thus crop growth, yielding large impacts on ecosystem-regulating/production provisions. However, to date, explicitly quantifying such impacts remains challenging partially due to lack of adequate methodology to capture spatial dimensions of ecosystem changes associated with nitrogen and water effects. A data fitting, where close-range remote-sensing measurements of vegetation indices derived from a handheld instrument and an unmanned aerial vehicle (UAV) system are linked to in situ leaf and canopy photosynthetic traits, was applied to capture and interpret inter- and intra-field variations in gross primary productivity (GPP) in lowland rice grown under flooded conditions (paddy rice, PD) subject to three nitrogen application rates and under rainfed conditions (RF) in an East Asian monsoon region of South Korea. Spatial variations (SVs) in both GPP and light use efficiency (LUEcabs) early in the growing season were enlarged by nitrogen addition. The nutritional effects narrowed over time. A shift in planting culture from flooded to rainfed conditions strengthened SVs in GPP and LUEcabs. Intervention of prolonged drought late in the growing season dramatically intensified SVs that were supposed to seasonally decrease. Nevertheless, nitrogen addition effects on SV of LUEcabs at the early growth stage made PD fields exert greater SVs than RF fields. SVs of GPP across PD and RF rice fields were likely related to leaf area index (LAI) development less than to LUEcabs, while numerical analysis suggested that considering strength in LUEcabs and its spatial variation for the same crop type tends to be vital for better evaluation in landscape/regional patterns of ecosystem photosynthetic productivity at critical phenology stages.

Letrozole increases ovarian growth and Cyp17a1 gene expression in the rat ovary

PubMed Central

Ortega, Israel; Sokalska, Anna; Villanueva, Jesus A.; Cress, Amanda B.; Wong, Donna H.; Stener-Victorin, Elisabet; Stanley, Scott D.; Duleba, Antoni J.

2012-01-01

Objective To evaluate the effects of letrozole on ovarian size and steroidogenesis in vivo, as well as on proliferation and steroidogenesis of theca-interstitial cells alone and in coculture with granulosa cells using an in vitro model. Design In vivo and in vitro studies. Setting Research laboratory. Animal(s) Immature Sprague-Dawley female rats. Intervention(s) In vivo effects of letrozole were studied in intact rats receiving either letrozole (90-day continuous-release SC pellets, 400 µg/d) or placebo pellets (control group). In in vitro experiments, theca cells were cultured alone or in coculture with granulosa cells in the absence or presence of letrozole. Main Outcome Measure(s) Deoxyribonucleic acid synthesis was determined by thymidine incorporation assay; steroidogenesis by mass spectrometry; and steroidogenic enzyme messenger RNA (mRNA) expression by polymerase chain reaction. Result(s) In vivo, letrozole induced an increase in ovarian size compared with the control group and also induced a profound increase of androgen, LH levels, and Cyp17a1 mRNA expression. Conversely, a decrease in Star, Cyp11a1, and Hsd3b1 transcripts was observed in letrozole-exposed rats. In vitro, letrozole did not alter either theca cell proliferation or Cyp17a1 mRNA expression. Similarly, letrozole did not affect Cyp17a1 transcripts in granulosa-theca cocultures. Conclusion(s) These findings suggest that letrozole exerts potent, but indirect, effect on growth of rat ovary and dramatically increases androgen levels and Cyp17a1 mRNA expression, the key enzyme regulating the androgen biosynthesis pathway. The present findings reveal novel mechanisms of action of letrozole in the rat ovary. PMID:23200686

Dihydrocapsiate improved age-associated impairments in mice by increasing energy expenditure.

PubMed

Ohyama, Kana; Suzuki, Katsuya

2017-11-01

Metabolic dysfunction is associated with aging and results in age-associated chronic diseases, including type 2 diabetes mellitus, cardiovascular disease, and stroke. Hence, there has been a focus on increasing energy expenditure in aged populations to protect them from age-associated diseases. Dihydrocapsiate (DCT) is a compound that belongs to the capsinoid family. Capsinoids are capsaicin analogs that are found in nonpungent peppers and increase whole body energy expenditure. However, their effect on energy expenditure has been reported only in young populations, and to date the effectiveness of DCT in increasing energy expenditure in aged populations has not been investigated. In this study, we investigated whether DCT supplementation in aged mice improves age-associated impairments. We obtained 5-wk-old and 1-yr-old male C57BL/6J mice and randomly assigned the aged mice to two groups, resulting in a total of three groups: 1 ) young mice, 2 ) old mice, and 3 ) old mice supplemented with 0.3% DCT. After 12 wk of supplementation, blood and tissue samples were collected and analyzed. DCT significantly suppressed age-associated fat accumulation, adipocyte hypertrophy, and liver steatosis. In addition, the DCT treatment dramatically suppressed age-associated increases in hepatic inflammation, immune cell infiltration, and oxidative stress. DCT exerted these suppression effects by increasing energy expenditure linked to upregulation of both the oxidative phosphorylation gene program and fatty acid oxidation in skeletal muscle. These results indicate that DCT efficiently improves age-associated impairments, including liver steatosis and inflammation, in part by increasing energy expenditure via activation of the fat oxidation pathway in skeletal muscle. Copyright © 2017 the American Physiological Society.

Second-generation antipsychotics cause a rapid switch to fat oxidation that is required for survival in C57BL/6J mice.

PubMed

Klingerman, Candice M; Stipanovic, Michelle E; Bader, Mohammad; Lynch, Christopher J

2014-03-01

Some second-generation antipsychotics (SGAs) increase insulin resistance and fat oxidation, but counter intuitively they do not activate lipolysis. This seems unsustainable for meeting energy demands. Here, we measured dose-dependent effects of SGAs on rates of oxygen consumption (VO2), respiratory exchange ratio (RER), and physical activity in C57BL/6J mice. The role of H1-histamine receptors and consequences of blocking fat oxidation were also examined. Olanzapine, risperidone, and clozapine (2.5-10mg/kg) elicited rapid drops in dark-cycle RER (~0.7) within minutes, whereas aripiprazole exerted only modest changes. Higher doses of olanzapine decreased VO2, and this was associated with accumulation of glucose in plasma. Clozapine and risperidone also lowered VO2, in contrast to aripiprazole, whereas all decreased physical activity. Astemizole and terfenadine had no significant effects on RER, VO2, or physical activity. The VO2 and RER effects appear independent of sedation/physical activity or H1-receptors. CPT-1 inhibitors can enhance muscle glucose utilization and prevent fat oxidation. However, after etomoxir (2 × 30 mg/kg), a low dose of olanzapine that did not significantly affect VO2 by itself caused precipitous drops in VO2 and body temperature, leading to death within hours or a moribund state requiring euthanasia. One 30 mg/kg dose of either etomoxir or 2-tetradecylglycidate followed by olanzapine, risperidone, or clozapine, but not aripiprazole, dramatically lowered VO2 and body temperature. Thus, mice treated with some SGAs shift their fuel utilization to mostly fat but are unable to either switch back to glucose or meet their energy demands when either higher doses are used or when fat oxidation is blocked.

Ifit2 Is a Restriction Factor in Rabies Virus Pathogenicity.

PubMed

Davis, Benjamin M; Fensterl, Volker; Lawrence, Tessa M; Hudacek, Andrew W; Sen, Ganes C; Schnell, Matthias J

2017-09-01

Understanding the interactions between rabies virus (RABV) and individual host cell proteins is critical for the development of targeted therapies. Here we report that interferon-induced protein with tetratricopeptide repeats 2 (Ifit2), an interferon-stimulated gene (ISG) with possible RNA-binding capacity, is an important restriction factor for rabies virus. When Ifit2 was depleted, RABV grew more quickly in mouse neuroblastoma cells in vitro This effect was replicated in vivo , where Ifit2 knockout mice displayed a dramatically more severe disease phenotype than wild-type mice after intranasal inoculation of RABV. This increase in pathogenicity correlated to an increase in RABV mRNA and live viral load in the brain, as well as to an accelerated spread to brain regions normally affected by this RABV model. These results suggest that Ifit2 exerts its antiviral effect mainly at the level of viral replication, as opposed to functioning as a mechanism that restricts viral entry/egress or transports RABV particles through axons. IMPORTANCE Rabies is a fatal zoonotic disease with a nearly 100% case fatality rate. Although there are effective vaccines for rabies, this disease still takes the lives of about 50,000 people each year. Victims tend to be children living in regions without comprehensive medical infrastructure who present to health care workers too late for postexposure prophylaxis. The protein discussed in our report, Ifit2, is found to be an important restriction factor for rabies virus, acting directly or indirectly against viral replication. A more nuanced understanding of this interaction may reveal a step of a pathway or site at which the system could be exploited for the development of a targeted therapy. Copyright © 2017 American Society for Microbiology.

Treatment of Myasthenia Gravis Based on Its Immunopathogenesis

PubMed Central

Kim, Jee Young; Park, Kee Duk

2011-01-01

The prognosis of myasthenia gravis (MG) has improved dramatically due to advances in critical-care medicine and symptomatic treatments. Its immunopathogenesis is fundamentally a T-cell-dependent autoimmune process resulting from loss of tolerance toward self-antigens in the thymus. Thymectomy is based on this immunological background. For MG patients who are inadequately controlled with sufficient symptomatic treatment or fail to achieve remission after thymectomy, remission is usually achieved through the addition of other immunotherapies. These immunotherapies can be classified into two groups: rapid induction and long-term maintenance. Rapid induction therapy includes intravenous immunoglobulin (IVIg) and plasma exchange (PE). These produce improvement within a few days after initiation, and so are useful for acute exacerbation including myasthenic crisis or in the perioperative period. High-dose prednisone has been more universally preferred for remission induction, but it acts more slowly than IVIg and PE, commonly only after a delay of several weeks. Slow tapering of steroids after a high-dose pulse offers a method of maintaining the state of remission. However, because of significant side effects, other immunosuppressants (ISs) are frequently added as "steroid-sparing agents". The currently available ISs exert their immunosuppressive effects by three mechanisms: 1) blocking the synthesis of DNA and RNA, 2) inhibiting T-cell activation and 3) depleting the B-cell population. In addition, newer drugs including antisense molecule, tumor necrosis factor alpha receptor blocker and complement inhibitors are currently under investigation to confirm their effectiveness. Until now, the treatment of MG has been based primarily on experience rather than gold-standard evidence from randomized controlled trials. It is hoped that well-organized studies and newer experimental trials will lead to improved treatments. PMID:22259613

Second-Generation Antipsychotics Cause a Rapid Switch to Fat Oxidation That Is Required for Survival in C57BL/6J Mice

PubMed Central

Lynch, Christopher J.

2014-01-01

Some second-generation antipsychotics (SGAs) increase insulin resistance and fat oxidation, but counter intuitively they do not activate lipolysis. This seems unsustainable for meeting energy demands. Here, we measured dose-dependent effects of SGAs on rates of oxygen consumption (VO2), respiratory exchange ratio (RER), and physical activity in C57BL/6J mice. The role of H1-histamine receptors and consequences of blocking fat oxidation were also examined. Olanzapine, risperidone, and clozapine (2.5–10mg/kg) elicited rapid drops in dark-cycle RER (~0.7) within minutes, whereas aripiprazole exerted only modest changes. Higher doses of olanzapine decreased VO2, and this was associated with accumulation of glucose in plasma. Clozapine and risperidone also lowered VO2, in contrast to aripiprazole, whereas all decreased physical activity. Astemizole and terfenadine had no significant effects on RER, VO2, or physical activity. The VO2 and RER effects appear independent of sedation/physical activity or H1-receptors. CPT-1 inhibitors can enhance muscle glucose utilization and prevent fat oxidation. However, after etomoxir (2 × 30mg/kg), a low dose of olanzapine that did not significantly affect VO2 by itself caused precipitous drops in VO2 and body temperature, leading to death within hours or a moribund state requiring euthanasia. One 30mg/kg dose of either etomoxir or 2-tetradecylglycidate followed by olanzapine, risperidone, or clozapine, but not aripiprazole, dramatically lowered VO2 and body temperature. Thus, mice treated with some SGAs shift their fuel utilization to mostly fat but are unable to either switch back to glucose or meet their energy demands when either higher doses are used or when fat oxidation is blocked. PMID:23328157

Treadmill Exercise Exerts Neuroprotection and Regulates Microglial Polarization and Oxidative Stress in a Streptozotocin-Induced Rat Model of Sporadic Alzheimer’s Disease

PubMed Central

Lu, Yujiao; Dong, Yan; Tucker, Donovan; Wang, Ruimin; Ahmed, Mohammad Ejaz; Brann, Darrell; Zhang, Quanguang

2017-01-01

Recent work has suggested that exercise may be beneficial in preventing or ameliorating symptoms of several neurological disorders, although the mechanism is not entirely understood. The current study was designed to examine the potential beneficial effect of treadmill exercise upon cognitive function in a streptozotocin (STZ)-induced rat model of Alzheimer’s disease (AD). Animals underwent treadmill exercise (30 min/day, 5 days/week) for 4 weeks after bilateral STZ intracerebroventricular injection (2.4 mg/kg). We demonstrated that treadmill exercise significantly attenuated STZ-induced neurodegeneration in the rat hippocampal CA1 region and strongly preserved hippocampal-dependent cognitive functioning. Further mechanistic investigation displayed a marked suppression of STZ-induced amyloid-β accumulation and tau phosphorylation. Intriguingly, treadmill exercise remarkably inhibited reactive gliosis following STZ insult and effectively shifted activated microglia from a pro-inflammatory M1 to an anti-inflammatory M2 phenotype, which was correlated with a significantly reduced expression of pro-inflammatory mediators and a corresponding enhancement of anti-inflammatory cytokine expression in the hippocampus. Furthermore, treadmill exercise caused a robust suppression of oxidative damage as evidenced by significantly reduced peroxynitrite production, lipid peroxidation, and oxidized DNA damage. Finally, treadmill exercise strongly attenuated STZ-induced mitochondrial dysfunction manifested by a dramatically elevated intra-mitochondrial cytochrome c oxidase activity and ATP synthesis, and markedly inhibited neuronal apoptosis in the hippocampus. These findings demonstrate that treadmill exercise has a multifactorial effect to attenuate many of the pathological processes that play a key role in AD, and provide further support for the beneficial role of exercise as a potential therapeutic option in AD treatment. PMID:28157094

Various effects of the photosystem II--inhibiting herbicides on 5-n-alkylresorcinol accumulation in rye seedlings.

PubMed

Magnucka, Elżbieta G; Pietr, Stanisław J; Kozubek, Arkadiusz; Zarnowski, Robert

2014-11-01

The effect of three PSII-inhibiting herbicides, lenacil, linuron, and pyrazon, on the accumulation of 5-n-alkylresorcinols in rye seedlings (Secale cereale L.) grown under various light and thermal conditions was studied. All used chemicals increased resorcinolic lipid content in both green and etiolated plants grown at 29 °C. At 22 °C pyrazon and lenacil decreased the content of alkylresorcinols in plants kept in the darkness and increased their amount in the light-grown seedlings. In turn, level of resorcinolic lipids was decreased by linuron in both etiolated and green plants. At the lowest tested temperature lenacil enhanced production of alkylresorcinols only in etiolated rye seedlings, whereas the light-independent stimulatory action of pyrazon on alkylresorcinol accumulation in rye grown at 15 °C was observed. Additionally, only the latter did not exert a negative effect on rye seedling growth under any of tested conditions. Compared with respective controls, the herbicides used also markedly modified the qualitative pattern of resorcinolic homologs. Interestingly, the observed changes generally favored the enhanced antifungal activity of these compounds. Our study provides novel information on the influence of PSII inhibitors on alkylresorcinol metabolism in rye seedlings. The unquestionable achievement of this work is the observation that low dose of pyrazon mainly stimulated both growth and alkylresorcinol synthesis in rye seedlings, a non-target plant. Moreover, our experimental work showed unambiguously that the observed pyrazon-driven accumulation and homolog pattern modification of alkylresorcinols dramatically improved the resistance of winter rye to infections caused by Rhizoctonia cerealis. Copyright © 2014 Elsevier Inc. All rights reserved.

Synergistic Substrate Inhibition of ent-Copalyl Diphosphate Synthase: A Potential Feed-Forward Inhibition Mechanism Limiting Gibberellin Metabolism1[OA

PubMed Central

Prisic, Sladjana; Peters, Reuben J.

2007-01-01

Gibberellins (GAs) or gibberellic acids are ubiquitous diterpenoid phytohormones required for many aspects of plant growth and development, including repression of photosynthetic pigment production (i.e. deetiolation) in the absence of light. The committed step in GA biosynthesis is catalyzed in plastids by ent-copalyl diphosphate synthase (CPS), whose substrate, (E,E,E,)-geranylgeranyl diphosphate (GGPP), is also a direct precursor of carotenoids and the phytol side chain of chlorophyll. Accordingly, during deetiolation, GA production is repressed, whereas flux toward these photosynthetic pigments through their common GGPP precursor is dramatically increased. How this is accomplished has been unclear because no mechanism for regulation of CPS activity has been reported. We present here kinetic analysis of recombinant pseudomature CPS from Arabidopsis (Arabidopsis thaliana; rAtCPS) demonstrating that Mg2+ and GGPP exert synergistic substrate inhibition effects on CPS activity. These results suggest that GA metabolism may be limited by feed-forward inhibition of CPS; in particular, the effect of Mg2+ because light induces increases in plastid Mg2+ levels over a similar range as that observed here to affect rAtCPS activity. Notably, this effect is most pronounced in the GA-specific AtCPS because the corresponding activity of the resin acid biosynthetic enzyme abietadiene synthase is 100-fold less sensitive to [Mg2+]. Furthermore, Mg2+ allosterically activates the plant porphobilinogen synthase involved in chlorophyll production. Hence, Mg2+ may have a broad role in regulating plastidial metabolic flux during deetiolation. Finally, the observed synergistic substrate/feed-forward inhibition of CPS also seems to provide a novel example of direct regulation of enzymatic activity in hormone biosynthesis. PMID:17384166

Effect of Dietary Fatty Acids on Inflammatory Gene Expression in Healthy Humans*

PubMed Central

Weaver, Kelly L.; Ivester, Priscilla; Seeds, Michael; Case, L. Douglas; Arm, Jonathan P.; Chilton, Floyd H.

2009-01-01

Over the past 100 years, changes in the food supply in Western nations have resulted in alterations in dietary fatty acid consumption, leading to a dramatic increase in the ratio of omega-6 (ω6) to ω3 polyunsaturated fatty acids (PUFA) in circulation and in tissues. Increased ω6/ω3 ratios are hypothesized to increase inflammatory mediator production, leading to higher incidence of inflammatory diseases, and may impact inflammatory gene expression. To determine the effect of reducing the ω6/ω3 ratio on expression of inflammatory pathway genes in mononuclear cells, healthy humans were placed on a controlled diet for 1 week, then given fish oil and borage oil for an additional 4 weeks. Serum and neutrophil fatty acid composition and ex vivo leukotriene B4 production from stimulated neutrophils were measured at the start and end of the supplementation period and after a 2-week washout. RNA was isolated from mononuclear cells and expression of PI3K, Akt, NFκB, and inflammatory cytokines was measured by real-time PCR. A marked increase was seen in serum and neutrophil levels of long-chain ω3 PUFA concomitant with a reduction in the ω6/ω3 PUFA ratio (40%). The ex vivo capacity of stimulated neutrophils to produce leukotriene B4 was decreased by 31%. Expression of PI3Kα and PI3Kγ and the quantity of PI3Kα protein in mononuclear cells was reduced after supplementation, as was the expression of several proinflammatory cytokines. These data reveal that PUFA may exert their clinical effects via their capacity to regulate the expression of signal transduction genes and genes for proinflammatory cytokines. PMID:19359242

Treadmill Exercise Exerts Neuroprotection and Regulates Microglial Polarization and Oxidative Stress in a Streptozotocin-Induced Rat Model of Sporadic Alzheimer's Disease.

PubMed

Lu, Yujiao; Dong, Yan; Tucker, Donovan; Wang, Ruimin; Ahmed, Mohammad Ejaz; Brann, Darrell; Zhang, Quanguang

2017-01-01

Recent work has suggested that exercise may be beneficial in preventing or ameliorating symptoms of several neurological disorders, although the mechanism is not entirely understood. The current study was designed to examine the potential beneficial effect of treadmill exercise upon cognitive function in a streptozotocin (STZ)-induced rat model of Alzheimer's disease (AD). Animals underwent treadmill exercise (30 min/day, 5 days/week) for 4 weeks after bilateral STZ intracerebroventricular injection (2.4 mg/kg). We demonstrated that treadmill exercise significantly attenuated STZ-induced neurodegeneration in the rat hippocampal CA1 region and strongly preserved hippocampal-dependent cognitive functioning. Further mechanistic investigation displayed a marked suppression of STZ-induced amyloid-β accumulation and tau phosphorylation. Intriguingly, treadmill exercise remarkably inhibited reactive gliosis following STZ insult and effectively shifted activated microglia from a pro-inflammatory M1 to an anti-inflammatory M2 phenotype, which was correlated with a significantly reduced expression of pro-inflammatory mediators and a corresponding enhancement of anti-inflammatory cytokine expression in the hippocampus. Furthermore, treadmill exercise caused a robust suppression of oxidative damage as evidenced by significantly reduced peroxynitrite production, lipid peroxidation, and oxidized DNA damage. Finally, treadmill exercise strongly attenuated STZ-induced mitochondrial dysfunction manifested by a dramatically elevated intra-mitochondrial cytochrome c oxidase activity and ATP synthesis, and markedly inhibited neuronal apoptosis in the hippocampus. These findings demonstrate that treadmill exercise has a multifactorial effect to attenuate many of the pathological processes that play a key role in AD, and provide further support for the beneficial role of exercise as a potential therapeutic option in AD treatment.

Effect of Dietary Purified Xanthohumol from Hop (Humulus lupulus L.) Pomace on Adipose Tissue Mass, Fasting Blood Glucose Level, and Lipid Metabolism in KK-Ay Mice.

PubMed

Takahashi, Koki; Osada, Kyoichi

2017-05-01

We previously showed that xanthohumol-rich hop extract (XRHE, ~18% xanthohumol) exerts anti-obesity effects in rats fed a high-fat diet through regulation of fatty acid metabolism. In this study, we examined the effects of dietary purified xanthohumol from XRHE (PX, ~91.9% xanthohumol) in KK-Ay mice in order to understand the anti-obesity effects of xanthohumol alone because XRHE contains 82% unknown compounds. Dietary consumption of PX significantly inhibited an increase in the visceral fat weight of mice compared to those fed control diet without PX. Plasma leptin level was significantly lower in the PX-fed group than in the control group. Dietary PX lowered hepatic fatty acid synthesis by down-regulation of SREBP1c mRNA expression in the liver. On the other hand, fatty acid β-oxidation in the liver was promoted by dietary PX through the up-regulation of PPARα mRNA expression. Moreover, the fecal levels of fatty acids and carbohydrates increased by dietary PX. PX inhibited lipase or α-amylase activity in vitro. Thus, we found that PX may exert anti-obesity effects through the regulation of lipid metabolism and inhibition of intestinal fat and carbohydrate absorption, and that xanthohumol alone may exert anti-obesity effects.

All Bariatric Surgeries Are Not Created Equal: Insights from Mechanistic Comparisons

PubMed Central

Stefater, Margaret A.; Wilson-Pérez, Hilary E.; Chambers, Adam P.; Sandoval, Darleen A.

2012-01-01

Despite considerable scientific progress on the biological systems that regulate energy balance, we have made precious little headway in providing new treatments to curb the obesity epidemic. Diet and exercise are the most popular treatment options for obesity, but rarely are they sufficient to produce long-term weight loss. Bariatric surgery, on the other hand, results in dramatic, sustained weight loss and for this reason has gained increasing popularity as a treatment modality for obesity. At least some surgical approaches also reduce obesity-related comorbidities including type 2 diabetes and hyperlipidemia. This success puts a premium on understanding how these surgeries exert their effects. This review focuses on the growing human and animal model literature addressing the underlying mechanisms. We compare three common procedures: Roux-en-Y Gastric Bypass (RYGB), vertical sleeve gastrectomy (VSG), and adjustable gastric banding (AGB). Although many would group together VSG and AGB as restrictive procedures of the stomach, VSG is more like RYGB than AGB in its effects on a host of endpoints including intake, food choice, glucose regulation, lipids and gut hormone secretion. Our strong belief is that to advance our understanding of these procedures, it is necessary to group bariatric procedures not on the basis of surgical similarity but rather on how they affect key physiological variables. This will allow for greater mechanistic insight into how bariatric surgery works, making it possible to help patients better choose the best possible procedure and to develop new therapeutic strategies that can help a larger portion of the obese population. PMID:22550271

Chronic intermittent hypobaric hypoxia attenuates radiation induced heart damage in rats.

PubMed

Wang, Jun; Wu, Yajing; Yuan, Fang; Liu, Yixian; Wang, Xuefeng; Cao, Feng; Zhang, Yi; Wang, Sheng

2016-09-01

Radiation-induced heart damage (RIHD) is becoming an increasing concern for patients and clinicians due to the use of radiotherapy for thoracic tumor. Chronic intermittent hypobaric hypoxia (CIHH) preconditioning has been documented to exert a cardioprotective effect. Here we hypothesized that CIHH was capable of attenuating functional and structural damage in a rat model of RIHD. Male adult Sprague-Dawley rats were randomly divided into 4 groups: control, radiation, CIHH and CIHH plus radiation. Cardiac function was measured using Langendorff perfusion in in vitro rat hearts. Cardiac fibrosis, oxidative stress and endoplasmic reticulum stress (ERS) was assessed by quantitative analysis of protein expression. No significant difference between any two groups was observed in baseline cardiac function as assessed by left ventricular end diastolic pressure (LVEDP), left ventricular developing pressure (LVDP) and the derivative of left ventricular pressure (±LVdp/dt). When challenged by ischemia/reperfusion, LVEDP was increased but LVDP and ±LVdp/dt was decreased significantly in radiation group compared with controls, accompanied by an enlarged infarct size and decreased coronary flow. Importantly, CIHH dramatically improved radiation-induced damage of cardiac function and blunted radiation-induced cardiac fibrosis in the perivascular and interstitial area. Furthermore, CIHH abrogated radiation-induced increase in malondialdehyde and enhanced total superoxide dismutase activity, as well as downregulated expression levels of ERS markers like GRP78 and CHOP. CIHH pretreatment alleviated radiation-induced damage of cardiac function and fibrosis. Such a protective effect was closely associated with suppression of oxidative stress and ERS responses. Copyright © 2016 Elsevier Inc. All rights reserved.

Unraveling the mechanisms underlying pulse dynamics of soil respiration in tropical dry forests

DOE PAGES

Waring, Bonnie G.; Powers, Jennifer S.

2016-10-14

Tropical dry forests are already undergoing changes in the quantity and timing of rainfall, but there is great uncertainty over how these shifts will affect belowground carbon (C) cycling. While it has long been known that dry soils quickly release carbon dioxide (CO 2) upon rewetting, the mechanisms underlying the so-called 'Birch effect' are still debated. Here, we quantified soil respiration pulses and their biotic predictors in response to simulated precipitation events in a regenerating tropical dry forest in Costa Rica. We also simulated the observed rewetting CO 2 pulses with two soil carbon models: a conventional model assuming first-ordermore » decay rates of soil organic matter, and an enzyme-catalyzed model with Michaelis–Menten kinetics. We found that rewetting of dry soils produced an immediate and dramatic pulse of CO 2, accompanied by rapid immobilization of nitrogen into the microbial biomass. However, the magnitude of the rewetting CO 2 pulse was highly variable at fine spatial scales, and was well correlated with the size of the dissolved organic C pool prior to rewetting. Both the enzyme-catalyzed and conventional models were able to reproduce the Birch effect when respiration was coupled directly to microbial C uptake, although models differed in their ability to yield realistic estimates of SOC and microbial biomass pool sizes and dynamics. Lastly, our results suggest that changes in the timing and intensity of rainfall events in tropical dry forests will exert strong influence on ecosystem C balance by affecting the dynamics of microbial biomass growth.« less

Indigo Naturalis Ameliorates Oxazolone-Induced Dermatitis but Aggravates Colitis by Changing the Composition of Gut Microflora.

PubMed

Adachi, Soichiro; Hoshi, Namiko; Inoue, Jun; Yasutomi, Eiichiro; Otsuka, Takafumi; Dhakhwa, Ramesh; Wang, Zi; Koo, Yuna; Takamatsu, Toshihiro; Matsumura, Yuriko; Yamairi, Haruka; Watanabe, Daisuke; Ooi, Makoto; Tanahashi, Toshihito; Nishiumi, Shin; Yoshida, Masaru; Azuma, Takeshi

2017-01-01

Indigo naturalis (IND) is an herbal medicine that has been used as an anti-inflammatory agent to treat diseases including dermatitis and inflammatory bowel disease in China. However, the mechanism by which IND exerts its immunomodulatory effect is not well understood. A murine model of dermatitis and inflammatory bowel disease, both induced by oxazolone (OXA), was treated with IND. The severity of dermatitis was evaluated based on ear thickness measurements and histological scoring. The severity of colitis was evaluated by measuring body weight, histological scoring, and endoscopic scoring. The expression of inflammatory cytokines in ear and colon tissue was evaluated using real-time PCR. 16S rRNA DNA sequencing of feces from OXA-induced colitis mice was performed before and after IND treatment. The effects of IND on OXA-induced colitis were also evaluated after depleting the gut flora with antibiotics to test whether alteration of the gut flora by IND influenced the course of intestinal inflammation in this model. IND treatment ameliorated OXA dermatitis with a reduction in IL-4 and eosinophil recruitment. However, OXA colitis was significantly aggravated in spite of a reduction in intestinal IL-13, a pivotal cytokine in the induction of the colitis. It was found that IND dramatically altered the gut flora and IND no longer exacerbated colitis when colitis was induced after gut flora depletion. Our data suggest that IND could modify the inflammatory immune response in multiple ways, either directly (i.e., modification of the allergic immune cell activity) or indirectly (i.e., alteration of commensal compositions). © 2017 S. Karger AG, Basel.

Unraveling the mechanisms underlying pulse dynamics of soil respiration in tropical dry forests

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

Waring, Bonnie G.; Powers, Jennifer S.

Tropical dry forests are already undergoing changes in the quantity and timing of rainfall, but there is great uncertainty over how these shifts will affect belowground carbon (C) cycling. While it has long been known that dry soils quickly release carbon dioxide (CO 2) upon rewetting, the mechanisms underlying the so-called 'Birch effect' are still debated. Here, we quantified soil respiration pulses and their biotic predictors in response to simulated precipitation events in a regenerating tropical dry forest in Costa Rica. We also simulated the observed rewetting CO 2 pulses with two soil carbon models: a conventional model assuming first-ordermore » decay rates of soil organic matter, and an enzyme-catalyzed model with Michaelis–Menten kinetics. We found that rewetting of dry soils produced an immediate and dramatic pulse of CO 2, accompanied by rapid immobilization of nitrogen into the microbial biomass. However, the magnitude of the rewetting CO 2 pulse was highly variable at fine spatial scales, and was well correlated with the size of the dissolved organic C pool prior to rewetting. Both the enzyme-catalyzed and conventional models were able to reproduce the Birch effect when respiration was coupled directly to microbial C uptake, although models differed in their ability to yield realistic estimates of SOC and microbial biomass pool sizes and dynamics. Lastly, our results suggest that changes in the timing and intensity of rainfall events in tropical dry forests will exert strong influence on ecosystem C balance by affecting the dynamics of microbial biomass growth.« less

Got worms? Perinatal exposure to helminths prevents persistent immune sensitization and cognitive dysfunction induced by early-life infection.

PubMed

Williamson, Lauren L; McKenney, Erin A; Holzknecht, Zoie E; Belliveau, Christine; Rawls, John F; Poulton, Susan; Parker, William; Bilbo, Staci D

2016-01-01

The incidence of autoimmune and inflammatory diseases has risen dramatically in post-industrial societies. "Biome depletion" - loss of commensal microbial and multicellular organisms such as helminths (intestinal worms) that profoundly modulate the immune system - may contribute to these increases. Hyperimmune-associated disorders also affect the brain, especially neurodevelopment, and increasing evidence links early-life infection to cognitive and neurodevelopmental disorders. We have demonstrated previously that rats infected with bacteria as newborns display life-long vulnerabilities to cognitive dysfunction, a vulnerability that is specifically linked to long-term hypersensitivity of microglial cell function, the resident immune cells of the brain. Here, we demonstrate that helminth colonization of pregnant dams attenuated the exaggerated brain cytokine response of their offspring to bacterial infection, and that combined with post-weaning colonization of offspring with helminths (consistent with their mothers treatment) completely prevented enduring microglial sensitization and cognitive dysfunction in adulthood. Importantly, helminths had no overt impact on adaptive immune cell subsets, whereas exaggerated innate inflammatory responses in splenic macrophages were prevented. Finally, helminths altered the effect of neonatal infection on the gut microbiome; neonatal infection with Escherichia coli caused a shift from genera within the Actinobacteria and Tenericutes phyla to genera in the Bacteroidetes phylum in rats not colonized with helminths, but helminths attenuated this effect. In sum, these data point toward an inter-relatedness of various components of the biome, and suggest potential mechanisms by which this helminth might exert therapeutic benefits in the treatment of neuroinflammatory and cognitive disorders. Copyright © 2015 Elsevier Inc. All rights reserved.

MicroRNA-1231 exerts a tumor suppressor role through regulating the EGFR/PI3K/AKT axis in glioma.

PubMed

Zhang, Jiale; Zhang, Jie; Qiu, Wenjin; Zhang, Jian; Li, Yangyang; Kong, Enjun; Lu, Ailin; Xu, Jia; Lu, Xiaoming

2018-05-17

MicroRNAs (miRNAs) have been shown to be involved in the initiation and progression of glioma. However, the underlying molecular mechanisms are still unclear. We performed microarray analysis to evaluate miRNA expression levels in 158 glioma tissue samples, and examined miR-1231 levels in glioma samples and healthy brain tissues using qRT-PCR. In vitro analyses were performed using miR-1231 mimics, inhibitors, and siRNA targeting EGFR. We used flow cytometry, CCK-8 assays, and colony formation assays to examine glioma proliferation and cell cycle analysis. A dual luciferase reporter assay was performed to examine miR-1231 regulation of EGFR, and the effect of upregulated miR-1231 was investigated in a subcutaneous GBM model. We found that miR-1231 expression was decreased in human glioma tissues and negatively correlated with EGFR levels. Moreover, the downregulation of miR-1231 negatively correlated with the clinical stage of human glioma patients. miR-1231 overexpression dramatically downregulated glioma cell proliferation, and suppressed tumor growth in a nude mouse model. Bioinformatics prediction and a luciferase assay confirmed EGFR as a direct target of miR-1231. EGFR overexpression abrogated the suppressive effect of miR-1231 on the PI3K/AKT pathway and G1 arrest. Taken together, these results demonstrated that EGFR is a direct target of miR-1231. Our findings suggest that the miR-1231/EGFR axis may be a helpful future diagnostic target for malignant glioma.

Depletion of regulatory T cells by anti-ICOS antibody enhances anti-tumor immunity of tumor cell vaccine in prostate cancer.

PubMed

Mo, Lijun; Chen, Qianmei; Zhang, Xinji; Shi, Xiaojun; Wei, Lili; Zheng, Dianpeng; Li, Hongwei; Gao, Jimin; Li, Jinlong; Hu, Zhiming

2017-10-13

ICOS + Treg cells exert important immunosuppressive effects in tumor immunity. We adopt a combination approach of ICOS + Treg cells depletion with tumor cell vaccine to evaluate anti-tumor immunity in mouse prostate cancer model. Streptavidin (SA)-mGM-CSF surface-modified RM-1 cells were prepared as the vaccine and the mouse subcutaneous prostate tumor model was used to evaluate the immunity. Tumor growth, flow cytometry, immunohistochemistry, immunofluorescence and enzyme linked immunosorbent assay (ELISA) were performed to evaluate the therapeutic effects. Our results demonstrated that SA-mGM-CSF vaccine was prepared successfully and tumor growth was inhibited. The tumor size in the combination group was much smaller than that in the vaccine with IgG mAb group. The portions of dendritic cells, CD8 + and CD4 + T cells in the mice blood and tumor tissues were increased after treatment with vaccine. There were more immune-suppressing Tregs infiltrated into tumor after treatment with tumor cell vaccine, and ICOS blocking could deplete the infiltrated Tregs, and T lymphocytes increased more dramatically in the combination therapy group. The concentrations of interferon-γ were increased in all vaccine group, the concentrations of Interleukin-10 and Interleukin-4 were much lower in the combination group. Our study demonstrated that ICOS blocking could deplete the tumor-infiltrated ICOS + Treg cells. Combining GM-CSF surface-modified RM-1 cell vaccine with Anti-ICOS antibody could induce better antitumor immunity than a vaccine alone. Copyright © 2017 Elsevier Ltd. All rights reserved.

Exosomes From Adipose-derived Mesenchymal Stem Cells Protect the Myocardium Against Ischemia/Reperfusion Injury Through Wnt/β-Catenin Signaling Pathway.

PubMed

Cui, Xiaojun; He, Zhangyou; Liang, Zihao; Chen, Zhenyi; Wang, Haifeng; Zhang, Jiankai

2017-10-01

Mesenchymal stem cells (MSCs) and their secreted exosomes exert a cardioprotective role in jeopardized myocardium. However, the specific effects and underlying mechanisms of exosomes derived from adipose-derived MSCs (ADMSCs) on myocardial ischemia/reperfusion (I/R) injury remain largely unclear. In this study, ADMSC-derived exosomes (ADMSCs-ex) were administrated into the rats subjected to I/R injury and H9c2 cells exposed to hypoxia/reoxygenation (H/R). Consequently, administration of ADMSCs-ex significantly reduced I/R-induced myocardial infarction, accompanied with a decrease in serum levels of creatine kinase-myocardial band, lactate dehydrogenase, and cardiac troponin I (cTnI). Simultaneously, ADMSCs-ex dramatically antagonized I/R-induced myocardial apoptosis, along with the upregulation of Bcl-2 and downregulation of Bax, and inhibition of Caspase 3 activity in rat myocardium. Similarly, ADMSCs-ex significantly reduced cell apoptosis and the expression of Bax, but markedly increased cell viability and the expression of Bcl-2 and Cyclin D1 under H/R. Furthermore, ADMSCs-ex observably induced the activation of Wnt/β-catenin signaling by attenuating I/R- and H/R-induced inhibition of Wnt3a, p-GSK-3β (Ser9), and β-catenin expression. Importantly, treatment with Wnt/β-catenin inhibitor XAV939 partly neutralized ADMSC-ex-induced antiapoptotic and prosurvival effects in H9c2 cells. In conclusion, we confirmed that ADMSCs-ex protect ischemic myocardium from I/R injury through the activation of Wnt/β-catenin signaling pathway.

