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Sample records for apoptotic mimicry model

  1. Mimicry for all modalities.

    Science.gov (United States)

    Dalziell, Anastasia H; Welbergen, Justin A

    2016-06-01

    Mimicry is a canonical example of adaptive signal design. In principle, what constitutes mimicry is independent of the taxonomic identity of the mimic, the ecological context in which it operates, and the sensory modality through which it is expressed. However, in practice the study of mimicry is inconsistent across research fields, with theoretical and empirical advances often failing to cross taxonomic and sensory divides. We propose a novel conceptual framework whereby mimicry evolves if a receiver perceives the similarity between a mimic and a model and as a result confers a selective benefit onto the mimic. Here, misidentification and/or deception are no longer formal requirements, and mimicry can evolve irrespective of the underlying proximate mechanisms. The centrality of receiver perception in this framework enables us to formally distinguish mimicry from perceptual exploitation and integrate mimicry and multicomponent signalling theory for the first time. In addition, it resolves inconsistencies in our understanding of the role of learning in mimicry evolution, and shows that imperfect mimicry is expected to be the norm. Mimicry remains a key model for understanding signal evolution and cognition, and we recommend the adoption of a unified approach to stimulate future interdisciplinary developments in this fascinating area of research. PMID:27117779

  2. The Hairy-Downy game: a model of interspecific social dominance mimicry.

    Science.gov (United States)

    Prum, Richard O; Samuelson, Larry

    2012-11-21

    The evolution of many forms of mimicry are well understood, but the evolution of mimicry in the absence of aposematic models or third party participants remains poorly understood. This paper presents a model of the evolution of interspecific social dominance mimicry (ISDM), that does not rely on third-party observers, in the context of the Hairy-Downy game. Members of a socially dominant species contest a resource by playing the hawk-dove game. Nonmimic members of a subordinate species surrender the resource whenever encountering a member of the dominant species, and split the resource whenever interacting among themselves. Mimicry allows members of the subordinate species to pose as members of the dominant species who play dove, splitting the resource when facing other dominant doves while continuing to surrender the resource to dominant hawks. We characterize the evolutionary dynamics and equilibrium behavior of this game, developing conditions under which evolution will select for mimicry, and under which the subordinate species will consist (almost or even literally) entirely of mimics. PMID:22910135

  3. Human mimicry

    NARCIS (Netherlands)

    Chartrand, T.L.; Baaren, R.B. van

    2009-01-01

    Human mimicry is ubiquitous, and often occurs without the awareness of the person mimicking or the person being mimicked. First, we briefly describe some of the major types of nonconscious mimicry—verbal, facial, emotional, and behavioral—and review the evidence for their automaticity. Next, we argu

  4. From Mimicry to Language: A Neuroanatomically Based Evolutionary Model of the Emergence of Vocal Language.

    Science.gov (United States)

    Poliva, Oren

    2016-01-01

    The auditory cortex communicates with the frontal lobe via the middle temporal gyrus (auditory ventral stream; AVS) or the inferior parietal lobule (auditory dorsal stream; ADS). Whereas the AVS is ascribed only with sound recognition, the ADS is ascribed with sound localization, voice detection, prosodic perception/production, lip-speech integration, phoneme discrimination, articulation, repetition, phonological long-term memory and working memory. Previously, I interpreted the juxtaposition of sound localization, voice detection, audio-visual integration and prosodic analysis, as evidence that the behavioral precursor to human speech is the exchange of contact calls in non-human primates. Herein, I interpret the remaining ADS functions as evidence of additional stages in language evolution. According to this model, the role of the ADS in vocal control enabled early Homo (Hominans) to name objects using monosyllabic calls, and allowed children to learn their parents' calls by imitating their lip movements. Initially, the calls were forgotten quickly but gradually were remembered for longer periods. Once the representations of the calls became permanent, mimicry was limited to infancy, and older individuals encoded in the ADS a lexicon for the names of objects (phonological lexicon). Consequently, sound recognition in the AVS was sufficient for activating the phonological representations in the ADS and mimicry became independent of lip-reading. Later, by developing inhibitory connections between acoustic-syllabic representations in the AVS and phonological representations of subsequent syllables in the ADS, Hominans became capable of concatenating the monosyllabic calls for repeating polysyllabic words (i.e., developed working memory). Finally, due to strengthening of connections between phonological representations in the ADS, Hominans became capable of encoding several syllables as a single representation (chunking). Consequently, Hominans began vocalizing and

  5. Mimicry and masquerade from the avian visual perspective

    Directory of Open Access Journals (Sweden)

    Mary Caswell STODDARD

    2012-08-01

    Full Text Available Several of the most celebrated examples of visual mimicry, like mimetic eggs laid by avian brood parasites and pala­table insects mimicking distasteful ones, involve signals directed at the eyes of birds. Despite this, studies of mimicry from the avian visual perspective have been rare, particularly with regard to defensive mimicry and masquerade. Defensive visual mimicry, which includes Batesian and Müllerian mimicry, occurs when organisms share a visual signal that functions to deter predators. Masquerade occurs when an organism mimics an inedible or uninteresting object, such as a leaf, stick, or pebble. In this paper, I present five case studies covering diverse examples of defensive mimicry and masquerade as seen by birds. The best-known cases of defensive visual mimicry typically come from insect prey, but birds themselves can exhibit defensive visual mimicry in an attempt to escape mobbing or dissuade avian predators. Using examples of defensive visual mimicry by both insects and birds, I show how quantitative models of avian color, luminance, and pattern vision can be used to enhance our understanding of mimicry in many systems and produce new hypotheses about the evolution and diversity of signals. Overall, I investigate examples of Batesian mimicry (1 and 2, Müllerian mimicry (3 and 4, and masquerade (5 as follows: 1 Polymorphic mimicry in African mocker swallowtail butterflies; 2 Cuckoos mimicking sparrowhawks; 3 Mimicry rings in Neotropical butterflies; 4 Plumage mimicry in toxic pitohuis; and 5 Dead leaf-mimicking butterflies and mantids [Current Zoology 58 (4: 630–648, 2012].

  6. Mimicry and masquerade from the avian visual perspective

    Institute of Scientific and Technical Information of China (English)

    Mary Caswell STODDARD

    2012-01-01

    Several of the most celebrated examples of visual mimicry,like mimetic eggs laid by avian brood parasites and palatable insects mimicking distasteful ones,involve signals directed at the eyes of birds.Despite this,studies of mimicry from the avian visual perspective have been rare,particularly with regard to defensive mimicry and masquerade.Defensive visual mimicry,which includes Batesian and Müllerian mimicry,occurs when organisms share a visual signal that functions to deter predators.Masquerade occurs when an organism mimics an inedible or uninteresting object,such as a leaf,stick,or pebble.In this paper,I present five case studies covering diverse examples of defensive mimicry and masquerade as seen by birds.The best-known cases of defensive visual mimicry typically come from insect prey,but birds themselves can exhibit defensive visual mimicry in an attempt to escape mobbing or dissuade avian predators.Using examples of defensive visual mimicry by both insects and birds,I show how quantitative models of avian color,luminance,and pattern vision can be used to enhance our understanding of mimicry in many systems and produce new hypotheses about the evolution and diversity of signals.Overall,I investigate examples of Batesian mimicry (1 and 2),Müllerian mimicry (3 and 4),and masquerade (5) as follows:1) Polymorphic mimicry in African mocker swallowtail butterflies; 2) Cuckoos mimicking sparrowhawks; 3) Mimicry rings in Neotropical butterflies; 4) Plumage mimicry in toxic pitohuis; and 5) Dead leaf-mimicking butterflies and mantids.

  7. Inflammatory breast cancer: Vasculogenic mimicry and its hemodynamics of an inflammatory breast cancer xenograft model

    International Nuclear Information System (INIS)

    We recently established a new human inflammatory breast cancer (IBC) xenograft (WIBC-9) originating from a patient with IBC. The original tumor and WIBC-9 revealed invasive ductal carcinoma with a hypervascular structure of solid nests and marked lymphatic permeation in the overlying dermis. In the central part of the solid nests, vasculogenic mimicry, which showed an absence of endothelial cells, was observed. Comparison of WIBC-9 with an established non-IBC xenograft (MC-5), using time-course dynamic micro-magnetic resonance angiography analysis (with a newly developed intravascular macromolecular contrast agent for magnetic resonance imaging) demonstrated that the WIBC-9 tumor had blood flow and a vascular mimicry–angiogenesis junction

  8. Mimicry Cycles, Traps, and Chains: The Coevolution of Toucan and Kiskadee Mimicry.

    Science.gov (United States)

    Prum, Richard O; Samuelson, Larry

    2016-06-01

    Interspecific social dominance mimicry (ISDM) is a form of social parasitism in which a subordinate species evolves to mimic and deceive a dominant interference competitor in order to avoid attack by the dominant species. ISDM has been proposed to result in (1) antagonistic coevolutionary arms races in appearance between the model and the mimic (e.g., Ramphastos toucans) and (2) the evolution of complexes of multiple species converging on a common visual appearance (e.g., kiskadee flycatchers). We present evolutionary games of antagonistic coevolution in appearance between pairs and triplets of sympatric species under interference competition. We identify conditions for the existence and stability of (1) coevolutionary mimicry cycles in appearance between evader and pursuer strategies of models and mimics, (2) mimicry chains in which three or more species are coevolutionarily entrained to evolve a single common appearance despite differences in their costs and benefits, and (3) mimicry traps in which a subdominant species is evolutionarily constrained from evading mimicry by a third, subordinate mimic species. Mimicry cycles will result in the evolutionary divergence of models and mimics from their ancestral phenotypes. The hierarchical evolutionary dynamics of ISDM traps and chains resemble Müllerian mimicry with variable costs to toxicity. PMID:27172594

  9. Galunisertib inhibits glioma vasculogenic mimicry formation induced by astrocytes.

    Science.gov (United States)

    Zhang, Chao; Chen, Wenliang; Zhang, Xin; Huang, Bin; Chen, Aanjing; He, Ying; Wang, Jian; Li, Xingang

    2016-01-01

    Gliomas are among the most lethal primary brain tumors found in humans. In high-grade gliomas, vasculogenic mimicry is often detected and has been correlated with prognosis, thus suggesting its potential as a therapeutic target. Vasculogenic mimicry mainly forms vascular-like channels independent of endothelial cells; however, little is known about the relationship between astrocytes and vasculogenic mimicry. In our study, we demonstrated that the presence of astrocytes promoted vasculogenic mimicry. With suspension microarray technology and in vitro tube formation assays, we identified that astrocytes relied on TGF-β1 to enhance vasculogenic mimicry. We also found that vasculogenic mimicry was inhibited by galunisertib, a promising TGF-β1 inhibitor currently being studied in an ongoing trial in glioma patients. The inhibition was partially attributed to a decrease in autophagy after galunisertib treatment. Moreover, we observed a decrease in VE-cadherin and smooth muscle actin-α expression, as well as down-regulation of Akt and Flk phosphorylation in galunisertib-treated glioma cells. By comparing tumor weight and volume in a xenograft model, we acquired promising results to support our theory. This study expands our understanding of the role of astrocytes in gliomas and demonstrates that galunisertib inhibits glioma vasculogenic mimicry induced by astrocytes. PMID:26976322

  10. Boolean model of Yeast Apoptosis as a tool to study yeast and human apoptotic regulations

    Directory of Open Access Journals (Sweden)

    MarijaCvijovic

    2012-12-01

    Full Text Available Programmed cell death (PCD is an essential cellular mechanism that is evolutionary conserved, mediated through various pathways and acts by integrating different stimuli. Many diseases such as neurodegenerative diseases and cancers are found to be caused by, or associated with, regulations in the cell death pathways. Yeast Saccharomyces cerevisiae, is a unicellular eukaryotic organism that shares with human cells components and pathways of the PCD and is therefore used as a model organism. Boolean modelling is becoming promising approach to capture qualitative behaviour and describe essential properties of such complex networks. Here we present large literature-based and to our knowledge first Boolean model that combines pathways leading to apoptosis (a type of PCD in yeast. Analysis of the yeast model confirmed experimental findings of anti-apoptotic role of Bir1p and pro-apoptotic role of Stm1p and revealed activation of the stress protein kinase Hog proposing the maximal level of activation upon heat stress. In addition we extended the yeast model and created an in silico humanized yeast in which human pro- and anti-apoptotic regulators Bcl-2 family and Valosin-contain protein (VCP are included in the model. We showed that accumulation of Bax in in silico humanized yeast shows apoptotic markers and that VCP is essential target of Akt Signaling. The presented Boolean model provides comprehensive description of yeast apoptosis network behaviour. Extended model of humanized yeast gives new insights of how complex human disease like neurodegenration can initially be tested.

  11. The functionality of spontaneous mimicry and its influences on affiliation: An implicit socialization account

    Directory of Open Access Journals (Sweden)

    Liam Connor Kavanagh

    2016-03-01

    Full Text Available There is a broad theoretical and empirical interest in spontaneous mimicry, or the automatic reproduction of a model’s behavior. Evidence shows that people mimic models they like, and that mimicry enhances liking for the mimic. Yet, there is no satisfactory account of this phenomenon, especially in terms of its functional significance. While affiliation is often cited as the driver of mimicry, we argue that mimicry is primarily driven by a learning process that helps to produce the appropriate bodily and emotional responses to relevant social situations. Because the learning process and the resulting knowledge is implicit, it cannot easily be rejected, criticized, revised, and employed by the learner in a deliberative or deceptive manner. We argue that these characteristics will lead individuals to preferentially mimic ingroup members, whose implicit information is worth incorporating. Conversely, mimicry of the wrong person is costly because individuals will internalize bad habits, including emotional reactions and mannerisms indicating wrong group membership. This pattern of mimicry, in turn, means that observed mimicry is an honest signal of group affiliation. We propose that the preferences of models for the mimic stems from this true signal value. Further, just like facial expressions, mimicry communicates a genuine disposition when it is truly spontaneous. Consequently, perceivers are attuned to relevant cues such as appropriate timing, fidelity, and selectivity. Our account, while assuming no previously unknown biological endowments, also explains greater mimicry of powerful people, and why affiliation can be signaled by mimicry of seemingly inconsequential behaviors.

  12. The Functionality of Spontaneous Mimicry and Its Influences on Affiliation: An Implicit Socialization Account

    Science.gov (United States)

    Kavanagh, Liam C.; Winkielman, Piotr

    2016-01-01

    There is a broad theoretical and empirical interest in spontaneous mimicry, or the automatic reproduction of a model’s behavior. Evidence shows that people mimic models they like, and that mimicry enhances liking for the mimic. Yet, there is no satisfactory account of this phenomenon, especially in terms of its functional significance. While affiliation is often cited as the driver of mimicry, we argue that mimicry is primarily driven by a learning process that helps to produce the appropriate bodily and emotional responses to relevant social situations. Because the learning process and the resulting knowledge is implicit, it cannot easily be rejected, criticized, revised, and employed by the learner in a deliberative or deceptive manner. We argue that these characteristics will lead individuals to preferentially mimic ingroup members, whose implicit information is worth incorporating. Conversely, mimicry of the wrong person is costly because individuals will internalize “bad habits,” including emotional reactions and mannerisms indicating wrong group membership. This pattern of mimicry, in turn, means that observed mimicry is an honest signal of group affiliation. We propose that the preferences of models for the mimic stems from this true signal value. Further, just like facial expressions, mimicry communicates a genuine disposition when it is truly spontaneous. Consequently, perceivers are attuned to relevant cues such as appropriate timing, fidelity, and selectivity. Our account, while assuming no previously unknown biological endowments, also explains greater mimicry of powerful people, and why affiliation can be signaled by mimicry of seemingly inconsequential behaviors. PMID:27064398

  13. Little chameleons: The development of social mimicry during early childhood.

    Science.gov (United States)

    van Schaik, Johanna E; Hunnius, Sabine

    2016-07-01

    Adults use behavioral mimicry to blend in with (or stand out from) their social environment. Adopting another's mannerisms and behaviors, or "mimicking", communicates liking and similarity between interaction partners and has been shown to serve as an implicit affiliation mechanism. Given this important social function, it is surprising that so little is known about the development of mimicry. In two studies, we investigated mimicry and its social sensitivity during early childhood. Children of 4 to 6years (Study 1) and 3years (Study 2) first chose a novel group based on their color preference. Following a baseline phase, children observed videos of in-group and out-group models performing behaviors that are typically mimicked in adults. Importantly, the children received neither instructions nor encouragement to copy the behaviors. Both 3-year-olds and 4- to 6-year-olds displayed behavioral mimicry. Furthermore, 4- to 6-year-olds mimicked the in-group model more than the out-group model, and this in-group bias was also evident in their explicit group preferences. Together, these studies present the first evidence for behavioral mimicry and its social sensitivity during early childhood. Placed in the context of social development, the findings provide a necessary contribution to current developmental and psychological theories on mimicry and behavior copying. PMID:27060416

  14. ImmunoPET imaging of phosphatidylserine in pro-apoptotic therapy treated tumor models

    International Nuclear Information System (INIS)

    An immunoPET imaging probe for the detection of phosphatidylserine was developed and tested in animal models of human cancer treated with pro-apoptotic therapy. We hypothesized that the relatively long plasma half-life of a probe based on a full-length antibody coupled with a residualizing radionuclide would be able to catch the wave of drug-induced apoptosis and lead to a specific accumulation in apoptotic tumor tissue. Methods: The imaging probe is based on a 89Zr-labeled monoclonal antibody PGN635 targeting phosphatidylserine. The probe was evaluated pre-clinically in four tumor xenograft models: one studied treatment with paclitaxel to trigger the intrinsic apoptotic pathway, and three others interrogated treatment with an agonistic death-receptor monoclonal antibody to engage the extrinsic apoptotic pathway. Results: High accumulation of 89Zr-PGN635 was observed in treated tumors undergoing apoptosis reaching 30 %ID/g and tumor-to-blood ratios up to 13. The tumor uptake in control groups treated with vehicle or imaged with a non-binding antibody probe was significantly lower. Conclusions: The results demonstrate the ability of 89Zr-PGN635 to image drug-induced apoptosis in animal models and corroborate our hypothesis that radiolabeled antibodies binding to intracellular targets transiently exposed on the cell surface during apoptosis can be employed for detection of tumor response to therapy.

  15. Pattern mimicry of host eggs by the common cuckoo, as seen through a bird's eye

    OpenAIRE

    Stoddard, Mary Caswell; Stevens, Martin

    2010-01-01

    Cuckoo–host interactions provide classical examples of coevolution. Cuckoos place hosts under selection to detect and reject foreign eggs, while host defences result in the evolution of host-egg mimicry in cuckoos. Despite a long history of research, egg pattern mimicry has never been objectively quantified, and so its coevolution with host defences has not been properly assessed. Here, we use digital image analysis and modelling of avian vision to quantify the level of pattern mimicry in eig...

  16. Coral snakes predict the evolution of mimicry across New World snakes.

    Science.gov (United States)

    Davis Rabosky, Alison R; Cox, Christian L; Rabosky, Daniel L; Title, Pascal O; Holmes, Iris A; Feldman, Anat; McGuire, Jimmy A

    2016-01-01

    Batesian mimicry, in which harmless species (mimics) deter predators by deceitfully imitating the warning signals of noxious species (models), generates striking cases of phenotypic convergence that are classic examples of evolution by natural selection. However, mimicry of venomous coral snakes has remained controversial because of unresolved conflict between the predictions of mimicry theory and empirical patterns in the distribution and abundance of snakes. Here we integrate distributional, phenotypic and phylogenetic data across all New World snake species to demonstrate that shifts to mimetic coloration in nonvenomous snakes are highly correlated with coral snakes in both space and time, providing overwhelming support for Batesian mimicry. We also find that bidirectional transitions between mimetic and cryptic coloration are unexpectedly frequent over both long- and short-time scales, challenging traditional views of mimicry as a stable evolutionary 'end point' and suggesting that insect and snake mimicry may have different evolutionary dynamics. PMID:27146100

  17. MIMICRY, DIFFERENCE AND REPETITION

    Directory of Open Access Journals (Sweden)

    Marcelo Mendes de Souza

    2008-07-01

    Full Text Available This article addresses Homi K. Bhabha’s concept of mimicry in a broader context, other than that of cultural studies and post-colonial studies, bringing together other concepts, such as that of Gilles Deleuze in Difference and repetition, among other texts, and other names, such as Silviano Santiago, Jorge Luís Borges, Franz Kafka and Giorgio Agamben. As a partial conclusion, the article intends to oppose Bhabha’s freudian-marxist view to Five propositions on Psychoanalysis (1973, Gilles Deleuze’s text about Psychoanalysis published right after his book The Anti-Oedipus.

  18. The Modulation of Mimicry by Ethnic Group-Membership and Emotional Expressions

    Science.gov (United States)

    Rauchbauer, Birgit; Majdandžić, Jasminka; Stieger, Stefan; Lamm, Claus

    2016-01-01

    Mimicry has been ascribed affiliative functions. In three experiments, we used a newly developed social-affective mimicry task (SAMT) to investigate mimicry´s modulation by emotional facial expressions (happy, angry) and ethnic group-membership (White in-group, Black out-group). Experiment 1 established the main consistent effect across experiments, which was enhanced mimicry to angry out-group faces compared to angry in-group faces. Hence the SAMT was useful for experimentally investigating the modulation of mimicry. Experiment 2 demonstrated that these effects were not confounded by general aspects of response conflict, as a Simon task resulted in different response patterns than the SAMT. Experiment 2 and pooled analysis of Experiments 1 and 2 also corroborated the finding of enhanced mimicry to angry out-group faces. Experiment 3 tested whether this effect was related to perceptions of threat, by framing angry persons as physically threatening, or not. Selective enhancement of mimicry to out-group persons framed as physically threatening confirmed this hypothesis. Further support for the role of threat was derived from implicit measures showing, in all experiments, that black persons were more strongly associated with threat. Furthermore, enhanced mimicry was consistently related to response facilitation in the execution of congruent movements. This suggests that mimicry acted as a social congruency signal. Our findings suggest that mimicry may serve as an appeasement signal in response to negative affiliative intent. This extends previous models of mimicry, which have predominantly focused on its role in reciprocating affiliation. It suggests that mimicry might not only be used to maintain and establish affiliative bonds, but also to ameliorate a negative social situation. PMID:27557135

  19. How spiders practice aggressive and Batesian mimicry

    Institute of Scientific and Technical Information of China (English)

    Ximena J.NELSON; Robert R.JACKSON

    2012-01-01

    To understand communication,the interests of the sender and the receiver/s of signals should be considered separately.When our goal is to understand the adaptive significance of specific responses to specific signals by the receiver,questions about signal information are useful.However,when our goal is to understand the adaptive significance to the sender of generating a signal,it may be better to envisage the receiver's response to signals as part of the sender's extended phenotype.By making signals,a sender interfaces with the receiver's model of the world and indirectly manipulates its behaviour.This is especially clear in cases of mimicry,where animals use deceptive signals that indirectly manipulate the behaviour of receivers.Many animals adopt Batesian mimicry to deceive their predators,or aggressive mimicry to deceive their prey.We review examples from the literature on spiders to illustrate how these phenomena,traditionally thought of as distinct,can become entangled in a web of lies.

  20. Macromolecular mimicry of nucleic acid and protein

    DEFF Research Database (Denmark)

    Nautrup Pedersen, Gitte; Nyborg, Jens; Clark, Brian F

    1999-01-01

    of the concept of macromolecular mimicry. Macromolecular mimicry has further been proposed among initiation and release factors, thereby adding a new element to the description of protein synthesis in bacteria. Such mimicry has also been observed in other biological processes such as autoimmunity, DNA repair...

  1. Predator mimicry, not conspicuousness, explains the efficacy of butterfly eyespots.

    Science.gov (United States)

    De Bona, Sebastiano; Valkonen, Janne K; López-Sepulcre, Andrés; Mappes, Johanna

    2015-05-01

    Large conspicuous eyespots on butterfly wings have been shown to deter predators. This has been traditionally explained by mimicry of vertebrate eyes, but recently the classic eye-mimicry hypothesis has been challenged. It is proposed that the conspicuousness of the eyespot, not mimicry, is what causes aversion due to sensory biases, neophobia or sensory overloads. We conducted an experiment to directly test whether the eye-mimicry or the conspicuousness hypothesis better explain eyespot efficacy. We used great tits (Parus major) as model predator, and tested their reaction towards animated images on a computer display. Birds were tested against images of butterflies without eyespots, with natural-looking eyespots, and manipulated spots with the same contrast but reduced resemblance to an eye, as well as images of predators (owls) with and without eyes. We found that mimetic eyespots were as effective as true eyes of owls and more efficient in eliciting an aversive response than modified, less mimetic but equally contrasting eyespots. We conclude that the eye-mimicry hypothesis explains our results better than the conspicuousness hypothesis and is thus likely to be an important mechanism behind the evolution of butterfly eyespots. PMID:25854889

  2. Experimental Study of the Relation of Inhibiting Vasculogenic Mimicry and Inducing Cell Apoptosis of Melittin on Osteosarcoma Xenotransplanted Models of Nude Mice%蜂毒素抑制骨肉瘤血管生成拟态与影响肿瘤细胞增殖、调亡的关系

    Institute of Scientific and Technical Information of China (English)

    高启龙; 姚亚民; 杨峰; 田同德; 陈永强

    2011-01-01

    目的:探讨蜂毒素抑制骨肉瘤裸鼠移植瘤的作用及机制.方法:建立裸鼠骨肉瘤原位移植瘤模型,裸鼠18只,随机分3组:生理盐水组,蜂毒素组,顺铂组.观察各组裸鼠骨肉瘤体积和瘤体质量抑制率;应用免疫组化CD34与PAS双重染色法检测各组裸鼠瘤体血管生成拟态密度;免疫组织化学法检测增值细胞核抗原(PCNA)蛋白表达;TUNEL法检测肿瘤细胞凋亡;运用相关性分析法研究蜂毒素抑制骨肉瘤血管生成拟态与影响肿瘤细胞增殖、凋亡的关系.结果:蜂毒素组瘤体积和瘤体质量抑制率分别为42.98%、39.03%,蜂毒素能明显抑制CD34与PAS双重染色法标记的肿瘤血管生成拟态密度,能明显抑制肿瘤细胞增殖、促进细胞凋亡,且蜂毒素抑制肿瘤血管生成拟态密度与肿瘤细胞增殖呈正相关、与细胞凋亡呈负相关.结论:蜂毒素具有抑制骨肉瘤裸鼠移植瘤生长的作用,其作用机制可能与其能够抑制肿瘤血管生成拟态、诱导肿瘤细胞凋亡、抑制细胞增殖有关.%Objective:To study the antitumor effects and mechanism of Melittin on osteosarcoma xenotransplanted models of nude mice. Methods ; Xenotransplanted models of nude mice osteosarcoma cell UMR - 106 in the laevo - hind tibia of nude mice were established. Inoculated mice were randomly divided into normal saline group, positive control group, Melittin group. All the nude mice were sacrificed after treatment, the size and weight of tumor were measured and the tumor volumes and the inhibition rates of tumor were calculated, Expression of PCNA was deteced by immunohistochemical method. The VM density in tumor tissues was detected by CD34 and PAS double staining in vivo. TUNEL semi - quantitative assay was used to study the melittin - induced apoptosis in OS cell line. To study mainly the relation of inhibiting vasculogenic mimicry and inducing cell apoptosis. Results : Inhibiting rate ofmelittin in tumor

  3. Male and Female Differences in Nonconscious Mimicry

    DEFF Research Database (Denmark)

    Lehane, Christine Marie

    2015-01-01

    Previous research on nonconscious mimicry suggests that females mimic their communication partners more often than males. Many studies have investigated the association between mimicry, emotion recognition, and empathy. However, there is a trend in this research area to recruit same-sex samples......, thus neglecting a discussion regarding the role of sex or gender as a moderator of nonconscious mimicry. This article reviews the research on nonconscious mimicry – facial, behavioural, and verbal, in order to identify whether or not there are male and female differences. The results indicate that...... mimicry may be moderated by participant sex or gender depending upon, among others, choice of mimicry measurement, stimulus exposure length, and social context. However, few studies address male and female differences in mimicry and many have methodological limitations. The review concludes with a...

  4. Applying robust control theory to solve problems in bio-medical sciences: study of an apoptotic model

    International Nuclear Information System (INIS)

    Biological models of an apoptotic process are studied using models describing a system of differential equations derived from reaction kinetics information. The mathematical model is re-formulated in a state-space robust control theory framework where parametric and dynamic uncertainty can be modelled to account for variations naturally occurring in biological processes. We propose to handle the nonlinearities using neural networks

  5. Anti-apoptotic treatment in mouse models of age-related hearing loss

    Institute of Scientific and Technical Information of China (English)

    Fengchan Han; Oumei Wang; Quanxiang Cai

    2016-01-01

    Age-related hearing loss (AHL), or presbycusis, is the most common neurodegenerative disorder and top communication deficit of the aged population. Genetic predisposition is one of the major factors in the development of AHL. Generally, AHL is associated with an age-dependent loss of sensory hair cells, spiral ganglion neurons and stria vascularis cells in the inner ear. Although the mechanisms leading to genetic hearing loss are not completely understood, caspase-family proteases function as important signals in the inner ear pathology. It is now accepted that mouse models are the best tools to study the mechanism of genetic hearing loss or AHL. Here, we provide a brief review of recent studies on hearing improvement in mouse models of AHL by anti-apoptotic treatment.

  6. Molecular mimicry and multiple sclerosis

    Institute of Scientific and Technical Information of China (English)

    Michael Namaka; Michael R. Mulvey; Sabina Kapoor; Leann Simms; Christine Leong; Amy Grossberndt; Michael Prouta; Emma Frost; Farid Esfahani; Andrew Gomori

    2011-01-01

    Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system. Although the exact underlying mechanism leading to myelin destruction is unknown, the molecular mimicry theory is the most commonly acknowledged elucidation of MS pathology. Although various antigens have been associated with MS induction, this review presents studies focused on key bacterial and viral antigens that lead to the development of MS. The research specific to a molecular mimicry theory of MS via each implicated agent is weak; however, collectively the reports provide credible support for this theory. Given that homologous sequences are not required to lead to antigenic cross-reactivity, it is reasonable to conclude that certain viral and bacterial antigens with 5-10 similar amino acids in sequence can lead to self destruction of similar myelin sequences. Thus, this literature review has provided insight to further the understanding of the etiology of multiple sclerosis.

  7. A complex mode of aggressive mimicry in a scale-eating cichlid fish.

    Science.gov (United States)

    Boileau, Nicolas; Cortesi, Fabio; Egger, Bernd; Muschick, Moritz; Indermaur, Adrian; Theis, Anya; Büscher, Heinz H; Salzburger, Walter

    2015-09-01

    Aggressive mimicry is an adaptive tactic of parasitic or predatory species that closely resemble inoffensive models in order to increase fitness via predatory gains. Although similarity of distantly related species is often intuitively implicated with mimicry, the exact mechanisms and evolutionary causes remain elusive in many cases. Here, we report a complex aggressive mimicry strategy in Plecodus straeleni, a scale-eating cichlid fish from Lake Tanganyika, which imitates two other cichlid species. Employing targeted sequencing on ingested scales, we show that P. straeleni does not preferentially parasitize its models but—contrary to prevailing assumptions—targets a variety of co-occurring dissimilar looking fish species. Combined with tests for visual resemblance and visual modelling from a prey perspective, our results suggest that complex interactions among different cichlid species are involved in this mimicry system. PMID:26399975

  8. Proposed Pharmacological Countermeasures Against Apoptotic Cell Death in Experimental Models Mimicking Space Environment Damage

    Science.gov (United States)

    Lulli, Matteo; Papucci, Laura; Witort, Ewa; Donnini, Martino; Lapucci, Andrea; Lazzarano, Stefano; Mazzoni, Tiziano; Simoncini, Madine; Falciani, Piergiuseppe; Capaccioli, Sergio

    2008-06-01

    Several damaging agents have been suggested to affect human vision during long term space travels. Recently, apoptosis induced by DNA-damaging agents has emerged as frequent pathogenetic mechanism of ophthalmologic pathologies. Here, we propose two countermeasures: coenzyme Q10 and bcl-2 downregulation preventing antisense oligoribonucleotides (ORNs), aimed to inhibit cellular apoptotic death. Our studies have been carried out on retina and neuronal cultured cells treated with the following apoptotic stimuli mimicking space environment: a several-day exposure to either 3H-labeled tymidine or to the genotoxic drug doxorubicin, UV irradiation, hypoxia and glucose/growth factor starvation (Locke medium). The preliminary results clearly indicate that CoQ10, as well as bcl-2 down-regulation preventing ORNs, significantly counteract apoptosis in response to different DNA damaging agents in cultured eye and in neuronal cells. This supports the possibility that both could be optimal countermeasures against ophthalmologic lesions during space explorations.

  9. Structural and Functional Studies of Peptide-Carbohydrate Mimicry

    Science.gov (United States)

    Johnson, Margaret A.; Pinto, B. Mario

    Certain peptides act as molecular mimics of carbohydrates in that they are specifically recognized by carbohydrate-binding proteins. Peptides that bind to anti-carbohydrate antibodies, carbohydrate-processing enzymes, and lectins have been identified. These peptides are potentially useful as vaccines and therapeutics; for example, immunologically functional peptide molecular mimics (mimotopes) can strengthen or modify immune responses induced by carbohydrate antigens. However, peptides that bind specifically to carbohydrate-binding proteins may not necessarily show the corresponding biological activity, and further selection based on biochemical studies is always required. The degree of structural mimicry required to generate the desired biological activity is therefore an interesting question. This review will discuss recent structural studies of peptide-carbohydrate mimicry employing NMR spectroscopy, X-ray crystallography, and molecular modeling, as well as relevant biochemical data. These studies provide insights into the basis of mimicry at the molecular level. Comparisons with other carbohydrate-mimetic compounds, namely proteins and glycopeptides, will be drawn. Finally, implications for the design of new therapeutic compounds will also be presented.

  10. Where is the love? The social aspects of mimicry

    OpenAIRE

    Van Baaren, R.; Janssen, L; Chartrand, T.L.; Dijksterhuis, A.

    2009-01-01

    One striking characteristic of human social interactions is unconscious mimicry; people have a tendency to take over each other's posture, mannerisms and behaviours without awareness. Our goal is to make the case that unconscious mimicry plays an important role in human social interaction and to show that mimicry is closely related to and moderated by our connectedness to others. First we will position human unconscious mimicry in relation to types of imitation used in cognitive psychology an...

  11. Male and Female Differences in Nonconscious Mimicry: A Systematic Review

    OpenAIRE

    Lehane, Christine M.

    2015-01-01

    Previous research on nonconscious mimicry suggests that females mimic their communication partners more often than males. Many studies have investigated the association between mimicry, emotion recognition, and empathy. However, there is a trend in this research area to recruit same-sex samples, thus neglecting a discussion regarding the role of sex or gender as a moderator of nonconscious mimicry. This article reviews the research on nonconscious mimicry – facial, behavioural, and verbal, in...

  12. The relationship between morphological and behavioral mimicry in hover flies (Diptera: Syrphidae).

    Science.gov (United States)

    Penney, Heather D; Hassall, Christopher; Skevington, Jeffrey H; Lamborn, Brent; Sherratt, Thomas N

    2014-02-01

    Palatable (Batesian) mimics of unprofitable models could use behavioral mimicry to compensate for the ease with which they can be visually discriminated or to augment an already close morphological resemblance. We evaluated these contrasting predictions by assaying the behavior of 57 field-caught species of mimetic hover flies (Diptera: Syrphidae) and quantifying their morphological similarity to a range of potential hymenopteran models. A purpose-built phylogeny for the hover flies was used to control for potential lack of independence due to shared evolutionary history. Those hover fly species that engage in behavioral mimicry (mock stinging, leg waving, wing wagging) were all large wasp mimics within the genera Spilomyia and Temnostoma. While the behavioral mimics assayed were good morphological mimics, not all good mimics were behavioral mimics. Therefore, while the behaviors may have evolved to augment good morphological mimicry, they do not advantage all good mimics. PMID:24464201

  13. Spectacular Batesian mimicry in ants

    Science.gov (United States)

    Ito, Fuminori; Hashim, Rosli; Huei, Yek Sze; Kaufmann, Eva; Akino, Toshiharu; Billen, Johan

    2004-10-01

    The mechanism by which palatable species take advantage of their similarity in appearance to those that are unpalatable, in order to avoid predation, is called Batesian mimicry. Several arthropods are thought to be Batesian mimics of social insects; however, social insects that are Batesian mimics among themselves are rare. In Malaysia we found a possible Batesian mimic in an arboreal ant species, Camponotus sp., which was exclusively observed on foraging trails of the myrmicine ant Crematogaster inflata. The bright yellow and black colouring pattern, as well as the walking behaviour, were very similar in both species. We observed general interactions between the two species, and tested their palatability and the significance of the remarkably similar visual colour patterns for predator avoidance. Prey offered to C. inflata was also eaten by Camponotus workers in spite of their being attacked by C. inflata, indicating that Camponotus sp. is a commensal of C. inflata. An experiment with chicks as potential predators suggests that Camponotus sp. is palatable whereas C. inflata is unpalatable. After tasting C. inflata, the chicks no longer attacked Camponotus sp., indicating that Camponotus sp. is a Batesian mimic of Crematogaster inflata.

  14. Male and Female Differences in Nonconscious Mimicry: A Systematic Review

    DEFF Research Database (Denmark)

    Lehane, Christine Marie

    2015-01-01

    Previous research on nonconscious mimicry suggests that females mimic their communication partners more often than males. Many studies have investigated the association between mimicry, emotion recognition, and empathy. However, there is a trend in this research area to recruit same-sex samples...... mimicry may be moderated by participant sex or gender depending upon, among others, choice of mimicry measurement, stimulus exposure length, and social context. However, few studies address male and female differences in mimicry and many have methodological limitations. The review concludes with a...

  15. Male and Female Differences in Nonconscious Mimicry: A Systematic Review

    Directory of Open Access Journals (Sweden)

    Christine M. Lehane

    2015-12-01

    Full Text Available Previous research on nonconscious mimicry suggests that females mimic their communication partners more often than males. Many studies have investigated the association between mimicry, emotion recognition, and empathy. However, there is a trend in this research area to recruit same-sex samples, thus neglecting a discussion regarding the role of sex or gender as a moderator of nonconscious mimicry. This article reviews the research on nonconscious mimicry – facial, behavioural, and verbal, in order to identify whether or not there are male and female differences. The results indicate that mimicry may be moderated by participant sex or gender depending upon, among others, choice of mimicry measurement, stimulus exposure length, and social context. However, few studies address male and female differences in mimicry and many have methodological limitations. The review concludes with a discussion and recommendations for future research.

  16. Rheumatic fever, autoimmunity, and molecular mimicry: the streptococcal connection.

    Science.gov (United States)

    Cunningham, Madeleine W

    2014-01-01

    The group A streptococcus, Streptococcus pyogenes, and its link to autoimmune sequelae, has acquired a new level of understanding. Studies support the hypothesis that molecular mimicry between the group A streptococcus and heart or brain are important in directing immune responses in rheumatic fever. Rheumatic carditis, Sydenham chorea and a new group of behavioral disorders called pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections are reviewed with consideration of autoantibody and T cell responses and the role of molecular mimicry between the heart, brain and group A streptococcus as well as how immune responses contribute to pathogenic mechanisms in disease. In rheumatic carditis, studies have investigated human monoclonal autoantibodies and T cell clones for their crossreactivity and their mechanisms leading to valve damage in rheumatic heart disease. Although studies of human and animal sera from group A streptococcal diseases or immunization models have been crucial in providing clues to molecular mimicry and its role in the pathogenesis of rheumatic fever, study of human monoclonal autoantibodies have provided important insights into how antibodies against the valve may activate the valve endothelium and lead to T cell infiltration. Passive transfer of anti-streptococcal T cell lines in a rat model of rheumatic carditis illustrates effects of CD4+ T cells on the valve. Although Sydenham chorea has been known as the neurological manifestation of rheumatic fever for decades, the combination of autoimmunity and behavior is a relatively new concept linking brain, behavior and neuropsychiatric disorders with streptococcal infections. In Sydenham chorea, human mAbs and their expression in transgenic mice have linked autoimmunity to central dopamine pathways as well as dopamine receptors and dopaminergic neurons in basal ganglia. Taken together, the studies reviewed provide a basis for understanding streptococcal sequelae and

  17. Galunisertib inhibits glioma vasculogenic mimicry formation induced by astrocytes

    OpenAIRE

    Chao Zhang; Wenliang Chen; Xin Zhang; Bin Huang; Aanjing Chen; Ying He; Jian Wang; Xingang Li

    2016-01-01

    Gliomas are among the most lethal primary brain tumors found in humans. In high-grade gliomas, vasculogenic mimicry is often detected and has been correlated with prognosis, thus suggesting its potential as a therapeutic target. Vasculogenic mimicry mainly forms vascular-like channels independent of endothelial cells; however, little is known about the relationship between astrocytes and vasculogenic mimicry. In our study, we demonstrated that the presence of astrocytes promoted vasculogenic ...

  18. Using Mimicry to Learn about Mental Representations

    OpenAIRE

    Kochanski, Greg

    2012-01-01

    Phonology typically describes speech in terms of discrete signs like features. The field of intonational phonology uses discrete accents to describe intonation and prosody. But, are such representations useful? The results of mimicry experiments indicate that discrete signs are not a useful representation of the shape of intonation contours. Human behaviour seems to be better represented by a attractors where memory retains substantial fine detail about an utterance. There is no evidence that...

  19. Carnosine attenuates early brain injury through its antioxidative and anti-apoptotic effects in a rat experimental subarachnoid hemorrhage model.

    Science.gov (United States)

    Zhang, Zong-yong; Sun, Bao-liang; Yang, Ming-feng; Li, Da-wei; Fang, Jie; Zhang, Shuai

    2015-03-01

    Carnosine (β-alanyl-L-histidine) has been demonstrated to provide antioxidative and anti-apoptotic roles in the animal of ischemic brain injuries and neurodegenerative diseases. The aim of this study was to examine whether carnosine prevents subarachnoid hemorrhage (SAH)-induced early brain injury (EBI) in rats. We found that intraperitoneal administration of carnosine improved neurobehavioral deficits, attenuated brain edema and blood-brain barrier permeability, and decreased reactive oxygen species level at 48 h following SAH in rat models. Carnosine treatment increased tissue copper/zinc superoxide dismutase (CuZn-SOD) and glutathione peroxidase (GSH-Px) enzymatic activities, and reduced post-SAH elevated lactate dehydrogenase (LDH) activity, the concentration of malondialdehyde (MDA), 3-nitrotyrosine (3-NT), 8-hydroxydeoxyguanosine (8-OHDG), interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) in rats. Furthermore, carnosine treatment attenuated SAH-induced microglia activation and cortical neuron apoptosis. These results indicated that administration of carnosine may provide neuroprotection in EBI following SAH in rat models. PMID:25179154

  20. Blocking mimicry makes true and false smiles look the same.

    Directory of Open Access Journals (Sweden)

    Magdalena Rychlowska

    Full Text Available Recent research suggests that facial mimicry underlies accurate interpretation of subtle facial expressions. In three experiments, we manipulated mimicry and tested its role in judgments of the genuineness of true and false smiles. Experiment 1 used facial EMG to show that a new mouthguard technique for blocking mimicry modifies both the amount and the time course of facial reactions. In Experiments 2 and 3, participants rated true and false smiles either while wearing mouthguards or when allowed to freely mimic the smiles with or without additional distraction, namely holding a squeeze ball or wearing a finger-cuff heart rate monitor. Results showed that blocking mimicry compromised the decoding of true and false smiles such that they were judged as equally genuine. Together the experiments highlight the role of facial mimicry in judging subtle meanings of facial expressions.

  1. Multi-trait mimicry and the relative salience of individual traits.

    Science.gov (United States)

    Kazemi, Baharan; Gamberale-Stille, Gabriella; Leimar, Olof

    2015-11-01

    Mimicry occurs when one species gains protection from predators by resembling an unprofitable model species. The degree of mimic-model similarity is variable in nature and is closely related to the number of traits that the mimic shares with its model. Here, we experimentally test the hypothesis that the relative salience of traits, as perceived by a predator, is an important determinant of the degree of mimic-model similarity required for successful mimicry. We manipulated the relative salience of the traits of a two-trait artificial model prey, and subsequently tested the survival of mimics of the different traits. The unrewarded model prey had two colour traits, black and blue, and the rewarded prey had two combinations of green, brown and grey shades. Blue tits were used as predators. We found that the birds perceived the black and blue traits to be similarly salient in one treatment, and mimic-model similarity in both traits was then required for high mimic success. In a second treatment, the blue trait was the most salient trait, and mimic-model similarity in this trait alone achieved high success. Our results thus support the idea that similar salience of model traits can explain the occurrence of multi-trait mimicry. PMID:26511051

  2. Refining mimicry: phenotypic variation tracks the local optimum.

    Science.gov (United States)

    Mérot, Claire; Le Poul, Yann; Théry, Marc; Joron, Mathieu

    2016-07-01

    Müllerian mimicry between chemically defended preys is a textbook example of natural selection favouring phenotypic convergence onto a shared warning signal. Studies of mimicry have concentrated on deciphering the ecological and genetic underpinnings of dramatic switches in mimicry association, producing a well-known mosaic distribution of mimicry patterns across geography. However, little is known about the accuracy of resemblance between natural comimics when the local phenotypic optimum varies. In this study, using analyses of wing shape, pattern and hue, we quantify multimodal phenotypic similarity between butterfly comimics sharing the so-called postman pattern in different localities with varying species composition. We show that subtle but consistent variation between populations of the localized species, Heliconius timareta thelxinoe, enhance resemblance to the abundant comimics which drive the mimicry in each locality. Those results suggest that rarer comimics track the changes in the phenotypic optimum caused by gradual changes in the composition of the mimicry community, providing insights into the process by which intraspecific diversity of mimetic pattern may arise. Furthermore, our results suggest a multimodal evolution of similarity, with coordinated convergence in different features of the phenotype such as wing outline, pattern and hue. Finally, multilocus genotyping allows estimating local hybridization rates between H. timareta and comimic H. melpomene in different populations, raising the hypothesis that mimicry refinement between closely related comimics may be enhanced by adaptive introgression at loci modifying the accuracy of resemblance. PMID:27003742

  3. (1) H-NMR relaxometric studies of interaction between apoptosis specific MRI paramagnetic contrast agents and micellar models of apoptotic cells.

    Science.gov (United States)

    Van Koninckxloo, Aurore; Henoumont, Céline; Laurent, Sophie; Muller, Robert N; Vander Elst, Luce

    2016-07-01

    (1) H-NMR was previously used to analyze the interaction between peptides (E3 and R826) selected by phage display to target apoptotic cells and phospholipidic models of these cells. In order to avoid the use of apoptotic cells and to obtain a fast evaluation of the efficiency of the potential MRI contrast agents obtained by grafting these peptides and their scramble analogs on a paramagnetic gadolinium complex, their proton relaxometric behavior was investigated in the presence of micelles mimicking healthy and apoptotic cells. Their preferential interaction with 1,2-dipalmitoyl-sn-glycero-3-phospho-l-serine micelles mimicking apoptotic cells as compared with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine micelles modeling healthy cells was shown by nuclear magnetic relaxation dispersion profiles and the enhancement of the transverse proton relaxation rates at 60 MHz. The association constant values confirm the stronger interaction of the selected conjugated peptides (Ka Gd-PMN-E3(gadolinium 2,2',2'',2'''-[((4-carboxy)pyridine-2,6-diyl)bis(methylenenitrilo)]-tetrakis acetate) grafted with E3 peptide): 2.43 10(4)  m(-1) ; Ka Gd-DTPA-R826(gadolinium ((1-p-isothiocyanatobenzyl)-diethylenetriaminepentaacetate) grafted with R826 peptide): 2.91 10(4)  m(-1) ) as compared with their conjugated scrambles (Ka Gd-PMN-E3sc(gadolinium 2,2',2'',2'''-[((4-carboxy)pyridine-2,6-diyl)bis(methylenenitrilo)]-tetrakis acetate) grafted with E3 scramble peptide): 0.18 10(4)  m(-1) ; Ka Gd-DTPA-R826sc(gadolinium ((1-p-isothiocyanatobenzyl)-diethylenetriaminepentaacetate) grafted with R826 scramble peptide): 0.32 10(4)  m(-1) ) even if the conjugation of E3 and R826 seems to decrease their interaction. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26647764

  4. Spontaneous human speech mimicry by a cetacean.

    Science.gov (United States)

    Ridgway, Sam; Carder, Donald; Jeffries, Michelle; Todd, Mark

    2012-10-23

    Although dolphins (Tursiops truncatus) have been trained to match numbers and durations of human vocal bursts and reported to spontaneously match computer-generated whistles, spontaneous human voice mimicry has not previously been demonstrated. The first to study white whale (Delphinapterus leucas) sounds in the wild, Schevill and Lawrence wrote that "occasionally the calls would suggest a crowd of children shouting in the distance". Fish and Mowbary described sound types and reviewed past descriptions of sounds from this vociferous species. At Vancouver Aquarium, Canada, keepers suggested that a white whale about 15 years of age, uttered his name "Lagosi". Other utterances were not perceptible, being described as "garbled human voice, or Russian, or similar to Chinese" by R.L. Eaton in a self-published account in 1979. However, hitherto no acoustic recordings have shown how such sounds emulate speech and deviate from the usual calls of the species. We report here sound recordings and analysis which demonstrate spontaneous mimicry of the human voice, presumably a result of vocal learning, by a white whale. PMID:23098588

  5. Cytotoxicity and apoptotic gene expression in an in vitro model of the blood-brain barrier following exposure to poly(butylcyanoacrylate) nanoparticles.

    Science.gov (United States)

    Hall, Andrew M; Hemmer, Ruth; Spaulding, Robert; Wetzel, Hanna N; Curcio, Joseph; Sabel, Bernhard A; Henrich-Noack, Petra; Pixley, Sarah; Hopkins, Tracy; Boyce, Richard L; Schultheis, Patrick J; Haik, Kristi L

    2016-08-01

    Background Poly(butylcyanoacrylate) (PBCA) nanoparticles (NPs) loaded with doxorubicin (DOX) and coated with polysorbate 80 (PS80) have shown efficacy in the treatment of rat glioblastoma. However, cytotoxicity of this treatment remains unclear. Purpose The purpose of this study was to investigate cytotoxicity and apoptotic gene expression using a proven in vitro co-culture model of the blood-brain barrier. Methods The co-cultures were exposed to uncoated PBCA NPs, PBCA-PS80 NPs or PBCA-PS80-DOX NPs at varying concentrations and evaluated using a resazurin-based cytotoxicity assay and an 84-gene apoptosis RT-PCR array. Results The cytotoxicity assays showed PBCA-PS80-DOX NPs exhibited a decrease in metabolic function at lower concentrations than uncoated PBCA NPs and PBCA-PS80 NPs. The apoptosis arrays showed differential expression of 18 genes in PBCA-PS80-DOX treated cells compared to the untreated control. Discussion As expected, the cytotoxicity assays demonstrated enhanced dose-dependent toxicity in the DOX loaded NPs. The differentially expressed apoptotic genes participate in both the tumor necrosis factor receptor-1 and mitochondria-associated apoptotic pathways implicated in current DOX chemotherapeutic toxicity. Conclusion The following data suggest that the cytotoxic effect may be attributed to DOX and not the NPs themselves, further supporting the use of PBCA-PS80 NPs as an effective drug delivery vehicle for treating central nervous system conditions. PMID:26707984

  6. Molecular mimicry and clonal deletion: A fresh look.

    Science.gov (United States)

    Rose, Noel R

    2015-06-21

    In this article, I trace the historic background of clonal deletion and molecular mimicry, two major pillars underlying our present understanding of autoimmunity and autoimmune disease. Clonal deletion originated as a critical element of the clonal selection theory of antibody formation in order to explain tolerance of self. If we did have complete clonal deletion, there would be major voids, the infamous "black holes", in our immune repertoire. For comprehensive, protective adaptive immunity, full deletion is necessarily a rare event. Molecular mimicry, the sharing of epitopes among self and non-self antigens, is extraordinary common and provides the evidence that complete deletion of self-reactive clones is rare. If molecular mimicry were not common, protective adaptive immunity could not be all-encompassing. By taking a fresh look at these two processes together we can envision their evolutionary basis and understand the need for regulatory devices to prevent molecular mimicry from progressing to autoimmune disease. PMID:25172771

  7. Autistic traits modulate mimicry of social but not nonsocial rewards

    OpenAIRE

    Haffey, Anthony; Press, Clare; O'Connell, Garret; Chakrabarti, Bhisma

    2013-01-01

    Autism Spectrum Conditions (ASC) are associated with diminished responsiveness to social stimuli, and especially to social rewards such as smiles. Atypical responsiveness to social rewards, which reinforce socially appropriate behavior in children, can potentially lead to a cascade of deficits in social behavior. Individuals with ASC often show diminished spontaneous mimicry of social stimuli in a natural setting. In the general population, mimicry is modulated both by the reward value and th...

  8. Pro-apoptotic activity of α-bisabolol in preclinical models of primary human acute leukemia cells

    Directory of Open Access Journals (Sweden)

    Fato Romana

    2011-04-01

    Full Text Available Abstract Background We previously demonstrated that the plant-derived agent α-bisabolol enters cells via lipid rafts, binds to the pro-apoptotic Bcl-2 family protein BID, and may induce apoptosis. Here we studied the activity of α-bisabolol in acute leukemia cells. Methods We tested ex vivo blasts from 42 acute leukemias (14 Philadelphia-negative and 14 Philadelphia-positive B acute lymphoid leukemias, Ph-/Ph+B-ALL; 14 acute myeloid leukemias, AML for their sensitivity to α-bisabolol in 24-hour dose-response assays. Concentrations and time were chosen based on CD34+, CD33+my and normal peripheral blood cell sensitivity to increasing α-bisabolol concentrations for up to 120 hours. Results A clustering analysis of the sensitivity over 24 hours identified three clusters. Cluster 1 (14 ± 5 μM α-bisabolol IC50 included mainly Ph-B-ALL cells. AML cells were split into cluster 2 and 3 (45 ± 7 and 65 ± 5 μM IC50. Ph+B-ALL cells were scattered, but mainly grouped into cluster 2. All leukemias, including 3 imatinib-resistant cases, were eventually responsive, but a subset of B-ALL cells was fairly sensitive to low α-bisabolol concentrations. α-bisabolol acted as a pro-apoptotic agent via a direct damage to mitochondrial integrity, which was responsible for the decrease in NADH-supported state 3 respiration and the disruption of the mitochondrial membrane potential. Conclusion Our study provides the first evidence that α-bisabolol is a pro-apoptotic agent for primary human acute leukemia cells.

  9. Unlinked Mendelian inheritance of red and black pigmentation in snakes: Implications for Batesian mimicry.

    Science.gov (United States)

    Davis Rabosky, Alison R; Cox, Christian L; Rabosky, Daniel L

    2016-04-01

    Identifying the genetic basis of mimetic signals is critical to understanding both the origin and dynamics of mimicry over time. For species not amenable to large laboratory breeding studies, widespread color polymorphism across natural populations offers a powerful way to assess the relative likelihood of different genetic systems given observed phenotypic frequencies. We classified color phenotype for 2175 ground snakes (Sonora semiannulata) across the continental United States to analyze morph ratios and test among competing hypotheses about the genetic architecture underlying red and black coloration in coral snake mimics. We found strong support for a two-locus model under simple Mendelian inheritance, with red and black pigmentation being controlled by separate loci. We found no evidence of either linkage disequilibrium between loci or sex linkage. In contrast to Batesian mimicry systems such as butterflies in which all color signal components are linked into a single "supergene," our results suggest that the mimetic signal in colubrid snakes can be disrupted through simple recombination and that color evolution is likely to involve discrete gains and losses of each signal component. Both outcomes are likely to contribute to the exponential increase in rates of color evolution seen in snake mimicry systems over insect systems. PMID:26959901

  10. Accumulation of the anandamide precursor and other N-acylethanolamine phospholipids in infant rat models of in vivo necrotic and apoptotic neuronal death

    DEFF Research Database (Denmark)

    Hansen, H.H.; Ikonomidou, C.; Bittigau, P.;

    2001-01-01

    the corresponding precursors, N-acylethanolamine phospholipids (NAPEs). However, it is unknown whether this key event for NAE formation is regulated differently in the context of insults causing necrotic or apoptotic neuronal death. To address this question, we monitored a range of Cortical NAPE...... species in three infant rat models of in vivo neurodegeneration: (i) necrosis caused by intrastriatal injection of NMDA (25 nmol); (ii) apoptosis induced by systemic administration of the NMDA-receptor antagonist (+)MK-801 (3 × 0.5 mg/kg, i.p.); and (iii) apoptosis following focal necrosis triggered by...

  11. The Face of the Chameleon: The Experience of Facial Mimicry for the Mimicker and the Mimickee

    OpenAIRE

    Kulesza, Wojciech Marek; Cisłak, Aleksandra; Vallacher, Robin R.; Nowak, Andrzej; Czekiel, Martyna; Bedynska, Sylwia

    2015-01-01

    ABSTRACT This research addressed three questions concerning facial mimicry: (a) Does the relationship between mimicry and liking characterize all facial expressions, or is it limited to specific expressions? (b) Is the relationship between facial mimicry and liking symmetrical for the mimicker and the mimickee? (c) Does conscious mimicry have consequences for emotion recognition? A paradigm is introduced in which participants interact over a computer setup with a confederate whose prerecorded...

  12. Radiation Sensitivity in a Preclinical Mouse Model of Medulloblastoma Relies on the Function of the Intrinsic Apoptotic Pathway.

    Science.gov (United States)

    Crowther, Andrew J; Ocasio, Jennifer K; Fang, Fang; Meidinger, Jessica; Wu, Jaclyn; Deal, Allison M; Chang, Sha X; Yuan, Hong; Schmid, Ralf; Davis, Ian; Gershon, Timothy R

    2016-06-01

    While treatments that induce DNA damage are commonly used as anticancer therapies, the mechanisms through which DNA damage produces a therapeutic response are incompletely understood. Here we have tested whether medulloblastomas must be competent for apoptosis to be sensitive to radiotherapy. Whether apoptosis is required for radiation sensitivity has been controversial. Medulloblastoma, the most common malignant brain tumor in children, is a biologically heterogeneous set of tumors typically sensitive to radiation and chemotherapy; 80% of medulloblastoma patients survive long-term after treatment. We used functional genetic studies to determine whether the intrinsic apoptotic pathway is required for radiation to produce a therapeutic response in mice with primary, Shh-driven medulloblastoma. We found that cranial radiation extended the survival of medulloblastoma-bearing mice and induced widespread apoptosis. Expression analysis and conditional deletion studies showed that Trp53 (p53) was the predominant transcriptional regulator activated by radiation and was strictly required for treatment response. Deletion of Bax, which blocked apoptosis downstream of p53, was sufficient to render tumors radiation resistant. In apoptosis-incompetent, Bax-deleted tumors, radiation activated p53-dependent transcription without provoking cell death and caused two discrete populations to emerge. Most radiated tumor cells underwent terminal differentiation. Perivascular cells, however, quickly resumed proliferation despite p53 activation, behaved as stem cells, and rapidly drove recurrence. These data show that radiation must induce apoptosis in tumor stem cells to be effective. Mutations that disable the intrinsic apoptotic pathways are sufficient to impart radiation resistance. We suggest that medulloblastomas are typically sensitive to DNA-damaging therapies, because they retain apoptosis competence. Cancer Res; 76(11); 3211-23. ©2016 AACR. PMID:27197166

  13. A Postcolonial Reading of Pygmalion: A Play of 'Mimicry'

    Directory of Open Access Journals (Sweden)

    Samira Sasani

    2015-03-01

    Full Text Available Bernard Shaw's Pygmalion portrays the mutually complex relationship between the colonizer and the colonized.  Pygmalion, a mimicry play, shows how the mimicry strategy, proposed by Homi K. Bhabha, paradoxically functions as both resemblance and menace in the hands of the colonizer and the Other.  Based on Homi K. Bhabha's theories, the Other employs the mimicry strategy either too perfectly or imperfectly as a sign of resistance to servitude; on the other hand, employing the colonial mimicry strategy, the colonizer desires a reformed recognizable Other as a subject of difference that is almost the same, but not quite. This paper tries to show how Higgins, the colonizer, and Eliza, the colonized enter the Third Space in which no party has priority over the other; in which power relationships are reciprocal and their identities are mutually constructed.  Pygmalion depicts an untenable situation in which both the colonizer and the colonized are entrapped. Keywords: Identity construction, power relations, colonial mimicry strategy, Third Space

  14. Viral mimicry of the complement system

    Indian Academy of Sciences (India)

    John Bernet; Jayati Mullick; Akhilesh K Singh; Arvind Sahu

    2003-04-01

    The complement system is a potent innate immune mechanism consisting of cascades of proteins which are designed to fight against and annul intrusion of all the foreign pathogens. Although viruses are smaller in size and have relatively simple structure, they are not immune to complement attack. Thus, activation of the complement system can lead to neutralization of cell-free viruses, phagocytosis of C3b-coated viral particles, lysis of virus-infected cells, and generation of inflammatory and specific immune responses. However, to combat host responses and succeed as pathogens, viruses not only have developed/adopted mechanisms to control complement, but also have turned these interactions to their own advantage. Important examples include poxviruses, herpesviruses, retroviruses, paramyxoviruses and picornaviruses. In this review, we provide information on the various complement evasion strategies that viruses have developed to thwart the complement attack of the host. A special emphasis is given on the interactions between the viral proteins that are involved in molecular mimicry and the complement system.