Quantifying the physical demands of a musical performance and their effects on performance quality.

PubMed

Drinkwater, Eric J; Klopper, Christopher J

2010-06-01

This study investigated the effects of fatigue on performance quality induced by a prolonged musical performance. Ten participants prepared 10 min of repertoire for their chosen wind instrument that they played three times consecutively. Prior to the performance and within short breaks between performances, researchers collected heart rate, respiratory rate, blood pressure, blood lactate concentration, rating of perceived exertion (RPE), and rating of anxiety. All performances were audio recorded and later analysed for performance errors. Reliability in assessing performance errors was assessed by typical error of measure (TEM) of 15 repeat performances. Results indicate all markers of physical stress significantly increased by a moderate to large amount (4.6 to 62.2%; d = 0.50 to 1.54) once the performance began, while heart rate, respirations, and RPE continued to rise by a small to large amount (4.9 to 23.5%; d = 0.28 to 0.93) with each performance. Observed changes in performance between performances were well in excess of the TEM of 7.4%. There was a significant small (21%, d = 0.43) decrease in errors after the first performance; after the second performance, there was a significant large increase (70.4%, d = 1.14). The initial increase in physiological stress with corresponding decrease in errors after the first performance likely indicates "warming up," while the continued increase in markers of physical stress with dramatic decrement in performance quality likely indicates fatigue. Musicians may consider the relevance of physical fitness to maintaining performance quality over the duration of a performance.

Obatoclax and LY3009120 Efficiently Overcome Vemurafenib Resistance in Differentiated Thyroid Cancer

PubMed Central

Wei, Wei-Jun; Sun, Zhen-Kui; Shen, Chen-Tian; Song, Hong-Jun; Zhang, Xin-Yun; Qiu, Zhong-Ling; Luo, Quan-Yong

2017-01-01

Although the prognosis of differentiated thyroid cancer (DTC) is relatively good, 30-40% of patients with distant metastases develop resistance to radioactive iodine therapy due to tumor dedifferentiation. For DTC patients harboring BRAFV600E mutation, Vemurafenib, a BRAF kinase inhibitor, has dramatically changed the therapeutic landscape, but side effects and drug resistance often lead to termination of the single agent treatment. In the present study, we showed that either LY3009120 or Obatoclax (GX15-070) efficiently inhibited cell cycle progression and induced massive death of DTC cells. We established that BRAF/CRAF dimerization was an underlying mechanism for Vemurafenib resistance. LY3009120, the newly discovered pan-RAF inhibitor, successfully overcame Vemurafenib resistance and suppressed the growth of DTC cells in vitro and in vivo. We also observed that expression of anti-apoptotic Bcl-2 increased substantially following BRAF inhibitor treatment in Vemurafenib-resistant K1 cells, and both Obatoclax and LY3009120 efficiently induced apoptosis of these resistant cells. Specifically, Obatoclax exerted its anti-cancer activity by inducing loss of mitochondrial membrane potential (ΔΨm), dysfunction of mitochondrial respiration, reduction of cellular glycolysis, autophagy, neutralization of lysosomes, and caspase-related apoptosis. Furthermore, the cancer killing effects of LY3009120 and Obatoclax extended to two more Vemurafenib-resistant DTC cell lines, KTC-1 and BCPAP. Taken together, our results highlighted the potential value of LY3009120 for both Vemurafenib-sensitive and -resistant DTC and provided evidence for the combination therapy using Vemurafenib and Obatoclax for radioiodine-refractory DTC. PMID:28382170

Antifungal activity and cytotoxicity of extracts and triterpenoid saponins obtained from the aerial parts of Anagallis arvensis L.

PubMed

Soberón, José R; Sgariglia, Melina A; Pastoriza, Ana C; Soruco, Estela M; Jäger, Sebastián N; Labadie, Guillermo R; Sampietro, Diego A; Vattuone, Marta A

2017-05-05

Anagallis arvensis L. (Primulaceae) is used in argentinean northwestern traditional medicine to treat fungal infections. We are reporting the isolation and identification of compounds with antifungal activity against human pathogenic yeast Candida albicans, and toxicity evaluation. to study the antifungal activity of extracts and purified compounds obtained form A. arvensis aerial parts, alone and in combinations with fluconazole (FLU), and to study the toxicity of the active compounds. Disk diffusion assays were used to perform an activity-guided isolation of antifungal compounds from the aerial parts of A. arvensis. Broth dilution checkerboard and viable cell count assays were employed to determine the effects of samples and combinations of FLU + samples against Candida albicans. The chemical structures of active compounds were elucidated by spectroscopic analysis. Genotoxic and haemolytic effects of the isolated compounds were determined. Four triterpenoid saponins (1-4) were identified. Anagallisin C (AnC), exerted the highest inhibitory activity among the assayed compounds against C. albicans reference strain (ATCC 10231), with MIC-0 =1µg/mL. The Fractional Inhibitory Concentration Index (FICI=0.129) indicated a synergistic effect between AnC (0.125µg/mL) and FLU (0.031µg/mL) against C. albicans ATCC 10231. AnC inhibited C. albicans 12-99 FLU resistant strain (MIC-0 =1µg/mL), and the FICI=0.188 indicated a synergistic effect between AnC (0.125µg/mL) and fluconazole (16µg/mL). The combination AnC+ FLU exerted fungicidal activity against both C. albicans strains. AnC exerted inhibitory activity against C. albicans ATCC 10231 sessile cells (MIC 5 0=0.5µg/mL and MIC 80 =1µg/mL) and against C. albicans 12-99 sessile cells (MIC 5 0=0.75µg/mL and MIC 80 =1.25µg/mL). AnC exerted haemolytic effect against human red blood cells at 15µg/mL and did not exerted genotoxic effect on Bacillus subtilis rec strains. The antifungal activity and lack of genotoxic effects of AnC give support to the traditional use of A. arvensis as antifungal and makes AnC a compound of interest to expand the available antifungal drugs. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

The Expression of Fos, Jun and AP-1 DNA Binding Activity in Rat Supraoptic Nucleus Neurons Following Acute Versus Repeated Osmotic Stimulation

DTIC Science & Technology

1995-06-22

heterodimers with each other, they may have very different effects upon gene expression (Mellstrom et al., 1991). Hypertonic saline injections may induce...1, fra 2, Jun-B and Jun-D, that in turn have dramatic effects upon hormone synthesis. How one should view hypertonic saline as an experimental...treatment is also a complex issue. Hypertonic saline administration has at least three effects upon an animal: it is an osmotic stimulus (dramatically

Interest Group Conflict Over Medicaid Expansion: The Surprising Impact of Public Advocates

PubMed Central

Callaghan, Timothy

2016-01-01

Objectives. We examined the potential economic, policy, and political influences on the decisions of the 50 US states to expand Medicaid under the Affordable Care Act. Methods. We related a measure of relative state progress toward Medicaid expansion updated to 2015 to each state’s economic circumstances, established policy frameworks in states, partisan control of state government, and lobbyists for businesses, medical professionals, unions, and public interest organizations. Results. The 9201 lobbyists working on health care reform in state capitols exerted a strong and significant impact on Medicaid expansion. Controlling for confounding factors (including partisanship and existing policy frameworks), we found that business and professional lobbyists exerted a negative effect on state Medicaid expansion and, unexpectedly, that public interest advocates exerted a positive effect. Conclusions. There are 3.1 million adults who lack coverage because they live in the 20 states that refused to expand Medicaid. Although political party and lobbyists for private interests present significant barriers in these states, legislative lobbying on behalf of the uninsured appears likely to be effective. PMID:26691109

Dramatic Variability of the Carbonate System at a Temperate Coastal Ocean Site (Beaufort, North Carolina, USA) Is Regulated by Physical and Biogeochemical Processes on Multiple Timescales

PubMed Central

Johnson, Zackary I.; Wheeler, Benjamin J.; Blinebry, Sara K.; Carlson, Christina M.; Ward, Christopher S.; Hunt, Dana E.

2013-01-01

Increasing atmospheric carbon dioxide (CO2) from anthropogenic sources is acidifying marine environments resulting in potentially dramatic consequences for the physical, chemical and biological functioning of these ecosystems. If current trends continue, mean ocean pH is expected to decrease by ~0.2 units over the next ~50 years. Yet, there is also substantial temporal variability in pH and other carbon system parameters in the ocean resulting in regions that already experience change that exceeds long-term projected trends in pH. This points to short-term dynamics as an important layer of complexity on top of long-term trends. Thus, in order to predict future climate change impacts, there is a critical need to characterize the natural range and dynamics of the marine carbonate system and the mechanisms responsible for observed variability. Here, we present pH and dissolved inorganic carbon (DIC) at time intervals spanning 1 hour to >1 year from a dynamic, coastal, temperate marine system (Beaufort Inlet, Beaufort NC USA) to characterize the carbonate system at multiple time scales. Daily and seasonal variation of the carbonate system is largely driven by temperature, alkalinity and the balance between primary production and respiration, but high frequency change (hours to days) is further influenced by water mass movement (e.g. tides) and stochastic events (e.g. storms). Both annual (~0.3 units) and diurnal (~0.1 units) variability in coastal ocean acidity are similar in magnitude to 50 year projections of ocean acidity associated with increasing atmospheric CO2. The environmental variables driving these changes highlight the importance of characterizing the complete carbonate system rather than just pH. Short-term dynamics of ocean carbon parameters may already exert significant pressure on some coastal marine ecosystems with implications for ecology, biogeochemistry and evolution and this shorter term variability layers additive effects and complexity, including extreme values, on top of long-term trends in ocean acidification. PMID:24358377

The effect of firefighter protective garments, self-contained breathing apparatus and exertion in the heat on postural sway.

PubMed

White, Scott C; Hostler, David

2017-08-01

Fire suppression wearing thermal protective clothing (TPC) and self-contained breathing apparatus (SCBA) challenges a firefighter's balance and may explain firefighter falls. Postural control based on force plate centre of pressure (COP) was compared for healthy subjects wearing TPC and SCBA before and after 20 min of heavy physical exertion in hot conditions. Baseline measures with and without TPC and SCBA (two different SCBA cylinder masses) were compared before and after exertion that included elements of fire suppression activities in an environmental chamber. COP excursion and variability increased with exertion for TPC and SCBA conditions compared to non-stressed conditions. The two different cylinder masses had no significant effect. Wearing TPC and SCBA when physically stressed in a hot environment increases postural sway and exacerbates postural control. Subjects compensated for the extra mass and adjusted to control postural sway with the addition of TPC and SCBA, but the stress protocol amplified these adjustments. Practitioner Summary: Firefighters wear thermal protective clothing (TPC) and self-contained breathing apparatus (SCBA) when heat-stressed and fatigued. Wearing TPC and SCBA was found to negatively impact balance when stressed, but not for non-stressed or two different sized SCBA tanks. Simulating fire-ground conditions wearing TPC and SCBA should be considered for improving balance.

Dramatic pretend play games uniquely improve emotional control in young children.

PubMed

Goldstein, Thalia R; Lerner, Matthew D

2017-09-15

Pretense is a naturally occurring, apparently universal activity for typically developing children. Yet its function and effects remain unclear. One theorized possibility is that pretense activities, such as dramatic pretend play games, are a possible causal path to improve children's emotional development. Social and emotional skills, particularly emotional control, are critically important for social development, as well as academic performance and later life success. However, the study of such approaches has been criticized for potential bias and lack of rigor, precluding the ability to make strong causal claims. We conducted a randomized, component control (dismantling) trial of dramatic pretend play games with a low-SES group of 4-year-old children (N = 97) to test whether such practice yields generalized improvements in multiple social and emotional outcomes. We found specific effects of dramatic play games only on emotional self-control. Results suggest that dramatic pretend play games involving physicalizing emotional states and traits, pretending to be animals and human characters, and engaging in pretend scenarios in a small group may improve children's emotional control. These findings have implications for the function of pretense and design of interventions to improve emotional control in typical and atypical populations. Further, they provide support for the unique role of dramatic pretend play games for young children, particularly those from low-income backgrounds. A video abstract of this article can be viewed at: https://youtu.be/2GVNcWKRHPk. © 2017 John Wiley & Sons Ltd.

The Effects of Supplementation with a Vitamin and Mineral Complex with Guaraná Prior to Fasted Exercise on Affect, Exertion, Cognitive Performance, and Substrate Metabolism: A Randomized Controlled Trial.

PubMed

Veasey, Rachel C; Haskell-Ramsay, Crystal F; Kennedy, David O; Wishart, Karl; Maggini, Silvia; Fuchs, Caspar J; Stevenson, Emma J

2015-07-27

Exercise undertaken in a fasted state can lead to higher post-exercise mental fatigue. The administration of a vitamin and mineral complex with guaraná (MVM + G) has been shown to attenuate mental fatigue and improve performance during cognitively demanding tasks. This placebo-controlled, double-blind, randomized, balanced cross-over study examined the effect of MVM + G consumed prior to morning exercise on cognitive performance, affect, exertion, and substrate metabolism. Forty active males (age 21.4 ± 3.0 year; body mass index (BMI) 24.0 ± 2.4 kg/m2; maximal oxygen consumption (V̇O2max) 57.6 ± 7.3 mL/min/kg) completed two main trials, consuming either MVM + G or placebo prior to a 30-min run at 60% V̇O2max. Supplementation prior to exercise led to a small but significant reduction in Rating of Perceived Exertion (RPE) during exercise compared to the placebo. The MVM + G combination also led to significantly increased accuracy of numeric working memory and increased speed of picture recognition, compared to the placebo. There were no significant effects of supplementation on any other cognitive or mood measures or on substrate metabolism during exercise. These findings demonstrate that consuming a vitamin and mineral complex containing guaraná, prior to exercise, can positively impact subsequent memory performance and reduce perceived exertion during a moderate-intensity run in active males.

The Effects of Supplementation with a Vitamin and Mineral Complex with Guaraná Prior to Fasted Exercise on Affect, Exertion, Cognitive Performance, and Substrate Metabolism: A Randomized Controlled Trial

PubMed Central

Veasey, Rachel C.; Haskell-Ramsay, Crystal F.; Kennedy, David O.; Wishart, Karl; Maggini, Silvia; Fuchs, Caspar J.; Stevenson, Emma J.

2015-01-01

Exercise undertaken in a fasted state can lead to higher post-exercise mental fatigue. The administration of a vitamin and mineral complex with guaraná (MVM + G) has been shown to attenuate mental fatigue and improve performance during cognitively demanding tasks. This placebo-controlled, double-blind, randomized, balanced cross-over study examined the effect of MVM + G consumed prior to morning exercise on cognitive performance, affect, exertion, and substrate metabolism. Forty active males (age 21.4 ± 3.0 year; body mass index (BMI) 24.0 ± 2.4 kg/m2; maximal oxygen consumption (V̇O2max) 57.6 ± 7.3 mL/min/kg) completed two main trials, consuming either MVM + G or placebo prior to a 30-min run at 60% V̇O2max. Supplementation prior to exercise led to a small but significant reduction in Rating of Perceived Exertion (RPE) during exercise compared to the placebo. The MVM + G combination also led to significantly increased accuracy of numeric working memory and increased speed of picture recognition, compared to the placebo. There were no significant effects of supplementation on any other cognitive or mood measures or on substrate metabolism during exercise. These findings demonstrate that consuming a vitamin and mineral complex containing guaraná, prior to exercise, can positively impact subsequent memory performance and reduce perceived exertion during a moderate-intensity run in active males. PMID:26225993

AT13148, a first-in-class multi-AGC kinase inhibitor, potently inhibits gastric cancer cells both in vitro and in vivo

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

Xi, Yu; Department of General Surgery, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang 832008; Niu, Jianhua

The AGC kinase family is important cell proliferation and survival. Dysregulation of this family contributes to gastric cancer progression. Here, we evaluated the potential activity of AT13148, a first-in-class multi-AGC kinase inhibitor, against gastric cancer cells. Our results showed that AT13148 exerted potent cytotoxic and anti-proliferative activities against a panel human gastric cancer cell lines (HGC-27, AGS, SNU-601, N87 and MKN-28), possibly via inducing cancer cell apoptotic death. Apoptosis inhibition by the Caspase blockers dramatically attenuated AT13148-caused cytotoxicity against gastric cancer cells. Intriguingly, same AT13148 treatment was not cytotoxic/pro-apoptotic to the non-cancerous human gastric epithelial GEC-1 cells. At the signaling level,more » AT13148 treatment in gastric cancer cells dramatically suppressed activation of multiple AGC kinases, including Akt (at p-Thr-308), p70S6 kinase (p70S6K), glycogen synthase kinase 3β (GSK-3β) and p90 ribosomal S6 kinase (RSK). Our in vivo studies demonstrated that daily oral gavage of AT13148 at well-tolerated doses significantly inhibited HGC27 xenograft tumor growth in nude mice. AGC activity was also dramatically decreased in AT13148-administrated HGC27 tumors. Therefore, targeting AGC kinases by AT13148 demonstrates superior anti-gastric cancer activity both in vitro and in vivo. The preclinical results of this study support the progression of this molecule into future evaluation as a valuable anti-gastric cancer candidate. - Highlights: • AT13148 is cytotoxic and anti-proliferative to human gastric cancer cells. • AT13148 induces gastric cancer cell apoptotic death, inhibited by Caspase inhibitors. • AT13148 inactivates multiple AGC kinases in human gastric cancer cells. • AT13148 oral administration suppresses HGC27 xenograft growth in nude mice. • AT13148 oral administration inhibits multiple AGC kinases in HGC27 xenograft tumors.« less

On the heating mechanism of magnetic flux loops in the solar atmosphere

NASA Technical Reports Server (NTRS)

Song, M. T.; Wu, S. T.

1984-01-01

An investigation is conducted of physical heating mechanisms due to the ponderomotive forces exerted by turbulent waves along the solar atmosphere's curved magnetic flux loops. Results indicate that the temperature difference between the inside and outside of the flux loop can be classified into three parts, two of which represent the cooling or heating effect exerted by the ponderomotive force, while the third is the heating effect due to turbulent energy conversion from the localized plasma. This heating mechanism is used to illustrate solar atmospheric heating by means of an example that leads to the formulation of plages.

["Entero-insular axis" and regulation of blood sugar and insulin levels following oral glucose loading].

PubMed

Kuznetsov, B G

1978-11-01

The mineral water Essentuki 17 administered per so with glucose exerted a modifying effect on the regulation of glycaemia and insulinaemia in intact rats. This effect undergoes a few phases of changing and disappears by the 30th day. Under conditions of this adaptation, the glycaemia regulation is somewhat worsening. After i.v. administration of glucose during this period the regulation of glycaemia and insulinaemia remains unaltered. This suggests that the mineral water exerts its biological effect, mainly, on the entero-insular axis system (Unger and Eisentraut, 1969) and that the modifying effect is due not to a concrete complex of the mineral water electrolytes but rather to the unspecific factor of "perturbation" in the enteral medium.

(Why) do victims become perpetrators? Intergenerational transmission of parental violence in a representative German sample.

PubMed

Hellmann, Deborah F; Stiller, Anja; Glaubitz, Christoffer; Kliem, Sören

2018-03-01

Child maltreatment can severely impair children's emotional and physical well-being as well as their individual development across the life span. In 2011, the Criminological Research Institute of Lower Saxony (Germany), conducted a nationally representative victim survey on diverse forms of victimizations (N = 11,428). Among other things, experienced and exerted parental violence as well as participants' knowledge regarding the abolition of the parental right of corporal punishment were assessed. Apart from providing current estimates of the prevalence of experienced and exerted parental violence in Germany, we identified specific risk markers for the intergenerational transmission of parental violence. In summary, 52.6% of the participants reported experiences of at least one incident of at least minor parental violence until the age of 16 years, and 22.9% had exerted at least once at least one act of minor violence against their own children. Nonparametric conditional inference tree analyses revealed experienced parental violence as the most important risk marker for exerting parental violence. Furthermore, the number of children currently cared for, parental age, and origin as well as knowledge about the current legal situation regarding corporal punishment were significantly associated with exerting parental violence. For individuals without a history of parental violence, lack of experienced parental warmth and an age between 33 and 40 years increased the risk of exerting parental violence. The results are discussed in terms of their implications for designing effective prevention and intervention strategies. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Protective effects of osthole, a natural derivative of coumarin, against intestinal ischemia-reperfusion injury in mice.

PubMed

Dong, Wenpeng; Zhang, Zhen; Liu, Zhengjun; Liu, Hao; Wang, Xianyue; Bi, Shenghui; Wang, Xiaowu; Ma, Tao; Zhang, Weida

2013-06-01

Intestinal ischemia/reperfusion (I/R) injury is considered to be associated with high morbidity and mortality rates. Osthole, a natural derivative of coumarin, has been shown to exert a variety of pharmacological and therapeutic effects under physiological and pathological conditions. In the present study, to investigate the protective effects of osthole against intestinal I/R injury, various doses of osthole (5, 10, 25 and 50 mg/kg) were pre-administered to mice subjected to intestinal I/R injury. A dose-dependent increase in the survival rate was observed in the osthole-treated mice. Pre-treatment with osthole (50 mg/kg) attenuated the destruction of epithelial cells within the villi induced by intestinal I/R injury, and suppressed oxidative stress, neutrophil infiltration and modulated nitric oxide (NO) levels. Moreover, the increased IκBα phosphorylation and nuclear factor (NF)-κB nuclear translocation induced by I/R injury were significantly decreased following pre-treatment with osthole. Taken together, our data demonstrate that osthole exerts protective effects against intestinal I/R injury in mice by suppressing oxidative stress, neutrophil infiltration and NO levels, partly through the inhibition of NF-κB nuclear translocation. Hence, the findings of the present study provide insight into the mechanisms through which osthole exerts its protective effects against intestinal I/R injury.

Curcumin Attenuates Amyloid-β Aggregate Toxicity and Modulates Amyloid-β Aggregation Pathway.

PubMed

Thapa, Arjun; Jett, Stephen D; Chi, Eva Y

2016-01-20

The abnormal misfolding and aggregation of amyloid-β (Aβ) peptides into β-sheet enriched insoluble deposits initiates a cascade of events leading to pathological processes and culminating in cognitive decline in Alzheimer's disease (AD). In particular, soluble oligomeric/prefibrillar Aβ have been shown to be potent neurotoxins. The naturally occurring polyphenol curcumin has been shown to exert a neuroprotective effect against age-related neurodegenerative diseases such as AD. However, its protective mechanism remains unclear. In this study, we investigated the effects of curcumin on the aggregation of Aβ40 as well as Aβ40 aggregate induced neurotoxicity. Our results show that the curcumin does not inhibit Aβ fibril formation, but rather enriches the population of "off-pathway" soluble oligomers and prefibrillar aggregates that were nontoxic. Curcumin also exerted a nonspecific neuroprotective effect, reducing toxicities induced by a range of Aβ conformers, including monomeric, oligomeric, prefibrillar, and fibrillar Aβ. The neuroprotective effect is possibly membrane-mediated, as curcumin reduced the extent of cell membrane permeabilization induced by Aβ aggregates. Taken together, our study shows that curcumin exerts its neuroprotective effect against Aβ induced toxicity through at least two concerted pathways, modifying the Aβ aggregation pathway toward the formation of nontoxic aggregates and ameliorating Aβ-induced toxicity possibly through a nonspecific pathway.

Mangiferin inhibits hippocampal NLRP3 inflammasome and exerts antidepressant effects in a chronic mild stress mice model.

PubMed

Cao, Changfu; Su, Meiqing; Zhou, Feng

2017-08-01

A growing body of evidence suggests that inflammation may contribute toward the development of major depressive disorder. Mangiferin, a glucosylxanthone from Mangifera indica, exerts a number of biological actions, including anti-inflammatory effects. Although mangiferin has potential antidepressant activity, the mechanisms of this effect remain unclear. The present study investigated the effects of mangiferin on behavioral changes and inflammatory responses induced by chronic mild stress (CMS) in mice. We found that treatment with mangiferin for 3 weeks significantly increased the body weight of mice and ameliorated CMS-induced behavioral abnormalities by increasing sucrose consumption, improving locomotor activities, and decreasing the immobility time in the forced-swimming test and tail-suspension test. It also suppressed increased serum corticosterone levels in CMS mice. In response to CMS induction, the NLR family, pyrin domain containing 3 (NLRP3) inflammasome was activated and interleukin (IL)-1β and IL-18 levels were increased in the mouse hippocampus. Mangiferin treatment downregulated the expression of NLRP3, the adaptor protein ASC, and caspase-1, which subsequently reduced the production of IL-1β and IL-18 in CMS mice. In sum, our results indicate that mangiferin exerts antidepressant-like effects in CMS model, possibly by inhibiting IL-1β production and NLRP3 inflammasome expression.

Mega-dose vitamin C attenuated lung inflammation in mouse asthma model.

PubMed

Jeong, Young-Joo; Kim, Jin-Hee; Kang, Jae Seung; Lee, Wang Jae; Hwang, Young-Il

2010-12-01

Asthma is a Th2-dependent disease mediated by IgE and Th2 cytokines, and asthmatic patients suffer from oxidative stresses from abnormal airway inflammation. Vitamin C is a micro-nutrient functioning as an antioxidant. When administered at a mega-dose, vitamin C has been reported to shift immune responses toward Th1. Thus, we tried to determine whether vitamin C exerted beneficial effects in asthma animal model. Asthma was induced in mice by sensitizing and challenging with ovalbumin. At the time of challenge, 3~5 mg of vitamin C was administered and the effects were evaluated. Vitamin C did not modulate Th1/Th2 balance in asthma model. However, it decreased airway hyperreactivity to methacholine, decreased inflammatory cell numbers in brochoalveolar lavage fluid, and moderate reduction of perivascular and peribronchiolar inflammatory cell infiltration. These results suggest that vitamin C administered at the time of antigen challenge exerted anti-inflammatory effects. Further studies based on chronic asthma model are needed to evaluate a long-term effect of vitamin C in asthma. In conclusion, even though vitamin C did not show any Th1/Th2 shifting effects in this experiment, it still exerted moderate anti-inflammatory effects. Considering other beneficial effects and inexpensiveness of vitamin C, mega-dose usage of vitamin C could be a potential supplementary modality for the management of asthma.

Additive antithrombotic effect of ASP6537, a selective cyclooxygenase (COX)-1 inhibitor, in combination with clopidogrel in guinea pigs.

PubMed

Sakata, Chinatsu; Suzuki, Ken-Ichi; Morita, Yoshiaki; Kawasaki, Tomihisa

2017-03-05

Clopidogrel (Plavix ® , Sanofi-Aventis), the adenosine diphosphate P2Y 12 receptor antagonist, is reported to be effective in the prevention of cardiovascular events and is often used in combination with aspirin, particularly in high-risk patients. ASP6537 is a reversible cyclooxygenase (COX)-1 inhibitor that is under investigation as an anti-platelet agent. First, we investigated the reversibility of the antiplatelet effect of ASP6537 and its interaction with ibuprofen to compare the usability of ASP6537 with that of aspirin. We then evaluated the antithrombotic effect of ASP6537 in combination with clopidogrel using a FeCl 3 -induced thrombosis model in guinea pigs. ASP6537 exerted reversible antiplatelet activity, and no pharmacodynamic interaction with ibuprofen was noted. When administered as monotherapy, ASP6537 exerted a significant antithrombotic effect at ≥3mg/kg, while aspirin inhibited thrombosis at 100mg/kg. ASP6537 exerted significant additive effects in combination with clopidogrel, and the minimum antithrombotic dose was reduced by concomitant administration of clopidogrel. Our study showed that ASP6537 did not interact with ibuprofen and has clear additive effects in combination with clopidogrel. ASP6537 may therefore represent a promising antiplatelet agent for use in clinical settings in combination with clopidogrel. Copyright © 2017 Elsevier B.V. All rights reserved.

Predicting right-wing authoritarianism via personality and dangerous world beliefs: direct, indirect, and interactive effects.

PubMed

Dallago, Francesca; Mirisola, Alberto; Roccato, Michele

2012-01-01

In an Italian sample (N = 483, 78.23% women, mean age = 27.61 years old), we used structural equation modeling with latent variables and interactions to analyze the direct, indirect, and interactive effects exerted on right-wing authoritarianism by the Big Five factors of personality and by dangerous world beliefs. Openness, Neuroticism, and Conscientiousness exerted direct effects on right-wing authoritarianism; the first two relationships were partially mediated by dangerous world beliefs. Most importantly, the relationship between dangerous world beliefs and right-wing authoritarianism was moderated by Openness: dangerous world beliefs significantly influenced right-wing authoritarianism solely for participants high in Openness. Limitations and possible developments of this research are discussed.

Reasons for living, social support, and Afrocentric worldview: assessing buffering factors related to Black Americans' suicidal behavior.

PubMed

Wang, Mei-Chuan; Joel Wong, Y; Tran, Kimberly K; Nyutu, Pius N; Spears, Angela

2013-01-01

This study utilized an ecological framework to explore the role of 4 culturally relevant protective factors-reasons for living, Afrocentric worldview, family support, and friend support-in protecting Black American college students from suicidal behavior. Participants were 289 Black American college students. We hypothesized that these 4 culturally relevant factors would exert indirect protective effects on suicidal behavior through their association with reduced depressive symptoms. Results indicated that reasons for living, perceived supportive behaviors from family, and Afrocentric worldview exerted indirect protective effects on suicidal behaviors through their negative associations with depressive symptoms. The mediation effect from friend support to depression and suicidal behavior was not significant.

Evidence for predatory control of the invasive round goby

USGS Publications Warehouse

Madenjian, C.P.; Stapanian, M.A.; Witzel, L.D.; Einhouse, D.W.; Pothoven, S.A.; Whitford, H.L.

2011-01-01

We coupled bioenergetics modeling with bottom trawl survey results to evaluate the capacity of piscivorous fish in eastern Lake Erie to exert predatory control of the invading population of round goby Neogobius melanostomus. In the offshore (>20 m deep) waters of eastern Lake Erie, burbot Lota lota is a native top predator, feeding on a suite of prey fishes. The round goby invaded eastern Lake Erie during the late 1990s, and round goby population size increased dramatically during 1999–2004. According to annual bottom trawl survey results, round goby abundance in offshore waters peaked in 2004, but then declined during 2004–2008. Coincidentally, round goby became an important component of burbot diet beginning in 2003. Using bottom trawling and gill netting, we estimated adult burbot abundance and age structure in eastern Lake Erie during 2007. Diet composition and energy density of eastern Lake Erie burbot were also determined during 2007. This information, along with estimates of burbot growth, burbot mortality, burbot water temperature regime, and energy densities of prey fish from the literature, were incorporated into a bioenergetics model application to estimate annual consumption of round goby by the adult burbot population. Results indicated that the adult burbot population in eastern Lake Erie annually consumed 1,361 metric tons of round goby. Based on the results of bottom trawling, we estimated the biomass of yearling and older round goby in offshore waters eastern Lake Erie during 2007–2008 to be 2,232 metric tons. Thus, the adult burbot population was feeding on round goby at an annual rate equal to 61% of the estimated round goby standing stock. We concluded that the burbot population had high potential to exert predatory control on round goby in offshore waters of eastern Lake Erie.

Estrogens facilitate memory processing through membrane mediated mechanisms and alterations in spine density

PubMed Central

Luine, Victoria N.; Frankfurt, Maya

2012-01-01

Estrogens exert sustained, genomically mediated effects on memory throughout the female life cycle, but here we review new studies documenting rapid effects of estradiol on memory, which are exerted through membrane-mediated mechanisms. Use of recognition memory tasks in rats, shows that estrogens enhance memory consolidation within one hour. 17α-estradiol is more potent than 17β-estradiol, and the dose response relationship between estrogens and memory is an inverted U shape. Use of specific estrogen receptor (ER) agonists suggests mediation by an ERβ-like membrane receptor. Enhanced memory is associated with increased spine density and altered noradrenergic activity in the medial prefrontal cortex and hippocampus within 30 min. of administration. The environmental chemical, bisphenol-A, rapidly antagonizes enhancements in memory in both sexes possibly through actions on spines. Thus, estradiol and related compounds exert rapid alterations in cognition through non-genomic mechanisms, a finding which may provide a basis for better understanding and treating memory impairments. PMID:22981654

Arthropod repellency, especially tick (Ixodes ricinus), exerted by extract from Artemisia abrotanum and essential oil from flowers of Dianthus caryophyllum.

PubMed

Tunón, H; Thorsell, W; Mikiver, A; Malander, I

2006-06-01

A toluene extract of southernwood (Artemisia abrotanum) and the essential oil from flowers of carnation (Dianthus caryophyllum ) exerted pronounced a repellent effect both against ticks (nymphs of Ixodes ricinus) and yellow fever mosquitoes (Aedes aegypti). The most potent repellents found were coumarin and thujyl alcohol from A. abrotanum and phenylethanol from D. caryophyllum where coumarin and thujyl alcohol were also detected.

Post-exertion neurocognitive test failure among student-athletes following concussion.

PubMed

McGrath, Neal; Dinn, Wayne M; Collins, Michael W; Lovell, Mark R; Elbin, R J; Kontos, Anthony P

2013-01-01

The purpose of the present study was to examine post-exertion (PE) neurocognitive performance among student-athletes following concussion who were asymptomatic and returned to baseline normal neurocognitive test levels at rest. This study examined the neurocognitive performance of a sub-set of student-athletes who 'failed' to perform at baseline levels of neurocognitive function, i.e. exhibited downward reliable change index (RCI) alterations following a moderate exertional protocol during recovery from concussion. A retrospective records review was carried out of Immediate Post-concussion Assessment and Cognitive Testing (ImPACT) and neuropsychological consultation data among athletes with sports-related concussion from a network of 22 schools and one junior hockey programme. Fifty-four student-athletes met inclusion criteria and participated in the study. A total of 27.7% of concussed student-athletes who were symptom-free and returned to baseline on ImPACT at rest (i.e. no longer demonstrated performance deficits on neurocognitive tests) exhibited cognitive decline following moderate physical exertion. The PE cognitive changes were not simply general performance effects, but significant changes in memory ability in the presence of intact processing speed functions. The PE-Pass and PE-Fail groups did not, however, differ on post-concussive symptoms or concussion history. Clinicians' return-to-play evaluation protocols should include post-exertional computerized neurocognitive testing.

Higher motivation - greater control? The effect of arousal on judgement.

PubMed

Riemer, Hila; Viswanathan, Madhu

2013-01-01

This research examines control over the effect of arousal, a dimension of affect, on judgement. Past research shows that high processing motivation enhances control over the effects of affect on judgement. Isolating and studying arousal as opposed to valence, the other dimension of affect, and its effect on judgement, we identify boundary conditions for past findings. Drawing from the literature on processes by which arousal influences judgement, we demonstrate that the role of motivation is contingent upon the type of judgement task (i.e., memory- versus stimulus-based judgement). In stimulus-based judgement, individuals exert greater control over the effect of arousal on judgement under low compared to high motivation. In contrast, in memory-based judgement individuals exert greater control over the effect of arousal under high compared to low motivation. Theoretical implications and avenues for future research are discussed.

Effects of retinoic acid-inducible gene-I-like receptors activations and ionizing radiation cotreatment on cytotoxicity against human non-small cell lung cancer in vitro.

PubMed

Yoshino, Hironori; Iwabuchi, Miyu; Kazama, Yuka; Furukawa, Maho; Kashiwakura, Ikuo

2018-04-01

Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) are pattern-recognition receptors that recognize pathogen-associated molecular patterns and induce antiviral immune responses. Recent studies have demonstrated that RLR activation induces antitumor immunity and cytotoxicity against different types of cancer, including lung cancer. However a previous report has demonstrated that ionizing radiation exerts a limited effect on RLR in human monocytic cell-derived macrophages, suggesting that RLR agonists may be used as effective immunostimulants during radiation therapy. However, it is unclear whether ionizing radiation affects the cytotoxicity of RLR agonists against cancer cells. Therefore, in the present study the effects of cotreatment with ionizing radiation and RLR agonists on cytotoxicity against human non-small cell lung cancer cells A549 and H1299 was investigated. Treatment with RLR agonist poly(I:C)/LyoVec™ [poly(I:C)] exerted cytotoxic effects against human non-small cell lung cancer. The cytotoxic effects of poly(I:C) were enhanced by cotreatment with ionizing radiation, and poly(I:C) pretreatment resulted in the radiosensitization of non-small cell lung cancer. Furthermore, cotreatment of A549 and H1299 cells with poly(I:C) and ionizing radiation effectively induced apoptosis in a caspase-dependent manner compared with treatment with poly(I:C) or ionizing radiation alone. These results indicate that RLR agonists and ionizing radiation cotreatment effectively exert cytotoxic effects against human non-small cell lung cancer through caspase-mediated apoptosis.

Infusions of allopregnanolone into the hippocampus and amygdala, but not into the nucleus accumbens and medial prefrontal cortex, produce antidepressant effects on the learned helplessness rats.

PubMed

Shirayama, Yukihiko; Muneoka, Katsumasa; Fukumoto, Makoto; Tadokoro, Shigenori; Fukami, Goro; Hashimoto, Kenji; Iyo, Masaomi

2011-10-01

Patients with depression showed a decrease in plasma and cerebrospinal fluid allopregnanolone (ALLO). But antidepressants increased the contents of ALLO in the rat brain. We examined the antidepressant-like effects of infusion of ALLO into the cerebral ventricle, hippocampus, amygdala, nucleus accumbens, or prefrontal cortex of learned helplessness (LH) rats (an animal model of depression). Of these regions, infusions of ALLO into the cerebral ventricle, the CA3 region of hippocampus, or the central region of amygdala exerted antidepressant-like effects. Infusion of ALLO into the hippocampal CA3 region or the central amygdala did not produce memory deficits or locomotor activation in the passive avoidance and open field tests. It is well documented that ALLO exerts its effects through GABA receptors. Therefore, we examined the antagonistic effects of flumazenil (a GABA receptor antagonist) on the antidepressant-like effects of ALLO. Coinfusion of flumazenil with ALLO into the hippocampal CA3 region, but not into the central amygdala, blocked the antidepressant-like effects of ALLO. However, coinfusion of (+)MK801 (an NMDA receptor antagonist), but not cycloheximide (a protein synthesis inhibitor), blocked the antidepressant-like effects of ALLO in the central amygdala. These results suggest that ALLO exerts antidepressant-like effects in the CA3 region of hippocampus through the GABA system and in the central region of amygdala, dependently on the activation of the glutamatergic mechanisms. Copyright © 2010 Wiley-Liss, Inc.

Opposite effects of dihydrotestosterone and estradiol on apoptosis in the anterior pituitary gland from male rats.

PubMed

Magri, María Laura; Gottardo, María Florencia; Zárate, Sandra; Eijo, Guadalupe; Ferraris, Jimena; Jaita, Gabriela; Ayala, Mariela Moreno; Candolfi, Marianela; Pisera, Daniel; Seilicovich, Adriana

2016-03-01

Hormones locally synthesized in the anterior pituitary gland are involved in regulation of pituitary cell renewal. In the pituitary, testosterone (T) may exert its actions per se or by conversion to dihydrotestosterone (DHT) or 17β-estradiol (E2) by 5α-reductase and aromatase activity, which are expressed in this gland. Previous reports from our laboratory showed that estrogens modulate apoptosis of lactotropes and somatotropes from female rats. Now, we examined the in vitro and in vivo effects of gonadal steroids on apoptosis of anterior pituitary cells from adult male rats. T in vitro did not modify apoptosis in anterior pituitary cells from gonadectomized (GNX) male rats. DHT, a non-aromatizable androgen, exerted direct antiapoptotic action on total anterior pituitary cells and folliculo-stellate cells, but not on lactotropes, somatotropes, or gonadotropes. On the contrary, E2 exerted a rapid apoptotic effect on total cells as well as on lactotropes and somatotropes. Incubation of anterior pituitary cells with T in presence of Finasteride, an inhibitor of 5α-reductase, increased the percentage of TUNEL-positive cells. In vivo administration of DHT to GNX rats reduced apoptosis in the anterior pituitary whereas E2 exerted proapoptotic action and reduced cells in G2/M-phase of the cell cycle. In summary, our results indicate that DHT and E2 have opposite effects on apoptosis in the anterior pituitary gland suggesting that local metabolization of T to these steroids could be involved in pituitary cell turnover in males. Changes in expression and/or activity of 5α-reductase and aromatase may play a role in the development of anterior pituitary tumors.

Passage through the Ocular Barriers and Beneficial Effects in Retinal Ischemia of Topical Application of PACAP1-38 in Rodents

PubMed Central

Werling, Dora; Banks, William A.; Salameh, Therese S.; Kvarik, Timea; Kovacs, Laszlo Akos; Vaczy, Alexandra; Szabo, Edina; Mayer, Flora; Varga, Rita; Tamas, Andrea; Toth, Gabor; Biro, Zsolt; Atlasz, Tamas; Reglodi, Dora

2017-01-01

The neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) has two active forms, PACAP1-27 and PACAP1-38. Among the well-established actions are PACAP’s neurotrophic and neuroprotective effects, which have also been proven in models of different retinopathies. The route of delivery is usually intravitreal in studies proving PACAP’s retinoprotective effects. Recently, we have shown that PACAP1-27 delivered as eye drops in benzalkonium-chloride was able to cross the ocular barriers and exert retinoprotection in ischemia. Since PACAP1-38 is the dominant form of the naturally occurring PACAP, our aim was to investigate whether the longer form is also able to cross the barriers and exert protective effects in permanent bilateral common carotid artery occlusion (BCCAO), a model of retinal hypoperfusion. Our results show that radioactive PACAP1-38 eye drops could effectively pass through the ocular barriers to reach the retina. Routine histological analysis and immunohistochemical evaluation of the Müller glial cells revealed that PACAP1-38 exerted retinoprotective effects. PACAP1-38 attenuated the damage caused by hypoperfusion, apparent in almost all retinal layers, and it decreased the glial cell overactivation. Overall, our results confirm that PACAP1-38 given in the form of eye drops is a novel protective therapeutic approach to treat retinal diseases. PMID:28335564

Fruit extract of the medicinal plant Crataegus oxyacantha exerts genotoxic and mutagenic effects in cultured cells.

PubMed

de Quadros, Ana Paula Oliveira; Mazzeo, Dania Elisa Christofoletti; Marin-Morales, Maria Aparecida; Perazzo, Fábio Ferreira; Rosa, Paulo Cesar Pires; Maistro, Edson Luis

2017-01-01

Crataegus oxyacantha, a plant of the Rosaceae family also known "English hawthorn, haw, maybush, or whitethorn," has long been used for medicinal purposes such as digestive disorders, hyperlipidemia, dyspnea, inducing diuresis, and preventing kidney stones. However, the predominant use of this plant has been to treat cardiovascular disorders. Due to a lack of studies on the genotoxicity of C. oxyacantha, this investigation was undertaken to determine whether its fruit extract exerts cytotoxic, genotoxic, or clastogenic/aneugenic effects in leukocytes and HepG2 (liver hepatocellular carcinoma) cultured human cells, or mutagenic effects in TA100 and TA98 strains of Salmonella typhimurium bacterium. Genotoxicity analysis showed that the extract produced no marked genotoxic effects at concentrations of 2.5 or 5 µg/ml in either cell type; however, at concentrations of 10 µg/ml or higher significant DNA damage was detected. The micronucleus test also demonstrated that concentrations of 10 µg/ml or higher produced clastogenic/aneugenic responses. In the Ames test, the extract induced mutagenic effects in TA98 strain of S. typhimurium with metabolic activation at all tested concentrations (2.5 to 500 µg/ml). Data indicate that, under certain experimental conditions, the fruit extract of C. oxyacantha exerts genotoxic and clastogenic/aneugenic effects in cultured human cells, and with metabolism mutagenicity occurs in bacteria cells.

Alterations in brain-derived neurotrophic factor (BDNF) and its precursor proBDNF in the brain regions of a learned helplessness rat model and the antidepressant effects of a TrkB agonist and antagonist.

PubMed

Shirayama, Yukihiko; Yang, Chun; Zhang, Ji-chun; Ren, Qian; Yao, Wei; Hashimoto, Kenji

2015-12-01

Role of brain-derived neurotrophic factor (BDNF)-TrkB signaling in a learned helplessness (LH) model of depression was investigated. LH rats showed a reduction of BDNF in the medial prefrontal cortex (mPFC), CA3, and dentate gyrus (DG) of the hippocampus, whereas LH rats showed an increase in BDNF in the nucleus accumbens (NAc). Furthermore, levels of proBDNF, a BDNF precursor, were higher in the mPFC, but lower in the NAc, of LH rats. A single bilateral infusion of a TrkB agonist 7,8-DHF, but not a TrkB antagonist ANA-12, into the infralimbic (IL) of mPFC, DG, and CA3, but not the prelimbic (PrL) of mPFC, exerted antidepressant effects in LH rats. In contrast, a single bilateral infusion of ANA-12, but not 7,8-DHF, into the core and shell of NAc exerted antidepressant-like effects in LH rats, with more potent effects observed for the NAc core than for NAc shell. Interestingly, a single administration of 7,8-DHF (10mg/kg, i.p.) significantly improved a decreased phosphorylation of TrkB in the mPFC, CA3, and DG of LH rats. Additionally, ANA-12 (0.5mg/kg, i.p.) significantly improved an increased phosphorylation of TrkB in the NAc of LH rats. In conclusion, these results suggest that LH causes depression-like behavior by altering BDNF in the brain regions, and that proBDNF-BDNF processing and transport may be altered in the mPFC-NAc circuit of LH rats. Therefore, TrkB agonists might exert antidepressant effects by stimulating TrkB in the IL, CA3, and DG, while TrkB antagonists might exert antidepressant effects by blocking TrkB in the NAc. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

Negotiating for Change: Modifying Collective Bargaining Agreements for School Turnaround

ERIC Educational Resources Information Center

Weinberg, Rebecca

2011-01-01

Dramatically improving student achievement in a school that has been failing for many years requires dramatically different conditions. Only the most effective teachers and leaders should be in the building, and the leadership must have the flexibility to respond strategically to the needs of the students, with regular input from teachers.…

Predicting wolf (Canis lupus)-cattle (Bos Taurus) encounters and consequential effects on cattle resource selection patterns

USDA-ARS?s Scientific Manuscript database

The gray wolf population in Idaho has grown dramatically from the original 35 reintroduced individuals in 1995-1996 to 94 documented packs and a minimum population of 835 individuals in 2009. Wolf depredation on livestock has also increased dramatically with this population growth. Substantial spa...

Potential behavioral and pro-oxidant effects of Petiveria alliacea L. extract in adult rats.

PubMed

de Andrade, Thaís Montenegro; de Melo, Ademar Soares; Dias, Rui Guilherme Cardoso; Varela, Everton Luís Pompeu; de Oliveira, Fábio Rodrigues; Vieira, José Luís Fernandes; de Andrade, Marcieni Ataíde; Baetas, Ana Cristina; Monteiro, Marta Chagas; Maia, Cristiane do Socorro Ferraz

2012-09-28

Petiveria alliacea (Phytolaccaceae) is a perennial shrub indigenous to the Amazon Rainforest and tropical areas of Central and South America, the Caribbean, and sub-Saharan Africa. In folk medicine, Petiveria alliacea has a broad range of therapeutic properties; however, it is also associated with toxic effects. The present study evaluated the putative effects of Petiveria alliacea on the central nervous system, including locomotor activity, anxiety, depression-like behavior, and memory, and oxidative stress. Two-month-old male and female Wistar rats (n=7-10 rats/group) were administered with 900 mg/kg of hydroalcoholic extracts of Petiveria alliacea L. The behavioral assays included open-field, forced swimming, and elevated T-maze tests. The oxidative stress levels were measured in rat blood samples after behavioral assays and methemoglobin levels were measured in vitro. Consistent with previous reports, Petiveria alliacea increased locomotor activity. It also exerted previously unreported anxiolytic and antidepressant effects in behavioral tests. In the oxidative stress assays, the Petiveria alliacea extract decreased Trolox equivalent antioxidant capacity levels and increased methemoglobin levels, which was related to the toxic effects. The Petiveria alliacea extract exerted motor stimulatory and anxiolytic effects in the OF test, antidepressant effects in the FS test, and elicited memory improvement in ETM. Furthermore, the Petiveria alliacea extract also exerted pro-oxidant effects in vitro and in vivo, inhibiting the antioxidant status and increasing MetHb levels in human plasma, respectively. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Tipepidine, a non-narcotic antitussive, exerts an antidepressant-like effect in the forced swimming test in adrenocorticotropic hormone-treated rats.

PubMed

Kawaura, Kazuaki; Ogata, Yukino; Honda, Sokichi; Soeda, Fumio; Shirasaki, Tetsuya; Takahama, Kazuo

2016-04-01

We investigated whether tipepidine exerts an antidepressant-like effect in the forced swimming test in adrenocorticotropic hormone (ACTH)-treated rats, which is known as a treatment-resistant depression model, and we studied the pharmacological mechanisms of the effects of tipepidine. Male Wistar rats (5-7 weeks old) were used in this study. Tipepidine (20 and 40 mg/kg, i.p.) decreased the immobility time in the forced swimming test in ACTH-treated rats. The anti-immobility effect of tipepidine was blocked by a catecholamine-depleting agent, alpha-methyl-p-tyrosine (300 mg/kg, s.c.), but not by a serotonin-depleting agent, p-chlorophenylalanine. The anti-immobility effect of tipepidine was also blocked by a dopamine D1 receptor antagonist, SCH23390 (0.02 mg/kg, s.c.) and an adrenaline α2 receptor antagonist, yohimbine (2 mg/kg, i.p.). In microdialysis technique, tipepidine (40 mg/kg, i.p.) increased the extracellular dopamine level of the nucleus accumbens (NAc) in ACTH-treated rats. These results suggest that tipepidine exerts an antidepressant-like effect in the forced swimming test in ACTH-treated rats, and that the effect of tipepidine is mediated by the stimulation of dopamine D1 receptors and adrenaline α2 receptors. The results also suggest that an increase in the extracellular dopamine level in the NAc may be involved in the antidepressant-like effect of tipepidine in ACTH-treated rats. Copyright © 2016. Published by Elsevier B.V.

The influence of a yoga exercise program for young adults with intellectual disabilities.

PubMed

Hawkins, Brent L; Stegall, Joanna B; Weber, Madalyn F; Ryan, Joseph B

2012-07-01

Individuals with intellectual disabilities (ID) have an increased risk of obesity and are significantly less likely to engage in physical activity compared to their nondisabled peers. A growing body of research supports the physical and mental health benefits of yoga. While the benefits of yoga have been studied across a host of populations with varying ages and physical disabilities, no studies could be identified investigating the benefits of yoga for young adults with ID. This study investigated the impact of participating in yoga classes on the amount of exercise behavior and perception of physical exertion when compared to non-structured exercise sessions between two young adults with ID in a post-secondary education setting. A single subject multiple baseline research design was implemented across two young adults with mild ID to determine the effects of a yoga exercise class on frequency of exercise behavior and perception of physical exertion when compared to non-structured exercise sessions. Partial interval recording, the Eston-Parfitt curvilinear rating of perceived exertion scale, and the physical activity enjoyment scale were implemented to collect data on dependent variables and consumer satisfaction during each non-structured exercise session and each yoga class. indicated that percentage of exercise behavior and perceived exertion levels during yoga group exercise sharply increased with large effect sizes when compared to non-structured exercise sessions.

Negative incidental emotions augment fairness sensitivity.

PubMed

Liu, Cuizhen; Chai, Jing Wen; Yu, Rongjun

2016-04-22

Previous studies have shown that task-unrelated emotions induced incidentally exert carryover effects on individuals' subsequent decisions in financial negotiations. However, the specificity of these emotion effects are not clear. In three experiments, we systematically investigated the role of seven transiently induced basic emotions (disgust, sadness, anger, fear, happiness, surprise and neutral) on rejection of unfair offers using the ultimatum game. We found that all negative emotions (disgust, sadness, anger and fear), but not happiness or surprise, significantly increased rejection rates, suggesting that the effect of incidental negative emotions on fairness is not specific to the type of negative emotion. Our findings highlight the role of fleeting emotions in biasing decision-making processes and suggest that all incidental negative emotions exert similar effects on fairness sensitivity, possibly by potentiating attention towards negative aspects of the situation.

Syringaldehyde exerts neuroprotective effect on cerebral ischemia injury in rats through anti-oxidative and anti-apoptotic properties

PubMed Central

Bozkurt, Aras Adem; Mustafa, Guven; Tarık, Akman; Adile, Ozkan; Murat, Sen Halil; Mesut, Kılıcoglu; Yıldıray, Kalkan; Coskun, Silan; Murat, Cosar

2014-01-01

There are few studies on the neuroprotective effects of syringaldehyde in a rat model of cerebral ischemia. The study aimed to elucidate the mechanisms underlying the neuroprotective effects of syringaldehyde on ischemic brain cells. Rat models of cerebral ischemia were intraperitoneally administered syringaldehyde. At 6 and 24 hours after syringaldehyde administration, cell damage in the brain of cerebral ischemia rats was obviously reduced, superoxide dismutase activity and nuclear respiratory factor 1 expression in the brain tissue were markedly increased, malondiadehyde level was obviously decreased, apoptosis-related cysteine peptidase caspase-3 and -9 immunoreactivity was obviously decreased, and neurological function was markedly improved. These findings suggest that syringaldehyde exerts neuroprotective effects on cerebral ischemia injury through anti-oxidation and anti-apoptosis. PMID:25558237

Syringaldehyde exerts neuroprotective effect on cerebral ischemia injury in rats through anti-oxidative and anti-apoptotic properties.

PubMed

Bozkurt, Aras Adem; Mustafa, Guven; Tarık, Akman; Adile, Ozkan; Murat, Sen Halil; Mesut, Kılıcoglu; Yıldıray, Kalkan; Coskun, Silan; Murat, Cosar

2014-11-01

There are few studies on the neuroprotective effects of syringaldehyde in a rat model of cerebral ischemia. The study aimed to elucidate the mechanisms underlying the neuroprotective effects of syringaldehyde on ischemic brain cells. Rat models of cerebral ischemia were intraperitoneally administered syringaldehyde. At 6 and 24 hours after syringaldehyde administration, cell damage in the brain of cerebral ischemia rats was obviously reduced, superoxide dismutase activity and nuclear respiratory factor 1 expression in the brain tissue were markedly increased, malondiadehyde level was obviously decreased, apoptosis-related cysteine peptidase caspase-3 and -9 immunoreactivity was obviously decreased, and neurological function was markedly improved. These findings suggest that syringaldehyde exerts neuroprotective effects on cerebral ischemia injury through anti-oxidation and anti-apoptosis.

The effects of acclimatization on blood clotting parameters in exertional heat stress.

PubMed

Vesić, Zoran; Vukasinović-Vesić, Milica; Dincić, Dragan; Surbatović, Maja; Radaković, Sonja S

2013-07-01

Exertional heat stress is a common problem in military services. Considering the coagulation abnormalities are of major importance in development of severe heat stroke, we wanted to examine changes in hemostatic parameters in soldiers during exertional heat stress test as well as the effects of a 10-day passive or active acclimatization in a climatic chamber. A total of 40 male soldiers with high aerobic capacity performed exertional heat stress test (EHST) either in cool [20 degrees C, 16 degrees C wet bulb globe temperature (WBGT)], or hot (40 degrees C, 29 degrees C, (WBGT) environment, unacclimatized (U) or after 10 days of passive (P) or active (A) acclimatization. Physiological strain was measured by tympanic temperatures (Tty) and heart rates (HR). Platelet count (PC), antithrombin III (AT), and prothrombin time (PT) were assessed in blood samples collected before and immediately after the EHST. EHST in hot conditions induced physiological heat stress (increase in Tty and HR), with a significant increase in prothrombin time in the groups U and A. Platelet counts were significantly higher after the EHST compared to the basic levels in all the investigated groups, regardless environmental conditions and acclimatization state. Antithrombin levels were not affected by EHST whatsoever. In the trained soldiers, physiological heat stress caused mild changes in some serum parameters of blood clotting such as prothrombin time, while others such as antithrombin levels were not affected. Platelet counts were increased after EHST in all groups. A 10-day passive or active acclimatization in climatic chamber showed no effect on parameters investigated.

Comfort and exertion while using filtering facepiece respirators with exhalation valve and an active venting system among male military personnel.

PubMed

Seng, Melvin; Wee, Liang En; Zhao, Xiahong; Cook, Alex R; Chia, Sin Eng; Lee, Vernon J

2017-07-06

This study aimed to determine if disposable filtering facepiece respirators (FFRs), with exhalation valve (EV) and a novel active venting system (AVS), provided greater perceived comfort and exertion when compared to standard N95 FFRs without these features among male military personnel performing prolonged essential outdoor duties. We used a randomised open-label controlled crossover study design to compare three FFR options: (a) standard FFR; (b) FFR with EV; and (c) FFR with EV+AVS. Male military personnel aged between 18 and 20 years completed a questionnaire at the beginning (baseline), after two hours of standardised non-strenuous outdoor duty and after 12 hours of duty divided into two-hour work-rest cycles. Participants rated the degree of discomfort, exertion and symptoms using a five-point Likert scale. The association between outcomes and the types of FFR was assessed using a multivariate ordered probit mixed-effects model. For a majority of the symptoms, study participants rated FFR with EV and FFR with EV+AVS with significantly better scores than standard FFR. Both FFR with EV and FFR with EV+AVS had significantly less discomfort (FFR with EV+AVS: 91.1%; FFR with EV: 57.6%) and exertion (FFR with EV+AVS: 83.5%; FFR with EV: 34.4%) than standard FFR. FFR with EV+AVS also had significantly better scores for exertion (53.4%) and comfort (39.4%) when compared to FFR with EV. Usage of FFR with EV+AVS resulted in significantly reduced symptoms, discomfort and exertion when compared to FFR with EV and standard FFR.

Dual towline spin-recovery device

NASA Technical Reports Server (NTRS)

White, W. L. (Inventor)

1985-01-01

A device which corrects aerodynamic spin is described wherein a parachute exerts antispin forces on an aircraft to effect spin recovery. The dual parachute towlines and are each attached to the parachute and are attached to the rear fuselage equidistant to and on opposite sides of the aircraft centerline. As the parachute is deployed during spin, the parachute force acts through only the towing and exerts its force outboard of center on the aircraft. As a result, the parachute exerts not only an antispin torque, but additionally causes the aircraft to roll, creating a gyroscopic antispin rolling moment. The additional antispin rolling moment facilitates spin recovery by permitting a relatively smaller parachute to accomplish spin recovery equivalent to that of a larger parachute attached to the center of the rear fuselage.

Effects of cognitive stimulation with a self-modeling video on time to exhaustion while running at maximal aerobic velocity: a pilot study.

PubMed

Hagin, Vincent; Gonzales, Benoît R; Groslambert, Alain

2015-04-01

This study assessed whether video self-modeling improves running performance and influences the rate of perceived exertion and heart rate response. Twelve men (M age=26.8 yr., SD=6; M body mass index=22.1 kg.m(-2), SD=1) performed a time to exhaustion running test at 100 percent maximal aerobic velocity while focusing on a video self-modeling loop to synchronize their stride. Compared to the control condition, there was a significant increase of time to exhaustion. Perceived exertion was lower also, but there was no significant change in mean heart rate. In conclusion, the video self-modeling used as a pacer apparently increased endurance by decreasing perceived exertion without affecting the heart rate.

Antioxidant and Renoprotective Effects of Mushroom Extract: Implication in Prevention of Nephrolithiasis

PubMed Central

Schulman, Ariel; Chaimowitz, Matthew; Choudhury, Muhammad; Eshghi, Majid; Konno, Sensuke

2016-01-01

Background The pathogenesis of nephrolithiasis (kidney stone) remains elusive, while several therapeutic options are available but not effective as we expected. Accumulating data yet suggest that oxidative stress (generation of oxygen free radicals) may play a primary role in its occurrence. Particularly, calcium oxalate (CaOx) is a key element in the most common form (> 75%) of kidney stones, and its crystal form known as CaOx monohydrate (COM) has been shown to exert oxidative stress, facilitating CaOx stone formation. Hence, diminishing oxidative stress with certain antioxidants could be a potential strategic approach. We are interested in a bioactive extract of Poria mushroom, PE, which has been shown to have antioxidant and renoprotective activities. Accordingly, we investigated if PE might have antioxidant activity that would have implication in prevention of kidney stone formation. Methods Renal epithelial LLC-PK1 cells were employed and exposed to COM or hydrogen peroxide (H2O2) as a positive control capable of exerting oxidative stress. Possible antioxidant and protective effects of PE against oxidative stress (exerted by COM or H2O2) were assessed by cell viability test and lipid peroxidation (LPO) assay. To explore its protective mechanism, two glycolytic parameters, hexokinase (HK) activity and ATP synthesis, were examined and cell cycle analysis was also performed. Results Both H2O2 and COM led to a significant (P < 0.05) reduction in cell viability, accompanied by severe oxidative stress assessed by LPO assay. Such oxidative stress also caused the significant decline in HK activity and cellular ATP level, indicating the inhibition of glycolysis. Cell cycle analysis further indicated that oxidative stress interfered with cell cycle, inducing a G1 cell cycle arrest that presumably results in the cessation of cell proliferation. However, PE was capable of significantly preventing or diminishing all these cellular effects mediated through oxidative stress (exerted by H2O2 and COM). Conclusions The present study shows that the mushroom extract PE appears to have antioxidant and renoprotective effects against oxidative stress exerted by COM in renal cells. Therefore, PE with antioxidant activity is considered a promising natural agent that may have clinical implications in prevention of nephrolithiasis primarily induced by oxidative stress. PMID:27829958

Mesozoic black shales, source mixing and carbon isotopes

NASA Astrophysics Data System (ADS)

Suan, Guillaume

2016-04-01

Over the last decades, considerable attention has been devoted to the paleoenvironmental and biogeochemical significance of Mesozoic black shales. Black shale-bearing successions indeed often display marked changes in the organic carbon isotope composition (δ13Corg), which have been commonly interpreted as evidence for dramatic perturbations of global carbon budgets and CO2 levels. Arguably the majority of these studies have discarded some more "local" explanations when interpreting δ13Corg profiles, most often because comparable profiles occur on geographically large and distant areas. Based on newly acquired data and selected examples from the literature, I will show that the changing contribution of organic components with distinct δ13C signatures exerts a major but overlooked influence of Mesozoic δ13Corg profiles. Such a bias occurs across a wide spectrum of sedimentological settings and ages, as shown by the good correlation between δ13Corg values and proxies of kerogen proportions (such as rock-eval, biomarker, palynofacies and palynological data) recorded in Mesozoic marginal to deep marine successions of Triassic, Jurassic and Cretaceous age. In most of these successions, labile, 12C-enriched amorphous organic matter of marine origin dominates strata deposited under anoxic conditions, while oxidation-resistant, 13C-rich terrestrial particles dominate strata deposited under well-oxygenated conditions. This influence is further illustrated by weathering profiles of Toarcian (Lower Jurassic) black shales from France, where weathered areas dominated by refractory organic matter show dramatic 13C-enrichment (and decreased total organic carbon and pyrite contents) compared to non-weathered portions of the same horizon. The implications of these results for chemostratigraphic correlations and pCO2 reconstructions of Mesozoic will be discussed, as well as strategies to overcome this major bias.

A candidate anti-HIV reservoir compound, auranofin, exerts a selective ‘anti-memory' effect by exploiting the baseline oxidative status of lymphocytes

PubMed Central

Chirullo, B; Sgarbanti, R; Limongi, D; Shytaj, I L; Alvarez, D; Das, B; Boe, A; DaFonseca, S; Chomont, N; Liotta, L; III Petricoin, E; Norelli, S; Pelosi, E; Garaci, E; Savarino, A; Palamara, A T

2013-01-01

Central memory (TCM) and transitional memory (TTM) CD4+ T cells are known to be the major cellular reservoirs for HIV, as these cells can harbor a transcriptionally silent form of viral DNA that is not targeted by either the immune system or current antiretroviral drug regimens. In the present study, we explored the molecular bases of the anti-HIV reservoir effects of auranofin (AF), a pro-oxidant gold-based drug and a candidate compound for a cure of AIDS. We here show that TCM and TTM lymphocytes have lower baseline antioxidant defenses as compared with their naive counterpart. These differences are mirrored by the effects exerted by AF on T-lymphocytes: AF was able to exert a pro-differentiating and pro-apoptotic effect, which was more pronounced in the memory subsets. AF induced an early activation of the p38 mitogen-activated protein kinase (p38 MAPK) followed by mitochondrial depolarization and a final burst in intracellular peroxides. The pro-differentiating effect was characterized by a downregulation of the CD27 marker expression. Interestingly, AF-induced apoptosis was inhibited by pyruvate, a well-known peroxide scavenger, but pyruvate did not inhibit the pro-differentiating effect of AF, indicating that the pro-apoptotic and pro-differentiating effects involve different pathways. In conclusion, our results demonstrate that AF selectively targets the TCM/TTM lymphocyte subsets, which encompass the HIV reservoir, by affecting redox-sensitive cell death pathways. PMID:24309931

Principal-Staff Relations: Situational Mediator of Effectiveness

ERIC Educational Resources Information Center

Williams, Leonard B.; Hoy, Wayne K.

1971-01-01

Explores the usefulness of the "Contingency Model" of leadership effectiveness -- effectiveness of a group is contingent upon the relationship between leadership style and the degree to which the situation enables the leader to exert his influence. (Author)

Activated protein C and its potential applications in prevention of islet β-cell damage and diabetes.

PubMed

Xue, Meilang; Jackson, Christopher J

2014-01-01

Activated protein C (APC) is derived from its precursor, protein C (PC). Originally thought to be synthesized exclusively by the liver, recent reports have shown that PC is also produced by many other cells including pancreatic islet β cells. APC functions as a physiological anticoagulant with anti-inflammatory, anti-apoptotic, and barrier-stabilizing properties. APC exerts its protective effects via an intriguing mechanism requiring combinations of endothelial PC receptor, protease-activated receptors, epidermal growth factor receptor, Tie2 or CD11b, depending on cell types. Diabetes is a chronic condition resulted from the body's inability to produce and/or properly use insulin. The prevalence of diabetes has risen dramatically and has become one of the major causes of premature mortality and morbidity worldwide. Diabetes prevention is an ideal approach to reduce this burden. Type 1 and type 2 diabetes are the major forms of diabetes mellitus, and both are characterized by an autoimmune response, intraislet inflammation, β-cell apoptosis, and progressive β-cell loss. Protecting β-cell from damage is critical in both prevention and treatment of diabetes. Recent in vitro and animal studies show that APC's strong anti-inflammatory and anti-apoptotic properties are beneficial in preventing β-cell destruction and diabetes in the NOD mouse model of type 1 diabetes. Future preventive and therapeutic uses of APC in diabetes look very promising. © 2014 Elsevier Inc. All rights reserved.

Role of Indigenous Lactobacilli in Gastrin-Mediated Acid Production in the Mouse Stomach ▿

PubMed Central

Takahashi, Hidenori; Nakano, Yasuhiro; Matsuoka, Takashi; Kumaki, Nobue; Asami, Yukio; Koga, Yasuhiro

2011-01-01

It is known that the stomach is colonized by indigenous lactobacilli in mice. The aim of this study was to examine the role of such lactobacilli in the development of the stomach. For a DNA microarray analysis, germ-free BALB/c mice were orally inoculated with 109 CFU lactobacilli, and their stomachs were excised after 10 days to extract RNA. As a result, lactobacillus-associated gnotobiotic mice showed dramatically decreased expression of the gastrin gene in comparison to germ-free mice. The mean of the log2 fold change in the gastrin gene was −4.3. Immunohistochemistry also demonstrated the number of gastrin-positive (gastrin+) cells to be significantly lower in the lactobacillus-associated gnotobiotic mice than in the germ-free mice. However, there was no significant difference in the number of somatostatin+ cells in these groups of mice. Consequently, gastric acid secretion also decreased in the mice colonized by lactobacilli. In addition, an increase in the expression of the genes related to muscle system development, such as nebulin and troponin genes, was observed in lactobacillus-associated mice. Moreover, infection of germ-free mice with Helicobacter pylori also showed the down- and upregulation of gastrin and muscle genes, respectively, in the stomach. These results thus suggested that indigenous lactobacilli in the stomach significantly affect the regulation of gastrin-mediated gastric acid secretion without affecting somatostatin secretion in mice, while H. pylori also exerts such an effect on the stomach. PMID:21803885

Promotion of interferon-gamma production by natural killer cells via suppression of murine peritoneal macrophage prostaglandin E₂ production using intravenous anesthetic propofol.

PubMed

Inada, Takefumi; Kubo, Kozue; Shingu, Koh

2010-10-01

Propofol is an intravenous anesthetic, widely used for general anesthesia during surgery, which inevitably involves tissue trauma with inflammation. At sites of inflammation, prostanoids, especially prostaglandin E₂ (PGE₂), are abundant. This study addresses the effect of propofol on macrophage PGE₂ production. Using thioglycollate-elicited murine peritoneal macrophages, propofol (7.5-30 μM) suppressed lipopolysaccharide-induced PGE₂ production. The suppression was via the direct inhibition of cyclooxygenase (COX) enzyme activity and due neither to the downregulation of COX expression nor the inhibition of arachidonic acid release from plasma membranes. In macrophage:natural killer (NK) cell co-culture, propofol dramatically increased interferon-gamma (IFN-γ) production, and the actions of propofol were mimicked by a selective COX-2 inhibitor, NS-398, as well as the selective EP4 receptor antagonist L-161,982, suggesting a role of PGE₂ suppression in the upregulation of IFN-γ production. Furthermore, in purified NK cell culture, PGE₂ directly suppressed the production of IFN-γ by activated NK cells, which was reversed by selective inhibition of EP4 activity. Taken together, our results show that, in macrophage:NK cell co-culture, propofol, through the suppression of macrophage PGE₂ production, upregulates NK cell IFN-γ production by alleviating EP4 receptor-mediated suppression of IFN-γ production. Propofol may potentially exert considerable influence on inflammation and immunity by suppressing PGE₂ synthesis. Copyright © 2010 Elsevier B.V. All rights reserved.

Novel hydrogen decrepitation behaviors of (La, Ce)-Fe-B strips

NASA Astrophysics Data System (ADS)

Jin, Jiaying; Bai, Guohua; Zhang, Yujing; Peng, Baixing; Liu, Yongsheng; Ma, Tianyu; Yan, Mi

2018-05-01

La and Ce substitution for Nd in the 2:14:1-type sintered magnet is of commercial interest to reduce the material cost and to balance the utilization of rare earth (RE) sources. As hydrogen decrepitation (HD) is widely utilized to prepare the magnetic powders during magnets fabrication, incorporating La and Ce into the Nd-Fe-B permanent magnets, however, may exert complex influences on the decrepitation behavior. In the present work, through a comparative study of the HD behaviors between the (La, Ce)-Fe-B strips and the conventional Nd-Fe-B ones, we find that similar to the Nd-Fe-B system, increasing hydrogen pressures from 2.5 to 5.5 MPa do not break the 2:14:1 tetragonal structure of (La, Ce)-Fe-B strips. The enhanced hydrogen absorption behaviors are observed with increasing pressure, which are still inferior to that of the Nd-Fe-B strips. This should be ascribed to the higher oxygen affinity of La and Ce than that of Nd, leading to the decreased amount of active RE-rich phase and limited hydrogen diffusion channel. As a result, the hydrogen absorption of 2:14:1 matrix phase is significantly suppressed, dramatically weakening the exothermic effect. This finding suggests that La and Ce with stable 2:14:1 tetragonal structure upon HD process are promising alternatives for Nd, despite that more precise oxygen control is necessary for the microstructure modification and magnetic performance enhancement of (La, Ce)-Fe-B sintered magnets.

Measuring the Erosion of River Channel Widths Impacted by Watershed Urbanization Using Historic Aerial Photographs and Modern Surveys

NASA Astrophysics Data System (ADS)

Galster, J. C.; Pazzaglia, F. J.; Germanoski, D.

2007-12-01

Land use in a watershed exerts a strong influence on trunk channel form and process. Land use changes act over human time scales which is short enough to measure their effects directly using historic aerial photographs. We show that high-resolution topographic surveys comparing channel form for paired watersheds in the Lehigh Valley, PA are indistinguishable, but have channel widths that have changed dramatically in the past five decades. The two watersheds, Little Lehigh Creek and Sacony Creek, are similar in all respects except they have different amount of urban land use. Aerial photographs of the urbanized Little Lehigh Creek show that a majority of the measured widths (67 of 85) were statistically wider in 1999 than in 1947. In contrast, the measured widths from the agricultural Sacony Creek are more evenly distributed among those that widened (18), narrowed (28), and those that were statistically unchanged (6) from 1946 to 1999. From 1946 to 1999 the only section of Sacony creek that widened was that reach downstream of the only sizable urban area in the watershed. The current land use in Sacony Creek watershed resembles that of 1946, while the Little Lehigh Creek watershed has more than tripled its urban area. These data suggest that the increase in urban areas that subsequently increases peak discharges is the mechanism behind the widening that occurred in the Little Lehigh Creek. These wider channels can affect water quality, aquatic habitat, suspended sediment loads, and river aesthetics.

Chromobacterium Csp_P reduces malaria and dengue infection in vector mosquitoes and has entomopathogenic and in vitro anti-pathogen activities.

PubMed

Ramirez, Jose Luis; Short, Sarah M; Bahia, Ana C; Saraiva, Raul G; Dong, Yuemei; Kang, Seokyoung; Tripathi, Abhai; Mlambo, Godfree; Dimopoulos, George

2014-10-01

Plasmodium and dengue virus, the causative agents of the two most devastating vector-borne diseases, malaria and dengue, are transmitted by the two most important mosquito vectors, Anopheles gambiae and Aedes aegypti, respectively. Insect-bacteria associations have been shown to influence vector competence for human pathogens through multi-faceted actions that include the elicitation of the insect immune system, pathogen sequestration by microbes, and bacteria-produced anti-pathogenic factors. These influences make the mosquito microbiota highly interesting from a disease control perspective. Here we present a bacterium of the genus Chromobacterium (Csp_P), which was isolated from the midgut of field-caught Aedes aegypti. Csp_P can effectively colonize the mosquito midgut when introduced through an artificial nectar meal, and it also inhibits the growth of other members of the midgut microbiota. Csp_P colonization of the midgut tissue activates mosquito immune responses, and Csp_P exposure dramatically reduces the survival of both the larval and adult stages. Ingestion of Csp_P by the mosquito significantly reduces its susceptibility to Plasmodium falciparum and dengue virus infection, thereby compromising the mosquito's vector competence. This bacterium also exerts in vitro anti-Plasmodium and anti-dengue activities, which appear to be mediated through Csp_P -produced stable bioactive factors with transmission-blocking and therapeutic potential. The anti-pathogen and entomopathogenic properties of Csp_P render it a potential candidate for the development of malaria and dengue control strategies.

Influence of ornithine decarboxylase antizymes and antizyme inhibitors on agmatine uptake by mammalian cells.

PubMed

Ramos-Molina, Bruno; López-Contreras, Andrés J; Lambertos, Ana; Dardonville, Christophe; Cremades, Asunción; Peñafiel, Rafael

2015-05-01

Agmatine (4-aminobutylguanidine), a dicationic molecule at physiological pH, exerts relevant modulatory actions at many different molecular target sites in mammalian cells, having been suggested that the administration of this compound may have therapeutic interest. Several plasma membrane transporters have been implicated in agmatine uptake by mammalian cells. Here we report that in kidney-derived COS-7 cell line, at physiological agmatine levels, the general polyamine transporter participates in the plasma membrane translocation of agmatine, with an apparent Km of 44 ± 7 µM and Vmax of 17.3 ± 3.3 nmol h(-1) mg(-1) protein, but that at elevated concentrations, agmatine can be also taken up by other transport systems. In the first case, the physiological polyamines (putrescine, spermidine and spermine), several diguanidines and bis(2-aminoimidazolines) and the polyamine transport inhibitor AMXT-1501 markedly decreased agmatine uptake. In cells transfected with any of the three ornithine decarboxylase antizymes (AZ1, AZ2 and AZ3), agmatine uptake was dramatically reduced. On the contrary, transfection with antizyme inhibitors (AZIN1 and AZIN2) markedly increased the transport of agmatine. Furthermore, whereas putrescine uptake was significantly decreased in cells transfected with ornithine decarboxylase (ODC), the accumulation of agmatine was stimulated, suggesting a trans-activating effect of intracellular putrescine on agmatine uptake. All these results indicate that ODC and its regulatory proteins (antizymes and antizyme inhibitors) may influence agmatine homeostasis in mammalian tissues.

Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer.

PubMed

Prendergast, George C; Smith, Courtney; Thomas, Sunil; Mandik-Nayak, Laura; Laury-Kleintop, Lisa; Metz, Richard; Muller, Alexander J

2014-07-01

Genetic and pharmacological studies of indoleamine 2,3-dioxygenase (IDO) have established this tryptophan catabolic enzyme as a central driver of malignant development and progression. IDO acts in tumor, stromal and immune cells to support pathogenic inflammatory processes that engender immune tolerance to tumor antigens. The multifaceted effects of IDO activation in cancer include the suppression of T and NK cells, the generation and activation of T regulatory cells and myeloid-derived suppressor cells, and the promotion of tumor angiogenesis. Mechanistic investigations have defined the aryl hydrocarbon receptor, the master metabolic regulator mTORC1 and the stress kinase Gcn2 as key effector signaling elements for IDO, which also exerts a non-catalytic role in TGF-β signaling. Small-molecule inhibitors of IDO exhibit anticancer activity and cooperate with immunotherapy, radiotherapy or chemotherapy to trigger rapid regression of aggressive tumors otherwise resistant to treatment. Notably, the dramatic antitumor activity of certain targeted therapeutics such as imatinib (Gleevec) in gastrointestinal stromal tumors has been traced in part to IDO downregulation. Further, antitumor responses to immune checkpoint inhibitors can be heightened safely by a clinical lead inhibitor of the IDO pathway that relieves IDO-mediated suppression of mTORC1 in T cells. In this personal perspective on IDO as a nodal mediator of pathogenic inflammation and immune escape in cancer, we provide a conceptual foundation for the clinical development of IDO inhibitors as a novel class of immunomodulators with broad application in the treatment of advanced human cancer.

Molecular mechanisms of programmed cell death-1 dependent T cell suppression: relevance for immunotherapy

PubMed Central

Zuazo, Miren; Gato-Cañas, Maria; Llorente, Noelia; Ibañez-Vea, María; Arasanz, Hugo

2017-01-01

Programmed cell death-1 (PD1) has become a significant target for cancer immunotherapy. PD1 and its receptor programmed cell death 1 ligand 1 (PDL1) are key regulatory physiological immune checkpoints that maintain self-tolerance in the organism by regulating the degree of activation of T and B cells amongst other immune cell types. However, cancer cells take advantage of these immunosuppressive regulatory mechanisms to escape T and B cell-mediated immunity. PD1 engagement on T cells by PDL1 on the surface of cancer cells dramatically interferes with T cell activation and the acquisition of effector capacities. Interestingly, PD1-targeted therapies have demonstrated to be highly effective in rescuing T cell anti-tumor effector functions. Amongst these the use of anti-PD1/PDL1 monoclonal antibodies are particularly efficacious in human therapies. Furthermore, clinical findings with PD1/PDL1 blockers over several cancer types demonstrate clinical benefit. Despite the successful results, the molecular mechanisms by which PD1-targeted therapies rescue T cell functions still remain elusive. Therefore, it is a key issue to uncover the molecular pathways by which these therapies exert its function in T cells. A profound knowledge of PDL1/PD1 mechanisms will surely uncover a new array of targets susceptible of therapeutic intervention. Here, we provide an overview of the molecular events underlying PD1-dependent T cell suppression in cancer. PMID:29114543

Memantine mediates neuroprotection via regulating neurovascular unit in a mouse model of focal cerebral ischemia.

PubMed

Chen, Zheng-Zhen; Yang, Dan-Dan; Zhao, Zhan; Yan, Hui; Ji, Juan; Sun, Xiu-Lan

2016-04-01

Memantine is a low-moderate affinity and uncompetitive N-methyl-d-aspartate receptor (NMDAR) antagonist, which is also a potential neuroprotectant in acute ischemic stroke for its particular action profiles. The present study was to reveal the mechanisms involved in the neuroprotection of memantine. We used a mouse model of permanent focal cerebral ischemia via middle cerebral artery occlusion to verify our hypothesis. 2,3,5-Triphenyltetrazolium chloride staining was used to compare infarct size. The amount of astrocytes and the somal volume of the microglia cell body were analyzed by immunohistochemistry and stereological estimates. Western blotting was used to determine the protein expressions. Memantine prevented cerebral ischemia-induced brain infarct and neuronal injury, and reduced oxygen-glucose deprivation-induced cortical neuronal apoptosis. Moreover, memantine reduced the amount of the damaged astrocytes and over activated microglia after 24h of ischemia. In the early phase of ischemia, higher production of MMP-9 was observed, and thereby collagen IV was dramatically disrupted. Meanwhile, the post-synaptic density protein 95(PSD-95) was also severely cleavaged. Memantine decreased MMP-9 secretion, prevented the degradation of collagen IV in mouse brain. PSD-95 cleavage was also inhibited by memantine. These results suggested that memantine exerted neuroprotection effects in acute ischemic brain damage, partially via improving the functions of neurovascular unit. Taking all these findings together, we consider that memantine might be a promising protective agent against ischemic stroke. Copyright © 2016 Elsevier Inc. All rights reserved.

Press/Pulse: Explaining selective terrestrial extinctions at the Cretaceous/Palaeogene boundary

NASA Astrophysics Data System (ADS)

Arens, Nan Crystal

2010-05-01

Single-cause mass extinction scenarios require extreme conditions to generate sufficiently strong kill mechanisms. Such dire effects are commonly at odds with the taxonomic selectivity that characterizes most extinction events. In response, some researchers have proposed that the interaction of a variety of factors typify episodes of elevated extinction. Previous work (Arens & West 2008 Paleobiology 34:456-471) has shown that a combination of press and pulse disturbances increases the probability of elevated extinction. The press/pulse contrast is borrowed from community ecology, where researchers have long recognized that the ecological response to long-term stress differs from that of an instantaneous catastrophe. Scaled to the macroevolutionary level, press disturbances alter community composition by placing multigenerational stress on populations. Press disturbances do not necessarily cause mortality, but reduce population size by a variety of mechanisms such as curtailed reproduction. Pulse disturbances are sudden catastrophic events that cause extensive mortality. Either press or pulse disturbances of sufficient magnitude can cause extinction, however elevated extinction occurs more commonly during the coincidence of lower-magnitude press and pulse events. The Cretaceous/Palaeogene (K/P) extinction is one of the best examples of a press/pulse extinction. Deccan Trap volcanism, which straddled the K/P boundary, altered atmospheric composition and climate. This episodic volcanism likely contributed to the climate instability observed in terrestrial ecosystems and exerted press stress. Pulse disturbance was produced by bolide impact, which punctuated the end of the Cretaceous. The press/pulse mechanism also more effectively explains selectivity in terrestrial vertebrate and plant extinctions at the K/P boundary than do single-mechanisms scenarios. For example, why do environmentally sensitive vertebrates such as amphibians experience no extinction? And why do mire plants preferentially survive? Deccan Trap volcanism generated climatic warming and instability during the last 500 Ka of the Cretaceous. This resulted in extensive rearrangement of terrestrial floras. Dramatic cooling in the millennia immediately preceding the K/P boundary caused regional diversity loss and an apparent increase in vegetation heterogeneity. These changes, coupled with the spread of wetland ecosystems across the western interior of North America in the latest Cretaceous, exerted stress—press disturbance—on some elements of the biota, while favoring others. This press stress may have rendered lineages requiring well-drained or large homogeneous habitats endangered and vulnerable to extinction in the face of the terminal-Cretaceous bolide impact(s)—pulse disturbance. And, in fact, the impact's survivors were primarily wetland plants and animals.

Intratracheal IL-6 protects against lung inflammation in direct, but not indirect, causes of acute lung injury in mice.

PubMed

Bhargava, Rhea; Janssen, William; Altmann, Christopher; Andrés-Hernando, Ana; Okamura, Kayo; Vandivier, R William; Ahuja, Nilesh; Faubel, Sarah

2013-01-01

Serum and bronchoalveolar fluid IL-6 are increased in patients with acute respiratory distress syndrome (ARDS) and predict prolonged mechanical ventilation and poor outcomes, although the role of intra-alveolar IL-6 in indirect lung injury is unknown. We investigated the role of endogenous and exogenous intra-alveolar IL-6 in AKI-mediated lung injury (indirect lung injury), intraperitoneal (IP) endotoxin administration (indirect lung injury) and, for comparison, intratracheal (IT) endotoxin administration (direct lung injury) with the hypothesis that IL-6 would exert a pro-inflammatory effect in these causes of acute lung inflammation. Bronchoalveolar cytokines (IL-6, CXCL1, TNF-α, IL-1β, and IL-10), BAL fluid neutrophils, lung inflammation (lung cytokines, MPO activity [a biochemical marker of neutrophil infiltration]), and serum cytokines were determined in adult male C57Bl/6 mice with no intervention or 4 hours after ischemic AKI (22 minutes of renal pedicle clamping), IP endotoxin (10 µg), or IT endotoxin (80 µg) with and without intratracheal (IT) IL-6 (25 ng or 200 ng) treatment. Lung inflammation was similar after AKI, IP endotoxin, and IT endotoxin. BAL fluid IL-6 was markedly increased after IT endotoxin, and not increased after AKI or IP endotoxin. Unexpectedly, IT IL-6 exerted an anti-inflammatory effect in healthy mice characterized by reduced BAL fluid cytokines. IT IL-6 also exerted an anti-inflammatory effect in IT endotoxin characterized by reduced BAL fluid cytokines and lung inflammation; IT IL-6 had no effect on lung inflammation in AKI or IP endotoxin. IL-6 exerts an anti-inflammatory effect in direct lung injury from IT endotoxin, yet has no role in the pathogenesis or treatment of indirect lung injury from AKI or IP endotoxin. Since intra-alveolar inflammation is important in the pathogenesis of direct, but not indirect, causes of lung inflammation, IT anti-inflammatory treatments may have a role in direct, but not indirect, causes of ARDS.

Sickle Cell Trait and Fatal Exertional Heat Illness: Implications for Exercise-Related Death of Young Ddults

DTIC Science & Technology

2008-10-22

athletes who utilize ordinary weather reports? Alpha- Thalassemia Protects Against Exertional Mortality with Sickle Cell Trait • 30% of African...Americans have alpha- thalassemia (2-3 alpha genes instead of 4). In those with sickle cell trait the main effect is to lower the Hb S fraction below 36...expected 15 cases with alpha- thalassemia & ប% S • Two cases had Hb S < 36% , implying about a 7.5-fold protection for those with alpha thalassemia

Effects of retinoic acid-inducible gene-I-like receptors activations and ionizing radiation cotreatment on cytotoxicity against human non-small cell lung cancer in vitro

PubMed Central

Yoshino, Hironori; Iwabuchi, Miyu; Kazama, Yuka; Furukawa, Maho; Kashiwakura, Ikuo

2018-01-01

Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) are pattern-recognition receptors that recognize pathogen-associated molecular patterns and induce antiviral immune responses. Recent studies have demonstrated that RLR activation induces antitumor immunity and cytotoxicity against different types of cancer, including lung cancer. However a previous report has demonstrated that ionizing radiation exerts a limited effect on RLR in human monocytic cell-derived macrophages, suggesting that RLR agonists may be used as effective immunostimulants during radiation therapy. However, it is unclear whether ionizing radiation affects the cytotoxicity of RLR agonists against cancer cells. Therefore, in the present study the effects of cotreatment with ionizing radiation and RLR agonists on cytotoxicity against human non-small cell lung cancer cells A549 and H1299 was investigated. Treatment with RLR agonist poly(I:C)/LyoVec™ [poly(I:C)] exerted cytotoxic effects against human non-small cell lung cancer. The cytotoxic effects of poly(I:C) were enhanced by cotreatment with ionizing radiation, and poly(I:C) pretreatment resulted in the radiosensitization of non-small cell lung cancer. Furthermore, cotreatment of A549 and H1299 cells with poly(I:C) and ionizing radiation effectively induced apoptosis in a caspase-dependent manner compared with treatment with poly(I:C) or ionizing radiation alone. These results indicate that RLR agonists and ionizing radiation cotreatment effectively exert cytotoxic effects against human non-small cell lung cancer through caspase-mediated apoptosis. PMID:29541243

Dopamine D2/D3 but not dopamine D1 receptors are involved in the rapid antidepressant-like effects of ketamine in the forced swim test.

PubMed

Li, Yan; Zhu, Zhuo R; Ou, Bao C; Wang, Ya Q; Tan, Zhou B; Deng, Chang M; Gao, Yi Y; Tang, Ming; So, Ji H; Mu, Yang L; Zhang, Lan Q

2015-02-15

Major depressive disorder is one of the most prevalent and life-threatening forms of mental illnesses. The traditional antidepressants often take several weeks, even months, to obtain clinical effects. However, recent clinical studies have shown that ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, exerts rapid antidepressant effects within 2h and are long-lasting. The aim of the present study was to investigate whether dopaminergic system was involved in the rapid antidepressant effects of ketamine. The acute administration of ketamine (20 mg/kg) significantly reduced the immobility time in the forced swim test. MK-801 (0.1 mg/kg), the more selective NMDA antagonist, also exerted rapid antidepressant-like effects. In contrast, fluoxetine (10 mg/kg) did not significantly reduced the immobility time in the forced swim test after 30 min administration. Notably, pretreatment with haloperidol (0.15 mg/kg, a nonselective dopamine D2/D3 antagonist), but not SCH23390 (0.04 and 0.1 mg/kg, a selective dopamine D1 receptor antagonist), significantly prevented the effects of ketamine or MK-801. Moreover, the administration of sub-effective dose of ketamine (10 mg/kg) in combination with pramipexole (0.3 mg/kg, a dopamine D2/D3 receptor agonist) exerted antidepressant-like effects compared with each drug alone. In conclusion, our results indicated that the dopamine D2/D3 receptors, but not D1 receptors, are involved in the rapid antidepressant-like effects of ketamine. Copyright © 2014 Elsevier B.V. All rights reserved.

Traditional used Plants against Cognitive Decline and Alzheimer Disease

PubMed Central

Eckert, Gunter Peter

2010-01-01

Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by progressive memory deficits, impaired cognitive function, and altered and inappropriate behavior. Aging represents the most important risk factor for AD and the global trend in the phenomenon of population aging has dramatic consequences for public health, healthcare financing, and delivery systems in the word and, especially in developing countries. Mounting evidence obtained in in vitro and in vivo studies, suggests that various traditionally used plants in Asia, India, and Europe significantly affect key metabolic alterations culminating in AD-typical neurodegeneration. The present article aims to bring the reader up-to-date on the most recent studies and advances describing the direct and indirect activities of traditional used plants and its constituents possibly relieving features of AD. A variety of traditional used plants and its extracts exerted activities on AD related drug targets including AChE activity, antioxidative activity, modulation of Aβ-producing secretase activities, Aβ-degradation, heavy metal chelating, induction of neurotrophic factors, and cell death mechanisms. Although pre-clinical investigations identified promising drug candidates for AD, clinical evidences are still pending. PMID:21833177

Fire and vegetation shifts in the Americas at the vanguard of Paleoindian migration

NASA Astrophysics Data System (ADS)

Pinter, Nicholas; Fiedel, Stuart; Keeley, Jon E.

2011-02-01

Across North and South America, the final millennia of the Pleistocene saw dramatic changes in climate, vegetation, fauna, fire regime, and other local and regional paleo-environmental characteristics. Rapid climate shifts following the Last Glacial Maximum (LGM) exerted a first-order influence, but abrupt post-glacial shifts in vegetation composition, vegetation structure, and fire regime also coincided with human arrival and transformative faunal extinctions in the Americas. We propose a model of post-glacial vegetation change in response to climatic drivers, punctuated by local fire regime shifts in response to megaherbivore-driven fuel changes and anthropogenic ignitions. The abrupt appearance of humans, disappearance of megaherbivores, and resulting changes in New World fire systems were transformative events that should not be dismissed in favor of climate-only interpretations of post-glacial paleo-environmental shifts in the Americas. Fire is a mechanism by which small human populations can have broad impacts, and growing evidence suggests that early anthropogenic influences on regional, even global, paleo-environments should be tested alongside other potential causal mechanisms.

Making Fat Work*

PubMed Central

Sargis, Robert M.; Brady, Matthew J.

2014-01-01

The burgeoning obesity and metabolic disease epidemics in the developed world are exerting a terrible toll on society, yet the precise mechanisms responsible for the emergence of these dramatic trends over a relatively short period of time remain poorly understood. Philip A. Wood’s book How Fat Works provides important insights into cellular lipid metabolism, as well as discussing some of the important external contributors to the development of human obesity. The foundation provided by this book allows for the exploration of how body fat has gone from hero during the millennia when starvation was the paramount nutritional risk to its current role as villain in our period of caloric excess. With the incredible personal and societal costs brought about by excess body weight, a comprehensive understanding of the mechanisms responsible for obesity is fundamentally necessary if we are to reverse these dire trends. Here, we delve deeper into some of the forces contributing to the obesity epidemic and discuss some individual measures as well as public policy decisions that may help reverse weight trends, while specifically focusing on the growing problem of pediatric obesity. PMID:21037416

The protective role of low-concentration alcohol in high-fructose induced adverse cardiovascular events in mice.

PubMed

Wu, Xiaoqi; Pan, Bo; Wang, Ying; Liu, Lingjuan; Huang, Xupei; Tian, Jie

2018-01-01

Cardiovascular disease remains a worldwide public health issue. As fructose consumption is dramatically increasing, it has been demonstrated that a fructose-rich intake would increase the risk of cardiovascular disease. In addition, emerging evidences suggest that low concentration alcohol intake may exert a protective effect on cardiovascular system. This study aimed to investigate whether low-concentration alcohol consumption would prevent the adverse effects on cardiovascular events induced by high fructose in mice. From the results of hematoxylin-eosin staining, echocardiography, heart weight/body weight ratio and the expression of hypertrophic marker ANP, we found high-fructose result in myocardial hypertrophy and the low-concentration alcohol consumption would prevent the cardiomyocyte hypertrophy from happening. In addition, we observed low-concentration alcohol consumption could inhibit mitochondria swollen induced by high-fructose. The elevated levels of glucose, triglyceride, total cholesterol in high-fructose group were reduced by low concentration alcohol. Low expression levels of SIRT1 and PPAR-γ induced by high-fructose were significantly elevated when fed with low-concentration alcohol. The histone lysine 9 acetylation (acH3K9) level was decreased in PPAR-γ promoter in high-fructose group but elevated when intake with low concentration alcohol. The binding levels of histone deacetylase SIRT1 were increased in the same region in high-fructose group, while the low concentration alcohol can prevent the increased binding levels. Overall, our study indicates that low-concentration alcohol consumption could inhibit high-fructose related myocardial hypertrophy, cardiac mitochondria damaged and disorders of glucose-lipid metabolism. Furthermore, these findings also provide new insights into histone acetylation-deacetylation mechanisms of low-concentration alcohol treatment that may contribute to the prevention of cardiovascular disease induced by high-fructose intake. Copyright © 2017 Elsevier Inc. All rights reserved.

Mast cells contribute to the mucosal adjuvant effect of CTA1-DD after IgG-complex formation.

PubMed

Fang, Yu; Larsson, Lisa; Mattsson, Johan; Lycke, Nils; Xiang, Zou

2010-09-01

Mast cell activation is one of the most dramatic immune-mediated responses the body can encounter. In the worst scenario (i.e., anaphylaxis), this response is fatal. However, the importance of mast cells as initiators and effectors of both innate and adaptive immunity in healthy individuals has recently been appreciated. It was reported that mast cell activation can be used as an adjuvant to promote Ag-specific humoral immune responses upon vaccination. In this study, we have used a clinically relevant mucosal adjuvant, cholera toxin A1 subunit (CTA1)-DD, which is a fusion protein composed of CTA1, the ADP-ribosylating part of cholera toxin, and DD, two Ig-binding domains derived from Staphylococcus aureus protein A. CTA1-DD in combination with polyclonal IgG induced degranulation and production of TNF-alpha from mouse mast cells. Furthermore, CTA1-DD and polyclonal IgG complex induced mast cell degranulation in mouse skin tissue and nasal mucosa. We also found that intranasal immunization with hapten (4-hydroxy-3-nitrophenyl) acetyl (NP) coupled to chicken gammaglobulin admixed with CTA1-DD complexed with polyclonal IgG greatly enhanced serum IgG anti-NP Ab responses and stimulated higher numbers of NP-specific plasma cells in the bone marrow as compared with that observed in mice immunized with NP-chicken gammaglobulin with CTA1-DD alone. This CTA1-DD/IgG complex-mediated enhancement was mast cell dependent because it was absent in mast cell-deficient Kit(W-sh/W-sh) mice. In conclusion, our data suggest that a clinically relevant adjuvant, CTA1-DD, exerts additional augmenting effects through activation of mucosal mast cells, clearly demonstrating that mast cells could be further exploited for improving the efficacy of mucosal vaccines.

Sexual differentiation of the brain: a model for drug-induced alterations of the reproductive system

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

Gorski, R.A.

1986-12-01

The process of the sexual differentiation of the brain represents a valuable model system for the study of the chemical modification of the mammalian brain. Although there are numerous functional and structural sex differences in the adult brain, these are imposed on an essentially feminine or bipotential brain by testicular hormones during a critical phase of perinatal development in the rat. It is suggested that a relatively marked structural sex difference in the rat brain, the sexually dimorphic nucleus of the preoptic area (SDN-POA), is a morphological signature of the permanent or organizational action of estradiol derived from the aromatizationmore » of testicular testosterone. The SDN-POA of the male rat is severalfold larger in volume and is composed of more neurons than that of the female. The observation that the mitotic formation of the neurons of the SDN-POA is specifically prolonged has enabled us to identify the time course and pathway of neuronal migration into the nucleus. Study of the development of the SDN-POA suggests that estradiol in the male increases the number of neurons which survive a phase of neuronal death by exerting a neurite growth promoting action and/or a direct neuronotrophic action. Finally, although it is clear that gonadal hormones have dramatic permanent effects on the brain during perinatal development, even after puberty and in adulthood gonadal steroids can alter neuronal structure and, perhaps as a corollary to this, have permanent effects on reproductive function. Although the brain may be most sensitive to gonadal hormones or exogenous chemical factors during perinatal development, such as sensitivity does not appear limited to this period.« less

Gray Wolves as Climate Change Buffers in Yellowstone

PubMed Central

Getz, Wayne M

2005-01-01

Understanding the mechanisms by which climate and predation patterns by top predators co-vary to affect community structure accrues added importance as humans exert growing influence over both climate and regional predator assemblages. In Yellowstone National Park, winter conditions and reintroduced gray wolves (Canis lupus) together determine the availability of winter carrion on which numerous scavenger species depend for survival and reproduction. As climate changes in Yellowstone, therefore, scavenger species may experience a dramatic reshuffling of food resources. As such, we analyzed 55 y of weather data from Yellowstone in order to determine trends in winter conditions. We found that winters are getting shorter, as measured by the number of days with snow on the ground, due to decreased snowfall and increased number of days with temperatures above freezing. To investigate synergistic effects of human and climatic alterations of species interactions, we used an empirically derived model to show that in the absence of wolves, early snow thaw leads to a substantial reduction in late-winter carrion, causing potential food bottlenecks for scavengers. In addition, by narrowing the window of time over which carrion is available and thereby creating a resource pulse, climate change likely favors scavengers that can quickly track food sources over great distances. Wolves, however, largely mitigate late-winter reduction in carrion due to earlier snow thaws. By buffering the effects of climate change on carrion availability, wolves allow scavengers to adapt to a changing environment over a longer time scale more commensurate with natural processes. This study illustrates the importance of restoring and maintaining intact food chains in the face of large-scale environmental perturbations such as climate change. PMID:15757363

Gray wolves as climate change buffers in Yellowstone.

PubMed

Wilmers, Christopher C; Getz, Wayne M

2005-04-01

Understanding the mechanisms by which climate and predation patterns by top predators co-vary to affect community structure accrues added importance as humans exert growing influence over both climate and regional predator assemblages. In Yellowstone National Park, winter conditions and reintroduced gray wolves (Canis lupus) together determine the availability of winter carrion on which numerous scavenger species depend for survival and reproduction. As climate changes in Yellowstone, therefore, scavenger species may experience a dramatic reshuffling of food resources. As such, we analyzed 55 y of weather data from Yellowstone in order to determine trends in winter conditions. We found that winters are getting shorter, as measured by the number of days with snow on the ground, due to decreased snowfall and increased number of days with temperatures above freezing. To investigate synergistic effects of human and climatic alterations of species interactions, we used an empirically derived model to show that in the absence of wolves, early snow thaw leads to a substantial reduction in late-winter carrion, causing potential food bottlenecks for scavengers. In addition, by narrowing the window of time over which carrion is available and thereby creating a resource pulse, climate change likely favors scavengers that can quickly track food sources over great distances. Wolves, however, largely mitigate late-winter reduction in carrion due to earlier snow thaws. By buffering the effects of climate change on carrion availability, wolves allow scavengers to adapt to a changing environment over a longer time scale more commensurate with natural processes. This study illustrates the importance of restoring and maintaining intact food chains in the face of large-scale environmental perturbations such as climate change.

Upregulation of SQSTM1/p62 contributes to nickel-induced malignant transformation of human bronchial epithelial cells.

PubMed

Huang, Haishan; Zhu, Junlan; Li, Yang; Zhang, Liping; Gu, Jiayan; Xie, Qipeng; Jin, Honglei; Che, Xun; Li, Jingxia; Huang, Chao; Chen, Lung-Chi; Lyu, Jianxin; Gao, Jimin; Huang, Chuanshu

2016-10-02

Chronic lung inflammation is accepted as being associated with the development of lung cancer caused by nickel exposure. Therefore, identifying the molecular mechanisms that lead to a nickel-induced sustained inflammatory microenvironment that causes transformation of human bronchial epithelial cells is of high significance. In the current studies, we identified SQSTM1/p62 as a novel nickel-upregulated protein that is important for nickel-induced inflammatory TNF expression, subsequently resulting in transformation of human bronchial epithelial cells. We found that nickel exposure induced SQSTM1 protein upregulation in human lung epithelial cells in vitro and in mouse lung tissues in vivo. The SQSTM1 upregulation was also observed in human lung squamous cell carcinoma. Further studies revealed that the knockdown of SQSTM1 expression dramatically inhibited transformation of human lung epithelial cells upon chronic nickel exposure, whereas ectopic expression of SQSTM1 promoted such transformation. Mechanistic studies showed that the SQSTM1 upregulation by nickel was the compromised result of upregulating SQSTM1 mRNA transcription and promoting SQSTM1 protein degradation. We demonstrated that nickel-initiated SQSTM1 protein degradation is mediated by macroautophagy/autophagy via an MTOR-ULK1-BECN1 axis, whereas RELA is important for SQSTM1 transcriptional upregulation following nickel exposure. Furthermore, SQSTM1 upregulation exhibited its promotion of nickel-induced cell transformation through exerting an impetus for nickel-induced inflammatory TNF mRNA stability. Consistently, the MTOR-ULK1-BECN1 autophagic cascade acted as an inhibitory effect on nickel-induced TNF expression and cell transformation. Collectively, our results demonstrate a novel SQSTM1 regulatory network that promotes a nickel-induced tumorigenic effect in human bronchial epithelial cells, which is negatively controlled by an autophagic cascade following nickel exposure.

The costly filtering of potential distraction: evidence for a supramodal mechanism.

PubMed

Marini, Francesco; Chelazzi, Leonardo; Maravita, Angelo

2013-08-01

When dealing with significant sensory stimuli, performance can be hampered by distracting events. Attention mechanisms lessen such negative effects, enabling selection of relevant information while blocking potential distraction. Recent work shows that preparatory brain activity, occurring before a critical stimulus, may reflect mechanisms of attentional control aimed to filter upcoming distracters. However, it is unknown whether the engagement of these filtering mechanisms to counteract distraction in itself taxes cognitive-brain systems, leading to performance costs. Here we address this question and, specifically, seek the behavioral signature of a mechanism for the filtering of potential distraction within and between sensory modalities. We show that, in potentially distracting contexts, a filtering mechanism is engaged to cope with forthcoming distraction, causing a dramatic behavioral cost in no-distracter trials during a speeded tactile discrimination task. We thus demonstrate an impaired processing caused by a potential, yet absent, distracter. This effect generalizes across different sensory modalities, such as vision and audition, and across different manipulations of the context, such as the distracter's sensory modality and pertinence to the task. Moreover, activation of the filtering mechanism relies on both strategic and reactive processes, as shown by its dynamic dependence on probabilistic and cross-trial contingencies. Crucially, across participants, the observed strategic cost is inversely related to the interference exerted by a distracter on distracter-present trials. These results attest to a mechanism for the monitoring and filtering of potential distraction in the human brain. Although its activation is indisputably beneficial when distraction occurs, it leads to robust costs when distraction is actually expected but currently absent. PsycINFO Database Record (c) 2013 APA, all rights reserved.

Middle-to-late Holocene palaeoenvironmental reconstruction from the A294 ice-cave record (Central Pyrenees, northern Spain)

NASA Astrophysics Data System (ADS)

Sancho, Carlos; Belmonte, Ánchel; Bartolomé, Miguel; Moreno, Ana; Leunda, María; López-Martínez, Jerónimo

2018-02-01

Perennial ice deposits in caves represent unique, but underexplored, terrestrial sequences that potentially contain outstanding palaeoclimatic records. Here, we present a pioneer palaeoenvironmental study of an ice deposit preserved in a small sag-type cave (A294) in the Central Pyrenees (northern Iberian Peninsula). The 9.25-m-thick sequence, which is dated from 6100 ± 107 to 1888 ± 64 cal BP, represents the oldest known firn ice record worldwide. The stratigraphy (detrital layers, unconformities, and cross stratification), plant macrofossils, and isotopic signature (similarity between the ice linear distribution, δ2H = 7.83δ18O + 8.4, and the Global Meteoric Water Line) of the ice point to the diagenesis of snow introduced to the cave by winter snowstorms. Four phases of rapid ice accumulation (6100-5515, 4945-4250, 3810-3155, and 2450-1890 cal BP) are related to wetter and colder winters. Comparison of the isotopic composition (δ18O and deuterium excess) of the ice with other paleoclimate records show that both source effects and the North Atlantic Oscillation (NAO) mechanism exert a dominant influence on the ice cave record. The NAO signal may be a combination of source effects and rainfall amount. Three intervals with low ice accumulation occurred between the phases of rapid accumulation and were related to drier, and possibly warmer, winters. These centennial-scale episodes appear to be in-phase with regional arid events, as established from high altitude lacustrine records and can be correlated to global Rapid Climate Change events. The current warming trend has dramatically decreased the volume of the ice deposit in cave A294.

Interaction of KCNE subunits with the KCNQ1 K+ channel pore

PubMed Central

Panaghie, Gianina; Tai, Kwok-Keung; Abbott, Geoffrey W

2006-01-01

KCNQ1 α subunits form functionally distinct potassium channels by coassembling with KCNE ancillary subunits MinK and MiRP2. MinK-KCNQ1 channels generate the slowly activating, voltage-dependent cardiac IKs current. MiRP2-KCNQ1 channels form a constitutively active current in the colon. The structural basis for these contrasting channel properties, and the mechanisms of α subunit modulation by KCNE subunits, are not fully understood. Here, scanning mutagenesis located a tryptophan-tolerant region at positions 338–340 within the KCNQ1 pore-lining S6 domain, suggesting an exposed region possibly amenable to interaction with transmembrane ancillary subunits. This hypothesis was tested using concomitant mutagenesis in KCNQ1 and in the membrane-localized ‘activation triplet’ regions of MinK and MiRP2 to identify pairs of residues that interact to control KCNQ1 activation. Three pairs of mutations exerted dramatic effects, ablating channel function or either removing or restoring control of KCNQ1 activation. The results place KCNE subunits close to the KCNQ1 pore, indicating interaction of MiRP2-72 with KCNQ1-338; and MinK-59,58 with KCNQ1-339, 340. These data are consistent either with perturbation of the S6 domain by MinK or MiRP2, dissimilar positioning of MinK and MiRP2 within the channel complex, or both. Further, the results suggest specifically that two of the interactions, MiRP2-72/KCNQ1-338 and MinK-58/KCNQ1-340, are required for the contrasting gating effects of MinK and MiRP2. PMID:16308347

Beneficial effect of diosgenin as a stimulator of NGF on the brain with neuronal damage induced by Aβ-42 accumulation and neurotoxicant injection.

PubMed

Koh, Eun-Kyoung; Yun, Woo-Bin; Kim, Ji-Eun; Song, Sung-Hwa; Sung, Ji-Eun; Lee, Hyun-Ah; Seo, Eun-Ji; Jee, Seung-Wan; Bae, Chang-Joon; Hwang, Dae-Youn

2016-06-01

To investigate the beneficial effects of diosgenin (DG) on the multiple types of brain damage induced by Aβ-42 peptides and neurotoxicants, alterations in the specific aspects of brain functions were measured in trimethyltin (TMT)-injected transgenic 2576 (TG) mice that had been pretreated with DG for 21 days. Multiple types of damage were successfully induced by Aβ-42 accumulation and TMT injection into the brains of TG mice. However, DG treatment significantly reduced the number of Aβ-stained plaques and dead cells in the granule cells layer of the dentate gyrus. Significant suppression of acetylcholinesterase (AChE) activity and Bax/Bcl-2 expression was also observed in the DG treated TG mice (TG+DG group) when compared with those of the vehicle (VC) treated TG mice (TG+VC group). Additionally, the concentration of nerve growth factor (NGF) was dramatically enhanced in TG+DG group, although it was lower in the TG+VC group than the non-transgenic (nTG) group. Furthermore, the decreased phosphorylation of downstream members in the TrkA high affinity receptor signaling pathway in the TG+VC group was significantly recovered in the TG+DG group. A similar pattern was observed in p75(NTR) expression and JNK phosphorylation in the NGF low affinity receptor signaling pathway. Moreover, superoxide dismutase (SOD) activity was enhanced in the TG+DG group, while the level of malondialdehyde (MDA), a marker of lipid peroxidation, was lower in the TG+DG group than the TG+VC group. These results suggest that DG could exert a wide range of beneficial activities for multiple types of brain damage through stimulation of NGF biosynthesis.

Beneficial effect of diosgenin as a stimulator of NGF on the brain with neuronal damage induced by Aβ-42 accumulation and neurotoxicant injection

PubMed Central

Koh, Eun-Kyoung; Yun, Woo-Bin; Kim, Ji-Eun; Song, Sung-Hwa; Sung, Ji-Eun; Lee, Hyun-Ah; Seo, Eun-Ji; Jee, Seung-Wan

2016-01-01

To investigate the beneficial effects of diosgenin (DG) on the multiple types of brain damage induced by Aβ-42 peptides and neurotoxicants, alterations in the specific aspects of brain functions were measured in trimethyltin (TMT)-injected transgenic 2576 (TG) mice that had been pretreated with DG for 21 days. Multiple types of damage were successfully induced by Aβ-42 accumulation and TMT injection into the brains of TG mice. However, DG treatment significantly reduced the number of Aβ-stained plaques and dead cells in the granule cells layer of the dentate gyrus. Significant suppression of acetylcholinesterase (AChE) activity and Bax/Bcl-2 expression was also observed in the DG treated TG mice (TG+DG group) when compared with those of the vehicle (VC) treated TG mice (TG+VC group). Additionally, the concentration of nerve growth factor (NGF) was dramatically enhanced in TG+DG group, although it was lower in the TG+VC group than the non-transgenic (nTG) group. Furthermore, the decreased phosphorylation of downstream members in the TrkA high affinity receptor signaling pathway in the TG+VC group was significantly recovered in the TG+DG group. A similar pattern was observed in p75NTR expression and JNK phosphorylation in the NGF low affinity receptor signaling pathway. Moreover, superoxide dismutase (SOD) activity was enhanced in the TG+DG group, while the level of malondialdehyde (MDA), a marker of lipid peroxidation, was lower in the TG+DG group than the TG+VC group. These results suggest that DG could exert a wide range of beneficial activities for multiple types of brain damage through stimulation of NGF biosynthesis. PMID:27382379

α-Lipoic acid inhibits human lung cancer cell proliferation through Grb2-mediated EGFR downregulation.

PubMed

Yang, Lan; Wen, Ya; Lv, Guoqing; Lin, Yuntao; Tang, Junlong; Lu, Jingxiao; Zhang, Manqiao; Liu, Wen; Sun, Xiaojuan

2017-12-09

Alpha lipoic acid (α -LA) is a naturally occurring antioxidant and metabolic enzyme co-factor. Recently, α -LA has been reported to inhibit the growth of various cancer cells, but the precise signaling pathways that mediate the effects of α -LA on non-small cell lung cancer (NSCLC) development remain unclear. The CCK-8 assay was used to assess cell proliferation in NSCLC cell lines after α -LA treatment. The expression of growth factor receptor-bound protein 2 (Grb2), cyclin-dependent kinase (CDK)-2, CDK4, CDK6, Cyclin D3, Cyclin E1, Ras, c-Raf, epidermal growth factor receptor (EGFR), ERK1/2 and activated EGFR and ERK1/2 was evaluated by western blotting. Grb2 levels were restored in α-LA-treated cells by transfection of a plasmid carrying Grb2 and were reduced in NSCLC cells via specific siRNA-mediated knockdown. α -LA dramatically decreased NSCLC cell proliferation by downregulating Grb2; in contrast, Grb2 overexpression significantly prevented α-LA-induced decrease in cell growth in vitro. Western blot analysis indicated that α-LA decreased the levels of phospho-EGFR, CDK2/4/6, Cyclins D3 and E1, which are associated with the inhibition of G1/S-phase transition. Additional experiments indicated that Grb2 inhibition partially abolished EGF-induced phospho-EGFR and phospho-ERK1/2 activity. In addition, α-LA exerted greater inhibitory effects than gefitinib on NSCLC cells by preventing EGF-induced EGFR activation. For the first time, these findings provide the first evidence that α-LA inhibits cell proliferation through Grb2 by suppressing EGFR phosphorylation and that MAPK/ERK is involved in this pathway. Copyright © 2017. Published by Elsevier Inc.

Gene therapy strategy for long-term myocardial protection using adeno-associated virus-mediated delivery of heme oxygenase gene.