  15. Mimicry Enhances Observational Learning in 16-Month-Old Infants.

    Directory of Open Access Journals (Sweden)

    Eszter Somogyi

    Full Text Available We examined the effect of mimicry on how 16-month-old infants learn by observation a novel tool use action, which consisted of using a rake to retrieve a toy. Across four conditions, we manipulated whether during an initial play phase, an adult mimicked the infant's play or not (testing the effect of mimicry, the infant played with the adult or played alone (controlling the effect of interacting with a contingent partner and whether the infant saw a demonstration of the tool's use or not (evaluating baseline performance. We found that infants who had been mimicked learned best from a demonstration of the rake's use and performed better than infants who only played with the experimenter without mimicry or played by themselves before the demonstration. As expected, infants did not learn from a demonstration of the rake's use when they played by themselves and thus had no previous interaction with an experimenter. The mechanisms driving this powerful learning effect of mimicry are discussed.

  16. Advergence in Müllerian mimicry: the case of the poison dart frogs of Northern Peru revisited

    OpenAIRE

    Chouteau, Mathieu; Summers, Kyle; Morales, Victor; Angers, Bernard

    2011-01-01

    Whether the evolution of similar aposematic signals in different unpalatable species (i.e. Müllerian mimicry) is because of phenotypic convergence or advergence continues to puzzle scientists. The poison dart frog Ranitomeya imitator provides a rare example in support of the hypothesis of advergence: this species was believed to mimic numerous distinct model species because of high phenotypic variability and low genetic divergence among populations. In this study, we test the evidence in supp...

  17. The Face of the Chameleon: The Experience of Facial Mimicry for the Mimicker and the Mimickee.

    Science.gov (United States)

    Kulesza, Wojciech Marek; Cisłak, Aleksandra; Vallacher, Robin R; Nowak, Andrzej; Czekiel, Martyna; Bedynska, Sylwia

    2015-01-01

    This research addressed three questions concerning facial mimicry: (a) Does the relationship between mimicry and liking characterize all facial expressions, or is it limited to specific expressions? (b) Is the relationship between facial mimicry and liking symmetrical for the mimicker and the mimickee? (c) Does conscious mimicry have consequences for emotion recognition? A paradigm is introduced in which participants interact over a computer setup with a confederate whose prerecorded facial displays of emotion are synchronized with participants' behavior to create the illusion of social interaction. In Experiment 1, the confederate did or did not mimic participants' facial displays of various subsets of basic emotions. Mimicry promoted greater liking for the confederate regardless of which emotions were mimicked. Experiment 2 reversed these roles: participants were instructed to mimic or not to mimic the confederate's facial displays. Mimicry did not affect liking for the confederate but it did impair emotion recognition. PMID:25811746

  18. Facial mimicry and the mirror neuron system:Simultaneous acquisition of facial electromyography and functional magnetic resonance imaging

    Directory of Open Access Journals (Sweden)

    Katja U Likowski

    2012-07-01

    Full Text Available Numerous studies have shown that humans automatically react with congruent facial reactions, i.e. facial mimicry, when seeing a vis-á-vis’ facial expressions. The current experiment is the first investigating the neuronal structures responsible for differences in the occurrence of such facial mimicry reactions by simultaneously measuring BOLD and facial EMG in an MRI scanner. Therefore, 20 female students viewed emotional facial expressions (happy, sad, and angry of male and female avatar characters. During Differentiation presentation, the BOLD signal as well as M. zygomaticus major and M. corrugator supercilii activity were recorded simultaneously. Results show prototypical patterns of facial mimicry after correction for MR-related artifacts: enhanced M. zygomaticus major activity in response to happy and enhanced M. corrugator supercilii activity in response to sad and angry expressions. Regression analyses show that these congruent facial reactions correlate significantly with activations in the IFG, SMA and cerebellum. Stronger zygomaticus reactions to happy faces were further associated to increased activities in the caudate, MTG and PCC. Corrugator reactions to angry expressions were further correlated with the hippocampus, insula and STS. Results are discussed in relation to core and extended models of the mirror neuron system.

  19. Bridging the Mechanical and the Human Mind: Spontaneous Mimicry of a Physically Present Android

    OpenAIRE

    Hofree, Galit; Ruvolo, Paul; Bartlett, Marian Stewart; Winkielman, Piotr

    2014-01-01

    The spontaneous mimicry of others' emotional facial expressions constitutes a rudimentary form of empathy and facilitates social understanding. Here, we show that human participants spontaneously match facial expressions of an android physically present in the room with them. This mimicry occurs even though these participants find the android unsettling and are fully aware that it lacks intentionality. Interestingly, a video of that same android elicits weaker mimicry reactions, occurring onl...

  20. Cognitive Dimensions of Predator Responses to Imperfect Mimicry

    OpenAIRE

    Lars Chittka; Daniel Osorio

    2007-01-01

    Many palatable animals, for example hoverflies, deter predators by mimicking well-defended insects such as wasps. However, for human observers, these flies often seem to be little better than caricatures of wasps—their visual appearance and behaviour are easily distinguishable from those which they are attempting to mimic. This imperfect mimicry baffles evolutionary biologists, because one might expect natural selection to do a more thorough job. Here we discuss two types of cognitive process...

  1. Emotion Mimicry in Humanoid Robots Using Computational Theory of Perception

    OpenAIRE

    Davoudi, Mohsen; Davoudi, Mehdi; Naraghi, Nima Seif

    2009-01-01

    Emotion mimicry is such an area, where presentation of the proper emotion is based on a combination of various quantitative as well as qualitative measurements. In this perspective, a major shortcoming of existing approaches is that, based as they are on bivalent, they don't provide tools for dealing with perception-based information. It is not possible to construct a computational theory of perceptions within the conceptual structure of bivalent logic and probability theory in this area. Wit...

  2. A Müllerian mimicry ring in Appalachian millipedes

    OpenAIRE

    Marek, Paul E.; Bond, Jason E.

    2009-01-01

    Few biological phenomena provide such an elegant and straightforward example of evolution by natural selection as color mimicry among unrelated organisms. By mimicking the appearance of a heavily defended aposematic species, members of a second species gain protection from predators and, potentially, enhanced fitness. Mimicking a preexisting warning advertisement is economical because a potentially costly novel one can be avoided; simultaneously, the addition of more aposematic individuals en...

  3. Relationships among Facial Mimicry, Emotional Experience, and Emotion Recognition

    OpenAIRE

    Wataru Sato; Tomomi Fujimura; Takanori Kochiyama; Naoto Suzuki

    2013-01-01

    BACKGROUND: The relationships between facial mimicry and subsequent psychological processes remain unclear. We hypothesized that the congruent facial muscle activity would elicit emotional experiences and that the experienced emotion would induce emotion recognition. METHODOLOGY/PRINCIPAL FINDINGS: To test this hypothesis, we re-analyzed data collected in two previous studies. We recorded facial electromyography (EMG) from the corrugator supercilii and zygomatic major and obtained ratings on ...

  4. Relationships among Facial Mimicry, Emotional Experience, and Emotion Recognition

    OpenAIRE

    Sato, Wataru; Fujimura, Tomomi; Kochiyama, Takanori; Suzuki, Naoto

    2013-01-01

    Background The relationships between facial mimicry and subsequent psychological processes remain unclear. We hypothesized that the congruent facial muscle activity would elicit emotional experiences and that the experienced emotion would induce emotion recognition. Methodology/Principal Findings To test this hypothesis, we re-analyzed data collected in two previous studies. We recorded facial electromyography (EMG) from the corrugator supercilii and zygomatic major and obtained ratings on sc...

  5. Vascular mimicry in cultured head and neck tumour cell lines

    OpenAIRE

    Upile, Tahwinder; Jerjes, Waseem; Radhi, Hani; Al-Khawalde, Mohammed; Kafas, Panagiotis; Nouraei, Seyed; Sudhoff, Holger

    2011-01-01

    Introduction Vascuologenesis is the de novo establishment of blood vessels and vascular networks from mesoderm-derived endothelial cell precursors (angioblasts). Recently a novel mechanism, by which some genetically deregulated and aggressive tumour cells generate "micro-vascular" channels without the participation of endothelial cells and independent of angiogenesis, has been proposed. This has been termed "vasculogenic mimicry" and has implications beyond angiogenesis and adds another layer...

  6. Colour mimicry and sexual deception by Tongue orchids ( Cryptostylis)

    Science.gov (United States)

    Gaskett, A. C.; Herberstein, M. E.

    2010-01-01

    Typically, floral colour attracts pollinators by advertising rewards such as nectar, but how does colour function when pollinators are deceived, unrewarded, and may even suffer fitness costs? Sexually deceptive orchids are pollinated only by male insects fooled into mating with orchid flowers and inadvertently transferring orchid pollinia. Over long distances, sexually deceptive orchids lure pollinators with counterfeit insect sex pheromones, but close-range deception with colour mimicry is a tantalising possibility. Here, for the first time, we analyse the colours of four sexually deceptive Cryptostylis orchid species and the female wasp they mimic ( Lissopimpla excelsa, Ichneumonidae), from the perspective of the orchids’ single, shared pollinator, male Lissopimpla excelsa. Despite appearing different to humans, the colours of the orchids and female wasps were effectively identical when mapped into a hymenopteran hexagonal colour space. The orchids and wasps reflected predominantly red-orange wavelengths, but UV was also reflected by raised bumps on two orchid species and by female wasp wings. The orchids’ bright yellow pollinia contrasted significantly with their overall red colour. Orchid deception may therefore involve accurate and species-specific mimicry of wavelengths reflected by female wasps, and potentially, exploitation of insects’ innate attraction to UV and yellow wavelengths. In general, mimicry may be facilitated by exploiting visual vulnerabilities and evolve more readily at the peripheries of sensory perception. Many sexually deceptive orchids are predominantly red, green or white: colours that are all potentially difficult for hymenoptera to detect or distinguish from the background.

  7. Emotional mimicry signals pain empathy as evidenced by facial electromyography.

    Science.gov (United States)

    Sun, Ya-Bin; Wang, Yu-Zheng; Wang, Jin-Yan; Luo, Fei

    2015-01-01

    Facial mimicry has been suggested to be a behavioral index for emotional empathy. The present study is the first to investigate the link between facial muscle activity and empathy for pain by facial electromyographic (EMG) recording while observers watched videos depicting real-life painful events. Three types of visual stimulus were used: an intact painful scene and arm-only (needle injection) and face only (painful expression) scenes. Enhanced EMG activity of the corrugator supercilii (CS) and zygomaticus major (ZM) muscles was found when observers viewed others in pain, supporting a unique pain expression that is distinct from the expression of basic emotions. In the intact video stimulus condition, CS activity was correlated positively with the empathic concern score and ZM activity, suggesting facial mimicry mediated empathy for pain. Cluster analysis of facial EMG responses revealed markedly different patterns among stimulus types, including response category, ratio, and temporal dynamics, indicating greater ecological validity of the intact scene in eliciting pain empathy as compared with partial scenes. This study is the first to quantitatively describe pain empathy in terms of facial EMG data. It may provide important evidence for facial mimicry as a behavioral indicator of pain empathy. PMID:26647740

  8.  Molecular mimicry in the etiology of autoimmune diseases

    Directory of Open Access Journals (Sweden)

    Jolanta Lis

    2012-07-01

    Full Text Available  There are currently more than 80 different autoimmune diseases, affecting approximately 100 million people worldwide. The etiology of most autoimmune diseases is unknown. The highest incidence of these diseases is in the developed countries and they are more common in women than in men. Among the most often listed factors responsible for the onset of autoimmunity are genetic predisposition and the phenomenon known as molecular mimicry. The latter stems from a similarity between microbial antigens and antigens present in the human body (self antigens. It is believed that such homology is responsible for the production of auto-antibodies and in consequence attack of the immune system against host tissues and organs. However, the main molecular factors responsible for these diseases in most cases remain unknown. While pathogenesis of many autoimmune diseases indicates the presence of molecular mimicry, at the same time the similarities between the own and foreign structures do not always result in autoimmunity. Therefore, prediction of such crucial homology responsible for the development of autoimmune disease is extremely difficult. In this paper we present examples of autoimmune diseases such as type 1 diabetes, multiple sclerosis, reactive arthritis and the potential contribution of micro-organisms to the mechanism of molecular mimicry.

  9. Gender differences in the neural network of facial mimicry of smiles – An rTMS study

    OpenAIRE

    Korb, Sebastian; Malsert, Jennifer; Rochas, Vincent; Rihs, Tonia; Rieger, Sebastian Walter; Schwab, Samir; Niedenthal, Paula M.; Grandjean, Didier Maurice

    2015-01-01

    Under theories of embodied emotion, exposure to a facial expression triggers facial mimicry. Facial feedback is then used to recognize and judge the perceived expression. However, the neural bases of facial mimicry and of the use of facial feedback remain poorly understood. Furthermore, gender differences in facial mimicry and emotion recognition suggest that different neural substrates might accompany the production of facial mimicry, and the processing of facial feedback, in men and women. ...

  10. Biological studies in animal models using [99mTc](CO)3 recombinant annexin V as diagnostic agent of apoptotic processes

    International Nuclear Information System (INIS)

    Introduction: There are many diseases associated with variations in the expression of apoptosis such as organ rejection after transplantation, myocardial ischemia or infarct and neurodegenerative diseases. For this reason, the early visualization of this process is relevant to set fast and effective therapeutic strategies. Methods: The precursor was prepared according to the procedure reported by R. Alberto, R. Schibli, P. Schubiger, U. Abram, and T. Kaden [Reactions with the technetium and rhenium carbonyl complexes (NEt4)[MX3(CO)3]. Synthesis and structure of Tc(CN-But)3(CO)3](NO3) and (Net4)[Tc2(μ-SCH2CH2OH)3(CO)3], Polyhedron 1996;15: 1079-89]. Recombinant annexin V was incubated with [99mTc](H2O)3(CO)3+ solution, previously neutralized with buffer. Biodistribution studies were performed in 8-week-old female Wistar rats. Animals were housed and treated in compliance with institutional guidelines related to animal experimentation. Work protocol was previously approved by the Animal Ethics Committee of the university. Two groups of rats were defined. One was used as control and the other group was previously injected with 150 mg/kg ip of cyclophosphamide to induce apoptosis. Results: The synthesis of carbonyl precursor achieved yields higher than 90%, and the radiolabeled protein was obtained with 92% of radiochemical purity and high stability in vitro. An important uptake in apoptotic tissues was confirmed by biodistributions, scintigraphic images and histological studies. Conclusions: Biodistribution studies revealed hepatobiliary elimination, high stability in vivo and important uptake in the reticuloendothelial system. In the pathologic model, higher uptake values correspond to the liver, spleen, lungs and femur. Histological studies confirmed the development of apoptosis at 8 and 24 h postinduction in the spleen and lymphocyte bulks in the peribronchial area. Scintigraphic images confirmed high uptake both the spleen and the lungs.

  11. Methanolic extract of white asparagus shoots activates TRAIL apoptotic death pathway in human cancer cells and inhibits colon carcinogenesis in a preclinical model.

    Science.gov (United States)

    Bousserouel, Souad; Le Grandois, Julie; Gossé, Francine; Werner, Dalal; Barth, Stephan W; Marchioni, Eric; Marescaux, Jacques; Raul, Francis

    2013-08-01

    Shoots of white asparagus are a popular vegetable dish, known to be rich in many bioactive phytochemicals reported to possess antioxidant, and anti-inflammatory and antitumor activities. We evaluated the anticancer mechanisms of a methanolic extract of Asparagus officinalis L. shoots (Asp) on human colon carcinoma cells (SW480) and their derived metastatic cells (SW620), and Asp chemopreventive properties were also assessed in a model of colon carcinogenesis. SW480 and SW620 cell proliferation was inhibited by 80% after exposure to Asp (80 µg/ml). We demonstrated that Asp induced cell death through the activation of TRAIL DR4/DR5 death receptors leading to the activation of caspase-8 and caspase-3 and to cell apoptosis. By specific blocking agents of DR4/DR5 receptors we were able to prevent Asp-triggered cell death confirming the key role of DR4/DR5 receptors. We found also that Asp (80 µg/ml) was able to potentiate the effects of the cytokine TRAIL on cell death even in the TRAIL-resistant metastatic SW620 cells. Colon carcinogenesis was initiated in Wistar rats by intraperitoneal injections of azoxymethane (AOM), once a week for two weeks. One week after (post-initiation) rats received daily Asp (0.01%, 14 mg/kg body weight) in drinking water. After 7 weeks of Asp-treatment the colon of rats exhibited a 50% reduction of the number of preneoplastic lesions (aberrant crypt foci). In addition Asp induced inhibition of several pro-inflammatory mediators, in association with an increased expression of host-defense mediators. In the colonic mucosa of Asp-treated rats we also confirmed the pro-apoptotic effects observed in vitro including the activation of the TRAIL death‑receptor signaling pathway. Taken together, our data highlight the chemopreventive effects of Asp on colon carcinogenesis and its ability to promote normal cellular homeostasis. PMID:23754197

  12. Bridging the mechanical and the human mind: spontaneous mimicry of a physically present android.

    Directory of Open Access Journals (Sweden)

    Galit Hofree

    Full Text Available The spontaneous mimicry of others' emotional facial expressions constitutes a rudimentary form of empathy and facilitates social understanding. Here, we show that human participants spontaneously match facial expressions of an android physically present in the room with them. This mimicry occurs even though these participants find the android unsettling and are fully aware that it lacks intentionality. Interestingly, a video of that same android elicits weaker mimicry reactions, occurring only in participants who find the android "humanlike." These findings suggest that spontaneous mimicry depends on the salience of humanlike features highlighted by face-to-face contact, emphasizing the role of presence in human-robot interaction. Further, the findings suggest that mimicry of androids can dissociate from knowledge of artificiality and experienced emotional unease. These findings have implications for theoretical debates about the mechanisms of imitation. They also inform creation of future robots that effectively build rapport and engagement with their human users.

  13. Bridging the Mechanical and the Human Mind: Spontaneous Mimicry of a Physically Present Android

    Science.gov (United States)

    Hofree, Galit; Ruvolo, Paul; Bartlett, Marian Stewart; Winkielman, Piotr

    2014-01-01

    The spontaneous mimicry of others' emotional facial expressions constitutes a rudimentary form of empathy and facilitates social understanding. Here, we show that human participants spontaneously match facial expressions of an android physically present in the room with them. This mimicry occurs even though these participants find the android unsettling and are fully aware that it lacks intentionality. Interestingly, a video of that same android elicits weaker mimicry reactions, occurring only in participants who find the android “humanlike.” These findings suggest that spontaneous mimicry depends on the salience of humanlike features highlighted by face-to-face contact, emphasizing the role of presence in human-robot interaction. Further, the findings suggest that mimicry of androids can dissociate from knowledge of artificiality and experienced emotional unease. These findings have implications for theoretical debates about the mechanisms of imitation. They also inform creation of future robots that effectively build rapport and engagement with their human users. PMID:25036365

  14. Apoptotic regulation of epithelial cellular extrusion

    OpenAIRE

    De Andrade, Daniel,; Rosenblatt, Jody

    2011-01-01

    Cellular extrusion is a mechanism that removes dying cells from epithelial tissues to prevent compromising their barrier function. Extrusion occurs in all observed epithelia in vivo and can be modeled in vitro by inducing apoptosis in cultured epithelial monolayers. We established that actin and myosin form a ring that contracts in the surrounding cells that drives cellular extrusion. It is not clear, however, if all apoptotic pathways lead to extrusion and how apoptosis and extrusion are mol...

  15. Small hive beetles survive in honeybee prisons by behavioural mimicry

    Science.gov (United States)

    Ellis, J. D.; Pirk, C. W. W.; Hepburn, H. R.; Kastberger, G.; Elzen, P. J.

    2002-05-01

    We report the results of a simple experiment to determine whether honeybees feed their small hive beetle nest parasites. Honeybees incarcerate the beetles in cells constructed of plant resins and continually guard them. The longevity of incarcerated beetles greatly exceeds their metabolic reserves. We show that survival of small hive beetles derives from behavioural mimicry by which the beetles induce the bees to feed them trophallactically. Electronic supplementary material to this paper can be obtained by using the Springer LINK server located at htpp://dx.doi.org/10.1007/s00114-002-0326-y.

  16. Nicotinamide inhibits vasculogenic mimicry, an alternative vascularization pathway observed in highly aggressive melanoma.

    Directory of Open Access Journals (Sweden)

    Orit Itzhaki

    Full Text Available Vasculogenic mimicry (VM describes functional vascular channels composed only of tumor cells and its presence predicts poor prognosis in melanoma patients. Inhibition of this alternative vascularization pathway might be of clinical importance, especially as several anti-angiogenic therapies targeting endothelial cells are largely ineffective in melanoma. We show the presence of VM structures histologically in a series of human melanoma lesions and demonstrate that cell cultures derived from these lesions form tubes in 3D cultures ex vivo. We tested the ability of nicotinamide, the amide form of vitamin B3 (niacin, which acts as an epigenetic gene regulator through unique cellular pathways, to modify VM. Nicotinamide effectively inhibited the formation of VM structures and destroyed already formed ones, in a dose-dependent manner. Remarkably, VM formation capacity remained suppressed even one month after the complete withdrawal of Nicotimamid. The inhibitory effect of nicotinamide on VM formation could be at least partially explained by a nicotinamide-driven downregulation of vascular endothelial cadherin (VE-Cadherin, which is known to have a central role in VM. Further major changes in the expression profile of hundreds of genes, most of them clustered in biologically-relevant clusters, were observed. In addition, nicotinamide significantly inhibited melanoma cell proliferation, but had an opposite effect on their invasion capacity. Cell cycle analysis indicated moderate changes in apoptotic indices. Therefore, nicotinamide could be further used to unravel new biological mechanisms that drive VM and tumor progression. Targeting VM, especially in combination with anti-angiogenic strategies, is expected to be synergistic and might yield substantial anti neoplastic effects in a variety of malignancies.

  17. Biological studies in animal models using [{sup 99m}Tc](CO){sub 3} recombinant annexin V as diagnostic agent of apoptotic processes

    Energy Technology Data Exchange (ETDEWEB)

    Teran, Mariella Adriana, E-mail: mteran@fq.edu.u [Catedra de Radioquimica, Departamento Estrella Campos, Facultad de Quimica, Universidad de la Republica, P.O. 11800, Montevideo (Uruguay); Martinez, Elena; Reyes, Ana L.; Paolino, Andrea [Catedra de Radioquimica, Departamento Estrella Campos, Facultad de Quimica, Universidad de la Republica, P.O. 11800, Montevideo (Uruguay); Vital, Marcelo; Esperon, Patricia [Catedra de Biologia Molecular, Departamento de Bioquimica Clinica, Facultad de Quimica, Universidad de la Republica, Montevideo (Uruguay); Pacheco, Jose P. [Instituto de Patobiologia, Facultad de Veterinaria, Universidad de la Republica, Montevideo (Uruguay); Savio, Eduardo [Catedra de Radioquimica, Departamento Estrella Campos, Facultad de Quimica, Universidad de la Republica, P.O. 11800, Montevideo (Uruguay)

    2011-02-15

    Introduction: There are many diseases associated with variations in the expression of apoptosis such as organ rejection after transplantation, myocardial ischemia or infarct and neurodegenerative diseases. For this reason, the early visualization of this process is relevant to set fast and effective therapeutic strategies. Methods: The precursor was prepared according to the procedure reported by R. Alberto, R. Schibli, P. Schubiger, U. Abram, and T. Kaden [Reactions with the technetium and rhenium carbonyl complexes (NEt{sub 4})[MX{sub 3}(CO){sub 3}]. Synthesis and structure of Tc(CN-But){sub 3}(CO){sub 3}](NO{sub 3}) and (Net{sub 4})[Tc{sub 2}({mu}-SCH{sub 2}CH{sub 2}OH){sub 3}(CO){sub 3}], Polyhedron 1996;15: 1079-89]. Recombinant annexin V was incubated with [{sup 99m}Tc](H{sub 2}O)3(CO){sub 3}{sup +} solution, previously neutralized with buffer. Biodistribution studies were performed in 8-week-old female Wistar rats. Animals were housed and treated in compliance with institutional guidelines related to animal experimentation. Work protocol was previously approved by the Animal Ethics Committee of the university. Two groups of rats were defined. One was used as control and the other group was previously injected with 150 mg/kg ip of cyclophosphamide to induce apoptosis. Results: The synthesis of carbonyl precursor achieved yields higher than 90%, and the radiolabeled protein was obtained with 92% of radiochemical purity and high stability in vitro. An important uptake in apoptotic tissues was confirmed by biodistributions, scintigraphic images and histological studies. Conclusions: Biodistribution studies revealed hepatobiliary elimination, high stability in vivo and important uptake in the reticuloendothelial system. In the pathologic model, higher uptake values correspond to the liver, spleen, lungs and femur. Histological studies confirmed the development of apoptosis at 8 and 24 h postinduction in the spleen and lymphocyte bulks in the peribronchial area

  18. Dysregulation of Autophagy, Mitophagy, and Apoptotic Genes in the Medial Temporal Lobe Cortex in an Ischemic Model of Alzheimer’s Disease

    Science.gov (United States)

    Ułamek-Kozioł, Marzena; Kocki, Janusz; Bogucka-Kocka, Anna; Petniak, Alicja; Gil-Kulik, Paulina; Januszewski, Sławomir; Bogucki, Jacek; Jabłoński, Mirosław; Furmaga-Jabłońska, Wanda; Brzozowska, Judyta; Czuczwar, Stanisław J.; Pluta, Ryszard

    2016-01-01

    Ischemic brain damage is a pathological incident that is often linked with medial temporal lobe cortex injury and finally its atrophy. Post-ischemic brain injury associates with poor prognosis since neurons of selectively vulnerable ischemic brain areas are disappearing by apoptotic program of neuronal death. Autophagy has been considered, after brain ischemia, as a guardian against neurodegeneration. Consequently, we have examined changes in autophagy (BECN 1), mitophagy (BNIP 3), and apoptotic (caspase 3) genes in the medial temporal lobe cortex with the use of quantitative reverse-transcriptase PCR following transient 10-min global brain ischemia in rats with survival 2, 7, and 30 days. The intense significant overexpression of BECN 1 gene was noted on the 2nd day, while on days 7–30 the expression of this gene was still upregulated. BNIP 3 gene was downregulated on the 2nd day, but on days 7–30 post-ischemia, there was a significant reverse tendency. Caspase 3 gene, associated with apoptotic neuronal death, was induced in the same way as BNIP 3 gene after brain ischemia. Thus, the demonstrated changes indicate that the considerable dysregulation of expression of BECN 1, BNIP 3, and caspase 3 genes may be connected with a response of neuronal cells in medial temporal lobe cortex to transient complete brain ischemia. PMID:27472881

  19. Mullerian mimicry as a result of codivergence between velvet ants and spider wasps.

    Directory of Open Access Journals (Sweden)

    Juanita Rodriguez

    Full Text Available Recent studies have delineated a large Nearctic Müllerian mimicry complex in Dasymutilla velvet ants. Psorthaspis spider wasps live in areas where this mimicry complex is found and are phenotypically similar to Dasymutilla. We tested the idea that Psorthaspis spider wasps are participating in the Dasymutilla mimicry complex and that they codiverged with Dasymutilla. We performed morphometric analyses and human perception tests, and tabulated distributional records to determine the fit of Psorthaspis to the Dasymutilla mimicry complex. We inferred a dated phylogeny using nuclear molecular markers (28S, elongation factor 1-alpha, long-wavelength rhodopsin and wingless for Psorthaspis species and compared it to a dated phylogeny of Dasymutilla. We tested for codivergence between the two groups using two statistical analyses. Our results show that Psorthaspis spider wasps are morphologically similar to the Dasymutilla mimicry rings. In addition, our tests indicate that Psorthaspis and Dasymutilla codiverged to produce similar color patterns. This study expands the breadth of the Dasymutilla Müllerian mimicry complex and provides insights about how codivergence influenced the evolution of mimicry in these groups.

  20. Immunosuppressive effects of apoptotic cells

    Science.gov (United States)

    Voll, Reinhard E.; Herrmann, Martin; Roth, Edith A.; Stach, Christian; Kalden, Joachim R.; Girkontaite, Irute

    1997-11-01

    Apoptotic cell death is important in the development and homeostasis of multicellular organisms and is a highly controlled means of eliminating dangerous, damaged or unnecessary cells without causing an inflammatory response or tissue damage,. We now show that the presence of apoptotic cells during monocyte activation increases their secretion of the anti-inflammatory and immunoregulatory cytokine interleukin 10 (IL-10) and decreases secretion of the proinflammatory cytokines tumour necrosis factor-α (TNF-α), IL-1 and IL-12. This may inhibit inflammation and contribute to impaired cell-mediated immunity in conditions associated with increased apoptosis, such as viral infections, pregnancy, cancer and exposure to radiation.

  1. Tumor blood vessels formation in osteosarcoma:vasculogenesis mimicry

    Institute of Scientific and Technical Information of China (English)

    蔡宣松; 贾永伟; 梅炯; 汤如勇

    2004-01-01

    Background Osteosarcoma is characterized by high neovascularization and a high propensity for metastasis through bloodstream. This study was to examine whether there is evidence for vasculogenic mimicry in osteosarcoma and to illustrate mechanism of tumor blood vessels formation in osteosarcoma.Methods Osteosarcoma cell lines (U-2OS) were tested for their ability to form tubular networks in three-dimensional culture containing type Ⅰ collagen. The structures of the tubular networks were observed with phase contrast microscope and transmission electron microscope (TEM). Morphometric studies using hematoxylin and eosin (HE) stain and CD31 immunohistochemical stain to show tumor-lined channels in human osteosarcoma were also performed.Results Observation with light microscope and TEM showed that highly aggressive osteosarcoma cell lines (U-2OS) formed networks containing channels when grown in three-dimensional culture containing type Ⅰ collagen, in the absence of endothelial cells or fibroblasts. Morphometric observation using HE stain and CD31 immunohistochemical stain showed that tumor cell-lined channels were also detected in vivo in osteosarcoma; by comparison, all vascular areas in the pedicel of osteochondroma or outside osteochondroma were endothelial-lined.Conclusion These observations strongly suggest that aggressive osteosarcoma cells may generate vascular channels that facilitate tumor perfusion independent of tumor angiogenesis and have the ability of vasculogenic mimicry.

  2. Study on vasculogenic mimicry in malignant esophageal stromal tumors

    Institute of Scientific and Technical Information of China (English)

    Hui Zhao; Xiao-Neng Gu

    2008-01-01

    AIM: To investigate whether malignant esophageal stromaltumors contain PAS-positive patterned matrix-associatedvascular channels, which are lined by tumor cells, but notvascular endothelial cells. That is vasculogenic mimicry(VN) independent of tumor angiogenesis.METHODS: Thirty-six tissue samples of/nalignantesophageal stromal tumors were analyzed. Tissuesections were stained for Vascular endothelial growthfactor (VEGF), CD31 and periodic acid Schiff (PAS). Thelevel of VEGF, the microvascular density (MVD) and thevasculogenic mimicry density (VID) were determined.RESULTS: PAS-positive patterned matrix-associatedvascular channels were detected in 33.3% (12/36)of tumor samples. Within these patterned channels,red blood cells were found. The level of VEGF and theMVD in tumors containing patterned channels weresignificantly higher than those in tumors not containingpatterned channels (P < 0.05). At the same time, themalignant degree of tumors was higher, the proportionsof tumors containing patterned channels were not onlymore, but also in the each kind of tumors containingpatterned channels.CONCLUSION: In malignant esophageal stromaltumors, a VM mechanism causes some tumor cells todeform themselves and secrete extracellular matrix;thus, PAS-positive patterned matrix-associated vascularchannels appear and supplying blood to the tumors tosustain their growth and metastasis.

  3. Spontaneous Facial Mimicry Is Enhanced by the Goal of Inferring Emotional States: Evidence for Moderation of “Automatic” Mimicry by Higher Cognitive Processes

    Science.gov (United States)

    Murata, Aiko; Saito, Hisamichi; Schug, Joanna; Ogawa, Kenji; Kameda, Tatsuya

    2016-01-01

    A number of studies have shown that individuals often spontaneously mimic the facial expressions of others, a tendency known as facial mimicry. This tendency has generally been considered a reflex-like “automatic” response, but several recent studies have shown that the degree of mimicry may be moderated by contextual information. However, the cognitive and motivational factors underlying the contextual moderation of facial mimicry require further empirical investigation. In this study, we present evidence that the degree to which participants spontaneously mimic a target’s facial expressions depends on whether participants are motivated to infer the target’s emotional state. In the first study we show that facial mimicry, assessed by facial electromyography, occurs more frequently when participants are specifically instructed to infer a target’s emotional state than when given no instruction. In the second study, we replicate this effect using the Facial Action Coding System to show that participants are more likely to mimic facial expressions of emotion when they are asked to infer the target’s emotional state, rather than make inferences about a physical trait unrelated to emotion. These results provide convergent evidence that the explicit goal of understanding a target’s emotional state affects the degree of facial mimicry shown by the perceiver, suggesting moderation of reflex-like motor activities by higher cognitive processes. PMID:27055206

  4. A "Mimic Octopus" in the Atlantic: Flatfish mimicry and camouflage by Macrotritopus defilippi.

    Science.gov (United States)

    Hanlon, Roger T; Watson, Anya C; Barbosa, Alexandra

    2010-02-01

    The sand-dwelling octopus Macrotritopus defilippi was filmed or photographed in five Caribbean locations mimicking the swimming behavior (posture, style, speed, duration) and coloration of the common, sand-dwelling flounder Bothus lunatus. Each species was exceptionally well camouflaged when stationary, and details of camouflaging techniques are described for M. defilippi. Octopuses implemented flounder mimicry only during swimming, when their movement would give away camouflage in this open sandy habitat. Thus, both camouflage and fish mimicry were used by the octopuses as a primary defense against visual predators. This is the first documentation of flounder mimicry by an Atlantic octopus, and only the fourth convincing case of mimicry for cephalopods, a taxon renowned for its polyphenism that is implemented mainly by neurally controlled skin patterning, but also-as shown here-by their soft flexible bodies. PMID:20203250

  5. Defects in mitochondrial fission protein dynamin-related protein 1 are linked to apoptotic resistance and autophagy in a lung cancer model.

    Directory of Open Access Journals (Sweden)

    Kelly Jean Thomas

    Full Text Available Evasion of apoptosis is implicated in almost all aspects of cancer progression, as well as treatment resistance. In this study, resistance to apoptosis was identified in tumorigenic lung epithelial (A549 cells as a consequence of defects in mitochondrial and autophagic function. Mitochondrial function is determined in part by mitochondrial morphology, a process regulated by mitochondrial dynamics whereby the joining of two mitochondria, fusion, inhibits apoptosis while fission, the division of a mitochondrion, initiates apoptosis. Mitochondrial morphology of A549 cells displayed an elongated phenotype-mimicking cells deficient in mitochondrial fission protein, Dynamin-related protein 1 (Drp1. A549 cells had impaired Drp1 mitochondrial recruitment and decreased Drp1-dependent fission. Cytochrome c release and caspase-3 and PARP cleavage were impaired both basally and with apoptotic stimuli in A549 cells. Increased mitochondrial mass was observed in A549 cells, suggesting defects in mitophagy (mitochondrial selective autophagy. A549 cells had decreased LC3-II lipidation and lysosomal inhibition suggesting defects in autophagy occur upstream of lysosomal degradation. Immunostaining indicated mitochondrial localized LC3 punctae in A549 cells increased after mitochondrial uncoupling or with a combination of mitochondrial depolarization and ectopic Drp1 expression. Increased inhibition of apoptosis in A549 cells is correlated with impeded mitochondrial fission and mitophagy. We suggest mitochondrial fission defects contribute to apoptotic resistance in A549 cells.

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

    International Nuclear Information System (INIS)

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

  7. Facial Mimicry in 6-7 Year Old Children with Disruptive Behavior Disorder and ADHD

    OpenAIRE

    Peter Deschamps; Nicolette Munsters; Leon Kenemans; Dennis Schutter; Walter Matthys

    2014-01-01

    BACKGROUND: Impairments in facial mimicry are considered a proxy for deficits in affective empathy and have been demonstrated in 10 year old children and in adolescents with disruptive behavior disorder (DBD). However, it is not known whether these impairments are already present at an earlier age. Emotional deficits have also been shown in children with attention-deficit/hyperactivity disorder (ADHD). AIMS: To examine facial mimicry in younger, 6-7 year old children with DBD and with ADHD. M...

  8. The function of animal ‘eyespots’: conspicuousness but not eye mimicry is key

    OpenAIRE

    Stevens, Martin; Cantor, Abi; Graham, Julia; Isabel S. WINNEY

    2009-01-01

    Many animals are marked with conspicuous circular features often called ‘eyespots’, which intimidate predators, preventing or halting an attack. It has long been assumed that eyespots work by mimicking the eyes of larger animals, but recent experiments have indicated that conspicuousness and contrast is important in eyespot function, and not eye mimicry. We undertake two further experiments to distinguish between the conspicuousness and mimicry hypotheses, by using artificial prey presented t...

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

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Wenming; Meng, Mei; Zhang, Bin; Du, Longsheng; Pan, Yanyan; Yang, Ping; Gu, Zhenlun; Zhou, Quansheng, E-mail: quanshengzhou@yahoo.com; Cao, Zhifei, E-mail: hunancao@163.com

    2015-09-01

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

  10. [Molecular Mimicry and Guillain-Barré Syndrome].

    Science.gov (United States)

    Yuki, Nobuhiro

    2015-11-01

    One-thirds of patients develop Guillain-Barré syndrome subsequent to Campylobacter jejuni enteritis. Molecular mimicry exists between C. jejuni lipo-oligosaccharides and human peripheral nerve gangliosides GM1 and GD1a. IgG antibodies against GM1 or GD1a are produced in one out of 5,000 patients with C. jejuni enteritis. The autoantibodies bind to gangliosides at the nodes of Ranvier in the peripheral motor nerves and activate complement in situ. This is followed by the disappearance of the voltage-gated sodium channel clusters at the nodes and disruption of axo-glial junctions at the paranodes. This results in the development of motor nerve conduction failure and muscle weakness in the four limbs. PMID:26560949

  11. Behavioural mimicry in flight path of Batesian intraspecific polymorphic butterfly Papilio polytes.

    Science.gov (United States)

    Kitamura, Tasuku; Imafuku, Michio

    2015-06-22

    Batesian mimics that show similar coloration to unpalatable models gain a fitness advantage of reduced predation. Beyond physical similarity, mimics often exhibit behaviour similar to their models, further enhancing their protection against predation by mimicking not only the model's physical appearance but also activity. In butterflies, there is a strong correlation between palatability and flight velocity, but there is only weak correlation between palatability and flight path. Little is known about how Batesian mimics fly. Here, we explored the flight behaviour of four butterfly species/morphs: unpalatable model Pachliopta aristolochiae, mimetic and non-mimetic females of female-limited mimic Papilio polytes, and palatable control Papilio xuthus. We demonstrated that the directional change (DC) generated by wingbeats and the standard deviation of directional change (SDDC) of mimetic females and their models were smaller than those of non-mimetic females and palatable controls. Furthermore, we found no significant difference in flight velocity among all species/morphs. By showing that DC and SDDC of mimetic females resemble those of models, we provide the first evidence for the existence of behavioural mimicry in flight path by a Batesian mimic butterfly. PMID:26041360

  12. Apoptotic Signaling in Mouse Odontogenesis

    OpenAIRE

    Matalova, Eva; Svandova, Eva; Tucker, Abigail S.

    2012-01-01

    Apoptosis is an important morphogenetic event in embryogenesis as well as during postnatal life. In the last 2 decades, apoptosis in tooth development (odontogenesis) has been investigated with gradually increasing focus on the mechanisms and signaling pathways involved. The molecular machinery responsible for apoptosis exhibits a high degree of conservation but also organ and tissue specific patterns. This review aims to discuss recent knowledge about apoptotic signaling networks during odon...

  13. Anticancer activity of taraxerol acetate in human glioblastoma cells and a mouse xenograft model via induction of autophagy and apoptotic cell death, cell cycle arrest and inhibition of cell migration.

    Science.gov (United States)

    Hong, Jing-Fang; Song, Ying-Fang; Liu, Zheng; Zheng, Zhao-Cong; Chen, Hong-Jie; Wang, Shou-Sen

    2016-06-01

    The aim of the present study was to investigate the in vitro and in vivo anticancer and apoptotic effects of taraxerol acetate in U87 human glioblastoma cells. The effects on cell cycle phase distribution, cell cycle-associated proteins, autophagy, DNA fragmentation and cell migration were assessed. Cell viability was determined using the MTT assay, and phase contrast and fluorescence microscopy was utilized to determine the viability and apoptotic morphological features of the U87 cells. Flow cytometry using propidium iodide and Annexin V-fluorescein isothiocyanate demonstrated the effect of taraxerol acetate on the cell cycle phase distribution and apoptosis induction. Western blot analysis was performed to investigate the effect of the taraxerol acetate on cell cycle‑associated proteins and autophagy‑linked LC3B‑II proteins. The results demonstrated that taraxerol acetate induced dose‑ and time‑dependent cytotoxic effects in the U87 cells. Apoptotic induction following taraxerol acetate treatment was observed and the percentage of apoptotic cells increased from 7.3% in the control cells, to 16.1, 44.1 and 76.7% in the 10, 50 and 150 µM taraxerol acetate‑treated cells, respectively. Furthermore, taraxerol acetate treatment led to sub‑G1 cell cycle arrest with a corresponding decrease in the number of S‑phase cells. DNA fragments were observed as a result of the gel electrophoresis experiment following taraxerol acetate treatment. To investigate the inhibitory effects of taraxerol acetate on the migration of U87 cell, a wound healing assay was conducted. The number of cells that migrated to the scratched area decreased significantly following treatment with taraxerol acetate. In addition, taraxerol acetate inhibited tumor growth in a mouse xenograft model. Administration of 0.25 and 0.75 µg/g taraxerol acetate reduced the tumor weight from 1.2 g in the phosphate‑buffered saline (PBS)‑treated group (control) to 0.81 and 0.42

  14. Anticancer activity of taraxerol acetate in human glioblastoma cells and a mouse xenograft model via induction of autophagy and apoptotic cell death, cell cycle arrest and inhibition of cell migration

    Science.gov (United States)

    HONG, JING-FANG; SONG, YING-FANG; LIU, ZHENG; ZHENG, ZHAO-CONG; CHEN, HONG-JIE; WANG, SHOU-SEN

    2016-01-01

    The aim of the present study was to investigate the in vitro and in vivo anticancer and apoptotic effects of taraxerol acetate in U87 human glioblastoma cells. The effects on cell cycle phase distribution, cell cycle-associated proteins, autophagy, DNA fragmentation and cell migration were assessed. Cell viability was determined using the MTT assay, and phase contrast and fluorescence microscopy was utilized to determine the viability and apoptotic morphological features of the U87 cells. Flow cytometry using propidium iodide and Annexin V-fluorescein isothiocyanate demonstrated the effect of taraxerol acetate on the cell cycle phase distribution and apoptosis induction. Western blot analysis was performed to investigate the effect of the taraxerol acetate on cell cycle-associated proteins and autophagy-linked LC3B-II proteins. The results demonstrated that taraxerol acetate induced dose- and time-dependent cytotoxic effects in the U87 cells. Apoptotic induction following taraxerol acetate treatment was observed and the percentage of apoptotic cells increased from 7.3% in the control cells, to 16.1, 44.1 and 76.7% in the 10, 50 and 150 µM taraxerol acetate-treated cells, respectively. Furthermore, taraxerol acetate treatment led to sub-G1 cell cycle arrest with a corresponding decrease in the number of S-phase cells. DNA fragments were observed as a result of the gel electrophoresis experiment following taraxerol acetate treatment. To investigate the inhibitory effects of taraxerol acetate on the migration of U87 cell, a wound healing assay was conducted. The number of cells that migrated to the scratched area decreased significantly following treatment with taraxerol acetate. In addition, taraxerol acetate inhibited tumor growth in a mouse xenograft model. Administration of 0.25 and 0.75 µg/g taraxerol acetate reduced the tumor weight from 1.2 g in the phosphate-buffered saline (PBS)-treated group (control) to 0.81 and 0.42 g, respectively. Similarly, 0.25 and 0

  15. Allograft tolerance induced by donor apoptotic lymphocytes requires phagocytosis in the recipient

    Science.gov (United States)

    Sun, E.; Gao, Y.; Chen, J.; Roberts, A. I.; Wang, X.; Chen, Z.; Shi, Y.

    2004-01-01

    Cell death through apoptosis plays a critical role in regulating cellular homeostasis. Whether the disposal of apoptotic cells through phagocytosis can actively induce immune tolerance in vivo, however, remains controversial. Here, we report in a rat model that without using immunosuppressants, transfusion of apoptotic splenocytes from the donor strain prior to transplant dramatically prolonged survival of heart allografts. Histological analysis verified that rejection signs were significantly ameliorated. Splenocytes from rats transfused with donor apoptotic cells showed a dramatically decreased response to donor lymphocyte stimulation. Most importantly, blockade of phagocytosis in vivo, either with gadolinium chloride to disrupt phagocyte function or with annexin V to block binding of exposed phosphotidylserine to its receptor on phagocytes, abolished the beneficial effect of transfused apoptotic cells on heart allograft survival. Our results demonstrate that donor apoptotic cells promote specific allograft acceptance and that phagocytosis of apoptotic cells in vivo plays a crucial role in maintaining immune tolerance.

  16. Phosphorylation of Puma modulates its apoptotic function by regulating protein stability

    OpenAIRE

    Fricker, M; O'Prey, J.; Tolkovsky, A M; Ryan, K M

    2010-01-01

    Puma is a potent BH3-only protein that antagonises anti-apoptotic Bcl-2 proteins, promotes Bax/Bak activation and has an essential role in multiple apoptotic models. Puma expression is normally kept very low, but can be induced by several transcription factors including p53, p73, E2F1 and FOXO3a, whereby it can induce an apoptotic response. As Puma can to bind and inactivate all anti-apoptotic members of the Bcl-2 family, its activity must be tightly controlled. We report here, for the first ...

  17. The Anti-Apoptotic Role of Neuroglobin

    Directory of Open Access Journals (Sweden)

    Thomas Brittain

    2012-11-01

    Full Text Available The small heme-protein neuroglobin is expressed at high concentrations in certain brain neurons and in the rod cells of the retina. This paper reviews the many studies which have recently identified a protective role for neuroglobin, in a wide range of situations involving apoptotic cell death. The origins of this protective mechanism are discussed in terms of both experimental results and computational modeling of the intrinsic pathway of apoptosis, which shows that neuroglobin can intervene in this process by a reaction with released mitochondrial cytochrome c. An integrated model, based on the various molecular actions of both neuroglobin and cytochrome c, is developed, which accounts for the cellular distribution of neuroglobin.

  18. Mimicry in Heliconius and Ithomiini butterflies: The profound consequences of an adaptation

    Directory of Open Access Journals (Sweden)

    Elias Marianne

    2015-01-01

    Full Text Available Prey populations have evolved multiple strategies to escape predation. Camouflage is a strategy resting on avoiding detection by potential predators, whereas aposematism relies on advertising chemical defences with conspicuous warning signals. While camouflaged phenotypes are subject to negative frequency-dependent selection, aposematic preys are under positive frequency-dependence, where the efficiency of a signal increases with its own local abundance. Because of his “strength-in-number” effect, multiple chemically-defended species exposed to the same suite of predators gain a selective advantage from converging on the same warning signals. Convergence in warning signals is called Müllerian mimicry. Here, we review the results of recent genetic and ecological research on two well-studied groups of neotropical Müllerian mimetic butterflies, the genus Heliconius and the tribe Ithomiini, which advertise their unpalatability through conspicuous wing colour patterns. Mimicry represents a major adaptation in these groups, where the effects of selection extend well beyond mere phenotypic resemblance. Selection acts on other traits used as mating cues, on the genetic architecture of colour pattern and even on the ecological niche of species. The origin of mimicry itself and the coexistence of multiple mimicry patterns are well understood, but the ultimate drivers of mimicry diversity remain unclear.

  19. Facial mimicry in 6-7 year old children with disruptive behavior disorder and ADHD.

    Directory of Open Access Journals (Sweden)

    Peter Deschamps

    Full Text Available BACKGROUND: Impairments in facial mimicry are considered a proxy for deficits in affective empathy and have been demonstrated in 10 year old children and in adolescents with disruptive behavior disorder (DBD. However, it is not known whether these impairments are already present at an earlier age. Emotional deficits have also been shown in children with attention-deficit/hyperactivity disorder (ADHD. AIMS: To examine facial mimicry in younger, 6-7 year old children with DBD and with ADHD. METHODS: Electromyographic (EMG activity in response to emotional facial expressions was recorded in 47 children with DBD, 18 children with ADHD and 35 healthy developing children. RESULTS: All groups displayed significant facial mimicry to the emotional expressions of other children. No group differences between children with DBD, children with ADHD and healthy developing children were found. In addition, no differences in facial mimicry were found between the clinical group (i.e., all children with a diagnosis and the typically developing group in an analysis with ADHD symptoms as a covariate, and no differences were found between the clinical children and the typically developing children with DBD symptoms as a covariate. CONCLUSION: Facial mimicry in children with DBD and ADHD throughout the first primary school years was unimpaired, in line with studies on empathy using other paradigms.

  20. Emotional Mimicry in Social Context: The Case of Disgust and Pride

    Directory of Open Access Journals (Sweden)

    AgnetaFischer

    2012-11-01

    Full Text Available A recent review on facial mimicry concludes that emotional mimicry is less ubiquitous than has been suggested, and only occurs in interactions that are potentially affiliative (see Hess & Fischer, 2012. We hypothesize that individuals do not mimic facial expressions that can be perceived as offensive, such as disgust, and mimic positive emotion displays, but only when the context is affiliative (i.e. with intimates. Second, we expect that in spontaneous interactions not mimicry, but empathic feelings with the other predict the accurateness of emotion recognition. Data were collected in a pseudo-experimental setting, during an event organized for subscribers of a large Dutch women’s magazine. One woman (expresser was exposed to two emotional stimuli (i.e., a vile smell, a compliment in order to evoke disgust and pride respectively. Another woman (observer: intimate or stranger was sitting opposite of her. We collected self-report measures on emotions and empathy, and coded facial expressions of disgust and smiling on the basis of FACS. The results show that participants do not mimic disgust. In contrast, smiles displayed after the vile smell and the compliment were mimicked, but only among intimates. We also found that self-reported empathy and not mimicry is related to the recognition of disgust. These findings are discussed in the light of a Social Contextual view on emotional mimicry.

  1. Vasculogenic mimicry: a novel target for glioma therapy

    Directory of Open Access Journals (Sweden)

    Yin-Sheng Chen

    2014-02-01

    Full Text Available Anti-angiogenic therapy has shown promising but insufficient efficacy on gliomas. Recent studies suggest that vasculogenic mimicry (VM, or the formation of non-endothelial, tumor-cell-lined microvascular channels, occurs in aggressive tumors, including gliomas. There is also evidence of a physiological connection between the endothelial-lined vasculature and VM channels. Tumor cells, by virtue of their high plasticity, can form vessel-like structures themselves, which may function as blood supply networks. Our previous study on gliomas showed that microvessel density was comparably less in VM-positive tumors than in VM-negative tumors. Thus, VM may act as a complement to ensure tumor blood supply, especially in regions with less microvessel density. Patients with VM-positive gliomas survived a shorter period of time than did patients with VM-negative gliomas. Although the detailed molecular mechanisms for VM are not fully understood, glioma stem cells might play a key role, since they are involved in tumor tissue remodeling and contribute to neovascularization via transdifferentiation. In the future, successful treatment of gliomas should involve targeting both VM and angiogenesis. In this review, we summarize the progress and challenges of VM in gliomas.

  2. Quantum Spacetime: Mimicry of Paths and Black Holes

    Science.gov (United States)

    Spaans, Marco

    2015-08-01

    Since its inception, general relativity has been unreceptive to a marriage with the quantum aspects of our universe. Following the ideas of Einstein, one may pursue an approach that allows spacetime itself to take center stage. The quantum properties of matter are then carried by the dynamics of spacetime shape and connectivity. This monograph introduces the reader to the foundations of quantum spacetime in a manner accessible to researchers and students. Likewise, interested laymen that lack a strong background in quantum mechanics or spacetime studies but are keen to learn will find this book worthwhile. It is shown from first principles how spacetime is globally built up by paths which constitute entire histories in four dimensions. The central physical idea is that the collective existence of observers and observed derives from one mimicking the other unremittingly, thereby inducing tangible reality. This world of identity by mimicry creates a multitude of interacting histories. Throughout the text, thought experiments are used to derive physical principles. Obtained results are therefore intuitive and accessible to non-experts. This monograph also discusses consequences of quantum spacetime for black holes, dark energy, inflation, the Higgs boson, and the multiverse.

  3. Automatic mimicry reactions as related to differences in emotional empathy.

    Science.gov (United States)

    Sonnby-Borgström, Marianne

    2002-12-01

    The hypotheses of this investigation were derived by conceiving of automatic mimicking as a component of emotional empathy. Differences between subjects high and low in emotional empathy were investigated. The parameters compared were facial mimicry reactions, as represented by electromyographic (EMG) activity when subjects were exposed to pictures of angry or happy faces, and the degree of correspondence between subjects' facial EMG reactions and their self-reported feelings. The comparisons were made at different stimulus exposure times in order to elicit reactions at different levels of information processing. The high-empathy subjects were found to have a higher degree of mimicking behavior than the low-empathy subjects, a difference that emerged at short exposure times (17-40 ms) that represented automatic reactions. The low-empathy subjects tended already at short exposure times (17-40 ms) to show inverse zygomaticus muscle reactions, namely "smiling" when exposed to an angry face. The high-empathy group was characterized by a significantly higher correspondence between facial expressions and self-reported feelings. No differences were found between the high- and low-empathy subjects in their verbally reported feelings when presented a happy or an angry face. Thus, the differences between the groups in emotional empathy appeared to be related to differences in automatic somatic reactions to facial stimuli rather than to differences in their conscious interpretation of the emotional situation. PMID:12500783

  4. Suppression of neuroinflammatory and apoptotic signaling cascade by curcumin alone and in combination with piperine in rat model of olfactory bulbectomy induced depression.

    Directory of Open Access Journals (Sweden)

    Puneet Rinwa

    Full Text Available OBJECTIVES: Bilateral destruction of the olfactory bulbs is known to cause behavioral changes analogous to symptoms of depression. Curcumin, a traditional Indian spice is currently being investigated in different psychiatric problems including depression. Dietary phytochemicals are currently used as an adjuvant therapy to accelerate their therapeutic efficacy. Therefore, the present study is an attempt to elucidate the neuroprotective mechanism of curcumin and its co-administration with piperine against olfactory bulbectomy induced depression in rats. METHODS: Rats undergone olfactory bulbs ablations were analyzed after post-surgical rehabilitation period of 2 weeks. Animals were then treated with different doses of curcumin (100, 200 and 400 mg/kg; p.o., piperine (20 mg/kg; p.o. and their combination daily for another 2 weeks. Imipramine (10 mg/kg; i.p. served as a standard control. Various behavioral tests like forced swim test (FST, open field behaviour and sucrose preference test (SPT were performed, followed by estimation of biochemical, mitochondrial, molecular and histopathological parameters in rat brain. RESULTS: Ablation of olfactory bulbs caused depression-like symptoms as evidenced by increased immobility time in FST, hyperactivity in open field arena, and anhedonic like response in SPT along with alterations in mitochondrial enzyme complexes, increased serum corticosterone levels and oxidative damage. These deficits were integrated with increased inflammatory cytokines (TNF-α and apoptotic factor (caspase-3 levels along with a marked reduction in neurogenesis factor (BDNF in the brain of olfactory bulbectomized (OBX rats. Curcumin treatment significantly and dose-dependently restored all these behavioral, biochemical, mitochondrial, molecular and histopathological alterations associated with OBX induced depression. Further, co-administration of piperine with curcumin significantly potentiated their neuroprotective effects as

  5. Exercise Ameliorates Renal Cell Apoptosis in Chronic Kidney Disease by Intervening in the Intrinsic and the Extrinsic Apoptotic Pathways in a Rat Model

    Directory of Open Access Journals (Sweden)

    Kuan-Chou Chen

    2013-01-01

    Full Text Available We hypothesized that doxorubicin (DR induced chronic kidney disease (CKD could trigger the intrinsic and the extrinsic renal cell apoptotic pathways, while treadmill exercise could help prevent adverse effects. Male Sprague-Dawley rats were subjected to treadmill running exercise at a speed of 30 m/min, 30 or 60 min/day, 3 times per week, for a total period of 11 weeks. The physiological and biochemical parameters were seen substantially improved (DR-CKD control, 30 min, 60 min exercise: the ratio of kidney weight/body weight (0.89, 0.74, and 0.72; the WBC (1.35, 1.08, and 1.42 × 104 cells/μL; RBC (5.30, 6.38, and 6.26 × 106 cells/μL; the platelet count (15.1, 12.8, and 11.3 × 105/μL; serum cholesterol (659, 360, and 75 mg/dL; serum triglyceride (542, 263, and 211 mg/dL; BUN (37, 25, and 22 mg/dL. Bcl-2 and intramitochondrial cytochrome c were upregulated, while the levels of Bax, SOD, MDA, cleaved caspases 9, 3, 8, 12, and calpain were all downregulated in DRCKD groups with exercise. CHOP (GADD153 and GRP78 were totally unaffected. FAS (CD95 was only slightly suppressed in the 60 min exercise DRCKD group. Conclusively, exercise can ameliorate CKD through the regulation of the intrinsic and extrinsic apoptosis pathways. The 60 min exercise yields more beneficial effect than the 30 min counterpart.

  6. OCT4 Expression and Vasculogenic Mimicry Formation Positively Correlate with Poor Prognosis in Human Breast Cancer

    Directory of Open Access Journals (Sweden)

    Tieju Liu

    2014-10-01

    Full Text Available To evaluate the prognostic value of OCT4 expression and vasculogenic mimicry (VM in human breast cancer, we examined OCT4 expression and VM formation using immunohistochemistry and CD31/PAS (periodic acid-schiff double staining on 90 breast cancer specimens. All patients were followed up for five–149 months following surgery. Survival curves were generated using Kaplan-Meier method. Multivariate analysis was performed using Cox regression model to assess the prognostic values. Results showed positive correlation between OCT4 expression and VM formation (p < 0.05. Both OCT4 expression and VM were also positively correlated with lymph node metastasis, higher histological grade, and Nottingham prognostic index (p < 0.05. Patients with OCT4 expression or VM formation exhibited poorer overall survival (OS and disease-free survival (DFS than OCT4-negative or VM-negative patients (p < 0.05. OCT4-positive/VM-positive patients also had the worst OS and DFS (p < 0.05. In multivariate survival analysis, VM, Nottingham prognostic index (NPI, and Her2 were independent prognostic factors related to OS and OCT4-positive/VM-positive patients, whereas NPI and Her2 were independent predictors of DFS. These results suggest that a combined OCT4 expression/VM could improve the prognostic judgment for breast cancer patients.

  7. Oncogene Mimicry as a Mechanism of Primary Resistance to BRAF Inhibitors

    Directory of Open Access Journals (Sweden)

    Martin L. Sos

    2014-08-01

    Full Text Available Despite the development of potent RAF/mitogen-activated protein kinase (MAPK pathway inhibitors, only a fraction of BRAF-mutant patients benefit from treatment with these drugs. Using a combined chemogenomics and chemoproteomics approach, we identify drug-induced RAS-RAF-MEK complex formation in a subset of BRAF-mutant cancer cells characterized by primary resistance to vemurafenib. In these cells, autocrine interleukin-6 (IL-6 secretion may contribute to the primary resistance phenotype via induction of JAK/STAT3 and MAPK signaling. In a subset of cell lines, combined IL-6/MAPK inhibition is able to overcome primary resistance to BRAF-targeted therapy. Overall, we show that the signaling plasticity exerted by primary resistant BRAF-mutant cells is achieved by their ability to mimic signaling features of oncogenic RAS, a strategy that we term “oncogene mimicry.” This model may guide future strategies for overcoming primary resistance observed in these tumors.

  8. Molecular mimicry: its evolution from concept to mechanism as a cause of autoimmune diseases.

    Science.gov (United States)

    Oldstone, Michael B A

    2014-06-01

    On a clonal level, certain antibodies and T cells can interact with dissimilar antigens found in microbes and in host cells. More than 5% of over 800 monoclonal antibodies derived from multiple RNA and DNA viruses, as well as from a large number of T cell clones, engage in such interactions. Several of these cross-reactions, which we termed molecular mimicry, are against unique host proteins involved in autoimmune responses and diseases. Thus, molecular mimicry initiated as a host response to a virus or a microbial infection, but alternatively cross-reacting with an appropriate host-antigen, can be a mechanism for instigating an autoimmune disease. Molecular mimicry provides an explanation for the genetic observation that identical twins rarely manifest the same autoimmune disease and the documented epidemiologic evidence that microbial and/or viral infections often precede autoimmune disorders. PMID:24694269

  9. Apoptotic engulfment pathway and schizophrenia.

    LENUS (Irish Health Repository)

    Chen, Xiangning

    2009-01-01

    BACKGROUND: Apoptosis has been speculated to be involved in schizophrenia. In a previously study, we reported the association of the MEGF10 gene with the disease. In this study, we followed the apoptotic engulfment pathway involving the MEGF10, GULP1, ABCA1 and ABCA7 genes and tested their association with the disease. METHODOLOGY\\/PRINCIPAL FINDINGS: Ten, eleven and five SNPs were genotyped in the GULP1, ABCA1 and ABCA7 genes respectively for the ISHDSF and ICCSS samples. In all 3 genes, we observed nominally significant associations. Rs2004888 at GULP1 was significant in both ISHDSF and ICCSS samples (p = 0.0083 and 0.0437 respectively). We sought replication in independent samples for this marker and found highly significant association (p = 0.0003) in 3 Caucasian replication samples. But it was not significant in the 2 Chinese replication samples. In addition, we found a significant 2-marker (rs2242436 * rs3858075) interaction between the ABCA1 and ABCA7 genes in the ISHDSF sample (p = 0.0022) and a 3-marker interaction (rs246896 * rs4522565 * rs3858075) amongst the MEGF10, GULP1 and ABCA1 genes in the ICCSS sample (p = 0.0120). Rs3858075 in the ABCA1 gene was involved in both 2- and 3-marker interactions in the two samples. CONCLUSIONS\\/SIGNIFICANCE: From these data, we concluded that the GULP1 gene and the apoptotic engulfment pathway are involved in schizophrenia in subjects of European ancestry and multiple genes in the pathway may interactively increase the risks to the disease.

  10. Metabolic connections during apoptotic cell engulfment

    OpenAIRE

    Han, Claudia Z.; Ravichandran, Kodi S.

    2011-01-01

    Billions of cells die via apoptosis every day and are swiftly and efficiently removed. When a phagocyte engulfs an apoptotic cell, it essentially doubles its cellular contents, raising the question of how a phagocyte may manage the excess metabolic load. This review discusses phagocyte cellular metabolism, the digestion of the ingested apoptotic cell and the impact of these processes on engulfment.

  11. Solvent mimicry with methylene carbene to probe protein topography.

    Science.gov (United States)

    Gómez, Gabriela Elena; Monti, José Luis E; Mundo, Mariana Rocío; Delfino, José María

    2015-10-01

    The solvent accessible surface area (SASA) of the polypeptide chain plays a key role in protein folding, conformational change, and interaction. This fundamental biophysical parameter is elusive in experimental measurement. Our approach to this problem relies on the reaction of the minimal photochemical reagent diazirine (DZN) with polypeptides. This reagent (i) exerts solvent mimicry because its size is comparable to water and (ii) shows scant chemical selectivity because it generates extremely reactive methylene carbene. Methylation gives rise to the EM (extent of modification) signal, which is useful for scrutinizing the conformational change triggered by Ca(2+) binding to calmodulin (CaM). The increased EM observed for the full protein is dominated by the enhanced exposure of hydrophobic area in Ca(2+)-CaM. Fragmentation allowed us to quantify the methylene incorporation at specific sites. Peptide 91-106 reveals a major reorganization around the calcium 151 binding site, resulting in local ordering and a greater exposure of the hydrophobic surface. Additionally, this technique shows a high sensitivity to probe recognition between CaM and melittin (Mel). The large decrease in EM indicates the occlusion of a significant hydrophobic area upon complexation. Protection from labeling reveals a larger involvement of the N-terminal and central regions of CaM in this interaction. Despite its smaller size, Mel's differential exposure can also be quantified. Moreover, MS/MS fragmentation realizes the goal of extending the resolution of labeled sites at the amino acid level. Overall, DZN labeling emerges as a useful footprinting method capable of shedding light on physiological conformational changes and interactions. PMID:26348271

  12. Effect of Adipocyte Secretome in Melanoma Progression and Vasculogenic Mimicry.

    Science.gov (United States)

    Coelho, Pedro; Almeida, Joana; Prudêncio, Cristina; Fernandes, Rúben; Soares, Raquel

    2016-07-01

    Obesity, favored by the modern lifestyle, acquired epidemic proportions nowadays. Obesity has been associated with various major causes of death and morbidity including malignant neoplasms. This increased prevalence has been accompanied by a worldwide increase in cutaneous melanoma incidence rates during the last decades. Obesity involvement in melanoma aetiology has been recognized, but the implicated mechanisms remain unclear. In the present study, we address this relationship and investigate the influence of adipocytes secretome on B16-F10 and MeWo melanoma cell lines. Using the 3T3-L1 adipocyte cell line, as well as ex vivo subcutaneous (SAT) and visceral (VAT) adipose tissue conditioned medium, we were able to show that adipocyte-released factors play a dual role in increasing melanoma cell overall survival, both by enhancing proliferation and decreasing apoptosis. B16-F10 cell migration and cell-cell and cell-matrix adhesion capacity were predominantly enhanced in the presence of SAT and VAT released factors. Melanocytes morphology and melanin content were also altered by exposure to adipocyte conditioned medium disclosing a more dedifferentiated phenotype of melanocytes. In addition, exposure to adipocyte-secreted molecules induced melanocytes to rearrange, on 3D cultures, into vessel-like structures, and generate characteristic vasculogenic mimicry patterns. These findings are corroborated by the released factors profile of 3T3-L1, SAT, and VAT assessed by microarrays, and led us to highlight the mechanisms by which adipose secretome from sub-cutaneous or visceral depots promote melanoma progression. J. Cell. Biochem. 117: 1697-1706, 2016. © 2015 Wiley Periodicals, Inc. PMID:26666522

  13. Function of AURKA protein kinase in the formation of vasculogenic mimicry in triple-negative breast cancer stem cells

    Directory of Open Access Journals (Sweden)

    Liu Y

    2016-06-01

    Full Text Available Ying Liu,1,2,* Baocun Sun,1–3,* Tieju Liu,1,2,* Xiulan Zhao,1,2 Xudong Wang,3 Yanlei Li,1,2 Jie Meng,2 Qiang Gu,1,2 Fang Liu,1,2 Xueyi Dong,1,2 Peimei Liu,2 Ran Sun,2 Nan Zhao1 1Department of Pathology, General Hospital of Tianjin Medical University, 2Department of Pathology, Tianjin Medical University, 3Department of Pathology, Cancer Hospital of Tianjin Medical University, Tianjin, People’s Republic of China *These authors contributed equally to this work Abstract: Tumor cell vasculogenic mimicry (VM, a newly defined pattern of tumor blood supply, signifies the functional plasticity of aggressive cancer cells forming vascular networks. VM and cancer stem cells (CSCs have been shown to be associated with tumor growth, local invasion, and distant metastasis. In our previous study, CSCs in triple-negative breast cancer were potential to participate in VM formation. In this study, breast CSCs were isolated from the triple-negative breast cancer cell line MDA-MB-231 by using mammosphere culture. Western blotting and reverse transcription polymerase chain reaction showed that mammosphere cells displayed an increased expression of AURKA protein kinase and stem cell marker c-myc and sox2. The VM formation by mammosphere cells was inhibited by AURKA knockdown or the addition of AURKA inhibitor MLN8237. In the meantime, MLN8237 induced the increased E-cadherin and decreased c-myc, sox2, and β-catenin expressions. The function of AURKA in VM formation was further confirmed using a xenograft-murine model. The results suggested that AURKA protein kinase is involved in VM formation of CSCs and may become a new treatment target in suppressing VM and metastasis of breast cancer. Keywords: AURKA, cancer stem cells, vasculogenic mimicry, breast cancer

  14. Exploiting death: apoptotic immunity in microbial pathogenesis.

    Science.gov (United States)

    Ucker, D S

    2016-06-01

    Innate immunity typically is responsible for initial host responses against infections. Independently, nucleated cells that die normally as part of the physiological process of homeostasis in mammals (including humans) suppress immunity. Specifically, the physiological process of cell death (apoptosis) generates cells that are recognized specifically by viable cells of all types and elicit a profound transient suppression of host immunity (termed 'innate apoptotic immunity' (IAI)). IAI appears to be important normally for the maintenance of self-tolerance and for the resolution of inflammation. In addition, pathogens are able to take advantage of IAI through a variety of distinct mechanisms, to enable their proliferation within the host and enhance pathogenicity. For example, the protist pathogen Leishmania amazonensis, at its infective stage, mimics apoptotic cells by expressing apoptotic-like protein determinants on the cell surface, triggering immunosuppression directly. In contrast, the pathogenic bacterium Listeria monocytogenes triggers cell death in host lymphocytes, relying on those apoptotic cells to suppress host immune control and facilitate bacterial expansion. Finally, although the inhibition of apoptotic cell death is a common attribute of many viruses which facilitates their extended replication, it is clear that adenoviruses also reprogram the non-apoptotic dead cells that arise subsequently to manifest apoptotic-like immunosuppressive properties. These three instances represent diverse strategies used by microbial pathogens to exploit IAI, focusing attention on the potency of this facet of host immune control. Further examination of these cases will be revealing both of varied mechanisms of pathogenesis and the processes involved in IAI control. PMID:26943319

  15. The functional basis of wing patterning in Heliconius butterflies: the molecules behind mimicry.

    Science.gov (United States)

    Kronforst, Marcus R; Papa, Riccardo

    2015-05-01

    Wing-pattern mimicry in butterflies has provided an important example of adaptation since Charles Darwin and Alfred Russell Wallace proposed evolution by natural selection >150 years ago. The neotropical butterfly genus Heliconius played a central role in the development of mimicry theory and has since been studied extensively in the context of ecology and population biology, behavior, and mimicry genetics. Heliconius species are notable for their diverse color patterns, and previous crossing experiments revealed that much of this variation is controlled by a small number of large-effect, Mendelian switch loci. Recent comparative analyses have shown that the same switch loci control wing-pattern diversity throughout the genus, and a number of these have now been positionally cloned. Using a combination of comparative genetic mapping, association tests, and gene expression analyses, variation in red wing patterning throughout Heliconius has been traced back to the action of the transcription factor optix. Similarly, the signaling ligand WntA has been shown to control variation in melanin patterning across Heliconius and other butterflies. Our understanding of the molecular basis of Heliconius mimicry is now providing important insights into a variety of additional evolutionary phenomena, including the origin of supergenes, the interplay between constraint and evolvability, the genetic basis of convergence, the potential for introgression to facilitate adaptation, the mechanisms of hybrid speciation in animals, and the process of ecological speciation. PMID:25953905

  16. Hindering facial mimicry in ad viewing: effects on consumers’ emotions, attitudes and purchase intentions

    NARCIS (Netherlands)

    P. Lewinski; E.S. Tan; M.L. Fransen; K. Czarna; C. Butler

    2016-01-01

    Recent findings in consumer psychology demonstrate that embodied cognition and bodily mimicry may influence consumers’ attitudes, intentions, and behavior (e.g. Hung & Labroo, 2011; Howard & Gengler, 2001). For example, when two friends (Bill and John) watch a funny advertisement and they both smile

  17. "The Elephant in the Dark Room": Merrick and Menacing Mimicry in Bernard Pomerance's "The Elephant Man"

    Science.gov (United States)

    Sasani, Samira

    2015-01-01

    This paper tries to look at Pomerance's "The Elephant Man," from a new perspective from which no critic has investigated the play, before. Applying postcolonial theory of Homi K. Bhabha to the play, the author scrutinizes how "mimicry strategy", employed by the colonizer and the Other, can be threatening for both and how the…

  18. Egg mimicry in cuckoos parasitizing four sympatric species of Acrocephalus warblers

    Czech Academy of Sciences Publication Activity Database

    Edvardsen, E.; Moksnes, A.; Roskaft, E.; Oien, I. J.; Honza, Marcel

    2001-01-01

    Roč. 103, č. 4 (2001), s. 829-837. ISSN 0010-5422 Institutional research plan: CEZ:AV0Z6093917 Keywords : brood parasitism * egg mimicry * Acrocephalus warblers Subject RIV: EG - Zoology Impact factor: 1.104, year: 2001 http://www.jstor.org/stable/1370116

  19. Facial Mimicry in 6-7 Year Old Children with Disruptive Behavior Disorder and ADHD

    NARCIS (Netherlands)

    Deschamps, Peter; Munsters, Nicolette; Kenemans, Leon; Schutter, Dennis; Matthys, Walter

    2014-01-01

    Background: Impairments in facial mimicry are considered a proxy for deficits in affective empathy and have been demonstrated in 10 year old children and in adolescents with disruptive behavior disorder (DBD). However, it is not known whether these impairments are already present at an earlier age.

  20. Do Dynamic Compared to Static Facial Expressions of Happiness and Anger Reveal Enhanced Facial Mimicry?

    Science.gov (United States)

    Rymarczyk, Krystyna; Żurawski, Łukasz; Jankowiak-Siuda, Kamila; Szatkowska, Iwona

    2016-01-01

    Facial mimicry is the spontaneous response to others' facial expressions by mirroring or matching the interaction partner. Recent evidence suggested that mimicry may not be only an automatic reaction but could be dependent on many factors, including social context, type of task in which the participant is engaged, or stimulus properties (dynamic vs static presentation). In the present study, we investigated the impact of dynamic facial expression and sex differences on facial mimicry and judgment of emotional intensity. Electromyography recordings were recorded from the corrugator supercilii, zygomaticus major, and orbicularis oculi muscles during passive observation of static and dynamic images of happiness and anger. The ratings of the emotional intensity of facial expressions were also analysed. As predicted, dynamic expressions were rated as more intense than static ones. Compared to static images, dynamic displays of happiness also evoked stronger activity in the zygomaticus major and orbicularis oculi, suggesting that subjects experienced positive emotion. No muscles showed mimicry activity in response to angry faces. Moreover, we found that women exhibited greater zygomaticus major muscle activity in response to dynamic happiness stimuli than static stimuli. Our data support the hypothesis that people mimic positive emotions and confirm the importance of dynamic stimuli in some emotional processing. PMID:27390867

  1. You give me the chills : Embodied reactions to inappropriate amounts of behavioral mimicry

    NARCIS (Netherlands)

    Leander, N. Pontus; Chartrand, Tanya L.; Bargh, John A.

    2012-01-01

    In the research reported here, we investigated how suspicious nonverbal cues from other people can trigger feelings of physical coldness. There exist implicit standards for how much nonverbal behavioral mimicry is appropriate in various types of social interactions, and individuals may react negativ

  2. New Perspectives on Emotional Contagion: A Review of Classic and Recent Research on Facial Mimicry and Contagion

    Directory of Open Access Journals (Sweden)

    Elaine Hatfield

    2014-12-01

    Full Text Available Recently, scholars from a wide variety of disciplines, using a variety of scientific techniques, have begun to study the influence of attention, facial mimicry, and social context on emotional contagion. In this paper we will review the classic evidence documenting the role of attention, facial mimicry, and feedback in sparking primitive emotional contagion. Then we will discuss the new evidence which scholars have amassed to help us better understand the role of facial mimicry in fostering contagion and the ability to “read” others’ thoughts, feelings, and emotions. Finally, we will briefly speculate as to where future research might be headed.

  3. Effect of Genistein on vasculogenic mimicry formation by human uveal melanoma cells

    Directory of Open Access Journals (Sweden)

    Gu Haijuan

    2009-09-01

    Full Text Available Abstract Background Vasculogenic mimicry (VM was increasingly recognized as a form of aggressive melanoma acquiring blood supply. Genistein had attracted much attention as a potential anticancer agent. Therefore, we examined the effect of Genistein on VM in human uveal melanoma cells. Methods VM structure was detected by periodic acid-Schiff (PAS staining for uveal melanoma C918 cells cultured on the three-dimensional type I collagen gels after exposed to Genistein. We used reverse transcription polymerase chain reaction (RT-PCR and Western Blot analysis to examine the effect of Genistein on vascular endothelial cadherin (VE-cadherin mRNA and protein expression. The nude mice models of human uveal melanoma C918 cells were established to assess the number of VM using immunohistochemical and PAS double-staining. Results Genistein inhibited the survival of C918 cells in vitro. The ectopic model study showed that VM in tumor tissue sections were significantly reduced by Genistein in vivo. In vitro, the VM structure was found in control, 25 and 50 μM Genistein-treatment groups but not in 100 and 200 μM. RT-PCR and Western Blot showed that 100 and 200 μM concentration of Genistein could significantly decrease VE-cadherin mRNA and protein expression of C918 cells compared with control (P 0.05. Conclusion Genistein inhibits VM formation of uveal melanoma cells in vivo and in vitro. One possible underlying molecular mechanism by which Genistein could inhibit VM formation of uveal melanoma is related to down-regulation of VE-cadherin.

  4. Intercellular transfer of apoptotic signals via electrofusion

    Energy Technology Data Exchange (ETDEWEB)

    Park, Jin Suk; Lee, Wilson; McCulloch, Christopher A., E-mail: christopher.mcculloch@utoronto.ca

    2012-05-01

    We determined whether cells that are induced to undergo anoikis by matrix detachment can initiate apoptosis in healthy cells following electroporation-induced fusion. Separate populations of MDCK cells undergoing anoikis and stained with FITC-annexin or viable MDCK cells that were labeled with spectrally discrete fluorescent beads were electroporated. Cells were analyzed by flow cytometry for enumeration of viable cells with beads, apoptotic cells or fused cells. Electroporation promoted a 49-fold increase of the percentage of viable cells that had fused with apoptotic cells. Apoptotic cell-viable cell fusions were 8-fold more likely to not attach to cell culture plastic and 2.3-fold less likely to proliferate after 24 hr incubation than viable cell fusion controls. These data demonstrate that apoptotic signals can be transferred between cells by electrofusion, possibly suggesting a novel investigative approach for optimizing targeted cell deletion in cancer treatment.

  5. The curious world of apoptotic cell clearance

    OpenAIRE

    Weitzman, Jonathan B

    2004-01-01

    Analysis of knockout mice has brought into question the previously proposed role of the phosphatidylserine receptor (Ptdsr) in the clearance of apoptotic cell corpses, and has suggested important functions in regulating differentiation and inflammation.

  6. Intercellular transfer of apoptotic signals via electrofusion

    International Nuclear Information System (INIS)

    We determined whether cells that are induced to undergo anoikis by matrix detachment can initiate apoptosis in healthy cells following electroporation-induced fusion. Separate populations of MDCK cells undergoing anoikis and stained with FITC-annexin or viable MDCK cells that were labeled with spectrally discrete fluorescent beads were electroporated. Cells were analyzed by flow cytometry for enumeration of viable cells with beads, apoptotic cells or fused cells. Electroporation promoted a 49-fold increase of the percentage of viable cells that had fused with apoptotic cells. Apoptotic cell-viable cell fusions were 8-fold more likely to not attach to cell culture plastic and 2.3-fold less likely to proliferate after 24 hr incubation than viable cell fusion controls. These data demonstrate that apoptotic signals can be transferred between cells by electrofusion, possibly suggesting a novel investigative approach for optimizing targeted cell deletion in cancer treatment.

  7. Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses vasculogenic mimicry and proliferation of highly aggressive pancreatic cancer PaTu8988 cells

    International Nuclear Information System (INIS)

    Pancreatic cancer is one of the most aggressive human malignancies with a extremely low 5-year survival rate. Hence, the search for more effective anti-pancreatic cancer agents is urgent. PaTu8988 pancreatic cancer cells were treated with different concentrations of suberoylanilide hydroxamic acid (SAHA), cell survival, proliferation, migration and vasculogenic mimicry (VM) were analyzed. Associated signaling changes were also analyzed by RT-PCR and Western blots. Here, we reported that SAHA, a histone deacetylase inhibitor (HDACi), exerted significant inhibitory efficiency against pancreatic cancer cell survival, proliferation, migration and VM. SAHA dose-dependently inhibited PaTu8988 pancreatic cancer cell growth with the IC-50 of 3.4 ± 0. 7 μM. Meanwhile, SAHA suppressed PaTu8988 cell cycle progression through inducing G2/M arrest, which was associated with cyclin-dependent kinase 1 (CDK-1)/cyclin-B1 degradation and p21/p27 upregulation. Further, SAHA induced both apoptotic and non-apoptotic death of PaTu8988 cells. Significantly, SAHA suppressed PaTu8988 cell in vitro migration and cell-dominant tube formation or VM, which was accompanied by semaphorin-4D (Sema-4D) and integrin-β5 down-regulation. Our evidences showed that Akt activation might be important for Sema-4D expression in PaTu8988 cells, and SAHA-induced Sema-4D down-regulation might be associated with Akt inhibition. This study is among the first to report the VM formation in cultured human pancreatic cancer cells. And we provided strong evidence to suggest that SAHA executes significant anti-VM efficiency in the progressive pancreatic cancer cells. Thus, SAHA could be further investigated as a promising anti-pancreatic cancer agent

  8. Distinct neural processes are engaged in the modulation of mimicry by social group-membership and emotional expressions.

    Science.gov (United States)

    Rauchbauer, Birgit; Majdandžić, Jasminka; Hummer, Allan; Windischberger, Christian; Lamm, Claus

    2015-09-01

    People often spontaneously engage in copying each other's postures and mannerisms, a phenomenon referred to as behavioral mimicry. Social psychology experiments indicate that mimicry denotes an implicit affiliative signal flexibly regulated in response to social requirements. Yet, the mediating processes and neural underpinnings of such regulation are largely unexplored. The present functional magnetic resonance imaging (fMRI) study examined mimicry regulation by combining an automatic imitation task with facial stimuli, varied on two social-affective dimensions: emotional expression (angry vs happy) and ethnic group membership (in- vs out-group). Behavioral data revealed increased mimicry when happy and when out-group faces were shown. Imaging results revealed that mimicry regulation in response to happy faces was associated with increased activation in the right temporo-parietal junction (TPJ), right dorsal premotor cortex (dPMC), and right superior parietal lobule (SPL). Mimicry regulation in response to out-group faces was related to increased activation in the left ventral premotor cortex (vPMC) and inferior parietal lobule (IPL), bilateral anterior insula, and mid-cingulate cortex (MCC). We suggest that mimicry in response to happy and to out-group faces is driven by distinct affiliative goals, and that mimicry regulation to attain these goals is mediated by distinct neuro-cognitive processes. Higher mimicry in response to happy faces seems to denote reciprocation of an affiliative signal. Higher mimicry in response to out-group faces, reflects an appeasement attempt towards an interaction partner perceived as threatening (an interpretation supported by implicit measures showing that out-group members are more strongly associated with threat). Our findings show that subtle social cues can result in the implicit regulation of mimicry. This regulation serves to achieve distinct affiliative goals, is mediated by different regulatory processes, and relies on

  9. Apoptotic clearance in rabbits with experimental pulmonary emphysema

    OpenAIRE

    Žunić-Božinovski Snežana; Žunić Svetlana; Mladenović-Đorđević Aleksandra; Ruždijić Sabera; Kanazir Selma

    2011-01-01

    In order to better understand pathogenesis of pulmonary emphysema, the model of experimentally induced pulmonary emphysema in Chinchilla rabbits was used for the estimation of apoptotic clearance of pulmonary tissue. Bronchoalveolar lavage was performed in three groups of animals: experimental group-E on hypercholesterolemic diet (4% edible oil solution of crystalline cholesterol), control group-C1 on standard diet for that animal species and animals on oil...

  10. Facial mimicry and the mirror neuron system: simultaneous acquisition of facial electromyography and functional magnetic resonance imaging

    OpenAIRE

    Likowski, Katja U.; Mühlberger, Andreas; Gerdes, Antje B. M.; Wieser, Matthias J.; Pauli, Paul; Weyers, Peter

    2012-01-01

    Numerous studies have shown that humans automatically react with congruent facial reactions, i.e., facial mimicry, when seeing a vis-á-vis’ facial expressions. The current experiment is the first investigating the neuronal structures responsible for differences in the occurrence of such facial mimicry reactions by simultaneously measuring BOLD and facial EMG in an MRI scanner. Therefore, 20 female students viewed emotional facial expressions (happy, sad, and angry) of male and female avatar c...

  11. Facial mimicry and the mirror neuron system: Simultaneous acquisition of facial electromyography and functional magnetic resonance imaging

    OpenAIRE

    Gerdes, Antje B. M.; Peter Weyers

    2012-01-01

    Numerous studies have shown that humans automatically react with congruent facial reactions, i.e. facial mimicry, when seeing a vis-á-vis’ facial expressions. The current experiment is the first investigating the neuronal structures responsible for differences in the occurrence of such facial mimicry reactions by simultaneously measuring BOLD and facial EMG in an MRI scanner. Therefore, 20 female students viewed emotional facial expressions (happy, sad, and angry) of male and female avat...

  12. Hepcidin Plays a Key Role in 6-OHDA Induced Iron Overload and Apoptotic Cell Death in a Cell Culture Model of Parkinson's Disease.

    Science.gov (United States)

    Xu, Qi; Kanthasamy, Anumantha G; Jin, Huajun; Reddy, Manju B

    2016-01-01

    Background. Elevated brain iron levels have been implicated in the pathogenesis of Parkinson's disease (PD). However, the precise mechanism underlying abnormal iron accumulation in PD is not clear. Hepcidin, a hormone primarily produced by hepatocytes, acts as a key regulator in both systemic and cellular iron homeostasis. Objective. We investigated the role of hepcidin in 6-hydroxydopamine (6-OHDA) induced apoptosis in a cell culture model of PD. Methods. We downregulated hepcidin using siRNA interference in N27 dopaminergic neuronal cells and made a comparison with control siRNA transfected cells to investigate the role of hepcidin in 6-OHDA induced neurodegeneration. Results. Hepcidin knockdown (32.3%, P export mediated by ferroportin 1. PMID:27298749

  13. Hepcidin Plays a Key Role in 6-OHDA Induced Iron Overload and Apoptotic Cell Death in a Cell Culture Model of Parkinson's Disease

    Science.gov (United States)

    Xu, Qi; Kanthasamy, Anumantha G.; Jin, Huajun; Reddy, Manju B.

    2016-01-01

    Background. Elevated brain iron levels have been implicated in the pathogenesis of Parkinson's disease (PD). However, the precise mechanism underlying abnormal iron accumulation in PD is not clear. Hepcidin, a hormone primarily produced by hepatocytes, acts as a key regulator in both systemic and cellular iron homeostasis. Objective. We investigated the role of hepcidin in 6-hydroxydopamine (6-OHDA) induced apoptosis in a cell culture model of PD. Methods. We downregulated hepcidin using siRNA interference in N27 dopaminergic neuronal cells and made a comparison with control siRNA transfected cells to investigate the role of hepcidin in 6-OHDA induced neurodegeneration. Results. Hepcidin knockdown (32.3%, P Hepcidin knockdown also reduced 6-OHDA induced caspase-3 activity by 42% (P hepcidin knockdown significantly attenuated 6-OHDA induced protein carbonyls by 52% (P hepcidin in oxidative stress. Conclusions. Our results demonstrate that hepcidin knockdown protected N27 cells from 6-OHDA induced apoptosis and that hepcidin plays a major role in reducing cellular iron burden and oxidative damage by possibly regulating cellular iron export mediated by ferroportin 1. PMID:27298749

  14. Hepcidin Plays a Key Role in 6-OHDA Induced Iron Overload and Apoptotic Cell Death in a Cell Culture Model of Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Qi Xu

    2016-01-01

    Full Text Available Background. Elevated brain iron levels have been implicated in the pathogenesis of Parkinson’s disease (PD. However, the precise mechanism underlying abnormal iron accumulation in PD is not clear. Hepcidin, a hormone primarily produced by hepatocytes, acts as a key regulator in both systemic and cellular iron homeostasis. Objective. We investigated the role of hepcidin in 6-hydroxydopamine (6-OHDA induced apoptosis in a cell culture model of PD. Methods. We downregulated hepcidin using siRNA interference in N27 dopaminergic neuronal cells and made a comparison with control siRNA transfected cells to investigate the role of hepcidin in 6-OHDA induced neurodegeneration. Results. Hepcidin knockdown (32.3%, P<0.0001 upregulated ferroportin 1 expression and significantly (P<0.05 decreased intracellular iron by 25%. Hepcidin knockdown also reduced 6-OHDA induced caspase-3 activity by 42% (P<0.05 and DNA fragmentation by 29% (P=0.086 and increased cell viability by 22% (P<0.05. In addition, hepcidin knockdown significantly attenuated 6-OHDA induced protein carbonyls by 52% (P<0.05 and intracellular iron by 28% (P<0.01, indicating the role of hepcidin in oxidative stress. Conclusions. Our results demonstrate that hepcidin knockdown protected N27 cells from 6-OHDA induced apoptosis and that hepcidin plays a major role in reducing cellular iron burden and oxidative damage by possibly regulating cellular iron export mediated by ferroportin 1.

  15. The status of supergenes in the 21st century: recombination suppression in Batesian mimicry and sex chromosomes and other complex adaptations.

    Science.gov (United States)

    Charlesworth, Deborah

    2016-01-01

    I review theoretical models for the evolution of supergenes in the cases of Batesian mimicry in butterflies, distylous plants and sex chromosomes. For each of these systems, I outline the genetic evidence that led to the proposal that they involve multiple genes that interact during 'complex adaptations', and at which the mutations involved are not unconditionally advantageous, but show advantages that trade-off against some disadvantages. I describe recent molecular genetic studies of these systems and questions they raise about the evolution of suppressed recombination. Nonrecombining regions of sex chromosomes have long been known, but it is not yet fully understood why recombination suppression repeatedly evolved in systems in distantly related taxa, but does not always evolve. Recent studies of distylous plants are tending to support the existence of recombination-suppressed genome regions, which may include modest numbers of genes and resemble recently evolved sex-linked regions. For Batesian mimicry, however, molecular genetic work in two butterfly species suggests a new supergene scenario, with a single gene mutating to produce initial adaptive phenotypes, perhaps followed by modifiers specifically refining and perfecting the new phenotype. PMID:27087840

  16. Phytochemical mimicry of reproductive hormones and modulation of herbivore fertility by phytoestrogens.

    OpenAIRE

    Hughes, C. L.

    1988-01-01

    Plants have physical and chemical mechanisms for defense from attack by animals. Phytochemical defenses that protect plants from attack by insects include antifeedants, insecticides, and insect growth regulators. Phytochemical options exist by which plants can modulate the fertility of the other major group of plant predators, vertebrate herbivores, and thereby reduce cumulative attacks by those herbivores. The success of such a defense depends upon phytochemical mimicry of vertebrate reprodu...

  17. The stereotyper and the chameleon: The effects of stereotype use on perceivers? mimicry

    OpenAIRE

    Castelli, Luigi; Pavan, Giulia; Ferrari, Elisabetta; Kashima, Yoshihisa

    2009-01-01

    Abstract Interpersonal dynamics may play a crucial role in the perpetuation of stereotypes. In an experimental study, participants interacted with a confederate who provided either stereotype-consistent or stereotype-inconsistent descriptions about the elderly. Based on the assumption that mimicry represents a social glue that fosters interpersonal liking and affiliation, we assessed the extent to which participants mimicked the nonverbal behaviors of the confederate as a function ...

  18. Gradual and contingent evolutionary emergence of leaf mimicry in butterfly wing patterns

    OpenAIRE

    Suzuki, Takao K; Tomita, Shuichiro; Sezutsu, Hideki

    2014-01-01

    Background Special resemblance of animals to natural objects such as leaves provides a representative example of evolutionary adaptation. The existence of such sophisticated features challenges our understanding of how complex adaptive phenotypes evolved. Leaf mimicry typically consists of several pattern elements, the spatial arrangement of which generates the leaf venation-like appearance. However, the process by which leaf patterns evolved remains unclear. Results In this study we show the...

  19. The effects of repetitive traumatic experiences on emotion recognition, facial mimicry and autonomic regulation

    OpenAIRE

    Ardizzi, Martina

    2015-01-01

    The present dissertation focuses on the influence of childhood experiences on social development. We aim to chart how the dynamic interplay of biological, social, and emotional influences shapes developmental trajectories. Specifically, we investigated the influence of childhood protracted conditions of maltreatment and neglect on the explicit recognition of facial expressions of emotions, along with, Facial Mimicry and vagal regulation in response to facial expressions of emotions - as physi...

  20. Phylogenetic evidence for colour pattern convergence in toxic pitohuis: Müllerian mimicry in birds?

    OpenAIRE

    Dumbacher, J. P.; Fleischer, R C

    2001-01-01

    Bird species in the genus Pitohui are chemically defended by a potent neurotoxic alkaloid in their skin and feathers. The two most toxic pitohui species, the hooded pitohui (Pitohui dichrous) and the variable pitohui (Pitohui kirhocephalus), are sometimes strikingly patterned and, in certain portions of their geographical ranges, both species share a nearly identical colour pattern, whereas in other areas they do not. Müllerian mimicry (the mutual resemblance of two chemically defended prey s...

  1. The enigmatic fast leaflet rotation in Desmodium motorium: Butterfly mimicry for defense?

    OpenAIRE

    Lev-Yadun, Simcha

    2013-01-01

    I propose that the enigmatic leaflet movements in elliptical circles every few minutes of the Indian telegraph (semaphore) plant Desmodium motorium ( = D. gyrans = Hedysarum gyrans = Codariocalyx motorius), which has intrigued scientists for centuries, is a new type of butterfly or general winged arthropod mimicry by this plant. Such leaflet movement may deceive a passing butterfly searching for an un-occupied site suitable to deposit its eggs, that the plant is already occupied. It may also ...

  2. Amino Acid Change in an Orchid Desaturase Enables Mimicry of the Pollinator's Sex Pheromone.

    Science.gov (United States)

    Sedeek, Khalid E M; Whittle, Edward; Guthörl, Daniela; Grossniklaus, Ueli; Shanklin, John; Schlüter, Philipp M

    2016-06-01

    Mimicry illustrates the power of selection to produce phenotypic convergence in biology [1]. A striking example is the imitation of female insects by plants that are pollinated by sexual deception of males of the same insect species [2-4]. This involves mimicry of visual, tactile, and chemical signals of females [2-7], especially their sex pheromones [8-11]. The Mediterranean orchid Ophrys exaltata employs chemical mimicry of cuticular hydrocarbons, particularly the 7-alkenes, in an insect sex pheromone to attract and elicit mating behavior in its pollinators, males of the cellophane bee Colletes cunicularius [11-13]. A difference in alkene double-bond positions is responsible for reproductive isolation between O. exaltata and closely related species, such as O. sphegodes [13-16]. We show that these 7-alkenes are likely determined by the action of the stearoyl-acyl-carrier-protein desaturase (SAD) homolog SAD5. After gene duplication, changes in subcellular localization relative to the ancestral housekeeping desaturase may have allowed proto-SAD5's reaction products to undergo further biosynthesis to both 7- and 9-alkenes. Such ancestral coproduction of two alkene classes may have led to pollinator-mediated deleterious pleiotropy. Despite possible evolutionary intermediates with reduced activity, amino acid changes at the bottom of the substrate-binding cavity have conferred enzyme specificity for 7-alkene biosynthesis by preventing the binding of longer-chained fatty acid (FA) precursors by the enzyme. This change in desaturase function enabled the orchid to perfect its chemical mimicry of pollinator sex pheromones by escape from deleterious pleiotropy, supporting a role of pleiotropy in determining the possible trajectories of adaptive evolution. PMID:27212404

  3. Dissection of the DNA Mimicry of the Bacteriophage T7 Ocr Protein using Chemical Modification

    OpenAIRE

    Stephanou, Augoustinos S.; Roberts, Gareth A.; Cooper, Laurie P.; Clarke, David J.; Thomson, Andrew R.; Mackay, C. Logan; Nutley, Margaret; Cooper, Alan; Dryden, David T. F.

    2009-01-01

    The homodimeric Ocr (overcome classical restriction) protein of bacteriophage T7 is a molecular mimic of double-stranded DNA and a highly effective competitive inhibitor of the bacterial type I restriction/modification system. The surface of Ocr is replete with acidic residues that mimic the phosphate backbone of DNA. In addition, Ocr also mimics the overall dimensions of a bent 24-bp DNA molecule. In this study, we attempted to delineate these two mechanisms of DNA mimicry by chemically modi...

  4. P17.18IMMUNOFLUORESCENCE OBSERVATION OF VASCULOGENIC MIMICRY CHANNELS IN HUMAN GLIOBLASTOMA SAMPLES

    OpenAIRE

    Mei, X.; Y. Chen; Chen, Z.

    2014-01-01

    BACKGROUND: Vasculogenic mimicry(VM) has been reported in many malignant human tumors, including gliomas. In the present study, we have found four types of microcirculation vessels in human glioblastomas. Method and material: Thirty-seven human glioblastoma samples were examined for VM by CD34 and PAS dual staining,as well as immunofluorescence dual staining for CD34 and GFAP. The GFAP positive (GFAP+) cells were considered as glioma cells. Even though CD34 positive (CD34+) was endothelial ce...

  5. Crying wolf to a predator: deceptive vocal mimicry by a bird protecting young.

    Science.gov (United States)

    Igic, Branislav; McLachlan, Jessica; Lehtinen, Inkeri; Magrath, Robert D

    2015-06-22

    Animals often mimic dangerous or toxic species to deter predators; however, mimicry of such species may not always be possible and mimicry of benign species seems unlikely to confer anti-predator benefits. We reveal a system in which a bird mimics the alarm calls of harmless species to fool a predator 40 times its size and protect its offspring against attack. Our experiments revealed that brown thornbills (Acanthiza pusilla) mimic a chorus of other species' aerial alarm calls, a cue of an Accipiter hawk in flight, when predators attack their nest. The absence of any flying predators in this context implies that these alarms convey deceptive information about the type of danger present. Experiments on the primary nest predators of thornbills, pied currawongs (Strepera graculina), revealed that the predators treat these alarms as if they themselves are threatened by flying hawks, either by scanning the sky for danger or fleeing, confirming a deceptive function. In turn, these distractions delay attack and provide thornbill nestlings with an opportunity to escape. This sophisticated defence strategy exploits the complex web of interactions among multiple species across several trophic levels, and in particular exploits a predator's ability to eavesdrop on and respond appropriately to heterospecific alarm calls. Our findings demonstrate that prey can fool predators by deceptively mimicking alarm calls of harmless species, suggesting that defensive mimicry could be more widespread because of indirect effects on predators within a web of eavesdropping. PMID:26041353

  6. The function of animal 'eyespots':Conspicuousness but not eye mimicry is key

    Institute of Scientific and Technical Information of China (English)

    Martin STEVENS; Abi CANTOR; Julia GRAHAM; Isabel S. WINNEY

    2009-01-01

    Many animals are marked with conspicuous circular features often called ' eyespots', which intimidate predators, preventing or halting an attack. It has long been assumed that eyespots work by mimicking the eyes of larger animals, but recent experiments have indicated that conspicuousness and contrast is important in eyespot function, and not eye mimicry. We undertake two further experiments to distinguish between the conspicuousness and mimicry hypotheses, by using artificial prey presented to wild avian predators in the field. In experiment 1, we test if eyespot effectiveness depends on the marking shape (bar or circle) and arrangement (eye-like and non-eye-like positions). We find no difference between shapes or arrangement; all spots were equally effective in scaring birds. In experiment 2, we test if the often yellow and black colors of eyespots mimic the eyes of birds of prey. We find no effect of shape, and no advantage to yellow and black spots over non-eye-like but equally conspicuous colors. The consistent finding is that eyespot function lies in being a conspicuous signal to predators, and not necessarily due to eye mimicry [Current Zoology 55 (5): 319-326, 2009].

  7. The function of animal ‘eyespots’: conspicuousness but not eye mimicry is key

    Directory of Open Access Journals (Sweden)

    Martin STEVENS

    2009-10-01

    Full Text Available Many animals are marked with conspicuous circular features often called ‘eyespots’, which intimidate predators, preventing or halting an attack. It has long been assumed that eyespots work by mimicking the eyes of larger animals, but recent experiments have indicated that conspicuousness and contrast is important in eyespot function, and not eye mimicry. We undertake two further experiments to distinguish between the conspicuousness and mimicry hypotheses, by using artificial prey presented to wild avian predators in the field. In experiment 1, we test if eyespot effectiveness depends on the marking shape (bar or circle and arrangement (eye-like and non-eye-like positions. We find no difference between shapes or arrangement; all spots were equally effective in scaring birds. In experiment 2, we test if the often yellow and black colors of eyespots mimic the eyes of birds of prey. We find no effect of shape, and no advantage to yellow and black spots over non-eye-like but equally conspicuous colors. The consistent finding is that eyespot function lies in being a conspicuous signal to predators, and not necessarily due to eye mimicry [Current Zoology 55 (5: –2009].

  8. Tissue Microarray Study of Vasculogenic Mimicry in Bi-directional Differentiated Malignant Tumors

    Institute of Scientific and Technical Information of China (English)

    XishanHao; BaocunSun; ShiwuZhang; XiulanZhao

    2004-01-01

    OBJECTIVE To determine if vasculogenic mimicry (VM) exists in bi-directional differentiated malignant tumors. METHODS The blood supply models for bi-directional differentiated tumors were studied with immunohistochemical and PAS double-staining techniques. New sections were made from 158 paraffin-embedded bi-directional malignant-tumor samples, including melanoma (high malignancy n=30, low malignancy n=30); synoviosarcoma(SS) (high malignancy n=26, low malignancy n=13); acinar rhabdomyosarcoma (All) (high malignancy n=16,low malignancy n=13); malignant mesothelioma (MM) (n=26), and epithelioid sarcoma (ES)(n=4). Tissue microarrays were made. The representative points in the paraffin sections were labeled and two tissue microarrays were made, one included 60 cases of melanoma, and the other included the other tumors. Immunohistochemical staining of the platelet-endothelial cell adhesive molecule(CD31 antigen) and periodic acid Schiff(PAS) staining were conducted. The areas were calculated of vessel-like channels consisting of CD31 antigen-positive tumor cells and of PAS positive materials. The VM was studied using the data obtained. RESULTS Some of these bi-directional tumor cells secreted PAS-positive materials and 0D31 positive materials. The walls of the VM consisted of PAS-positive materials lined with CD31 negative tumor cells with red blood cells inside the channel, whereas the walls of the epithelium-dependent vessels were comprised of CD31 positive materials. The positive areas of CD31 were significantly less than that of PAS (P<0.01). The number of cases with VM in highly malignant tumors was greater than that found in the lowly malignant tumors. CONCLUSIONS Bi-directional differentiated malignant tumor cells have the ability to auto-transform and might interact with the extracellular matrix to form a vessel channel system which mimics blood vessels for transporting blood. That process is called VM. Results in this study show that bi

  9. Antiproliferative and apoptotic effects of spanish honeys

    OpenAIRE

    Paloma Morales; Ana Isabel Haza

    2013-01-01

    Background: Current evidence supports that consumption of polyphenols has beneficial effects against numerous diseases mostly associated with their antioxidant activity. Honey is a good source of antioxidants since it contains a great variety of phenolic compounds. Objective: The main objective of this work was to investigate the antiproliferative and apoptotic effects of three crude commercial honeys of different floral origin (heather, rosemary and polyfloral honey) from Madrid Autonomic Co...

  10. Bioinformatics evaluation of the possibility of heat shock proteins as autoantigens in multiple sclerosis based on molecular mimicry hypothesis.

    Science.gov (United States)

    Ansari Qeshmi, Safa; Dabbagh, Fatemeh; Borhani Haghighi, Afshin; Ghasemi, Younes

    2016-06-15

    Molecular mimicry is the explanatory link between the heat shock proteins (HSPs) of infectious agents and triggering multiple sclerosis. Considering that there are many similarities between self- and bacterial-HSPs, the goal was to investigate a panel of 60- and 70kDa HSPs from a variety of bacteria in order to predict the role of each microorganism in triggering or progression of the disease under the molecular mimicry hypothesis. By clarifying the peptides meeting criteria for cross-reactivity and elucidating the role of each microorganism in MS pathogenesis, it would be easier to suggest more effective treatment and preventive strategies for this disease. PMID:27235356

  11. [Sphingolipid-mediated apoptotic signaling pathways].

    Science.gov (United States)

    Cuvillier, Olivier; Andrieu-Abadie, Nathalie; Ségui, Bruno; Malagarie-Cazenave, Sophie; Tardy, Claudine; Bonhoure, Elisabeth; Levade, Thierry

    2003-01-01

    Various sphingolipids are being viewed as bioactive molecules and/or second messengers. Among them, ceramide (or N-acylsphingosine) and sphingosine generally behave as pro-apoptotic mediators. Indeed, ceramide mediates the death signal initiated by numerous stress agents which either stimulate its de novo synthesis or activate sphingomyelinases that release ceramide from sphingomyelin. For instance, the early generation of ceramide promoted by TNF is mediated by a neutral sphingomyelinase the activity of which is regulated by the FAN adaptor protein, thereby controlling caspase activation and the cell death programme. In addition, the activity of this neutral sphingomyelinase is negatively modulated by caveolin, a major constituent of some membrane microdomains. The enzyme sphingosine kinase also plays a crucial role in apoptosis signalling by regulating the intracellular levels of two sphingolipids having opposite effects, namely the pro-apoptotic sphingosine and the anti-apoptotic sphingosine 1-phosphate molecule. Ceramide and sphingosine metabolism therefore appears as a pivotal regulatory pathway in the determination of cell fate. PMID:14708343

  12. Biophysical study of the DNA charge mimicry displayed by the T7 Ocr protein

    OpenAIRE

    Stephanou, Augoustinos S.

    2010-01-01

    The homodimeric Ocr protein of bacteriophage T7 is a molecular mimic of a bent double-stranded DNA molecule ~24 bp in length. As such, Ocr is a highly effective competitive inhibitor of the bacterial Type I restriction modification (R/M) system. Thus, Ocr facilitates phage infection of the bacterial cell to proceed unhindered by the action of the R/M defense system. The main aim of this work was to understand the basis of the DNA mimicry displayed by Ocr. The surface of the ...

  13. Hippocampal expression of apoptotic protease activating factor-1 following diffuse axonal injury under mild hypothermia

    Institute of Scientific and Technical Information of China (English)

    Peng Yang; Limin Zhang; Yunhe Zhang; Xifeng Zou; Qunxi Li; Yun Li; Jun Zhu; Jianmin Li; Aijun Fu; Qingjun Liu; Tong Chen; Zelin Sun; Zhiyong Zhang

    2011-01-01

    The influence of mild hypothermia on neural cell apoptosis remains poorly understood. Therefore, the present study established rat models of diffuse axonal injury (DAI) at 33 °C. Morris water maze results demonstrated significantly better learning and memory functions in DAI rats with hypothermia compared with DAI rats with normothermia. Expression of apoptotic protease activating factor-1 in the hippocampal CA1 region was significantly lower in the DAI hypothermia group compared with the DAI normothermia group. Expression of apoptotic protease activating factor-1 positively correlated with latency, but negatively correlated with platform location times and time of swimming in the quadrant area. Results suggested that post-traumatic mild hypothermia in a rat model of DAI could provide cerebral protection by attenuating expression of apoptotic protease activating factor-1.

  14. Pericytic mimicry in well-differentiated liposarcoma/atypical lipomatous tumor.

    Science.gov (United States)

    Shen, Jia; Shrestha, Swati; Rao, P Nagesh; Asatrian, Greg; Scott, Michelle A; Nguyen, Vi; Giacomelli, Paulina; Soo, Chia; Ting, Kang; Eilber, Fritz C; Peault, Bruno; Dry, Sarah M; James, Aaron W

    2016-08-01

    Pericytes are modified smooth muscle cells that closely enwrap small blood vessels, regulating and supporting the microvasculature through direct endothelial contact. Pericytes demonstrate a distinct immunohistochemical profile, including expression of smooth muscle actin, CD146, platelet-derived growth factor receptor β, and regulator of G-protein signaling 5. Previously, pericyte-related antigens have been observed to be present among a group of soft tissue tumors with a perivascular growth pattern, including glomus tumor, myopericytoma, and angioleiomyoma. Similarly, malignant tumor cells have been shown to have a pericyte-like immunoprofile when present in a perivascular location, seen in malignant melanoma, glioblastoma, and adenocarcinoma. Here, we examine well-differentiated liposarcoma specimens, which showed some element of perivascular areas with the appearance of smooth muscle (n = 7 tumors). Immunohistochemical staining was performed for pericyte antigens, including smooth muscle actin, CD146, platelet-derived growth factor receptor β, and regulator of G-protein signaling 5. Results showed consistent pericytic marker expression among liposarcoma tumor cells within a perivascular distribution. MDM2 immunohistochemistry and fluorescence in situ hybridization for MDM2 revealed that these perivascular cells were of tumor origin (7/7 tumors), whereas double immunohistochemical detection for CD31/CD146 ruled out an endothelial cell contribution. These findings further support the concept of pericytic mimicry, already established in diverse malignancies, and its presence in well-differentiated liposarcoma. The extent to which pericytic mimicry has prognostic significance in liposarcoma is as yet unknown. PMID:27063472

  15. Antiproliferative and apoptotic effects of spanish honeys

    Directory of Open Access Journals (Sweden)

    Paloma Morales

    2013-01-01

    Full Text Available Background: Current evidence supports that consumption of polyphenols has beneficial effects against numerous diseases mostly associated with their antioxidant activity. Honey is a good source of antioxidants since it contains a great variety of phenolic compounds. Objective: The main objective of this work was to investigate the antiproliferative and apoptotic effects of three crude commercial honeys of different floral origin (heather, rosemary and polyfloral honey from Madrid Autonomic Community (Spain as well as of an artificial honey in human peripheral blood promyelocytic leukemia cells (HL-60. Material and Methods: HL-60 cells were cultured in the presence of honeys at various concentrations for up to 72 hours and the percentage of cell viability was evaluated by MTT assay. Apoptotic cells were identified by chromatin condensation and flow cytometry analysis. ROS production was determined using 2΄,7΄-dichlorodihydrofluorescein diacetate (H 2 DCFDA. Results: The three types of crude commercial honey induced apoptosis in a concentration and time dependent-manner. In addition, honeys with the higher phenolic content, heather and polyfloral, were the most effective to induce apoptosis in HL-60 cells. However, honeys did not generate reactive oxygen species (ROS and N-acetyl-L-cysteine (NAC could not block honeys-induced apoptosis in HL-60 cells. Conclusion: These data support that honeys induced apoptosis in HL-60 cells through a ROS-independent cell death pathway.Moreover, our findings indicate that the antiproliferative and apoptotic effects of honey varied according to the floral origin and the phenolic content.

  16. Impaired Overt Facial Mimicry in Response to Dynamic Facial Expressions in High-Functioning Autism Spectrum Disorders

    Science.gov (United States)

    Yoshimura, Sayaka; Sato, Wataru; Uono, Shota; Toichi, Motomi

    2015-01-01

    Previous electromyographic studies have reported that individuals with autism spectrum disorders (ASD) exhibited atypical patterns of facial muscle activity in response to facial expression stimuli. However, whether such activity is expressed in visible facial mimicry remains unknown. To investigate this issue, we videotaped facial responses in…

  17. Relaxin has anti-apoptotic effects on human trophoblast-derived HTR-8/SV neo cells.

    Science.gov (United States)

    Lodhi, Romana S Z; Nakabayashi, Koji; Suzuki, Kaho; Yamada, Ai Y; Hazama, Rhoichi; Ebina, Yasuhiko; Yamada, Hideto

    2013-12-01

    The study was conducted to evaluate the effects of human relaxin on apoptosis in the human trophoblast derived HTR-8/SV neo cell line, which is a possible model of human extravillous trophoblasts (EVTs). HTR-8/SV neo cells, cultured in phenol red free RPMI1640 medium, were treated with different doses of human recombinant (rH2) relaxin in serum-deprived conditions. RT-PCR was used for evaluating relaxin receptor: RXFP1 and RXFP2 expression in HTR-8/SV neo cells. The cell death was examined by TUNEL assay. Furthermore, we investigated caspase-3, cleaved PARP and Bcl-2 expressions by Western blot analysis to recognize the translational effects of anti-apoptotic and pro-apoptotic proteins. RXFP1 and RXFP2 mRNA expression was observed in HTR-8/SV neo cells. Compared with untreated control cultures, treatment with rH2 relaxin, decreased TUNEL-positive rate in HTR-8/SV neo cells was observed. Western blot analysis revealed that treatment with rH2 relaxin decreased the expression of caspase-3 and cleaved PARP, but in contrast increased Bcl-2 expression in those cells. These results suggest that rH2 relaxin has anti-apoptotic effects on HTR8/SV neo cells by decreasing pro-apoptotic caspase-3 and cleaved PARP expression and up-regulating anti-apoptotic Bcl-2 expression. PMID:24070111

  18. Selection of apoptotic cell specific human antibodies from adult bone marrow.

    Directory of Open Access Journals (Sweden)

    Caroline Grönwall

    Full Text Available Autoreactive antibodies that recognize neo-determinants on apoptotic cells in mice have been proposed to have protective, homeostatic and immunoregulatory properties, although our knowledge about the equivalent antibodies in humans has been much more limited. In the current study, human monoclonal antibodies with binding specificity for apoptotic cells were isolated from the bone marrow of healthy adults using phage display technology. These antibodies were shown to recognize phosphorylcholine (PC-associated neo-determinants. Interestingly, three of the four identified apoptotic cell-specific antibody clones were encoded by VH3 region rearrangements with germline or nearly germline configuration without evidence of somatic hypermutation. Importantly, the different identified antibody clones had diverse heavy chain CDR3 and deduced binding surfaces as suggested by structure modeling. This may suggest a potentially great heterogeneity in human antibodies recognizing PC-related epitopes on apoptotic cells. To re-construct the postulated structural format of the parental anti-PC antibody, the dominant clone was also expressed as a recombinant human polymeric IgM, which revealed a substantially increased binding reactivity, with dose-dependent and antigen-inhibitable binding of apoptotic cells. Our findings may have implication for improved prognostic testing and therapeutic interventions in human inflammatory disease.

  19. Leptin suppresses non-apoptotic cell death in ischemic rat cardiomyocytes by reduction of iPLA{sub 2} activity

    Energy Technology Data Exchange (ETDEWEB)

    Takatani-Nakase, Tomoka, E-mail: nakase@mukogawa-u.ac.jp; Takahashi, Koichi, E-mail: koichi@mukogawa-u.ac.jp

    2015-07-17

    Caspase-independent, non-apoptotic cell death is an important therapeutic target in myocardial ischemia. Leptin, an adipose-derived hormone, is known to exhibit cytoprotective effects on the ischemic heart, but the mechanisms are poorly understood. In this research, we found that pretreatment of leptin strongly suppressed ischemic-augmented nuclear shrinkage and non-apoptotic cell death on cardiomyocytes. Leptin was also shown to significantly inhibit the activity of iPLA{sub 2}, which is considered to play crucial roles in non-apoptotic cell death, resulting in effective prevention of ischemia-induced myocyte death. These findings provide the first evidence of a protective mechanism of leptin against ischemia-induced non-apoptotic cardiomyocyte death. - Highlights: • Myocardial ischemia-model induces in caspase-independent, non-apoptotic cell death. • Leptin strongly inhibits ischemic-augmented non-apoptotic cell death. • Leptin reduces iPLA{sub 2} activity, leading to avoidance of non-apoptotic cell death.

  20. Leptin suppresses non-apoptotic cell death in ischemic rat cardiomyocytes by reduction of iPLA2 activity

    International Nuclear Information System (INIS)

    Caspase-independent, non-apoptotic cell death is an important therapeutic target in myocardial ischemia. Leptin, an adipose-derived hormone, is known to exhibit cytoprotective effects on the ischemic heart, but the mechanisms are poorly understood. In this research, we found that pretreatment of leptin strongly suppressed ischemic-augmented nuclear shrinkage and non-apoptotic cell death on cardiomyocytes. Leptin was also shown to significantly inhibit the activity of iPLA2, which is considered to play crucial roles in non-apoptotic cell death, resulting in effective prevention of ischemia-induced myocyte death. These findings provide the first evidence of a protective mechanism of leptin against ischemia-induced non-apoptotic cardiomyocyte death. - Highlights: • Myocardial ischemia-model induces in caspase-independent, non-apoptotic cell death. • Leptin strongly inhibits ischemic-augmented non-apoptotic cell death. • Leptin reduces iPLA2 activity, leading to avoidance of non-apoptotic cell death

  1. Non-apoptotic function of apoptotic proteins in the development of Malpighian tubules of Drosophila melanogaster

    Indian Academy of Sciences (India)

    Madhu G Tapadia; Naveen K Gautam

    2011-08-01

    Drosophila metamorphosis is characterized by the histolysis of larval structures by programmed cell death, which paves the way for the establishment of adult-specific structures under the influence of the steroid hormone ecdysone. Malpighian tubules function as an excretory system and are one of the larval structures that are not destroyed during metamorphosis and are carried over to adulthood. The pupal Malpighian tubules evade destruction in spite of expressing apoptotic proteins, Reaper, Hid, Grim, Dronc and Drice. Here we show that in the Malpighian tubules expression of apoptotic proteins commences right from embryonic development and continues throughout the larval stages. Overexpression of these proteins in the Malpighian tubules causes larval lethality resulting in malformed tubules. The number and regular organization of principal and stellate cells of Malpighian tubules is disturbed, in turn disrupting the physiological functioning of the tubules as well. Strikingly, the localization of -tubulin, F-actin and Disclarge (Dlg) is also disrupted. These results suggest that the apoptotic proteins could be having non-apoptotic function in the development of Malpighian tubules.

  2. Distinct mathematical behavior of apoptotic versus non-apoptotic tumor cell death

    International Nuclear Information System (INIS)

    Purpose: The presence or absence of a p53-dependent apoptosis response has previously been shown to greatly influence radiosensitivity in tumor cells. Here, we examine clonogenic survival curves for two genetically related oncogene transformed cell lines differing in the presence or absence of p53 and apoptosis. Solid tumor radiosensitivity patterns have been previously described for these lines. Materials and Methods: Oncogene-transformed fibroblasts derived from E1A + Ras transfection of p53-wild-type or p53-null mouse embryonic fibroblasts were plated as single cells and irradiated at increasing radiation doses in single fractions from 1.5 to 11 Gy. Clonogenic cell survival assays were obtained. Survival data are fit to a linear-quadratic relationship: S = e-αD-βD2. Apoptosis was assessed and quantitated morphologically by staining with the fluorescent nuclear dye DAPI, by TUNEL assay for DNA fragmentation, and by measurement of apoptotic cysteine protease cleavage activity in cytosolic extracts. Results: Whereas radiation triggers massive apoptosis in the presence of p53, it produces no measurable DNA fragmentation, apoptotic cysteine protease cleavage activity, or morphological changes of apoptosis in the cells lacking p53. These contrasting mechanisms of death display dramatically different quantitative behavior: log-survival of apoptotic cells is linearly proportional to dose (S = e-αD), whereas survival of non-apoptotic (p53 null) is linear-quadratic with a significant quadratic contribution. The surviving fraction at 2 Gy (SF-2) for p53-null cells was 70% verses 12% for p53-intact cells. Conclusions: In this system, apoptosis appears to exhibit a dominance of single-event which produces a very high α/β ratio, and no significant shoulder; whereas non-apoptotic death in this system exhibits a comparatively small linear component, a low α/β ratio, and a larger shoulder

  3. Abnormalities in Alternative Splicing of Apoptotic Genes and Cardiovascular Diseases

    OpenAIRE

    Zodwa Dlamini; Tshidino, Shonisani C.; Rodney Hull

    2015-01-01

    Apoptosis is required for normal heart development in the embryo, but has also been shown to be an important factor in the occurrence of heart disease. Alternative splicing of apoptotic genes is currently emerging as a diagnostic and therapeutic target for heart disease. This review addresses the involvement of abnormalities in alternative splicing of apoptotic genes in cardiac disorders including cardiomyopathy, myocardial ischemia and heart failure. Many pro-apoptotic members of the Bcl-2 f...