PubMed

Melo, Luis G; Agrawal, Reitu; Zhang, Lunan; Rezvani, Mojgan; Mangi, Abeel A; Ehsan, Afshin; Griese, Daniel P; Dell'Acqua, Giorgio; Mann, Michael J; Oyama, Junichi; Yet, Shaw-Fang; Layne, Matthew D; Perrella, Mark A; Dzau, Victor J

2002-02-05

Ischemia and oxidative stress are the leading mechanisms for tissue injury. An ideal strategy for preventive/protective therapy would be to develop an approach that could confer long-term transgene expression and, consequently, tissue protection from repeated ischemia/reperfusion injury with a single administration of a therapeutic gene. In the present study, we used recombinant adeno-associated virus (rAAV) as a vector for direct delivery of the cytoprotective gene heme oxygenase-1 (HO-1) into the rat myocardium, with the purpose of evaluating this strategy as a therapeutic approach for long-term protection from ischemia-induced myocardial injury. Human HO-1 gene (hHO-1) was delivered to normal rat hearts by intramyocardial injection. AAV-mediated transfer of the hHO-1 gene 8 weeks before acute coronary artery ligation and release led to a dramatic reduction (>75%) in left ventricular myocardial infarction. The reduction in infarct size was accompanied by decreases in myocardial lipid peroxidation and in proapoptotic Bax and proinflammatory interleukin-1beta protein abundance, concomitant with an increase in antiapoptotic Bcl-2 protein level. This suggested that the transgene exerts its cardioprotective effects in part by reducing oxidative stress and associated inflammation and apoptotic cell death. This study documents the beneficial therapeutic effect of rAAV-mediated transfer, before myocardial injury, of a cytoprotective gene that confers long-term myocardial protection from ischemia/reperfusion injury. Our data suggest that this novel "pre-event" gene transfer approach may provide sustained tissue protection from future repeated episodes of injury and may be beneficial as preventive therapy for patients with or at risk of developing coronary ischemic events.

Downregulation of a putative plastid PDC E1α subunit impairs photosynthetic activity and triacylglycerol accumulation in nitrogen-starved photoautotrophic Chlamydomonas reinhardtii

PubMed Central

Shtaida, Nastassia; Khozin-Goldberg, Inna; Solovchenko, Alexei; Chekanov, Konstantin; Didi-Cohen, Shoshana; Leu, Stefan; Cohen, Zvi; Boussiba, Sammy

2014-01-01

The chloroplast pyruvate dehydrogenase complex (cpPDC) catalyses the oxidative decarboxylation of pyruvate forming acetyl-CoA, an immediate primer for the initial reactions of de novo fatty acid (FA) synthesis. Little is known about the source of acetyl-CoA in the chloroplasts of photosynthetic microalgae, which are capable of producing high amounts of the storage lipid triacylglycerol (TAG) under conditions of nutrient stresses. We generated Chlamydomonas reinhardtii CC-1618 mutants with decreased expression of the PDC2_E1α gene, encoding the putative chloroplast pyruvate dehydrogenase subunit E1α, using artificial microRNA. A comparative study on the effects of PDC2_E1α silencing on FAs and TAG production in C. reinhardtii, grown photoautotrophically and mixotrophically, with and without a nitrogen source in the nutrient medium, was carried out. Reduced expression of PDC2 _E1α led to a severely hampered photoautotrophic growth phenotype with drastic impairment in TAG accumulation under nitrogen deprivation. In the presence of acetate, downregulation of PDC2_E1α exerted little to no effect on TAG production and photosynthetic activity. In contrast, under photoautotrophic conditions, especially in the absence of a nitrogen source, a dramatic decline in photosynthetic oxygen evolution and photosystem II quantum yield against a background of the apparent over-reduction of the photosynthetic electron chain was recorded. Our results suggest an essential role of cpPDC in the supply of carbon precursors for de novo FA synthesis in microalgae under conditions of photoautotrophy. A shortage of this supply is detrimental to the nitrogen-starvation-induced synthesis of storage TAG, an important carbon and energy sink in stressed Chlamydomonas cells, thereby impairing the acclimation ability of the microalga. PMID:25210079

Upregulation of SQSTM1/p62 contributes to nickel-induced malignant transformation of human bronchial epithelial cells

PubMed Central

Huang, Haishan; Zhu, Junlan; Li, Yang; Zhang, Liping; Gu, Jiayan; Xie, Qipeng; Jin, Honglei; Che, Xun; Li, Jingxia; Huang, Chao; Chen, Lung-Chi; Lyu, Jianxin; Gao, Jimin; Huang, Chuanshu

2016-01-01

ABSTRACT Chronic lung inflammation is accepted as being associated with the development of lung cancer caused by nickel exposure. Therefore, identifying the molecular mechanisms that lead to a nickel-induced sustained inflammatory microenvironment that causes transformation of human bronchial epithelial cells is of high significance. In the current studies, we identified SQSTM1/p62 as a novel nickel-upregulated protein that is important for nickel-induced inflammatory TNF expression, subsequently resulting in transformation of human bronchial epithelial cells. We found that nickel exposure induced SQSTM1 protein upregulation in human lung epithelial cells in vitro and in mouse lung tissues in vivo. The SQSTM1 upregulation was also observed in human lung squamous cell carcinoma. Further studies revealed that the knockdown of SQSTM1 expression dramatically inhibited transformation of human lung epithelial cells upon chronic nickel exposure, whereas ectopic expression of SQSTM1 promoted such transformation. Mechanistic studies showed that the SQSTM1 upregulation by nickel was the compromised result of upregulating SQSTM1 mRNA transcription and promoting SQSTM1 protein degradation. We demonstrated that nickel-initiated SQSTM1 protein degradation is mediated by macroautophagy/autophagy via an MTOR-ULK1-BECN1 axis, whereas RELA is important for SQSTM1 transcriptional upregulation following nickel exposure. Furthermore, SQSTM1 upregulation exhibited its promotion of nickel-induced cell transformation through exerting an impetus for nickel-induced inflammatory TNF mRNA stability. Consistently, the MTOR-ULK1-BECN1 autophagic cascade acted as an inhibitory effect on nickel-induced TNF expression and cell transformation. Collectively, our results demonstrate a novel SQSTM1 regulatory network that promotes a nickel-induced tumorigenic effect in human bronchial epithelial cells, which is negatively controlled by an autophagic cascade following nickel exposure. PMID:27467530

Role of diabetes- and obesity-related protein in the regulation of osteoblast differentiation

PubMed Central

Linares, Gabriel R.; Xing, Weirong; Burghardt, Hans; Baumgartner, Bernhard; Chen, Shin-Tai; Ricart, Wifredo; Fernández-Real, José Manuel; Zorzano, Antonio

2011-01-01

Although thyroid hormone (TH) is known to exert important effects on the skeleton, the nuclear factors constituting the TH receptor coactivator complex and the molecular pathways by which TH mediates its effects on target gene expression in osteoblasts remain poorly understood. A recent study demonstrated that the actions of TH on myoblast differentiation are dependent on diabetes- and obesity-related protein (DOR). However, the role of DOR in osteoblast differentiation is unknown. We found DOR expression increased during in vitro differentiation of bone marrow stromal cells into osteoblasts and also in MC3T3-E1 cells treated with TH. However, DOR expression decreased during cellular proliferation. To determine whether DOR acts as a modulator of TH action during osteoblast differentiation, we examined whether overexpression or knockdown of DOR in MC3T3-E1 cells affects the ability of TH to induce osteoblast differentiation by evaluating alkaline phosphatase (ALP) activity. ALP activity was markedly increased in DOR-overexpressing cells treated with TH. In contrast, loss of DOR dramatically reduced TH stimulation of ALP activity in MC3T3-E1 cells and primary calvaria osteoblasts transduced with lentiviral DOR shRNA. Consistent with reduced ALP activity, mRNA levels of osteocalcin, ALP, and Runx2 were decreased significantly in DOR shRNA cells. In addition, a common single nucleotide polymorphism (SNP), DOR1 found on the promoter of human DOR gene, was associated with circulating osteocalcin levels in nondiabetic subjects. Based on these data, we conclude that DOR plays an important role in TH-mediated osteoblast differentiation, and a DOR SNP associates with plasma osteocalcin in men. PMID:21467300

Changes in Alaskan soft-bottom prey communities along a gradient in sea otter predation

USGS Publications Warehouse

Kvitek, R.G.; Oliver, J.S.; DeGange, A.R.; Anderson, B.S.

1992-01-01

Sea Otter (Enhydra lutris), well documented as "keystone" predators in rocky marine communities, were found to exert a strong influence on infaunal prey communities in soft-sediment habitats. Direct and indirect effects of sea otter predation on subtidal soft-bottom prey communities were evaluated along a temporal gradient of sea otter occupancy around the Kodiak Archipelago. The results indicate that Kodiak otters forage primarily on bivalve prey and dramatically reduce infaunal bivalve and green sea urchin (Strongylocentrotus droebachiensis) prey populations. Bivalve prey abundance, biomass, and size were inversely related to duration of sea otter occupancy. The relative conditions of shells discarded by otters in shallow (<10 m) vs. deep (> 20 m) water at the same sites indicate that otters first exploited Saxidomus in shallow-water feeding areas, and later switched to Macoma spp. in deeper water. Otter-cracked shells of the deep-burrowing clam Tresus capax were rarely found, even at otter foraging sites where the clam accounted for the majority of available prey biomass, suggesting that it has a partial depth refuge from otter predation. The indirect effects of otter predation included substratum disturbance and the facilitation of sea star predation on infaunal prey. Sea stars, Pycnopodia helianthoides, were attracted to experimentally dug excavations as well as natural sea otter foraging pits, where the sea stars foraged on smaller size classes of infaunal bivalves than those eaten by otters. Otters also discard clam shells on the sediment surface and expose old, buried shells during excavation. Surface shells were found to provide attachment sites for large anemones and kelp. Our study shows that sea otters can affect soft-sediment communities, not only through predation, as in rocky habitats, but also through disturbance, and thus retain a high degree of influence in two very different habitat types.

Adaptive effort investment in cognitive and physical tasks: a neurocomputational model

PubMed Central

Verguts, Tom; Vassena, Eliana; Silvetti, Massimo

2015-01-01

Despite its importance in everyday life, the computational nature of effort investment remains poorly understood. We propose an effort model obtained from optimality considerations, and a neurocomputational approximation to the optimal model. Both are couched in the framework of reinforcement learning. It is shown that choosing when or when not to exert effort can be adaptively learned, depending on rewards, costs, and task difficulty. In the neurocomputational model, the limbic loop comprising anterior cingulate cortex (ACC) and ventral striatum in the basal ganglia allocates effort to cortical stimulus-action pathways whenever this is valuable. We demonstrate that the model approximates optimality. Next, we consider two hallmark effects from the cognitive control literature, namely proportion congruency and sequential congruency effects. It is shown that the model exerts both proactive and reactive cognitive control. Then, we simulate two physical effort tasks. In line with empirical work, impairing the model's dopaminergic pathway leads to apathetic behavior. Thus, we conceptually unify the exertion of cognitive and physical effort, studied across a variety of literatures (e.g., motivation and cognitive control) and animal species. PMID:25805978

Protective effects of acerola juice on genotoxicity induced by iron in vivo

PubMed Central

Horta, Roberta Nunes; Kahl, Vivian Francilia Silva; Sarmento, Merielen da Silva; Nunes, Marisa Fernanda Silva; Porto, Carem Rejane Maglione; de Andrade, Vanessa Moraes; Ferraz, Alexandre de Barros Falcão; Silva, Juliana Da

2016-01-01

Abstract Metal ions such as iron can induce DNA damage by inducing reactive oxygen species (ROS) and oxidative stress. Vitamin C is one of the most widely consumed antioxidants worldwide, present in many fruits and vegetables, especially inMalpighia glabra L., popularly known as acerola, native to Brazil. Acerola is considered a functional fruit due to its high antioxidant properties and phenolic contents, and therefore is consumed to prevent diseases or as adjuvant in treatment strategies. Here, the influence of ripe and unripe acerola juices on iron genotoxicity was analyzed in vivo using the comet assay and micronucleus test. The comet assay results showed that acerola juice exerted no genotoxic or antigenotoxic activity. Neither ripe nor unripe acerola juices were mutagenic to animals treated with juices, in micronucleus test. However, when compared to iron group, the pre-treatment with acerola juices exerted antimutagenic activity, decreasing significantly micronucleus mean values in bone marrow. Stage of ripeness did not influence the interaction of acerola compounds with DNA, and both ripe and unripe acerola juices exerted protective effect over DNA damage generated by iron. PMID:27007905

A Mild Impairment of Mitochondrial Electron Transport Has Sex-Specific Effects on Lifespan and Aging in Mice

PubMed Central

Hughes, Bryan G.; Hekimi, Siegfried

2011-01-01

Impairments of various aspects of mitochondrial function have been associated with increased lifespan in various model organisms ranging from Caenorhabditis elegans to mice. For example, disruption of the function of the ‘Rieske’ iron-sulfur protein (RISP) of complex III of the mitochondrial electron transport chain can result in increased lifespan in the nematode worm C. elegans. However, the mechanisms by which impaired mitochondrial function affects aging remain under investigation, including whether or not they require decreased electron transport. We have generated knock-in mice with a loss-of-function Risp mutation that is homozygous lethal. However, heterozygotes (Risp+/P224S) were viable and had decreased levels of RISP protein and complex III enzymatic activity. This decrease was sufficient to impair mitochondrial respiration and to decrease overall metabolic rate in males, but not females. These defects did not appear to exert an overtly deleterious effect on the health of the mutants, since young Risp+/P224S mice are outwardly normal, with unaffected performance and fertility. Furthermore, biomarkers of oxidative stress were unaffected in both young and aged animals. Despite this, the average lifespan of male Risp+/P224S mice was shortened and aged Risp+/P224S males showed signs of more rapidly deteriorating health. In spite of these differences, analysis of Gompertz mortality parameters showed that Risp heterozygosity decreased the rate of increase of mortality with age and increased the intrinsic vulnerability to death in both sexes. However, the intrinsic vulnerability was increased more dramatically in males, which resulted in their shortened lifespan. For females, the slower acceleration of age-dependent mortality results in significantly increased survival of Risp+/P224S mice in the second half of lifespan. These results demonstrate that even relatively small perturbations of the mitochondrial electron transport chain can have significant physiological effects in mammals, and that the severity of those effects can be sex-dependent. PMID:22028811

Selective Inhibition of Alpha/Beta-Hydrolase Domain 6 Attenuates Neurodegeneration, Alleviates Blood Brain Barrier Breakdown, and Improves Functional Recovery in a Mouse Model of Traumatic Brain Injury

PubMed Central

Tchantchou, Flaubert

2013-01-01

Abstract 2-arachidonylglycerol (2-AG) is the most abundant endocannabinoid in the central nervous system and is elevated after brain injury. Because of its rapid hydrolysis, however, the compensatory and neuroprotective effect of 2-AG is short-lived. Although inhibition of monoacylglycerol lipase, a principal enzyme for 2-AG degradation, causes a robust increase of brain levels of 2-AG, it also leads to cannabinoid receptor desensitization and behavioral tolerance. Alpha/beta hydrolase domain 6 (ABHD6) is a novel 2-AG hydrolytic enzyme that accounts for a small portion of 2-AG hydrolysis, but its inhibition is believed to elevate the levels of 2-AG within the therapeutic window without causing side effect. Using a mouse model of traumatic brain injury (TBI), we found that post-insult chronic treatment with a selective ABHD6 inhibitor WWL70 improved motor coordination and working memory performance. WWL70 treatment reduced lesion volume in the cortex and neurodegeneration in the dendate gyrus. It also suppressed the expression of inducible nitric oxide synthase and cyclooxygenase-2 and enhanced the expression of arginase-1 in the ipsilateral cortex at 3 and 7 days post-TBI, suggesting microglia/macrophages shifted from M1 to M2 phenotypes after treatment. The blood-brain barrier dysfunction at 3 and 7 days post-TBI was dramatically reduced. Furthermore, the beneficial effects of WWL70 involved up-regulation and activation of cannabinoid type 1 and type 2 receptors and were attributable to the phosphorylation of the extracellular signal regulated kinase and the serine/threonine protein kinase AKT. This study indicates that the fine-tuning of 2-AG signaling by modulating ABHD6 activity can exert anti-inflammatory and neuroprotective effects in TBI. PMID:23151067

Base-Pairing Energies of Protonated Nucleoside Base Pairs of dCyd and m5dCyd: Implications for the Stability of DNA i-Motif Conformations

NASA Astrophysics Data System (ADS)

Yang, Bo; Rodgers, M. T.

2015-08-01

Hypermethylation of cytosine in expanded (CCG)n•(CGG)n trinucleotide repeats results in Fragile X syndrome, the most common cause of inherited mental retardation. The (CCG)n•(CGG)n repeats adopt i-motif conformations that are preferentially stabilized by base-pairing interactions of protonated base pairs of cytosine. Here we investigate the effects of 5-methylation and the sugar moiety on the base-pairing energies (BPEs) of protonated cytosine base pairs by examining protonated nucleoside base pairs of 2'-deoxycytidine (dCyd) and 5-methyl-2'-deoxycytidine (m5dCyd) using threshold collision-induced dissociation techniques. 5-Methylation of a single or both cytosine residues leads to very small change in the BPE. However, the accumulated effect may be dramatic in diseased state trinucleotide repeats where many methylated base pairs may be present. The BPEs of the protonated nucleoside base pairs examined here significantly exceed those of Watson-Crick dGuo•dCyd and neutral dCyd•dCyd base pairs, such that these base-pairing interactions provide the major forces responsible for stabilization of DNA i-motif conformations. Compared with isolated protonated nucleobase pairs of cytosine and 1-methylcytosine, the 2'-deoxyribose sugar produces an effect similar to the 1-methyl substituent, and leads to a slight decrease in the BPE. These results suggest that the base-pairing interactions may be slightly weaker in nucleic acids, but that the extended backbone is likely to exert a relatively small effect on the total BPE. The proton affinity (PA) of m5dCyd is also determined by competitive analysis of the primary dissociation pathways that occur in parallel for the protonated (m5dCyd)H+(dCyd) nucleoside base pair and the absolute PA of dCyd previously reported.

Synthesis and characterization of bactericidal oligopeptides designed on the basis of an insect anti-bacterial peptide.

PubMed Central

Saido-Sakanaka, H; Ishibashi, J; Sagisaka, A; Momotani, E; Yamakawa, M

1999-01-01

Defensin from a beetle, Allomyrina dichotoma, is known to have anti-bacterial activity against Gram-positive bacteria. This peptide, which comprises 43 amino acid residues, was effective against methicillin-resistant Staphylococcus aureus. We identified the active site of beetle defensin by measuring anti-bacterial activity against S. aureus of 64 overlapping 12-mer peptides with either a free carboxylate or a free amide group at their C-termini. An LCAAHCLAIGRR-NH2 (19L-30R-NH2) fragment showed the greatest activity of the synthetic oligopeptides. The 19L-30R-NH2 fragment was effective against both Gram-positive and Gram-negative bacteria. CD spectra showed that the 19L-30R-NH2 fragment formed an alpha-helical structure in the lipidic environment. The anti-bacterial effect of the 19L-30R-NH2 fragment was due to its interaction with bacterial membranes, judging from the leakage of liposome-entrapped glucose. Its anti-bacterial activity was increased when certain amino acid residues were replaced. Truncated peptides having had some amino acids removed from the N-terminus of the 19L-30R-NH2 fragment (8-10-mer peptides) still had strong anti-bacterial activity. Deleting some amino acids from the C-terminal region of the fragment dramatically reduced activity, indicating that the C-terminal region of the 19L-30R-NH2 fragment, i.e. RR-NH2, is important for exerting anti-bacterial activity. The AHCLAIGRR-NH2 (22A-30R-NH2) fragment and its analogues exhibited about 3-fold and 9-12-fold higher activity against S. aureus than did the 19L-30R-NH2 fragment, and these analogues were effective against methicillin-resistant S. aureus and Pseudomonas aeruginosa isolated from patients. These oligopeptides showed no haemolytic activity and did not inhibit the growth of murine fibroblast cells. PMID:9931294

Mechanism of allosteric activation of TMEM16A/ANO1 channels by a commonly used chloride channel blocker

PubMed Central

Ta, Chau M; Adomaviciene, Aiste; Rorsman, Nils J G; Garnett, Hannah

2016-01-01

Background and Purpose Calcium‐activated chloride channels (CaCCs) play varied physiological roles and constitute potential therapeutic targets for conditions such as asthma and hypertension. TMEM16A encodes a CaCC. CaCC pharmacology is restricted to compounds with relatively low potency and poorly defined selectivity. Anthracene‐9‐carboxylic acid (A9C), an inhibitor of various chloride channel types, exhibits complex effects on native CaCCs and cloned TMEM16A channels providing both activation and inhibition. The mechanisms underlying these effects are not fully defined. Experimental Approach Patch‐clamp electrophysiology in conjunction with concentration jump experiments was employed to define the mode of interaction of A9C with TMEM16A channels. Key Results In the presence of high intracellular Ca2+, A9C inhibited TMEM16A currents in a voltage‐dependent manner by entering the channel from the outside. A9C activation, revealed in the presence of submaximal intracellular Ca2+ concentrations, was also voltage‐dependent. The electric distance of A9C inhibiting and activating binding site was ~0.6 in each case. Inhibition occurred according to an open‐channel block mechanism. Activation was due to a dramatic leftward shift in the steady‐state activation curve and slowed deactivation kinetics. Extracellular A9C competed with extracellular Cl−, suggesting that A9C binds deep in the channel's pore to exert both inhibiting and activating effects. Conclusions and Implications A9C is an open TMEM16A channel blocker and gating modifier. These effects require A9C to bind to a region within the pore that is accessible from the extracellular side of the membrane. These data will aid the future drug design of compounds that selectively activate or inhibit TMEM16A channels. PMID:26562072

Tissue-Specific Effects of Reduced β-catenin Expression on Adenomatous Polyposis Coli Mutation-Instigated Tumorigenesis in Mouse Colon and Ovarian Epithelium

PubMed Central

Feng, Ying; Sakamoto, Naoya; Wu, Rong; Liu, Jie-yu; Wiese, Alexandra; Green, Maranne E.; Green, Megan; Akyol, Aytekin; Roy, Badal C.; Zhai, Yali; Cho, Kathleen R.; Fearon, Eric R.

2015-01-01

Adenomatous polyposis coli (APC) inactivating mutations are present in most human colorectal cancers and some other cancers. The APC protein regulates the β-catenin protein pool that functions as a co-activator of T cell factor (TCF)-regulated transcription in Wnt pathway signaling. We studied effects of reduced dosage of the Ctnnb1 gene encoding β-catenin in Apc-mutation-induced colon and ovarian mouse tumorigenesis and cell culture models. Concurrent somatic inactivation of one Ctnnb1 allele, dramatically inhibited Apc mutation-induced colon polyposis and greatly extended Apc-mutant mouse survival. Ctnnb1 hemizygous dose markedly inhibited increases in β-catenin levels in the cytoplasm and nucleus following Apc inactivation in colon epithelium, with attenuated expression of key β-catenin/TCF-regulated target genes, including those encoding the EphB2/B3 receptors, the stem cell marker Lgr5, and Myc, leading to maintenance of crypt compartmentalization and restriction of stem and proliferating cells to the crypt base. A critical threshold for β-catenin levels in TCF-regulated transcription was uncovered for Apc mutation-induced effects in colon epithelium, along with evidence of a feed-forward role for β-catenin in Ctnnb1 gene expression and CTNNB1 transcription. The active β-catenin protein pool was highly sensitive to CTNNB1 transcript levels in colon cancer cells. In mouse ovarian endometrioid adenocarcinomas (OEAs) arising from Apc- and Pten-inactivation, while Ctnnb1 hemizygous dose affected β-catenin levels and some β-catenin/TCF target genes, Myc induction was retained and OEAs arose in a fashion akin to that seen with intact Ctnnb1 gene dose. Our findings indicate Ctnnb1 gene dose exerts tissue-specific differences in Apc mutation-instigated tumorigenesis. Differential expression of selected β-catenin/TCF-regulated genes, such as Myc, likely underlies context-dependent effects of Ctnnb1 gene dosage in tumorigenesis. PMID:26528816

Renin inhibitor aliskiren exerts beneficial effect on trabecular bone by regulating skeletal renin-angiotensin system and kallikrein-kinin system in ovariectomized mice.

PubMed

Zhang, Y; Wang, L; Song, Y; Zhao, X; Wong, M S; Zhang, W

2016-03-01

The skeletal renin-angiotensin system contributes to the development of osteoporosis. The renin inhibitor aliskiren exhibited beneficial effects on trabecular bone of osteoporotic mice, and this action might be mediated through angiotensin and bradykinin receptor pathways. This study implies the potential application of renin inhibitor in the management for postmenopausal osteoporosis. The skeletal renin-angiotensin system plays key role in the pathological process of osteoporosis. The present study is designed to elucidate the effect of renin inhibitor aliskiren on trabecular bone and its potential action mechanism in ovariectomized (OVX) mice. The OVX mice were treated with low dose (5 mg/kg) or high dose (25 mg/kg) of aliskiren or its vehicle for 8 weeks. The bone turnover markers were measured by ELISA. The structural parameters of trabecular bone at lumbar vertebra (LV) and distal femoral metaphysis were measured by micro-CT. The expression of messenger RNA (mRNA) and protein was studied by RT-PCR and immunoblotting, respectively. Aliskiren treatment reduced urinary excretion of calcium and serum level of tartrate-resistant acid phosphatase in OVX mice. The treatment with aliskiren significantly increased bone volume (BV/TV) and connectivity density (Conn.D) of trabecular bone at LV-2 and LV-5 as well as dramatically enhanced BV/TV, Conn.D, bone mineral density (BMD/BV) and decreased bone surface (BS/BV) at the distal femoral end. Aliskiren significantly down-regulated the expression of angiotensinogen, angiotensin II (Ang II), Ang II type 1 receptor, bradykinin receptor (BR)-1, and osteocytic-specific gene sclerostin as well as the osteoclast-specific genes, including carbonic anhydrase II, matrix metalloproteinase-9, and cathepsin K. This study revealed that renin inhibitor aliskiren exhibited the beneficial effects on trabecular bone of ovariectomy-induced osteoporotic mice, and the underlying mechanism for this action might be mediated through Ang II and BR signaling pathways in bone.

Differential intensity-dependent effects of magnetic stimulation on the longest neurites and shorter dendrites in neuroscreen-1 cells

NASA Astrophysics Data System (ADS)

Lin, Ching-Yi; Huang, Whitney J.; Li, Kevin; Swanson, Roy; Cheung, Brian; Lin, Vernon W.; Lee, Yu-Shang

2015-04-01

Objective. Magnetic stimulation (MS) is a potential treatment for neuropsychiatric disorders. This study investigates whether MS-regulated neuronal activity can translate to specific changes in neuronal arborization and thus regulate synaptic activity and function. Approach. To test our hypotheses, we examined the effects of MS on neurite growth of neuroscreen-1 (NS-1) cells over the pulse frequencies of 1, 5 and 10 Hz at field intensities controlled via machine output (MO). Cells were treated with either 30% or 40% MO. Due to the nature of circular MS coils, the center region of the gridded coverslip (zone 1) received minimal (∼5%) electromagnetic current density while the remaining area (zone 2) received maximal (∼95%) current density. Plated NS-1 cells were exposed to MS twice per day for three days and then evaluated for length and number of neurites and expression of brain-derived neurotrophic factor (BDNF). Main results. We show that MS dramatically affects the growth of the longest neurites (axon-like) but does not significantly affect the growth of shorter neurites (dendrite-like). Also, MS-induced changes in the longest neurite growth were most evident in zone 1, but not in zone 2. MS effects were intensity-dependent and were most evident in bolstering longest neurite outgrowth, best seen in the 10 Hz MS group. Furthermore, we found that MS-increased BDNF expression and secretion was also frequency-dependent. Taken together, our results show that MS exerts distinct effects when different frequencies and intensities are applied to the neuritic compartments (longest neurite versus shorter dendrite(s)) of NS-1 cells. Significance. These findings support the concept that MS increases BDNF expression and signaling, which sculpts longest neurite arborization and connectivity by which neuronal activity is regulated. Understanding the mechanisms underlying MS is crucial for efficiently incorporating its use into potential therapeutic strategies.

Negative incidental emotions augment fairness sensitivity

PubMed Central

Liu, Cuizhen; Chai, Jing Wen; Yu, Rongjun

2016-01-01

Previous studies have shown that task-unrelated emotions induced incidentally exert carryover effects on individuals’ subsequent decisions in financial negotiations. However, the specificity of these emotion effects are not clear. In three experiments, we systematically investigated the role of seven transiently induced basic emotions (disgust, sadness, anger, fear, happiness, surprise and neutral) on rejection of unfair offers using the ultimatum game. We found that all negative emotions (disgust, sadness, anger and fear), but not happiness or surprise, significantly increased rejection rates, suggesting that the effect of incidental negative emotions on fairness is not specific to the type of negative emotion. Our findings highlight the role of fleeting emotions in biasing decision-making processes and suggest that all incidental negative emotions exert similar effects on fairness sensitivity, possibly by potentiating attention towards negative aspects of the situation. PMID:27101931

The Effects of Hempseed Meal Intake and Linoleic Acid on Drosophila Models of Neurodegenerative Diseases and Hypercholesterolemia

PubMed Central

Lee, Min Jung; Park, Seung Hwan; Han, Ju Hua; Hong, Yoon Ki; Hwang, Soojin; Lee, Soojin; Kim, Darae; Han, Seung Yeop; Kim, Eun Soo; Cho, Kyoung Sang

2011-01-01

Hempseed is rich in polyunsaturated fatty acids (PUFAs), which have potential as therapeutic compounds for the treatment of neurodegenerative and cardiovascular dis-ease. However, the effect of hempseed meal (HSM) intake on the animal models of these diseases has yet to be elucidated. In this study, we assessed the effects of the intake of HSM and PUFAs on oxidative stress, cytotoxicity and neurological phenotypes, and cholesterol uptake, using Drosophila models. HSM intake was shown to reduce H2O2 toxicity markedly, indicating that HSM exerts a profound antioxidant effect. Meanwhile, intake of HSM, as well as linoleic or linolenic acids (major PUFA components of HSM) was shown to ameliorate Aβ42-induced eye degeneration, thus suggesting that these compounds exert a protective effect against Aβ42 cytotoxicity. On the contrary, locomotion and longevity in the Parkinson’s disease model andeye degeneration in the Huntington’s disease model were unaffected by HSM feeding. Additionally, intake of HSM or linoleic acid was shown to reduce cholesterol uptake significantly. Moreover, linoleic acid intake has been shown to delay pupariation, and cholesterol feeding rescued the linoleic acid-induced larval growth delay, thereby indicating that linoleic acid acts antagonistically with cholesterol during larval growth. In conclusion, our results indicate that HSM and linoleic acid exert inhibitory effects on both Aβ42 cytotoxicity and cholesterol uptake, and are potential candidates for the treatment of Alzheimer’s disease and cardiovasculardisease. PMID:21331775

Potential beneficial effects of butyrate in intestinal and extraintestinal diseases

PubMed Central

Canani, Roberto Berni; Costanzo, Margherita Di; Leone, Ludovica; Pedata, Monica; Meli, Rosaria; Calignano, Antonio

2011-01-01

The multiple beneficial effects on human health of the short-chain fatty acid butyrate, synthesized from non-absorbed carbohydrate by colonic microbiota, are well documented. At the intestinal level, butyrate plays a regulatory role on the transepithelial fluid transport, ameliorates mucosal inflammation and oxidative status, reinforces the epithelial defense barrier, and modulates visceral sensitivity and intestinal motility. In addition, a growing number of studies have stressed the role of butyrate in the prevention and inhibition of colorectal cancer. At the extraintestinal level, butyrate exerts potentially useful effects on many conditions, including hemoglobinopathies, genetic metabolic diseases, hypercholesterolemia, insulin resistance, and ischemic stroke. The mechanisms of action of butyrate are different; many of these are related to its potent regulatory effects on gene expression. These data suggest a wide spectrum of positive effects exerted by butyrate, with a high potential for a therapeutic use in human medicine. PMID:21472114

Glucose level determines excitatory or inhibitory effects of adiponectin on arcuate POMC neuron activity and feeding.

PubMed

Suyama, Shigetomo; Maekawa, Fumihiko; Maejima, Yuko; Kubota, Naoto; Kadowaki, Takashi; Yada, Toshihiko

2016-08-09

Adiponectin regulates glucose and lipid metabolism, acting against metabolic syndrome and atherosclerosis. Accumulating evidence suggest that adiponectin acts on the brain including hypothalamic arcuate nucleus (ARC), where proopiomelanocortin (POMC) neurons play key roles in feeding regulation. Several studies have examined intracerebroventricular (ICV) injection of adiponectin and reported opposite effects, increase or decrease of food intake. These reports used different nutritional states. The present study aimed to clarify whether adiponectin exerts distinct effects on food intake and ARC POMC neurons depending on the glucose concentration. Adiponectin was ICV injected with or without glucose for feeding experiments and administered to ARC slices with high or low glucose for patch clamp experiments. We found that adiponectin at high glucose inhibited POMC neurons and increased food intake while at low glucose it exerted opposite effects. The results demonstrate that glucose level determines excitatory or inhibitory effects of adiponectin on arcuate POMC neuron activity and feeding.

Oral contraceptives and mood in women with and without premenstrual dysphoria: a theoretical model.

PubMed

Kurshan, N; Neill Epperson, C

2006-01-01

Despite numerous studies on the topic, there is no consensus to date on the effects of oral contraceptives on mood or the mechanism(s) by which they exert these effects. This review article presents a theoretical model to explain the way in which oral contraceptives may affect mood. Specifically, it is argued that progestins exert differential effects on endogenous levels of neurosteroids, thereby altering mood. After providing an overview of the effects of estrogen, progesterone, and progesterone's metabolites on cortical excitability and the role of neurosteroids in depression and premenstrual dysphoria, this article reviews the research that has been conducted on the relationship between oral contraceptives and neurosteroids. Finally, suggestions for future research are made with the dual aim of improving existing studies on the relationship between oral contraceptives and mood and further investigating the possibility that fluctuations in neurosteroid levels are responsible for the effects of oral contraceptives on mood.

Microviscoelasticity of the apical cell surface of human umbilical vein endothelial cells (HUVEC) within confluent monolayers.

PubMed

Feneberg, Wolfgang; Aepfelbacher, Martin; Sackmann, Erich

2004-08-01

We studied the local viscoelasticity of the apical membrane of human umbilical vein endothelial cells within confluent layers by magnetic tweezers microrheometry. Magnetic beads are coupled to various integrins by coating with fibronectin or invasin. By analyzing the deflection of beads evoked by various force scenarios we demonstrate that the cell envelope behaves as a linear viscoelastic body if forces up to 2 nN are applied for short times (<20 s) but can respond in an adaptive way if stress pulses are applied longer (>30 s). The time-dependent shear relaxation modulus G(t) exhibits three time regimes: a fast response (t < 0.05 s) where the relaxation modulus G(t) obeys a power law G(t) approximately t(-0.82+/-0.02); a plateau-like behavior (at 0.05 s < t < 0.15 s); and a slow flow-like response which is, however, partially reversible. Strain field mapping experiments with colloidal probes show that local forces induce a strain field exhibiting a range of zeta = 10 +/- 1 microm, but which could only be observed if nonmagnetic beads were coupled to the cell surface by invasin. By application of the theory of elasticity of planar bodies we estimated a surface shear modulus of 2.5 x10(-4) N/m. By assuming a thickness of the actin cortex of approximately 0.5 microm we estimate a Young modulus micro approximately 400 Pa for the apical membrane. The value agrees with a plateau modulus of an entangled or weakly cross-linked actin network of an actin concentration of 100 microM (mesh size 0.2 microm). This result together with our observation of a strong reduction of the shear modulus by the actin destabilizing agent latrunculin A suggests that the shear modulus measured by our technique is determined by the actin cortex. The effect of two ligands inducing actin stress fiber formation and centripetal contraction of cells (associated with the formation of gaps in the confluent cell monolayer) on the viscoelastic responses were studied: histamine and lysophosphatidic acid (LPA). Histamine evoked a dramatic increase of the cell stiffness by >1 order of magnitude within <30 s, which is attributed to a transient rise of the intracellular Ca(2+) level, since DMSO exerted a similar effect. The stiffening is accompanied by a concomitant rounding of the cells as observed by microinterferometry and relaxes partially in the timescale of 5 min, whereas gaps between cells close after approximately 30 min. LPA did not exert a remarkable and reproducible effect other than an occasional very weak transient increase of the shear stiffness, which shows that the gap formation activated by LPA is mediated by a different mechanism than that induced by histamine.

Metoprolol vs ivabradine in patients with mitral stenosis in sinus rhythm.

PubMed

Agrawal, Vikas; Kumar, Niraj; Lohiya, Balalji; Sihag, Bhupendra K; Prajapati, Rajpal; Singh, T B; Subramanian, Geetha

2016-10-15

Severe mitral stenosis is usually symptomatic and is treated by BMV or surgery, whereas mild to moderate mitral stenosis is usually asymptomatic or mildly symptomatic and managed medically. Patients in the later group may become symptomatic during episodes of exercise and increased heart rate. Beta-blockers are frequently used in patients with mitral stenosis to control the heart rate and alleviate exercise-related symptoms. The objective of our study was to investigate the comparative efficacy of ivabradine versus metoprolol in patients with mitral stenosis in sinus rhythm. We studied 97 patients of mitral stenosis in sinus rhythm presented with exertional symptoms. The effectiveness of Metoprolol was compared with ivabradine in alleviating these exertional symptoms in a randomized, open label non crossover study. We also assessed various stress ECG parameters, 24 hour Holter parameters and 2D Echo parameters to objectively compare the effects of ivabradine and metoprolol in these patients. Ivabradine and metoprolol both were effective in controlling exertional symptoms. Significant improvement in objective parameters like TMT (work capacity, baseline heart rate and maximal heart rate) and 2D echocardiography (right ventricular systolic pressure) are seen with both drugs. Ivabradine controls the exertional symptoms significantly more than metoprolol. On head to head comparison there was a significant benefit of working capacity and heart rate at maximal exercise in favour of ivabradine. Ivabradine should be strongly considered in medical management of mitral stenosis patients where beta blockers are contraindicated such as reactive airway disease. The cost of ivabradine is higher than metoprolol which might possess constraints as most of the rheumatic heat disease patients belong to low socio economic status. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Pressure effects on the nose by an in-flight oxygen mask during simulated flight conditions.