  4. Bcl-2 Inhibitors: Targeting Mitochondrial Apoptotic Pathways in Cancer Therapy

    OpenAIRE

    Kang, Min H.; Reynolds, C. Patrick

    2009-01-01

    Defects in apoptotic pathways can promote cancer cell survival and also confer resistance to antineoplastic drugs. One pathway being targeted for antineoplastic therapy is the anti-apoptotic B-cell lymphoma-2 (Bcl-2) family of proteins (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, Bfl1/A-1, and Bcl-B) that bind to and inactivate BH3-domain pro-apoptotic proteins. Signals transmitted by cellular damage (including antineoplastic drugs) or cytokine deprivation can initiate apoptosis via the intrinsic apoptotic ...

  5. The regulation of apoptotic cell death

    Directory of Open Access Journals (Sweden)

    Amarante-Mendes G.P.

    1999-01-01

    Full Text Available Apoptosis is a fundamental biological phenomenon in which the death of a cell is genetically and biochemically regulated. Different molecules are involved in the regulation of the apoptotic process. Death receptors, coupled to distinct members of the caspases as well as other adapter molecules, are involved in the initiation of the stress signals (The Indictment. Members of the Bcl-2 family control at the mitochondrial level the decision between life and death (The Judgement. The effector caspases are responsible for all morphological and biochemical changes related to apoptosis including the "eat-me" signals perceived by phagocytes and neighboring cells (The Execution. Finally, apoptosis would have little biological significance without the recognition and removal of the dying cells (The Burial.

  6. Morphological and behavioral evidence of Batesian mimicry in nestlings of a lowland Amazonian bird.

    Science.gov (United States)

    Londoño, Gustavo A; García, Duván A; Sánchez Martínez, Manuel A

    2015-01-01

    Because predation is the main cause of avian nest failure, selection should favor strategies that reduce the probability of nest predation. We describe apparent Batesian mimicry in the morphology and behavior of a Laniocera hypopyrra nestling. On hatching, the nestling had a distinctive bright orange color and modified feathers all over its body, and 6 days after hatching, it started to move its head very slowly from side to side (in a "caterpillar" movement) when disturbed. These traits gave it a resemblance to a hairy, aposematic caterpillar. This species has a long nestling period for its size (20 days), perhaps due to slow provisioning rates (about one feeding per hour). We argue that the slow growth rate, combined with high nest predation, favors the evolution of antipredation mechanisms such as the unique morphological and behavioral characteristics of L. hypopyrra nestlings. PMID:25560558

  7. The enigmatic fast leaflet rotation in Desmodium motorium: butterfly mimicry for defense?

    Science.gov (United States)

    Lev-Yadun, Simcha

    2013-06-01

    I propose that the enigmatic leaflet movements in elliptical circles every few minutes of the Indian telegraph (semaphore) plant Desmodium motorium ( = D. gyrans = Hedysarum gyrans = Codariocalyx motorius), which has intrigued scientists for centuries, is a new type of butterfly or general winged arthropod mimicry by this plant. Such leaflet movement may deceive a passing butterfly searching for an un-occupied site suitable to deposit its eggs, that the plant is already occupied. It may also attract insectivorous birds, reptiles or arthropods to the plant because it looks as if it is harboring a potential prey and while they patrol there, they can find insects or other invertebrates that indeed attack the plant. The possibility that diurnal mammalian herbivores may also be deterred by these movements should not be dismissed. PMID:23603964

  8. Imperfect chemical female mimicry in males of the ant Cardiocondyla obscurior

    DEFF Research Database (Denmark)

    Cremer, S.; D'Ettorre, P.; Drijfhout, F.P.;

    2008-01-01

    Winged and wingless males coexist in the ant Cardiocondyla obscurior. Wingless ("ergatoid") males never leave their maternal colony and fight remorselessly among each other for the access to emerging females. The peaceful winged males disperse after about 10 days, but beforehand also mate in the...... exemplifies that the analysis of rare malfunctioning can add valuable insight on functioning under normal conditions and allows the conclusion that older winged males from normal colonies of the ant C. obscurior are guarded through an imperfect chemical female mimicry, still close enough to protect against...... tolerated, which so far has been puzzling. Contrasting this general pattern, we have identified a single aberrant colony in which all winged males were attacked and killed by the ergatoid males. A comparative analysis of the morphology and chemical profile of these untypical attacked winged males and the...

  9. Major transcriptome reprogramming underlies floral mimicry induced by the rust fungus Puccinia monoica in Boechera stricta.

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    Liliana M Cano

    Full Text Available Pucciniamonoica is a spectacular plant parasitic rust fungus that triggers the formation of flower-like structures (pseudoflowers in its Brassicaceae host plant Boecherastricta. Pseudoflowers mimic in shape, color, nectar and scent co-occurring and unrelated flowers such as buttercups. They act to attract insects thereby aiding spore dispersal and sexual reproduction of the rust fungus. Although much ecological research has been performed on P. monoica-induced pseudoflowers, this system has yet to be investigated at the molecular or genomic level. To date, the molecular alterations underlying the development of pseudoflowers and the genes involved have not been described. To address this, we performed gene expression profiling to reveal 256 plant biological processes that are significantly altered in pseudoflowers. Among these biological processes, plant genes involved in cell fate specification, regulation of transcription, reproduction, floral organ development, anthocyanin (major floral pigments and terpenoid biosynthesis (major floral volatile compounds were down-regulated in pseudoflowers. In contrast, plant genes involved in shoot, cotyledon and leaf development, carbohydrate transport, wax biosynthesis, cutin transport and L-phenylalanine metabolism (pathway that results in phenylethanol and phenylacetaldehyde volatile production were up-regulated. These findings point to an extensive reprogramming of host genes by the rust pathogen to induce floral mimicry. We also highlight 31 differentially regulated plant genes that are enriched in the biological processes mentioned above, and are potentially involved in the formation of pseudoflowers. This work illustrates the complex perturbations induced by rust pathogens in their host plants, and provides a starting point for understanding the molecular mechanisms of pathogen-induced floral mimicry.

  10. Molecular mimicry as a mechanism for food immune reactivities and autoimmunity.

    Science.gov (United States)

    Vojdani, Aristo

    2015-01-01

    The mucosal immune system is constantly exposed to challenges from the antigenic substances found in food and released from the body's own microbial flora. The body's normal tolerance to friendly antigenic substances can be disrupted by a number of factors, such as disease, injury, shock, trauma, surgery, drugs, blood transfusion, environmental triggers, etc. When this disruption happens, the ingestion of foods containing antigenic substances that have compositions similar to those of the body's autoantigens can result in the production of antibodies that react not only against the food antigens but also the body's own tissues. This response is known as food autoimmune reactivity. Between 7% and 10% of the world's population suffers from some form of autoimmune disease. Each patient's antibodies, both immunoglobulin A (IgA) + immunoglobulin M (IgM) in the saliva and immunoglobulin G (IgG) and IgA in the blood must be examined to give a complete picture of food immune reactivity. A host of health problems and autoimmune disorders have increasingly become associated with some of the most commonly consumed foods in the world, such as wheat and milk. Many of these problems can be traced to molecular mimicry. The peptide sequences of foods such as milk and wheat are similar to those of human molecules, such as myelin oligodendrocyte glycoprotein, human islet cell tissue, and human aquaporin 4 (AQP4). This similarity can result in cross-reactivity that leads to food autoimmunity and even autoimmune disorders, such as multiple sclerosis (MS), celiac disease (CD), and neuromyelitis optica. Further research is needed to determine what other foods have dangerous sequence similarities to human tissues and what methods are available to test for the autoantibodies resulting from these molecular, mimicry-induced misfires of the immune system. The identification and removal of corresponding food triggers can then be used as the basis of therapy. PMID:25599184

  11. Investigations of extracellular matrix proteases, apoptotic and anti-apoptotic factors in the bovine corpus luteum

    OpenAIRE

    Kliem, Heike

    2006-01-01

    The study is subdivided into two different parts: the first part deals with the development of a method to gain uterus milk in vivo during the preimplantation periode in cattle for the investigation of regulatory factors. The second part investigates different proteases in bovine follicles 20 hours after GnRH (Gonadotropin releasing hormone) injection (shortly bevor ovulation) for comparable as well as in the corpus luteum (CL) during oestrous cycle and induced luteolysis. In addition apoptot...

  12. Nitric oxide as a pro-apoptotic as well as anti-apoptotic modulator.

    Science.gov (United States)

    Choi, Byung-Min; Pae, Hyun-Ock; Jang, Seon Il; Kim, Young-Myeong; Chung, Hun-Taeg

    2002-01-31

    Nitric oxide (NO), synthesized from L-arginine by NO synthases, is a small, lipophilic, diffusible, highly reactive molecule with dichotomous regulatory roles in many biological events under physiological and pathological conditions. NO can promote apoptosis (pro-apoptosis) in some cells, whereas it inhibits apoptosis (anti-apoptosis) in other cells. This complexity is a consequence of the rate of NO production and the interaction with biological molecules such as metal ion, thiol, protein tyrosine, and reactive oxygen species. Long-lasting overproduction of NO acts as a pro-apoptotic modulator, activating caspase family proteases through the release of mitochondrial cytochrome c into cytosol, up-regulation of the p53 expression, and alterations in the expression of apoptosis-associated proteins, including the Bcl-2 family. However, low or physiological concentrations of NO prevent cells from apoptosis that is induced by the trophic factor withdrawal, Fas, TNFalpha/ActD, and LPS. The anti-apoptotic mechanism is understood on the basis of gene transcription of protective proteins. These include: heat shock protein, hemeoxygenase, or cyclooxygenase-2 and direct inhibition of the apoptotic executive effectors caspase family protease by S-nitrosylation of the cysteine thiol group in their catalytic site in a cell specific way. Our current understanding of the mechanisms by which NO exerts both pro- and anti-apototic action is discussed in this review article. PMID:16248976

  13. The Effects of NAD+ on Apoptotic Neuronal Death and Mitochondrial Biogenesis and Function after Glutamate Excitotoxicity

    Directory of Open Access Journals (Sweden)

    Xiaowan Wang

    2014-11-01

    Full Text Available NAD+ is an essential co-enzyme for cellular energy metabolism and is also involved as a substrate for many cellular enzymatic reactions. It has been shown that NAD+ has a beneficial effect on neuronal survival and brain injury in in vitro and in vivo ischemic models. However, the effect of NAD+ on mitochondrial biogenesis and function in ischemia has not been well investigated. In the present study, we used an in vitro glutamate excitotoxicity model of primary cultured cortical neurons to study the effect of NAD+ on apoptotic neuronal death and mitochondrial biogenesis and function. Our results show that supplementation of NAD+ could effectively reduce apoptotic neuronal death, and apoptotic inducing factor translocation after neurons were challenged with excitotoxic glutamate stimulation. Using different approaches including confocal imaging, mitochondrial DNA measurement and Western blot analysis of PGC-1 and NRF-1, we also found that NAD+ could significantly attenuate glutamate-induced mitochondrial fragmentation and the impairment of mitochondrial biogenesis. Furthermore, NAD+ treatment effectively inhibited mitochondrial membrane potential depolarization and NADH redistribution after excitotoxic glutamate stimulation. Taken together, our results demonstrated that NAD+ is capable of inhibiting apoptotic neuronal death after glutamate excitotoxicity via preserving mitochondrial biogenesis and integrity. Our findings provide insights into potential neuroprotective strategies in ischemic stroke.

  14. Distinct mathematical behavior of apoptotic vs. non-apoptotic tumor cell death

    International Nuclear Information System (INIS)

    Purpose: A quantitative description of cancer cell death behavior is of potential importance in identifying prognostically meaningful treatment responses and mechanisms underlying those responses. Here we examine clonogenic survival curves for two genetically related tumor cell lines differing in the presence or absence of p53, for whom solid tumor radiosensitivity patterns have been previously described. Materials and Methods: Oncogene-transformed fibroblasts derived from E1A+Ras tranfections of p53 wildtype or p53 null mouse embryonic fibroblasts were plated in single cell suspension. Cells were irradiated at increasing radiation doses from 1.5 Gy to 11 Gy. Dishes were scored for colonies at day 11. Survival curves were generated by least-squares regression over dose of log (survival) onto the quadratic (αD + βD2), each point being weighted inversely to the variance among replicates. Apoptosis was assessed morphologically by staining with flourescent nuclear dye DAPI, by DNA fragmentation with the APOPTAG Apoptosis Detection Kit (Oncor), and by measurement of apoptotic cysteine protease cleavage activity in cytosolic extracts. Results: Whereas radiation triggers massive apoptosis in the presence of p53, in this system it produces no measurable DNA fragmentation, apoptotic cysteine protease cleavage activity, or morphologic changes of apoptosis in the cells lacking p53. These contrasting mechanisms of death display dramatically different quantitative behavior: log-survival of apoptotic cells is linearly proportional to dose (S=e-nD) whereas non-apoptotic survival is quadratically related to dose (S=e-nD2). Radioresistance at clinical doses (about 2 Gy) were largely mirrored by the initial slopes. For quadratic killing, survival was nearly flat at 77%, whereas it was only 12% for apoptosis owing to its steep linear slope. Conclusions: Apoptosis exhibits single hit kinetics and is seen to produce a high α/β ratio and no significant shoulder, whereas non-apoptotic

  15. In vitro apoptotic cell death during erythroid differentiation.

    Science.gov (United States)

    Zamai, L; Burattini, S; Luchetti, F; Canonico, B; Ferri, P; Melloni, E; Gonelli, A; Guidotti, L; Papa, S; Falcieri, E

    2004-03-01

    Erythropoiesis occurs in bone marrow and it has been shown that during in vivo erythroid differentiation some immature erythroblasts undergo apoptosis. In this regard, it is known that immature erythroblasts are FasL- and TRAIL-sensitive and can be killed by cells expressing these ligand molecules. In the present study, we have investigated the cell death phenomenon that occurs during a common unilineage model of erythroid development. Purified CD34+ human haemopoietic progenitors were cultured in vitro in the presence of SCF, IL-3 and erythropoietin. Their differentiation stages and apoptosis were followed by multiple technical approaches. Flow cytometric evaluation of surface and intracellular molecules revealed that glycophorin A appeared at day 3-4 of incubation and about 75% of viable cells co-expressed high density glycophorin A (Gly(bright)) and adult haemoglobin at day 14 of culture, indicating that this system reasonably recapitulates in vivo normal erythropoiesis. Interestingly, when mature (Gly(bright)) erythroid cells reached their higher percentages (day 14) almost half of cultured cells were apoptotic. Morphological studies indicated that the majority of dead cells contained cytoplasmic granular material typical of basophilic stage, and DNA analysis by flow cytometry and TUNEL reaction revealed nuclear fragmentation. These observations indicate that in vitro unilineage erythroid differentiation, as in vivo, is associated with apoptotic cell death of cells with characteristics of basophilic erythroblasts. We suggest that the interactions between different death receptors on immature basophilic erythroblasts with their ligands on more mature erythroblasts may contribute to induce apoptosis in vitro. PMID:15004520

  16. PARP Inhibition Restores Extrinsic Apoptotic Sensitivity in Glioblastoma

    Science.gov (United States)

    Karpel-Massler, Georg; Pareja, Fresia; Aimé, Pascaline; Shu, Chang; Chau, Lily; Westhoff, Mike-Andrew; Halatsch, Marc-Eric; Crary, John F.; Canoll, Peter; Siegelin, Markus D.

    2014-01-01

    Background Resistance to apoptosis is a paramount issue in the treatment of Glioblastoma (GBM). We show that targeting PARP by the small molecule inhibitors, Olaparib (AZD-2281) or PJ34, reduces proliferation and lowers the apoptotic threshold of GBM cells in vitro and in vivo. Methods The sensitizing effects of PARP inhibition on TRAIL-mediated apoptosis and potential toxicity were analyzed using viability assays and flow cytometry in established GBM cell lines, low-passage neurospheres and astrocytes in vitro. Molecular analyses included western blots and gene silencing. In vivo, effects on tumor growth were examined in a murine subcutaneous xenograft model. Results The combination treatment of PARP inhibitors and TRAIL led to an increased cell death with activation of caspases and inhibition of formation of neurospheres when compared to single-agent treatment. Mechanistically, pharmacological PARP inhibition elicited a nuclear stress response with up-regulation of down-stream DNA-stress response proteins, e.g., CCAAT enhancer binding protein (C/EBP) homology protein (CHOP). Furthermore, Olaparib and PJ34 increased protein levels of DR5 in a concentration and time-dependent manner. In turn, siRNA-mediated suppression of DR5 mitigated the effects of TRAIL/PARP inhibitor-mediated apoptosis. In addition, suppression of PARP-1 levels enhanced TRAIL-mediated apoptosis in malignant glioma cells. Treatment of human astrocytes with the combination of TRAIL/PARP inhibitors did not cause toxicity. Finally, the combination treatment of TRAIL and PJ34 significantly reduced tumor growth in vivo when compared to treatment with each agent alone. Conclusions PARP inhibition represents a promising avenue to overcome apoptotic resistance in GBM. PMID:25531448

  17. PARP inhibition restores extrinsic apoptotic sensitivity in glioblastoma.

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    Georg Karpel-Massler

    Full Text Available BACKGROUND: Resistance to apoptosis is a paramount issue in the treatment of Glioblastoma (GBM. We show that targeting PARP by the small molecule inhibitors, Olaparib (AZD-2281 or PJ34, reduces proliferation and lowers the apoptotic threshold of GBM cells in vitro and in vivo. METHODS: The sensitizing effects of PARP inhibition on TRAIL-mediated apoptosis and potential toxicity were analyzed using viability assays and flow cytometry in established GBM cell lines, low-passage neurospheres and astrocytes in vitro. Molecular analyses included western blots and gene silencing. In vivo, effects on tumor growth were examined in a murine subcutaneous xenograft model. RESULTS: The combination treatment of PARP inhibitors and TRAIL led to an increased cell death with activation of caspases and inhibition of formation of neurospheres when compared to single-agent treatment. Mechanistically, pharmacological PARP inhibition elicited a nuclear stress response with up-regulation of down-stream DNA-stress response proteins, e.g., CCAAT enhancer binding protein (C/EBP homology protein (CHOP. Furthermore, Olaparib and PJ34 increased protein levels of DR5 in a concentration and time-dependent manner. In turn, siRNA-mediated suppression of DR5 mitigated the effects of TRAIL/PARP inhibitor-mediated apoptosis. In addition, suppression of PARP-1 levels enhanced TRAIL-mediated apoptosis in malignant glioma cells. Treatment of human astrocytes with the combination of TRAIL/PARP inhibitors did not cause toxicity. Finally, the combination treatment of TRAIL and PJ34 significantly reduced tumor growth in vivo when compared to treatment with each agent alone. CONCLUSIONS: PARP inhibition represents a promising avenue to overcome apoptotic resistance in GBM.

  18. Minimizing motor mimicry by myself: self-focus enhances online action-control mechanisms during motor contagion.

    Science.gov (United States)

    Spengler, Stephanie; Brass, Marcel; Kühn, Simone; Schütz-Bosbach, Simone

    2010-03-01

    Ideomotor theory of human action control proposes that activation of a motor representation can occur either through internally-intended or externally-perceived actions. Critically, sometimes these alternatives of eliciting a motor response may be conflicting, for example, when intending one action and perceiving another, necessitating the recruitment of enhanced action-control to avoid motor mimicry. Based on previous neuroimaging evidence, suggesting that reduced mimicry is associated with self-related processing, we aimed to experimentally enhance these action-control mechanisms during motor contagion by inducing self-focus. In two within-subjects experiments, participants had to enforce their action intention against an external motor contagion tendency under heightened and normal self-focus. During high self-focus participants showed reduced motor mimicry, induced either by mirror self-observation or self-referential judgments. This indicates that a self-focus provoking situation can enhance online action-control mechanisms, needed to resist unintentional motor contagion tendencies and thereby enables a modulation of automatic mirroring responses. PMID:20116291

  19. Skeletal muscle stem cells express anti-apoptotic ErbB receptors during activation from quiescence

    International Nuclear Information System (INIS)

    To be effective for tissue repair, satellite cells (the stem cells of adult muscle) must survive the initial activation from quiescence. Using an in vitro model of satellite cell activation, we show that erbB1, erbB2 and erbB3, members of the EGF receptor tyrosine kinase family, appear on satellite cells within 6 h of activation. We show that signalling via erbB2 provides an anti-apoptotic survival mechanism for satellite cells during the first 24 h, as they progress to a proliferative state. Inhibition of erbB2 signalling with AG825 reduced satellite cell numbers, concomitant with elevated caspase-8 activation and TUNEL labelling of apoptotic satellite cells. In serum-free conditions, satellite cell apoptosis could be largely prevented by a mixture of erbB1, erbB3 and erbB4 ligand growth factors, but not by neuregulin alone (erbB3/erbB4 ligand). Furthermore, using inhibitors specific to discrete intracellular signalling pathways, we identify MEK as a pro-apoptotic mediator, and the erbB-regulated factor STAT3 as an anti-apoptotic mediator during satellite cell activation. These results implicate erbB2 signalling in the preservation of a full compliment of satellite cells as they activate in the context of a damaged muscle

  20. A plant natriuretic peptide-like gene in the bacterial pathogen Xanthomonas axonopodis may induce hyper-hydration in the plant host: a hypothesis of molecular mimicry

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    Sayed Muhammed

    2004-03-01

    Full Text Available Abstract Background Plant natriuretic peptides (PNPs are systemically mobile molecules that regulate homeostasis at nanomolar concentrations. PNPs are up-regulated under conditions of osmotic stress and PNP-dependent processes include changes in ion transport and increases of H2O uptake into protoplasts and whole tissue. Presentation of the hypothesis The bacterial citrus pathogen Xanthomonas axonopodis pv. Citri str. 306 contains a gene encoding a PNP-like protein. We hypothesise that this bacterial protein can alter plant cell homeostasis and thus is likely to represent an example of molecular mimicry that enables the pathogen to manipulate plant responses in order to bring about conditions favourable to the pathogen such as the induced plant tissue hyper-hydration seen in the wet edged lesions associated with Xanthomonas axonopodis infection. Testing the hypothesis We found a Xanthomonas axonopodis PNP-like protein that shares significant sequence similarity and identical domain organisation with PNPs. We also observed a significant excess of conserved residues between the two proteins within the domain previously identified as being sufficient to induce biological activity. Structural modelling predicts identical six stranded double-psi β barrel folds for both proteins thus supporting the hypothesis of similar modes of action. No significant similarity between the Xanthomonas axonopodis protein and other bacterial proteins from GenBank was found. Sequence similarity of the Xanthomonas axonopodis PNP-like protein with the Arabidopsis thaliana PNP (AtPNP-A, shared domain organisation and incongruent phylogeny suggest that the PNP-gene may have been acquired by the bacteria in an ancient lateral gene transfer event. Finally, activity of a recombinant Xanthomonas axonopodis protein in plant tissue and changes in symptoms induced by a Xanthomonas axonopodis mutant with a knocked-out PNP-like gene will be experimental proof of molecular mimicry

  1. In vitro study of immunosuppressive effect of apoptotic cells

    Institute of Scientific and Technical Information of China (English)

    ZHANG Wen-jin; ZHENG Shu-sen

    2005-01-01

    Recent studies revealed that apoptotic cells are actively involved in immunosuppression and anti-inflammation. After being phagocytosed by macrophages, apoptotic cells can actively regulate cytokines secretion from lipopolysaccharide (LPS)-stimulated macrophages, in which the secretion of immunosuppressive cytokines such as interleukin-10 (IL-10) is increased while the pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNFα), interleukin-1beta (IL-1β) and leukin-8 (IL-8) are suppressed. In this paper, we first present evidence that phagocytosed apoptotic cells regulate cytokine secretion of LPS-stimulated macrophages, but also inhibit the activation of T lymphocytes stimulated by ConA. These data suggest that apoptotic cells can alter the biological behavior of macrophages which gain immunosuppressive property.

  2. Molecular mimicry by an F-box effector of Legionella pneumophila hijacks a conserved polyubiquitination machinery within macrophages and protozoa.

    Directory of Open Access Journals (Sweden)

    Christopher T Price

    2009-12-01

    Full Text Available The ability of Legionella pneumophila to proliferate within various protozoa in the aquatic environment and in macrophages indicates a remarkable evolution and microbial exploitation of evolutionarily conserved eukaryotic processes. Ankyrin B (AnkB of L. pneumophila is a non-canonical F-box-containing protein, and is the only known Dot/Icm-translocated effector of L. pneumophila essential for intra-vacuolar proliferation within both macrophages and protozoan hosts. We show that the F-box domain of AnkB and the (9L(10P conserved residues are essential for intracellular bacterial proliferation and for rapid acquisition of polyubiquitinated proteins by the Legionella-containing vacuole (LCV within macrophages, Dictyostelium discoideum, and Acanthamoeba. Interestingly, translocation of AnkB and recruitment of polyubiquitinated proteins in macrophages and Acanthamoeba is rapidly triggered by extracellular bacteria within 5 min of bacterial attachment. Ectopically expressed AnkB within mammalian cells is localized to the periphery of the cell where it co-localizes with host SKP1 and recruits polyubiquitinated proteins, which results in restoration of intracellular growth to the ankB mutant similar to the parental strain. While an ectopically expressed AnkB-(9L(10P/AA variant is localized to the cell periphery, it does not recruit polyubiquitinated proteins and fails to trans-rescue the ankB mutant intracellular growth defect. Direct in vivo interaction of AnkB but not the AnkB-(9L(10P/AA variant with the host SKP1 is demonstrated. Importantly, RNAi-mediated silencing of expression of SKP1 renders the cells non-permissive for intracellular proliferation of L. pneumophila. The role of AnkB in exploitation of the polyubiquitination machinery is essential for intrapulmonary bacterial proliferation in the mouse model of Legionnaires' disease. Therefore, AnkB exhibits a novel molecular and functional mimicry of eukaryotic F-box proteins that exploits

  3. Apoptotic Genes are Differentially Expressed in Aged Gingival Tissue

    OpenAIRE

    González, O. A.; Stromberg, A.J.; Huggins, P. M.; Gonzalez-Martinez, J.; Novak, M.J.; Ebersole, J. L.

    2011-01-01

    Cellular and molecular changes of the periodontium associated with a higher prevalence of oral diseases (e.g., chronic periodontitis) in aged populations have received little attention. Since impaired apoptosis during aging appears to be related to chronic inflammatory disorders, we hypothesized that the expression of genes associated with apoptotic processes are altered in aged healthy and periodontitis-affected gingival tissue. Ontology analysis of 88 genes related to apoptotic pathways was...

  4. Genes of the mitochondrial apoptotic pathway in Mytilus galloprovincialis.

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    Noelia Estévez-Calvar

    Full Text Available Bivalves play vital roles in marine, brackish, freshwater and terrestrial habitats. In recent years, these ecosystems have become affected through anthropogenic activities. The ecological success of marine bivalves is based on the ability to modify their physiological functions in response to environmental changes. One of the most important mechanisms involved in adaptive responses to environmental and biological stresses is apoptosis, which has been scarcely studied in mollusks, although the final consequence of this process, DNA fragmentation, has been frequently used for pollution monitoring. Environmental stressors induce apoptosis in molluscan cells via an intrinsic pathway. Many of the proteins involved in vertebrate apoptosis have been recognized in model invertebrates; however, this process might not be universally conserved. Mytilus galloprovincialis is presented here as a new model to study the linkage between molecular mechanisms that mediate apoptosis and marine bivalve ecological adaptations. Therefore, it is strictly necessary to identify the key elements involved in bivalve apoptosis. In the present study, six mitochondrial apoptotic-related genes were characterized, and their gene expression profiles following UV irradiation were evaluated. This is the first step for the development of potential biomarkers to assess the biological responses of marine organisms to stress. The results confirmed that apoptosis and, more specifically, the expression of the genes involved in this process can be used to assess the biological responses of marine organisms to stress.

  5. Intact Rapid Facial Mimicry as well as Generally Reduced Mimic Responses in Stable Schizophrenia Patients

    Science.gov (United States)

    Chechko, Natalya; Pagel, Alena; Otte, Ellen; Koch, Iring; Habel, Ute

    2016-01-01

    Spontaneous emotional expressions (rapid facial mimicry) perform both emotional and social functions. In the current study, we sought to test whether there were deficits in automatic mimic responses to emotional facial expressions in patients (15 of them) with stable schizophrenia compared to 15 controls. In a perception-action interference paradigm (the Simon task; first experiment), and in the context of a dual-task paradigm (second experiment), the task-relevant stimulus feature was the gender of a face, which, however, displayed a smiling or frowning expression (task-irrelevant stimulus feature). We measured the electromyographical activity in the corrugator supercilii and zygomaticus major muscle regions in response to either compatible or incompatible stimuli (i.e., when the required response did or did not correspond to the depicted facial expression). The compatibility effect based on interactions between the implicit processing of a task-irrelevant emotional facial expression and the conscious production of an emotional facial expression did not differ between the groups. In stable patients (in spite of a reduced mimic reaction), we observed an intact capacity to respond spontaneously to facial emotional stimuli. PMID:27303335

  6. Peptide Mimicrying Between SARS Coronavirus Spike Protein and Human Proteins Reacts with SARS Patient Serum

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    K.-Y. Hwa

    2008-01-01

    Full Text Available Molecular mimicry, defined as similar structures shared by molecules from dissimilar genes or proteins, is a general strategy used by pathogens to infect host cells. Severe acute respiratory syndrome (SARS is a new human respiratory infectious disease caused by SARS coronavirus (SARS-CoV. The spike (S protein of SARS-CoV plays an important role in the virus entry into a cell. In this study, eleven synthetic peptides from the S protein were selected based on its sequence homology with human proteins. Two of the peptides D07 (residues 927–937 and D08 (residues 942–951 were recognized by the sera of SARS patients. Murine hyperimmune sera against these peptides bound to proteins of human lung epithelial cells A549. Another peptide D10 (residues 490–502 stimulated A549 to proliferate and secrete IL-8. The present results suggest that the selected S protein regions, which share sequence homology with human proteins, may play important roles in SARS-CoV infection.

  7. Soral Crypsis: Protective Mimicry of a Coccid on an Indian Fern

    Institute of Scientific and Technical Information of China (English)

    Biplab Patra; Subir Bera; R. James Hickey

    2008-01-01

    Herbivory with crypsis is not well documented in ferns. The present record of cryptic coloration of coccid Saissetia filicum Boisduval (Homoptera: Coccidae) to the sori of a fern species Asplenium nidus L. (Aspleniaceae) is unique. Predatory beetles (Jauravia sp., Coleoptera: Coccinellidae) that feed on the coccids, are suggested to be selective pressure for the development of the present homopteran soral crypsis. A higher rate of effective predation is noticed in the vegetative leaves than the fertile leaves. Aggressive ants were found harvesting honeydew secretions from the coccids and defending the trophobionts as well as the host fern from their natural enemies. In addition, a possible three-way mutualistic relationship among the coccids, its host fern and the tending ant is suggested. Differential numbers of coccids on vegetative and fertile leaves is correlated with their phenol content and degree of predation by beetles. Such coloration mimicry by the coccids may enable them to obtain the necessary blend of sorus of the host fern needed to evade beetle detection and attack.

  8. PREPARATION OF ANTI-IDIOTYPIC ANTIBODIES SPECIFIC FOR ANTI- HEL AND ANALYSIS OF THEIR FUNCTIONAL MIMICRY

    Institute of Scientific and Technical Information of China (English)

    李明远; 肖玉; 肖丽英; 李虹; 蒋中华; 牟家琬; 王道若

    2000-01-01

    Objective. This study is to investigate the functional mimicry by using anfi-idiotypic antibodies of enzymes. Methods. Monoclonal anti-idiotypic antibodies against anfi-HEL(hen egg-white lysozyme, HEL) antibodies were obtained by fusion of Sp2/0 myeloma ceils with spleen ceils of syngeneic mice immunized with monoclonal anti-HEL antibodies against HEL's different antigenic epitopes. Then bacteriolysis of the anti-idiotypic antibodies were ohserved. Results. Eight hybridomas strains secreting anti-idiotypic antibodies were observed and characterized. It was shown that two of eight anti-idiotypic antibodies secreted by two hybridomas( 1A10C9 and 2AllC1B3) could mimic HEL catalytic activity to lyse Micrococcus lysodeikticus and that the catalytic effect of mixed anti-idiotypic antibodies of 1A10 G9 and 2A11C1B3 was stronger than that of one of them, but less than HEL. Conclusion. The results demonstrated that the anti-idiotypic antibodies that could mimic enzyme activity existed in the idiotype network during anti-enzymatic immune response.

  9. Autoimmunity in Rheumatic Diseases Is Induced by Microbial Infections via Crossreactivity or Molecular Mimicry

    Directory of Open Access Journals (Sweden)

    Taha Rashid

    2012-01-01

    Full Text Available A general consensus supports fundamental roles for both genetic and environmental, mainly microbial, factors in the development of autoimmune diseases. One form of autoimmune rheumatic diseases is confined to a group of nonpyogenic conditions which are usually preceded by or associated with either explicit or occult infections. A previous history of clinical pharyngitis, gastroenteritis/urethritis, or tick-borne skin manifestation can be obtained from patients with rheumatic fever, reactive arthritis, or Lyme disease, respectively, whilst, other rheumatic diseases like rheumatoid arthritis (RA, ankylosing spondylitis (AS, and Crohn’s disease (CD are usually lacking such an association with a noticeable microbial infection. A great amount of data supports the notion that RA is most likely caused by Proteus asymptomatic urinary tract infections, whilst AS and CD are caused by subclinical bowel infections with Klebsiella microbes. Molecular mimicry is the main pathogenetic mechanism that can explain these forms of microbe-disease associations, where the causative microbes can initiate the disease with consequent productions of antibacterial and crossreactive autoantibodies which have a great impact in the propagation and the development of these diseases.

  10. Vasculogenic mimicry contributes to lymph node metastasis of laryngeal squamous cell carcinoma

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    Cai Wenjuan

    2010-06-01

    Full Text Available Abstract Background Survival of laryngeal squamous cell carcinoma (LSCC patients has remained unchanged over recent years due to its uncontrolled recurrence and local lymph node metastasis. Vasculogenic mimicry (VM is an alternative type of blood supplement related to more aggressive tumor biology and increased tumor-related mortality. This study aimed to investigate the unique role of VM in the progression of LSCC. Methods We reviewed clinical pathological data of 203 cases of LSCC both prospectively and retrospectively. VM and endothelium-dependent vessel (EDV were detected by immunohistochemistry and double staining to compare their different clinical pathological significance in LSCC. Survival analyses were performed to assess their prognostic significance as well. Results Both VM and EDV existed in LSCC type of blood supply. VM is related to pTNM stage, lymph node metastasis and pathology grade. In contrust, EDV related to location, pTNM stage, T stage and distant metastasis. Univariate analysis showed VM, pTNM stage, T classification, nodal status, histopathological grade, tumor size, and radiotherapy to be related to overall survival (OS. While, VM, location, tumor size and radiotherapy were found to relate to disease free survival (DFS. Multivariate analysis indicated that VM, but not EDV, was an adverse predictor for both OS and DFS. Conclusions VM existed in LSCC. It contributed to the progression of LSCC by promoting lymph node metastasis. It is an independent predictors of a poor prognosis of LSCC.

  11. Infectious Mimicry Complicates Diagnosis in Hemophagocytic Syndrome Caused by Anaplastic Large-Cell Lymphoma

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    Michael J. Peluso

    2012-01-01

    Full Text Available Hemophagocytic syndrome (HPS arises secondary to genetic, rheumatologic, neoplastic, and infectious causes. We discuss a patient whose presentation was consistent with systemic infection but was discovered to have HPS of unknown etiology. The presenting symptoms, as well as unremarkable malignancy and rheumatologic workups, led to the pursuit of an infectious cause, but the patient was ultimately discovered to have an occult anaplastic large-cell lymphoma (ALCL. This case demonstrates the diagnostic challenges that result from infectious mimicry in the context of HPS—first, in distinguishing noninfectious HPS from the systemic inflammation that can result from a widespread infectious process, second, in the identification of the precipitating cause of HPS. While evidence of these challenges has been suggested by the limited literature on HPS and ALCL, our case illustrates the diagnostic dilemma that arises when tissue biopsy does not quickly reveal an etiology. It is important that all physicians be aware that HPS can mimic infection and be prepared to redirect the workup when an infectious etiology for HPS cannot be identified.

  12. Yersinia Virulence Depends on Mimicry of Host Rho-Family Nucleotide Dissociation Inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Prehna,G.; Ivanov, M.; Blisha, J.; Stebbins, C.

    2006-01-01

    Yersinia spp. cause gastroenteritis and the plague, representing historically devastating pathogens that are currently an important biodefense and antibiotic resistance concern. A critical virulence determinant is the Yersinia protein kinase A, or YpkA, a multidomain protein that disrupts the eukaryotic actin cytoskeleton. Here we solve the crystal structure of a YpkA-Rac1 complex and find that YpkA possesses a Rac1 binding domain that mimics host guanidine nucleotide dissociation inhibitors (GDIs) of the Rho GTPases. YpkA inhibits nucleotide exchange in Rac1 and RhoA, and mutations that disrupt the YpkA-GTPase interface abolish this activity in vitro and impair in vivo YpkA-induced cytoskeletal disruption. In cell culture experiments, the kinase and the GDI domains of YpkA act synergistically to promote cytoskeletal disruption, and a Y. pseudotuberculosis mutant lacking YpkA GDI activity shows attenuated virulence in a mouse infection assay. We conclude that virulence in Yersinia depends strongly upon mimicry of host GDI proteins by YpkA.

  13. Sialylated immunoglobulin G can neutralize influenza virus infection through receptor mimicry

    Science.gov (United States)

    Zhao, Conghui; Liu, Xingmu; Zhang, Zaiping; Li, Tongfei; Sun, Ruiman; Gu, Huan; Gu, Jiang

    2016-01-01

    Influenza viruses possess a great threat to human health, but there is still no effective drug to deal with the outbreak of possible new influenza subtypes. In this study, we first fractionated sialylated immunoglobulin G (IgG), mainly Fab sialylated fraction, with sambucus nigra agglutinin affinity chromatography. We then demonstrated that sialylated IgG possessed more effective neutralizing activity against 2009 A (H1N1) subtype than that of IgG mixture, and sialosides on the Fab is crucial in this neutralization reaction as when such residues were removed with neuraminidase A digestion the blocking effect was significantly reduced. It appears that sialic acid residues attached to Fab could serve as binding moieties to receptor binding site of influenza virus. These findings indicate that sialylated IgG probably is an effective anti-influenza broad-spectrum drug utilizing its receptor mimicry to competitively inhibit the attachment of influenza viruses with sialic acid receptors on target cells. This property would be particularly useful if it can be applied to prevent newly emerged influenza virus strain infections in future epidemics. PMID:26870994

  14. Mimicry and eavesdropping enable a new form of social parasitism in ants.

    Science.gov (United States)

    Powell, Scott; Del-Claro, Kleber; Feitosa, Rodrigo M; Brandão, Carlos Roberto F

    2014-10-01

    Social parasitism is defined by the exploitation of the social mechanisms of one society by another whole society. Here, we use quantitative ecological data and experiments to identify the components of a new form of social parasitism by the recently discovered "mirror turtle ant," Cephalotes specularis. We show that C. specularis workers visually mimic and actively avoid contact with foragers of the hyperaggressive host ant Crematogaster ampla, allowing them to move freely in the extensive and otherwise defended foraging networks of host colonies. Workers from parasite colonies have immediate access to these networks by nesting exclusively within host territories, and 89% of all potential host territories were parasitized. Inside the network, parasite workers eavesdrop on the host's trail pheromones to locate and exploit food resources that are defended by the host to the exclusion of all other ants. Experiments demonstrated the unprecedented capacity of the parasite for superior foraging performance on its host's pheromone trails than on trails of its own. Considered together, the apparent Batesian-Wallacian mimicry, pheromone-based interceptive eavesdropping, kleptoparasitism, and xenobiotic nesting ecology displayed by C. specularis within the territory and foraging network of a host ant represents a novel adaptive syndrome for social exploitation. PMID:25226185

  15. Ganglioside GM1 mimicry in Campylobacter strains from sporadic infections in the United States.

    Science.gov (United States)

    Nachamkin, I; Ung, H; Moran, A P; Yoo, D; Prendergast, M M; Nicholson, M A; Sheikh, K; Ho, T; Asbury, A K; McKhann, G M; Griffin, J W

    1999-05-01

    To determine whether GM1-like epitopes in Campylobacter species are specific to O serotypes associated with Guillain-Barré syndrome (GBS) or whether they are frequent among random Campylobacter isolates causing enteritis, 275 random enteritis-associated isolates of Campylobacter jejuni were analyzed. To determine whether GM1-like epitopes in Campylobacter species are specific to O serotypes associated with Guillan-Barre syndrome (GBS) or whether they are frequent among random Campylobacter isolates causing enteritis, 275 enteritis-associated isolates, randomly collected in the United States, were analyzed using a cholera-toxin binding assay [corrected]. Overall, 26.2% of the isolates were positive for the GM1-like epitope. Of the 36 different O serotypes in the sample, 21 (58.3%) contained no strains positive for GM1, whereas in 6 serotypes (16.7%), >50% of isolates were positive for GM1. GBS-associated serotypes were more likely to contain strains positive for GM1 than were non-GBS-associated serotypes (37.8% vs. 15.1%, P=.0116). The results suggest that humans are frequently exposed to strains exhibiting GM1-like mimicry and, while certain serotypes may be more likely to possess GM1-like epitopes, the presence of GM1-like epitopes on Campylobacter strains does not itself trigger GBS. PMID:10191221

  16. Tyrosine-sulfated V2 peptides inhibit HIV-1 infection via coreceptor mimicry.

    Science.gov (United States)

    Cimbro, Raffaello; Peterson, Francis C; Liu, Qingbo; Guzzo, Christina; Zhang, Peng; Miao, Huiyi; Van Ryk, Donald; Ambroggio, Xavier; Hurt, Darrell E; De Gioia, Luca; Volkman, Brian F; Dolan, Michael A; Lusso, Paolo

    2016-08-01

    Tyrosine sulfation is a post-translational modification that facilitates protein-protein interaction. Two sulfated tyrosines (Tys173 and Tys177) were recently identified within the second variable (V2) loop of the major HIV-1 envelope glycoprotein, gp120, and shown to contribute to stabilizing the intramolecular interaction between V2 and the third variable (V3) loop. Here, we report that tyrosine-sulfated peptides derived from V2 act as structural and functional mimics of the CCR5 N-terminus and potently block HIV-1 infection. Nuclear magnetic and surface plasmon resonance analyses indicate that a tyrosine-sulfated V2 peptide (pV2α-Tys) adopts a CCR5-like helical conformation and directly interacts with gp120 in a CD4-dependent fashion, competing with a CCR5 N-terminal peptide. Sulfated V2 mimics, but not their non-sulfated counterparts, inhibit HIV-1 entry and fusion by preventing coreceptor utilization, with the highly conserved C-terminal sulfotyrosine, Tys177, playing a dominant role. Unlike CCR5 N-terminal peptides, V2 mimics inhibit a broad range of HIV-1 strains irrespective of their coreceptor tropism, highlighting the overall structural conservation of the coreceptor-binding site in gp120. These results document the use of receptor mimicry by a retrovirus to occlude a key neutralization target site and provide leads for the design of therapeutic strategies against HIV-1. PMID:27389109

  17. Crossing fitness valleys: empirical estimation of a fitness landscape associated with polymorphic mimicry.

    Science.gov (United States)

    Arias, Mónica; le Poul, Yann; Chouteau, Mathieu; Boisseau, Romain; Rosser, Neil; Théry, Marc; Llaurens, Violaine

    2016-04-27

    Characterizing fitness landscapes associated with polymorphic adaptive traits enables investigation of mechanisms allowing transitions between fitness peaks. Here, we explore how natural selection can promote genetic mechanisms preventing heterozygous phenotypes from falling into non-adaptive valleys. Polymorphic mimicry is an ideal system to investigate such fitness landscapes, because the direction of selection acting on complex mimetic colour patterns can be predicted by the local mimetic community composition. Using more than 5000 artificial butterflies displaying colour patterns exhibited by the polymorphic Müllerian mimic Heliconius numata, we directly tested the role of wild predators in shaping fitness landscapes. We compared predation rates on mimetic phenotypes (homozygotes at the supergene controlling colour pattern), intermediate phenotypes (heterozygotes), exotic morphs (absent from the local community) and palatable cryptic phenotypes. Exotic morphs were significantly more attacked than local morphs, highlighting predators' discriminatory capacities. Overall, intermediates were attacked twice as much as local homozygotes, suggesting the existence of deep fitness valleys promoting strict dominance and reduced recombination between supergene alleles. By including information on predators' colour perception, we also showed that protection on intermediates strongly depends on their phenotypic similarity to homozygous phenotypes and that ridges exist between similar phenotypes, which may facilitate divergence in colour patterns. PMID:27122560

  18. Rho family GTPase Chp/RhoV induces PC12 apoptotic cell death via JNK activation

    OpenAIRE

    Shepelev, Mikhail V; Chernoff, Jonathan; Korobko, Igor V

    2011-01-01

    Rho GTPases regulate numerous cellular processes including apoptosis. Chp/RhoV is an atypical Rho GTPase which functions are poorly understood. Here we investigated the role of Chp in regulation of cell viability using PC12 cells with inducible expression of Chp as a model. We found that expression of Chp results in apoptosis in PC12 cells. Chp-induced apoptosis was accompanied by activation of JNK signaling and both death receptor-mediated and mitochondrial apoptotic pathways as justified by...

  19. Effect of ethanol on pro-apoptotic mechanisms in polarized hepatic cells

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Chronic ethanol consumption is associated with serious and potentially fatal alcohol-related liver injuries such as hepatomegaly, alcoholic hepatitis and cirrhosis. Moreover,it has been documented that the clinical progression of alcohol-induced liver damage may be associated with an increase in hepatocellular death that involves apoptotic mechanisms. Although much information has been learned about the clinical manifestations associated with alcohol-related diseases, the search continues for a better understanding of the molecular and/or cellular mechanisms by which ethanol exerts its deleterious effects such as the induction of pro-apoptotic mechanisms and related cell damaging events. As part of the effort to enhance our understanding of those particular cellular pathways and mechanisms associated with ethanol toxicity, researchers over the years have utilized a variety of model systems. Recently, work has come forth demonstrating the utility of a hybrid cell line (WIF-B) as a cell culture model system for the study of alcohol-associated alterations in hepatocellular mechanisms. Success with such emerging model systems could aid in the development of potential therapeutic treatments for the prevention of alcoholinduced apoptotic cell death that may ultimately serve as a significant target in delaying the onset and/or progression of clinical symptoms of alcohol-mediated liver disease. This review article summarizes the current understanding of ethanol-mediated modifications in cell survival and thus the promotion of pro-apoptotic events with emphasis on analyses made in various experimental model systems, particularly the more recently characterized WIF-B cell system.

  20. A Batesian mimic and its model share color production mechanisms

    Institute of Scientific and Technical Information of China (English)

    David W.KIKUCHI; David W.PFENNIG

    2012-01-01

    Batesian mimics are harmless prey species that resemble dangerous ones (models),and thus receive protection from predators.How such adaptive resemblances evolve is a classical problem in evolutionary biology.Mimicry is typically thought to be difficult to evolve,especially if the model and mimic produce the convergent phenotype through different proximate mechanisms.However,mimicry may evolve more readily if mimic and model share similar pathways for producing the convergent phenotype.In such cases,these pathways can be co-opted in ancestral mimic populations to produce high-fidelity mimicry without the need for major evolutionary innovations.Here,we show that a Batesian mimic,the scarlet kingsnake Lampropettis elapsoides,produces its coloration using the same physiological mechanisms as does its model,the eastern coral snake Micrurus fulvius.Therefore,precise color mimicry may have been able to evolve easily in this system.Generally,we know relatively little about the proximate mechanisms underlying mimicry.

  1. Surface code—biophysical signals for apoptotic cell clearance

    International Nuclear Information System (INIS)

    Apoptotic cell death and the clearance of dying cells play an important and physiological role in embryonic development and normal tissue turnover. In contrast to necrosis, apoptosis proceeds in an anti-inflammatory manner. It is orchestrated by the timed release and/or exposure of so-called ‘find-me’, ‘eat me’ and ‘tolerate me’ signals. Mononuclear phagocytes are attracted by various ‘find-me’ signals, including proteins, nucleotides, and phospholipids released by the dying cell, whereas the involvement of granulocytes is prevented via ‘stay away’ signals. The exposure of anionic phospholipids like phosphatidylserine (PS) by apoptotic cells on the outer leaflet of the plasma membrane is one of the main ‘eat me’ signals. PS is recognized by a number of innate receptors as well as by soluble bridging molecules on the surface of phagocytes. Importantly, phagocytes are able to discriminate between viable and apoptotic cells both exposing PS. Due to cytoskeleton remodeling PS has a higher lateral mobility on the surfaces of apoptotic cells thereby promoting receptor clustering on the phagocyte. PS not only plays an important role in the engulfment process, but also acts as ‘tolerate me’ signal inducing the release of anti-inflammatory cytokines by phagocytes. An efficient and fast clearance of apoptotic cells is required to prevent secondary necrosis and leakage of intracellular danger signals into the surrounding tissue. Failure or prolongation of the clearance process leads to the release of intracellular antigens into the periphery provoking inflammation and development of systemic inflammatory autoimmune disease like systemic lupus erythematosus. Here we review the current findings concerning apoptosis-inducing pathways, important players of apoptotic cell recognition and clearance as well as the role of membrane remodeling in the engulfment of apoptotic cells by phagocytes. (paper)

  2. Leptin is an anti-apoptotic effector in placental cells involving p53 downregulation.

    Directory of Open Access Journals (Sweden)

    Ayelén Rayen Toro

    Full Text Available Leptin, a peripheral signal synthetized by the adipocyte to regulate energy metabolism, can also be produced by placenta, where it may work as an autocrine hormone. We have previously demonstrated that leptin promotes proliferation and survival of trophoblastic cells. In the present work, we aimed to study the molecular mechanisms that mediate the survival effect of leptin in placenta. We used the human placenta choriocarcinoma BeWo and first trimester Swan-71 cell lines, as well as human placental explants. We tested the late phase of apoptosis, triggered by serum deprivation, by studying the activation of Caspase-3 and DNA fragmentation. Recombinant human leptin added to BeWo cell line and human placental explants, showed a decrease on Caspase-3 activation. These effects were dose dependent. Maximal effect was achieved at 250 ng leptin/ml. Moreover, inhibition of endogenous leptin expression with 2 µM of an antisense oligonucleotide, reversed Caspase-3 diminution. We also found that the cleavage of Poly [ADP-ribose] polymerase-1 (PARP-1 was diminished in the presence of leptin. We analyzed the presence of low DNA fragments, products from apoptotic DNA cleavage. Placental explants cultivated in the absence of serum in the culture media increased the apoptotic cleavage of DNA and this effect was prevented by the addition of 100 ng leptin/ml. Taken together these results reinforce the survival effect exerted by leptin on placental cells. To improve the understanding of leptin mechanism in regulating the process of apoptosis we determined the expression of different intermediaries in the apoptosis cascade. We found that under serum deprivation conditions, leptin increased the anti-apoptotic BCL-2 protein expression, while downregulated the pro-apoptotic BAX and BID proteins expression in Swan-71 cells and placental explants. In both models leptin augmented BCL-2/BAX ratio. Moreover we have demonstrated that p53, one of the key cell cycle

  3. Circumstantial evidences for mimicry of scorpions by the neotropical gecko Coleodactylus brachystoma (Squamata, Gekkonidae in the Cerrados of central Brazil

    Directory of Open Access Journals (Sweden)

    Reuber Albuquerque Brandão

    2005-12-01

    Full Text Available There are few records of invertebrates mimicry by reptiles. In the Cerrados of central Brazil, the small Coleodactylus brachystoma is an endemic species common in the islands and margins of the Serra da Mesa hydroelectric dam reservoir. When cornered, this lizard folds the tail over the body exposing the pale-orange ventral surface. Lizard behavior, tail length and color pattern confer to this lizard a strong resemblance with syntopic buthid scorpions Rhopalurus agamenon, Tytius matogrossensis, and Anantheris balzani. Lizards and scorpions share the same tail color, size, and shape. Ecologically, they use the same microhabitats, are exposed to the same potential predators, and present similar behaviors when threatened.

  4. Resveratrol engages selective apoptotic signals in gastric adenocarcinoma cells

    Institute of Scientific and Technical Information of China (English)

    William L Riles; Jason Erickson; Sanjay Nayyar; Mary Jo Atten; Bashar M Attar; Oksana Holian

    2006-01-01

    AIM: To investigate the intracellular apoptotic signals engaged by resveratrol in three gastric adenocarcinoma cancer cell lines, two of which (AGS and SNU-1) express p53 and one (KATO-Ⅲ) with deleted p53.METHODS: Nuclear fragmentation was used to quantitate apoptotic cells; caspase activity was determined by photometric detection of cleaved substrates; formation of oxidized cytochrome C was used to measure cytochrome C activity, and Western blot analysis was used to determine protein expression.RESULTS: Gastric cancer cells, irrespective of their p53 status, responded to resveratrol with fragmentation of DNA and cleavage of nuclear lamins A and B and PARP, Resveratrol, however, has no effect on mitochondria-associated apoptotic proteins Bcl-2, Bclxl, Bax, Bid or Smac/Diablo, and did not promote subcellular redistribution of cytochrome C, indicating that resveratrol-induced apoptosis of gastric carcinoma cells does not require breakdown of mitochondrial membrane integrity. Resveratrol up-regulated p53 protein in SNU-1 and AGS cells but there was a difference in response of intracellular apoptotic signals between these cell lines.SNU-1 cells responded to resveratrol treatment with down-regulation of survivin, whereas in AGS and KATO-Ⅲ cells resveratrol stimulated caspase 3 and cytochrome C oxidase activities.CONCLUSION: These findings indicate that even within a specific cancer the intracellular apoptotic signals engaged by resveratrol are cell type dependent and suggest that such differences may be related to differentiation or lack of differentiation of these cells.

  5. Vasculogenic mimicry in non-small cell lung cancer and its relationship with tumor stage

    Institute of Scientific and Technical Information of China (English)

    Xiangqian Lu; Xiao Li; Fangzhen Shen; Wenjing Xiao

    2014-01-01

    Objective:The purpose of the study was to study the mechanism of vasculogenic mimicry (VM) and its relation-ship with tumor stage in non-smal celllung cancer (NSCLC). Methods:Forty-two patients with NSCLC were col ected, 19 belonged to the early stage (stages I+II) while 23 were late stage (stages III+IV). Moreover, 20 patients got surgical treat-ment and 22 got chemotherapy. We studied the relationship of VM with stage, chemotherapeutic ef ect, HIF-1α, microves-sel density (MVD) and clinicopathologic features. Results:VM in patients of early stages were significantly more than late stages (68.4%vs 26.1%, P=0.006), and the positive rate of VM was proportional to HIF-1α(P=0.034). But no correlation was found between VM and chemotherapeutic ef ect (14.3%vs 26.7%, P=1.00) or MVD (P>0.05). Furthermore, we found VM also showed a negative correlation with distant metastases and lymph nodes metastases (P<0.05) while no correlation was found with other clinicopathologic. Conclusion:VM was generated during the early stage in NSCLC and correlated with lymph nodes metastases. As the disease progressed, VM may be replaced by vascular endothelial cells, so the late-stage patients especial y people with distant metastases had fewer VM. As the main factor produced by hypoxia, HIF-1αmay make a dif erence in VM formation. Thus we inferred VM might be a new target for targeted therapy, and could provide help for clinical staging and treatment.

  6. Faces in the mirror, from the neuroscience of mimicry to the emergence of mentalizing.

    Science.gov (United States)

    Tramacere, Antonella; Ferrari, Pier Francesco

    2016-06-20

    In the current opinion paper, we provide a comparative perspective on specific aspects of primate empathic abilities, with particular emphasis on the mirror neuron system associated with mouth/face actions and expression. Mouth and faces can be very salient communicative classes of stimuli that allow an observer access to the emotional and physiological content of other individuals. We thus describe patterns of activations of neural populations related to observation and execution of specific mouth actions and emotional facial expressions in some species of monkeys and in humans. Particular attention is given to dynamics of face-to-face interactions in the early phases of development and to the differences in the anatomy of facial muscles among different species of primates. We hypothesize that increased complexity in social environments and patterns of social development have promoted specializations of facial musculature, behavioral repertoires related to production and recognition of facial emotional expression, and their neural correlates. In several primates, mirror circuits involving parietal-frontal regions, insular regions, cingulate cortices, and amygdala seem to support automatic forms of embodied empathy, which probably contribute to facial mimicry and behavioural synchrony. In humans these circuits interact with specific prefrontal and temporo-parietal cortical regions, which facilitates higher order cognitive functions such as cognitive empathy and mental state attribution. Our analysis thus suggests that the evolution of higher forms of empathy, such as mentalizing, is also linked to the coupling between the perceptual and motor system related to face processing, which may have undergone a process of exaptation during primate phylogeny. PMID:27176898

  7. Pro-apoptotic Sorafenib signaling in murine hepatocytes depends on malignancy and is associated with PUMA expression in vitro and in vivo

    OpenAIRE

    Sonntag, R; Gassler, N.; Bangen, J-M; Trautwein, C; Liedtke, C

    2014-01-01

    The multi-kinase inhibitor Sorafenib increases the survival of patients with advanced hepatocellular carcinoma (HCC). Current data suggest that Sorafenib inhibits cellular proliferation and angiogenesis and promotes apoptosis. However, the underlying pro-apoptotic molecular mechanisms are incompletely understood. Here we compared the pro-apoptotic and anti-proliferative properties of Sorafenib in murine hepatoma cells and syngeneic healthy hepatocytes in vitro and in animal models of HCC and ...

  8. Axon Degeneration Gated by Retrograde Activation of Somatic Pro-apoptotic Signaling.

    Science.gov (United States)

    Simon, David J; Pitts, Jason; Hertz, Nicholas T; Yang, Jing; Yamagishi, Yuya; Olsen, Olav; Tešić Mark, Milica; Molina, Henrik; Tessier-Lavigne, Marc

    2016-02-25

    During development, sensory axons compete for limiting neurotrophic support, and local neurotrophin insufficiency triggers caspase-dependent axon degeneration. The signaling driving axon degeneration upon local deprivation is proposed to reside within axons. Our results instead support a model in which, despite the apoptotic machinery being present in axons, the cell body is an active participant in gating axonal caspase activation and axon degeneration. Loss of trophic support in axons initiates retrograde activation of a somatic pro-apoptotic pathway, which, in turn, is required for distal axon degeneration via an anterograde pro-degenerative factor. At a molecular level, the cell body is the convergence point of two signaling pathways whose integrated action drives upregulation of pro-apoptotic Puma, which, unexpectedly, is confined to the cell body. Puma then overcomes inhibition by pro-survival Bcl-xL and Bcl-w and initiates the anterograde pro-degenerative program, highlighting the role of the cell body as an arbiter of large-scale axon removal. PMID:26898330

  9. The molecular mimicry and its possible role in origin of false-positive results in HCV-infection testing

    Directory of Open Access Journals (Sweden)

    Benkovskaya L. K.

    2013-09-01

    Full Text Available The main reason for the false positive results of the detection of antibodies to HCV is considered the unspecific binding of the blood serum immunoglobulins with the components of the test-systems’ immunosorbent, what is observed in various pathologies. When considering the issues of diagnosis, prevention and treatment of infectious diseases examined the impact of antigenic heterogeneity and molecular mimicry. With regarding to hepatitis C this phenomenon more illustrated in terms of pathogenesis, autoimmune, extrahepatic lesions. This does not exclude the influence of antigenic mimicry on the specificity of serological tests for anti-HCV detection. Aim. Estimation the frequency of false-positive reactions of anti-HCV testing in patients with chronic somatic diseases and assessment of the antigenic mimicry’s role in their occurrence. Methods. Total anti-HCV, antibodies to the single viruses’ protein, and false positive sera antibodies’ interaction with microbial origin combinations (mimicrins were determined by ELISA. Mimicrins were separated from the cultural medium after cultivation Staphylococcus aureus, Micobacterium tuberculosis and Candida albicans. Results. Upon detection of anti-HCV in patients with chronic pathologies detected a significant number of false-positive results are more likely in patients with diabetes and among healthy individuals – in pregnant women.The majorities of false positive sera interacted with mimicrins. Conclusions. The antigenic crossings over between mimicrins and antibodies in the structure of false positive sera must be considered during the evaluation of the specific diagnostics’ results in the persons with different pathologic states.

  10. Mimicry of the Legal: Translating de jure Land Formalization Processes Into de facto Local Action in Jambi Province, Sumatra

    Directory of Open Access Journals (Sweden)

    Yvonne Kunz

    2016-06-01

    Full Text Available In Indonesia, as in many other countries of the global South, processes to formalize rights over land have been implemented with the intention to reduce deforestation, decrease poverty and increase tenure security. Literature on de jure processes of land formalization is widely available. There is a gap, however, on the discrepancy of de jure land titling procedures and de facto strategies to legitimize land claims. Led by the theoretical concepts of “law as process” and “politics of scale”, this study closes this gap by analyzing the impact of national tenure formalization processes on de facto local patterns of land titling. Using empirical material from 16 villages in Jambi province, we show that the outcomes of the state-led land reforms and land tenure formalization processes are imitated and translated into locally feasible actions. We refer to these translation processes as “mimicry of the legal”. The land formalization endeavors fostering mimicry of the legal allow for resource exploitation and rent-seeking behavior.

  11. [In silico identification of molecular mimicry between T-cell epitopes of Neisseria meningitidis B and the human proteome].

    Science.gov (United States)

    Batista-Duharte, Alexander; Téllez, Bruno; Tamayo, Maybia; Portuondo, Deivys; Cabrera, Osmir; Sierra, Gustavo; Pérez, Oliver

    2013-07-01

    The objective of the study was to determine the T-cell epitopes of four of the most frequent antigenic proteins of the outer membrane of Neisseria meningitidis B, and to identify the most relevant sites for molecular mimicry with T-cell epitopes in humans. In order to do so, an in silico study -a type of study that uses bioinformatic tools- was carried out using SWISS-PROT/TrEMBL, SYFPEITHI and FASTA databases, which helped to determine the protein sequences, CD4 and CD8 T-cell epitope prediction, as well as the molecular mimicry with humans, respectively. Molecular similarity was found in several human proteins present in different organs and tissues such as: liver, skin and epithelial tissues, brain, lymphatic system and testicles. Of these, those found in testicles were more similar, showing the highest frequency of mimetic sequences. This finding shed light on the success of N. meningitidis B to colonize human tissues and the failure of certain vaccines against this bacterium, and it even helps to explain possible autoimmune reactions associated with the infection or vaccination. PMID:24100820

  12. Dynamic coupling of 99mTc-MIBI efflux and apoptotic pathway activation in untreated breast cancer patients

    International Nuclear Information System (INIS)

    Our previous studies showed that the efflux rate of technetium-99m methoxyisobutylisonitrile (MIBI) is directly correlated to P-glycoprotein (Pgp) levels in breast carcinoma. The aim of this study was to test whether the Pgp-dependent efflux of 99mTc-MIBI is related to the apoptotic pathway activation in breast carcinoma. Thirty-three untreated non-consecutive patients were intravenously injected with 740 MBq 99mTc-MIBI and serial images were obtained up to 4 h. The rate of efflux was determined by mono-exponential fitting of decay-corrected time-activity curves. Tumour specimens were then obtained at surgery and processed for the determination of the apoptotic index by in situ end-labelling of DNA fragments (Tunel). The rate of tumour cell proliferation was also determined using Ki67 monoclonal antibody. All breast carcinomas showed focal uptake of 99mTc-MIBI and the time to half clearance varied between 85 and 574 min. The apoptotic index ranged between 0.3% and 4.2%, whereas the rate of proliferation varied between 13% and 40%. We found a positive and significant correlation between the apoptotic index and the rate of proliferation (r=0.79, P99mTc-MIBI was directly and significantly correlated with the apoptotic index (r=0.74, P99mTc-MIBI (r=0.57, P99mTc-MIBI sequestration, a model for the dynamic coupling of Pgp-dependent 99mTc-MIBI efflux and apoptotic pathway activation may be derived. (orig.)

  13. Abnormalities in Alternative Splicing of Apoptotic Genes and Cardiovascular Diseases

    Directory of Open Access Journals (Sweden)

    Zodwa Dlamini

    2015-11-01

    Full Text Available Apoptosis is required for normal heart development in the embryo, but has also been shown to be an important factor in the occurrence of heart disease. Alternative splicing of apoptotic genes is currently emerging as a diagnostic and therapeutic target for heart disease. This review addresses the involvement of abnormalities in alternative splicing of apoptotic genes in cardiac disorders including cardiomyopathy, myocardial ischemia and heart failure. Many pro-apoptotic members of the Bcl-2 family have alternatively spliced isoforms that lack important active domains. These isoforms can play a negative regulatory role by binding to and inhibiting the pro-apoptotic forms. Alternative splicing is observed to be increased in various cardiovascular diseases with the level of alternate transcripts increasing elevated in diseased hearts compared to healthy subjects. In many cases these isoforms appear to be the underlying cause of the disease, while in others they may be induced in response to cardiovascular pathologies. Regardless of this, the detection of alternate splicing events in the heart can serve as useful diagnostic or prognostic tools, while those splicing events that seem to play a causative role in cardiovascular disease make attractive future drug targets.

  14. The apoptotic thanatotranscriptome associated with the liver of cadavers.

    Science.gov (United States)

    Javan, Gulnaz T; Can, Ismail; Finley, Sheree J; Soni, Shivani

    2015-12-01

    Gene expression investigations are well-established components of ante mortem studies with broad applications ranging from elucidating basic mechanisms responsible for normal physiological processes to discovering therapeutic targets in pathophysiological conditions. However, gene expression studies and their application in the medico-legal field are still in their infancy. Therefore, the present study focuses on RNA using PCR array in the analysis of gene expression associated with tissues taken from actual criminal cases. RNA was extracted from the liver tissues of bodies with PMIs between 6 and 48 h. The results demonstrated that mRNA was stable up to 48 h postmortem. Further, as cell death is an indispensable and necessary part of the biological life cycle, apoptotic gene expression profiles were investigated. The gene expression related to the programmed cell death found in body tissues after death is defined as the apoptotic thanatotranscriptome (thanatos-, Greek for death). On comparison of control and decaying tissues, the results show that with time, pro-apoptotic genes such as caspases are up-regulated and the expression of genes responsible for anti-apoptosis such as BCL2 and BAG3 were down-regulated. Thus, this current work gives a unique perspective of the apoptotic thanatotranscriptome that is affected after death. Up to the present time, gene expression in bodies from criminal cases has not been reported in literature using PCR array techniques. Thus, this thanatotranscriptome study provides insight into postmortem gene activity with potential applications in medico-legal investigations. PMID:26318598

  15. Photosynthetic antenna-reaction center mimicry: sequential energy- and electron transfer in a self-assembled supramolecular triad composed of boron dipyrrin, zinc porphyrin and fullerene.

    Science.gov (United States)

    Maligaspe, Eranda; Tkachenko, Nikolai V; Subbaiyan, Navaneetha K; Chitta, Raghu; Zandler, Melvin E; Lemmetyinen, Helge; D'Souza, Francis

    2009-07-30

    A self-assembled supramolecular triad, a model to mimic the photochemical events of photosynthetic antenna-reaction center, viz., sequential energy and electron transfer, has been newly constructed and studied. Boron dipyrrin, zinc porphyrin, and fullerene respectively constitute the energy donor, electron donor, and electron acceptor segments of the antenna-reaction center mimicry. For the construction, first, boron dipyrrin was covalently attached to a zinc porphyrin entity bearing a benzo-18-crown-6 host segment at the opposite end of the porphyrin ring. Next, an alkyl ammonium functionalized fullerene was used to self-assemble the crown ether entity via ion-dipole interactions. The newly formed supramolecular triad was fully characterized by spectroscopic, computational, and electrochemical methods. Selective excitation of the boron dipyrrin moiety in the dyad resulted in energy transfer over 97% efficiency creating singlet excited zinc porphyrin. The rate of energy transfer from the decay measurements of time-correlated singlet photon counting (TCSPC) and up-conversion techniques agreed well with that obtained by the pump-probe technique and revealed efficient photoinduced energy transfer in the dyad (time constant in the order of 10-60 ps depending upon the conformer). Upon forming the supramolecular triad by self-assembling fullerene, the excited zinc porphyrin resulted in electron transfer to the coordinated fullerene yielding a charge-separated state, thus mimicking the antenna-reaction center functionalities of photosynthesis. Nanosecond transient absorption studies yielded a lifetime of the charge-separated state to be 23 micros indicating charge stabilization in the supramolecular triad. The present supramolecular system represents a successful model to mimic the rather complex "combined antenna-reaction center" events of photosynthesis. PMID:19580310

  16. 《耻》中的模仿行为%The mimicry in "Disgrace"

    Institute of Scientific and Technical Information of China (English)

    刘建平

    2013-01-01

    John Maxwell Coetzee is the winner of Nobel Prize for Literature in 2003 and the winner of two Booker Prizes. Disgrace is one of his great works published in 1999.The novel depicts a series of disgraceful events between the white and the black in post-apartheid South Africa. The whites lost their dominant position and became the victims of the blacks’ retaliation. The blacks imitated the behavior of the previous colonizers and became the real masters. The writer uses Homi.Bhabha’s famous concept of postcolonialism-“mimicry”to analyze the novel. Through mimicry, the once-colonized learned a way to live and the once-colonizers learned to accept the reality and live harmoniously with the natives.%  2003年诺贝尔文学奖的获得者是约翰·马克斯韦尔·库切,他也是布克奖的两度获得者。他获奖的力作是出版于1999年的《耻》。小说描绘了在种族隔离结束的新南非发生在白人和黑人之间的一系列可耻的事情。曾经的白人统治者失去了他们的优越地位,不得不接受来自黑人的报复行为。而曾经的被统治者黑人则通过模仿前殖民者的各种行为而逐步成为了新南非真正的主人。笔者运用后殖民主义大家霍米·芭芭的理论模仿来解读这部小说的主题。通过模仿,曾经的被殖民者学会了生存,曾经的殖民者也学会放下身份与曾经的被殖民者和谐生存。

  17. Apoptotic bone marrow CD34+ cells in cirrhotic patients

    Institute of Scientific and Technical Information of China (English)

    Shuang-Suo Dang; Wen-Jun Wang; Ning Gao; Shun-Da Wang; Mei Li; La-Yang Liu; Ming-Zhun Sun; Tao Dong

    2011-01-01

    AIM: To access the frequency and level of apoptotic CD34+ cells isolated from the marrow fluid of patients with post-hepatitis cirrhosis.METHODS: The frequency of bone marrow CD34+ cells and apoptotic bone marrow CD34+ cells in 31 in-patients with post-hepatitis cirrhosis (cirrhosis group), and 15 out-patients without liver or blood disorders (control group) was calculated by flow cytometry. Pa-rameters were collected to evaluate liver functions of patients in cirrhosis group.RESULTS: The percentage of normal bone marrow CD34+ cells was 6.30% ± 2.48% and 1.87% ± 0.53% (t = 3.906, P < 0.01) while that of apoptotic marrow CD34+ cells was 15.00% ± 15.81% and 5.73% ± 1.57% (t = 2.367, P < 0.05) in cirrhosis and control groups, re-spectively. The percentage of apoptotic marrow CD34+ cells was 6.25% ± 3.30% and 20.92 ± 18.5% (t = 2.409, P < 0.05) in Child-Pugh A and Child-Pugh B + C cirrhotic patients, respectively. The percentage of late apoptotic marrow CD34+ cells was positively correlated with the total bilirubin and aspartate aminotransferase serum levels in patients with cirrhosis.CONCLUSION: The status of CD34+ marrow cells in cirrhotic patients may suggest that the ability of he-matopoietic progenitor cells to transform into mature blood cells is impaired.

  18. Elevated Levels of Uterine Anti-Apoptotic Signaling May Activate NFKB and Potentially Confer Resistance to Caspase 3-Mediated Apoptotic Cell Death During Pregnancy in Mice1

    Science.gov (United States)

    Jeyasuria, Pancharatnam; Subedi, Kalpana; Suresh, Arvind; Condon, Jennifer C.

    2011-01-01

    Preserving the uterus in a state of relative quiescence is vital to the maintenance of a successful pregnancy. Elevated cytoplasmic levels of uterine caspase 3 during pregnancy have been proposed as a potential regulator of uterine quiescence through direct targeting and disabling of the uterine contractile architecture. However, despite highly elevated levels of uterine caspase 3 during pregnancy, there is minimal evidence of apoptosis. This current study defines the mechanism whereby the pregnant uterine myocyte may harness the tocolytic activity of active caspases while avoiding apoptotic cell death. Using the pregnant mouse model, we have analyzed the uterus for changes in pro- and antiapoptotic signaling patterns associated with the advancing stages of pregnancy. Briefly, we have found that members of the IAP family, such as SURVIVIN and XIAP, and the Bcl2 family members, such as MCL1, are elevated in the uterine myocyte during late gestation. The IAP family members are the only endogenous inhibitors of active caspase 3, and MCL1 limits activation of caspase 3 by suppressing proapoptotic signaling. Elevated XIAP levels partner with SURVIVIN, resulting in increased levels of the antiapoptotic MCL1 via NFKB activation; these together have the potential to limit both the activity and level of active caspase 3 in the pregnant uterus as term approaches. We propose that modification of these antiapoptotic signaling partners allows the pregnant uterus to escape the apoptotic action of elevated active caspase 3 levels but also functions to limit the levels of active uterine caspase 3 near term. PMID:21566000

  19. Two independent positive feedbacks and bistability in the Bcl-2 apoptotic switch.

    Directory of Open Access Journals (Sweden)

    Jun Cui

    Full Text Available BACKGROUND: The complex interplay between B-cell lymphoma 2 (Bcl-2 family proteins constitutes a crucial checkpoint in apoptosis. Its detailed molecular mechanism remains controversial. Our former modeling studies have selected the 'Direct Activation Model' as a better explanation for experimental observations. In this paper, we continue to extend this model by adding interactions according to updating experimental findings. METHODOLOGY/PRINCIPAL FINDINGS: Through mathematical simulation we found bistability, a kind of switch, can arise from a positive (double negative feedback in the Bcl-2 interaction network established by anti-apoptotic group of Bcl-2 family proteins. Moreover, Bax/Bak auto-activation as an independent positive feedback can enforce the bistability, and make it more robust to parameter variations. By ensemble stochastic modeling, we also elucidated how intrinsic noise can change ultrasensitive switches into gradual responses. Our modeling result agrees well with recent experimental data where bimodal Bax activation distributions in cell population were found. CONCLUSIONS/SIGNIFICANCE: Along with the growing experimental evidences, our studies successfully elucidate the switch mechanism embedded in the Bcl-2 interaction network and provide insights into pharmacological manipulation of Bcl-2 apoptotic switch as further cancer therapies.

  20. A novel bispecific immunotoxin delivered by human bone marrow-derived mesenchymal stem cells to target blood vessels and vasculogenic mimicry of malignant gliomas

    Directory of Open Access Journals (Sweden)

    Zhang Y

    2015-06-01

    Full Text Available Yonghong Zhang,1,2 Xinlin Sun,1 Min Huang,1 Yiquan Ke,1 Jihui Wang,1 Xiao Liu1 1National Key Clinic Specialty, Neurosurgery Institute of Guangdong Province, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 2Department of Neurosurgery, First Hospital of Lanzhou University, Lanzhou, People’s Republic of China Background: In previous years, immunotoxins have been shown to be a greatly promising therapeutic tool for brain malignancies, such as gliomas. Human mesenchymal stem cells (hMSCs exhibit tropism to tumor tissue. However, the effect of bispecific immunotoxins in malignant gliomas is still unknown. The aim of this study was to investigate the function of bispecific immunotoxins in human malignant gliomas.Materials and methods: In the present study, the bispecific immunotoxin VEGF165-ephrin A1-PE38KDEL was established using deoxyribonucleic acid shuffling and cloning techniques. The VEGF165-ephrin A1-PE38KDEL was delivered by hMSCs to mouse malignant gliomas. The effects of the bispecific immunotoxins on glioma-derived blood vessels and vasculogenic mimicry to elucidate the molecular mechanisms underlying the antitumorigenic effects of immunotoxins were examined in vivo.Results: In vitro, transfected hMSCs significantly inhibited the cell viability of gliomas cell lines U87 and U251 in a dose-dependent manner compared with untransfected hMSCs (P<0.01. In vivo, the intratumoral injection of engineered hMSCs was effective at inhibiting tumor growth in a malignant glioma tumor model.Conclusion: The bispecific immunotoxin secreted from hMSCs acts as a novel strategy for improving treatment options for malignant gliomas in the clinic. Keywords: bispecific immunotoxin, human mesenchymal stem cells, ephrin A1, VEGF165, malignant glioma

  1. Apoptotic Cells Are Cleared by Directional Migration and elmo1-Dependent Macrophage Engulfment

    OpenAIRE

    van Ham, Tjakko J.; Kokel, David; Peterson, Randall T.

    2012-01-01

    Apoptotic cell death is essential for development and tissue homeostasis [1, 2]. Failure to clear apoptotic cells can ultimately cause inflammation and autoimmunity [3, 4]. Apoptosis has primarily been studied by staining of fixed tissue sections, and a clear understanding of the behavior of apoptotic cells in living tissue has been elusive. Here, we use a newly developed technique [5] to track apoptotic cells in real time as they emerge and are cleared from the zebrafish brain. We find that ...

  2. Apoptotic cell death and its relationship to gastric carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    Ferda Bir; Nese Calli-Demirkan; A Cevik Tufan; Metin Akbulut; N Lale Satiroglu-Tufan

    2007-01-01

    AIM: To investigate the apoptotic process of cells within the intestinal metaplasia areas co-localizing with chronic gastritis and gastric carcinomas and to analyze the involvement of proteins regulating apoptosis in the process of intestinal metaplasia related gastric carcinogenesis.METHODS: Forty-two gastric carcinoma and seventeen chronic gastritis cases were included in this study. All cases were examined for the existence of intestinal metaplasia. Ten cases randomly selected from each group were processed for TUNEL assay. TUNEL positive cells within the intestinal metaplasia areas, colocalizing either to gastric carcinoma or chronic gastritis,were counted and converted to apoptotic indices.In addition, p53, bcl-2 and bax expression patterns within these tissues were analyzed on the basis of immunohistochemistry.RESULTS: Twenty-eight of the cases were intestinal and 14 of the cases were diffuse type adenocarcinomas.64% (27/42) of the gastric carcinoma cases had intestinal metaplasia. Intestinal metaplasia co-localized more with intestinal type carcinomas compared with diffuse type carcinomas [75% (21/28) vs 42% (6/14),respectively; P≤0.05]. The mean apoptotic index in tumor cells was 0.70±0.08. The mean apoptotic index in intestinal metaplasias co-localizing to tumors was significantly higher than that of intestinal metaplasias co-localizing to chronic gastritis (0.70±0.03 vs 0.09±0.01, respectively; P≤0.05). P53 positivity was not observed in areas of intestinal metaplasia adjacent to tumors or chronic gastritis. Intestinal metaplasia areas adjacent to tumors showed lower cytoplasmic bcl-2 positivity compared to intestinal metaplasia areas adjacent to chronic gastritis [55.5% (15/27) vs 70.5%(12/17), respectively]. On the other hand, intestinal metaplasia areas adjacent to tumors showed significantly higher cytoplasmic bax positivity compared to intestinal metaplasia areas adjacent to chronic gastritis [44.4%(12/27) vs 11.7% (2/17), respectively; P≤0

  3. Apoptotic machinery diversity in Multiple Myeloma molecular subtypes.

    Directory of Open Access Journals (Sweden)

    Patricia eGomez-Bougie

    2013-12-01

    Full Text Available Multiple myeloma (MM is a plasma cell malignancy that is heterogeneous in its clinical presentation and prognosis. Monoclonal gammopathy of undetermined significance (MGUS consistently preceded development of MM. The presence of primary IgH translocations and the universal over-expression of cyclin D genes led to a molecular classification of MM patients into different disease subtypes. Since Bcl-2 family proteins determine cell fate, we analyzed a publicly available Affymetrix gene expression of 44 MGUS and 414 newly diagnosed MM patients to investigate (1 the global change of Bcl-2 family members in MM versus MGUS (2 whether the four major subtypes defined as hyperdiploid, CCND1, MAF and MMSET, display specific apoptotic machineries.We showed that among the main anti-apoptotic members (Bcl-2, Bcl-xL and Mcl-1, Mcl-1 up-regulation discriminated MM from MGUS, in agreement with the prominent role of Mcl-1 in plasma cell differentiation. Surprisingly, the expression of multi-domain pro-apoptotic Bak and Bax were increased during the progression of MGUS to MM. The combined profile of Bcl-2, Bcl-xL and Mcl-1 was sufficient to distinguish MM molecular groups. While specific pro-apoptotic members expression was observed for each MM subtypes, CCDN1 subgroup, was identified as a particular entity characterized by a low expression of both BH3-only (Puma, Bik and Bad and multi-domain pro-apoptotic members (Bax and Bak. Our analysis supports the notion that MM heterogeneity is extended to the differential expression of the Bcl-2 family content in each MM subgroup. The influence of Bcl-2 family profile in the survival of the different patient groups will be further discussed to establish the potential consequences for therapeutic interventions. Finally, the use of distinct pro-survival members in the different steps of immune responses to antigen rise also the question of whether the different Bcl-2 anti-apoptotic profile could reflect a different origin of

  4. PREPARATION OF ANTI-IDIOTYPIC ANTIBODIES SPECIFIC FOR ANTI-HEL AND ANALYSIS OF THEIR FUNCTIONAL MIMICRY

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Objective. This study is to investigate the functional mimicry by using anti-idiotypic antibodies of enzymes.Results.Eight hybridomas strains secreting anti-idiotypic antibodies were selected and characterized. It was shown that two of eight anti-idiotypic antibodies secreted by two hybridomas(1A10C9 and 2A11 C1B3) could mimic HEL catalytic activity to lyse Micrococcus lysodeikticus and that the catalytic effect of mixed anti-idiotypic antibodies of 1A10C9 and 2A11C1B3 was stronger than that of one of them, but less than HEL.Conclusion. The results demonstrated that the anti-idiotypic antibodies that could mimic enzyme activity existed in the idiotype network during anti-enzymatic immune response.

  5. Dual-functional bio-derived nanoparticulates for apoptotic antitumor therapy.

    Science.gov (United States)

    Ding, Yang; Wang, Yazhe; Opoku-Damoah, Yaw; Wang, Cheng; Shen, Lingjia; Yin, Lifang; Zhou, Jianping

    2015-12-01

    The application of bio-derived nanoparticulates has gained a remarkable degree of interest as a promising sustained-release, site-targeted and completely biodegradable delivery system for chemotherapeutics. We hereby introduce a dual-functionalized biomimetic nanovector, cell-penetrating peptide (CPP)-anchored recombinant high density lipoproteins (cp-rHDL), which affords high payload and improved targeting of gambogic acid (GA), a therapeutic agent for apoptotic antitumor therapy. GA-loaded cp-rHDL nanoparticles (cp-rHDL/GA) consisted of hydrophobic core modulating GA, apolipoprotein A-I (apo A-I) for attractive integrating and tumor-homing, and lipophilic anchored R6H4 (RRRRRRHHHH, a pH-responsive CPP) offering a pH-controlled penetrating potential. Upon stepwise incubation with apo A-I and R6H4, cp-rHDL/GA presented several merits, including desirable physicochemical properties, superior biostability, and favorable buffering capacity resulting in proton sponge effect. Synergistic intracellular mechanism for scavenger receptor class B type I (SR-BI)-mediated direct transmembrane delivery, and pH-responsive R6H4 associated endocytotic pathway with rapid endo-lysosomal escape was also observed. This tailored cp-rHDL/GA displayed remarkable cytotoxicity and apoptotic effect via triggering p53 pathway, and provided approximately 5-fold increase in IC50 compared to free GA. Moreover, this rational biomimetic therapeutic strategy attained superior tumor accumulation and significant inhibition of tumor growth in HepG2 xenograft tumor animal models without measurable adverse effect. Results of this study demonstrated that bio-derived cp-rHDL/GA presents pH-responsive penetrating potential and efficient cellular internalization. This dual-functionalization model will open an avenue for exploration of multi-functional bio-derived drug delivery, thereby rendering potential broad applications in apoptotic anticancer therapy. PMID:26344366

  6. Reducing VDAC1 expression induces a non-apoptotic role for pro-apoptotic proteins in cancer cell differentiation.

    Science.gov (United States)

    Arif, Tasleem; Krelin, Yakov; Shoshan-Barmatz, Varda

    2016-08-01

    Proteins initially identified as essential for apoptosis also mediate a wide range of non-apoptotic functions that include cell cycle progression, differentiation and metabolism. As this phenomenon was mostly reported with non-cancer cells, we considered non-conventional roles for the apoptotic machinery in the cancer setting. We found that treating glioblastoma (GBM) tumors with siRNA against VDAC1, a mitochondrial protein found at the crossroads of metabolic and survival pathways and involved in apoptosis, inhibited tumor growth while leading to differentiation of tumor cells into neuronal-like cells, as reflected in the expression of specific markers. Although VDAC1 depletion did not induce apoptosis, the expression levels of several pro-apoptotic regulatory proteins were changed. Specifically, VDAC1 deletion led to up-regulation of caspases, p53, cytochrome c, and down-regulation of SMAC/Diablo, AIF and TSPO. The down-regulated group was highly expressed in U-87MG xenografts, as well as in GBMs from human patients. We also showed that the rewired cancer-cell metabolism resulting from VDAC1 depletion reinforced cell growth arrest and differentiation via alterations in the transcription factors p53, c-Myc, HIF-1α and NF-κB. The decrease in c-Myc, HIF-1α and NF-κB levels was in accord with reduced cell proliferation, whereas increased p53 expression promoted differentiation. Thus, upon metabolic re-programing induced by VDAC1 depletion, the levels of pro-apoptotic proteins associated with cell growth decreased, while those connected to cell differentiation increased, converting GBM cells into astrocyte- and neuron-like cells. The results reveal that in tumors, pro-apoptotic proteins can perform non-apoptotic functions, acting as regulators of cell growth and differentiation, making these molecules potential new targets for cancer therapy. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy

  7. ELMO1 signaling in apoptotic germ cell clearance and spermatogenesis.

    Science.gov (United States)

    Elliott, Michael R; Ravichandran, Kodi S

    2010-10-01

    Apoptosis and the subsequent removal of dying cells are crucial processes for tissue development and maintenance. Although we are beginning to understand the signaling pathways that control the phagocytic clearance of apoptotic cells, the physiological relevance of these pathways is lacking. During spermatogenesis, over half of the developing germ cells eventually die by apoptosis, yet the signaling pathways that regulate the phagocytic clearance of these dying cells or the impact of this clearance on development and maintenance of the germ cell population is not well understood. The ELMO1/Dock180 proteins form an evolutionarily conserved signaling module that functions as a bipartite guanine nucleotide exchange factor for the small GTPase Rac. The subsequent Rac-dependent cytoskeletal changes play an important role in the physical engulfment of apoptotic cells. Recent findings demonstrate an in vivo role for ELMO1-dependent clearance in the testes, with implications for spermatogenesis. Here we will discuss the role of apoptotic cell clearance during spermatogenesis, with a particular emphasis on ELMO1/Dock180 signaling. PMID:20958313

  8. PDT-treated apoptotic cells induce macrophage synthesis NO

    Science.gov (United States)

    Song, S.; Xing, D.; Zhou, F. F.; Chen, W. R.

    2009-11-01

    Nitric oxide (NO) is a biologically active molecule which has multi-functional in different species. As a second messenger and neurotransmitter, NO is not only an important regulatory factor between cells' information transmission, but also an important messenger in cell-mediated immunity and cytotoxicity. On the other side, NO is involving in some diseases' pathological process. In pathological conditions, the macrophages are activated to produce a large quantity of nitric oxide synthase (iNOS), which can use L-arginine to produce an excessive amount of NO, thereby killing bacteria, viruses, parasites, fungi, tumor cells, as well as in other series of the immune process. In this paper, photofrin-based photodynamic therapy (PDT) was used to treat EMT6 mammary tumors in vitro to induce apoptotic cells, and then co-incubation both apoptotic cells and macrophages, which could activate macrophage to induce a series of cytotoxic factors, especially NO. This, in turn, utilizes macrophages to activate a cytotoxic response towards neighboring tumor cells. These results provided a new idea for us to further study the immunological mechanism involved in damaging effects of PDT, also revealed the important function of the immune effect of apoptotic cells in PDT.

  9. Cell shape and organelle modification in apoptotic U937 cells

    Directory of Open Access Journals (Sweden)

    MR Montinari

    2009-12-01

    Full Text Available U937 cells induced to apoptosis, progressively and dramatically modified their cell shape by intense blebbing formation, leading to the production of apoptotic bodies. The blebs evolved with time; milder forms of blebbing involving only a region or just the cortical part of the cytoplasm were observed within the first hour of incubation with puromycin; blebbing involving the whole cell body with very deep constrictions is the most frequent event observed during late times of incubation. The ultrastructural analysis of apoptotic cells revealed characteristic features of nuclear fragmentation (budding and cleavage mode and cytoplasmatic modifications. The cytoplasm of blebs does not contain organelles, such as ribosomes or mitochondria. Scarce presence of endoplasmic reticulum can be observed at the site of bleb detachment. However, blebbing is a dispensable event as evaluated by using inhibitor of actin polymerization. In the present study, the progressive modifications of the nucleus, mitochondria, nuclear fragmentation, cytoplasmic blebs formation and production of apoptotic bodies in U937 monocytic cells induced to apoptosis by puromycin (an inhibitor of protein synthesis were simultaneously analyzed.

  10. Concise Review: Mechanisms Behind Apoptotic Cell-Based Therapies Against Transplant Rejection and Graft versus Host Disease.

    Science.gov (United States)

    Morelli, Adrian E; Larregina, Adriana T

    2016-05-01

    The main limitations to the success of transplantation are the antigraft response developed by the recipient immune system, and the adverse side effects of chronic immunosuppression. Graft-versus-host disease (GVHD) triggered by donor-derived T lymphocytes against the recipient tissues is another serious obstacle in the field of hematopoietic stem cell transplantation. Several laboratories have tested the possibility of promoting antigen (Ag)-specific tolerance for therapy of graft rejection, GVHD, and autoimmune disorders, by developing methodologies that mimic the mechanisms by which the immune system maintains peripheral tolerance in the steady state. It has been long recognized that the silent clearance of cells undergoing apoptosis exerts potent immune-regulatory effects and provides apoptotic cell-derived Ags to those Ag-presenting cells (APCs) that internalize them, in particular macrophages and dendritic cells. Therefore, in situ-targeting of recipient APCs by systemic administration of leukocytes in early apoptosis and bearing donor Ags represents a relatively simple approach to control the antidonor response against allografts. Here, we review the mechanisms by which apoptotic cells are silently cleared by phagocytes, and how such phenomenon leads to down-regulation of the innate and adaptive immunity. We discuss the evolution of apoptotic cell-based therapies from murine models of organ/tissue transplantation and GVHD, to clinical trials. We make emphasis on potential limitations and areas of concern of apoptotic cell-based therapies, and on how other immune-suppressive therapies used in the clinics or tested experimentally likely also function through the silent clearance of apoptotic cells by the immune system. Stem Cells 2016;34:1142-1150. PMID:26865545

  11. WNT signaling controls expression of pro-apoptotic BOK and BAX in intestinal cancer

    International Nuclear Information System (INIS)

    Research highlights: → Intestinal adenomas initiated by aberrant activation of the WNT pathway displayed an increased sensitivity to apoptosis. → Expression profiling of apoptosis-related genes in ApcMin/+ mice revealed the differential expression of pro-apoptotic Bok and Bax. → APC-mutant adenomatous crypts in FAP patients showed strongly increased BAX immunoreactivity. → Blocking of β-catenin/TCF-4-mediated signaling in colon cancer cells reduced the expression of BOK and BAX. -- Abstract: In a majority of cases, colorectal cancer is initiated by aberrant activation of the WNT signaling pathway. Mutation of the genes encoding the WNT signaling components adenomatous polyposis coli or β-catenin causes constitutively active β-catenin/TCF-mediated transcription, driving the transformation of intestinal crypts to cancer precursor lesions, called dysplastic aberrant crypt foci. Deregulated apoptosis is a hallmark of adenomatous colon tissue. However, the contribution of WNT signaling to this process is not fully understood. We addressed this role by analyzing the rate of epithelial apoptosis in aberrant crypts and adenomas of the ApcMin/+ mouse model. In comparison with normal crypts and adenomas, aberrant crypts displayed a dramatically increased rate of apoptotic cell death. Expression profiling of apoptosis-related genes along the crypt-villus axis and in Apc mutant adenomas revealed increased expression of two pro-apoptotic Bcl-2 family members in intestinal adenomas, Bok and Bax. Analysis of the colon of familial adenomatous polyposis (FAP) patients along the crypt-to-surface axis, and of dysplastic crypts, corroborated this expression pattern. Disruption of β-catenin/TCF-4-mediated signaling in the colorectal cancer cell line Ls174T significantly decreased BOK and BAX expression, confirming WNT-dependent regulation in intestinal epithelial cells. Our results suggest a feedback mechanism by which uncontrolled epithelial cell proliferation in the stem

  12. Exocytosis of macrophage lysosomes leads to digestion of apoptotic adipocytes and foam cell formation[S

    Science.gov (United States)

    Haka, Abigail S.; Barbosa-Lorenzi, Valéria C.; Lee, Hyuek Jong; Falcone, Domenick J.; Hudis, Clifford A.; Dannenberg, Andrew J.

    2016-01-01

    Many types of apoptotic cells are phagocytosed and digested by macrophages. Adipocytes can be hundreds of times larger than macrophages, so they are too large to be digested by conventional phagocytic processes. The nature of the interaction between macrophages and apoptotic adipocytes has not been studied in detail. We describe a cellular process, termed exophagy, that is important for macrophage clearance of dead adipocytes and adipose tissue homeostasis. Using mouse models of obesity, human tissue, and a cell culture model, we show that macrophages form hydrolytic extracellular compartments at points of contact with dead adipocytes using local actin polymerization. These compartments are acidic and contain lysosomal enzymes delivered by exocytosis. Uptake and complete degradation of adipocyte fragments, which are released by extracellular hydrolysis, leads to macrophage foam cell formation. Exophagy-mediated foam cell formation is a highly efficient means by which macrophages internalize large amounts of lipid, which may ultimately overwhelm the metabolic capacity of the macrophage. This process provides a mechanism for degradation of objects, such as dead adipocytes, that are too large to be phagocytosed by macrophages. PMID:27044658

  13. Exocytosis of macrophage lysosomes leads to digestion of apoptotic adipocytes and foam cell formation.

    Science.gov (United States)

    Haka, Abigail S; Barbosa-Lorenzi, Valéria C; Lee, Hyuek Jong; Falcone, Domenick J; Hudis, Clifford A; Dannenberg, Andrew J; Maxfield, Frederick R

    2016-06-01

    Many types of apoptotic cells are phagocytosed and digested by macrophages. Adipocytes can be hundreds of times larger than macrophages, so they are too large to be digested by conventional phagocytic processes. The nature of the interaction between macrophages and apoptotic adipocytes has not been studied in detail. We describe a cellular process, termed exophagy, that is important for macrophage clearance of dead adipocytes and adipose tissue homeostasis. Using mouse models of obesity, human tissue, and a cell culture model, we show that macrophages form hydrolytic extracellular compartments at points of contact with dead adipocytes using local actin polymerization. These compartments are acidic and contain lysosomal enzymes delivered by exocytosis. Uptake and complete degradation of adipocyte fragments, which are released by extracellular hydrolysis, leads to macrophage foam cell formation. Exophagy-mediated foam cell formation is a highly efficient means by which macrophages internalize large amounts of lipid, which may ultimately overwhelm the metabolic capacity of the macrophage. This process provides a mechanism for degradation of objects, such as dead adipocytes, that are too large to be phagocytosed by macrophages. PMID:27044658

  14. Rediscovery of Eremobittacus spinulatus Byers (Mecoptera, Bittacidae) in Mexico, with description of the female and comments on sexual dimorphism and potential mimicry.

    Science.gov (United States)

    Villagomez, Fernando; Contreras-Ramos, Atilano; Marquez-López, Yesenia

    2015-01-01

    The female of Eremobittacus spinulatus Byers, 1997 is described for the first time. A key to the two species known of this genus endemic to Mexico is provided, and species distribution is illustrated. A case is made for adults of Eremobittacus to be sexually dimorphic, which appears to be an exceptional occurrence in Bittacidae. It is claimed that Eremobittacus spinulatus habitus has a wasp-like appearance, which may potentially depict a case of mimicry. PMID:26798248

  15. Rediscovery of Eremobittacus spinulatus Byers (Mecoptera, Bittacidae) in Mexico, with description of the female and comments on sexual dimorphism and potential mimicry

    OpenAIRE

    Villagomez, Fernando; Contreras-Ramos, Atilano; Marquez-López,Yesenia

    2015-01-01

    Abstract The female of Eremobittacus spinulatus Byers, 1997 is described for the first time. A key to the two species known of this genus endemic to Mexico is provided, and species distribution is illustrated. A case is made for adults of Eremobittacus to be sexually dimorphic, which appears to be an exceptional occurrence in Bittacidae . It is claimed that Eremobittacus spinulatus habitus has a wasp-like appearance, which may potentially depict a case of mimicry.

  16. Transmission of the Tourism Image of Mimicry Environment and Colorful Guizhou%拟态环境与多彩贵州旅游形象传播

    Institute of Scientific and Technical Information of China (English)

    王启宏

    2012-01-01

    大众传播构建了贵州旅游的拟态环境,由于拟态环境的多样性和从结构化向非结构化转变,引发了贵州旅游形象的争论:从神奇贵州到国家公园省,从文化千岛到多彩贵州。多彩贵州在多方的争论与博弈中脱颖而出,其关键便在于它是贵州旅游拟态环境的最佳表述。本文诠释拟态环境与多彩贵州旅游形象,通过旅游标示物的传播和旅游拟态景观的塑造,更好更快地推进多彩贵州“文化旅游发展创新区”的和谐发展。%Mass communication construct a mimicry environment of Guizhou. Due to the diversity of the mimicry environment and its change from the structured to the unstructured change, a controversy has been tou- ched off with a focus on the image of Guizhou : from mysterious Guizhou to national park province, and from the cultural diversities to colorful Guizhou. Now through the multi -sided controversy and intense competitions, Col- orful Guizhou has stood out. The key point for its success is that it has best presented the mimicry environment for Guizhou tourism. This paper explains the pseudo environment and colorful image of Guizhou tourism through the popularity of tourism markers and the creation of mimicry tourism landscape to promote the quicker and better harmonious development of "Cultural Tourism Development Zone" of colorful Guizhou.

  17. Rediscovery of Eremobittacus spinulatus Byers (Mecoptera, Bittacidae) in Mexico, with description of the female and comments on sexual dimorphism and potential mimicry

    Science.gov (United States)

    Villagomez, Fernando; Contreras-Ramos, Atilano; Marquez-López, Yesenia

    2015-01-01

    Abstract The female of Eremobittacus spinulatus Byers, 1997 is described for the first time. A key to the two species known of this genus endemic to Mexico is provided, and species distribution is illustrated. A case is made for adults of Eremobittacus to be sexually dimorphic, which appears to be an exceptional occurrence in Bittacidae. It is claimed that Eremobittacus spinulatus habitus has a wasp-like appearance, which may potentially depict a case of mimicry. PMID:26798248

  18. All-trans retinoic acid impairs the vasculogenic mimicry formation ability of U87 stem-like cells through promoting differentiation

    OpenAIRE

    LING, GENG-QIANG; LIU, YI-JING; Ke, Yi-Quan; Chen, Lei; JIANG, XIAO-DAN; JIANG, CHUAN-LU; Ye, Wei

    2015-01-01

    The poor therapeutic effect of traditional antiangiogenic therapy on glioblastoma multiforme (GBM) may be attributed to vasculogenic mimicry (VM), which was previously reported to be promoted by cancer stem-like cells (SLCs). All-trans retinoic acid (ATRA), a potent reagent which drives differentiation, was reported to be able to eradicate cancer SLCs in certain malignancies. The aim of the present study was to investigate the effects of ATRA on the VM formation ability of U87 glioblastoma SL...

  19. Evolution of sexual mimicry in the orchid subtribe orchidinae: the role of preadaptations in the attraction of male bees as pollinators

    OpenAIRE

    Cozzolino Salvatore; Schiestl Florian P

    2008-01-01

    Abstract Background Within the astonishing diversity of orchid pollination systems, sexual deception is one of the most stunning. An example is the genus Ophrys, where plants attract male bees as pollinators by mimicking female mating signals. Unsaturated hydrocarbons (alkenes) are often the key signal for this chemical mimicry. Here we investigate the evolution of these key compounds within Orchidinae by mapping their production in flowers of selected species onto their estimated phylogeny. ...

  20. Evolution of sexual mimicry in the orchid subtribe orchidinae: the role of preadaptations in the attraction of male bees as pollinators

    OpenAIRE

    Schiestl, F. P.; Cozzolino, S.

    2008-01-01

    BACKGROUND: Within the astonishing diversity of orchid pollination systems, sexual deception is one of the most stunning. An example is the genus Ophrys, where plants attract male bees as pollinators by mimicking female mating signals. Unsaturated hydrocarbons (alkenes) are often the key signal for this chemical mimicry. Here we investigate the evolution of these key compounds within Orchidinae by mapping their production in flowers of selected species onto their estimated phylogeny. RESULTS:...

  1. Phylogenetic relationships and the evolution of mimicry in the Chauliognathus yellow-black species complex (Coleoptera: Cantharidae) inferred from mitochondrial COI sequences

    OpenAIRE

    Vilmar Machado; Aldo M. Araujo; José Serrano; José Galián

    2004-01-01

    The phylogenetic relationships of twelve species of Chauliognathus were investigated by studying the mitochondrial cytochrome oxidase I gene. A 678 bp fragment of the COI gene was sequenced to test the hypothesis that the Müllerian mimicry species of the "yellow-black" complex make up a monophyletic clade, separated from species with other colour patterns. The data set was analysed by neighbour-joining, maximum parsimony and maximum likelihood procedures. The results support a single origin o...

  2. Characterisation of Anti-Apoptotic Signalling Pathways in Hepatocytes activated by alpha-Lipoic Acid and Atrial Natriuretic Peptide

    OpenAIRE

    Kulhanek-Heinze, Stefanie

    2004-01-01

    Both, the R-enantiomer of the antioxidant alpha-lipoic acid (R-LA) and the hormone atrial natriuretic peptide (ANP) are known to exert potent hepatoprotective action. The present work characterises alpha-lipoic acid- and ANP-mediated signal transduction pathways involved in the regulation of apoptotic cell death in two different models: primary hepatocytes and ischemic isolated perfused rat livers. alpha-lipoic acid was shown to protect isolated hepatocytes from TNF-alpha-/ActinomycinD-in...

  3. Association of Anti-GT1a Antibodies with an Outbreak of Guillain-Barre Syndrome and Analysis of Ganglioside Mimicry in an Associated Campylobacter jejuni Strain.

    Directory of Open Access Journals (Sweden)

    Maojun Zhang

    Full Text Available An outbreak of Guillain-Barré syndrome (GBS, subsequent to Campylobacter jejuni enteritis, occurred in China in 2007. Serum anti-ganglioside antibodies were measured in GBS patients and controls. Genome sequencing was used to determine the phylogenetic relationship among three C. jejuni strains from a patient with GBS (ICDCCJ07001, a patient with gastroenteritis (ICDCCJ07002 and a healthy carrier (ICDCCJ07004, which were all associated with the outbreak. The ganglioside-like structures of the lipo-oligosaccharides of these strains were determined by mass spectrometry. Seventeen (53% of the GBS patients had anti-GT1a IgG antibodies. GT1a mimicry was found in the lipo-oligosaccharides of strain ICDCCJ07002 and ICDCCJ07004; but a combination of GM3/GD3 mimics was observed in ICDCCJ07001, although this patient had anti-GT1a IgG antibodies. A single-base deletion in a glycosyltransferase gene caused the absence of GT1a mimicry in ICDCCJ07001. The phylogenetic tree showed that ICDCCJ07002 and ICDCCJ07004 were genetically closer to each other than to ICDCCJ07001. C. jejuni, bearing a GT1a-like lipo-oligosaccharide, might have caused the GBS outbreak and the loss of GT1a mimicry may have helped ICDCCJ07001 to survive in the host.

  4. Curcumin suppresses invasiveness and vasculogenic mimicry of squamous cell carcinoma of the larynx through the inhibition of JAK-2/STAT-3 signaling pathway.

    Science.gov (United States)

    Hu, An; Huang, Jing-Juan; Jin, Xiao-Jie; Li, Ji-Ping; Tang, Yuan-Jia; Huang, Xin-Fang; Cui, Hui-Juan; Xu, Wei-Hua; Sun, Guang-Bin

    2015-01-01

    To determine the role of JAK-2/STAT-3 signaling pathway in invasion and vasculogenic mimicry of laryngeal squamous cell carcinoma. HEp-2 cells were treated with 1 or 10 μmol/L curcumin and AG490 (the inhibitor of JAK-2) for 48 h, the invasion and vasculogenic mimicry of tumor cells were tested with Transwell chamber test and tube formation experiment. RT-PCR was used to measure the expression of MMP-2 and VEGF. Western blot assay was employed to determine the expression of JAK-2, STAT3, p-STAT3, MMP-2 and VEGF. Compared to control group,there were less tumor cells permeating membrane and less formed tubes after curcumin or AG490 treatment, RT-PCR showed that the expression of MMP-2 and VEGF at mRNA level were decreased (P 0.05). Immunofluorescence staining demonstrated that the expression of eNOS was down-regulated (P < 0.01). Curcumin and AG490 significantly inhibits invasion and vasculogenic mimicry of laryngeal squamous cell carcinoma in vitro, and JAK-2/STAT-3 signaling pathway promotes above processes. PMID:25628937

  5. Prognostic significance of an apoptotic index and apoptosis/proliferation ratio for patients with high-grade astrocytomas.

    Science.gov (United States)

    Kuriyama, Hiroko; Lamborn, Kathleen R.; O'Fallon, Judith R.; Iturria, N.; Sebo, Thomas; Schaefer, Paul L.; Scheithauer, Bernd W.; Buckner, Jan C.; Kuriyama, Nagato; Jenkins, Robert B.; Israel, Mark A.

    2002-01-01

    We evaluated the association of spontaneous apoptosis and an apoptosis/proliferation index with survival to determine the potential of such measures to serve as predictive markers for patients with glioblastoma multiforme (GBM). We examined the extent of spontaneous apoptosis in tumors from newly diagnosed patients, 75 with GBM and 21 with anaplastic astrocytoma, who were entered on treatment protocols of the North Central Cancer Treatment Group. In the group of GBM patients, those with a higher apoptotic index tended to live longer ( P = 0.04; Cox proportional hazards model including performance score, age, and extent of resection in a multivariate model). We found that the apoptotic index values for anaplastic astrocytoma patients tended to be lower than those in the GBM patients, although with small sample sizes, the result was not statistically significant ( P = 0.1). We also examined expression of the Ki-67 cell proliferation antigen immunohistochemically using the MIB-1 monoclonal antibody. Ki-67 expression did not provide additional information regarding the survival of patients with GBM. In this group of GBM patients, those patients with higher apoptotic index/proliferation ratios had a better prognosis than did those with a low ratio ( P < 0.021, same model as above). These findings suggest that both apoptosis and a cell death/cell proliferation ratio are associated with patient survival, and they may be useful for either the clinical evaluation of patients with GBM or the stratification of patients for treatment evaluation. PMID:12084348

  6. The nuclear receptor Nr4a1 mediates anti-inflammatory effects of apoptotic cells.

    Science.gov (United States)

    Ipseiz, Natacha; Uderhardt, Stefan; Scholtysek, Carina; Steffen, Martin; Schabbauer, Gernot; Bozec, Aline; Schett, Georg; Krönke, Gerhard

    2014-05-15

    Uptake of apoptotic cells (ACs) by macrophages ensures the nonimmunogenic clearance of dying cells, as well as the maintenance of self-tolerance to AC-derived autoantigens. Upon ingestion, ACs exert an inhibitory influence on the inflammatory signaling within the phagocyte. However, the molecular signals that mediate these immune-modulatory properties of ACs are incompletely understood. In this article, we show that the phagocytosis of apoptotic thymocytes was enhanced in tissue-resident macrophages where this process resulted in the inhibition of NF-κB signaling and repression of inflammatory cytokines, such as IL-12. In parallel, ACs induced a robust expression of a panel of immediate early genes, which included the Nr4a subfamily of nuclear receptors. Notably, deletion of Nr4a1 interfered with the anti-inflammatory effects of ACs in macrophages and restored both NF-κB signaling and IL-12 expression. Accordingly, Nr4a1 mediated the anti-inflammatory properties of ACs in vivo and was required for maintenance of self-tolerance in the murine model of pristane-induced lupus. Thus, our data point toward a key role for Nr4a1 as regulator of the immune response to ACs and of the maintenance of tolerance to "dying self." PMID:24740500

  7. Galectin-1 and Galectin-3 induce mitochondrial apoptotic pathway in Jurkat cells

    Science.gov (United States)

    Vasil'eva, O. A.; Isaeva, A. V.; Prokhorenko, T. S.; Zima, A. P.; Novitsky, V. V.

    2016-08-01

    Cellular malignant transformation is often accompanied by increased gene expression of low-molecular proteins of lectins family-galectins. But it is unknown how galectins promote tumor growth and malignization. Galectins-1 and galectin-3 are thought to be possible immunoregulators exerting their effects by regulating the balance of CD4+ lymphocytes. In addition it is known that tumor cells overexpressing galectins are capable of escaping immunological control, causing apoptosis of lymphocytes. The aim of the study is to investigate the role of galectin-1 and galectin-3 in the implementation of mitochondrial apoptotic pathway in Jurkat cells. Methods: Jurkat cells were used as a model for the study of T-lymphocytes. Jurkat cells were activated with antibodies to CD3 and CD28 and cultured with recombinant galectin-1 and -3. Apoptosis of Jurkat cells and depolarization of the mitochondrial membrane were assessed by flow cytometry. It was found that galectin-1 and galectin-3 have a dose-dependent pro-apoptotic effect on Jurkat cells in vitro and enlarge the number of cells with decreased mitochondrial membrane potential compared with intact cells.

  8. Apoptotic effects on maturation of mouse oocytes, fertilization and fetal development by puerarin.

    Science.gov (United States)

    Huang, Fu-Jen; Chan, Wen-Hsiung

    2016-10-01

    Previously we identified puerarin, an isoflavone compound, as a risk factor for normal embryonic development that triggers apoptotic processes in the inner cell mass of mouse blastocysts, leading to retardation of embryonic development and cell viability. In the current study, we investigated whether puerarin exerts deleterious effects on mouse oocyte maturation, in vitro fertilization (IVF) and subsequent pre- and post-implantation development, both in vitro and in vivo. Notably, puerarin caused significant impairment of these processes in vitro. Pre-incubation of oocytes with puerarin during in vitro maturation led to increased post-implantation embryo resorption and decreased mouse fetal weight. In an in vivo animal model, intravenous injection with or without puerarin (1, 3 and 5 mg/kg body weight/day) for 4 days caused a decrease in oocyte maturation and IVF, and led to deleterious effects on early embryonic development. Importantly, pre-incubation of oocytes with a caspase-3-specific inhibitor effectively blocked puerarin-triggered deleterious effects, clearly implying that embryonic injury induced by puerarin is mediated by a caspase-dependent apoptotic mechanism. These results clearly demonstrate that puerarin has deleterious effects on mouse oocyte maturation, fertilization and subsequent embryonic development in vitro and in vivo. PMID:26712108

  9. Inhibition of mitochondria responsible for the anti-apoptotic effects of melatonin during ischemia-reperfusion

    Institute of Scientific and Technical Information of China (English)

    HAN Yi-xiang; ZHANG Sheng-hui; WANG Xi-ming; WU Jian-bo

    2006-01-01

    Objective: To investigate a possible mechanism responsible for anti-apoptotic effects of melatonin and provide theoretical evidences for clinical therapy. Methods: Ischemia-reperfusion mediated neuronal cell injury model was constructed in cerebellar granule neurons (CGNs) by deprivation of glucose, serum and oxygen in media. After ischemia, melatonin was added to the test groups to reach differential concentration during reperfusion. DNA fragmentation, mitochondrial transmembrane potential,mitochondrial cytochrome c release and caspase-3 activity were observed after subjecting cerebellar granule neurons to oxygen-glucose deprivation (OGD). Results: The results showed that OGD induced typical cell apoptosis change, DNA ladder and apoptosis-related alterations in mitochondrial functions including depression of mitochondrial transmembrane potential (its maximal protection ratio was 73.26%) and release of cytochrome c (its maximal inhibition ratio was 42.52%) and the subsequent activation of caspase-3 (its maximal protection ratio was 59.32%) in cytoplasm. Melatonin reduced DNA damage and inhibited release of mitochondrial cytochrome c and activation of caspase-3. Melatonin can strongly prevent the OGD-induced loss of the mitochondria membrane potential. Conclusion: Our findings suggested that the direct inhibition of mitochondrial pathway might essentially contribute to its anti-apoptotic effects in neuronal ischemia-reperfusion.

  10. Impact of Antioxidants on Cardiolipin Oxidation in Liposomes: Why Mitochondrial Cardiolipin Serves as an Apoptotic Signal?

    Science.gov (United States)

    Lokhmatikov, Alexey V.; Voskoboynikova, Natalia; Cherepanov, Dmitry A.; Skulachev, Maxim V.; Steinhoff, Heinz-Jürgen; Skulachev, Vladimir P.; Mulkidjanian, Armen Y.

    2016-01-01

    Molecules of mitochondrial cardiolipin (CL) get selectively oxidized upon oxidative stress, which triggers the intrinsic apoptotic pathway. In a chemical model most closely resembling the mitochondrial membrane—liposomes of pure bovine heart CL—we compared ubiquinol-10, ubiquinol-6, and alpha-tocopherol, the most widespread naturally occurring antioxidants, with man-made, quinol-based amphiphilic antioxidants. Lipid peroxidation was induced by addition of an azo initiator in the absence and presence of diverse antioxidants, respectively. The kinetics of CL oxidation was monitored via formation of conjugated dienes at 234 nm. We found that natural ubiquinols and ubiquinol-based amphiphilic antioxidants were equally efficient in protecting CL liposomes from peroxidation; the chromanol-based antioxidants, including alpha-tocopherol, were 2-3 times less efficient. Amphiphilic antioxidants, but not natural ubiquinols and alpha-tocopherol, were able, additionally, to protect the CL bilayer from oxidation by acting from the water phase. We suggest that the previously reported therapeutic efficiency of mitochondrially targeted amphiphilic antioxidants is owing to their ability to protect those CL molecules that are inaccessible to natural hydrophobic antioxidants, being trapped within respiratory supercomplexes. The high susceptibility of such occluded CL molecules to oxidation may have prompted their recruitment as apoptotic signaling molecules by nature. PMID:27313834

  11. Cytotoxicity of carteolol to human corneal epithelial cells by inducing apoptosis via triggering the Bcl-2 family protein-mediated mitochondrial pro-apoptotic pathway.

    Science.gov (United States)

    Shan, Ming; Fan, Ting-Jun

    2016-09-01

    Carteolol is a frequently used nonselective β-adrenoceptor antagonist for glaucoma and ocular hypertension treatment, and its repeated/prolonged usage might be cytotoxic to the cornea, especially the outmost human corneal epithelium (HCEP). The aim of the present study was to characterize the cytotoxicity of carteolol to HCEP and its underlying cellular and molecular mechanisms using an in vitro model of HCEP cells. After HCEP cells were treated with carteolol at concentrations varying from 2% to 0.015625%, the cytotoxicity, apoptosis-inducing effect and pro-apoptotic pathway was investigated, respectively. Our results showed that carteolol at concentrations above 0.03125% induced time- and dose-dependent growth retardation, cytopathic morphological changes and viability decline of HCEP cells. Moreover, carteolol induced G1 phase arrest, plasma membrane permeability elevation, phosphatidylserine externalization, DNA fragmentation, and apoptotic body formation of HCEP cells. Furthermore, carteolol also induced activation of caspase-9 and -3, disruption of mitochondrial transmembrane potential, up-regulation the cytoplasmic amount of cytochrome c and apoptosis-inducing factor, and up-regulation of pro-apoptotic Bax and Bad, down-regulation of anti-apoptotic Bcl-2 and Bcl-xL. In conclusion, carteolol above 1/64 of its clinical therapeutic dosage has a time- and dose-dependent cytotoxicity to HCEP cells, which is achieved by inducing apoptosis via triggering Bcl-2 family protein-mediated mitochondrial pro-apoptotic pathway. PMID:27216471

  12. Identification of a lupus-susceptibility locus leading to impaired clearance of apoptotic debris on New Zealand Black chromosome 13

    Science.gov (United States)

    Pau, Evelyn; Loh, Christina; Minty, Gillian E.S.; Chang, Nan-Hua; Wither, Joan E.