PubMed

Schreinemakers, J Rieneke C; Boer, C; van Amerongen, P C G M; Kon, M

2016-12-01

Dutch F-16 fighter pilots experience oxygen mask inflicted nasal trauma, including discomfort, pain, skin abrasions, bruises and bone remodelling. Pressure and shear forces on the nose might contribute to causing these adverse effects. In this study, it was evaluated how flight conditions affected the exerted pressure, and whether shear forces were present. The pressure exerted by the oxygen mask was measured in 20 volunteers by placing pressure sensors on the nose and chin underneath the mask. In the human centrifuge, the effects on the exerted pressure during different flight conditions were evaluated (+3G z , +6G z , +9G z , protocolised head movements, mounted visor or night vision goggles, NVG). The runs were recorded to evaluate if the mask's position changed during the run, which would confirm the presence of shear forces. Head movements increased the median pressure on the nose by 50 mm Hg and on the chin by 37 mm Hg. NVG, a visor and accelerative forces also increased the median pressure on the nose. Pressure drops on the nose were also observed, during mounted NVG (-63 mm Hg). The recordings showed the mask slid downwards, especially during the acceleration phase of the centrifuge run, signifying the presence of shear forces. The exerted pressure by the oxygen mask changes during different flight conditions. Exposure to changing pressures and to shear forces probably contributes to mask-inflicted nasal trauma. 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/.

Effects of Dramatized Depictions of Accidents on Grade School Children's Reception of Safety Guidelines.

ERIC Educational Resources Information Center

Omdahl, Becky L.; Cantor, Joanne

A study examined a format for fear appeal messages that introduced a threat through one medium (i.e., a segment of dramatic television programming) and the recommended action through another medium (i.e., the verbal presentation of safety guidelines by an adult to a child). Subjects, 138 elementary school children from a middle-class elementary…

Novel Investigations of Flavonoids as Chemopreventive Agents for Hepatocellular Carcinoma

PubMed Central

Liao, Chen-Yi; Lee, Ching-Chang; Tsai, Chi-chang; Hsueh, Chao-Wen; Wang, Chih-Chiang; Chen, I-Hung; Tsai, Ming-Kai; Liu, Mei-Yu; Hsieh, An-Tie; Su, Kuan-Jen; Wu, Hau-Ming; Huang, Shih-Chung; Wang, Yi-Chen; Wang, Chien-Yao; Huang, Shu-Fang; Yeh, Yen-Cheng; Ben, Ren-Jy; Chien, Shang-Tao; Hsu, Chin-Wen; Kuo, Wu-Hsien

2015-01-01

We would like to highlight the application of natural products to hepatocellular carcinoma (HCC). We will focus on the natural products known as flavonoids, which target this disease at different stages of hepatocarcinogenesis. In spite of the use of chemotherapy and radiotherapy in treating HCC, patients with HCC still face poor prognosis because of the nature of multidrug resistance and toxicity derived from chemotherapy and radiotherapy. Flavonoids can be found in many vegetables, fruits, and herbal medicines that exert their different anticancer effects via different intracellular signaling pathways and serve as antioxidants. In this review, we will discuss seven common flavonoids that exert different biological effects against HCC via different pathways. PMID:26858957

Vaticaffinol, a resveratrol tetramer, exerts more preferable immunosuppressive activity than its precursor in vitro and in vivo through multiple aspects against activated T lymphocytes

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

Feng, Li-Li; Wu, Xue-Feng; Liu, Hai-Liang

2013-03-01

In the present study, we aimed to investigate the immunosuppressive activity of vaticaffinol, a resveratrol tetramer isolated from Vatica mangachapoi, on T lymphocytes both in vitro and in vivo, and further explored its potential molecular mechanism. Resveratrol had a wide spectrum of healthy beneficial effects with multiple targets. Interestingly, its tetramer, vaticaffinol, exerted more intensive immunosuppressive activity than resveratrol. Vaticaffinol significantly inhibited T cells proliferation activated by concanavalin A (Con A) or anti-CD3 plus anti-CD28 in a dose- and time-dependent manner. It also induced Con A-activated T cells undergoing apoptosis through mitochondrial pathway. Moreover, this compound prevented cells from enteringmore » S phase and G2/M phase during T cells activation. In addition, vaticaffinol inhibited ERK and AKT signaling pathways in Con A-activated T cells. Furthermore, vaticaffinol significantly ameliorated ear swelling in a mouse model of picryl chloride-induced ear contact dermatitis in vivo. In most of the aforementioned experiments, however, resveratrol had only slight effects on the inhibition of T lymphocytes compared with vaticaffinol. Taken together, our findings suggest that vaticaffinol exerts more preferable immunosuppressive activity than its precursor resveratrol both in vitro and in vivo by affecting multiple targets against activated T cells. - Graphical abstract: Vaticaffinol, a resveratrol tetramer isolated from Vatica mangachapoi, exerts more intensive immunosuppressive activity than its precursor resveratrol does in vitro and in vivo. Its mechanism may involve multiple effects against activated T cells: regulation of signalings involved in cell proliferation, G0/G1 arrest of T cells, as well as an apoptosis induction in activated effector T cells. Highlights: ► Vaticaffinol, a resveratrol tetramer, exerts more potent activity than its precursor. ► It inhibited T cells proliferation and prevented them from entering cell cycles. ► It led to apoptosis of activated T cells through mitochondrial pathway. ► It down-regulated ERK and AKT signaling pathways in Con A-activated T cells. ► It significantly ameliorated picryl chloride-induced ear swelling.« less

Effectiveness of cold water immersion for treating exertional heat stress when immediate response is not possible.

PubMed

Flouris, A D; Friesen, B J; Carlson, M J; Casa, D J; Kenny, G P

2015-06-01

Immediate treatment with cold water immersion (CWI) is the gold standard for exertional heatstroke. In the field, however, treatment is often delayed due to delayed paramedic response and/or inaccurate diagnosis. We examined the effect of treatment (reduction of rectal temperature to 37.5 °C) delays of 5, 20, and 40 min on core cooling rates in eight exertionally heat-stressed (40.0 °C rectal temperature) individuals. We found that rectal temperature was elevated above baseline (P < 0.05) at the end of all delay periods (5 min: 40.08 ± 0.32; 20 min: 39.92 ± 0.40; 40 min: 39.57 ± 0.29 °C). Mean arterial pressure was reduced (P < 0.05) below baseline (92 ± 1.8 mm Hg) after all delay periods (5 min: 75 ± 2.6; 20 min: 74 ± 1.7; 40 min: 70 ± 2.1 mm Hg; P > 0.05). Rectal core cooling rates were similar among conditions (5 min: 0.20 ± 0.01; 20 min: 0.17 ± 0.02; 40 min: 0.17 ± 0.01 °C/min; P > 0.05). The rectal temperature afterdrop following CWI was similar across conditions (5 min: 35.95; 20 min: 35.61; 40 min: 35.87 °C; P > 0.05). We conclude that the effectiveness of 2 °C CWI as a treatment for exertional heat stress remains high even when applied with a delay of 40 min. Therefore, our results support that CWI is the most appropriate treatment for exertional heatstroke as it is capable of quickly reversing hyperthermia even when treatment is commenced with a significant delay. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Individual differences in dopamine level modulate the ego depletion effect.

PubMed

Dang, Junhua; Xiao, Shanshan; Liu, Ying; Jiang, Yumeng; Mao, Lihua

2016-01-01

Initial exertion of self-control impairs subsequent self-regulatory performance, which is referred to as the ego depletion effect. The current study examined how individual differences in dopamine level, as indexed by eye blink rate (EBR), would moderate ego depletion. An inverted-U-shaped relationship between EBR and subsequent self-regulatory performance was found when participants initially engaged in self-control but such relationship was absent in the control condition where there was no initial exertion, suggesting individuals with a medium dopamine level may be protected from the typical ego depletion effect. These findings are consistent with a cognitive explanation which considers ego depletion as a phenomenon similar to "switch costs" that would be neutralized by factors promoting flexible switching. Copyright © 2015 Elsevier B.V. All rights reserved.

Novel Interventions for Heat/Exercise Induced Sudden Death and Fatigue

DTIC Science & Technology

2013-10-01

mutations associated with enhanced susceptibility to Exertional Heat Stroke (EHS), Exertional Rhabdomyolysis (ER), and Malignant Hyperthermia (MH) by...reduces the probability of a hypermetabolic response in YS mice. 15. SUBJECT TERMS: Exertional Heat Stroke, Exertional Rhabdomyolysis ...and exertional rhabdomyolysis (ER) have been reported in subjects with diagnosis of Malignant Hyperthermia (MH). MH is a life- threatening

What are the implications of rapid global warming for landslide-triggered turbidity current activity?

NASA Astrophysics Data System (ADS)

Clare, Michael; Peter, Talling; James, Hunt

2014-05-01

A geologically short-lived (~170kyr) episode of global warming occurred at ~55Ma, termed the Initial Eocene Thermal Maximum (IETM). Global temperatures rose by up to 8oC over only ~10kyr and a massive perturbation of the global carbon cycle occurred; creating a negative carbon isotopic (~-4% δ13C) excursion in sedimentary records. This interval has relevance to study of future climate change and its influence on geohazards including submarine landslides and turbidity currents. We analyse the recurrence frequency of turbidity currents, potentially initiated from large-volume slope failures. The study focuses on two sedimentary intervals that straddle the IETM and we discuss implications for turbidity current triggering. We present the results of statistical analyses (regression, generalised linear model, and proportional hazards model) for extensive turbidite records from an outcrop at Zumaia in NE Spain (N=285; 54.0 to 56.5 Ma) and based on ODP site 1068 on the Iberian Margin (N=1571; 48.2 to 67.6 Ma). The sedimentary sequences provide clear differentiation between hemipelagic and turbiditic mud with only negligible evidence of erosion. We infer dates for turbidites by converting hemipelagic bed thicknesses to time using interval-averaged accumulation rates. Multi-proxy dating techniques provide good age constraint. The background trend for the Zumaia record shows a near-exponential distribution of turbidite recurrence intervals, while the Iberian Margin shows a log-normal response. This is interpreted to be related to regional time-independence (exponential) and the effects of additive processes (log-normal). We discuss how a log-normal response may actually be generated over geological timescales from multiple shorter periods of random turbidite recurrence. The IETM interval shows a dramatic departure from both these background trends, however. This is marked by prolonged hiatuses (0.1 and 0.6 Myr duration) in turbidity current activity in contrast to the arithmetic mean recurrence, λ, for the full records (λ=0.007 and 0.0125 Myr). This period of inactivity is coincident with a dramatic carbon isotopic excursion (i.e. warmest part of the IETM) and heavily skews statistical analyses for both records. Dramatic global warming appears to exert a strong control on inhibiting turbidity current activity; whereas the effects of sea level change are not shown to be statistically significant. Rapid global warming is often implicated as a potential landslide trigger, due to dissociation of gas hydrates in response to elevated ocean temperatures. Other studies have suggested that intense global warming may actually be attributed to the atmospheric release of gas hydrates following catastrophic failure of large parts of a continental slope. Either way, a greater intensity of landslide and resultant turbidity current activity would be expected during the IETM; however, our findings are to the contrary. We offer some explanations in relation to potential triggers. Our work suggests that previous rapid global warming at the IETM did not trigger more frequent turbidity currents. This has direct relevance to future assessments relating to landslide-triggered tsunami hazard, and breakage of subsea cables by turbidity currents.

Investigation of properties of the Ca2+ influx and of the Ca2+-activated K+ efflux (Gárdos effect) in vanadate-treated and ATP-depleted human red blood cells.

PubMed

Kaiserová, K; Lakatos, B; Peterajová, E; Orlický, J; Varecka, L'

2002-12-01

In this study the properties of the 45Ca2+ influx in human red blood cells (RBC) induced by NaVO3 or ATP-depletion were compared. Both NaVO3-induced and ATP-depletion-induced 45Ca2+ influxes were in the range 10(-6)-10(-5) mol Ca2+ x l(-1)cells x h(-1). The saturatability of ATP-depletion-induced 45Ca2+ influx with Ca2+ was much less pronounced than that of NaVO3-induced 45Ca2+ influx. The NaVO3-induced Ca2+ influx was sensitive to nifedipine (IC50 = 50 micromol/l) and Cu2+ (IC50 = 9 micromol/l) but these inhibitors had only a marginal effect when ATP-depletion was used as the Ca2+ influx inducer. On the other hand, polymyxin B (PXB) (1-5 mg/ml) strongly stimulated the ATP-depletion-induced 45Ca2+ influx whereas its effect on the NaVO3-induced Ca2+ influx was biphasic, with about 10% stimulation at lower PXB concentrations and an inhibition of 40% at higher concentrations. SDS-PAGE revealed that both NaVO3 and PXB induced changes in the protein phosphorylation pattern in the presence of Ca2+. NaVO3 stimulated the phosphorylation of several proteins and this effect was counteracted by PXB. The comparison of the kinetics and temperature dependencies of the Gárdos effect induced by NaVO3 and the ATP-depletion showed marked differences. The ability of NaVO3 to induce the Gárdos effect dramatically increased in ATP-depleted cells. These findings indicate that the 45Ca2+ influxes preceding the activation of the Ca2+-activated K+ efflux (Gárdos effect) stimulated by NaVO3 and by ATP-depletion, are mediated by different transport pathways. In addition, obtained results demonstrate that ATP-depletion and NaVO3-treatment exert additive action in triggering the Gárdos effect.

The Effects of Direction of Exertion, Path, and Load Placement in Nursing Cart Pushing and Pulling Tasks: An Electromyographical Study.

PubMed

Kao, Huei Chu; Lin, Chiuhsiang Joe; Lee, Yung Hui; Chen, Su Huang

2015-01-01

The purpose of this study was to explore the effects of direction of exertion (DOE) (pushing, pulling), path (walking in a straight line, turning left, walking uphill), and load placement (LP) (the 18 blocks were indicated by X, Y and Z axis; there were 3 levels on the X axis, 2 levels on the Y axis, and 3 levels on the Z axis) on muscle activity and ratings of perceived exertion in nursing cart pushing and pulling tasks. Ten participants who were female students and not experienced nurses were recruited to participate in the experiment. Each participant performed 108 experimental trials in the study, consisting of 2 directions of exertion (push and pull), 3 paths, and 18 load placements (indicated by X, Y and Z axes). A 23kg load was placed into one load placement. The dependent variables were electromyographic (EMG) data of four muscles collected bilaterally as follows: Left (L) and right (R) trapezius (TR), flexor digitorum superficialis (FDS), extensor digitorum (ED), and erector spinae (ES) and subjective ratings of perceived exertion (RPE). Split-split-plot ANOVA was conducted to analyze significant differences between DOE, path, and LP in the EMG and RPE data. Pulling cart tasks produced a significantly higher activation of the muscles (RTR:54.4%, LTR:50.3%, LFDS:57.0%, LED:63.4%, RES:40.7%, LES:36.7%) than pushing cart tasks (RTR:42.4%, LTR:35.1%, LFDS:32.3%, LED:55.1%, RES:33.3%, LES:32.1%). A significantly greater perceived exertion was found in pulling cart tasks than pushing cart tasks. Significantly higher activation of all muscles and perceived exertion were observed for walking uphill than walking in a straight line and turning left. Significantly lower muscle activity of all muscles and subject ratings were observed for the central position on the X axis, the bottom position on the Y axis, and the posterior position on the Z axis. These findings suggest that nursing staff should adopt forward pushing when moving a nursing cart, instead of backward pulling, and that uphill paths should be avoided in the design of work environments. In terms of distribution of the load in a nursing cart, heavier materials should be positioned at bottom of the cabinet, centered on the horizontal plane and close to the handle, to reduce the physical load of the nursing staff.

The Effects of Direction of Exertion, Path, and Load Placement in Nursing Cart Pushing and Pulling Tasks: An Electromyographical Study

PubMed Central

Kao, Huei Chu; Lin, Chiuhsiang Joe; Lee, Yung Hui; Chen, Su Huang

2015-01-01

The purpose of this study was to explore the effects of direction of exertion (DOE) (pushing, pulling), path (walking in a straight line, turning left, walking uphill), and load placement (LP) (the 18 blocks were indicated by X, Y and Z axis; there were 3 levels on the X axis, 2 levels on the Y axis, and 3 levels on the Z axis) on muscle activity and ratings of perceived exertion in nursing cart pushing and pulling tasks. Ten participants who were female students and not experienced nurses were recruited to participate in the experiment. Each participant performed 108 experimental trials in the study, consisting of 2 directions of exertion (push and pull), 3 paths, and 18 load placements (indicated by X, Y and Z axes). A 23kg load was placed into one load placement. The dependent variables were electromyographic (EMG) data of four muscles collected bilaterally as follows: Left (L) and right (R) trapezius (TR), flexor digitorum superficialis (FDS), extensor digitorum (ED), and erector spinae (ES) and subjective ratings of perceived exertion (RPE). Split-split-plot ANOVA was conducted to analyze significant differences between DOE, path, and LP in the EMG and RPE data. Pulling cart tasks produced a significantly higher activation of the muscles (RTR:54.4%, LTR:50.3%, LFDS:57.0%, LED:63.4%, RES:40.7%, LES:36.7%) than pushing cart tasks (RTR:42.4%, LTR:35.1%, LFDS:32.3%, LED:55.1%, RES:33.3%, LES:32.1%). A significantly greater perceived exertion was found in pulling cart tasks than pushing cart tasks. Significantly higher activation of all muscles and perceived exertion were observed for walking uphill than walking in a straight line and turning left. Significantly lower muscle activity of all muscles and subject ratings were observed for the central position on the X axis, the bottom position on the Y axis, and the posterior position on the Z axis. These findings suggest that nursing staff should adopt forward pushing when moving a nursing cart, instead of backward pulling, and that uphill paths should be avoided in the design of work environments. In terms of distribution of the load in a nursing cart, heavier materials should be positioned at bottom of the cabinet, centered on the horizontal plane and close to the handle, to reduce the physical load of the nursing staff. PMID:26485039

Research on the Reproductive Effects of Endocrine Disrupting Chemicals

EPA Pesticide Factsheets

Reproductive hormones exert their effects at many life stages. During embryo and fetus development in the womb, these hormones direct formation of sex organs and the cells that give rise to sperm and eggs.

Shikonin exerts anti-inflammatory effects in a murine model of lipopolysaccharide-induced acute lung injury by inhibiting the nuclear factor-kappaB signaling pathway.

PubMed

Liang, Dejie; Sun, Yong; Shen, Yongbin; Li, Fengyang; Song, Xiaojing; Zhou, Ershun; Zhao, Fuyi; Liu, Zhicheng; Fu, Yunhe; Guo, Mengyao; Zhang, Naisheng; Yang, Zhengtao; Cao, Yongguo

2013-08-01

Shikonin, an analog of naphthoquinone pigments isolated from the root of Lithospermum erythrorhyzon, was recently reported to exert beneficial anti-inflammatory effects both in vivo and in vitro. The present study aimed to investigate the potential therapeutic effect of shikonin in a murine model of lipopolysaccharide (LPS)-induced acute lung injury (ALI). Dexamethasone was used as a positive control to evaluate the anti-inflammatory effect of shikonin in the study. Pretreatment with shikonin (intraperitoneal injection) significantly inhibited LPS-induced increases in the macrophage and neutrophil infiltration of lung tissues and markedly attenuated myeloperoxidase activity. Furthermore, shikonin significantly reduced the concentrations of TNF-α, IL-6 and IL-1β in bronchoalveolar lavage fluid induced by LPS. Compared with the LPS group, lung histopathologic changes were less pronounced in the shikonin-pretreated mice. Additionally, Western blotting results showed that shikonin efficiently decreased nuclear factor-kappaB (NF-κB) activation by inhibiting the degradation and phosphorylation of IκBα. These results suggest that shikonin exerts anti-inflammatory properties in LPS-mediated ALI, possibly through inhibition of the NF-κB signaling pathway, which mediates the expression of pro-inflammatory cytokines. Shikonin may be a potential agent for the prophylaxis of ALI. Copyright © 2013 Elsevier B.V. All rights reserved.

Vitamin E δ-tocotrienol triggers endoplasmic reticulum stress-mediated apoptosis in human melanoma cells

PubMed Central

Montagnani Marelli, Marina; Marzagalli, Monica; Moretti, Roberta M.; Beretta, Giangiacomo; Casati, Lavinia; Comitato, Raffaella; Gravina, Giovanni L.; Festuccia, Claudio; Limonta, Patrizia

2016-01-01

Malignant melanoma is the leading cause of death from skin cancer. Drug toxicity and resistance represent a serious challange for melanoma treatments. Evidence demonstrates that natural compounds may play a crucial role in cancer prevention, growth and progression. Vitamin E tocotrienols (TT) were shown to possess antitumor activity. Here, we analyzed the effects of δ-TT on melanoma cell growth and the involvement of the endoplasmic reticulum (ER) stress in this activity. The experiments were performed on human melanoma cell lines, BLM and A375. δ-TT exerted a significant proapoptotic effect on both cell lines, involving the intrinsic apoptosis pathway; importantly, this compound did not affect the viability of normal human melanocytes. In melanoma cells, δ-TT exerted its antitumor effect through activation of the PERK/p-eIF2α/ATF4/CHOP, IRE1α and caspase-4 ER stress-related branches. Salubrinal, an inhibitor of the ER stress, counteracted the cytotoxic activity of δ-TT. In vivo experiments performed in nude mice bearing A375 xenografts evidenced that δ-TT reduces tumor volume and tumor mass; importantly, tumor progression was significantly delayed by δ-TT treatment. In conclusion, δ-TT exerts a proapoptotic activity on melanoma cells, through activation of the ER stress-related pathways. δ-TT might represent an effective option for novel chemopreventive/therapeutic strategies for melanoma. PMID:27461002

Catechol-O-methyltransferase (COMT) polymorphisms modulate working memory in individuals with schizophrenia and healthy controls.

PubMed

Matsuzaka, Camila T; Christofolini, Denise; Ota, Vanessa K; Gadelha, Ary; Berberian, Arthur A; Noto, Cristiano; Mazzotti, Diego R; Spindola, Leticia M; Moretti, Patricia N; Smith, Marilia A C; Melaragno, Maria I; Belangero, Sintia I; Bressan, Rodrigo A

2017-01-01

Cognitive impairment is a core feature of schizophrenia, related to dopaminergic dysfunction in the prefrontal cortex (PFC). It is hypothesized that functional single nucleotide polymorphism (SNP) rs4680 of the catechol-O-methyltransferase (COMT) gene could mediate the relationship between cognition and dopamine activity in the PFC. Other COMT SNPs could also play a role. We evaluated the role of three COMT SNPs (rs737865, rs165599, and rs4680) in schizophrenia and their impact on three working memory tasks. For genetic association analyses, 212 individuals with schizophrenia and 257 healthy controls (HCs) were selected. The Visual Working Memory (VWM) Task, Keep Track Task, and Letter Memory Task were administered to 133 schizophrenics and 93 HCs. We found a significant association of rs737865, with the GG genotype exerting a protective effect and the GA haplotype (rs4680/rs165599) exerting a risk effect for schizophrenia. COMT rs4680 AA carriers and rs737865 AA carriers scored lowest on the Keep Track Task. When the genotype*group interaction effect was evaluated, rs165599 exerted opposite effects for VWM and Keep Track task performance in patients and controls, with AA carriers scoring lowest on both tests among controls, but highest among patients. These data support the hypothesis that COMT polymorphisms may be associated with schizophrenia and modulate cognition in patients and controls.

Pirfenidone exerts antifibrotic effects through inhibition of GLI transcription factors.

PubMed

Didiasova, Miroslava; Singh, Rajeev; Wilhelm, Jochen; Kwapiszewska, Grazyna; Wujak, Lukasz; Zakrzewicz, Dariusz; Schaefer, Liliana; Markart, Philipp; Seeger, Werner; Lauth, Matthias; Wygrecka, Malgorzata

2017-05-01

Pirfenidone is an antifibrotic drug, recently approved for the treatment of patients with idiopathic pulmonary fibrosis (IPF). Although pirfenidone exhibits anti-inflammatory, antioxidant, and antifibrotic properties, the molecular mechanism underlying its protective effects remains unknown. Here, we link pirfenidone action with the regulation of the profibrotic hedgehog (Hh) signaling pathway. We demonstrate that pirfenidone selectively destabilizes the glioma-associated oncogene homolog (GLI)2 protein, the primary activator of Hh-mediated gene transcription. Consequently, pirfenidone decreases overall Hh pathway activity in patients with IPF and in patient-derived primary lung fibroblasts and leads to diminished levels of Hh target genes, such as GLI1, Hh receptor Patched-1, α-smooth muscle actin, and fibronectin, and to reduced cell migration and proliferation. Interestingly, Hh-triggered TGF-β1 expression potentiated Hh responsiveness of primary lung fibroblasts by elevating the available pool of glioma-associated oncogene homolog (GLI)1/GLI2, thus creating a vicious cycle of amplifying fibrotic processes. Because GLI transcription factors are not only crucial for Hh-mediated changes but are also required as mediators of TGF-β signaling, our findings suggest that pirfenidone exerts its clinically beneficial effects through dual Hh/TGF-β inhibition by targeting the GLI2 protein.-Didiasova, M., Singh, R., Wilhelm, J., Kwapiszewska, G., Wujak, L., Zakrzewicz, D., Schaefer, L., Markart, P., Seeger, W., Lauth, M., Wygrecka, M. Pirfenidone exerts antifibrotic effects through inhibition of GLI transcription factors. © FASEB.

Quercetin protects human peripheral blood mononuclear cells from OTA-induced oxidative stress, genotoxicity, and inflammation.

PubMed

Periasamy, Ramyaa; Kalal, Iravathy Goud; Krishnaswamy, Rajashree; Viswanadha, VijayaPadma

2016-07-01

Ochratoxin A (OTA) is one of the most abundant food-contaminating mycotoxins world wide, and is detrimental to human and animal health. This study evaluated the protective effect of quercetin against OTA-induced cytotoxicity, genotoxicity, and inflammatory response in lymphocytes. Cytotoxicity determined by MTT assay revealed IC20 value of OTA to be 20 µM, which was restored to near control values by pretreatment with quercetin. Oxidative stress parameters such as antioxidant enzymes, LPO and PCC levels indicated that quercetin exerted a protective effect on OTA-induced oxidative stress. Quercetin exerted an antigenotoxic effect on OTA-induced genotoxicity, by significantly reducing the number of structural aberrations in chromosomes and comet parameters like, % olive tail moment from 2.76 ± 0.02 to 0.56 ± 0.02 and % tail DNA from 56.23 ± 2.56 to 12.36 ± 0.56 as determined by comet assay. OTA-induced NO, TNF-α, IL-6, and IL-8 were significantly reduced in the quercetin pretreated samples indicating its anti-inflammatory role. Our results demonstrate for the first time that quercetin exerts a cytoprotective effect against OTA-induced oxidative stress, genotoxicity, and inflammation in lymphocytes. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 855-865, 2016. © 2014 Wiley Periodicals, Inc.

Oleoylethanolamide exerts anti-inflammatory effects on LPS-induced THP-1 cells by enhancing PPARα signaling and inhibiting the NF-κB and ERK1/2/AP-1/STAT3 pathways.

PubMed

Yang, Lichao; Guo, Han; Li, Ying; Meng, Xianglan; Yan, Lu; Dan Zhang; Wu, Sangang; Zhou, Hao; Peng, Lu; Xie, Qiang; Jin, Xin

2016-10-10

The present study aimed to examine the anti-inflammatory actions of oleoylethanolamide (OEA) in lipopolysaccharide (LPS)-induced THP-1 cells. The cells were stimulated with LPS (1 μg/ml) in the presence or absence of OEA (10, 20 and 40 μM). The pro-inflammatory cytokines were evaluated by qRT-PCR and ELISA. The THP-1 cells were transiently transfected with PPARα small-interfering RNA, and TLR4 activity was determined with a blocking test using anti-TLR4 antibody. Additionally, a special inhibitor was used to analyse the intracellular signaling pathway. OEA exerted a potent anti-inflammatory effect by reducing the production of pro-inflammatory cytokines and TLR4 expression, and by enhancing PPARα expression. The modulatory effects of OEA on LPS-induced inflammation depended on PPARα and TLR4. Importantly, OEA inhibited LPS-induced NF-κB activation, IκBα degradation, expression of AP-1, and the phosphorylation of ERK1/2 and STAT3. In summary, our results demonstrated that OEA exerts anti-inflammatory effects by enhancing PPARα signaling, inhibiting the TLR4-mediated NF-κB signaling pathway, and interfering with the ERK1/2-dependent signaling cascade (TLR4/ERK1/2/AP-1/STAT3), which suggests that OEA may be a therapeutic agent for inflammatory diseases.

Protective and therapeutic effects of fucoxanthin against sunburn caused by UV irradiation.

PubMed

Matsui, Mio; Tanaka, Kosuke; Higashiguchi, Naoki; Okawa, Hisato; Yamada, Yoichi; Tanaka, Ken; Taira, Soichiro; Aoyama, Tomoko; Takanishi, Misaki; Natsume, Chika; Takakura, Yuuki; Fujita, Norihisa; Hashimoto, Takeshi; Fujita, Takashi

2016-09-01

Mild exposure to ultraviolet (UV) radiation is also harmful and hazardous to the skin and often causes a photosensitivity disorder accompanied by sunburn. To understand the action of UV on the skin we performed a microarray analysis to isolate UV-sensitive genes. We show here that UV irradiation promoted sunburn and downregulated filaggrin (Flg); fucoxanthin (FX) exerted a protective effect. In vitro analysis showed that UV irradiation of human dermal fibroblasts caused production of intracellular reactive oxygen species (ROS) without cellular toxicity. ROS production was diminished by N-acetylcysteine (NAC) or FX, but not by retinoic acid (RA). In vivo analysis showed that UV irradiation caused sunburn and Flg downregulation, and that FX, but not NAC, RA or clobetasol, exerted a protective effect. FX stimulated Flg promoter activity in a concentration-dependent manner. Flg promoter deletion and chromatin immunoprecipitation analysis showed that caudal type homeo box transcription factor 1 (Cdx1) was a key factor for Flg induction. Cdx1 was also downregulated in UV-exposed skin. Therefore, our data suggested that the protective effects of FX against UV-induced sunburn might be exerted by promotion of skin barrier formation through induction of Flg, unrelated to quenching of ROS or an RA-like action. Copyright © 2016 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

H-Ras Exerts Opposing Effects on Type I Interferon Responses Depending on Its Activation Status.

PubMed

Chen, Guann-An; Lin, Yun-Ru; Chung, Hai-Ting; Hwang, Lih-Hwa

2017-01-01

Using shRNA high-throughput screening, we identified H-Ras as a regulator of antiviral activity, whose depletion could enhance Sindbis virus replication. Further analyses indicated that depletion of H-Ras results in a robust increase in vesicular stomatitis virus infection and a decrease in Sendai virus (SeV)-induced retinoic acid-inducible gene-I-like receptor (RLR) signaling. Interestingly, however, ectopic expression of wild-type H-Ras results in a biphasic mode of RLR signaling regulation: while low-level expression of H-Ras enhances SeV-induced RLR signaling, high-level expression of H-Ras significantly inhibits this signaling. The inhibitory effects correlate with the activation status of H-Ras. As a result, oncogenic H-Ras, H-RasV12, strongly inhibits SeV-induced IFN-β promoter activity and type I interferon signaling. Conversely, the positive effects exerted by H-Ras on RLR signaling are independent of its signaling activity, as a constitutively inactive form of H-Ras, H-RasN17, also positively regulates RLR signaling. Mechanistically, we demonstrate that depletion of H-Ras reduces the formation of MAVS-TNF receptor-associated factor 3 signaling complexes. These results reveal that the H-Ras protein plays a role in promoting MAVS signalosome assembly in the mitochondria, whereas oncogenic H-Ras exerts a negative effect on type I IFN responses.

Antidepressant Potential of (R)-Ketamine in Rodent Models: Comparison with (S)-Ketamine.

PubMed

Fukumoto, Kenichi; Toki, Hidetoh; Iijima, Michihiko; Hashihayata, Takashi; Yamaguchi, Jun-Ichi; Hashimoto, Kenji; Chaki, Shigeyuki

2017-04-01

The rapid-acting and long-lasting antidepressant effects of ( R,S )-ketamine have recently gained much attention. Although ( S )-ketamine has been studied as an active isomer, recent evidence suggests that ( R )-ketamine exhibits longer-lasting antidepressant effects than ( S )-ketamine in rodents. However, the antidepressant potential of ( R )-ketamine has not been fully addressed. In the present study, we compared the antidepressant effects of ( R )-ketamine with those of ( S )-ketamine in animal models of depression, including a model that is refractory to current medications. Both ( R )-ketamine and ( S )-ketamine exhibited antidepressant effects at 30 minutes as well as at 24 hours after administration in forced-swimming and tail-suspension tests in mice. At 48 hours after administration, however, ( R )-ketamine still exerted a significant antidepressant effect in the tail-suspension test, whereas the effect of ( S )-ketamine was no longer observed. Moreover, ( R )-ketamine, but not ( S )-ketamine, significantly reversed the depressive-like behavior induced by repeated treatments with corticosterone in rats at 24 hours after a single administration. This effect was attenuated by an α -amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist, suggesting the involvement of AMPA receptor stimulation in the effects. Both ( R )-ketamine and ( S )-ketamine exhibited practically the same exposure levels in plasma, brain, and cerebrospinal fluid in mice and rats, and both compounds were rapidly eliminated from plasma (<4-8 hours). The present results confirmed the previous findings that ( R )-ketamine exerted longer-lasting antidepressant effects than ( S )-ketamine in animal models of depression. Moreover, our study is the first to demonstrate that ( R )-ketamine exerted a sustained antidepressant effect even in a model that is refractory to currently prescribed antidepressants. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Extracts from Lentinula edodes (Shiitake) Edible Mushrooms Enriched with Vitamin D Exert an Anti-Inflammatory Hepatoprotective Effect.

PubMed

Drori, Ariel; Shabat, Yehudit; Ben Ya'acov, Ami; Danay, Ofer; Levanon, Dan; Zolotarov, Lidya; Ilan, Yaron

2016-04-01

Vitamin D has been known for its anti-inflammatory properties. Extracts derived from Lentinula edodes (Shiitake) edible mushroom exert an anti-inflammatory effect. These extracts contain high levels of ergosterol, which converts into ergocalciferol (vitamin D2) following exposure to ultraviolet light, followed by absorption and hydroxylation into the active form 25-hydroxyvitamin D [25(OH)D]. To determine the anti-inflammatory effect of overexpression of vitamin D in edible mushrooms, L. edodes mushrooms were exposed to ultraviolet-B light, freeze-dried, followed by measurement of vitamin D2 contents, in their dry weight. C57B1/6 mice were orally treated with vitamin D2-enriched or nonenriched mushroom extract prior and during concanavalin A-immune-mediated liver injury. Exposure to ultraviolet light increased vitamin D2 content in Shiitake edible mushrooms. Following feeding of vitamin D-enriched mushroom extracts to mice with immune-mediated hepatitis, a significant decrease in liver damage was noted. This was shown by a decrease in alanine aminotransferase and aspartate aminotransferase serum levels, a decrease in proportion of mice with severe liver injury, and by improvement in liver histology. These effects were associated with a decrease in serum interferon gamma levels. A synergistic effect was noted between the anti-inflammatory effect of the mushroom extracts and that of vitamin D. Oral administration of vitamin D-enriched L. edodes edible mushroom exerts a synergistic anti-inflammatory effect in the immune-mediated hepatitis. The data support its potential use as safe immunomodulatory adjuvant for the treatment of HCV and nonalcoholic steatohepatitis.

Caffeine ingestion, affect and perceived exertion during prolonged cycling.

PubMed

Backhouse, Susan H; Biddle, Stuart J H; Bishop, Nicolette C; Williams, Clyde

2011-08-01

Caffeine's metabolic and performance effects have been widely reported. However, caffeine's effects on affective states during prolonged exercise are unknown. Therefore, this was examined in the present study. Following an overnight fast and in a randomised, double-blind, counterbalanced design, twelve endurance trained male cyclists performed 90 min of exercise at 70% VO(₂ max) 1h after ingesting 6 mg kg⁻¹ BM of caffeine (CAF) or placebo (PLA). Dimensions of affect and perceived exertion were assessed at regular intervals. During exercise, pleasure ratings were better maintained (F(₃,₃₈)=4.99, P < 0.05) in the CAF trial compared to the PLA trial with significantly higher ratings at 15, 30 and 75 min (all P < 0.05). Perceived exertion increased (F(₃,₃₈) = 19.86, P < 0.01) throughout exercise and values, overall, were significantly lower (F(₁,₁₁) = 9.26, P < 0.05) in the CAF trial compared to the PLA trial. Perceived arousal was elevated during exercise but did not differ between trials. Overall, the results suggest that a moderate dose of CAF ingested 1h prior to exercise maintains a more positive subjective experience during prolonged cycling. This observation may partially explain caffeine's ergogenic effects. Copyright © 2011 Elsevier Ltd. All rights reserved.

Proanthocyanidins and hydrolysable tannins: occurrence, dietary intake and pharmacological effects.

PubMed

Smeriglio, Antonella; Barreca, Davide; Bellocco, Ersilia; Trombetta, Domenico

2017-06-01

Tannins are a heterogeneous group of high MW, water-soluble, polyphenolic compounds, naturally present in cereals, leguminous seeds and, predominantly, in many fruits and vegetables, where they provide protection against a wide range of biotic and abiotic stressors. Tannins exert several pharmacological effects, including antioxidant and free radical scavenging activity as well as antimicrobial, anti-cancer, anti-nutritional and cardio-protective properties. They also seem to exert beneficial effects on metabolic disorders and prevent the onset of several oxidative stress-related diseases. Although the bioavailability and pharmacokinetic data for these phytochemicals are still sparse, gut absorption of these compounds seems to be inversely correlated with the degree of polymerization. Further studies are mandatory to better clarify how these molecules and their metabolites are able to cross the intestinal barrier in order to exert their biological properties. This review summarizes the current literature on tannins, focusing on the main, recently proposed mechanisms of action that underlie their pharmacological and disease-prevention properties, as well as their bioavailability, safety and toxicology. This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc. © 2016 The British Pharmacological Society.