    2016-01-01

    Systemic lupus erythematosus is a chronic multi-organ autoimmune disease marked mainly by the production of anti-nuclear antibodies. Nuclear antigens become accessible to the immune system following apoptosis and defective clearance of apoptotic debris has been shown in several knockout mouse models to promote lupus. However, genetic loci associated with defective clearance are not well defined in spontaneously arising lupus models. We previously showed that introgression of the chromosome 13 interval from lupus-prone New Zealand Black (NZB) mice onto a non-autoimmune B6 genetic background (B6.NZBc13) recapitulated many of the NZB autoimmune phenotypes. Here, we show that B6.NZBc13 mice have impaired clearance of apoptotic debris by peritoneal and tingible-body macrophages and have narrowed down the chromosomal interval of this defect using subcongenic mice with truncated NZB chromosome 13 intervals. This chromosomal region (81–94 Mb) is sufficient to produce polyclonal B and T cell activation, and expansion of dendritic cells. To fully recapitulate the autoimmune phenotypes seen in B6.NZBc13 mice, at least one additional locus located in the centromeric portion of the interval is required. Thus, we have identified a novel lupus susceptibility locus on NZB chromosome 13 that is associated with impaired clearance of apoptotic debris. PMID:23328841

  13. Development of novel cyclic peptides as pro-apoptotic agents.

    Science.gov (United States)

    Brindisi, Margherita; Maramai, Samuele; Brogi, Simone; Fanigliulo, Emanuela; Butini, Stefania; Guarino, Egeria; Casagni, Alice; Lamponi, Stefania; Bonechi, Claudia; Nathwani, Seema M; Finetti, Federica; Ragonese, Francesco; Arcidiacono, Paola; Campiglia, Pietro; Valenti, Salvatore; Novellino, Ettore; Spaccapelo, Roberta; Morbidelli, Lucia; Zisterer, Daniela M; Williams, Clive D; Donati, Alessandro; Baldari, Cosima; Campiani, Giuseppe; Ulivieri, Cristina; Gemma, Sandra

    2016-07-19

    Our recent finding that paclitaxel behaves as a peptidomimetic of the endogenous protein Nur77 inspired the design of two peptides (PEP1 and PEP2) reproducing the effects of paclitaxel on Bcl-2 and tubulin, proving the peptidomimetic nature of paclitaxel. Starting from these peptide-hits, we herein describe the synthesis and the biological investigation of linear and cyclic peptides structurally related to PEP2. While linear peptides (2a,b, 3a,b, 4, 6a-f) were found inactive in cell-based assays, biological analysis revealed a pro-apoptotic effect for most of the cyclic peptides (5a-g). Cellular permeability of 5a (and also of 2a,b) on HL60 cells was assessed through confocal microscopy analysis. Further cellular studies on a panel of leukemic cell lines (HL60, Jurkat, MEC, EBVB) and solid tumor cell lines (breast cancer MCF-7 cells, human melanoma A375 and 501Mel cells, and murine melanoma B16F1 cells) confirmed the pro-apoptotic effect of the cyclic peptides. Cell cycle analysis revealed that treatment with 5a, 5c, 5d or 5f resulted in an increase in the number of cells in the sub-G0/G1 peak. Direct interaction with tubulin (turbidimetric assay) and with microtubules (immunostaining experiments) was assessed in vitro for the most promising compounds. PMID:27150036

  14. A Survey of Model Evaluation Approaches with a Tutorial on Hierarchical Bayesian Methods

    Science.gov (United States)

    Shiffrin, Richard M.; Lee, Michael D.; Kim, Woojae; Wagenmakers, Eric-Jan

    2008-01-01

    This article reviews current methods for evaluating models in the cognitive sciences, including theoretically based approaches, such as Bayes factors and minimum description length measures; simulation approaches, including model mimicry evaluations; and practical approaches, such as validation and generalization measures. This article argues…

  15. Apoptosis Regulation via the Mitochondrial Pathway : Membrane Response upon Apoptotic Stimuli

    OpenAIRE

    Sani, Marc-Antoine

    2008-01-01

    The aim of this thesis was the investigation of the mitochondrial response mechanisms upon apoptotic stimuli. The specific objectives were the biophysical characterization of membrane dynamics and the specific roles of lipids in the context of apoptotic regulation occurring at the mitochondrion and its complex membrane systems. The BH4 domain is an anti-apoptotic specific domain of the Bcl-2 protein. Solid phase peptide synthesis was used to produce large amount of the peptide for biophysical...

  16. Decreased Apoptotic Rate of Alveolar Macrophages of Patients with Idiopathic Pulmonary Fibrosis

    OpenAIRE

    Fotios Drakopanagiotakis; Areti Xifteri; Evaggelos Tsiambas; Andreas Karameris; Konstantina Tsakanika; Napoleon Karagiannidis; Demetrios Mermigkis; Vlasis Polychronopoulos; Demosthenes Bouros

    2012-01-01

    Introduction. Increased apoptosis of epithelial cells and decreased apoptosis of myofibroblasts are involved in the pathogenesis of IPF. The apoptotic profile of alveolar macrophages (AMs) in IPF is unclear. Aim. To investigate whether AMs of patients with IPF exhibit a different apoptotic profile compared to normal subjects. Methods. We analyzed, by immunohistochemistry, the expression of the apoptotic markers fas, fas ligand , bcl-2, and bax in AM obtained from bronchoalveolar lavage fluid ...

  17. HMM Search for Apoptotic Domains (MOLECULAR BIOLOGY AND INFORMATION-Biological Information Science)

    OpenAIRE

    Hattori, Masahiro; Kanehisa, Minoru

    2000-01-01

    For the purpose of analyzing apoptotic molecular interactions, we have developed a knowledge base, which consists of apoptotic molecular interactions, together with the WWW interface for it. This database and the user interface enabled us to find out entries containing various information about cell death. This information tells us that the apoptotic molecular interactions are likely to be controlled under a series of specific conserved domains. Thus, the viewpoint of domain seems to be more ...

  18. Age-related activation of mitochondrial caspase-independent apoptotic signaling in rat gastrocnemius muscle

    OpenAIRE

    Marzetti, Emanuele; Wohlgemuth, Stephanie Eva; Lees, Hazel Anne; Chung, Hae-young; Giovannini, Silvia; Leeuwenburgh, Christiaan

    2008-01-01

    Mitochondria-mediated apoptosis represents a central process driving age-related muscle loss. However, the temporal relation between mitochondrial apoptotic signaling and sarcopenia as well as the regulation of release of pro-apoptotic factors from the mitochondria has not been elucidated. In this study, we investigated mitochondrial apoptotic signaling in skeletal muscle of rats across a wide age range. We also investigated whether mitochondrial-driven apoptosis was accompanied by changes in...

  19. Apoptotic cells are cleared by directional migration and elmo1- dependent macrophage engulfment.

    Science.gov (United States)

    van Ham, Tjakko J; Kokel, David; Peterson, Randall T

    2012-05-01

    Apoptotic cell death is essential for development and tissue homeostasis. Failure to clear apoptotic cells can ultimately cause inflammation and autoimmunity. Apoptosis has primarily been studied by staining of fixed tissue sections, and a clear understanding of the behavior of apoptotic cells in living tissue has been elusive. Here, we use a newly developed technique to track apoptotic cells in real time as they emerge and are cleared from the zebrafish brain. We find that apoptotic cells are remarkably motile, frequently migrating several cell diameters to the periphery of living tissues. F-actin remodeling occurs in surrounding cells, but also within the apoptotic cells themselves, suggesting a cell-autonomous component of motility. During the first 2 days of development, engulfment is rare, and most apoptotic cells lyse at the brain periphery. By 3 days postfertilization, most cell corpses are rapidly engulfed by macrophages. This engulfment requires the guanine nucleotide exchange factor elmo1. In elmo1-deficient macrophages, engulfment is rare and may occur through macropinocytosis rather than directed engulfment. These findings suggest that clearance of apoptotic cells in living vertebrates is accomplished by the combined actions of apoptotic cell migration and elmo1-dependent macrophage engulfment. PMID:22503503

  20. How to be a dioecious fig: Chemical mimicry between sexes matters only when both sexes flower synchronously.

    Science.gov (United States)

    Hossaert-McKey, M; Proffit, M; Soler, C C L; Chen, C; Bessière, J-M; Schatz, B; Borges, R M

    2016-01-01

    In nursery pollination mutualisms, which are usually obligate interactions, olfactory attraction of pollinators by floral volatile organic compounds (VOCs) is the main step in guaranteeing partner encounter. However, mechanisms ensuring the evolutionary stability of dioecious fig-pollinator mutualisms, in which female fig trees engage in pollination by deceit resulting in zero reproductive success of pollinators that visit them, are poorly understood. In dioecious figs, individuals of each sex should be selected to produce odours that their pollinating wasps cannot distinguish, especially since pollinators have usually only one choice of a nursery during their lifetime. To test the hypothesis of intersexual chemical mimicry, VOCs emitted by pollen-receptive figs of seven dioecious species were compared using headspace collection and gas chromatography-mass spectrometry analysis. First, fig-flower scents varied significantly among species, allowing host-species recognition. Second, in species in which male and female figs are synchronous, intersexual VOC variation was not significant. However, in species where figs of both sexes flower asynchronously, intersexual variation of VOCs was detectable. Finally, with one exception, there was no sexual dimorphism in scent quantity. We show that there are two ways to use scent to be a dioecious fig based on differences in flowering synchrony between the sexes. PMID:26888579

  1. Receptor mimicry by antibody F045–092 facilitates universal binding to the H3 subtype of influenza virus

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Peter S.; Ohshima, Nobuko; Stanfield, Robyn L.; Yu, Wenli; Iba, Yoshitaka; Okuno, Yoshinobu; Kurosawa, Yoshikazu; Wilson, Ian A.

    2014-04-10

    Influenza viruses present a significant health challenge each year, as in the H3N2 epidemic of 2012–2013. Here we describe an antibody, F045–092, that possesses broadly neutralizing activity against the entire H3 subtype and accommodates the natural variation and additional glycosylation in all strains tested from 1963 to 2011. Crystal structures of F045–092 in complex with HAs from 1975 and 2011 H3N2 viruses reveal the structural basis for its neutralization breadth through insertion of its 23-residue HCDR3 into the receptor-binding site that involves striking receptor mimicry. F045–092 extends its recognition to divergent subtypes, including H1, H2 and H13, using the enhanced avidity of its IgG to overcome lower-affinity Fab binding, as observed with other antibodies that target the receptor-binding site. This unprecedented level of antibody cross-reactivity against the H3 subtype can potentially inform on development of a pan-H3 vaccine or small-molecule therapeutics.

  2. Etiology of Crohn's disease: Do certain food additives cause intestinal inflammation by molecular mimicry of mycobacterial lipids?

    Science.gov (United States)

    Traunmüller, F

    2005-01-01

    Crohn's disease is a chronic granulomatous inflammation of the gastrointestinal tract which was first described in the beginning of the 20th century. The histological similarity with intestinal tuberculosis has led to the assumption of an involvement of mycobacteria and mycobacterial antigens, respectively, in the etiology. A major defense mechanism against mycobacterial lipid antigens is the CD1 system which includes CD1 molecules for antigen presentation and natural killer T cells for recognition and subsequent production of cytokines like interferon-gamma and tumour necrosis factor-alpha. These cytokines promote granulomatous transformation. Various food additives, especially emulsifiants, thickeners, surface-finishing agents and contaminants like plasticizers share structural domains with mycobacterial lipids. It is therefore hypothesized, that these compounds are able to stimulate by molecular mimicry the CD1 system in the gastrointestinal mucosa and to trigger the pro-inflammatory cytokine cascade. The understanding of Crohn's disease as a CD1-mediated delayed-type hypersensitivity to certain food additives would lead to strong emphasis on a dietary treatment. Related aspects of pathology, physiology and epidemiology of Crohn's disease are presented. PMID:16043304

  3. Endostatin combined with radiotherapy suppresses vasculogenic mimicry formation through inhibition of epithelial-mesenchymal transition in esophageal cancer.

    Science.gov (United States)

    Chen, Xiaochen; Zhang, Hao; Zhu, Hongcheng; Yang, Xi; Yang, Yuehua; Yang, Yan; Min, Hua; Chen, Guangzong; Liu, Jia; Lu, Jing; Cheng, Hongyan; Sun, Xinchen

    2016-04-01

    The growth of solid tumors requires angiogenesis to provide oxygen and nutrients and to support cell proliferation. The switch from an avascular to a vascular phenotype is typically related to acceleration of tumor growth. Anti-angiogenic therapy is becoming a very promising way for malignant tumors. Meanwhile, malignant tumor cells themselves were able to develop the formation of cell-lined vessels that contribute to tumor neovascularization and supply the nutrients and oxygen, which is called vasculogenic mimicry (VM). However, the molecular mechanism of VM remains unclear. The purpose of this study was to investigate the efficacy of the novel recombinant human endostatin (rh-Endo) protein combined with radiotherapy on human esophageal squamous cell carcinoma (ESCC) cell lines Eca-109 and TE13. Our results showed that rh-Endo combined with radiotherapy significantly inhibited the proliferation, migration, invasion, and VM of human esophageal cancer cells in a dose-dependent manner; however, it has no direct effect on apoptosis of carcinoma cells, which indicated that rh-Endo combined with radiotherapy significantly changed the microenvironment of esophageal carcinoma, and played an important role in preventing distant metastasis. Our findings suggested that rh-Endo inhibited the metastasis of esophageal cancer and the activation of AKT pathway, and the down-regulation of epithelial-mesenchymal transition (EMT) may be associated with such effect of rh-Endo. These results also supported the bright prospect of rh-Endo combined with radiotherapy for clinical applications in the future. PMID:26511968

  4. Potential T cell epitopes of Mycobacterium tuberculosis that can instigate molecular mimicry against host: implications in autoimmune pathogenesis

    Directory of Open Access Journals (Sweden)

    Babu Chodisetti Sathi

    2012-03-01

    Full Text Available Abstract Background Molecular mimicry between microbial antigens and host-proteins is one of the etiological enigmas for the occurrence of autoimmune diseases. T cells that recognize cross-reactive epitopes may trigger autoimmune reactions. Intriguingly, autoimmune diseases have been reported to be prevalent in tuberculosis endemic populations. Further, association of Mycobacterium tuberculosis (M. tuberculosis has been implicated in different autoimmune diseases, including rheumatoid arthritis and multiple sclerosis. Although, in silico analyses have identified a number of M. tuberculosis specific vaccine candidates, the analysis on prospective cross-reactive epitopes, that may elicit autoimmune response, has not been yet attempted. Here, we have employed bioinformatics tools to determine T cell epitopes of homologous antigenic regions between M. tuberculosis and human proteomes. Results Employing bioinformatics tools, we have identified potentially cross-reactive T cell epitopes restricted to predominant class I and II alleles of human leukocyte antigens (HLA. These are similar to peptides of mycobacterial proteins and considerable numbers of them are promiscuous. Some of the identified antigens corroborated with established autoimmune diseases linked with mycobacterial infection. Conclusions The present study reveals many target proteins and their putative T cell epitopes that might have significant application in understanding the molecular basis of possible T cell autoimmune reactions during M. tuberculosis infections.

  5. PEGylated apoptotic protein-loaded PLGA microspheres for cancer therapy

    Directory of Open Access Journals (Sweden)

    Byeon HJ

    2015-01-01

    Full Text Available Hyeong Jun Byeon,1 Insoo Kim,1 Ji Su Choi,1 Eun Seong Lee,2 Beom Soo Shin,3 Yu Seok Youn11Department of Pharmaceutical Sciences, School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea; 2Division of Biotechnology, The Catholic University of Korea, Bucheon-si, Republic of Korea; 3Department of Pharmacy, College of Pharmacy, Catholic University of Daegu, Gyeongsan-si, Republic of KoreaAbstract: The aim of the current study was to investigate the antitumor potential of poly(D,L-lactic-co-glycolic acid microspheres (PLGA MSs containing polyethylene glycol (PEG-conjugated (PEGylated tumor necrosis factor–related apoptosis-inducing ligand (PEG-TRAIL. PEG-TRAIL PLGA MSs were prepared by using a water-in-oil-in-water double-emulsion method, and the apoptotic activities of supernatants released from the PLGA MSs at days 1, 3, and 7 were examined. The antitumor effect caused by PEG-TRAIL PLGA MSs was evaluated in pancreatic Mia Paca-2 cell-xenografted mice. PEG-TRAIL PLGA MS was found to be spherical and 14.4±1.06 µm in size, and its encapsulation efficiency was significantly greater than that of TRAIL MS (85.7%±4.1% vs 43.3%±10.9%, respectively. The PLGA MS gradually released PEG-TRAIL for 14 days, and the released PEG-TRAIL was shown to have clear apoptotic activity in Mia Paca-2 cells, whereas TRAIL released after 1 day had a negligible activity. Finally, PEG-TRAIL PLGA MS displayed remarkably greater antitumor efficacy than blank or TRAIL PLGA MS in Mia Paca-2 cell-xenografted mice in terms of tumor volume and weight, apparently due to increased stability and well-retained apoptotic activity of PEG-TRAIL in PLGA MS. We believe that this PLGA MS system, combined with PEG-TRAIL, should be considered a promising candidate for treating pancreatic cancer.Keywords: Poly(D,L-lactic-co-glycolic acid, controlled release, PEGylation, TRAIL, pancreatic cancer

  6. Alterations in oxidative, inflammatory and apoptotic events in short-lived and long-lived mice testes

    Science.gov (United States)

    Matzkin, María Eugenia; Miquet, Johanna Gabriela; Fang, Yimin; Hill, Cristal Monique; Turyn, Daniel; Calandra, Ricardo Saúl; Bartke, Andrzej; Frungieri, Mónica Beatriz

    2016-01-01

    Aged testes undergo profound histological and morphological alterations leading to a reduced functionality. Here, we investigated whether variations in longevity affect the development of local inflammatory processes, the oxidative state and the occurrence of apoptotic events in the testis. To this aim, well-established mouse models with delayed (growth hormone releasing hormone-knockout and Ames dwarf mice) or accelerated (growth hormone-transgenic mice) aging were used. We hereby show that the testes of short-lived mice show a significant increase in cyclooxygenase 2 expression, PGD2 production, lipid peroxidation, antioxidant enzymes expression, local macrophages and TUNEL-positive germ cells numbers, and the levels of both pro-caspase-3 and cleaved caspase-3. In contrast, although the expression of antioxidant enzymes remained unchanged in testes of long-lived mice, the remainder of the parameters assessed showed a significant reduction. This study provides novel evidence that longevity confers anti-inflammatory, anti-oxidant and anti-apoptotic capacities to the adult testis. Oppositely, short-lived mice suffer testicular inflammatory, oxidative and apoptotic processes. PMID:26805572

  7. The effector caspases drICE and dcp-1 have partially overlapping functions in the apoptotic pathway in Drosophila.

    Science.gov (United States)

    Xu, D; Wang, Y; Willecke, R; Chen, Z; Ding, T; Bergmann, A

    2006-10-01

    Caspases are essential components of the apoptotic machinery in both vertebrates and invertebrates. Here, we report the isolation of a mutant allele of the Drosophila effector caspase drICE as a strong suppressor of hid- (head involution defective-) induced apoptosis. This mutant was used to determine the apoptotic role of drICE. Our data are consistent with an important function of drICE for developmental and irradiation-induced cell death. Epistatic analysis suggests that drICE acts genetically downstream of Drosophila inhibitor of apoptosis protein 1 (Diap1). However, although cell death is significantly reduced in drICE mutants in all assays, it is not completely blocked. A double-mutant analysis between drICE and death caspase-1 (dcp-1), another effector caspase, reveals that some cells (type I) strictly require drICE for apoptosis, whereas other cells (type II) require either drICE or dcp-1. Thus, these data demonstrate a barely appreciated complexity in the apoptotic pathway, and are consistent with current models about effector caspase regulation in both vertebrates and invertebrates. PMID:16645642

  8. Preparation of 99Tcm-Annexin V and in vitro study of its binding characteristics in dopaminergic apoptotic neurons

    International Nuclear Information System (INIS)

    Objective: The aims of this study were two. One was to find out an optimal method for 99Tcm-Annexin V preparation and the other was to investigate the binding characteristics of 99Tcm-Annexin V in dopaminergic apoptotic neurons in vitro. Methods: For 99Tcm-Annexin V preparation, hydrazine nicotinamide (HYNIC), a bifunctional chelating agent was used. Product was purified by Sephadex G-25 column chromatography and analyzed with instant thin layer chromatography (ITLC). To test the binding characteristics in dopaminergic apoptotic neurons in vitro, a rat pheoehromocytoma cell line (PC12) treated with l-methyl-4-phenylpyridinium (MPP+) was used. Tests including time-temperature binding, saturable bind- ing, competition binding between dopaminergic apoptotic neurons and 99Tcm-HYNIC-Annexin V and dose- dependent MPP+ studies were performed and evaluated. Results: The labeling rate of 99Tcm was (64.56 ± 6.23)%. The specific activity of 99Tcm-HYNIC-Annexin V was (3.7-74)xl05 kBq/mg protein. The radiochemical purity was (93.6±2.48)% and was >90% after 4 hours storage at room temperature. Seat- chard plotting suggested that the concentrations of Kd was (7.16±1.78) nmol/L, and Bmax was (178.73± 32.62) fmoL/106 ceils. Conclusions: The preliminary results show that an optimal 99Tcm-HYNIC-Annexin V preparation method can be provided. The 99Tcm-HYNIC-Annexin V prepared in our laboratory has good receptor-binding activity and may possibly be a potential drug in studying the apoptotic phenomenon in Parkin- son's disease at early stage in an animal model. (authors)

  9. A functional yeast survival screen of tumor-derived cDNA libraries designed to identify anti-apoptotic mammalian oncogenes.

    Directory of Open Access Journals (Sweden)

    Moritz Eißmann

    Full Text Available Yeast cells can be killed upon expression of pro-apoptotic mammalian proteins. We have established a functional yeast survival screen that was used to isolate novel human anti-apoptotic genes overexpressed in treatment-resistant tumors. The screening of three different cDNA libraries prepared from metastatic melanoma, glioblastomas and leukemic blasts allowed for the identification of many yeast cell death-repressing cDNAs, including 28% of genes that are already known to inhibit apoptosis, 35% of genes upregulated in at least one tumor entity and 16% of genes described as both anti-apoptotic in function and upregulated in tumors. These results confirm the great potential of this screening tool to identify novel anti-apoptotic and tumor-relevant molecules. Three of the isolated candidate genes were further analyzed regarding their anti-apoptotic function in cell culture and their potential as a therapeutic target for molecular therapy. PAICS, an enzyme required for de novo purine biosynthesis, the long non-coding RNA MALAT1 and the MAST2 kinase are overexpressed in certain tumor entities and capable of suppressing apoptosis in human cells. Using a subcutaneous xenograft mouse model, we also demonstrated that glioblastoma tumor growth requires MAST2 expression. An additional advantage of the yeast survival screen is its universal applicability. By using various inducible pro-apoptotic killer proteins and screening the appropriate cDNA library prepared from normal or pathologic tissue of interest, the survival screen can be used to identify apoptosis inhibitors in many different systems.

  10. Identification and apoptotic potential of T-2 toxin metabolites in human cells.

    Science.gov (United States)

    Weidner, Maria; Welsch, Tanja; Hübner, Florian; Schwerdt, Gerald; Gekle, Michael; Humpf, Hans-Ulrich

    2012-06-01

    The mycotoxin T-2 toxin, produced by various Fusarium species, is a widespread contaminant of grain and grain products. Knowledge about its toxicity and metabolism in the human body is crucial for any risk assessment as T-2 toxin can be detected in processed and unprocessed food samples. Cell culture studies using cells of human origin represent a potent model system to study the metabolic fate of T-2 toxin as well as the cytotoxicity in vitro. In this study the metabolism of T-2 toxin was analyzed in a cell line derived from human colon carcinoma cells (HT-29) and primary human renal proximal tubule epithelial cells (RPTEC) using high-performance liquid chromatography coupled with Fourier transformation mass spectrometry (HPLC-FTMS). Both cell types metabolized T-2 toxin to a variety of compounds. Furthermore, cell cycle analysis in RPTEC proved the apoptotic effect of T-2 toxin and its metabolites HT-2 toxin and neosolaniol in micromolar concentrations. PMID:22551244

  11. Implication of the apoptotic process in the modulation of chromosomal damages

    International Nuclear Information System (INIS)

    In this research thesis in the field of biology, the author reports that the study of radio-induced chromosomal reorganizations during cellular proliferation revealed the occurrence of other radio-induced 'de novo' chromosomal anomalies present in the lineage of irradiated cells. Three cellular models have been studied. The obtained results show the role on a short term of the apoptosis in maintaining chromosomal damages, an inhibition of this death process along with an increase of the number of aberration in the first cellular generations following an irradiation or an extended exposure to H2O2. But the apoptotic process does not seem to influence the appearance of chromosomal damages on a long term. The author concludes that apoptosis as an early response to a stress, and chromosomal unsteadiness as a late response are not directly associated

  12. Conformational Heterogeneity of Bax Helix 9 Dimer for Apoptotic Pore Formation

    Science.gov (United States)

    Liao, Chenyi; Zhang, Zhi; Kale, Justin; Andrews, David W.; Lin, Jialing; Li, Jianing

    2016-07-01

    Helix α9 of Bax protein can dimerize in the mitochondrial outer membrane (MOM) and lead to apoptotic pores. However, it remains unclear how different conformations of the dimer contribute to the pore formation on the molecular level. Thus we have investigated various conformational states of the α9 dimer in a MOM model — using computer simulations supplemented with site-specific mutagenesis and crosslinking of the α9 helices. Our data not only confirmed the critical membrane environment for the α9 stability and dimerization, but also revealed the distinct lipid-binding preference of the dimer in different conformational states. In our proposed pathway, a crucial iso-parallel dimer that mediates the conformational transition was discovered computationally and validated experimentally. The corroborating evidence from simulations and experiments suggests that, helix α9 assists Bax activation via the dimer heterogeneity and interactions with specific MOM lipids, which eventually facilitate proteolipidic pore formation in apoptosis regulation.

  13. Conformational Heterogeneity of Bax Helix 9 Dimer for Apoptotic Pore Formation.

    Science.gov (United States)

    Liao, Chenyi; Zhang, Zhi; Kale, Justin; Andrews, David W; Lin, Jialing; Li, Jianing

    2016-01-01

    Helix α9 of Bax protein can dimerize in the mitochondrial outer membrane (MOM) and lead to apoptotic pores. However, it remains unclear how different conformations of the dimer contribute to the pore formation on the molecular level. Thus we have investigated various conformational states of the α9 dimer in a MOM model - using computer simulations supplemented with site-specific mutagenesis and crosslinking of the α9 helices. Our data not only confirmed the critical membrane environment for the α9 stability and dimerization, but also revealed the distinct lipid-binding preference of the dimer in different conformational states. In our proposed pathway, a crucial iso-parallel dimer that mediates the conformational transition was discovered computationally and validated experimentally. The corroborating evidence from simulations and experiments suggests that, helix α9 assists Bax activation via the dimer heterogeneity and interactions with specific MOM lipids, which eventually facilitate proteolipidic pore formation in apoptosis regulation. PMID:27381287

  14. Defining the Apoptotic Trigger: THE INTERACTION OF CYTOCHROME c AND CARDIOLIPIN.

    Science.gov (United States)

    O'Brien, Evan S; Nucci, Nathaniel V; Fuglestad, Brian; Tommos, Cecilia; Wand, A Joshua

    2015-12-25

    The interaction between cytochrome c and the anionic lipid cardiolipin has been proposed as a primary event in the apoptotic signaling cascade. Numerous studies that have examined the interaction of cytochrome c with cardiolipin embedded in a variety of model phospholipid membranes have suggested that partial unfolding of the protein is a precursor to the apoptotic response. However, these studies lacked site resolution and used model systems with negligible or a positive membrane curvature, which is distinct from the large negative curvature of the invaginations of the inner mitochondrial membrane where cytochrome c resides. We have used reverse micelle encapsulation to mimic the potential effects of confinement on the interaction of cytochrome c with cardiolipin. Encapsulation of oxidized horse cytochrome c in 1-decanoyl-rac-glycerol/lauryldimethylamine-N-oxide/hexanol reverse micelles prepared in pentane yields NMR spectra essentially identical to the protein in free aqueous solution. The structure of encapsulated ferricytochrome c was determined to high precision (bb ∼ 0.23 Å) using NMR-based methods and is closely similar to the cryogenic crystal structure (bb ∼ 1.2 Å). Incorporation of cardiolipin into the reverse micelle surfactant shell causes localized chemical shift perturbations of the encapsulated protein, providing the first view of the cardiolipin/cytochrome c interaction interface at atomic resolution. Three distinct sites of interaction are detected: the so-called A- and L-sites, plus a previously undocumented interaction centered on residues Phe-36, Gly-37, Thr-58, Trp-59, and Lys-60. Importantly, in distinct contrast to earlier studies of this interaction, the protein is not significantly disturbed by the binding of cardiolipin in the context of the reverse micelle. PMID:26487716

  15. An in vivo root hair assay for determining rates of apoptotic-like programmed cell death in plants

    Directory of Open Access Journals (Sweden)

    Hogg Bridget V

    2011-12-01

    Full Text Available Abstract In Arabidopsis thaliana we demonstrate that dying root hairs provide an easy and rapid in vivo model for the morphological identification of apoptotic-like programmed cell death (AL-PCD in plants. The model described here is transferable between species, can be used to investigate rates of AL-PCD in response to various treatments and to identify modulation of AL-PCD rates in mutant/transgenic plant lines facilitating rapid screening of mutant populations in order to identify genes involved in AL-PCD regulation.

  16. Freezing and post-thaw apoptotic behaviour of cells in the presence of palmitoyl nanogold particles

    Energy Technology Data Exchange (ETDEWEB)

    Thirumala, Sreedhar [Department of Mechanical Engineering, Louisiana State University, Baton Rouge, LA (United States); Forman, Julianne M [Department of Biological and Agricultural Engineering, Louisiana State University and Agricultural Center, Baton Rouge, LA (United States); Monroe, W Todd [Department of Biological and Agricultural Engineering, Louisiana State University and Agricultural Center, Baton Rouge, LA (United States); Devireddy, Ram V [Department of Mechanical Engineering, Louisiana State University, Baton Rouge, LA (United States)

    2007-05-16

    The aim of this study was to evaluate the freezing response of HeLa and Jurkat cells in the presence of commercially available nanoparticles, NPs (Palmitoyl Nanogold[reg], Nanoprobes). The cells were incubated with NPs for either 5 min or 3 h, and a calorimeter technique was then used to generate the volumetric shrinkage response during freezing at 20 deg. C min{sup -1}. Concomitantly, we also examined the effect of a commonly used cryoprotectant, dimethylsulfoxide, DMSO (10% v/v ratio) on the freezing response of HeLa and Jurkat cells. By fitting a model of water transport to the experimentally determined volumetric shrinkage data, the reference hydraulic conductivity, L{sub pg} ({mu}m/min-atm) and activation energy, E{sub Lp} (kcal mol{sup -1}) were obtained. For HeLa cells, the values of L{sub pg} ranged from 0.08 to 0.23 {mu}m/min-atm, while E{sub Lp} ranged from 10.9 to 37.4 kcal mol{sup -1}. For Jurkat cells these parameter values ranged from 0.05 to 0.16 {mu}m/min-atm and 9.5 to 35.9 kcal mol{sup -1}. A generic optimal cooling rate equation was then used to predict the optimal rates of freezing HeLa and Jurkat cells in the presence and absence of DMSO and NPs. The post-thaw viability and apoptotic response of HeLa and Jurkat cells was further investigated by cooling cells at three rates in the presence and absence of DMSO and NPs using a commercially available controlled rate freezer. Jurkat cells treated in this manner demonstrated an increase in their adhesive properties after 18 h incubation and adhered strongly to the bottom of the culture plate. This observation prevented further analysis of Jurkat apoptotic and necrotic post-thaw responses. There was no significant effect of NPs or DMSO alone on HeLa cell viability prior to freezing. The post-thaw results from HeLa cells show that the NPs increased the measured post-freeze apoptotic response when cooled at 1 deg. C min{sup -1}, suggesting a possible therapeutic use of NPs in cryodestructive procedures.

  17. Rethinking Molecular Mimicry in Rheumatic Heart Disease andAutoimmune Myocarditis: Laminin, Collagen IV, CAR and B1AR as Initial Targets of Disease

    Directory of Open Access Journals (Sweden)

    Robert eRoot-Bernstein

    2014-08-01

    Full Text Available Rationale: Molecular mimicry theory (MMT suggests that epitope mimicry between pathogens and human proteins can activate autoimmune disease. Group A streptococci (GAS mimics human cardiac myosin in rheumatic heart disease (RHD and coxsackie viruses (CX mimic actin in autoimmune myocarditis (AM. But myosin and actin are immunologically inaccessible and unlikely initial targets. Extracellular cardiac proteins that mimic GAS and CX would be more likely.Objectives: To determine whether extracellular cardiac proteins such as coxsackie and adenovirus receptor (CAR, beta 1 adrenergic receptor (B1AR, CD55/DAF, laminin, and collagen IV mimic GAS, CX and/or cardiac myosin or actin. Methods: BLAST 2.0 and LALIGN searches of the UniProt protein database were employed to identify potential molecular mimics. Quantitative ELISA was used to measure antibody cross-reactivity. Measurements: Similarities were considered to be significant if a sequence contained at least 5 identical amino acids in 10. Antibodies were considered to be cross-reactive if the binding constant had a Kd less than 10-9 M. Main Results: GAS mimics laminin, CAR and myosin. CX mimics actin and collagen IV and B1AR. The similarity search results are mirrored by antibody cross-reactivities. Additionally, antibodies against laminin recognize antibodies against collagen IV; antibodies against actin recognize antibodies against myosin, and antibodies against GAS recognize antibodies against CX. Thus, there is both mimicry of extracellular proteins and antigenic complementarity between GAS-CX in RHD/AM.Conclusions: RHD/AM may be due to combined infections of GAS with CX localize at cardiomyocytes may produce a synergistic, hyperinflammatory response that cross-reacts with laminin, collagen IV, CAR and/or B1AR. Epitope drift shifts the immune response to myosin and actin after cardiomyocytes become damaged.

  18. Hepatitis E virus ORF2 protein activates the pro-apoptotic gene CHOP and anti-apoptotic heat shock proteins.

    Directory of Open Access Journals (Sweden)

    Lijo John

    Full Text Available BACKGROUND: Hepatitis E virus (HEV is a non-enveloped plus-strand RNA virus that causes acute hepatitis. The capsid protein open reading frame 2 (ORF2 is known to induce endoplasmic reticulum stress in ORF2 expressing cells. METHODOLOGY/PRINCIPAL FINDINGS: In this study we found that HEV ORF2 activates the expression of the pro-apoptotic gene C/EBP homologous protein (CHOP. ORF2 stimulates the CHOP promoter mainly through AARE (amino acid response elements and to a minor extent the ERSE (endoplasmic reticulum stress response elements. Activating transcription factor 4 (ATF4 protein binds and activates the AARE regulatory sites of the CHOP promoter. ORF2 expression also leads to increased phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α that in turn initiates the translation of ATF4 mRNA. The pro-apoptotic gene CHOP is an important trigger to initiate endoplasmic reticulum stress induced apoptosis. However, the activation of CHOP by ORF2 in this study did not induce apoptosis, nor did BCL2-associated X protein (Bax translocate to mitochondria. Microarray analysis revealed an ORF2 specific increased expression of chaperones Hsp72, Hsp70B', and co-chaperone Hsp40. Co-immunoprecipitation (Co-IP and in silico molecular docking analysis suggests that HEV ORF2 interacts with Hsp72. In addition, Hsp72 shows nuclear accumulation in ORF2 expressing cells. CONCLUSIONS/SIGNIFICANCE: These data provide new insight into simultaneously occurring counter-acting effects of HEV ORF2 that may be part of a strategy to prevent host suicide before completion of the viral replication cycle.

  19. STAT3, p-STAT3 and HIF-1α are associated with vasculogenic mimicry and impact on survival in gastric adenocarcinoma

    OpenAIRE

    Song, Yan-Yan; SUN, LI-DAN; LIU, MIN-LI; LIU, ZHONG-LIANG; Chen, Fei; ZHANG, YING-ZHE; Zheng, Yan; Zhang, Jian-Ping

    2014-01-01

    Vasculogenic mimicry (VM) formation is important for invasion and metastasis of tumor cells in gastric adenocarcinoma (GAC). The present study aimed to investigate the association between signal transducer and activator of transcription-3 (STAT3), phosphor-STAT3 (p-STAT3), hypoxia-inducible factor-1α (HIF-1α) and VM formation in GAC, and discuss their clinical significance and correlation with the prognosis of patients with GAC. The expression levels of STAT3, p-STAT3, HIF-1α and VM were asse...

  20. GOING GLOBAL? CITY-BASED STATUS, MIMICRY, AND EXPANSION PATH IDIOSYNCRASY IN THE DIFFUSION OF A GLOBAL IDENTITY AMONG U.S. LAW FIRMS, 1980-2011

    OpenAIRE

    Eunjung Hyun

    2014-01-01

    This paper investigates the determinants and contingencies of corporate law firm’s adoption of a global form. I find that the likelihood of a U.S. law firm to open a foreign branch office increased with its affiliated cities’ level of status up to a point and then decreased during the period of 1980-2011. To further assess whether some of the rush to go global is generated by contagion-driven competitive mimicry, I also examined the influence of structurally equivalent firms – firms that are ...

  1. Sperm midpiece apoptotic markers: impact on fertilizing potential in in vitro fertilization and intracytoplasmic sperm injection.

    Science.gov (United States)

    Talarczyk-Desole, Joanna; Kotwicka, Małgorzata; Jendraszak, Magdalena; Pawelczyk, Leszek; Murawski, Marek; Jędrzejczak, Piotr

    2016-04-01

    The aim of this study was to investigate the relationship between apoptotic markers present in human spermatozoa, namely phosphatidylserine translocation (PST) from the inner to the outer layer of the cytomembrane and the active form of caspase-3 (c3) versus the fertilizing potential of male gametes in conventional in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) models. A total of 116 male patients treated with their partners for infertility underwent basic semen analysis and an assessment of the presence of PST and the active c3 in sperm using flow cytometry. Forty patients underwent IVF, group A, while 76 patients underwent ICSI, group B. The fertilizing potential of the gametes was measured as the percentage of oocytes with pronuclei present after either procedure. PST and active c3 were identified in vital gametes, mainly in the midpiece area. Concentration, motility, morphology, and viability of spermatozoa strongly negatively correlated with both markers. In group A, a negative correlation between both markers and the success rate of conventional IVF was observed (r = -0.4, p = 0.04 for PST; r = -0.4, p = 0.02 for active c3, respectively). In group B, the success rate of ICSI did not correlate with either marker (r = -0.2, p = 0.85 for PST and r = 0.1, p = 0.51 for active c3). The two apoptotic markers localized in the sperm midpiece area may affect their function not only by decreasing basic andrologic parameters but also by reducing the probability of conception. Therefore, analysis of PST and active c3 in the sperm of patients undergoing infertility treatment should be recommended. PMID:26791536

  2. Evaluation of Arsenic Trioxide Potential for Lung Cancer Treatment: Assessment of Apoptotic Mechanisms and Oxidative Damage

    Science.gov (United States)

    Walker, Alice M; Stevens, Jacqueline J; Ndebele, Kenneth; Tchounwou, Paul B

    2016-01-01

    Background Lung cancer is one of the most lethal and common cancers in the world, causing up to 3 million deaths annually. The chemotherapeutic drugs that have been used in treating lung cancer include cisplatin-pemetrexed, cisplastin-gencitabinoe, carboplatin-paclitaxel and crizotinib. Arsenic trioxide (ATO) has been used in the treatment of acute promyelocytic leukemia. However, its effects on lung cancer are not known. We hypothesize that ATO may also have a bioactivity against lung cancer, and its mechanisms of action may involve apoptosis, DNA damage and changes in stress-related proteins in lung cancer cells. Methods To test the above stated hypothesis, lung carcinoma (A549) cells were used as the test model. The effects of ATO were examined by performing 6-diamidine-2 phenylindole (DAPI) nuclear staining for morphological characterization of apoptosis, flow cytometry analysis for early apoptosis, and western blot analysis for stress-related proteins (Hsp70 and cfos) and apoptotic protein expressions. Also, the single cell gel electrophoresis (Comet) assay was used to evaluate the genotoxic effect. Results ATO-induced apoptosis was evidenced by chromatin condensation and formation of apoptotic bodies as revealed by DAPI nuclear staining. Cell shrinkage and membrane blebbing were observed at 4 and 6 µg/ml of ATO. Data from the western blot analysis revealed a significant dose-dependent increase (p < 0.05) in the Hsp 70, caspase 3 and p53 protein expression, and a significant (p < 0.05) decrease in the cfos, and bcl-2 protein expression at 4 and 6 µg/ml of ATO. There was a slight decrease in cytochrome c protein expression at 4 and 6 µg/ ml of ATO. Comet assay data revealed significant dose-dependent increases in the percentages of DNA damage, Comet tail lengths, and Comet tail moment. Conclusion Taken together our results indicate that ATO is cytotoxic to lung cancer cells and its bioactivity is associated with oxidative damage, changes in cellular

  3. Structure-based redesign of the binding specificity of anti-apoptotic Bcl-x(L).

    Science.gov (United States)

    Chen, T Scott; Palacios, Hector; Keating, Amy E

    2013-01-01

    Many native proteins are multi-specific and interact with numerous partners, which can confound analysis of their functions. Protein design provides a potential route to generating synthetic variants of native proteins with more selective binding profiles. Redesigned proteins could be used as research tools, diagnostics or therapeutics. In this work, we used a library screening approach to reengineer the multi-specific anti-apoptotic protein Bcl-x(L) to remove its interactions with many of its binding partners, making it a high-affinity and selective binder of the BH3 region of pro-apoptotic protein Bad. To overcome the enormity of the potential Bcl-x(L) sequence space, we developed and applied a computational/experimental framework that used protein structure information to generate focused combinatorial libraries. Sequence features were identified using structure-based modeling, and an optimization algorithm based on integer programming was used to select degenerate codons that maximally covered these features. A constraint on library size was used to ensure thorough sampling. Using yeast surface display to screen a designed library of Bcl-x(L) variants, we successfully identified a protein with ~1000-fold improvement in binding specificity for the BH3 region of Bad over the BH3 region of Bim. Although negative design was targeted only against the BH3 region of Bim, the best redesigned protein was globally specific against binding to 10 other peptides corresponding to native BH3 motifs. Our design framework demonstrates an efficient route to highly specific protein binders and may readily be adapted for application to other design problems. PMID:23154169

  4. Multimodal Interaction with BCL-2 Family Proteins Underlies the Pro-Apoptotic Activity of PUMA BH3

    OpenAIRE

    Edwards, Amanda L.; Gavathiotis, Evripidis; LaBelle, James L.; Braun, Craig R.; Opoku-Nsiah, Kwadwo A.; Bird, Gregory H.; Walensky, Loren D.

    2013-01-01

    PUMA is a pro-apoptotic BCL-2 family member that drives the apoptotic response to a diversity of p53-dependent and independent cellular insults. Deciphering the spectrum of PUMA interactions that confer its context-dependent pro-apoptotic properties remains a high priority goal. Here, we report the synthesis of PUMA SAHBs, structurally-stabilized PUMA BH3 helices that, in addition to broadly targeting anti-apoptotic proteins, directly bind to BAX. NMR, photocrosslinking, and biochemical analy...

  5. The replication of human immunodeficiency virus type 1 in macrophages is enhanced after phagocytosis of apoptotic cells

    OpenAIRE

    Lima, Rosangela G; Van Weyenbergh, Johan; Saraiva, Elvira M. B.; Barral-Netto, Manoel; Galvão-Castro, Bernardo; Bou-Habib, Dumith Chequer

    2002-01-01

    Clearance of apoptotic cells increases macrophage secretion of antiinflammatory mediators and might modulate viral replication in human immunodeficiency virus (HIV) type 1-infected macrophages. To study this, primary macrophages were infected with HIV-1 and exposed to apoptotic cells. It was found that phagocytosis of apoptotic cells potently enhanced HIV-1 growth. The peptide Arg-Gly-Asp-Ser, which binds to integrin receptors, inhibited the uptake of apoptotic cells and the subsequent enhanc...

  6. Systems analysis reveals down-regulation of a network of pro-survival miRNAs drives the apoptotic response in dilated cardiomyopathy

    Science.gov (United States)

    Isserlin, Ruth; Merico, Daniele; Wang, Dingyan; Vuckovic, Dajana; Bousette, Nicolas; Gramolini, Anthony O.; Bader, Gary D.; Emili, Andrew

    2016-01-01

    Apoptosis is a hallmark of multiple etiologies of heart failure, including dilated cardiomyopathy. Since microRNAs are master regulators of cardiac development and key effectors of intracellular signaling, they represent novel candidates for understanding the mechanisms driving the increased dysfunction and loss of cardiomyocytes during cardiovascular disease progression. To determine the role of cardiac miRNAs in the apoptotic response, we used microarray technology to monitor miRNA levels in a validated murine phospholambam mutant model of dilated cardiomyopathy. 24 miRNAs were found to be differentially expressed, most of which have not been previously linked to dilated cardiomyopathy. We showed that individual silencing of 7 out of 8 significantly down-regulated miRNAs (mir-1, −29c, −30c, −30d, −149, −486, −499) led to a strong apoptotic phenotype in cell culture, suggesting they repress pro-apoptotic factors. To identify putative miRNA targets most likely relevant to cell death, we computationally integrated transcriptomic, proteomic and functional annotation data. We showed the dependency of prioritized target abundance on miRNA expression using RNA interference and quantitative mass spectrometry. We concluded that down regulation of key pro-survival miRNAs causes up-regulation of apoptotic signaling effectors that contribute to cardiac cell loss, potentially leading to system decompensation and heart failure. PMID:25361207

  7. Bak apoptotic function is not directly regulated by phosphorylation.

    Science.gov (United States)

    Tran, V H; Bartolo, R; Westphal, D; Alsop, A; Dewson, G; Kluck, R M

    2013-01-01

    During apoptosis, Bak and Bax permeabilize the mitochondrial outer membrane by undergoing major conformational change and oligomerization. This activation process in Bak is reported to require dephosphorylation of tyrosine-108 close to an activation trigger site. To investigate how dephosphorylation of Bak contributes to its activation and conformational change, one-dimensional isoelectric focusing (1D-IEF) and mutagenesis was used to monitor Bak phosphorylation. On 1D-IEF, Bak extracted from a range of cell types migrated as a single band near the predicted isoelectric point of 5.6 both before and after phosphatase treatment, indicating that Bak is not significantly phosphorylated at any residue. In contrast, three engineered 'phosphotagged' Bak variants showed a second band at lower pI, indicating phosphorylation. Apoptosis induced by several stimuli failed to alter Bak pI, indicating little change in phosphorylation status. In addition, alanine substitution of tyrosine-108 and other putative phosphorylation sites failed to enhance Bak activation or pro-apoptotic function. In summary, Bak is not significantly phosphorylated at any residue, and Bak activation during apoptosis does not require dephosphorylation. PMID:23303126

  8. Thyroid hormone regulation of apoptotic tissue remodeling during anuran metamorphosis

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Anuran metamorphosis involves systematic transformations of individual organs in a thyroid hormone (TH)-dependent manner. Morphological and cellular studies have shown that the removal of larval or gans/tissues such the tail and the tadpole intestinal epithelium is through programmed cell death or apop tosis. Recent molecular investigations suggest that TH regulates metamorphosis by regulating target gene expression through thyroid hormone receptors (TRs), which are DNA-binding transcription factors. Cloning and characterization of TH response genes show that diverse groups of early response genes are induced by TH. The products of these TH response genes are believed to directly or indirectly affect the expression and/or functions of cell death genes, which are conserved at both sequence and function levels in different animal species. A major challenge for future research lies at determining the signaling pathways leading to the activation of apoptotic processes and whether different death genes are involved in the regulation of apoptosis in different tissues/organs to effect tissue-specific transformations.

  9. Genotoxic and apoptotic effects of Goeckerman therapy for psoriasis

    Energy Technology Data Exchange (ETDEWEB)

    Borska, L.; Andrys, C.; Krejsek, J.; Hamakova, K.; Kremlacek, J.; Palicka, V.; Ranna, D.; Fiala, Z. [Charles University Prague, Prague (Czech Republic). Faculty of Medicine

    2010-03-15

    Goeckerman therapy (GT) for psoriasis is based on cutaneous application of crude coal tar (polycyclic aromatic hydrocarbons (PAH)) and exposure to ultraviolet radiation (UVR). PAH and UVR are mutagenic, carcinogenic and immunotoxic agents that promote apoptosis. We evaluated dermal absorption of PAH as well as the genotoxic and apoptotic effects of GT in 20 patients with psoriasis, by determining numbers of chromosomal abnormalities in peripheral lymphocytes, and levels of 1-hydroxypyrene (1-OHP), p53 protein and soluble FasL (sFasL) in urine and/or blood, before and after GT. Psoriasis Area and Severity Index (PASI) score was used to evaluate clinical efficacy of GT. Compared with pre-treatment levels, there was a significant increase in urine 1-OHP, indicating a high degree of dermal absorption of PAH (P <0.01). We also found a significant increase in the number of chromosomal abnormalities in peripheral blood lymphocytes (P <0.001), suggesting that GT is genotoxic; significantly increased p53 protein in plasma (P <0.05), an indicator of cell response to DNA damage; and significantly increased sFasL in serum (P <0.01), an indicator of apoptosis. The PASI score was significantly decreased after GT (P <0.001), confirming clinical benefit of this treatment. Our results demonstrate high dermal absorption of PAH during GT and provide evidence that GT promotes genotoxicity and apoptosis.

  10. Apoptotic cells trigger a membrane-initiated pathway to increase ABCA1.

    Science.gov (United States)

    Fond, Aaron M; Lee, Chang Sup; Schulman, Ira G; Kiss, Robert S; Ravichandran, Kodi S

    2015-07-01

    Macrophages clear millions of apoptotic cells daily and, during this process, take up large quantities of cholesterol. The membrane transporter ABCA1 is a key player in cholesterol efflux from macrophages and has been shown via human genetic studies to provide protection against cardiovascular disease. How the apoptotic cell clearance process is linked to macrophage ABCA1 expression is not known. Here, we identified a plasma membrane-initiated signaling pathway that drives a rapid upregulation of ABCA1 mRNA and protein. This pathway involves the phagocytic receptor brain-specific angiogenesis inhibitor 1 (BAI1), which recognizes phosphatidylserine on apoptotic cells, and the intracellular signaling intermediates engulfment cell motility 1 (ELMO1) and Rac1, as ABCA1 induction was attenuated in primary macrophages from mice lacking these molecules. Moreover, this apoptotic cell-initiated pathway functioned independently of the liver X receptor (LXR) sterol-sensing machinery that is known to regulate ABCA1 expression and cholesterol efflux. When placed on a high-fat diet, mice lacking BAI1 had increased numbers of apoptotic cells in their aortic roots, which correlated with altered lipid profiles. In contrast, macrophages from engineered mice with transgenic BAI1 overexpression showed greater ABCA1 induction in response to apoptotic cells compared with those from control animals. Collectively, these data identify a membrane-initiated pathway that is triggered by apoptotic cells to enhance ABCA1 within engulfing phagocytes and with functional consequences in vivo. PMID:26075824

  11. Parameter identification using stochastic simulations reveals a robustness in CD95 apoptotic response.

    Science.gov (United States)

    Zimmer, Christoph; Schleich, Kolja; Lavrik, Inna

    2016-04-26

    A number of mathematical models of apoptosis generated recently allowed us to understand intrinsic mechanisms of life/death decisions in a cell. Nevertheless, the parameters for the mathematical models are often experimentally difficult to obtain and there is an emerging need for the development of efficient approaches for parameter estimation. In this study we suggest a new method for parameter estimation, which is based on stochastic simulations and can be used when the number of molecules in the system is small. Our approach comprised the following steps: we start from the selection of parameters that lead to a good ordinary differential equation (ODE) fit. We continued by carrying out stochastic simulations for each of these parameters. Comparing the correlation structure of these simulations with the data, we finally could identify the best parameter set. The method was applied for a model of CD95-induced apoptosis, the new best identified parameters fit well to the experimental data. The best parameter set allowed us to get new insights into CD95 apoptosis regulation and can be applied for the comprehensive analysis of other signaling networks. The modeling approach allowed us to get new insights into network regulation, in particular, to identify robustness in CD95 apoptotic response. Taken together, this new method provides valuable predictions and can be applied for the analysis of other signaling networks. PMID:27004466

  12. Scorpion-Toxin Mimics of CD4 in Complex with Human Immunodeficiency Virus gp120: Crystal Structures, Molecular Mimicry, and Neutralization Breadth

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Chih-chin; Stricher, Francois; Martin, Loic; Decker, Julie M.; Majeed, Shahzad; Barthe, Phillippe; Hendrickson, Wayne A.; Robinson, James; Roumestand, Christian; Sodroski, Joseph; Wyatt, Richard; Shaw, George M.; Vita, Claudio; Kwong, Peter D. (Havard-Med); (NIH); (UAB); (Columbia); (CEA Saclay); (Tulane); (Faculty of Pharmacy)

    2010-07-19

    The binding surface on CD4 for the HIV-1 gp120 envelope glycoprotein has been transplanted previously onto a scorpion-toxin scaffold. Here, we use X-ray crystallography to characterize atomic-level details of gp120 with this transplant, CD4M33. Despite known envelope flexibility, the conformation of gp120 induced by CD4M33 was so similar to that induced by CD4 that localized measures were required to distinguish ligand-induced differences from lattice variation. To investigate relationships between structure, function, and mimicry, an F23 analog of CD4M33 was devised. Structural and thermodynamic analyses showed F23 to be a better molecular mimic of CD4 than CD4M33. F23 also showed increased neutralization breadth, against diverse isolates of HIV-1, HIV-2, and SIVcpz. Our results lend insight into the stability of the CD4 bound conformation of gp120, define measures that quantify molecular mimicry as a function of evolutionary distance, and suggest how such evaluations might be useful in developing mimetic antagonists with increased neutralization breadth.

  13. Preclinical studies identify non-apoptotic low-level caspase-3 as therapeutic target in pemphigus vulgaris.

    Directory of Open Access Journals (Sweden)

    Camille Luyet

    Full Text Available The majority of pemphigus vulgaris (PV patients suffer from a live-threatening loss of intercellular adhesion between keratinocytes (acantholysis. The disease is caused by auto-antibodies that bind to desmosomal cadherins desmoglein (Dsg 3 or Dsg3 and Dsg1 in mucous membranes and skin. A currently unresolved controversy in PV is whether apoptosis is involved in the pathogenic process. The objective of this study was to perform preclinical studies to investigate apoptotic pathway activation in PV pathogenesis with the goal to assess its potential for clinical therapy. For this purpose, we investigated mouse and human skin keratinocyte cultures treated with PV antibodies (the experimental Dsg3 monospecific antibody AK23 or PV patients IgG, PV mouse models (passive transfer of AK23 or PVIgG into adult and neonatal mice as well as PV patients' biopsies (n=6. A combination of TUNEL assay, analyses of membrane integrity, early apoptotic markers such as cleaved poly-ADP-ribose polymerase (PARP and the collapse of actin cytoskeleton failed to provide evidence for apoptosis in PV pathogenesis. However, the in vitro and in vivo PV models, allowing to monitor progression of lesion formation, revealed an early, transient and low-level caspase-3 activation. Pharmacological inhibition confirmed the functional implication of caspase-3 in major events in PV such as shedding of Dsg3, keratin retraction, proliferation including c-Myc induction, p38MAPK activation and acantholysis. Together, these data identify low-level caspase-3 activation downstream of disrupted Dsg3 trans- or cis-adhesion as a major event in PV pathogenesis that is non-synonymous with apoptosis and represents, unlike apoptotic components, a promising target for clinical therapy. At a broader level, these results posit that an impairment of adhesive functions in concert with low-level, non-lethal caspase-3 activation can evoke profound cellular changes which may be of relevance for other

  14. Crystal Structure of CRN-4: Implications for Domain Function in Apoptotic DNA Degradation▿

    OpenAIRE

    Hsiao, Yu-Yuan; Nakagawa, Akihisa; Shi, Zhonghao; Mitani, Shohei; Xue, Ding; Yuan, Hanna S.

    2008-01-01

    Cell death related nuclease 4 (CRN-4) is one of the apoptotic nucleases involved in DNA degradation in Caenorhabditis elegans. To understand how CRN-4 is involved in apoptotic DNA fragmentation, we analyzed CRN-4's biochemical properties, in vivo cell functions, and the crystal structures of CRN-4 in apo-form, Mn2+-bound active form, and Er3+-bound inactive form. CRN-4 is a dimeric nuclease with the optimal enzyme activity in cleaving double-stranded DNA in apoptotic salt conditions. Both mut...

  15. Interaction of a putative BH3 domain of clusterin with anti-apoptotic Bcl-2 family proteins as revealed by NMR spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Dong-Hwa; Ha, Ji-Hyang [Medical Proteomics Research Center, KRIBB, Daejeon 305-806 (Korea, Republic of); Kim, Yul [Department of Bio and Brain Engineering, KAIST, Daejeon 305-701 (Korea, Republic of); Bae, Kwang-Hee [Medical Proteomics Research Center, KRIBB, Daejeon 305-806 (Korea, Republic of); Park, Jae-Yong [Department of Physiology, Institute of Health Science, School of Medicine, Gyeongsang National University, Jinju, Gyeongnam 660-751 (Korea, Republic of); Choi, Wan Sung [Department of Anatomy and Neurobiology, Institute of Health Science, School of Medicine, Gyeongsang National University, Jinju, Gyeongnam 660-751 (Korea, Republic of); Yoon, Ho Sup [Division of Structural and Computational Biology, School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637511 (Singapore); Park, Sung Goo; Park, Byoung Chul [Medical Proteomics Research Center, KRIBB, Daejeon 305-806 (Korea, Republic of); Yi, Gwan-Su, E-mail: gsyi@kaist.ac.kr [Department of Bio and Brain Engineering, KAIST, Daejeon 305-701 (Korea, Republic of); Chi, Seung-Wook, E-mail: swchi@kribb.re.kr [Medical Proteomics Research Center, KRIBB, Daejeon 305-806 (Korea, Republic of)

    2011-05-20

    Highlights: {yields} Identification of a conserved BH3 motif in C-terminal coiled coil region of nCLU. {yields} The nCLU BH3 domain binds to BH3 peptide-binding grooves in both Bcl-X{sub L} and Bcl-2. {yields} A conserved binding mechanism of nCLU BH3 and the other pro-apoptotic BH3 peptides with Bcl-X{sub L}. {yields} The absolutely conserved Leu323 and Asp328 of nCLU BH3 domain are critical for binding to Bcl-X{sub L.} {yields} Molecular understanding of the pro-apoptotic function of nCLU as a novel BH3-only protein. -- Abstract: Clusterin (CLU) is a multifunctional glycoprotein that is overexpressed in prostate and breast cancers. Although CLU is known to be involved in the regulation of apoptosis and cell survival, the precise molecular mechanism underlying the pro-apoptotic function of nuclear CLU (nCLU) remains unclear. In this study, we identified a conserved BH3 motif in C-terminal coiled coil (CC2) region of nCLU by sequence analysis and characterized the molecular interaction of the putative nCLU BH3 domain with anti-apoptotic Bcl-2 family proteins by nuclear magnetic resonance (NMR) spectroscopy. The chemical shift perturbation data demonstrated that the nCLU BH3 domain binds to pro-apoptotic BH3 peptide-binding grooves in both Bcl-X{sub L} and Bcl-2. A structural model of the Bcl-X{sub L}/nCLU BH3 peptide complex reveals that the binding mode is remarkably similar to those of other Bcl-X{sub L}/BH3 peptide complexes. In addition, mutational analysis confirmed that Leu323 and Asp328 of nCLU BH3 domain, absolutely conserved in the BH3 motifs of BH3-only protein family, are critical for binding to Bcl-X{sub L}. Taken altogether, our results suggest a molecular basis for the pro-apoptotic function of nCLU by elucidating the residue specific interactions of the BH3 motif in nCLU with anti-apoptotic Bcl-2 family proteins.

  16. Interaction of a putative BH3 domain of clusterin with anti-apoptotic Bcl-2 family proteins as revealed by NMR spectroscopy

    International Nuclear Information System (INIS)

    Highlights: → Identification of a conserved BH3 motif in C-terminal coiled coil region of nCLU. → The nCLU BH3 domain binds to BH3 peptide-binding grooves in both Bcl-XL and Bcl-2. → A conserved binding mechanism of nCLU BH3 and the other pro-apoptotic BH3 peptides with Bcl-XL. → The absolutely conserved Leu323 and Asp328 of nCLU BH3 domain are critical for binding to Bcl-XL. → Molecular understanding of the pro-apoptotic function of nCLU as a novel BH3-only protein. -- Abstract: Clusterin (CLU) is a multifunctional glycoprotein that is overexpressed in prostate and breast cancers. Although CLU is known to be involved in the regulation of apoptosis and cell survival, the precise molecular mechanism underlying the pro-apoptotic function of nuclear CLU (nCLU) remains unclear. In this study, we identified a conserved BH3 motif in C-terminal coiled coil (CC2) region of nCLU by sequence analysis and characterized the molecular interaction of the putative nCLU BH3 domain with anti-apoptotic Bcl-2 family proteins by nuclear magnetic resonance (NMR) spectroscopy. The chemical shift perturbation data demonstrated that the nCLU BH3 domain binds to pro-apoptotic BH3 peptide-binding grooves in both Bcl-XL and Bcl-2. A structural model of the Bcl-XL/nCLU BH3 peptide complex reveals that the binding mode is remarkably similar to those of other Bcl-XL/BH3 peptide complexes. In addition, mutational analysis confirmed that Leu323 and Asp328 of nCLU BH3 domain, absolutely conserved in the BH3 motifs of BH3-only protein family, are critical for binding to Bcl-XL. Taken altogether, our results suggest a molecular basis for the pro-apoptotic function of nCLU by elucidating the residue specific interactions of the BH3 motif in nCLU with anti-apoptotic Bcl-2 family proteins.

  17. tRNA-mRNA mimicry drives translation initiation from a viral IRES.