Proanthocyanidins and hydrolysable tannins: occurrence, dietary intake and pharmacological effects

PubMed Central

Smeriglio, Antonella; Bellocco, Ersilia; Trombetta, Domenico

2016-01-01

Tannins are a heterogeneous group of high MW, water‐soluble, polyphenolic compounds, naturally present in cereals, leguminous seeds and, predominantly, in many fruits and vegetables, where they provide protection against a wide range of biotic and abiotic stressors. Tannins exert several pharmacological effects, including antioxidant and free radical scavenging activity as well as antimicrobial, anti‐cancer, anti‐nutritional and cardio‐protective properties. They also seem to exert beneficial effects on metabolic disorders and prevent the onset of several oxidative stress‐related diseases. Although the bioavailability and pharmacokinetic data for these phytochemicals are still sparse, gut absorption of these compounds seems to be inversely correlated with the degree of polymerization. Further studies are mandatory to better clarify how these molecules and their metabolites are able to cross the intestinal barrier in order to exert their biological properties. This review summarizes the current literature on tannins, focusing on the main, recently proposed mechanisms of action that underlie their pharmacological and disease‐prevention properties, as well as their bioavailability, safety and toxicology. Linked Articles This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc PMID:27646690

Growth performance, carcass trait, meat quality and oxidative stability of beef cattle offered alternative silages in a finishing ration.

PubMed

He, L; Yang, J; Chen, W; Zhou, Z; Wu, H; Meng, Q

2018-03-01

As lack of forage resource, alternative roughage sources have been developed for ruminant production and their inclusion would exert a great effect on the dietary nutrition, consequently affecting animal performance. Four silages (corn silage (CS), corn stalk silage (SS), inoculated CS and inoculated SS) were separately offered to 60 Bohai Black cattle (15 cattle/group) during a 24-week finishing period, in which the growth performance, carcass trait, beef quality and oxidative stability of steers were determined. Neither silage material nor silage inoculant exerted a significant effect on the growth performance, carcass trait and oxidative stability of beef cattle (P>0.05). As to beef quality, cattle offered CS had higher (P0.05) on the proximate components and fatty acids profile of beef muscle. There was neither an interaction (P>0.05) between inoculated treatment and silage material. There were no differences (P>0.05) in cholesterol content and meat quality traits in animals fed alternative silages. The collective findings suggest that it is not economical to substitute high-quality forage for relative low-quality forage in a high-concentrate finishing ration of beef cattle and silage inoculant inclusion would not exert a direct effect on animal performance.

Activity-rest schedules in physically demanding work and the variation of responses with age.

PubMed

Kakarot, Nadine; Mueller, Friedrich; Bassarak, Claudia

2012-01-01

Workers in physically demanding occupations require work breaks to recover from exertion. In a laboratory setting, we investigated the impact of ergometer cycling for 7 h in two conditions with an identical total break time but with two different activity-rest schedules. We hypothesised that more frequent but shorter breaks lead to less psychophysical strain and its effects than do less frequent but longer breaks, particularly for older workers. Twenty-nine participants representing three different age groups were tested in both conditions. Heart rate, perceived exertion/tension and feelings of fatigue were assessed and used as dependent variables. Results indicate no general activity-rest differences as well as no age-related differences of break effects under the condition of subjectively equal straining load. However, heart rate was found to be lower at some measurement points in the frequent-short-break condition and perceived exertion was lower in the infrequent-long-break condition. Design of activity-rest schedules in physically demanding occupations is a key issue in the prevention of strain and hence of interest to ergonomists. Our study suggests that breaks during physically demanding work have the same effect if they are frequent and short or infrequent and long, regardless of age.

The crowbar chronicles and other tales

USGS Publications Warehouse

Hough, Susan E.

2009-01-01

The analysis of historical earthquakes often relies heavily on archival accounts describing the effects of shaking on structures and people. Newspaper articles are among the most common, useful, and easily found sources of information. Dramatic earthquake effects are almost certain to have made the news during historic times; the challenge for modern seismologists is not to be overly swayed by articles that focus on the most dramatic rather than the representative effects in a region. At the other end of the spectrum, rarely does a historical newspaper explicitly note that an earthquake was not felt in a certain area: it is not news when nothing happens. When earthquake effects are subtle, the vexing question is often, did they go unreported entirely?

Estrogen Receptors Modulation of Anxiety-Like Behavior

PubMed Central

Borrow, A.P.; Handa, R.J.

2018-01-01

Estrogens exert profound effects on the expression of anxiety in humans and rodents; however, the directionality of these effects varies considerably within both clinical and preclinical literature. It is believed that discrepancies regarding the nature of estrogens’ effects on anxiety are attributable to the differential effects of specific estrogen receptor (ER) subtypes. In this chapter we will discuss the relative impact on anxiety and anxiety-like behavior of each of the three main ERs: ERα, which has a generally anxiogenic effect, ERβ, which has a generally anxiolytic effect, and the G-protein-coupled ER known as GPR30, which has been found to both increase and decrease anxiety-like behavior. In addition, we will describe the known mechanisms by which these receptor subtypes exert their influence on emotional responses, focusing on the hypothalamic–pituitary–adrenal axis and the oxytocinergic and serotonergic systems. The impact of estrogens on the expression of anxiety is likely the result of their combined effects on all of these neurobiological systems. PMID:28061972

Estrogen Receptors Modulation of Anxiety-Like Behavior.

PubMed

Borrow, A P; Handa, R J

2017-01-01

Estrogens exert profound effects on the expression of anxiety in humans and rodents; however, the directionality of these effects varies considerably within both clinical and preclinical literature. It is believed that discrepancies regarding the nature of estrogens' effects on anxiety are attributable to the differential effects of specific estrogen receptor (ER) subtypes. In this chapter we will discuss the relative impact on anxiety and anxiety-like behavior of each of the three main ERs: ERα, which has a generally anxiogenic effect, ERβ, which has a generally anxiolytic effect, and the G-protein-coupled ER known as GPR30, which has been found to both increase and decrease anxiety-like behavior. In addition, we will describe the known mechanisms by which these receptor subtypes exert their influence on emotional responses, focusing on the hypothalamic-pituitary-adrenal axis and the oxytocinergic and serotonergic systems. The impact of estrogens on the expression of anxiety is likely the result of their combined effects on all of these neurobiological systems. © 2017 Elsevier Inc. All rights reserved.

ESC expert statement on the effects on mood of the natural cycle and progestin-only contraceptives.

PubMed

Merki-Feld, G S; Apter, D; Bartfai, G; Grandi, G; Haldre, K; Lech, M; Lertxundi, R; Lete, I; Lobo Abascal, P; Raine, S; Roumen, F; Serfaty, D; Shulman, L P; Skouby, S; Bitzer, J

2017-08-01

Hormonal fluctuations during the natural cycle, as well as progestins used for hormonal contraception, can exert effects on mood especially in vulnerable women. Negative effects of levonorgestrel-releasing intrauterine contraception on mood are rare.

Azoxystrobin, a mitochondrial complex III Qo site inhibitor, exerts beneficial metabolic effects in vivo and in vitro.

PubMed

Gao, An-Hui; Fu, Yan-Yun; Zhang, Kun-Zhi; Zhang, Mei; Jiang, Hao-Wen; Fan, Li-Xia; Nan, Fa-Jun; Yuan, Chong-Gang; Li, Jia; Zhou, Yu-Bo; Li, Jing-Ya

2014-07-01

Several anti-diabetes drugs exert beneficial effects against metabolic syndrome by inhibiting mitochondrial function. Although much progress has been made toward understanding the role of mitochondrial function inhibitors in treating metabolic diseases, the potential effects of these inhibitors on mitochondrial respiratory chain complex III remain unclear. We investigated the metabolic effects of azoxystrobin (AZOX), a Qo inhibitor of complex III, in a high-fat diet-fed mouse model with insulin resistance in order to elucidate the mechanism by which AZOX improves glucose and lipid metabolism at the metabolic cellular level. Acute administration of AZOX in mice increased the respiratory exchange ratio. Chronic treatment with AZOX reduced body weight and significantly improved glucose tolerance and insulin sensitivity in high-fat diet-fed mice. AZOX treatment resulted in decreased triacylglycerol accumulation and down-regulated the expression of genes involved in liver lipogenesis. AZOX increased glucose uptake in L6 myotubes and 3T3-L1 adipocytes and inhibited de novo lipogenesis in HepG2 cells. The findings indicate that AZOX-mediated alterations to lipid and glucose metabolism may depend on AMP-activated protein kinase (AMPK) signaling. AZOX, a Qo inhibitor of mitochondrial respiratory complex III, exerts whole-body beneficial effects on the regulation of glucose and lipid homeostasis in high-fat diet-fed mice. These findings provide evidence that a Qo inhibitor of mitochondrial respiratory complex III could represent a novel approach for the treatment of obesity. Copyright © 2014 Elsevier B.V. All rights reserved.

Expression of IGF-1, IL-27 and IL-35 Receptors in Adjuvant Induced Rheumatoid Arthritis Model.

PubMed

Abdi, Elham; Najafipour, Hamid; Joukar, Siyavash; Dabiri, Shahriar; Esmaeli-Mahani, Saeed; Abbasloo, Elham; Houshmandi, Nasrin; Afsharipour, Abbas

2018-03-01

IGF-1 and certain other cytokines have been shown to exert inflammatory/anti-inflammatory roles in chronic joint diseases. To assess the effect of IGF-1, IL-27 and IL-35, their interaction and their receptor expression in a rheumatoid arthritis model. Freund's adjuvant-induced chronic joint inflammation was operated on 160 male rats. Animals were divided into histopathology and receptor expression groups, each composed of 10 subgroups including; control, vehicle, IGF-1, IL-27, IL-35, their antagonists, IGF-1+IL-27 antagonist and IGF-1+IL-35 antagonist. After two weeks, vehicle or agonist/antagonists were injected into the joint space every other day until day 28 where joint histopathology was performed. The expression of IGF-1, IL-27 and IL-35 receptors were assessed by western blot analysis. IGF-1 did not show pro- or anti- inflammatory functions; endogenous IL-27 and IL-35, on the other hand, exerted inflammatory effects. IL-27 and IL-35 antagonists exerted the highest anti-inflammatory effects. The total inflammation scores were 0.55 ± 0.06, 4.63 ± 0.40, 3.63 ± 0.60, 2.50 ± 0.38 and 1.63 ± 0.40 regarding control, vehicle, IGF-1 Ant., IL-27 Ant. and IL-35 Ant., respectively. IGF-1 receptor expression was reduced in chronic joint inflammation and all three antagonists augmented the IGF-1 receptor expression. IL-27 and IL-35 receptors were up-regulated by chronic joint inflammation. Overall, the results demonstrated the pro-inflammatory role of endogenous IL-27 and IL-35 along with the over expression of their receptors in chronic joint inflammation. IL-27 and IL-35 antagonists exerted the most anti-inflammatory effects and increased IGF-1 receptor expression. These two antagonists may be potential agents for new treatment strategies in chronic joint inflammatory diseases.

Principle component analysis (PCA) for investigation of relationship between population dynamics of microbial pathogenesis, chemical and sensory characteristics in beef slices containing Tarragon essential oil.

PubMed

Alizadeh Behbahani, Behrooz; Tabatabaei Yazdi, Farideh; Shahidi, Fakhri; Mortazavi, Seyed Ali; Mohebbi, Mohebbat

2017-04-01

Principle component analysis (PCA) was employed to examine the effect of the exerted treatments on the beef shelf life as well as discovering the correlations between the studied responses. Considering the variability of the dimensions of the responses, correlation coefficients were applied to form the matrix and extract the eigenvalue. Antimicrobial effect was evaluated on 10 pathogenic microorganisms through the methods of hole-plate diffusion method, disk diffusion method, pour plate method, minimum inhibitory concentration and minimum bactericidal/fungicidal concentration. Antioxidant potential and total phenolic content were examined through the method of 2,2-diphenyl-1-picrylhydrazyl (DPPH) and Folin-Ciocalteu method, respectively. The components were identified through gas chromatography and gas chromatography/mass spectrometry. Barhang seed mucilage (BSM) based edible coating containing 0, 0.5, 1 and 1.5% (w/w) Tarragon (T) essential oil mix were applied on beef slices to control the growth of pathogenic microorganisms. Microbiological (total viable count, psychrotrophic count, Escherichia coli, Staphylococcus aureus and fungi), chemical (thiobarbituric acid, peroxide value and pH) and sensory characteristics (odor, color and overall acceptability) analysis measurements were made during the storage periodically. PCA was employed to examine the effect of the exerted treatments on the beef shelf life as well as discovering the correlations between the studied responses. Considering the variability of the dimensions of the responses, correlation coefficients were applied to form the matrix and extract the eigenvalue. The PCA showed that the properties of the uncoated meat samples on the 9th, 12th, 15th and 18th days of storage are continuously changing independent of the exerted treatments on the other samples. This reveals the effect of the exerted treatments on the samples. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effect of a Patient-Repositioning Device in an Intensive Care Unit On Hospital-Acquired Pressure Injury Occurences and Cost: A Before-After Study.

PubMed

Edger, Melinda

The principal aim of this study was to determine the hospital-acquired pressure injury (HAPI) rate before and after introduction of a repositioning device, measure staff-perceived level of exertion with device use, and assess return on investment. 1 group, before-and-after study. The sample comprised 717 patients cared for in a 17-bed intensive care unit. The study setting was the neonatal intensive care unit at Bon Secours Maryview Medical Center located in the mid-Atlantic United States (Portsmouth, Virginia). A safe patient-handling intervention was implemented as part of a quality improvement initiative. The effect of this system was measured using several outcome measures: (1) HAPI occurrences on the sacral area and buttocks, (2) perceived effort of use by staff, and (3) cost analysis. We used the validated Borg Scale to measure perceived exertion that was ranked on a scale from 6 to 20, where higher scores indicate greater exertion. Cost comparisons were completed before and after introduction of the patient-repositioning system. Cost analysis was determined using internal dollar amounts calculated for each stage of pressure injury. The return on investment was calculated by comparing the cost of HAPIs and the product after the intervention with the costs of HAPIs before the intervention. Analysis revealed a statistically significant reduction in HAPI occurrence from 1.3% to 0% (P = .004) when baseline manual repositioning (standard of care) was compared with use of the repositioning system. Caregivers reported significantly less exertion when using the repositioning device as compared with standard of care repositioning (P < .001). The return on investment was estimated to be $16,911. Use of a repositioning device resulted in significantly reduced HAPIs. Perceived exertion for repositioning the patient with a repositioning device was significantly less than repositioning with standard of care. A cost analysis estimated a return on investment as a result of the intervention on HAPI prevention.

Pharmacological Effects of Active Components of Chinese Herbal Medicine in the Treatment of Alzheimer's Disease: A Review.

PubMed

Wang, Zhi-Yong; Liu, Jian-Gang; Li, Hao; Yang, Hui-Ming

2016-01-01

Alzheimer's disease (AD), the most common neurodegenerative disorder associated with dementia, not only severely decreases the quality of life for its victims, but also brings a heavy economic burden to the family and society. Unfortunately, few chemical drugs designed for clinical applications have reached the expected preventive or therapeutic effect so far, and combined with their significant side-effects, there is therefore an urgent need for new strategies to be developed for AD treatment. Traditional Chinese Medicine has accumulated many experiences in the treatment of dementia during thousands of years of practice; modern pharmacological studies have confirmed the therapeutic effects of many active components derived from Chinese herbal medicines (CHM). Ginsenoside Rg1, extracted from Radix Ginseng, exerts a [Formula: see text]-secretase inhibitor effect so as to decrease A[Formula: see text] aggregation. It can also inhibit the apoptosis of neuron cells. Tanshinone IIA, extracted from Radix Salviae miltiorrhizae, and baicalin, extracted from Radix Scutellariae[Formula: see text] can inhibit the oxidative stress injury in neuronal cells. Icariin, extracted from Epimedium brevicornum, can decrease A[Formula: see text] levels and the hyperphosphorylation of tau protein, and can also inhibit oxidative stress and apoptosis. Huperzine A, extracted from Huperzia serrata, exerts a cholinesterase inhibitor effect. Evodiamine, extracted from Fructus Evodiae, and curcumin, extracted from Rhizoma Curcumae Longae, exert anti-inflammatory actions. Curcumin can act on A[Formula: see text] and tau too. Due to the advantages of multi-target effects and fewer side effects, Chinese medicine is more appropriate for long-term use. In this present review, the pharmacological effects of commonly used active components derived from Chinese herbal medicines in the treatment of AD are discussed.

Differences between novice and experienced caregivers in muscle activity and perceived exertion while repositioning bedridden patients.

PubMed

Daikoku, Rie; Saito, Yayoi

2008-11-01

The aim of this study was to investigate the impact of caregiver knowledge and experience on muscle activity and perceived exertion while repositioning bedridden patients. Subjects were 40- to 65-year-old female caregivers divided into novice and experienced groups. Subjects from both groups performed home-care repositioning techniques on bedridden patients while muscle activity was recorded via electromyogram. Recordings were made from four muscles on the subjects' dominant side: the latissimus dorsi, the biceps brachii, the erector spinae, and the rectus femoris. The subjective burden involved in repositioning was also assessed using the rate of perceived exertion (RPE) and visual analog scales (VAS). Rectus femoris percentage of maximum voluntary contraction (%MVC) values were significantly lower than latissimus dorsi, erector spinae, and biceps brachii values in the novice group. %MVC values from the latissimus dorsi and biceps brachii were significantly higher among the novice group compared to the experienced group. RPE ratings from the novice group were significantly higher than those of the experienced group, and there was a non-significant trend for higher VAS values for the low back, arms, and legs in the novice group compared to the experienced group. Novice caregivers tended to change the patient's position by pulling with the upper limbs without using the lower limbs. In contrast, experienced caregivers exerted less energy by communicating with the patient and utilizing the patient's own movements. They used large, distributed muscle groups that effectively harnessed body mechanics and prevented excess exertion.

Solar powered automobile automation for heatstroke prevention

NASA Astrophysics Data System (ADS)

Singh, Navtej Swaroop; Sharma, Ishan; Jangid, Santosh

2016-03-01

Heatstroke inside a car has been critical problem in every part of the world. Non-exertional heat stroke results from exposure to a high environmental temperature. Exertional heat stroke happens from strenuous exercise. This paper presents a solution for this fatal problem and proposes an embedded solution, which is cost effective and shows the feasibility in implementation. The proposed system consists of information sharing platform, interfacing of sensors, Global System Mobile (GSM), real time monitoring system and the system is powered by the solar panel. The system has been simulated and tested with experimental setup.

Adenosine and Ischemic Preconditioning

PubMed Central

Liang, Bruce T.; Swierkosz, Tomasz A.; Herrmann, Howard C.; Kimmel, Stephen; Jacobson, Kenneth A.

2012-01-01

Adenosine is released in large amounts during myocardial ischemia and is capable of exerting potent cardioprotective effects in the heart. Although these observations on adenosine have been known for a long time, how adenosine acts to achieve its anti-ischemic effect remains incompletely understood. However, recent advances on the chemistry and pharmacology of adenosine receptor ligands have provided important and novel information on the function of adenosine receptor subtypes in the cardiovascular system. The development of model systems for the cardiac actions of adenosine has yielded important insights into its mechanism of action and have begun to elucidate the sequence of signalling events from receptor activation to the actual exertion of its cardioprotective effect. The present review will focus on the adenosine receptors that mediate the potent anti-ischemic effect of adenosine, new ligands at the receptors, potential molecular signalling mechanisms downstream of the receptor, mediators for cardioprotection, and possible clinical applications in cardiovascular disorders. PMID:10607860

Neuroendocrine Consequences of Androgen Excess in Female Rodents

PubMed Central

Foecking, Eileen M.; McDevitt, Melissa A.; Acosta-Martínez, Maricedes; Horton, Teresa H.; Levine, Jon E.

2008-01-01

Androgens exert significant organizational and activational effects on the nervous system and behavior. Despite the fact that female mammals generally produce low levels of androgens, relative to the male of the same species, increasing evidence suggests that androgens can exert profound effects on the normal physiology and behavior of females during fetal, neonatal, and adult stages of life. This review examines the effects of exposure to androgens at three stages of development – as an adult, during early postnatal life and as a fetus, on reproductive hormone secretions in female rats. We examine the effects of androgen exposure both as a model of neuroendocrine sexual differentiation and with respect to the role androgens play in the normal female. We then discuss the hypothesis that androgens may cause epigenetic modification of estrogen target genes in the brain. Finally we consider the clinical consequences of excess androgen exposure in women. PMID:18374922

Phloretin exerts hypoglycemic effect in streptozotocin-induced diabetic rats and improves insulin resistance in vitro.

PubMed

Shen, Xin; Zhou, Nan; Mi, Le; Hu, Zishuo; Wang, Libin; Liu, Xueying; Zhang, Shengyong

2017-01-01

The present study investigated the possible antiobesity and hypoglycemic effects of phloretin (Ph). In an attempt to discover the hypoglycemic effect and potential mechanism of Ph, we used the streptozotocin-induced diabetic rats and (L6) myotubes. Daily oral treatment with Ph for 4 weeks significantly ( P <0.05) reduced postprandial blood glucose and improved islet injury and lipid metabolism. Glucose consumption and glucose tolerance were improved by Ph via GOD-POD method. Western blot results revealed that the expression of Akt, PI3K, IRS-1, and GLUT4 were upregulated in skeletal muscle of type 2 diabetes (T2D) rats and in L6 myotubes by Ph. The immunofluorescence studies confirmed that Ph improved the translocation of GLUT4 in L6 myotubes. Ph exerted hypoglycemic effects in vivo and in vitro, hence it may play an important role in the management of diabetes.

Phloretin exerts hypoglycemic effect in streptozotocin-induced diabetic rats and improves insulin resistance in vitro

PubMed Central

Shen, Xin; Zhou, Nan; Mi, Le; Hu, Zishuo; Wang, Libin; Liu, Xueying; Zhang, Shengyong

2017-01-01

The present study investigated the possible antiobesity and hypoglycemic effects of phloretin (Ph). In an attempt to discover the hypoglycemic effect and potential mechanism of Ph, we used the streptozotocin-induced diabetic rats and (L6) myotubes. Daily oral treatment with Ph for 4 weeks significantly (P<0.05) reduced postprandial blood glucose and improved islet injury and lipid metabolism. Glucose consumption and glucose tolerance were improved by Ph via GOD–POD method. Western blot results revealed that the expression of Akt, PI3K, IRS-1, and GLUT4 were upregulated in skeletal muscle of type 2 diabetes (T2D) rats and in L6 myotubes by Ph. The immunofluorescence studies confirmed that Ph improved the translocation of GLUT4 in L6 myotubes. Ph exerted hypoglycemic effects in vivo and in vitro, hence it may play an important role in the management of diabetes. PMID:28223777

Environmental epigenetics: a role in endocrine disease?

PubMed

Fleisch, Abby F; Wright, Robert O; Baccarelli, Andrea A

2012-10-01

Endocrine disrupting chemicals that are structurally similar to steroid or amine hormones have the potential to mimic endocrine endpoints at the receptor level. However, more recently, epigenetic-induced alteration in gene expression has emerged as an alternative way in which environmental compounds may exert endocrine effects. We review concepts related to environmental epigenetics and relevance for endocrinology through three broad examples: 1) effect of early-life nutritional exposures on future obesity and insulin resistance, 2) effect of lifetime environmental exposures such as ionizing radiation on endocrine cancer risk, and 3) potential for compounds previously classified as endocrine disrupting to additionally or alternatively exert effects through epigenetic mechanisms. The field of environmental epigenetics is still nascent, and additional studies are needed to confirm and reinforce data derived from animal models and preliminary human studies. Current evidence suggests that environmental exposures may significantly impact expression of endocrine-related genes and thereby affect clinical endocrine outcomes.

[Modulating effect of weak combined magnetic fields on duration of mealworm beetle Tenebrio molitor metamorphosis stage].

PubMed

Novikov, V V; Sheĭman, I M; Iablokova, E V; Fesenko, E E

2014-01-01

It is shown that an exposure of pupae of the mealworm beetle Tenebrio molitor to the combined static (42 μT) and very weak alternating (250 nT) magnetic fields exerts different influence, depending on the frequency of the alternating magnetic field, on duration of metamorphosis processes in these insects. For instance, an exposure of pupae to weak combined magnetic fields, adjusted to the frequency of ion cyclotron resonance for glutaminic acid (4,4 Hz), stimulates metamorphosis process--a transitional stage from pupae to imago lasts shorter. An inhibiting effect was observed when adjusted to the frequency of ion cyclotron resonance for Ca2 (32,2 Hz). At some frequencies this effect is not seen. For instance, an exposure at a frequency of ion cyclotron resonance for K+ (16,5 Hz) exerts no noticeable effect on the duration of the pupal metamorphosis stage.

Experimental support for the effects of a probiotic/digestive enzyme supplement on serum cholesterol concentrations and the intestinal microbiome.

PubMed

Ichim, Thomas E; Patel, Amit N; Shafer, Kim A

2016-06-22

Elevated levels of blood cholesterol are associated with cardiovascular disease, a leading cause of morbidity and mortality worldwide. Current therapies for addressing elevated blood cholesterol can be inadequate, ineffective or associated with side effects; therefore, the search for additional therapies is ongoing. This study evaluated Daily Body Restore (DBR), a proprietary blend of 9 probiotic organisms of the genera Lactobacillus and Bifidobacterium, and 10 digestive enzymes, for its effects on cholesterol metabolism using an in vitro system and a mouse model. We used a murine model of hypercholesterolemia induced by a high fat diet to evaluate the effects of DBR on blood cholesterol concentrations. Hypercholesterolemic mice were supplemented with DBR in their drinking water for 8 weeks and compared to control mice given low fat diets or unsupplemented high fat diets. To evaluate the effects of DBR on the activity of gut microbiota in vitro, the Shime(®) system consisting of sequential colon reactors was supplemented with DBR for analysis of short chain fatty acid production. Analysis of hypercholesterolemic mice after 4 and 8 weeks of DBR supplementation revealed significant decreases in blood concentrations of low-density lipoprotein (LDL) and increases in high-density lipoprotein (HDL) while triglyceride concentrations were unaltered. Specifically, after 4 weeks of DBR supplementation, there was a 47 % decrease in LDL and a 32 % increase in HDL in peripheral blood compared to unsupplemented, high fat diet-fed mice. After 8 weeks of DBR treatment, LDL concentrations were dramatically reduced by 78 % and HDL was increased by 52 % relative to control mice. Addition of DBR to the Shime(®) system led to significantly increased production of propionate in colon reactors, indicative of microbial production of short chain fatty acids known to inhibit cholesterol synthesis. DBR, a probiotic and digestive enzyme supplement, lowered harmful LDL and increased HDL levels in a mouse model and also exerted in vitro effects consistent with cholesterol-lowering activity. Given the magnitude of the effects of DBR, these findings are promising for clinical implementation of DBR for treating hypercholesterolemia.

Self-perceived successful weight regulators are less affected by self-regulatory depletion in the domain of eating behavior.

PubMed

Friese, Malte; Engeler, Michèle; Florack, Arnd

2015-01-01

Weight loss and maintenance goals are highly prevalent in many affluent societies, but many weight regulators are not successful in the long term. Research started to reveal psychological mechanisms that help successful weight regulators in being successful. In the present study, we tested the assumption that these mechanisms facilitate successful self-regulation particularly under conditions of self-regulatory depletion. Participants exerted or did not exert self-control in a first task before engaging in a taste test of a tempting but unhealthy food. Participants who had initially exerted self-control ate more than participants in the control condition. This effect was reduced in self-perceived successful weight regulators as compared to perceived unsuccessful self-regulators. A reduced susceptibility to self-regulatory depletion may be an important contributor to long-term weight regulation success in successful weight regulators. Copyright © 2014 Elsevier Ltd. All rights reserved.

Effects of rest interval length on Smith machine bench press performance and perceived exertion in trained men.

PubMed

Tibana, Ramires A; Vieira, Denis C L; Tajra, Vitor; Bottaro, Martim; de Salles, Belmiro F; Willardson, Jeffrey M; Prestes, Jonato

2013-12-01

This study compared two different rest intervals (RI) between sets of resistance exercise. Ten resistance-trained men (M age = 24.3, SD = 3.5 yr.; M weigh t= 80.0 kg, SD = 15.3; M height = 1.75 m, SD = 0.04) performed five sets of Smith machine bench presses at 60% of one repetition maximum, either with 1.5 min. or 3 min. RI between sets. Their repetition performance, total training volume, velocity, fatigue, rating of perceived exertion, and muscular power were measured. All of these measures indicated that performance was significantly better and fatigue was significantly lower in the 3 min. RI as compared with the 1.5 min. RI, except the rating of perceived exertion which did not show a significant difference. A longer RI between sets promotes superior performance for the bench press.

Perceived exertion. Antecedents and applications.

PubMed

Watt, B; Grove, R

1993-04-01

The field of perceived exertion has largely concerned itself with the problem of identifying the primary antecedents to this psychophysiological phenomenon. A vast literature has evolved addressing this problem, but it is fraught with contradictions. At this stage a comprehensive theory of perceived exertion does not exist. It is generally accepted that perception of exertion is dominated by physiological determinants. Physiological sensory cues have been separated into 2 categories: local factors (sensations from the working muscles and joints), and central factors (sensations from the cardiopulmonary system). Major reviews in this area generally agree that local factors dominate perception of exertion. Recent work in perceived exertion has placed an emphasis on examining the contributing psychological factors. Research into the psychological factors affecting perceived exertion has been highly fragmented with no apparent theoretical framework as a base. At the same time it is clear that an integration of psychological and physiological variables is required to obtain theoretically meaningful knowledge of this multidimensional construct. The assumed dominance of physiological factors has been challenged by the contention that in field situations, in which a variety of social psychological influences operate, psychological determinants of perceived exertion may be vastly more influential than previously estimated. Identification of the primary determinants of perceived exertion and knowledge of how these factors are integrated is vital for a concrete theory of perceived exertion to evolve.

Effects of an Environmentally-relevant Mixture of Pyrethroid Insecticides on Spontaneous Activity in Primary Cortical Networks on Microelectrode Arrays

EPA Science Inventory

Pyrethroid insecticides exert their insecticidal and toxicological effects primarily by disrupting voltage-gated sodium channel (VGSC) function, resulting in altered neuronal excitability. Numerous studies of individual pyrethroids have characterized effects on mammalian VGSC fun...

Vasorelaxing effects and inhibition of nitric oxide in macrophages by new iron-containing carbon monoxide-releasing molecules (CO-RMs).

PubMed

Motterlini, Roberto; Sawle, Philip; Hammad, Jehad; Mann, Brian E; Johnson, Tony R; Green, Colin J; Foresti, Roberta

2013-02-01

Carbon monoxide-releasing molecules (CO-RMs) are a class of organometallo carbonyl complexes capable of delivering controlled quantities of CO gas to cells and tissues thus exerting a broad spectrum of pharmacological effects. Here we report on the chemical synthesis, CO releasing properties, cytotoxicity profile and pharmacological activities of four novel structurally related iron-allyl carbonyls. The major difference among the new CO-RMs tested was that three compounds (CORM-307, CORM-308 and CORM-314) were soluble in dimethylsulfoxide (DMSO), whereas a fourth one (CORM-319) was rendered water-soluble by reacting the iron-carbonyl with hydrogen tetrafluoroborate. We found that despite the fact all compounds liberated CO, CO-RMs soluble in DMSO caused a more pronounced toxic effect both in vascular and inflammatory cells as well as in isolated vessels. More specifically, iron carbonyls soluble in DMSO released CO with a fast kinetic and displayed a marked cytotoxic effect in smooth muscle cells and RAW 247.6 macrophages despite exerting a rapid and pronounced vasorelaxation ex vivo. In contrast, CORM-319 that is soluble in water and liberated CO with a slower rate, preserved smooth muscle cell viability, relaxed aortic tissue and exerted a significant anti-inflammatory effect in macrophages challenged with endotoxin. These data suggest that iron carbonyls can be used as scaffolds for the design and synthesis of pharmacologically active CO-RMs and indicate that increasing water solubility and controlling the rate of CO release are important parameters for limiting their potential toxic effects. Copyright © 2012 Elsevier Ltd. All rights reserved.

Correlates of healthcare and financial decision making among older adults without dementia.

PubMed

Stewart, Christopher C; Yu, Lei; Wilson, Robert S; Bennett, David A; Boyle, Patricia A

2018-03-22

Healthcare and financial decision making among older persons has been previously associated with cognition, health and financial literacy, and risk aversion; however, the manner by which these resources support decision making remains unclear, as past studies have not systematically investigated the pathways linking these resources with decision making. In the current study, we use path analysis to examine the direct and indirect pathways linking age, education, cognition, literacy, and risk aversion with decision making. We also decomposed literacy into its subcomponents, conceptual knowledge and numeracy, in order to examine their associations with decision making. Participants were 937 community-based older adults without dementia from the Rush Memory and Aging Project who completed a battery of cognitive tests and assessments of healthcare and financial decision making, health and financial literacy, and risk aversion. Age and education exerted effects on decision making, but nearly two thirds of their effects were indirect, working mostly through cognition and literacy. Cognition exerted a strong direct effect on decision making and a robust indirect effect working primarily through literacy. Literacy also exerted a powerful direct effect on decision making, as did its subcomponents, conceptual knowledge and numeracy. The direct effect of risk aversion was comparatively weak. In addition to cognition, health and financial literacy emerged as independent and primary correlates of healthcare and financial decision making. These findings suggest specific actions that might be taken to optimize healthcare and financial decision making and, by extension, improve health and well-being in advanced age. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Impact of plant extracts tested in attention-deficit/hyperactivity disorder treatment on cell survival and energy metabolism in human neuroblastoma SH-SY5Y cells.

PubMed

Schmidt, Andreas Johannes; Krieg, Jürgen-Christian; Hemmeter, Ulrich Michael; Kircher, Tilo; Schulz, Eberhard; Clement, Hans-Willi; Heiser, Philip

2010-10-01

Plant extracts such as Hypericum perforatum and Pycnogenol have been tested as alternatives to the classical ADHD drugs. It has been possible to describe neuroprotective effects of such plant extracts. A reduction of ADHD symptoms could be shown in clinical studies after the application of Pycnogenol, which is a pine bark extract. The impacts of the standardized herbal extracts Hypericum perforatum, Pycnogenol and Enzogenol up to a concentration of 5000 ng/mL on cell survival and energy metabolism in human SH-SY5Y neuroblastoma cells has been investigated in the present examination. Hypericum perforatum significantly decreased the survival of cells after treatment with a concentration of 5000 ng/mL, whereas lower concentrations exerted no significant effects. Pycnogenol( induced a significant increase of cell survival after incubation with a concentration of 32.25 ng/mL and a concentration of 250 ng/mL. Other applied concentrations of Pycnogenol failed to exert significant effects. Treatment with Enzogenol did not lead to significant changes in cell survival.Concerning energy metabolism, the treatment of cells with a concentration of 5000 ng/mL Hypericum perforatum led to a significant increase of ATP levels, whereas treatment with a concentration of 500 ng/mL had no significant effect. Incubation of cells with Pycnogenol and Enzogenol exerted no significant effects.None of the tested substances caused any cytotoxic effect when used in therapeutically relevant concentrations. Copyright © 2010 John Wiley & Sons, Ltd.

Protective effects of peroxisome proliferator-activated receptor agonists on human podocytes: proposed mechanisms of action

PubMed Central

Miglio, Gianluca; Rosa, Arianna Carolina; Rattazzi, Lorenza; Grange, Cristina; Camussi, Giovanni; Fantozzi, Roberto

2012-01-01

BACKGROUND AND PURPOSE Peroxisome proliferator-activated receptor (PPAR) agonists exert anti-albuminuric effects. However, the nephroprotective effects of these drugs remain to be fully understood. We have investigated whether gemfibrozil, GW0742 and pioglitazone protect human podocytes against nutrient deprivation (ND)-induced cell death and the role of mitochondrial biogenesis as a cytoprotective process. EXPERIMENTAL APPROACH Immortalized human podocytes were pre-treated with the PPAR agonists and exposed to ND (5 h) under normoxia, hypoxia or in the presence of pyruvate. Cell death was measured at the end of the ND and of the recovery phase (24 h). Mitochondrial mass, cytochrome c oxidase (COX) subunits 1 and 4 were measured as markers of mitochondrial cell content, while membrane potential as an index of mitochondrial function. PGC-1α, NRF1 and Tfam expression was studied, as crucial regulators of mitochondrial biogenesis. KEY RESULTS Cell pre-treatment with gemfibrozil, GW0742, or pioglitazone significantly decreased the ND-induced cell loss, necrosis and apoptosis. These effects were attenuated by hypoxia and potentiated by pyruvate. Pre-treatment with these drugs significantly increased mitochondrial cell content, while it did not affect mitochondrial function. In all these experiments pioglitazone exerted significantly larger effects than gemfibrozil or GW0742. CONCLUSIONS AND IMPLICATIONS Gemfibrozil, GW0742 and pioglitazone may exert direct protective effects on human podocytes. Mitochondrial biogenesis is a cell response to the PPAR agonists related to their cytoprotective activity. These results provide a mechanistic support to the clinical evidence indicating PPAR agonists as disease-modifying agents for glomerular diseases. PMID:22594945

[Comparative evaluation of the efficiency of the effect of very high frequency electromagnetic waves on platelet functional activity].

PubMed

Kirichuk, V F; Maĭborodin, A V; Volin, M V; Krenitskiĭ, A P; Tupikin, V D

2001-01-01

A comparative analysis was made of the effect of two kinds of EMI MMD-radiation: EMI MMD-waves, generated by a vehicle "Jav-1 M" (42.2 and 53.5 HHz), and EMI MMD-waves exerting influence with frequencies of molecular spectrum of radiation and nitric oxide absorption (150.176-150.644 HHz), obtained with a specially created generator, with respect to their influence on the functional ability of platelets of unstable angina pectoris patients. It was shown that in vitro EMI MMD-fluctuations with frequencies of molecular spectrum of radiation and nitric oxide absorption exert a stronger inhibiting influence on the functional activity of platelets of unstable angina pectoris patients. Features of the action of various kinds of EMI MMD-effect on the activative-high-speed characteristics of platelet aggregation are shown.

Effect of electromagnetic waves on human reproduction.