    Science.gov (United States)

    Costantino, David A; Pfingsten, Jennifer S; Rambo, Robert P; Kieft, Jeffrey S

    2008-01-01

    Internal ribosome entry site (IRES) RNAs initiate protein synthesis in eukaryotic cells by a noncanonical cap-independent mechanism. IRESes are critical for many pathogenic viruses, but efforts to understand their function are complicated by the diversity of IRES sequences as well as by limited high-resolution structural information. The intergenic region (IGR) IRESes of the Dicistroviridae viruses are powerful model systems to begin to understand IRES function. Here we present the crystal structure of a Dicistroviridae IGR IRES domain that interacts with the ribosome's decoding groove. We find that this RNA domain precisely mimics the transfer RNA anticodon-messenger RNA codon interaction, and its modeled orientation on the ribosome helps explain translocation without peptide bond formation. When combined with a previous structure, this work completes the first high-resolution description of an IRES RNA and provides insight into how RNAs can manipulate complex biological machines. PMID:18157151

  18. tRNA–mRNA mimicry drives translation initiation from a viral IRES

    OpenAIRE

    Costantino, David A.; Pfingsten, Jennifer S; Rambo, Robert P.; Kieft, Jeffrey S.

    2007-01-01

    Internal ribosome entry site (IRES) RNAs initiate protein synthesis in eukaryotic cells by a noncanonical cap-independent mechanism. IRESes are critical for many pathogenic viruses, but efforts to understand their function are complicated by the diversity of IRES sequences as well as by limited high-resolution structural information. The intergenic region (IGR) IRESes of the Dicistroviridae viruses are powerful model systems to begin to understand IRES function. Here we present the crystal st...

  19. Macrophages programmed by apoptotic cells inhibit epithelial-mesenchymal transition in lung alveolar epithelial cells via PGE2, PGD2, and HGF

    Science.gov (United States)

    Yoon, Young-So; Lee, Ye-Ji; Choi, Youn-Hee; Park, Young Mi; Kang, Jihee Lee

    2016-01-01

    Apoptotic cell clearance results in the release of growth factors and the action of signaling molecules involved in tissue homeostasis maintenance. Here, we investigated whether and how macrophages programmed by apoptotic cells inhibit the TGF-β1-induced Epithelial-mesenchymal transition (EMT) process in lung alveolar epithelial cells. Treatment with conditioned medium derived from macrophages exposed to apoptotic cells, but not viable or necrotic cells, inhibited TGF-β1-induced EMT, including loss of E-cadherin, synthesis of N-cadherin and α-smooth muscle actin, and induction of EMT-activating transcription factors, such as Snail1/2, Zeb1/2, and Twist1. Exposure of macrophages to cyclooxygenase (COX-2) inhibitors (NS-398 and COX-2 siRNA) or RhoA/Rho kinase inhibitors (Y-27632 and RhoA siRNA) and LA-4 cells to antagonists of prostaglandin E2 (PGE2) receptor (EP4 [AH-23848]), PGD2 receptors (DP1 [BW-A868C] and DP2 [BAY-u3405]), or the hepatocyte growth factor (HGF) receptor c-Met (PHA-665752), reversed EMT inhibition by the conditioned medium. Additionally, we found that apoptotic cell instillation inhibited bleomycin-mediated EMT in primary mouse alveolar type II epithelial cells in vivo. Our data suggest a new model for epithelial cell homeostasis, by which the anti-EMT programming of macrophages by apoptotic cells may control the progressive fibrotic reaction via the production of potent paracrine EMT inhibitors. PMID:26875548

  20. Macrophages programmed by apoptotic cells inhibit epithelial-mesenchymal transition in lung alveolar epithelial cells via PGE2, PGD2, and HGF.

    Science.gov (United States)

    Yoon, Young-So; Lee, Ye-Ji; Choi, Youn-Hee; Park, Young Mi; Kang, Jihee Lee

    2016-01-01

    Apoptotic cell clearance results in the release of growth factors and the action of signaling molecules involved in tissue homeostasis maintenance. Here, we investigated whether and how macrophages programmed by apoptotic cells inhibit the TGF-β1-induced Epithelial-mesenchymal transition (EMT) process in lung alveolar epithelial cells. Treatment with conditioned medium derived from macrophages exposed to apoptotic cells, but not viable or necrotic cells, inhibited TGF-β1-induced EMT, including loss of E-cadherin, synthesis of N-cadherin and α-smooth muscle actin, and induction of EMT-activating transcription factors, such as Snail1/2, Zeb1/2, and Twist1. Exposure of macrophages to cyclooxygenase (COX-2) inhibitors (NS-398 and COX-2 siRNA) or RhoA/Rho kinase inhibitors (Y-27632 and RhoA siRNA) and LA-4 cells to antagonists of prostaglandin E2 (PGE2) receptor (EP4 [AH-23848]), PGD2 receptors (DP1 [BW-A868C] and DP2 [BAY-u3405]), or the hepatocyte growth factor (HGF) receptor c-Met (PHA-665752), reversed EMT inhibition by the conditioned medium. Additionally, we found that apoptotic cell instillation inhibited bleomycin-mediated EMT in primary mouse alveolar type II epithelial cells in vivo. Our data suggest a new model for epithelial cell homeostasis, by which the anti-EMT programming of macrophages by apoptotic cells may control the progressive fibrotic reaction via the production of potent paracrine EMT inhibitors. PMID:26875548

  1. Gene delivery of the elastase inhibitor elafin protects macrophages from neutrophil elastase-mediated impairment of apoptotic cell recognition.

    Science.gov (United States)

    Henriksen, Peter A; Devitt, Andrew; Kotelevtsev, Yuri; Sallenave, Jean-Michel

    2004-09-10

    The resolution of inflammation is dependent on recognition and phagocytic removal of apoptotic cells by macrophages. Receptors for apoptotic cells are sensitive to degradation by human neutrophil elastase (HNE). We show in the present study that HNE cleaves macrophage cell surface CD14 and in so doing, reduces phagocytic recognition of apoptotic lymphocytic cells (Mutu 1). Using an improved method of adenovirus-mediated transfection of macrophages with the HNE inhibitor elafin, we demonstrate that elafin overexpression prevents CD14 cleavage and restores apoptotic cell recognition by macrophages. This approach of genetic modification of macrophages could be used to restore apoptotic cell recognition in inflammatory conditions. PMID:15358543

  2. Maternal epileptic seizure induced by Pentylenetetrazol: Apoptotic neurodegeneration and decreased GABAB1 receptor expression in prenatal rat brain

    Directory of Open Access Journals (Sweden)

    Naseer Muhammad

    2009-06-01

    Full Text Available Abstract Epilepsy is a prominent sign of neurological dysfunction in children with various fetal and maternal deficiencies. However, the detailed mechanism and influences underlying epileptic disorders are still unrevealed. The hippocampal neurons are vulnerable to epilepsy-induced pathologic changes and often manifests as neuronal death. The present study was designed to investigate the effect of maternal epileptic seizure on apoptotic neuronal death, modulation of GABAB1 receptor (R, and protein kinase A-α (PKA in prenatal rat hippocampal neurons at gestational days (GD 17.5. Seizure was induced in pregnant rat using intraperitoneal injection of pentylenetetrazol (PTZ (40 mg/kg for 15 days. To confirm the seizure electroencephalography (EEG data was obtained by the Laxtha EEG-monitoring device in the EEG recording room and EEG were monitored 5 min and 15 min after PTZ injection. The RT-PCR and Western blot results showed significant increased expression of cytochrome-c and caspases-3, while decreased levels of GABAB1R, and PKA protein expression upon ethanol, PTZ and ethanol plus PTZ exposure in primary neuronal cells cultured from PTZ-induced seizure model as compare to non-PTZ treated maternal group. Apoptotic neurodegeneration was further confirmed with Fluoro-Jade B and propidium iodide staining, where neurons were scattered and shrunken, with markedly condensed nuclei in PTZ treated group compared with control. This study for the first time indicate that PTZ-induced seizures triggered activation of caspases-3 to induce widespread apoptotic neuronal death and decreased GABAB1R expression in hippocampal neurons, providing a possible mechanistic link between maternal epilepsy induced neurodegeneration alteration of GABAB1R and PKA expression level during prenatal brain development. This revealed new aspects of PTZ and ethanol's modulation on GABAB1R, learning and memory. Further, explain the possibility that children delivered by epileptic

  3. Docetaxel induces Bcl-2- and pro-apoptotic caspase-independent death of human prostate cancer DU145 cells.

    Science.gov (United States)

    Ogura, Takeharu; Tanaka, Yoshiyuki; Tamaki, Hiroki; Harada, Mamoru

    2016-06-01

    Docetaxel is a useful chemotherapeutic agent for the first-line treatment of hormone-refractory prostate cancer. Abnormal expression of Bcl-2 is commonly found in cancer cells, which increases their anti-apoptotic potency and chemoresistance. We investigated the effects of Bcl-2 expression status on the susceptibility of DU145 cells, an androgen-independent human prostate cancer cell line, to docetaxel and other anticancer agents. A panel of Bcl-2-expressing DU145 cell lines was established. Bcl-2 expression levels were unrelated to the susceptibility of DU145 cells to docetaxel. The sensitivity of DU145 cells to cisplatin fluctuated, and the sensitivity to tumor necrosis factor (TNF)-α was decreased by Bcl-2 overexpression. In a xenograft mouse model, overexpression of Bcl-2 drastically decreased the sensitivity of DU145 cells to cisplatin and TNF-α; however, there was no change in the response to docetaxel. Fluorescent microscopy revealed that Bcl-2-overexpression had no effect on the docetaxel-induced death of DU145 cells, but significantly decreased DU145 cell death induced by cisplatin or TNF-α. Interestingly, docetaxel hardly induced caspase-3/7 activation in control or Bcl-2-overexpressing DU145 cells, but did at a low level in LNCaP cells, another prostate cancer cell line. Moreover, in contrast to LNCaP cells, the reduced viabilities of docetaxel-treated control and Bcl-2-overexpressing DU145 cells were not restored by the addition of either a Bid inhibitor or a panel of pro-apoptotic caspase inhibitors. These findings indicate that the antitumor effects of docetaxel on DU145 cells are independent of both Bcl-2 and pro-apoptotic caspases. PMID:27082738

  4. Regulation of apoptotic mediators reveals dynamic responses to thermal stress in the reef building coral Acropora millepora.

    Directory of Open Access Journals (Sweden)

    Mathieu Pernice

    Full Text Available BACKGROUND: Mass coral bleaching is increasing in scale and frequency across the world's coral reefs and is being driven primarily by increased levels of thermal stress arising from global warming. In order to understand the impacts of projected climate change upon corals reefs, it is important to elucidate the underlying cellular mechanisms that operate during coral bleaching and subsequent mortality. In this respect, increased apoptotic cell death activity is an important cellular process that is associated with the breakdown of the mutualistic symbiosis between the cnidarian host and their dinoflagellate symbionts. METHODOLOGY/PRINCIPAL FINDINGS: The PRESENT study reports the impacts of different stressors (colchicine and heat stress on three phases of apoptosis: (i the potential initiation by differential expression of Bcl-2 members, (ii the execution of apoptotic events by activation of caspase 3-like proteases and (iii and finally, the cell disposal indicated by DNA fragmentation in the reef building coral Acropora millepora. In corals incubated with colchicine, an increase in caspase 3-like activity and DNA fragmentation was associated with a relative down-regulation of Bcl-2, suggesting that the initiation of apoptosis may be mediated by the suppression of an anti-apoptotic mechanism. In contrast, in the early steps of heat stress, the induction of caspase-dependent apoptosis was related to a relative up-regulation of Bcl-2 consecutively followed by a delayed decrease in apoptosis activity. CONCLUSIONS/SIGNIFICANCE: In the light of these results, we propose a model of heat stress in coral hosts whereby increasing temperatures engage activation of caspase 3-dependent apoptosis in cells designated for termination, but also the onset of a delayed protective response involving overexpression of Bcl-2 in surviving cells. This mitigating response to thermal stress could conceivably be an important regulatory mechanism for cell survival in

  5. Structural insights into the transcription-independent apoptotic pathway of p53

    OpenAIRE

    Chi, Seung-Wook

    2014-01-01

    Reactivating the p53 pathway in tumors is an important strategy for anticancer therapy. In response to diverse cellular stresses, the tumor suppressor p53 mediates apoptosis in a transcriptionindependent and transcription-dependent manner. Although extensive studies have focused on the transcription-dependent apoptotic pathway of p53, the transcription-independent apoptotic pathway of p53 has only recently been discovered. Molecular interactions between p53 and Bcl-2 family proteins in the mi...

  6. Apoptotic cells trigger a membrane-initiated pathway to increase ABCA1

    OpenAIRE

    Fond, Aaron M.; Lee, Chang Sup; Schulman, Ira G.; Kiss, Robert S.; Ravichandran, Kodi S.

    2015-01-01

    Macrophages clear millions of apoptotic cells daily and, during this process, take up large quantities of cholesterol. The membrane transporter ABCA1 is a key player in cholesterol efflux from macrophages and has been shown via human genetic studies to provide protection against cardiovascular disease. How the apoptotic cell clearance process is linked to macrophage ABCA1 expression is not known. Here, we identified a plasma membrane–initiated signaling pathway that drives a rapid upregulatio...

  7. The role of airway macrophages in apoptotic cell clearance following acute and chronic lung inflammation.

    Science.gov (United States)

    Grabiec, Aleksander M; Hussell, Tracy

    2016-07-01

    Acute and chronic inflammatory responses in the lung are associated with the accumulation of large quantities of immune and structural cells undergoing apoptosis, which need to be engulfed by phagocytes in a process called 'efferocytosis'. Apoptotic cell recognition and removal from the lung is mediated predominantly by airway macrophages, though immature dendritic cells and non-professional phagocytes, such as epithelial cells and mesenchymal cells, can also display this function. Efficient clearance of apoptotic cells from the airways is essential for successful resolution of inflammation and the return to lung homeostasis. Disruption of this process leads to secondary necrosis of accumulating apoptotic cells, release of necrotic cell debris and subsequent uncontrolled inflammatory activation of the innate immune system by the released 'damage associated molecular patterns' (DAMPS). To control the duration of the immune response and prevent autoimmune reactions, anti-inflammatory signalling cascades are initiated in the phagocyte upon apoptotic cell uptake, mediated by a range of receptors that recognise specific phospholipids or proteins externalised on, or secreted by, the apoptotic cell. However, prolonged activation of apoptotic cell recognition receptors, such as the family of receptor tyrosine kinases Tyro3, Axl and MerTK (TAM), may delay or prevent inflammatory responses to subsequent infections. In this review, we will discuss recent advances in our understanding of the mechanism controlling apoptotic cell recognition and removal from the lung in homeostasis and during inflammation, the contribution of defective efferocytosis to chronic inflammatory lung diseases, such as chronic obstructive pulmonary disease, asthma and cystic fibrosis, and implications of the signals triggered by apoptotic cells in the susceptibility to pulmonary microbial infections. PMID:26957481

  8. Effect of Transient Maternal Hypotension on Apoptotic Cell Death in Foetal Rat Brain

    OpenAIRE

    Özyürek, Hamit; Bayrak, Sibel; Pehlivanoğlu, Bilge; Atilla, Pergin; Balkancı, Zeynep Dicle; Çakar, Nur; Anlar, Banu

    2014-01-01

    Background: Intrauterine perfusion insufficiency induced by transient maternal hypotension has been reported to be associated with foetal brain malformations. However, the effects of maternal hypotension on apoptotic processes in the foetal brain have not been investigated experimentally during the intrauterine period. Aims: The aim of this study was to investigate the effects of transient maternal hypotension on apoptotic cell death in the intrauterine foetal brain. Study...

  9. Apoptotic-like programed cell death in fungi: the benefits in filamentous species

    OpenAIRE

    Shlezinger, Neta; Goldfinger, Nir; Sharon, Amir

    2012-01-01

    Studies conducted in the early 1990s showed for the first time that Saccharomyces cerevisiae can undergo cell death with hallmarks of animal apoptosis. These findings came as a surprise, since suicide machinery was unexpected in unicellular organisms. Today, apoptosis in yeast is well-documented. Apoptotic death of yeast cells has been described under various conditions and S. cerevisiae homologs of human apoptotic genes have been identified and characterized. These studies also revealed fund...

  10. BCL2 suppresses PARP1 function and non-apoptotic cell death

    OpenAIRE

    Dutta, Chaitali; Day, Tovah; Kopp, Nadja; van Bodegom, Diederik; Davids, Matthew S.; Ryan, Jeremy; Bird, Liat; Kommajosyula, Naveen; Weigert, Oliver; Yoda, Akinori; Fung, Hua; Brown, Jennifer R; Shapiro, Geoffrey I.; Letai, Anthony; Weinstock, David M.

    2012-01-01

    BCL2 suppresses apoptosis by binding the BH3 domain of pro-apoptotic factors and thereby regulating outer mitochondrial membrane permeabilization. Many tumor types, including B-cell lymphomas and chronic lymphocytic leukemia, are dependent on BCL2 for survival, but become resistant to apoptosis after treatment. Here we identified a direct interaction between the anti-apoptotic protein BCL2 and the enzyme poly(ADP) ribose polymerase 1 (PARP1), which suppresses PARP1 enzymatic activity and inhi...

  11. Salivary apoptotic cells in oral (pre-) cancer as a potential diagnostic means

    OpenAIRE

    Kaur, Jasdeep; Politis, Constantinus; Jacobs, Reinhilde

    2015-01-01

    Background Apoptosis is a genetically programmed form of cell death which is indispensable for development and homeostasis of multi-cellular organism. Objectives The aim of this study was to find out the salivary apoptotic cells in oral precancerous and cancerous patients and furthermore to observe the potential diagnostic value of salivary apoptotic cells in detection of oral pre-cancer and cancer. Material and Methods Unsimulated saliva was collected from a group of 103 subjects diagnosed w...

  12. Impaired Clearance of Apoptotic Cells in Chronic Inflammatory Diseases: Therapeutic Implications

    OpenAIRE

    Szondy, Zsuzsa; Garabuczi, Éva; Joós, Gergely; Tsay, Gregory J.; Sarang, Zsolt

    2014-01-01

    In healthy individuals, billions of cells die by apoptosis every day. Removal of the dead cells by phagocytosis (a process called efferocytosis) must be efficient to prevent secondary necrosis and the consequent release of pro-inflammatory cell contents that damages the tissue environment and provokes autoimmunity. In addition, detection and removal of apoptotic cells generally induces an anti-inflammatory response. As a consequence improper clearance of apoptotic cells, being the result of e...

  13. Adiponectin modulates inflammatory reactions via calreticulin receptor–dependent clearance of early apoptotic bodies

    OpenAIRE

    Takemura, Yukihiro; Ouchi, Noriyuki; Shibata, Rei; Aprahamian, Tamar; Kirber, Michael T.; Summer, Ross S; Kihara, Shinji; Walsh, Kenneth

    2007-01-01

    Obesity and type 2 diabetes are associated with chronic inflammation. Adiponectin is an adipocyte-derived hormone with antidiabetic and antiinflammatory actions. Here, we demonstrate what we believe to be a previously undocumented activity of adiponectin, facilitating the uptake of early apoptotic cells by macrophages, an essential feature of immune system function. Adiponectin-deficient (APN-KO) mice were impaired in their ability to clear apoptotic thymocytes in response to dexamethasone tr...

  14. Self healing of open circuit faults: With active re-configurability and mimicry of synaptic plasticity

    Science.gov (United States)

    Yaswant, Vaddi; Kumar, Amit; Sambandan, Sanjiv

    2016-07-01

    We discuss the self-repair of open faults in circuits using electrically conductive particles dispersed in an insulating fluid. The repair is triggered by the electric field developed across the open circuit in a current carrying interconnect and results in the formation of a bridge of particles across the gap. We illustrate and model the dynamics of the resistance of the self-healed route, Rb, in low field conditions. Furthermore, active control of Rb and active re-wiring are also demonstrated. Considering Rb to be akin to weights between nodes, the formation and re-wiring of routes and the control of Rb mimic synaptic plasticity in biological systems and open interesting possibilities for computing.

  15. Overexpression of the anti-apoptotic protein AVEN contributes to increased malignancy in hematopoietic neoplasms.

    Science.gov (United States)

    Eißmann, M; Melzer, I M; Fernández, S B M; Michel, G; Hrabě de Angelis, M; Hoefler, G; Finkenwirth, P; Jauch, A; Schoell, B; Grez, M; Schmidt, M; Bartholomae, C C; Newrzela, S; Haetscher, N; Rieger, M A; Zachskorn, C; Mittelbronn, M; Zörnig, M

    2013-05-16

    AVEN has been identified as an inhibitor of apoptosis, which binds to the adaptor protein, APAF-1, and thereby prevents apoptosome formation and mitochondrial apoptosis. Recent data have demonstrated high expression levels of AVEN messenger RNA in acute leukemias as well as a positive correlation between AVEN mRNA overexpression and poor prognosis in childhood acute lymphoblastic leukemia. On the basis of these data, we investigated the potential involvement of AVEN in tumorigenesis. First, we confirmed the overexpression of AVEN in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) patient samples. We then established a transgenic mouse model with T-cell-specific overexpression of AVEN, with which we demonstrated the oncogenic cooperation of AVEN with heterozygous loss of p53. Finally, we used a subcutaneous xenograft mouse model to show that AVEN knockdown in the T-ALL cell lines, MOLT-4 and CCRF-CEM, and in the acute myeloblastic leukemia cell line, Kasumi-1, leads to a halt in tumor growth owing to the increased apoptosis and decreased proliferation of tumor cells. Collectively, our data demonstrate that the anti-apoptotic molecule, AVEN, functions as an oncoprotein in hematopoietic neoplasms. PMID:22751129

  16. Apoptotic imaging of experimental hypoxic ischemic brain injury in neonatal rabbits

    International Nuclear Information System (INIS)

    Objective: Hypoxic ischemic brain injury(HIBD) is a severe abnormality of new-born babies causing disability in their future lives. Early detection of HIBD is thereafter of great clinical significance. The current study was to investigate the value of apoptotic imaging with 99Tcm-hydrazinonicotinamide (HYNIC) Annexin V in detecting HIBD in a neonatal rabbit model. Methods: Twenty-one baby rabbits (8-10 d after birth) were modeled after Rice's method and divided into the sham, HIBD 4 h and HIBD 40 h groups. Planar imaging at different time points[60 min (sham, HIBD 4 h); 5, 30, 60, 120 min (HIBD 40 h)] after injection of 99Tcm-Annexin V were carried out and paraffin sections were performed after sacrifice of the animals when imaging completed. The ratio of counts or pixel at injury side to the opposite side (T/NT) was calculated. Routine MRI and diffusion weighted imaging (DWI) were performed in HIBD 4 h group and shame group. Results: The 60 min T/NT ratios from the sham, HIBD 4 h and HIBD 40 h groups were 0.94 ± 0.14, 1.32 ± 0.11 and 1.81 ± 0.07, respectively(F=82.385, P99Tcm-HYNIC-Annexin V, which appears to be of clinical potential in neonatal ischemic-hypoxic brain injury. (authors)

  17. Phagocytosis mechanism of apoptotic granulosa cells regulated by milk-fat globule-EGF factor 8.

    Science.gov (United States)

    Naka, Mayumi; Kusakabe, Ken; Takeshita, Ai; Nakagawa, Hiroshi; Ito, Yuko; Shibata, Masa-Aki; Otsuki, Yoshinori

    2009-09-01

    In the process of ovary sexual maturation, most immature ovarian follicles degrade into atretic follicles accompanied by apoptosis in granulosa cells. Macrophages can recognize apoptotic cells through specific binding with phosphatidylserine (PS), exposed on the surface of apoptotic cells, which is mediated by milk-fat globule-EGF factor 8 (MFG-E8). In the present research, we examined the involvement of the MFG-E8-dependent phagocytosis system in the atretic follicles of developing mouse ovaries. The number of atretic follicles and DNA-fragmented granulosa cells significantly increased in B6C3F1 mice during 2 to 6 weeks. Chromatin-condensed granulosa cells were engulfed by macrophages, which existed in the stroma or atretic follicles, or by neighboring normal granulosa cells. MFG-E8 mRNA increased in ovaries during 2 to 6 weeks, and immunoreactivity of MFG-E8 was detected at the surface of apoptotic cells existing around the antrum. Immunoelectron microscopic study revealed MFG-E8-positive signals on the membrane of apoptotic cells near macrophages, but apoptotic cells engulfed by neighboring granulosa cells showed few signals. Anti-Fas antibody elevated the annexin-V-positive reaction in isolated granulosa cells from 3-week-old mouse ovaries. MFG-E8 seems to act on the phagocytosis of apoptotic granulosa cells via macrophages and contribute to the regression process of atretic follicles. PMID:19784740

  18. Vasculogenic mimicry formation in hepatocellular carcinoma%肝细胞肝癌中拟态血管生成的三维细胞培养及组织学研究

    Institute of Scientific and Technical Information of China (English)

    Jing Zhao; Chenyu Wang; Aijun Yang; Wei Liu; Min Li

    2008-01-01

    Objective:To explore possibility of vasculogenic mimicry (VM) in hepatocellular carcinoma (HCC) by constructing tumor cell three-dimensional culture system and liver cancer tissues.Methods:Based on three-dimensional cell culture system developed by matrigel,liver cancer cell lines HepG2 were tested for evidence of VM.Fifteen HCC simples were collected.Potential formation of tumor channels and their characterization of network were observed by immunohistochemical and histological double staining of CD31 and PAS,or Ferritin and PAS.Results:Three-dimensional culture model of HCC cell line proved the liver cancer cells stretch out thin and long tubers at the second day,and the cells linked each other to form wreath and network structure at the seventh day.In fifteen HCC simples,endothelial cells were all stained by CD31,and tumor calls were all stained by Ferritin.The immunohistochemical and histological double staining also exhibited evidence of VM in seven simples of HCC,CD31-negative and Ferritin-positive tumor cells were observed to form tubal structure.Tumor cells were separated by PAS-positive matter like basement membrane from the tube.Red blood cells could be seen in the tube.In well-differentiated simples,VM was less than that in poorly differentiated ones,and several CD31-positive tumor cells could be observed in poorly differentiated simples.Conclusion:HepG2 cells have the capacity of self-metamorphose and vascularized trend.The tumor cells can obtain oxygen and nutrition through this structure.

  19. Quasi-periodical variations of pulsars spin as mimicry of differential rotation

    Science.gov (United States)

    Kitiashvili, I.; Gusev, A.

    2008-09-01

    ABSTRACT Observation of pulsars is a powerful source of information for studying the dynamics and internal structure of neutron stars. Known about quasi-periodical fluctuations of the time-of-arrival of radiation(TOA) for some pulsars, which we explain as Chandler wobble, Free core nutation, Free inner core nutation and Inner core wobble in case three layer model. Using hamilton approximation to theory rotation of multilayer celestial bodies we estimate dynamical flattening for different layers for PSR B1828-11. It is known that an innate feature of pulsar radiation is high stability of the time-of-arrival (TOA) of pulses, and therefore the analysis of TOA fluctuations can reflect subtle effects of neutron stars dynamics. TOA variations of pulsars can be interpreted by three reasons: gravitational perturbation of pulsar by planetary bodies, peculiarities of a pulsar interior like Tkachenko oscillations and free precession motion, when axis of rotation do not coincide with vectors of the angular moment of solid crust, liquid outer core and crystal core. The radial velocity of a star is obtained by measuring the magnitude of the Doppler effect in its spectrum. Stars showing a small amplitude variation of the radial velocity can be interpreted as systems having planetary companions. Assuming that the pulsar PSR B1257+12 has a mass of 1:35M¯, the Keplerian orbital radii are 0.9, 1.4 and 2.1 AU and with masses are 3:1M©=sin(i), 10:2M©=sin(i), 4:6M©=sin(i), where i is the orbital inclination [7]. In 2000, Stairs, Lyne and Shemar reported about their discovery of long-term, highly-periodic and correlated variations of pulse shape and the rate of slow-down of the pulsar PSR B182811 with period variations approximately 1000, 500, 250 and 167 days, which may be a result of the spin axis caused by an asymmetry in the shape of the pulsar. The long-periodic precession phenomenon was also detected for a few pulsars: PSR 2217+47, PSR 0531+21, PSR B083345, PSR B182811, PSR B

  20. Autoantibodies from mice exposed to Libby amphibole asbestos bind SSA/Ro52-enriched apoptotic blebs of murine macrophages

    International Nuclear Information System (INIS)

    Asbestos exposure is associated with increased autoimmune responses in humans. For example, in Libby, MT where significant asbestos exposure has occurred due to an asbestos-contaminated vermiculite mine near the community, residents have developed increased autoimmune responses compared to an unexposed population. However, the exact mechanism by which Libby amphibole asbestos generates autoimmune responses is unclear. A murine model of amphibole asbestos-induced autoimmunity was recently established, and one of the targets of the autoantibodies (AAs) was the SSA/Ro52 autoantigen. The purpose of this study was to determine whether the SSA/Ro52 autoantigen is exposed at the surface of cells as a result of asbestos exposure as a possible mechanism leading to antigenicity. Our results indicate that Libby asbestos induces apoptosis in murine macrophages as determined by phosphatidylserine exposure, cleavage of poly(ADP-ribose) polymerase and morphological changes such as nuclear condensation. Moreover, asbestos-induced apoptosis results in the formation of apoptotic cell surface blebs enriched in SSA/Ro52 as determined by confocal microscopy. Most importantly, apoptotic cell surface blebs are recognized by AAs from mice exposed to amphibole asbestos suggesting that these cell surface structures may be antigenic when presented in a pro-inflammatory context. This study supports the hypothesis that the induction of apoptosis plays a key role in environmentally induced autoimmunity through cell surface exposure of a known autoantigen

  1. Macrophage-expressed IFN-β contributes to apoptotic alveolar epithelial cell injury in severe influenza virus pneumonia.

    Directory of Open Access Journals (Sweden)

    Katrin Högner

    2013-02-01

    Full Text Available Influenza viruses (IV cause pneumonia in humans with progression to lung failure and fatal outcome. Dysregulated release of cytokines including type I interferons (IFNs has been attributed a crucial role in immune-mediated pulmonary injury during severe IV infection. Using ex vivo and in vivo IV infection models, we demonstrate that alveolar macrophage (AM-expressed IFN-β significantly contributes to IV-induced alveolar epithelial cell (AEC injury by autocrine induction of the pro-apoptotic factor TNF-related apoptosis-inducing ligand (TRAIL. Of note, TRAIL was highly upregulated in and released from AM of patients with pandemic H1N1 IV-induced acute lung injury. Elucidating the cell-specific underlying signalling pathways revealed that IV infection induced IFN-β release in AM in a protein kinase R- (PKR- and NF-κB-dependent way. Bone marrow chimeric mice lacking these signalling mediators in resident and lung-recruited AM and mice subjected to alveolar neutralization of IFN-β and TRAIL displayed reduced alveolar epithelial cell apoptosis and attenuated lung injury during severe IV pneumonia. Together, we demonstrate that macrophage-released type I IFNs, apart from their well-known anti-viral properties, contribute to IV-induced AEC damage and lung injury by autocrine induction of the pro-apoptotic factor TRAIL. Our data suggest that therapeutic targeting of the macrophage IFN-β-TRAIL axis might represent a promising strategy to attenuate IV-induced acute lung injury.

  2. Supraadditive apoptotic response of R3327-G rat prostate tumors to androgen ablation and radiation

    International Nuclear Information System (INIS)

    Purpose: Androgen ablation is often combined with radiation in the treatment of patients with prostate cancer, yet, the optimal sequencing and the mechanisms governing the interaction are not understood. The objectives were to determine if cell killing via apoptosis is enhanced when the combined treatment is administered and to define the relationship of changes in this form of cell killing to tumor volume growth delay. Materials and Methods: Dunning R3327-G rat prostate tumors, grown in the flanks of Copenhagen rats, were used at a volume of approximately 1 cc. Androgen ablation was initiated by castration, and androgen restoration was achieved with 0.5 cm silastic tube implants containing testosterone. 60Co was used for irradiation. The terminal deoxynucleotidyl transferase (TUNEL) histochemical assay was used to quantify apoptosis. Results: Tumors from intact and castrate unirradiated control rats had average apoptotic indices (percent of apoptotic cells) of 0.4 and 1.0%, respectively. The apoptotic index varied only slightly over time (3 h to 28 days) after castration (range 0.75-1.43%). Irradiation of intact rats to 7 Gy resulted in a peak apoptotic response at 6 h of 2.3%. A supra additive apoptotic response was seen when castration was initiated 3 days prior to 7 Gy radiation, with peak levels of about 10.1%. When the radiation was administered at increasing times beyond 3 days after castration, the apoptotic response gradually diminished and was back to levels seen in intact rats by 28 days after castration. Tumor volume growth delay studies were consistent with, but not conclusive proof of, a supra additive effect when the combination was used. Discussion: A supra additive apoptotic response was seen when androgen ablation and radiation were used to treat androgen sensitive R3327-G rat prostate tumors. This supra additive effect was dependent on the timing of the two treatments. Further studies are required to more fully define the optimal timing and

  3. A cuckoo in wolves' clothing? Chemical mimicry in a specialized cuckoo wasp of the European beewolf (Hymenoptera, Chrysididae and Crabronidae

    Directory of Open Access Journals (Sweden)

    Herzner Gudrun

    2008-01-01

    female beewolves, cuckoo wasps, and honeybee workers. Cuticle extracts of Hedychrum nobile (Hymenoptera: Chrysididae and Cerceris arenaria (Hymenoptera: Crabronidae were used as outgroups. There was little congruence with regard to cuticular compounds between H. rutilans females and honeybees as well as females of C. arenaria and H. nobile. However, there was a considerable similarity between beewolf females and H. rutilans females. Beewolf females show a striking dimorphism regarding their cuticular hydrocarbons with one morph having (Z-9-C25:1 and the other morph having (Z-9-C27:1 as the major component. H. rutilans females were more similar to the morph having (Z-9-C27:1 as the main component. Conclusion We conclude that H. rutilans females closely mimic the composition of cuticular compounds of their host species P. triangulum. The occurrence of isomeric forms of certain compounds on the cuticles of the cuckoo wasps but their absence on beewolf females suggests that cuckoo wasps synthesize the cuticular compounds rather than sequester them from their host. Thus, the behavioral data and the chemical analysis provide evidence that a specialized cuckoo wasp exhibits chemical mimicry of the odor of its host. This probably allows the cuckoo wasp to enter the nest with a reduced risk of being detected by olfaction and without leaving traitorous chemical traces.

  4. Modafinil abrogates methamphetamine-induced neuroinflammation and apoptotic effects in the mouse striatum.

    Directory of Open Access Journals (Sweden)

    Mariana Raineri

    Full Text Available Methamphetamine is a drug of abuse that can cause neurotoxic damage in humans and animals. Modafinil, a wake-promoting compound approved for the treatment of sleeping disorders, is being prescribed off label for the treatment of methamphetamine dependence. The aim of the present study was to investigate if modafinil could counteract methamphetamine-induced neuroinflammatory processes, which occur in conjunction with degeneration of dopaminergic terminals in the mouse striatum. We evaluated the effect of a toxic methamphetamine binge in female C57BL/6 mice (4 × 5 mg/kg, i.p., 2 h apart and modafinil co-administration (2 × 90 mg/kg, i.p., 1 h before the first and fourth methamphetamine injections on glial cells (microglia and astroglia. We also evaluated the striatal expression of the pro-apoptotic BAX and anti-apoptotic Bcl-2 proteins, which are known to mediate methamphetamine-induced apoptotic effects. Modafinil by itself did not cause reactive gliosis and counteracted methamphetamine-induced microglial and astroglial activation. Modafinil also counteracted the decrease in tyrosine hydroxylase and dopamine transporter levels and prevented methamphetamine-induced increases in the pro-apoptotic BAX and decreases in the anti-apoptotic Bcl-2 protein expression. Our results indicate that modafinil can interfere with methamphetamine actions and provide protection against dopamine toxicity, cell death, and neuroinflammation in the mouse striatum.

  5. Apoptotic cell-based therapies against transplant rejection: role of recipient’s dendritic cells

    Science.gov (United States)

    Larregina, Adriana T.

    2010-01-01

    One of the ultimate goals in transplantation is to develop novel therapeutic methods for induction of donor-specific tolerance to reduce the side effects caused by the generalized immunosuppression associated to the currently used pharmacologic regimens. Interaction or phagocytosis of cells in early apoptosis exerts potent anti-inflammatory and immunosuppressive effects on antigen (Ag)-presenting cells (APC) like dendritic cells (DC) and macrophages. This observation led to the idea that apoptotic cell-based therapies could be employed to deliver donor-Ag in combination with regulatory signals to recipient’s APC as therapeutic approach to restrain the anti-donor response. This review describes the multiple mechanisms by which apoptotic cells down-modulate the immuno-stimulatory and pro-inflammatory functions of DC and macrophages, and the role of the interaction between apoptotic cells and APC in self-tolerance and in apoptotic cell-based therapies to prevent/treat allograft rejection and graft-versus-host disease in murine experimental systems and in humans. It also explores the role that in vivo-generated apoptotic cells could have in the beneficial effects of extracorporeal photopheresis, donor-specific transfusion, and tolerogenic DC-based therapies in transplantation. PMID:20140521

  6. Approaches to augment CAR T-cell therapy by targeting the apoptotic machinery.

    Science.gov (United States)

    Karlsson, Hannah

    2016-04-15

    Chimaeric antigen receptor (CAR) T-cells have shown impressive results in patients with B-cell leukaemia. Yet, in patients with lymphoma durable responses are still rare and heavy preconditioning required. Apoptosis resistance is considered a hallmark of cancer, often conveyed by a halted apoptosis signalling. Tumours regularly skew the balance of the components of the apoptotic machinery either through up-regulating anti-apoptotic proteins or silencing pro-apoptotic ones. Malignant B-cells frequently up-regulate anti-apoptotic B-cell lymphoma 2 (Bcl-2) family proteins leading to therapy resistance. CAR T-cells kill tumour cells via apoptosis induction and their efficacy may be affected by the level of Bcl-2 family proteins. Hence, there is an interesting possibility to increase the effect of CAR T-cell therapy by combining it with apoptosis inhibitor blockade agents. Compounds that inhibit Bcl-2, B-cell lymphoma extra large (Bcl-xL) and Bcl-2-like protein 2 (Bcl-w), can restore execution of apoptosis in tumour cells or sensitize them to other apoptosis-dependent treatments. Hence, there is a great interest to combine such agents with CAR T-cell therapy to potentiate the effect of CAR T-cell killing. This review will focus on the potential of targeting the apoptotic machinery to sensitize tumour cells to CAR T-cell killing. PMID:27068942

  7. Attenuation of cisplatin-induced acute renal failure is associated with less apoptotic cell death.

    Science.gov (United States)

    Zhou, H; Miyaji, T; Kato, A; Fujigaki, Y; Sano, K; Hishida, A

    1999-12-01

    To clarify the pathophysiologic role of apoptosis in acute renal failure (ARF), we examined whether the attenuation of cisplatin-induced ARF is associated with the change in the degree of apoptotic cell death. The administration of cisplatin (CDDP) (6 mg/kg body weight) in rats induced ARF at day 5, as manifested by a significant increase in serum creatinine (Scr) and tubular damage. CDDP-induced apoptotic cell death was confirmed by electron microscopic examination, agarose gel electrophoresis, and increased cells positive for TaT-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) in the outer medulla of the kidney. Treatment with dimethylthiourea (DMTU)--a scavenger of hydroxyl radicals--or glycine abrogated CDDP-induced increases in Scr, the tubular damage score, and the number of TUNEL-positive cells. Pretreatment with uranyl acetate (UA) induced a significant expression of Bcl-2 in the kidney and ameliorated CDDP-induced increases in Scr, the tubular damage score, and TUNEL-positive cells in the outer stripe of the outer medulla. Our findings indicate (1) that the attenuation of CDDP-induced ARF was associated with less apoptotic cell death and (2) that the induction of the anti-apoptotic protein Bcl-2 attenuated apoptosis and tubular damage. Our results suggest that apoptotic cell death may play an important role in the development of cisplatin-induced ARF. PMID:10595794

  8. Role of membrane and cellular oxidative damage in gamma radiation induced apoptotic death in mouse thymocytes

    International Nuclear Information System (INIS)

    Full text: Involvement of plasma membrane in the molecular mechanism of radiation-induced apoptotic death has increasingly been recognized by radiobiologists in the recent years. In present investigation, alterations in plasma membrane and the associated cytoplasmic / nuclear events were studied in apoptotic mouse thymocytes after gamma radiation exposure. The membrane oxidative damage in irradiated thymocytes was determined by thiobarbituric acid reactive species (TBARS) method and change in membrane permeability was estimated employing fluorescein diacetate (FDA) as fluorescent probe. Radiation-induced apoptotic thymocytes showed an increase in membrane permeability as observed by leakage of FDA, while trypan blue failed to respond. Moreover, using fluorescence technique, the changes in thymocytes membrane permeability could be sensitively determined within low to moderate radiation doses (2 cGy to 2 Gy). The dose dependent increase in intra-cellular reactive oxygen species (ROS) generation was found in irradiated thymocytes determined by fluorescence method, which could sensitively detect the radiation exposure in sub cGy range. Radiation induced membrane changes were found correlated with induction of apoptotic death determined by annexin-V method, caspase-3 assay, measuring nuclear diameter using propidium iodide (PI) staining and DNA fragmentation by gel electrophoresis. It has been also shown that membrane associated events observed in radiation induced apoptotic thymocytes are prior to nuclear / cytosolic processes. The membrane lipid peroxidation, cellular oxidative damage and apoptosis in radiation treated thymocytes were significantly inhibited by membrane-localized antioxidants suggesting significant contribution of membrane damage and oxidative stress in radiation mediated apoptosis in thymocytes

  9. APOPTOTIC AND PROLIFERATIVE ACTIVITY IN OVARIAN BENIGN,BORDERLINE AND MALIGNANT TUMORS

    Institute of Scientific and Technical Information of China (English)

    刘爱军; 陈乐真; 颜婉嫦; 邱玮璇; 赵昀; 张雅贤

    2002-01-01

    Objective.To determine the apoptotic and proliferative activities in various ovarian epithelial tumors.Methods.Formalin fixed,paraffin embedded tissues of 86 ovarian epithelial tumors,including 52 adenocarcinomas,23 borderline tumors and 11 cystadenomas,were retrieved.Apoptotic (AI) and proliferative (PI) index were estimated using the monoclonal antibodies: M30,Ki 67 and Ki S1 in these tumors.Quantitative assessment of AI and PI was estimated by calculating the percentage of positive cells among no less than 1000 tumor cells.Results.Statistically significant difference in AI was found between benign and borderline tumors or carcinomas (P=0.028,0.001,respectively).Significant differences in PI,as assessed by both Ki 67 and topo IIα,were demonstrated between carcinomas and benign or borderline tumors (both P< 0.001).Benign tumors had both low PI and AI; borderline tumors had lower PI but higher AI,while adenocarcinomas had both high proliferative and high apoptotic rates.Among borderline tumors,serous tumors had significantly lower AI and higher PI than mucinous ones.Conclusions.The results suggest that apoptotic and proliferative activities play important roles in the pathogenesis and development of ovarian borderline and malignant tumors.The high apoptotic rate in borderline tumor may explain its relatively indolent behavior while the high proliferative rate in carcinomas tends to explain its aggressive behavior.

  10. Structural study of TTR-52 reveals the mechanism by which a bridging molecule mediates apoptotic cell engulfment

    OpenAIRE

    Kang, Yanyong; Zhao, Dongfeng; Liang, Huanhuan; Liu, Bin; Zhang, Yan; Liu, Qinwen; Wang, Xiaochen; Liu, Yingfang

    2012-01-01

    Apoptotic cells display various “eat me” signals that can be recognized through bridging molecules that cross-link the dying cells to phagocytes. This work illustrates the first full-length structure of such a bridging molecule, TTR-52. The study elucidates the binding of these bridging molecules with the apoptotic cell signals and phagocyte receptors, providing valuable new insight into the process of apoptotic cell recognition.

  11. A cross-species analysis method to analyze animal models' similarity to human's disease state

    OpenAIRE

    Yu Shuhao; Zheng Lulu; Li Yun; Li Chunyan; Ma Chenchen; Li Yixue; Li Xuan; Hao Pei

    2012-01-01

    Abstract Background Animal models are indispensable tools in studying the cause of human diseases and searching for the treatments. The scientific value of an animal model depends on the accurate mimicry of human diseases. The primary goal of the current study was to develop a cross-species method by using the animal models' expression data to evaluate the similarity to human diseases' and assess drug molecules' efficiency in drug research. Therefore, we hoped to reveal that it is feasible an...

  12. The 20S proteasome core, active within apoptotic exosome-like vesicles, induces autoantibody production and accelerates rejection.

    Science.gov (United States)

    Dieudé, Mélanie; Bell, Christina; Turgeon, Julie; Beillevaire, Deborah; Pomerleau, Luc; Yang, Bing; Hamelin, Katia; Qi, Shijie; Pallet, Nicolas; Béland, Chanel; Dhahri, Wahiba; Cailhier, Jean-François; Rousseau, Matthieu; Duchez, Anne-Claire; Lévesque, Tania; Lau, Arthur; Rondeau, Christiane; Gingras, Diane; Muruve, Danie; Rivard, Alain; Cardinal, Héloise; Perreault, Claude; Desjardins, Michel; Boilard, Éric; Thibault, Pierre; Hébert, Marie-Josée

    2015-12-16

    Autoantibodies to components of apoptotic cells, such as anti-perlecan antibodies, contribute to rejection in organ transplant recipients. However, mechanisms of immunization to apoptotic components remain largely uncharacterized. We used large-scale proteomics, with validation by electron microscopy and biochemical methods, to compare the protein profiles of apoptotic bodies and apoptotic exosome-like vesicles, smaller extracellular vesicles released by endothelial cells downstream of caspase-3 activation. We identified apoptotic exosome-like vesicles as a central trigger for production of anti-perlecan antibodies and acceleration of rejection. Unlike apoptotic bodies, apoptotic exosome-like vesicles triggered the production of anti-perlecan antibodies in naïve mice and enhanced anti-perlecan antibody production and allograft inflammation in mice transplanted with an MHC (major histocompatibility complex)-incompatible aortic graft. The 20S proteasome core was active within apoptotic exosome-like vesicles and controlled their immunogenic activity. Finally, we showed that proteasome activity in circulating exosome-like vesicles increased after vascular injury in mice. These findings open new avenues for predicting and controlling maladaptive humoral responses to apoptotic cell components that enhance the risk of rejection after transplantation. PMID:26676607

  13. Proinflammatory cytokines activate the intrinsic apoptotic pathway in beta-cells

    DEFF Research Database (Denmark)

    Grunnet, Lars G; Aikin, Reid; Tonnesen, Morten F;

    2009-01-01

    OBJECTIVE: Proinflammatory cytokines are cytotoxic to beta-cells and have been implicated in the pathogenesis of type 1 diabetes and islet graft failure. The importance of the intrinsic mitochondrial apoptotic pathway in cytokine-induced beta-cell death is unclear. Here, cytokine activation of the...... intrinsic apoptotic pathway and the role of the two proapoptotic Bcl-2 proteins, Bad and Bax, were examined in beta-cells. RESEARCH DESIGN AND METHODS: Human and rat islets and INS-1 cells were exposed to a combination of proinflammatory cytokines (interleukin-1beta, interferon-gamma, and/or tumor necrosis...... factor-alpha). Activation of Bad was determined by Ser136 dephosphorylation, mitochondrial stress by changes in mitochondrial metabolic activity and cytochrome c release, downstream apoptotic signaling by activation of caspase-9 and -3, and DNA fragmentation. The inhibitors FK506 and V5 were used to...

  14. Expression of caspase-3 gene in apoptotic HL-60 cell and different human tumor cell lines

    International Nuclear Information System (INIS)

    Objective: To research the expression of caspase-3 gene in the apoptotic and the control HL-60 cells and in the different human tumor cell lines. Methods: Caspase-3 mRNA in the control and γ-radiation-induced apoptotic HL-60 cells, and in the 6 types of human tumor cell lines, was analysed by Northern blot. Results: The caspase-3 gene transcript was more highly expressed in leukemia cells HL-60, CEM, K562 and neuroblastoma SH-SY5Y than in cervical adenocarcinoma HeLa and breast carcinoma MCF7, and more highly in the radiation-induced apoptotic HL-60 than in the control HL-60 cells. Conclusion: The high level of expression of caspase-3 may aid the efforts to understand the tumor cell sensitivity to radiation, apoptosis and its inherent ability to survive

  15. Crosstalk between tumor suppressors p53 and PKCδ: Execution of the intrinsic apoptotic pathways.

    Science.gov (United States)

    Dashzeveg, Nurmaa; Yoshida, Kiyotsugu

    2016-07-28

    p53 and PKCδ are tumor suppressors that execute apoptotic mechanisms in response to various cellular stresses. p53 is a transcription factor that is frequently mutated in human cancers; it regulates apoptosis in transcription-dependent and -independent ways in response to genotoxic stresses. PKCδ is a serine/threonine protein kinase and mutated in human cancers. Available evidence shows that PKCδ activates p53 by direct and/or indirect mechanisms. Moreover, PKCδ is also implicated in the transcriptional regulation of p53 in response to DNA damage. Recent findings demonstrated that p53, in turn, binds onto the PKCδ promoter and induces its expression upon DNA damage to facilitate apoptosis. Both p53 and PKCδ are associated with the apoptotic mechanisms in the mitochondria by regulating Bcl-2 family proteins to provide mitochondrial outer membrane permeabilization. This review discusses the crosstalk between p53 and PKCδ in the context of apoptotic cell death and cancer therapy. PMID:27130668

  16. Impaired clearance of apoptotic cells in chronic inflammatory diseases: therapeutic implications

    Directory of Open Access Journals (Sweden)

    Zsuzsa eSzondy

    2014-08-01

    Full Text Available In healthy individuals billions of cells die by apoptosis every day. Removal of the dead cells by phagocytosis (a process called efferocytosis must be efficient to prevent secondary necrosis and the consequent release of proinflammatory cell contents that damages the tissue environment and provokes autoimmunity. In addition, detection and removal of apoptotic cells generally induces an anti-inflammatory response. As a consequence improper clearance of apoptotic cells, being the result of either genetic anomalies and /or a persistent disease state, contributes to the establishment and progression of a number of human chronic inflammatory diseases such as autoimmune and neurological disorders, inflammatory lung diseases, obesity, type 2 diabetes or atherosclerosis. During the past decade our knowledge about the mechanism of efferocytosis has significantly increased, providing therapeutic targets through which impaired phagocytosis of apoptotic cells and the consequent inflammation could be influenced in these diseases.

  17. Anti-apoptotic peptides protect against radiation-induced cell death

    International Nuclear Information System (INIS)

    The risk of terrorist attacks utilizing either nuclear or radiological weapons has raised concerns about the current lack of effective radioprotectants. Here it is demonstrated that the BH4 peptide domain of the anti-apoptotic protein Bcl-xL can be delivered to cells by covalent attachment to the TAT peptide transduction domain (TAT-BH4) and provide protection in vitro and in vivo from radiation-induced apoptotic cell death. Isolated human lymphocytes treated with TAT-BH4 were protected against apoptosis following exposure to 15 Gy radiation. In mice exposed to 5 Gy radiation, TAT-BH4 treatment protected splenocytes and thymocytes from radiation-induced apoptotic cell death. Most importantly, in vivo radiation protection was observed in mice whether TAT-BH4 treatment was given prior to or after irradiation. Thus, by targeting steps within the apoptosis signaling pathway it is possible to develop post-exposure treatments to protect radio-sensitive tissues

  18. Anti-apoptotic signaling and failure of apoptosis in the ischemic rat hippocampus

    DEFF Research Database (Denmark)

    Müller, Georg Johannes; Lassmann, Hans; Johansen, Flemming Fryd

    2007-01-01

    colchicine injection severed as a reference for classical apoptosis. Heat shock protein 70 (Hsp70), neuronal apoptosis inhibitory protein (NAIP) and manganese superoxide dismutase (MnSOD) were upregulated in the majority of intact CA1 neurons paralleling the occurrence of CA1 neuronal death (days 3-7) as...... well as in a proportion of apoptosis-(<50%) and necrosis-like (<30%) CA1 neurons. Colchicine did not provoke an anti-apoptotic response in DGC at all. In addition, more than 70% of apoptosis- and necrosis-like CA1 neurons had completely lost their RCC subunits suggesting bioenergetic failure; by...... contrast, following colchicine injection, 88% of all apoptotic DGC presented RCC subunits. Thus, anti-apoptotic proteins may, in a subset of ischemic CA1 neurons, prevent cell death, while in others, affected by pronounced energy failure, they may cause secondary necrosis....

  19. Involvement of ER stress and activation of apoptotic pathways in fisetin induced cytotoxicity in human melanoma.

    Science.gov (United States)

    Syed, Deeba N; Lall, Rahul K; Chamcheu, Jean Christopher; Haidar, Omar; Mukhtar, Hasan

    2014-12-01

    The prognosis of malignant melanoma remains poor in spite of recent advances in therapeutic strategies for the deadly disease. Fisetin, a dietary flavonoid is currently being investigated for its growth inhibitory properties in various cancer models. We previously showed that fisetin inhibited melanoma growth in vitro and in vivo. Here, we evaluated the molecular basis of fisetin induced cytotoxicity in metastatic human melanoma cells. Fisetin treatment induced endoplasmic reticulum (ER) stress in highly aggressive A375 and 451Lu human melanoma cells, as revealed by up-regulation of ER stress markers including IRE1α, XBP1s, ATF4 and GRP78. Time course analysis indicated that the ER stress was associated with activation of the extrinsic and intrinsic apoptotic pathways. Fisetin treated 2-D melanoma cultures displayed autophagic response concomitant with induction of apoptosis. Prolonged treatment (16days) with fisetin in a 3-D reconstituted melanoma model resulted in inhibition of melanoma progression with significant apoptosis, as evidenced by increased staining of cleaved Caspase-3 in the treated constructs. However, no difference in the expression of autophagic marker LC-3 was noted between treated and control groups. Fisetin treatment to 2-D melanoma cultures resulted in phosphorylation and activation of the multifunctional AMP-activated protein kinase (AMPK) involved in the regulation of diverse cellular processes, including autophagy and apoptosis. Silencing of AMPK failed to prevent cell death indicating that fisetin induced cytotoxicity is mediated through both AMPK-dependent and -independent mechanisms. Taken together, our studies confirm apoptosis as the primary mechanism through which fisetin inhibits melanoma cell growth and that activation of both extrinsic and intrinsic pathways contributes to fisetin induced cytotoxicity. PMID:25016296

  20. The Possible Role of Transplacentally-Acquired Antibodies to Infectious Agents, With Molecular Mimicry to Nervous System Sialic Acid Epitopes, as Causes of Neuromental Disorders: Prevention and Vaccine Implications

    Directory of Open Access Journals (Sweden)

    André J. Nahmias

    2006-01-01

    Full Text Available Proof of causality of most neuromental disorders (NMD's is largely unavailable. Lessons from four-decade investigations of the epidemiology, immunology, pathogenesis, prevention and therapy of perinatal infectious agents, which invade directly the nervous system, have led us to propose a new indirect effect hypothesis: maternal transplacentally-acquired antibodies, to agents with epitope molecular mimicry with the developing nervous system, can cross the fetus/infant's blood–nervous system barriers to cause NMD's, clinically manifest years later.

  1. Tributyltin induces apoptotic signaling in hepatocytes through pathways involving the endoplasmic reticulum and mitochondria

    International Nuclear Information System (INIS)

    Tri-n-butyltin is a widespread environmental toxicant, which accumulates in the liver. This study investigates whether tri-n-butyltin induces pro-apoptotic signaling in rat liver hepatocytes through pathways involving the endoplasmic reticulum and mitochondria. Tri-n-butyltin activated the endoplasmic reticulum pathway of apoptosis, which was demonstrated by the activation of the protease calpain, its translocation to the plasma membrane, followed by cleavage of the calpain substrates, cytoskeletal protein vinculin, and caspase-12. Caspase-12 is localized to the cytoplasmic side of the endoplasmic reticulum and is involved in apoptosis mediated by the endoplasmic reticulum. Tri-n-butyltin also caused translocation of the pro-apoptotic proteins Bax and Bad from the cytosol to mitochondria, as well as changes in mitochondrial membrane permeability, events which can activate the mitochondrial death pathway. Tri-n-butyltin induced downstream apoptotic events in rat hepatocytes at the nuclear level, detected by chromatin condensation and by confocal microscopy using acridine orange. We investigated whether the tri-n-butyltin-induced pro-apoptotic events in hepatocytes could be linked to perturbation of intracellular calcium homeostasis, using confocal microscopy. Tri-n-butyltin caused changes in intracellular calcium distribution, which were similar to those induced by thapsigargin. Calcium was released from a subcellular compartment, which is likely to be the endoplasmic reticulum, into the cytosol. Cytosolic acidification, which is known to trigger apoptosis, also occurred and involved the Cl-/HCO3- exchanger. Pro-apoptotic events in hepatocytes were inhibited by the calcium chelator, Bapta-AM, and by a calpain inhibitor, which suggests that changes in intracellular calcium homeostasis are involved in tri-n-butyltin-induced apoptotic signaling in rat hepatocytes

  2. Photocontrolled Exposure of Pro-apoptotic Peptide Sequences in LOV Proteins Modulates Bcl-2 Family Interactions.

    Science.gov (United States)

    Mart, Robert J; Meah, Dilruba; Allemann, Rudolf K

    2016-04-15

    LOV domains act as biomolecular sensors for light, oxygen or the environment's redox potential. Conformational changes upon the formation of a covalent cysteinyl flavin adduct are propagated through hydrogen-bonding networks in the core of designed hybrid phototropin LOV2 domains that incorporate the Bcl homology region 3 (BH3) of the key pro-apoptotic protein BH3-interacting-domain death agonist (BID). The resulting change in conformation of a flanking amphiphilic α-helix creates a light-dependent optogenetic tool for the modulation of interactions with the anti-apoptotic B-cell leukaemia-2 (Bcl-2) family member Bcl-xL . PMID:26493687

  3. Anti-apoptotic signaling as a cytoprotective mechanism in mammalian hibernation

    Directory of Open Access Journals (Sweden)

    Andrew N. Rouble

    2013-02-01

    Full Text Available In the context of normal cell turnover, apoptosis is a natural phenomenon involved in making essential life and death decisions. Apoptotic pathways balance signals which promote cell death (pro-apoptotic pathways or counteract these signals (anti-apoptotic pathways. We proposed that changes in anti-apoptotic proteins would occur during mammalian hibernation to aid cell preservation during prolonged torpor under cellular conditions that are highly injurious to most mammals (e.g. low body temperatures, ischemia. Immunoblotting was used to analyze the expression of proteins associated with pro-survival in six tissues of thirteen-lined ground squirrels, Ictidomys tridecemlineatus. The brain showed a concerted response to torpor with significant increases in the levels of all anti-apoptotic targets analyzed (Bcl-2, Bcl-xL, BI-1, Mcl-1, cIAP1/2, xIAP as well as enhanced phosphorylation of Bcl-2 at S70 and T56. Heart responded similarly with most anti-apoptotic proteins elevated significantly during torpor except for Bcl-xL and xIAP that decreased and Mcl-1 that was unaltered. In liver, BI-1 increased whereas cIAP1/2 decreased. In kidney, there was an increase in BI-1, cIAP and xIAP but decreases in Bcl-xL and p-Bcl-2(T56 content. In brown adipose tissue, protein levels of BI-1, cIAP1/2, and xIAP decreased significantly during torpor (compared with euthermia whereas Bcl-2, Bcl-xL, Mcl-1 were unaltered; however, Bcl-2 showed enhanced phosphorylation at Thr56 but not at Ser70. In skeletal muscle, only xIAP levels changed significantly during torpor (an increase. The data show that anti-apoptotic pathways have organ-specific responses in hibernators with a prominent potential role in heart and brain where coordinated enhancement of anti-apoptotic proteins occurred in response to torpor.

  4. Cloning and sequencing of a DNA fragment encoding N37 apoptotic peptide derived from p53

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Objective It was reported that p53 apoptotic peptide (N37) could inhibit p73 gene through being bound with iASPP,which could induce tumor cell apoptosis. To further explore the function of N37,we constructed the cloning plasmid of DNA fragment encoding p53 (N37) apoptotic peptide by using DNA synthesis and molecular biology methods. Methods According to human p53 sequence from the GenBank database,the primer of p53(N37) gene was designed using Primer V7.0 software. The DNA fragment encoding p53 (N37) apopto...