PubMed

Wdowiak, Artur; Mazurek, Paweł A; Wdowiak, Anita; Bojar, Iwona

2017-03-31

Electromagnetic radiation (EMR) emitting from the natural environment, as well as from the use of industrial and everyday appliances, constantly influence the human body. The effect of this type of energy on living tissues may exert various effects on their functioning, although the mechanisms conditioning this phenomenon have not been fully explained. It may be expected that the interactions between electromagnetic radiation and the living organism would depend on the amount and parameters of the transmitted energy and type of tissue exposed. Electromagnetic waves exert an influence on human reproduction by affecting the male and female reproductive systems, the developing embryo, and subsequently, the foetus. Knowledge concerning this problem is still being expanded; however, all the conditionings of human reproduction still remain unknown. The study presents the current state of knowledge concerning the problem, based on the latest scientific reports.

Does Child Temperament Play a Role in the Association Between Parenting Practices and Child Attention Deficit/Hyperactivity Disorder?

PubMed

Ullsperger, Josie M; Nigg, Joel T; Nikolas, Molly A

2016-01-01

Ineffective parenting practices may maintain or exacerbate attention deficit/hyperactivity disorder (ADHD) symptoms and shape subsequent development of disruptive behavior disorders (DBD's) in youth with ADHD. Recent theoretical models have suggested that parenting may exert effects on ADHD via its role in child temperament. The current study aimed to evaluate the indirect effects of parenting dimensions on child ADHD symptoms via child temperament. Youth ages 6-17 years (N = 498; 50.4 % ADHD, 55 % male) completed a multi-stage, multi-informant assessment that included parent, child, and teacher report measures of parenting practices, child temperament, and ADHD symptoms. Statistical models examined the direct and indirect effects of maternal and paternal involvement, poor supervision, and inconsistent discipline on inattention and hyperactivity-impulsivity via child temperament and personality traits. Results indicated differential patterns of effect for negative and positive parenting dimensions. First, inconsistent discipline exerted indirect effects on both ADHD symptom dimensions via child conscientiousness, such that higher levels of inconsistency predicted lower levels of conscientiousness, which in turn, predicted greater ADHD symptomatology. Similarly, poor supervision also exerted indirect effects on inattention via child conscientiousness as well as significant indirect effects on hyperactivity-impulsivity via its impact on both child reactive control and conscientiousness. In contrast, primarily direct effects of positive parenting (i.e., involvement) on ADHD emerged. Secondary checks revealed that similar pathways may also emerge for comorbid disruptive behavior disorders. Current findings extend upon past work by examining how parenting practices influence child ADHD via with-in child mechanisms and provide support for multi-pathway models accounting for heterogeneity in the disorder.

Supraphysiological doses of performance enhancing anabolic-androgenic steroids exert direct toxic effects on neuron-like cells

PubMed Central

Basile, John R.; Binmadi, Nada O.; Zhou, Hua; Yang, Ying-Hua; Paoli, Antonio; Proia, Patrizia

2013-01-01

Anabolic-androgenic steroids (AAS) are lipophilic hormones often taken in excessive quantities by athletes and bodybuilders to enhance performance and increase muscle mass. AAS exert well known toxic effects on specific cell and tissue types and organ systems. The attention that androgen abuse has received lately should be used as an opportunity to educate both athletes and the general population regarding their adverse effects. Among numerous commercially available steroid hormones, very few have been specifically tested for direct neurotoxicity. We evaluated the effects of supraphysiological doses of methandienone and 17-α-methyltestosterone on sympathetic-like neuron cells. Vitality and apoptotic effects were analyzed, and immunofluorescence staining and western blot performed. In this study, we demonstrate that exposure of supraphysiological doses of methandienone and 17-α-methyltestosterone are toxic to the neuron-like differentiated pheochromocytoma cell line PC12, as confirmed by toxicity on neurite networks responding to nerve growth factor and the modulation of the survival and apoptosis-related proteins ERK, caspase-3, poly (ADP-ribose) polymerase and heat-shock protein 90. We observe, in contrast to some previous reports but in accordance with others, expression of the androgen receptor (AR) in neuron-like cells, which when inhibited mitigated the toxic effects of AAS tested, suggesting that the AR could be binding these steroid hormones to induce genomic effects. We also note elevated transcription of neuritin in treated cells, a neurotropic factor likely expressed in an attempt to resist neurotoxicity. Taken together, these results demonstrate that supraphysiological exposure to the AAS methandienone and 17-α-methyltestosterone exert neurotoxic effects by an increase in the activity of the intrinsic apoptotic pathway and alterations in neurite networks. PMID:23675320

Does Child Temperament Play a Role in the Association Between Parenting Practices and Child Attention Deficit/Hyperactivity Disorder?

PubMed Central

Nigg, Joel T.; Nikolas, Molly A.

2015-01-01

Ineffective parenting practices may maintain or exacerbate attention deficit/hyperactivity disorder (ADHD) symptoms and shape subsequent development of disruptive behavior disorders (DBD’s) in youth with ADHD. Recent theoretical models have suggested that parenting may exert effects on ADHD via its role in child temperament. The current study aimed to evaluate the indirect effects of parenting dimensions on child ADHD symptoms via child temperament. Youth ages 6–17 years (N=498; 50.4 % ADHD, 55 % male) completed a multi-stage, multi-informant assessment that included parent, child, and teacher report measures of parenting practices, child temperament, and ADHD symptoms. Statistical models examined the direct and indirect effects of maternal and paternal involvement, poor supervision, and inconsistent discipline on inattention and hyperactivity-impulsivity via child temperament and personality traits. Results indicated differential patterns of effect for negative and positive parenting dimensions. First, inconsistent discipline exerted indirect effects on both ADHD symptom dimensions via child conscientiousness, such that higher levels of inconsistency predicted lower levels of conscientiousness, which in turn, predicted greater ADHD symptomatology. Similarly, poor supervision also exerted indirect effects on inattention via child conscientiousness as well as significant indirect effects on hyperactivity-impulsivity via its impact on both child reactive control and conscientiousness. In contrast, primarily direct effects of positive parenting (i.e., involvement) on ADHD emerged. Secondary checks revealed that similar pathways may also emerge for comorbid disruptive behavior disorders. Current findings extend upon past work by examining how parenting practices influence child ADHD via within child mechanisms and provide support for multi-pathway models accounting for heterogeneity in the disorder. PMID:25684446

48 CFR 3.401 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-10-01

... for the purpose of securing business, that neither exerts nor proposes to exert improper influence to... contract or contracts through improper influence. Bona fide employee, means a person, employed by a... performance, who neither exerts nor proposes to exert improper influence to solicit or obtain Government...

20 CFR 220.132 - Physical exertion requirements.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 20 Employees' Benefits 1 2010-04-01 2010-04-01 false Physical exertion requirements. 220.132... ACT DETERMINING DISABILITY Vocational Considerations § 220.132 Physical exertion requirements. To determine the physical exertion requirements of work in the national economy, jobs are classified as...

20 CFR 220.132 - Physical exertion requirements.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 20 Employees' Benefits 1 2013-04-01 2012-04-01 true Physical exertion requirements. 220.132... ACT DETERMINING DISABILITY Vocational Considerations § 220.132 Physical exertion requirements. To determine the physical exertion requirements of work in the national economy, jobs are classified as...

20 CFR 220.132 - Physical exertion requirements.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 20 Employees' Benefits 1 2011-04-01 2011-04-01 false Physical exertion requirements. 220.132... ACT DETERMINING DISABILITY Vocational Considerations § 220.132 Physical exertion requirements. To determine the physical exertion requirements of work in the national economy, jobs are classified as...

20 CFR 220.132 - Physical exertion requirements.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 20 Employees' Benefits 1 2014-04-01 2012-04-01 true Physical exertion requirements. 220.132... ACT DETERMINING DISABILITY Vocational Considerations § 220.132 Physical exertion requirements. To determine the physical exertion requirements of work in the national economy, jobs are classified as...

20 CFR 220.132 - Physical exertion requirements.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 20 Employees' Benefits 1 2012-04-01 2012-04-01 false Physical exertion requirements. 220.132... ACT DETERMINING DISABILITY Vocational Considerations § 220.132 Physical exertion requirements. To determine the physical exertion requirements of work in the national economy, jobs are classified as...

Fat and fibre interfere with the dramatic effect that nanoemulsified d-limonene has on the heat resistance of Listeria monocytogenes.

PubMed

Maté, Javier; Periago, Paula M; Ros-Chumillas, María; Grullón, Coralin; Huertas, Juan Pablo; Palop, Alfredo

2017-04-01

The application of d-limonene in form of nanoemulsion has been proved to reduce dramatically the thermal resistance of Listeria monocytogenes in culture media. The present research shows very promising results on the application in food products. The thermal resistance of L. monocytogenes was reduced 90 times when 0.5 mM nanoemulsified d-limonene was added to apple juice. This is the biggest reduction in the heat resistance of a microorganism caused by an antimicrobial described ever. However, no effect was found in carrot juice. A carrot juice system was prepared in an attempt to unravel which juice constituents were responsible for the lack of effect. When fat and fibre were not included in the carrot juice system formulation, the thermal resistance of L. monocytogenes was, again, dramatically reduced in presence of nanoemulsified d-limonene, so these components were shown to interfere with the effect. Once this interaction with food constituents becomes solved, the addition of nanoemulsified antimicrobials would allow to reduce greatly the intensity of the thermal treatments currently applied in the food processing industry. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Sickle Cell Trait, Rhabdomyolysis, and Mortality among U.S. Army Soldiers

PubMed Central

Nelson, D. Alan; Deuster, Patricia A.; Carter, Robert; Hill, Owen T.; Wolcott, Vickee L.; Kurina, Lianne M.

2016-01-01

Background Studies have suggested that sickle cell trait elevates the risks of exertional rhabdomyolysis and death. We conducted a study of sickle cell trait in relation to these outcomes, controlling for known risk factors for exertional rhabdomyolysis, in a large population of active persons who had undergone laboratory tests for hemoglobin AS (HbAS) and who were subject to exertional-injury precautions. Methods We used Cox proportional-hazards models to test whether the risks of exertional rhabdomyolysis and death varied according to sickle cell trait status among 47,944 black soldiers who had undergone testing for HbAS and who were on active duty in the U.S. Army between January 2011 and December 2014. We used the Stanford Military Data Repository, which contains comprehensive medical and administrative data on all active-duty soldiers. Results There was no significant difference in the risk of death among soldiers with sickle cell trait, as compared with those without the trait (hazard ratio, 0.99; 95% confidence interval [CI], 0.46 to 2.13; P = 0.97), but the trait was associated with a significantly higher adjusted risk of exertional rhabdomyolysis (hazard ratio, 1.54; 95% CI, 1.12 to 2.12; P = 0.008). This effect was similar in magnitude to that associated with tobacco use, as compared with no use (hazard ratio, 1.54; 95% CI, 1.23 to 1.94; P<0.001), and to that associated with having a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 30.0 or more, as compared with a BMI of less than 25.0 (hazard ratio, 1.39; 95% CI, 1.04 to 1.86; P = 0.03). The effect was less than that associated with recent use of a statin, as compared with no use (hazard ratio, 2.89; 95% CI, 1.51 to 5.55; P = 0.001), or an antipsychotic agent (hazard ratio, 3.02; 95% CI, 1.34 to 6.82; P = 0.008). Conclusions Sickle cell trait was not associated with a higher risk of death than absence of the trait, but it was associated with a significantly higher risk of exertional rhabdomyolysis. (Funded by the National Heart, Lung, and Blood Institute and the Uniformed Services University of the Health Sciences.) PMID:27518662

Lactate and pH evaluation in exhausted humans with prolonged TASER X26 exposure or continued exertion.

PubMed

Ho, Jeffrey D; Dawes, Donald M; Cole, Jon B; Hottinger, Julie C; Overton, Kenneth G; Miner, James R

2009-09-10

Safety concerns about TASER Conducted Electrical Weapon (CEW) use and media reports of deaths after exposure have been expressed. CEWs are sometimes used on exhausted subjects to end resistance. The alternative is often a continued struggle. It is unclear if CEW use is metabolically different than allowing a continued struggle. We sought to determine if CEW exposure on exhausted humans caused worsening acidosis when compared with continued exertion. This was a prospective study of human volunteers recruited during a CEW training course. Volunteers were from several different occupations and represented a wide range of ages and body mass index characteristics. Medical histories, baseline pH and lactate values were obtained. Patients were assigned to one of four groups: 2 control groups consisting of Exertion only and CEW Exposure only, and the 2 experimental groups that were Exertion plus CEW Exposure and Exertion plus additional Exertion. Blood sampling occurred after Exertion and after any CEW exposure. This was repeated every 2-min until 20 min after protocol completion. Descriptive statistics were used to compare the four groups. The experimental groups and the control groups were compared individually at each time point using Wilcoxon rank sum tests. Lactate and pH association was assessed using multiple linear regression. Forty subjects were enrolled. There were no median pH or lactate differences between CEW Exposure groups at baseline, or between Exertion protocol groups immediately after completion. The CEW Exposure only group had higher pH and lower lactate values at all time points after exposure than the Exertion only group. After completing the Exertion protocol, there was no difference in the pH or lactate values between the continued Exertion group and the CEW Exposure group at any time points. Subjects who had CEW Exposure only had higher pH and lower lactate values than subjects who completed the Exertion protocol only. CEW exposure does not appear to worsen acidosis in exhausted subjects any differently than briefly continued exertion.

Motivational incentives lead to a strong increase in lateral prefrontal activity after self-control exertion

PubMed Central

Luethi, Matthias S.; Binder, Julia; Boesiger, Peter; Luechinger, Roger; Rasch, Björn

2016-01-01

Self-control is key to success in life. Initial acts of self-control temporarily impair subsequent self-control performance. Why such self-control failures occur is unclear, with prominent models postulating a loss of a limited resource vs a loss of motivation, respectively. Here, we used functional magnetic resonance imaging to identify the neural correlates of motivation-induced benefits on self-control. Participants initially exerted or did not exert self-control. In a subsequent Stroop task, participants performed worse after exerting self-control, but not if they were motivated to perform well by monetary incentives. On the neural level, having exerted self-control resulted in decreased activation in the left inferior frontal gyrus. Increasing motivation resulted in a particularly strong activation of this area specifically after exerting self-control. Thus, after self-control exertion participants showed more prefrontal neural activity without improving performance beyond baseline level. These findings suggest that impaired performance after self-control exertion may not exclusively be due to a loss of motivation. PMID:27217108

[Study of the radioprotective effects of TMG on teratogenic malformations in irradiated mice].

PubMed

Gu, Y; Hasegawa, T; Kim, H; Suzuki, I; Mori, T; Yamamoto, Y

2000-12-01

ICR mice fetuses in the organogenesis stage were used to clarify experimentally the mechanism of the protective effect of vitamin E derivant (TMG: 2-(alpha-D-Glucopyranosyl) methyl-2, -5, -7, -8-Teramethylchorman-6-working woman) on the effects of radiation. The authors paid careful attention to radiation, and the radioprotective effects of TMG on the induction of malformations was examined. Radiation is an important consideration because of its widespread use in the areas of medicine, nuclear energy, and industry. Malformations induced by radiation at the organogenesis stage, skeletal malformations, and the effects at the cellular level of embryos were examined in this research. Further, the mechanism of the protection effect of TMG against radiation-induced malformations was analyzed and observed experimentally. Thus, this study was done to provide fundamental data on the radioprotective agent TMG. It was clear that TMG exerted radioprotective effects against embryonic death and the rate of teratogenesis when administered before exposure. Such effects were also exerted against skeletal malformations and fetal body weight. In summary, radioprotective effects were observed at the whole-body level as well as at the cellular level.

High Tumor Penetration of Paclitaxel Loaded pH Sensitive Cleavable Liposomes by Depletion of Tumor Collagen I in Breast Cancer.

PubMed

Zhang, Li; Wang, Yang; Yang, Yuting; Liu, Yayuan; Ruan, Shaobo; Zhang, Qianyu; Tai, Xiaowei; Chen, Jiantao; Xia, Tai; Qiu, Yue; Gao, Huile; He, Qin

2015-05-13

The network of collagen I in tumors could prevent the penetration of drugs loaded in nanoparticles, and this would lead to impaired antitumor efficacy. In this study, free losartan (an angiotensin inhibitor) was injected before treatment to reduce the level of collagen I, which could facilitate the penetration of nanoparticles. Then the pH-sensitive cleavable liposomes (Cl-Lip) were injected subsequently to exert the antitumor effect. The Cl-Lip was constituted by PEG(5K)-Hydrazone-PE and DSPE-PEG(2K)-R8. When the Cl-Lip reached to the tumor site by the enhanced permeability and retention (EPR) effect, PEG(5K)-Hydrazone-PE was hydrolyzed from the Cl-Lip under the low extra-cellular pH conditions of tumors, then the R8 peptide was exposed, and finally liposomes could be internalized into tumor cells by the mediation of R8 peptide. In vitro experiments showed both the cellular uptake of Cl-Lip by 4T1 cells and cytotoxicity of paclitaxel loaded Cl-Lip (PTX-Cl-Lip) were pH sensitive. In vivo experiments showed the Cl-Lip had a good tumor targeting ability. After depletion of collagen I, Cl-Lip could penetrate into the deep place of tumors, the tumor accumulation of Cl-Lip was further increased by 22.0%, and the oxygen distributed in tumor tissues was also enhanced. The antitumor study indicated free losartan in combination with PTX-Cl-Lip (59.8%) was more effective than injection with PTX-Cl-Lip only (37.8%) in 4T1 tumor bearing mice. All results suggested that depletion of collagen I by losartan dramatically increased the penetration of PTX-Cl-Lip and combination of free losartan and PTX-CL-Lip could lead to better antitumor efficacy of chemical drugs. Thus, the combination strategy might be a promising tactic for better treatment of solid tumors with a high level of collagen I.

Curcumin Attenuates Acute Graft-versus-Host Disease Severity via In Vivo Regulations on Th1, Th17 and Regulatory T Cells

PubMed Central

Lee, Sung-Hee; Yang, Eun-Ji; Min, Jun-Ki; Cho, Seok-Goo; Yang, Chul-Woo; Park, Sung-Hwan; Kim, Ho-Youn; Cho, Mi-La

2013-01-01

Background In this study we examined the in vivo and in vitro effects and mechanisms of action of curcumin on the development of acute graft-versus-host disease (GVHD) using a murine model. Methodology/Principal Findings Mixed lymphocyte reactions were used to determine the in vitro effects of curcumin. Treatment with curcumin attenuated alloreactive T cell proliferation and inhibited the production of interferon (IFN)-γ and interleukin (IL)-17. In a murine acute GVHD model, transplantation of curcumin-treated allogeneic splenocytes into irradiated recipient mice significantly reduced the clinical severity scores of acute GVHD manifested in the liver, skin, colon and lung as compared with animals receiving vehicle-treated splenocytes. c-Fos and c-Jun expression levels in the skin and intestine, which are major target organs, were analyzed using immunohistochemical staining. Expression of both proteins was reduced in epithelial tissues of skin and intestine from curcumin-treated GVHD animals. The IFN-γ-expressing CD4+ splenocytes and IFN-γ-expressing lymph node cells were dramatically decreased in curcumin-treated mice. In contrast, CD4+Foxp3+ splenocytes were increased in the curcumin-treated acute GVHD animals. Flow cytometric analysis revealed that animals transplanted with curcumin-treated allogeneic splenocytes showed increased populations of CD4+ regulatory T cells (Tregs) as well as CD8+ Treg cells, compared to animals administered vehicle-treated splenocytes. Curcumin-treated acute GVHD animals could have a change in B cell subpopulations. Conclusion/Significance In the present study, we investigated the efficacy and mechanism of action of curcumin treatment against acute GVHD. The acute GVHD mice administered with curcumin-treated splenocytes showed significantly reduced severity of acute GVHD. Curcumin exerted in vivo preventive effects on acute GVHD by reciprocal regulation of T helper 1 (Th1) and Treg (both CD4+ and CD8+ Treg) cell lineages as well as B cell homeostasis. PMID:23840617

Functional Requirements for DjlA- and RraA-Mediated Enhancement of Recombinant Membrane Protein Production in the Engineered Escherichia coli Strains SuptoxD and SuptoxR.

PubMed

Gialama, Dimitra; Delivoria, Dafni Chrysanthi; Michou, Myrsini; Giannakopoulou, Artemis; Skretas, Georgios

2017-06-16

In previous work, we have generated the engineered Escherichia coli strains SuptoxD and SuptoxR, which upon co-expression of the effector genes djlA or rraA, respectively, are capable of suppressing the cytotoxicity caused by membrane protein (MP) overexpression and of producing dramatically enhanced yields for a variety of recombinant MPs of both prokaryotic and eukaryotic origin. Here, we investigated the functional requirements for DnaJ-like protein A (DjlA)- and regulator of ribonuclease activity A (RraA)-mediated enhancement of recombinant MP production in these strains and show that: (i) DjlA and RraA act independently, that is, the beneficial effects of each protein on recombinant MP production occur through a mechanism that does not involve the other, and in a non-additive manner; (ii) full-length and membrane-bound DjlA is required for exerting its beneficial effects on recombinant MP production in E. coli SuptoxD; (iii) the MP production-promoting properties of DjlA in SuptoxD involve the action of the molecular chaperone DnaK but do not rely on the activation of the regulation of capsular synthesis response, a well-established consequence of djlA overexpression; (iv) the observed RraA-mediated effects in E. coli SuptoxR involve the ribonucleolytic activity of RNase E, but not that of its paralogous ribonuclease RNase G; and (v) DjlA and RraA are unique among similar E. coli proteins in their ability to promote bacterial recombinant MP production. These observations provide important clues about the molecular requirements for suppressed toxicity and enhanced MP accumulation in SuptoxD/SuptoxR and will guide future studies aiming to decipher the exact mechanism of DjlA- and RraA-mediated enhancement of recombinant MP production in these strains. Copyright © 2017 Elsevier Ltd. All rights reserved.

The Multifaceted Effects of Agmatine on Functional Recovery after Spinal Cord Injury through Modulations of BMP-2/4/7 Expressions in Neurons and Glial Cells

PubMed Central

Park, Yu Mi; Lee, Won Taek; Bokara, Kiran Kumar; Seo, Su Kyoung; Park, Seung Hwa; Kim, Jae Hwan; Yenari, Midori A.; Park, Kyung Ah; Lee, Jong Eun

2013-01-01

Presently, few treatments for spinal cord injury (SCI) are available and none have facilitated neural regeneration and/or significant functional improvement. Agmatine (Agm), a guanidinium compound formed from decarboxylation of L-arginine by arginine decarboxylase, is a neurotransmitter/neuromodulator and been reported to exert neuroprotective effects in central nervous system injury models including SCI. The purpose of this study was to demonstrate the multifaceted effects of Agm on functional recovery and remyelinating events following SCI. Compression SCI in mice was produced by placing a 15 g/mm2 weight for 1 min at thoracic vertebra (Th) 9 segment. Mice that received an intraperitoneal (i.p.) injection of Agm (100 mg/kg/day) within 1 hour after SCI until 35 days showed improvement in locomotor recovery and bladder function. Emphasis was made on the analysis of remyelination events, neuronal cell preservation and ablation of glial scar area following SCI. Agm treatment significantly inhibited the demyelination events, neuronal loss and glial scar around the lesion site. In light of recent findings that expressions of bone morphogenetic proteins (BMPs) are modulated in the neuronal and glial cell population after SCI, we hypothesized whether Agm could modulate BMP- 2/4/7 expressions in neurons, astrocytes, oligodendrocytes and play key role in promoting the neuronal and glial cell survival in the injured spinal cord. The results from computer assisted stereological toolbox analysis (CAST) demonstrate that Agm treatment dramatically increased BMP- 2/7 expressions in neurons and oligodendrocytes. On the other hand, BMP- 4 expressions were significantly decreased in astrocytes and oligodendrocytes around the lesion site. Together, our results reveal that Agm treatment improved neurological and histological outcomes, induced oligodendrogenesis, protected neurons, and decreased glial scar formation through modulating the BMP- 2/4/7 expressions following SCI. PMID:23349763

Effects of trees on momentum exchange within and above a real urban environment

NASA Astrophysics Data System (ADS)

Salesky, S.; Giometto, M. G.; Christen, A.; Egli, P. E.; Schmid, M. F.; Tooke, T. R.; Coops, N. C.; Parlange, M. B.

2017-12-01

Large-eddy simulations (LES) are used to gain insight into the effects of trees on momentum transfer rates characterizing the atmosphere within and above a real urban canopy. Several areas are considered that are part of a neighbourhood in the city of Vancouver, BC, Canada where a small fraction of trees are taller than buildings. In this area, eight years of continuous wind and turbulence measurements are available from a 30 m meteorological tower. Buildings and vegetation geometries are obtained from airborne light detection and ranging (LiDAR) data. In the LES algorithm, buildings are accounted through an immersed boundary method, whereas vegetation is parameterized via a location-specific leaf area density. LES are performed varying wind direction and leaf area densities. Surface roughness lengths (z0) from both LES and tower measurements are sensitive to the 0 ≤ LAI/λ < 3 parameter, where LAI is the leaf area index and λ is the frontal area fraction of buildings characterizing a given canopy. For instance, tower measurements predict a 19% seasonal increase in z0, slightly lower than the 27% increase featured by LES for the most representative canopy (leaves-off LAI/λ = 0.74, leaves-on LAI/λ = 2.24). Removing vegetation from such a canopy would cause a dramatic drop of approximately 50% in z0 when compared to the reference summer value. The momentum displacement height (d) from LES also consistently increases as LAI/λ increases, due to the disproportionate amount of drag that the (few) relatively taller trees exert on the flow. Within the urban canopy, the effects of trees are twofold: on one hand, they act as a direct momentum sink for the mean flow; on the other, they reduce downward turbulent transport of high-momentum fluid, significantly reducing the wind intensity at the heights where people live and buildings consume energy.

Evolution of the Antisense Overlap between Genes for Thyroid Hormone Receptor and Rev-erbα and Characterization of an Exonic G-Rich Element That Regulates Splicing of TRα2 mRNA

PubMed Central

Munroe, Stephen H.; Morales, Christopher H.; Duyck, Tessa H.; Waters, Paul D.

2015-01-01

The α-thyroid hormone receptor gene (TRα) codes for two functionally distinct proteins: TRα1, the α-thyroid hormone receptor; and TRα2, a non-hormone-binding variant. The final exon of TRα2 mRNA overlaps the 3’ end of Rev-erbα mRNA, which encodes another nuclear receptor on the opposite strand of DNA. To understand the evolution of this antisense overlap, we sequenced these genes and mRNAs in the platypus Orthorhynchus anatinus. Despite its strong homology with other mammals, the platypus TRα/Rev-erbα locus lacks elements essential for expression of TRα2. Comparative analysis suggests that alternative splicing of TRα2 mRNA expression evolved in a stepwise fashion before the divergence of eutherian and marsupial mammals. A short G-rich element (G30) located downstream of the alternative 3’splice site of TRα2 mRNA and antisense to the 3’UTR of Rev-erbα plays an important role in regulating TRα2 splicing. G30 is tightly conserved in eutherian mammals, but is absent in marsupials and monotremes. Systematic deletions and substitutions within G30 have dramatically different effects on TRα2 splicing, leading to either its inhibition or its enhancement. Mutations that disrupt one or more clusters of G residues enhance splicing two- to three-fold. These results suggest the G30 sequence can adopt a highly structured conformation, possibly a G-quadruplex, and that it is part of a complex splicing regulatory element which exerts both positive and negative effects on TRα2 expression. Since mutations that strongly enhance splicing in vivo have no effect on splicing in vitro, it is likely that the regulatory role of G30 is mediated through linkage of transcription and splicing. PMID:26368571

[Inhibiting effect of transforming growth factor β3 on IL-6 expression in MG63 induced by lipopolysaccharide].

PubMed

Wang, Gui-Ling; Yu, Ya-Qiong; Guo, Jia-Jie; Qiu, Li-Hong

2017-02-01

To explore the effect of transforming growth factor β3 (TGF-β3) on IL-6 expression in inflammatory MG63, and the mechanism by which TGF-β3 exert its anti-inflammatory effect. Cell line MG63 was stimulated by 20 μg/mL lipopolysaccharide of Porphyromonas endodontalis (P.e-LPS) to establish the inflammatory model of osteoblast. TGF-β3 or TGFβ1 varying from 5 to 20 ng/mL was added together with P.e-LPS for 24 h, then the mRNA expression of IL-6 was detected by real-time PCR, the role of TGF-β3 on IL-6 protein was further verified by ELISA. MG63 was pretreated with 10 ng/mL TGF-β3 for 30 min in RPMI 1640 medium without fetal bovine serum (FBS), then the cells were cultured for another 20 min with 20 μg/mL P.e-LPS, the phosphorylation level of ERK1/2 was measured by Western blot. Statistical analysis was performed using one-way ANOVA with SPSS13.0 software package. The results of real-time PCR revealed that, when MG63 was treated with 20 μg/mL P.e-LPS alone, the mRNA expression of IL-6 increased significantly(P<0.01). When TGF-β1 was added with P.e-LPS, it could barely decrease IL-6 prominently at the highest concentration (P<0.05).Whereas, the inhibition effect of TGF-β3 on IL-6 was dramatic (P<0.01), ELISA results showed that 10-20 ng/mL TGF-β3 blocked the IL-6 expression at protein level (P<0.05). 20 μg/mL P.e-LPS promoted the phosphorylation level of ERK1/2 in MG63(P<0.01), while with 10 ng/mL TGF-β3, the effect of P.e-LPS on ERK1/2 was blocked(P<0.05). TGF-β3 is more potent than TGF-β1 in inhibiting MG63, and ERK1/2 is involved in its anti-inflammatory effect.

Variables affecting resolution of lung phospholipids in one-dimensional thin-layer chromatography.

PubMed

Krahn, J

1987-01-01

Resolution of the confusion in the literature about the separation of lung phospholipids in thin-layer chromatographic systems has awaited a systematic study of the variables that potentially affect this separation. In this study I show that: incorporation of ammonium sulfate into silica gel "GHL" has a dramatic effect on separation of lung phospholipids; this effect is equally dramatic but different in activated and nonactivated gels; when it picks up moisture, ammonium sulfate-activated gel very rapidly loses its ability to resolve lecithin from phosphatidylinositol; in gel containing ammonium sulfate, small amounts of phosphatidylethanolamine are hydrolyzed to lyso-phosphatidylethanolamine.

Immunomodulatory effects of Santolina chamaecyparissus leaf extracts on human neutrophil functions.

PubMed

Boudoukha, Chahra; Bouriche, Hamama; Ortega, Eduardo; Senator, Abderrahmane

2016-01-01

Santolina chamaecyparissus L. (Asteraceae) is an aromatic plant wide spread in the Mediterranean region. It is used in folk medicine for its anti-inflammatory properties. The effects of S. chamaecyparissus aqueous extract (SCAE) and polyphenolic extract (SCPE) on human polymorphonuclear neutrophil (PMN) degranulation, chemotaxis, phagocytosis, and microbicidal capacity were examined in vitro. Aqueous and polyphenolic extracts were prepared from S. chamaecyparissus leaves. The elastase release was used as a marker for measuring PMN degranulation, while chemotaxis was performed using a 48-microwell chemotaxis chamber. The phagocytosis and the microbicidal capacity were evaluated using fresh cultures of Candida albicans. The treatment of neutrophils with different concentrations (10-200 µg/ml) of SCAE and SCPE caused a significant (p < 0.001) and dose-dependent inhibitory effect on elastase release in fMLP/Cytochalasin B (CB)-stimulated neutrophils. Indeed, 100 µg/ml of SCAE exerted an inhibitory effect of 51.97 ± 6.2%, whereas SCPE at the same concentration abolished completely PMN degranulation. Moreover, both extracts inhibited markedly (p < 0.01) fMLP-induced chemotactic migration. At 200 µg/ml, SCAE and SCPE exerted an inhibitory effect of 54.61 ± 7.3% and 57.71 ± 7.44%, respectively. In addition, a decline in both phagocytosis and microbicidal capacity against Candida albicans was observed when PMNs were exposed to 100 and 200 µg/ml of SCAE or SCPE. The exerted effects on neutrophil functions support the anti-inflammatory activity and show new mechanisms of action and effectiveness of S. chamaecyparissus leaf extracts. This plant may be considered as an interesting source of anti-inflammatory and immunomodulatory agents.

Assessing effects of stocked trout on nongame fish assemblages in southern Appalachian Mountain streams

USGS Publications Warehouse

Weaver, D.; Kwak, Thomas J.

2013-01-01

Fisheries managers are faced with the challenge of balancing the management of recreational fisheries with that of conserving native species and preserving ecological integrity. The negative effects that nonnative trout species exert on native trout are well documented and include alteration of competitive interactions, habitat use, and production. However, the effects that nonnative trout may exert on nongame fish assemblages are poorly understood. Our objectives were to quantify the effects of trout stocking on native nongame fish assemblages intensively on one newly stocked river, the North Toe River, North Carolina, and extensively on other southern Appalachian Mountain streams that are annually stocked with trout. In the intensive study, we adopted a before-after, control-impact (BACI) experimental design to detect short-term effects on the nongame fish assemblage and found no significant differences in fish density, species richness, species diversity, or fish microhabitat use associated with trout stocking. We observed differences in fish microhabitat use between years, however, which suggests there is a response to environmental changes, such as the flow regime, which influence available habitat. In the extensive study, we sampled paired stocked and unstocked stream reaches to detect long-term effects from trout stocking; however, we detected no differences in nongame fish density, species richness, species diversity, or population size structure between paired sites. Our results revealed high inherent system variation caused by natural and anthropogenic factors that appear to overwhelm any acute or chronic effect of stocked trout. Furthermore, hatchery-reared trout may be poor competitors in a natural setting and exert a minimal or undetectable impact on native fish assemblages in these streams. These findings provide quantitative results necessary to assist agencies in strategic planning and decision making associated with trout fisheries, stream management, and conservation of native fishes.

Nitrite exerts antioxidant effects, inhibits the mTOR pathway and reverses hypertension-induced cardiac hypertrophy.

PubMed

Guimaraes, Danielle A; Dos Passos, Madla A; Rizzi, Elen; Pinheiro, Lucas C; Amaral, Jefferson H; Gerlach, Raquel F; Castro, Michele M; Tanus-Santos, Jose E

2018-05-20

Cardiac hypertrophy is a common consequence of chronic hypertension and leads to heart failure and premature death. The anion nitrite is now considered as a bioactive molecule able to exert beneficial cardiovascular effects. Previous results showed that nitrite attenuates hypertension-induced increases in reactive oxygen species (ROS) production in the vasculature. Whether antioxidant effects induced by nitrite block critical signaling pathways involved in cardiac hypertrophy induced by hypertension has not been determined yet. The Akt/mTOR signaling pathway is responsible to activate protein synthesis during cardiac remodeling and is activated by increased ROS production, which is commonly found in hypertension. Here, we investigated the effects of nitrite treatment on cardiac remodeling and activation of this hypertrophic signaling pathway in 2 kidney-1 clip (2K1C) hypertension. Sham and 2K1C rats were treated with oral nitrite at 1 or 15 mg/kg for four weeks. Nitrite treatment (15 mg/kg) reduced systolic blood pressure and decreased ROS production in the heart tissue from hypertensive rats. This nitrite dose also blunted hypertension-induced activation of mTOR pathway and cardiac hypertrophy. While the lower nitrite dose (1 mg/kg) did not affect blood pressure, it exerted antioxidant effects and tended to attenuate mTOR pathway activation and cardiac hypertrophy induced by hypertension. Our findings provide strong evidence that nitrite treatment decreases cardiac remodeling induced by hypertension as a result of its antioxidant effects and downregulation of mTOR signaling pathway. This study may help to establish nitrite as an effective therapy in hypertension-induced cardiac hypertrophic remodeling. Copyright © 2018 Elsevier Inc. All rights reserved.

THG113.31, a specific PGF2alpha receptor antagonist, induces human myometrial relaxation and BKCa channel activation

PubMed Central

Doheny, Helen C; O'Reilly, Michael J; Sexton, Donal J; Morrison, John J

2007-01-01

Background PGF2alpha exerts a significant contractile effect on myometrium and is central to human labour. THG113.31, a specific non-competitive PGF2alpha receptor (FP) antagonist, exerts an inhibitory effect on myometrial contractility. The BKCa channel is ubiquitously encountered in human uterine tissue and plays a significant role in modulating myometrial cell membrane potential and excitability. The objective of this study was to investigate potential BKCa channel involvement in the response of human myometrium to THG113.31. Methods Single and whole-cell electrophysiological BKCa channel recordings from freshly dispersed myocytes, were investigated in the presence and absence of THG113.31. Functional studies investigated the effects of THG113.31 on isolated spontaneous myometrial contractions, in the presence and absence of the BKCa channel blocker, iberiotoxin. Results Single channel recordings identified the BKCa channel as a target of THG113.31. THG113.31 significantly increased the open state probability of these channels [control 0.023+/-0.006; 10 microM THG113.31 0.087+/-0.012 (P = 0.009); and 50 microM THG113.31 0.1356+/-0.018 (P = 0.001)]. In addition, THG113.31 increased whole-cell BKCa currents over a range of membrane potentials, and this effect was reversed by 100 nanoM IbTX. Isometric tension studies demonstrated that THG113.31 exerted a significant concentration-dependent relaxant effect on human myometrial tissue and pre-incubation of strips with IbTX abolished this effect on spontaneously occurring contractions. Conclusion These data suggests that activation of the BKCa channel may contribute, at least partially, to the uterorelaxant effect of THG113.31. PMID:17367527

Glucose level determines excitatory or inhibitory effects of adiponectin on arcuate POMC neuron activity and feeding

PubMed Central

Suyama, Shigetomo; Maekawa, Fumihiko; Maejima, Yuko; Kubota, Naoto; Kadowaki, Takashi; Yada, Toshihiko

2016-01-01

Adiponectin regulates glucose and lipid metabolism, acting against metabolic syndrome and atherosclerosis. Accumulating evidence suggest that adiponectin acts on the brain including hypothalamic arcuate nucleus (ARC), where proopiomelanocortin (POMC) neurons play key roles in feeding regulation. Several studies have examined intracerebroventricular (ICV) injection of adiponectin and reported opposite effects, increase or decrease of food intake. These reports used different nutritional states. The present study aimed to clarify whether adiponectin exerts distinct effects on food intake and ARC POMC neurons depending on the glucose concentration. Adiponectin was ICV injected with or without glucose for feeding experiments and administered to ARC slices with high or low glucose for patch clamp experiments. We found that adiponectin at high glucose inhibited POMC neurons and increased food intake while at low glucose it exerted opposite effects. The results demonstrate that glucose level determines excitatory or inhibitory effects of adiponectin on arcuate POMC neuron activity and feeding. PMID:27503800