  5. Synthesis of apoptotic chalcone analogues in HepG2 human hepatocellular carcinoma cells.

    Science.gov (United States)

    Park, Cheon-Soo; Ahn, Yongchel; Lee, Dahae; Moon, Sung Won; Kim, Ki Hyun; Yamabe, Noriko; Hwang, Gwi Seo; Jang, Hyuk Jai; Lee, Heesu; Kang, Ki Sung; Lee, Jae Wook

    2015-12-15

    Eight chalcone analogues were prepared and evaluated for their cytotoxic effects in human hepatoma HepG2 cells. Compound 5 had a potent cytotoxic effect. The percentage of apoptotic cells was significantly higher in compound 5-treated cells than in control cells. Exposure to compound 5 for 24h induced cleavage of caspase-8 and -3, and poly (ADP-ribose) polymerase (PARP). Our findings suggest that compound 5 is the active chalcone analogue that contributes to cell death in HepG2 cells via the extrinsic apoptotic pathway. PMID:26564263

  6. Inhibition of BET bromodomain-dependent XIAP and FLIP expression sensitizes KRAS-mutated NSCLC to pro-apoptotic agents.

    Science.gov (United States)

    Klingbeil, Olaf; Lesche, Ralf; Gelato, Kathy A; Haendler, Bernard; Lejeune, Pascale

    2016-01-01

    Non-small cell lung cancer (NSCLC) has the highest incidence of cancer-related death worldwide and a high medical need for more effective therapies. Small-molecule inhibitors of the bromodomain and extra terminal domain (BET) family such as JQ1, I-BET762 and OTX-015 are active in a wide range of different cancer types, including lung cancer. Although their activity on oncogene expression such as c-Myc has been addressed in many studies, the effects of BET inhibition on the apoptotic pathway remain largely unknown. Here we evaluated the activity of BET bromodomain inhibitors on cell cycle distribution and on components of the apoptosis response. Using a panel of 12 KRAS-mutated NSCLC models, we found that cell lines responsive to BET inhibitors underwent apoptosis and reduced their S-phase population, concomitant with downregulation of c-Myc expression. Conversely, ectopic c-Myc overexpression rescued the anti-proliferative effect of JQ1. In the H1373 xenograft model, treatment with JQ1 significantly reduced tumor growth and downregulated the expression of c-Myc. The effects of BET inhibition on the expression of 370 genes involved in apoptosis were compared in sensitive and resistant cells and we found the expression of the two key apoptosis regulators FLIP and XIAP to be highly BET dependent. Consistent with this, combination treatment of JQ1 with the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or the pro-apoptotic chemotherapeutic agent cisplatin enhanced induction of apoptosis in both BET inhibitor sensitive and resistant cells. Further we showed that combination of JQ1 with cisplatin led to significantly improved anti-tumor efficacy in A549 tumor-bearing mice. Altogether, these results show that the identification of BET-dependent genes provides guidance for the choice of drug combinations in cancer treatment. They also demonstrate that BET inhibition primes NSCLC cells for induction of apoptosis and that a combination with pro-apoptotic

  7. Antiproliferative and pro-apoptotic activity of eugenol-related biphenyls on malignant melanoma cells

    Directory of Open Access Journals (Sweden)

    Dettori Maria

    2007-01-01

    Full Text Available Abstract Background Malignant melanoma is one of the most aggressive skin cancer and chemotherapeutic agents currently in use are still unsatisfactory. Prevention and early diagnosis are the only effective tools against this tumour whose incidence and mortality rates are highly increased during the last decades in fair skin populations. Therefore the search for novel therapeutic approaches is warranted. Aim of this work was to identify and test new compounds with antiproliferative and cytotoxic activity on melanoma cells. We tested eugenol together with six natural and synthetic eugenol-related compounds for their capability to inhibit cell growth on primary melanoma cell lines established from patients' tissue samples. Results Eugenol and isoeugenol monomers and their respective O-methylated forms did not show to inhibit melanoma cells proliferation. Conversely, the dimeric forms (biphenyls showed some antiproliferative activity which was mild for dehydrodieugenol, higher for its O,O'-methylated form (O,O'-dimethyl-dehydrodieugenol, and markedly pronounced for the racemic mixture of the brominated biphenyl (6,6'-dibromo-dehydrodieugenol (S7, being its enantiomeric form (S the most effective compared to the other compounds. Such activity resulted to be selective against tumour cells, without affecting cultured normal human skin fibroblasts. Dose and time dependence curves have been obtained for the enantiomeric form S7-(S. Then IC50 and minimal effective doses and times have been established for the melanoma cell lines tested. TUNEL and phosphatidylserine exposure assays demonstrated the occurrence of apoptotic events associated with the antiproliferative activity of S7-(S. Cytotoxic activity and apoptosis induced by treating melanoma cells with eugenol-related biphenyls was partially dependent by caspase activation. Conclusion Our findings demonstrate that the eugenol related biphenyl (S-6,6'-dibromo-dehydrodieugenol elicits specific

  8. Natural proteasome inhibitor celastrol suppresses androgen-independent prostate cancer progression by modulating apoptotic proteins and NF-kappaB.

    Directory of Open Access Journals (Sweden)

    Yao Dai

    Full Text Available Celastrol is a natural proteasome inhibitor that exhibits promising anti-tumor effects in human malignancies, especially the androgen-independent prostate cancer (AIPC with constitutive NF-κB activation. Celastrol induces apoptosis by means of proteasome inhibition and suppresses prostate tumor growth. However, the detailed mechanism of action remains elusive. In the current study, we aim to test the hypothesis that celastrol suppresses AIPC progression via inhibiting the constitutive NF-κB activity as well as modulating the Bcl-2 family proteins.We examined the efficacy of celastrol both in vitro and in vivo, and evaluated the role of NF-κB in celastrol-mediated AIPC regression. We found that celastrol inhibited cell proliferation in all three AIPC cell lines (PC-3, DU145 and CL1, with IC₅₀ in the range of 1-2 µM. Celastrol also suppressed cell migration and invasion. Celastrol significantly induced apoptosis as evidenced by increased sub-G1 population, caspase activation and PARP cleavage. Moreover, celastrol promoted cleavage of the anti-apoptotic protein Mcl-1 and activated the pro-apoptotic protein Noxa. In addition, celastrol rapidly blocked cytosolic IκBα degradation and nuclear translocation of RelA. Likewise, celastrol inhibited the expression of multiple NF-κB target genes that are involved in proliferation, invasion and anti-apoptosis. Celastrol suppressed AIPC tumor progression by inhibiting proliferation, increasing apoptosis and decreasing angiogenesis, in PC-3 xenograft model in nude mouse. Furthermore, increased cellular IκBα and inhibited expression of various NF-κB target genes were observed in tumor tissues.Our data suggest that, via targeting the proteasome, celastrol suppresses proliferation, invasion and angiogenesis by inducing the apoptotic machinery and attenuating constitutive NF-κB activity in AIPC both in vitro and in vivo. Celastrol as an active ingredient of traditional herbal medicine could thus be

  9. Combination phenylbutyrate/gemcitabine therapy effectively inhibits in vitro and in vivo growth of NSCLC by intrinsic apoptotic pathways

    Directory of Open Access Journals (Sweden)

    Schniewind Bodo

    2006-11-01

    Full Text Available Abstract Background Standard chemotherapy protocols in NSCLC are of limited clinical benefit. Histone deacetylase (HDAC inhibitors represent a new strategy in human cancer therapy. In this study the combination of the HDAC inhibitor phenylbutyrate (PB and the nucleoside analogue gemcitabine (GEM was evaluated and the mechanisms underlying increased cell death were analyzed. Methods Dose escalation studies evaluating the cytotoxicity of PB (0.01–100 mM, GEM (0.01–100 μg/ml and a combination of the two were performed on two NSCLC cell lines (BEN and KNS62. Apoptotic cell death was quantified. The involvement of caspase-dependent cell death and MAP-kinase activation was analyzed. Additionally, mitochondrial damage was determined. In an orthotopic animal model the combined effect of PB and GEM on therapy was analyzed. Results Applied as a single drug both GEM and PB revealed limited potential to induce apoptosis in KNS62 and Ben cells. Combination therapy was 50–80% (p = 0.012 more effective than either agent alone. On the caspase level, combination therapy significantly increased cleavage of the pro-forms compared to single chemotherapy. The broad spectrum caspase-inhibitor zVAD was able to inhibit caspase cleavage completely, but reduced the frequency of apoptotic cells only by 30%. Combination therapy significantly increased changes in MTP and the release of cyto-c, AIF and Smac/Diabolo into the cytoplasm. Furthermore, the inhibitors of apoptosis c-IAP1 and c-IAP2 were downregulated and it was shown that in combination therapy JNK activation contributed significantly to induction of apoptosis. The size of the primary tumors growing orthotopically in SCID mice treated for 4 weeks with GEM and PB was significantly reduced (2.2–2.7 fold compared to GEM therapy alone. The Ki-67 (KNS62: p = 0.015; Ben: p = 0.093 and topoisomerase IIα (KNS62: p = 0.008; Ben: p = 0.064 proliferation indices were clearly reduced in tumors treated by combination

  10. Gingerol sensitizes TRAIL-induced apoptotic cell death of glioblastoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Dae-Hee, E-mail: leedneo@gmail.com [Departments of Surgery and Pharmacology and Cell Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA (United States); Kim, Dong-Wook [Department of Microbiology, Immunology, and Cancer Biology, University of VA (United States); Jung, Chang-Hwa [Division of Metabolism and Functionality Research, Korea Food Research Institute (Korea, Republic of); Lee, Yong J. [Departments of Surgery and Pharmacology and Cell Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA (United States); Park, Daeho, E-mail: daehopark@gist.ac.kr [School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712 (Korea, Republic of)

    2014-09-15

    Glioblastoma multiforme (GBM) is the most lethal and aggressive astrocytoma of primary brain tumors in adults. Although there are many clinical trials to induce the cell death of glioblastoma cells, most glioblastoma cells have been reported to be resistant to TRAIL-induced apoptosis. Here, we showed that gingerol as a major component of ginger can induce TRAIL-mediated apoptosis of glioblastoma. Gingerol increased death receptor (DR) 5 levels in a p53-dependent manner. Furthermore, gingerol decreased the expression level of anti-apoptotic proteins (survivin, c-FLIP, Bcl-2, and XIAP) and increased pro-apoptotic protein, Bax and truncate Bid, by generating reactive oxygen species (ROS). We also found that the sensitizing effects of gingerol in TRAIL-induced cell death were blocked by scavenging ROS or overexpressing anti-apoptotic protein (Bcl-2). Therefore, we showed the functions of gingerol as a sensitizing agent to induce cell death of TRAIL-resistant glioblastoma cells. This study gives rise to the possibility of applying gingerol as an anti-tumor agent that can be used for the purpose of combination treatment with TRAIL in TRAIL-resistant glioblastoma tumor therapy. - Highlights: • Most GBM cells have been reported to be resistant to TRAIL-induced apoptosis. • Gingerol enhances the expression level of anti-apoptotic proteins by ROS. • Gingerol enhances TRAIL-induced apoptosis through actions on the ROS–Bcl2 pathway.

  11. Cloning and analysis of a defender against apoptotic cell death (DAD1) homologue from tomato

    NARCIS (Netherlands)

    Hoeberichts, F.A.; Woltering, E.J.

    2001-01-01

    A cDNA clone homologous to the human defender against apoptotic cell death (DAD1) gene, which is believed to be a conserved inhibitor of programmed cell death, was isolated from tomato (Lycopersicon esculentum cv. Prisca). The 351 basepairs open reading frame predicted a 116 amino acid protein seque

  12. Investigation of apoptotic events at molecular level induced by SERS guided targeted theranostic nanoprobe.

    Science.gov (United States)

    Narayanan, Nisha; Nair, Lakshmi V; Karunakaran, Varsha; Joseph, Manu M; Nair, Jyothi B; N, Ramya A; Jayasree, Ramapurath S; Maiti, Kaustabh Kumar

    2016-06-01

    Herein, we have examined distinctive structural and functional variations of cellular components during apoptotic cell death induced by a targeted theranostic nanoprobe, MMP-SQ@GNR@LAH-DOX, which acted as a SERS "on/off" probe in the presence of a MMP protease and executed synergistic photothermal chemotherapy, as reflected by the SERS fingerprinting, corresponding to the phosphodiester backbone of DNA. PMID:27211810

  13. Gingerol sensitizes TRAIL-induced apoptotic cell death of glioblastoma cells

    International Nuclear Information System (INIS)

    Glioblastoma multiforme (GBM) is the most lethal and aggressive astrocytoma of primary brain tumors in adults. Although there are many clinical trials to induce the cell death of glioblastoma cells, most glioblastoma cells have been reported to be resistant to TRAIL-induced apoptosis. Here, we showed that gingerol as a major component of ginger can induce TRAIL-mediated apoptosis of glioblastoma. Gingerol increased death receptor (DR) 5 levels in a p53-dependent manner. Furthermore, gingerol decreased the expression level of anti-apoptotic proteins (survivin, c-FLIP, Bcl-2, and XIAP) and increased pro-apoptotic protein, Bax and truncate Bid, by generating reactive oxygen species (ROS). We also found that the sensitizing effects of gingerol in TRAIL-induced cell death were blocked by scavenging ROS or overexpressing anti-apoptotic protein (Bcl-2). Therefore, we showed the functions of gingerol as a sensitizing agent to induce cell death of TRAIL-resistant glioblastoma cells. This study gives rise to the possibility of applying gingerol as an anti-tumor agent that can be used for the purpose of combination treatment with TRAIL in TRAIL-resistant glioblastoma tumor therapy. - Highlights: • Most GBM cells have been reported to be resistant to TRAIL-induced apoptosis. • Gingerol enhances the expression level of anti-apoptotic proteins by ROS. • Gingerol enhances TRAIL-induced apoptosis through actions on the ROS–Bcl2 pathway

  14. Reversal of Apoptotic Resistance by Lycium barbarum Glycopeptide 3 in Aged T Cells

    Institute of Scientific and Technical Information of China (English)

    LONG-GUO YUAN; HONG-BIN DENG; LI-HUI CHEN; DIAN-DONG LI; QI-YANG HE

    2008-01-01

    Objective To study whether Lycium barbarian glycopeptide 3 (LBGP3) affects T cell apeptosis in aged mice. Methods LBGP3 was purified with DEAE cellulose and Sephadex columns. Apoptotic "sub-Gl peak" was detected by flow cytometry and DNA ladder was resolved by agarose gel electrophoresis. Levels of IFN-γ, and IL-10 were measured with specific kits and mRNA expression was detected by RT-PCR. Apoptosis-related proteins of FLIP, FasL, and Bcl-2 were determined by Western blotting. Resdts LBGP3 was purified from Fructus Lycii water extracts and identified as a 41 kD glycopeptide.Treatment with 200 μg/mL LBGP3 increased the apoptotic rate of T cells from aged mice and showed a similar DNA ladder pattern to that in young T ceils. The reversal of apoptotic resistance was involved in down-regulating the expression of Bcl-2 and FLIP, and up-regulating the expression of FasL. Conclusion Lycium barbarum glycopeptide 3 reverses apoptotic resistance of aged T cells by modulating the expression of apoptosis-related molecules.

  15. Expression of defender against apoptotic death (DAD-1) in iris and dianthus petals

    NARCIS (Netherlands)

    Kop, van der D.A.M.; Ruys, G.; Dees, D.; Schoot, van der C.; Boer, de A.D.; Doorn, van W.G.

    2003-01-01

    The gene defender against apoptotic death (DAD-1) prevents programmed cell death in animal cells. We investigated the expression pattern of DAD-1 in petals of iris (Iris x hollandica cv. Blue Magic) and carnation (Dianthus caryophyllus cv. Etarro). DAD-1 expression in Iris petals was strongly reduce

  16. Relationship between apoptotic markers in semen from fertile men and demographic, hormonal and seminal characteristics

    DEFF Research Database (Denmark)

    O Specht, Ina; Spanò, Marcello; S Hougaard, Karin; C Manicardi, Gian; Bizzaro, Davide; Toft, Gunnar; Giwercman, Aleksander; E Bonde, Jens-Peter

    2012-01-01

    World Health Organization. Immunofluorescence coupled to flow cytometry was utilized for detection of apoptotic markers in the sperm cell. DNA damage was assessed by flow cytometry using both the sperm chromatin structure assay (SCSA) and the terminal deoxynucleotidyl transferase dUTP nick end labelling...

  17. Unexpected requirement for ELMO1 in clearance of apoptotic germ cells in vivo.

    Science.gov (United States)

    Elliott, Michael R; Zheng, Shuqiu; Park, Daeho; Woodson, Robin I; Reardon, Michael A; Juncadella, Ignacio J; Kinchen, Jason M; Zhang, Jun; Lysiak, Jeffrey J; Ravichandran, Kodi S

    2010-09-16

    Apoptosis and the subsequent clearance of dying cells occurs throughout development and adult life in many tissues. Failure to promptly clear apoptotic cells has been linked to many diseases. ELMO1 is an evolutionarily conserved cytoplasmic engulfment protein that functions downstream of the phosphatidylserine receptor BAI1, and, along with DOCK1 and the GTPase RAC1, promotes internalization of the dying cells. Here we report the generation of ELMO1-deficient mice, which we found to be unexpectedly viable and grossly normal. However, they had a striking testicular pathology, with disrupted seminiferous epithelium, multinucleated giant cells, uncleared apoptotic germ cells and decreased sperm output. Subsequent in vitro and in vivo analyses revealed a crucial role for ELMO1 in the phagocytic clearance of apoptotic germ cells by Sertoli cells lining the seminiferous epithelium. The engulfment receptor BAI1 and RAC1 (upstream and downstream of ELMO1, respectively) were also important for Sertoli-cell-mediated engulfment. Collectively, these findings uncover a selective requirement for ELMO1 in Sertoli-cell-mediated removal of apoptotic germ cells and make a compelling case for a relationship between engulfment and tissue homeostasis in vivo. PMID:20844538

  18. Cloning and sequencing of a DNA fragment encoding N37 apoptotic peptide derived from p53

    Institute of Scientific and Technical Information of China (English)

    Yan-xia Bai; Qing-yong Ma; Guang-xiao Yang

    2009-01-01

    Objective It was reported that p53 apoptotic peptide (N37) could inhibit p73 gene through being bound with iASPP, which could induce tumor cell apoptosis. To further explore the function of N37, we constructed the cloning plasmid of DNA fragment encoding p53 (N37) apoptotic peptide by using DNA synthesis and molecular biology methods. Methods According to human p53 sequence from the GenBank database, the primer of p53(N37) gene was designed using Primer V7.0 software. The DNA fragment encoding p53 (N37) apoptotic peptide was amplified by using self-complementation polymerase chain reaction (PCR) method and cloned into the pGEM-T Easy vector. The constructed plasmid was confirmed by endonuclease analysis and sequencing. Results The insertion of objective DNA fragment was confirmed by plasmid DNA enzyme spectrum analysis, p53 (N37) gene was successfully synthesized chemically in vitro. The sequencing result of positive clone was completely identical to the human p53(N37) sequence in GenBank using BLAST software (http://www. ncbi. him. nih. gov/cgi-bin /BLASTn). Conclusion The cloning of DNA fragment encoding p53(N37) apoptotic peptide was constructed by using DNA synthesis and pGEM-T Easy cloning methods. With the constructed plasmid, we could further investigate the function of N37 peptide.

  19. Cytotoxicity and apoptotic effects of nickel oxide nanoparticles in cultured HeLa cells

    International Nuclear Information System (INIS)

    The aim of this study was to observe the cytotoxicity and apoptotic effects of nickel oxide nanoparticles on human cervix epithelioid carcinoma cell line (HeLa). Nickel oxide precursors were synthesized by an nickel sulphate-excess urea reaction in boiling aqueous solution. The synthesized NiO nanoparticles (< 200 nm) were investigated by X-ray diffraction analysis and transmission electron microscopy techniques. For cytotoxicity experiments, HeLa cells were incubated in 50-500 micro g/ml NiO for 2, 6, 12 and 16 hours. The viable cells were counted with a haemacytometer using light microscopy. The cytotoxicity was observed low in 50-200 micro g/ml concentration for 16 h, but high in 400-500 micro g/ml concentration for 2-6 h. HeLa cells cytoplasm membrane was lysed and detached from the well surface in 400 micro g/ml concentration NiO nanoparticles. Double staining and M30 immunostaining were performed to quantify the number of apoptotic cells in culture on the basis of apoptotic cell nuclei scores. The apoptotic effect was observed 20% for 16 h incubation. (authors)

  20. Antiproliferative and pro-apoptotic effects of Uncaria tomentosa in human medullary thyroid carcinoma cells.

    Science.gov (United States)

    Rinner, Beate; Li, Zeng Xia; Haas, Helga; Siegl, Veronika; Sturm, Sonja; Stuppner, Hermann; Pfragner, Roswitha

    2009-11-01

    Medullary thyroid carcinoma (MTC), a rare calcitonin-producing tumor, is derived from parafollicular C-cells of the thyroid and is characterized by constitutive Bcl-2 overexpression. The tumor is relatively insensitive to radiation therapy as well as conventional chemotherapy. To date, the only curative treatment is the early and complete surgical removal of all neoplastic tissue. In this study, the antiproliferative and pro-apoptotic effects of fractions obtained from Uncaria tomentosa (Willd.) DC, commonly known as uña de gato or cat's claw were investigated. Cell growth of MTC cells as well as enzymatic activity of mitochondrial dehydrogenase was markedly inhibited after treatment with different fractions of the plant. Furthermore, there was an increase in the expressions of caspase-3 and -7 and poly(ADP-ribose) polymerase (PARP) fraction, while bcl-2 overexpression remained constant. In particular, the alkaloids isopterpodine and pteropodine of U. tomentosa exhibited a significant pro-apoptotic effect on MTC cells, whereas the alkaloid-poor fraction inhibited cell proliferation but did not show any pro-apoptotic effects. These promising results indicate the growth-restraining and apoptotic potential of plant extracts against neuroendocrine tumors, which may add to existing therapies for cancer. PMID:20032400

  1. Cytotoxicity and apoptotic effects of nickel oxide nanoparticles in cultured HeLa cells

    Directory of Open Access Journals (Sweden)

    Kezban Ada

    2010-04-01

    Full Text Available The aim of this study was to observe the cytotoxicity and apoptotic effects of nickel oxide nanoparticles on humancervix epithelioid carcinoma cell line (HeLa. Nickel oxide precursors were synthesized by an nickel sulphate-excess ureareaction in boiling aqueous solution. The synthesized NiO nanoparticles (<200 nm were investigated by X-ray diffractionanalysis and transmission electron microscopy techniques. For cytotoxicity experiments, HeLa cells were incubated in50-500 μg/mL NiO for 2, 6, 12 and 16 hours. The viable cells were counted with a haemacytometer using light microscopy.The cytotoxicity was observed low in 50-200 μg/mL concentration for 16 h, but high in 400-500 μg/mL concentration for2-6 h. HeLa cells' cytoplasm membrane was lysed and detached from the well surface in 400 μg/mL concentration NiOnanoparticles. Double staining and M30 immunostaining were performed to quantify the number of apoptotic cells in cultureon the basis of apoptotic cell nuclei scores. The apoptotic effect was observed 20% for 16 h incubation.

  2. The calcimimetic R-568 induces apoptotic cell death in prostate cancer cells

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    Cheng Guangming

    2009-07-01

    Full Text Available Abstract Background Increased serum level of parathyroid hormone (PTH was found in metastatic prostate cancers. Calcimimetic R-568 was reported to reduce PTH expression, to suppress cell proliferation and to induce apoptosis in parathyroid cells. In this study, we investigated the effect of R-568 on cellular survival of prostate cancer cells. Methods Prostate cancer cell lines LNCaP and PC-3 were used in this study. Cellular survival was determined with MTT, trypan blue exclusion and fluorescent Live/Death assays. Western blot assay was utilized to assess apoptotic events induced by R-568 treatment. JC-1 staining was used to evaluate mitochondrial membrane potential. Results In cultured prostate cancer LNCaP and PC-3 cells, R-568 treatment significantly reduced cellular survival in a dose- and time-dependent manner. R-568-induced cell death was an apoptotic event, as evidenced by caspase-3 processing and PARP cleavage, as well as JC-1 color change in mitochondria. Knocking down calcium sensing receptor (CaSR significantly reduced R-568-induced cytotoxicity. Enforced expression of Bcl-xL gene abolished R-568-induced cell death, while loss of Bcl-xL expression led to increased cell death in R-568-treated LNCaP cells,. Conclusion Taken together, our data demonstrated that calcimimetic R-568 triggers an intrinsic mitochondria-related apoptotic pathway, which is dependent on the CaSR and is modulated by Bcl-xL anti-apoptotic pathway.

  3. Caspase dependent apoptotic inhibition of melanoma and lung cancer cells by tropical Rubus extracts.

    Science.gov (United States)

    George, Blassan Plackal Adimuriyil; Abrahamse, Heidi; Hemmaragala, Nanjundaswamy M

    2016-05-01

    Rubus fairholmianus Gard. inhibits human melanoma (A375) and lung cancer (A549) cell growth by the caspase dependent apoptotic pathway. Herbal products have a long history of clinical use and acceptance. They are freely available natural compounds that can be safely used to prevent various ailments. The plants and plant derived products became the basis of traditional medicine system throughout the world for thousands of years. The effects of R. fairholmianus root acetone extract (RFRA) on the proliferation of A375 and A549 cells was examined in this study. RFRA led to a decrease in cell viability, proliferation and an increase in cytotoxicity in a dose dependent manner when compared with control and normal skin fibroblast cells (WS1). The morphology of treated cells supported apoptotic cell death. Annexin V/propidium iodide staining indicated that RFRA induced apoptosis in A375 and A549 cells and the percentages of early and late apoptotic populations significantly increased. Moreover, the apoptotic inducing ability of RFRA when analysing effector caspase 3/7 activity, indicated a marked increase in treated cells. In summary, we have shown the anticancer effects of RFRA in A375 and A549 cancer cells via induction of caspase dependent apoptosis in vitro. The extract is more effective against melanoma; which may suggest the usefulness of RFRA-based anticancer therapies. PMID:27133056

  4. Apoptotic Susceptibility to DNA Damage of Pluripotent Stem Cells Facilitates Pharmacologic Purging of Teratoma Risk

    OpenAIRE

    Smith, Alyson J.; Nelson, Natalie G.; Oommen, Saji; Hartjes, Katherine A.; Folmes, Clifford D.; Terzic, Andre; Nelson, Timothy J.

    2012-01-01

    The pluripotent cell-purging assay validated herein demonstrates that pluripotent cells are selectively hypersensitive to DNA damage-induced apoptosis as a function of the specific apoptotic inducer protein Puma. Risk of dysregulated growth is decreased and the safety profile of transplant-ready, bioengineered progenitor cells is augmented.

  5. SIRT1 inhibition restores apoptotic sensitivity in p53-mutated human keratinocytes

    Energy Technology Data Exchange (ETDEWEB)

    Herbert, Katharine J.; Cook, Anthony L., E-mail: Anthony.Cook@utas.edu.au; Snow, Elizabeth T., E-mail: elizabeth.snow@utas.edu.au

    2014-06-15

    Mutations to the p53 gene are common in UV-exposed keratinocytes and contribute to apoptotic resistance in skin cancer. P53-dependent activity is modulated, in part, by a complex, self-limiting feedback loop imposed by miR-34a-mediated regulation of the lysine deacetylase, SIRT1. Expression of numerous microRNAs is dysregulated in squamous and basal cell carcinomas; however the contribution of specific microRNAs to the pathogenesis of skin cancer remains untested. Through use of RNAi, miRNA target site blocking oligonucleotides and small molecule inhibitors, this study explored the influence of p53 mutational status, SIRT1 activity and miR-34a levels on apoptotic sensitivity in primary (NHEK) and p53-mutated (HaCaT) keratinocyte cell lines. SIRT1 and p53 are overexpressed in p53-mutated keratinocytes, whilst miR-34a levels are 90% less in HaCaT cells. HaCaTs have impaired responses to p53/SIRT1/miR-34a axis manipulation which enhanced survival during exposure to the chemotherapeutic agent, camptothecin. Inhibition of SIRT1 activity in this cell line increased p53 acetylation and doubled camptothecin-induced cell death. Our results demonstrate that p53 mutations increase apoptotic resistance in keratinocytes by interfering with miR-34a-mediated regulation of SIRT1 expression. Thus, SIRT1 inhibitors may have a therapeutic potential for overcoming apoptotic resistance during skin cancer treatment. - Highlights: • Impaired microRNA biogenesis promotes apoptotic resistance in HaCaT keratinocytes. • TP53 mutations suppress miR-34a-mediated regulation of SIRT1 expression. • SIRT1 inhibition increases p53 acetylation in HaCaTs, restoring apoptosis.

  6. Pro‑apoptotic effects of pycnogenol on HT1080 human fibrosarcoma cells.

    Science.gov (United States)

    Harati, Kamran; Slodnik, Pawel; Chromik, Ansgar Michael; Behr, Björn; Goertz, Ole; Hirsch, Tobias; Kapalschinski, Nicolai; Klein-Hitpass, Ludger; Kolbenschlag, Jonas; Uhl, Waldemar; Lehnhardt, Marcus; Daigeler, Adrien

    2015-04-01

    Complete surgical resection with clear margins remains the mainstay of therapy for localised fibrosarcomas. Nevertheless, metastatic fibrosarcomas still represent a therapeutic dilemma. Commonly used chemotherapeutic agents like doxorubicin have proven to be effective in pycnogenol and its constituents on human fibrosarcoma cells (HT1080). Ten healthy subjects (six females, four males, mean age 24.8 ± 6 years) received a single dose of 300 mg pycnogenol orally. Blood plasma samples were obtained before and 6 h after intake of pycnogenol. HT1080 cells were treated with these plasma samples. Additionally, HT1080 were incubated separately with catechin, epicatechin and taxifolin that are known as the main constituents of pycnogenol. Vital, apoptotic and necrotic cells were quantified using flow cytometric analysis. Gene expression was analyzed by RNA microarray. The results showed that single application of taxifolin, catechin and epicatechin reduced cell viability of HT1080 cells only moderately. A single dose of 300 mg pycnogenol given to 10 healthy adults produced plasma samples that led to significant apoptotic cell death ex vivo whereas pycnogenol-negative serum displayed no apoptotic activity. Microarray analysis revealed remarkable expression changes induced by pycnogenol in a variety of genes, which are involved in different apoptotic pathways of cancer cells [Janus kinase 1 (JAK1), DUSP1, RHOA, laminin γ1 (LAMC1), fibronectin 1 (FN1), catenin α1 (CTNNA1), ITGB1]. In conclusion, metabolised pycnogenol induces apoptosis in human fibrosarcoma cells. Pycnogenol exhibits its pro-apoptotic activity as a mixture and is more effective than its main constituents catechin, epicatechin and taxifolin indicating that the metabolised components interact synergistically. These results provide experimental support for in vivo trials assessing the effect of the pine bark extract pycnogenol. PMID:25625225

  7. SIRT1 inhibition restores apoptotic sensitivity in p53-mutated human keratinocytes

    International Nuclear Information System (INIS)

    Mutations to the p53 gene are common in UV-exposed keratinocytes and contribute to apoptotic resistance in skin cancer. P53-dependent activity is modulated, in part, by a complex, self-limiting feedback loop imposed by miR-34a-mediated regulation of the lysine deacetylase, SIRT1. Expression of numerous microRNAs is dysregulated in squamous and basal cell carcinomas; however the contribution of specific microRNAs to the pathogenesis of skin cancer remains untested. Through use of RNAi, miRNA target site blocking oligonucleotides and small molecule inhibitors, this study explored the influence of p53 mutational status, SIRT1 activity and miR-34a levels on apoptotic sensitivity in primary (NHEK) and p53-mutated (HaCaT) keratinocyte cell lines. SIRT1 and p53 are overexpressed in p53-mutated keratinocytes, whilst miR-34a levels are 90% less in HaCaT cells. HaCaTs have impaired responses to p53/SIRT1/miR-34a axis manipulation which enhanced survival during exposure to the chemotherapeutic agent, camptothecin. Inhibition of SIRT1 activity in this cell line increased p53 acetylation and doubled camptothecin-induced cell death. Our results demonstrate that p53 mutations increase apoptotic resistance in keratinocytes by interfering with miR-34a-mediated regulation of SIRT1 expression. Thus, SIRT1 inhibitors may have a therapeutic potential for overcoming apoptotic resistance during skin cancer treatment. - Highlights: • Impaired microRNA biogenesis promotes apoptotic resistance in HaCaT keratinocytes. • TP53 mutations suppress miR-34a-mediated regulation of SIRT1 expression. • SIRT1 inhibition increases p53 acetylation in HaCaTs, restoring apoptosis

  8. Protein S blocks the extrinsic apoptotic cascade in tissue plasminogen activator/N-methyl D-aspartate-treated neurons via Tyro3-Akt-FKHRL1 signaling pathway

    Directory of Open Access Journals (Sweden)

    Freeman Robert S

    2011-02-01

    phosphorylation of FHKRL1 that is required for PS-mediated neuronal protection after tPA/NMDA-induced injury. Conclusions PS blocks the extrinsic apoptotic cascade through a novel mechanism mediated by Tyro3-dependent FKHRL1 phosphorylation which inhibits FasL-dependent caspase-8 activation and can control tPA-induced neurotoxicity associated with pathologic activation of NMDA receptors. The present findings should encourage future studies in animal stroke models to determine whether PS can increase the therapeutic window of tPA by reducing its post-ischemic neuronal toxicity.

  9. Tat-NOL3 protects against hippocampal neuronal cell death induced by oxidative stress through the regulation of apoptotic pathways.

    Science.gov (United States)

    Sohn, Eun Jeong; Shin, Min Jea; Eum, Won Sik; Kim, Dae Won; Yong, Ji In; Ryu, Eun Ji; Park, Jung Hwan; Cho, Su Bin; Cha, Hyun Ju; Kim, Sang Jin; Yeo, Hyeon Ji; Yeo, Eun Ji; Choi, Yeon Joo; Im, Seung Kwon; Kweon, Hae Young; Kim, Duk-Soo; Yu, Yeon Hee; Cho, Sung-Woo; Park, Meeyoung; Park, Jinseu; Cho, Yong-Jun; Choi, Soo Young

    2016-07-01

    Oxidative stress-induced apoptosis is associated with neuronal cell death and ischemia. The NOL3 [nucleolar protein 3 (apoptosis repressor with CARD domain)] protein protects against oxidative stress-induced cell death. However, the protective mechanism responsible for this effect as well as the effects of NOL3 against oxidative stress in ischemia remain unclear. Thus, we examined the protective effects of NOL3 protein on hydrogen peroxide (H2O2)-induced oxidative stress and the mechanism responsible for these effects in hippocampal neuronal HT22 cells and in an animal model of forebrain ischemia using Tat-fused NOL3 protein (Tat-NOL3). Purified Tat-NOL3 protein transduced into the H2O2-exposed HT22 cells and inhibited the production of reactive oxygen species (ROS), DNA fragmentation and reduced mitochondrial membrane potential (ΔΨm). In addition, Tat-NOL3 prevented neuronal cell death through the regulation of apoptotic signaling pathways including Bax, Bcl-2, caspase-2, -3 and -8, PARP and p53. In addition, Tat-NOL3 protein transduced into the animal brains and significantly protected against neuronal cell death in the CA1 region of the hippocampus by regulating the activation of microglia and astrocytes. Taken together, these findings demonstrate that Tat-NOL3 protein protects against oxidative stress-induced neuronal cell death by regulating oxidative stress and by acting as an anti-apoptotic protein. Thus, we suggest that Tat-NOL3 represents a potential therapeutic agent for protection against ischemic brain injury. PMID:27221790

  10. JNK controls the onset of mitosis in planarian stem cells and triggers apoptotic cell death required for regeneration and remodeling.

    Directory of Open Access Journals (Sweden)

    María Almuedo-Castillo

    2014-06-01

    Full Text Available Regeneration of lost tissues depends on the precise interpretation of molecular signals that control and coordinate the onset of proliferation, cellular differentiation and cell death. However, the nature of those molecular signals and the mechanisms that integrate the cellular responses remain largely unknown. The planarian flatworm is a unique model in which regeneration and tissue renewal can be comprehensively studied in vivo. The presence of a population of adult pluripotent stem cells combined with the ability to decode signaling after wounding enable planarians to regenerate a complete, correctly proportioned animal within a few days after any kind of amputation, and to adapt their size to nutritional changes without compromising functionality. Here, we demonstrate that the stress-activated c-jun-NH2-kinase (JNK links wound-induced apoptosis to the stem cell response during planarian regeneration. We show that JNK modulates the expression of wound-related genes, triggers apoptosis and attenuates the onset of mitosis in stem cells specifically after tissue loss. Furthermore, in pre-existing body regions, JNK activity is required to establish a positive balance between cell death and stem cell proliferation to enable tissue renewal, remodeling and the maintenance of proportionality. During homeostatic degrowth, JNK RNAi blocks apoptosis, resulting in impaired organ remodeling and rescaling. Our findings indicate that JNK-dependent apoptotic cell death is crucial to coordinate tissue renewal and remodeling required to regenerate and to maintain a correctly proportioned animal. Hence, JNK might act as a hub, translating wound signals into apoptotic cell death, controlled stem cell proliferation and differentiation, all of which are required to coordinate regeneration and tissue renewal.

  11. Diacerein-mediated inhibition of IL-6/IL-6R signaling induces apoptotic effects on breast cancer.

    Science.gov (United States)

    Bharti, R; Dey, G; Ojha, P K; Rajput, S; Jaganathan, S K; Sen, R; Mandal, M

    2016-07-28

    Interleukin-6 (IL-6) signaling network has been implicated in oncogenic transformations making it attractive target for the discovery of novel cancer therapeutics. In this study, potent antiproliferative and apoptotic effect of diacerein were observed against breast cancer. In vitro apoptosis was induced by this drug in breast cancer cells as verified by increased sub-G1 population, LIVE/DEAD assay, cell cytotoxicity and presence of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells, as well as downregulation of antiapoptotic proteins Bcl-2 and Bcl-xL and upregulation of apoptotic protein Bax. In addition, apoptosis induction was found to be caspase dependent. Further molecular investigations indicated that diacerein instigated apoptosis was associated with inhibition of IL-6/IL-6R autocrine signaling axis. Suppression of STAT3, MAPK and Akt pathways were also observed as a consequence of diacerein-mediated upstream inhibition of IL-6/IL-6R. Fluorescence study and western blot analysis revealed cytosolic accumulation of STAT3 in diacerein-treated cells. The docking study showed diacerein/IL-6R interaction that was further validated by competitive binding assay and isothermal titration calorimetry. Most interestingly, it was found that diacerein considerably suppressed tumor growth in MDA-MB-231 xenograft model. The in vivo antitumor effect was correlated with decreased proliferation (Ki-67), increased apoptosis (TUNEL) and inhibition of IL-6/IL-6R-mediated STAT3, MAPK and Akt pathway in tumor remnants. Taken together, diacerein offered a novel blueprint for cancer therapy by hampering IL-6/IL-6R/STAT3/MAPK/Akt network. PMID:26616855

  12. Proteolytic activation of latent TGF-beta precedes caspase-3 activation and enhances apoptotic death of lung epithelial cells.

    Science.gov (United States)

    Solovyan, Victor T; Keski-Oja, Jorma

    2006-05-01

    Transforming growth factors beta (TGF-betas) are multifunctional cytokines, which are secreted in latent forms in large latent TGF-beta complexes (LL-TGF-beta) with subsequent deposition to the extracellular matrix (ECM). While a variety of mechanisms capable of activating latent TGF-beta in vitro have been described, the physiological conditions, which promote the activation of TGF-beta in vivo are poorly understood. Mink lung epithelial cells (Mv1Lu) are a widely used model for evaluation of the effects of exogenous TGF-beta both in transcriptional and growth inhibitor assays. We find here that apoptosis of Mv1Lu cells, induced either by staurosporine or serum deprivation, is accompanied by proteolytic processing of LL-TGF-beta and the activation of endogenous TGF-beta. Activation of TGF-beta preceded caspase-3 activation and was almost completely suppressed by the serine protease inhibitor, AEBSF. Both exogenous and endogenously activated TGF-betas were able to enhance the apoptotic response of Mv1Lu cells leading to potentiation of cell death. Potentiation of cell death by activated TGF-beta was associated with downregulation of Akt and p38 MAPK, which were both activated at the initial stages of Mv1Lu apoptosis and were suppressed by exogenous TGF-beta. Pharmacological interruption of either phosphoinositide-3-kinase (PI-3K)/Akt or p38 MAPK signaling by the specific inhibitors mimicked the effect of TGF-beta leading to potentiation of cell death. Current results suggest that proteolytic activation of endogenous TGF-beta is a component of the apoptotic response, capable of modulating the death of Mv1Lu cells by inhibition of both PI-3K/Akt and p38 MAPK-dependent survival pathways. PMID:16447253

  13. Evidence for immunomodulation and apoptotic processes induced by cationic polystyrene nanoparticles in the hemocytes of the marine bivalve Mytilus.

    Science.gov (United States)

    Canesi, L; Ciacci, C; Bergami, E; Monopoli, M P; Dawson, K A; Papa, S; Canonico, B; Corsi, I

    2015-10-01

    Polymeric nanoparticles can reach the marine environment from different sources as weathering of plastic debris and nanowaste. Nevertheless, few data are available on their fate and impact on marine biota. Polystyrene nanoparticles (PS NPs) can be considered as a model for studying the effects of nanoplastics in marine organisms: recent data on amino-modified PS NPs (PS-NH2) toxicity in sea urchin embryos underlined that marine invertebrates can be biological targets of nanoplastics. Cationic PS NPs have been shown to be toxic to mammalian cells, where they can induce apoptotic processes; however, no information is available on their effects and mechanisms of action in the cells of marine organisms. In this work, the effects of 50 nm PS-NH2 were investigated in the hemocytes of the marine bivalve Mytilus galloprovincialis. Hemocytes were exposed to different concentrations (1, 5, 50 μg/ml) of PS-NH2 suspension in ASW. Clear signs of cytoxicity were evident only at the highest concentrations (50 μg/ml). On the other hand, a dose dependent decrease in phagocytic activity and increase in lysozyme activity were observed. PS-NH2 NPs also stimulated increase in extracellular ROS (reactive oxygen species) and NO (nitric oxide) production, with maximal effects at lower concentrations. Moreover, at the highest concentration tested, PS-NH2 NPs induced apoptotic process, as evaluated by Flow cytometry (Annexin V binding and mitochondrial parameters). The results demonstrate that in marine invertebrates the immune function can represent a significant target for PS-NPs. Moreover, in Mytilus hemocytes, PS-NH2 NPs can act through mechanisms similar to those observed in mammalian cells. Further research is necessary on specific mechanisms of toxicity and cellular uptake of nanoplastics in order to assess their impact on marine biota. PMID:26115607

  14. Prediction of localization and interactions of apoptotic proteins

    Directory of Open Access Journals (Sweden)

    Matula Pavel

    2009-07-01

    Full Text Available Abstract During apoptosis several mitochondrial proteins are released. Some of them participate in caspase-independent nuclear DNA degradation, especially apoptosis-inducing factor (AIF and endonuclease G (endoG. Another interesting protein, which was expected to act similarly as AIF due to the high sequence homology with AIF is AIF-homologous mitochondrion-associated inducer of death (AMID. We studied the structure, cellular localization, and interactions of several proteins in silico and also in cells using fluorescent microscopy. We found the AMID protein to be cytoplasmic, most probably incorporated into the cytoplasmic side of the lipid membranes. Bioinformatic predictions were conducted to analyze the interactions of the studied proteins with each other and with other possible partners. We conducted molecular modeling of proteins with unknown 3D structures. These models were then refined by MolProbity server and employed in molecular docking simulations of interactions. Our results show data acquired using a combination of modern in silico methods and image analysis to understand the localization, interactions and functions of proteins AMID, AIF, endonuclease G, and other apoptosis-related proteins.

  15. Structural Basis of Semaphorin-Plexin Recognition and Viral Mimicry from Sema7A and A39R Complexes with PlexinC1

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Heli; Juo, Z. Sean; Shim, Ann Hye-Ryong; Focia, Pamela J.; Chen, Xiaoyan; Garcia, K. Christopher; He, Xiaolin (Stanford-MED); (NWU)

    2010-10-18

    Repulsive signaling by Semaphorins and Plexins is crucial for the development and homeostasis of the nervous, immune, and cardiovascular systems. Sema7A acts as both an immune and a neural Semaphorin through PlexinC1, and A39R is a Sema7A mimic secreted by smallpox virus. We report the structures of Sema7A and A39R complexed with the Semaphorin-binding module of PlexinC1. Both structures show two PlexinC1 molecules symmetrically bridged by Semaphorin dimers, in which the Semaphorin and PlexinC1 {beta} propellers interact in an edge-on, orthogonal orientation. Both binding interfaces are dominated by the insertion of the Semaphorin's 4c-4d loop into a deep groove in blade 3 of the PlexinC1 propeller. A39R appears to achieve Sema7A mimicry by preserving key Plexin-binding determinants seen in the mammalian Sema7A complex that have evolved to achieve higher affinity binding to the host-derived PlexinC1. The complex structures support a conserved Semaphorin-Plexin recognition mode and suggest that Plexins are activated by dimerization.

  16. Estrogen treatment following severe burn injury reduces brain inflammation and apoptotic signaling

    Directory of Open Access Journals (Sweden)

    Idris Ahamed H

    2009-10-01

    Full Text Available Abstract Background Patients with severe burn injury experience a rapid elevation in multiple circulating pro-inflammatory cytokines, with the levels correlating with both injury severity and outcome. Accumulations of these cytokines in animal models have been observed in remote organs, however data are lacking regarding early brain cytokine levels following burn injury, and the effects of estradiol on these levels. Using an experimental animal model, we studied the acute effects of a full-thickness third degree burn on brain levels of TNF-α, IL-1β, and IL-6 and the protective effects of acute estrogen treatment on these levels. Additionally, the acute administration of estrogen on regulation of inflammatory and apoptotic events in the brain following severe burn injury were studied through measuring the levels of phospho-ERK, phospho-Akt, active caspase-3, and PARP cleavage in the placebo and estrogen treated groups. Methods In this study, 149 adult Sprague-Dawley male rats received 3rd degree 40% total body surface area (TBSA burns. Fifteen minutes following burn injury, the animals received a subcutaneous injection of either placebo (n = 72 or 17 beta-estradiol (n = 72. Brains were harvested at 0.5, 1, 2, 4, 6, 8, 12, 18, and 24 hours after injury from the control (n = 5, placebo (n = 8/time point, and estrogen treated animals (n = 8/time point. The brain cytokine levels were measured using the ELISA method. In addition, we assessed the levels of phosphorylated-ERK, phosphorylated-Akt, active caspase-3, and the levels of cleaved PARP at the 24 hour time-point using Western blot analysis. Results In burned rats, 17 beta-estradiol significantly decreased the levels of brain tissue TNF-α (~25%, IL-1β (~60%, and IL-6 (~90% when compared to the placebo group. In addition, we determined that in the estrogen-treated rats there was an increase in the levels of phospho-ERK (p p p p Conclusion Following severe burn injury, estrogens decrease both

  17. Copper induced immunotoxicity promote differential apoptotic pathways in spleen and thymus

    International Nuclear Information System (INIS)

    Highlights: ► Copper-induced ROS generation and mitochondrial trans-membrane potential changes result in different consequences in spleen and thymus. ► Inflammation appeared in both the spleen and thymus after to copper treatment. ► Apoptosis in the spleen appears to follow a p53-independent pathway. ► Apoptosis in the thymus appears to follow a p53-dependent intrinsic and extrinsic pathway. ► In both the spleen and thymus, the CD4+ T cell population decreased and CD8+ T cell population increased after copper treatment. - Abstract: Inorganic copper, such as that in drinking water and copper supplements, largely bypasses the liver and enters the free copper pool of the blood directly and that promote immunosuppression. Nevertheless, the signaling pathways underlying copper-induced immune cell death remains largely unclear. According to our previous in vivo report, to evaluate the further details of the apoptotic mechanism, we have investigated how copper regulates apoptotic pathways in spleen and thymus. We have analyzed different protein expression by western blotting and immunohistochemistry and mRNA expression by RT-PCR and gel electrophoresis. We also have measured mitochondrial trans-membrane potential, ROS and CD4+ and CD8+ population by flow cytometry. Sub lethal doses of copper in spleen and thymus of in vivo Swiss albino mice promote different apoptotic pathways. In case of spleen, ROS generation and mitochondrial trans-membrane potential changes promotes intrinsic pathway of apoptosis that was p53 independent, ultimately leads to decrease in CD4+ T cell population and increase in CD8+ T cell population. However in case of thymus, ROS generation and mitochondrial trans-membrane potential changes lead to death receptor that regulate extrinsic and intrinsic pathways of apoptosis and the apoptotic mechanism which was p53 dependent. Due to copper treatment, thymic CD4+ T cell population decreased and CD8+ T cell population was increased or

  18. Histone demethylase Jmjd3 regulates osteoblast apoptosis through targeting anti-apoptotic protein Bcl-2 and pro-apoptotic protein Bim.

    Science.gov (United States)

    Yang, Di; Okamura, Hirohiko; Teramachi, Jumpei; Haneji, Tatsuji

    2016-04-01

    Posttranslational modifications including histone methylation regulate gene transcription through directly affecting the structure of chromatin. Trimethylation of histone H3K27 (H3K27me3) contributes to gene silencing and the histone demethylase Jumonji domain-containing 3 (Jmjd3) specifically removes the methylation of H3K27me3, followed by the activation of gene expression. In the present study, we explored the roles of Jmjd3 in regulating osteoblast apoptosis. Knockdown of Jmjd3 promoted osteoblast apoptosis induced by serum deprivation with decreased mitochondrial membrane potential and increased levels of caspase-3 activation, PARP cleavage, and DNA fragmentation. B cell lymphoma-2 (Bcl-2), an anti-apoptotic protein, was down-regulated by knockdown of Jmjd3 through retaining H3K27me3 on its promoter region. Knockdown of Jmjd3 increased the pro-apoptotic activity of Bim through inhibiting ERK-dependent phosphorylation of Bim. Protein kinase D1 (PKD1), which stimulates ERK phosphorylation, decreased in the Jmjd3-knockdown cells and introduction of PKD1 relieved osteoblast apoptosis in the Jmjd3-knockdown cells through increasing ERK-regulated Bim phosphorylation. These results suggest that Jmjd3 regulates osteoblast apoptosis through targeting Bcl-2 expression and Bim phosphorylation. PMID:26795455

  19. Fumanjian, a Classic Chinese Herbal Formula, Can Ameliorate the Impairment of Spatial Learning and Memory through Apoptotic Signaling Pathway in the Hippocampus of Rats with Aβ 1–40 -Induced Alzheimer's Disease

    OpenAIRE

    Hai-yan Hu; Zhi-hui Cui; Hui-qin Li; Yi-ru Wang; Xiang Chen; Ji-huang Li; Dong-mei Xv; Guo-qing Zheng

    2014-01-01

    Alzheimer's disease (AD) is the most common form of dementia and lacks disease-altering treatments. Fumanjian (FMJ), a famous classic Chinese herbal prescription for dementia, was first recorded in the Complete Works of Jingyue during the Ming Dynasty. This study aimed to investigate whether FMJ could prevent cognitive deficit and take neuroprotective effects in Aβ 1–40-induced rat model through apoptotic signaling pathway. AD model was established by bilateral injection of Aβ 1–40 into hippo...

  20. TRPV1 stimulation triggers apoptotic cell death of rat cortical neurons

    International Nuclear Information System (INIS)

    Transient receptor potential vanilloid 1 (TRPV1) functions as a polymodal nociceptor and is activated by several vanilloids, including capsaicin, protons and heat. Although TRPV1 channels are widely distributed in the brain, their roles remain unclear. Here, we investigated the roles of TRPV1 in cytotoxic processes using TRPV1-expressing cultured rat cortical neurons. Capsaicin induced severe neuronal death with apoptotic features, which was completely inhibited by the TRPV1 antagonist capsazepine and was dependent on extracellular Ca2+ influx. Interestingly, nifedipine, a specific L-type Ca2+ channel blocker, attenuated capsaicin cytotoxicity, even when applied 2-4 h after the capsaicin. ERK inhibitor PD98059 and several antioxidants, but not the JNK and p38 inhibitors, attenuated capsaicin cytotoxicity. Together, these data indicate that TRPV1 activation triggers apoptotic cell death of rat cortical cultures via L-type Ca2+ channel opening, Ca2+ influx, ERK phosphorylation, and reactive oxygen species production.

  1. Investigation of apoptotic events at molecular level induced by SERS guided targeted theranostic nanoprobe

    Science.gov (United States)

    Narayanan, Nisha; Nair, Lakshmi V.; Karunakaran, Varsha; Joseph, Manu M.; Nair, Jyothi B.; N, Ramya A.; Jayasree, Ramapurath S.; Maiti, Kaustabh Kumar

    2016-06-01

    Herein, we have examined distinctive structural and functional variations of cellular components during apoptotic cell death induced by a targeted theranostic nanoprobe, MMP-SQ@GNR@LAH-DOX, which acted as a SERS ``on/off'' probe in the presence of a MMP protease and executed synergistic photothermal chemotherapy, as reflected by the SERS fingerprinting, corresponding to the phosphodiester backbone of DNA.Herein, we have examined distinctive structural and functional variations of cellular components during apoptotic cell death induced by a targeted theranostic nanoprobe, MMP-SQ@GNR@LAH-DOX, which acted as a SERS ``on/off'' probe in the presence of a MMP protease and executed synergistic photothermal chemotherapy, as reflected by the SERS fingerprinting, corresponding to the phosphodiester backbone of DNA. Electronic supplementary information (ESI) available. See DOI: 10.1039/c6nr03385g

  2. Pro-apoptotic NOXA is implicated in atmospheric-pressure plasma-induced melanoma cell death

    Science.gov (United States)

    Ishaq, M.; Bazaka, K.; Ostrikov, K.

    2015-11-01

    Atmospheric-pressure plasma (APP) has been successfully used to treat several types of cancers in vivo and in vitro, with the effect being primarily attributed to the generation of reactive oxygen species (ROS). However, the mechanisms by which APP induces apoptosis in cancer cells require further elucidation. In this study, the effects of APP on the expression of 500 genes in melanoma Mel007 cancer cells were examined. Pro-apoptotic phorbol-12-myristate-13-acetate-induced protein (PMAIP1), also known as NOXA, was highly expressed as a result of APP treatment in a dose-dependent manner. Blocking of ROS using scavenger NAC or silencing of NOXA gene by RNA interference inhibited the APP-induced NOXA genes upregulation and impaired caspases 3/7 mediated apoptosis, confirming the important role plasma-generated ROS species and pro-apoptotic NOXA play in APP-induced cancer cell death.

  3. The anti-apoptotic members of the Bcl-2 family are attractive tumor-associated antigens

    DEFF Research Database (Denmark)

    Straten, Per thor; Andersen, Mads Hald

    2010-01-01

    Anti-apoptotic members of the Bcl-2 family (Bcl-2, Bcl-X(L) and Mcl-2) are pivotal regulators of apoptotic cell death. They are all highly overexpressed in cancers of different origin in which they enhance the survival of the cancer cells. Consequently, they represent prime candidates for anti......, spontaneous cellular immune responses against the Bcl-2 family proteins have been identified as frequent features in cancer patients underscoring that these proteins are natural targets for the immune system. Thus, Bcl-2 family may serve as an important and widely applicable target for anti......-cancer immunotherapeutic strategies, alone or in the combination with conventional therapy. Here, we summarize the current knowledge of Bcl-2 family proteins as T-cell antigens, which has set the stage for the first explorative trial using these antigens in therapeutic vaccinations against cancer, and discuss future...

  4. The apoptotic effects of escin in the H-Ras transformed 5RP7 cell line.

    Science.gov (United States)

    Güney, G; Kutlu, H M; Işcan, A

    2013-06-01

    Extracts of Aesculus hippocastanum L. (horse chestnut) seed have been used in the treatment of chronic venous insufficiency, edema and hemorrhoids. Most of the beneficial effects of horse chestnut are attributed to its principal component β-escin or escin. We have evaluated the cytotoxic and apoptotic effects of escin in the H-Ras 5RP7 cell line by analyzing cell growth inhibition, apoptosis and caspase-3 dependent activity. We have also shown structural and ultrastructural changes in these cell using confocal and transmission electron microscopy. The results indicated that escin has significant inhibitory effects on cell growth and the percentage of apoptotic cells increased after treatment with escin, and the micrographs confirmed that escin damaged these cells and induced apoptosis. PMID:22911540

  5. Cocaine Causes Apoptotic Death in Rat Mesencephalon and Striatum Primary Cultures

    Directory of Open Access Journals (Sweden)

    Lucilia B. Lepsch

    2015-01-01

    Full Text Available To study cocaine’s toxic effects in vitro, we have used primary mesencephalic and striatal cultures from rat embryonic brain. Treatment with cocaine causes a dramatic increase in DNA fragmentation in both primary cultures. The toxicity induced by cocaine was paralleled with a concomitant decrease in the microtubule associated protein 2 (MAP2 and/or neuronal nucleus protein (NeuN staining. We also observed in both cultures that the cell death caused by cocaine was induced by an apoptotic mechanism, confirmed by TUNEL assay. Therefore, the present paper shows that cocaine causes apoptotic cell death and inhibition of the neurite prolongation in striatal and mesencephalic cell culture. These data suggest that if similar neuronal damage could be produced in the developing human brain, it could account for the qualitative or quantitative defects in neuronal pathways that cause a major handicap in brain function following prenatal exposure to cocaine.

  6. Nucleo-cytoplasmic communication in apoptotic response to genotoxic and inflammatory stress

    Institute of Scientific and Technical Information of China (English)

    Jean Y. J. WANG

    2005-01-01

    Genotoxic agents or inflammatory cytokines activate cellular stress responses and trigger programmed cell death.We have identified a signal transduction module, including three nuclear proteins that participate in the regulation of cell death induced by chemotherapeutic agents and tumor necrosis factor (TNF). In this nuclear signaling module, retinoblastoma protein (Rb) functions as an inhibitor of apoptotic signal transduction. Inactivation of Rb by phosphorylation or caspase-dependent cleavage/degradation is required for cell death to occur. Rb inhibits the Abl tyrosine kinase. Thus,Rb inactivation is a pre-requisite for Abl activation by DNA damage or TNF. Activation of nuclear Abl and its downstream effector p73 induces mitochondriadependent cell death. The involvement of these nuclear signal transducers in TNF induced apoptosis, which does not require new gene expression, indicates that nuclear events other than transcription can contribute to extrinsic apoptotic signal transduction.

  7. Modulation of Apoptotic Pathways by Human Papillomaviruses (HPV: Mechanisms and Implications for Therapy

    Directory of Open Access Journals (Sweden)

    Chung-Hsiang Yuan

    2012-12-01

    Full Text Available The ability of the host to trigger apoptosis in infected cells is perhaps the most powerful tool by which viruses can be cleared from the host organism. To avoid elimination by this mechanism, human papillomaviruses (HPV have developed several mechanisms that enable the cells they infect to elude both extrinsic and intrinsic apoptosis. In this manuscript, we review the current literature regarding how HPV-infected cells avoid apoptosis and the molecular mechanisms involved in these events. In particular, we will discuss the modifications in intrinsic and extrinsic apoptotic pathways caused by proteins encoded by HPV early genes. Many of the current efforts regarding anti-cancer drug development are focused on directing tumor cells to undergo apoptosis. However, the ability of HPV-infected cells to resist apoptotic signals renders such therapies ineffective. Possible mechanisms for overcoming the resistance of HPV-infected tumor cells to anticancer drugs will be discussed.

  8. Cell-Centric View of Apoptosis and Apoptotic Cell Death-Inducing Antitumoral Strategies

    International Nuclear Information System (INIS)

    Programmed cell death and especially apoptotic cell death, occurs under physiological conditions and is also desirable under pathological circumstances. However, the more we learn about cellular signaling cascades, the less plausible it becomes to find restricted and well-limited signaling pathways. In this context, an extensive description of pathway-connections is necessary in order to point out the main regulatory molecules as well as to select the most appropriate therapeutic targets. On the other hand, irregularities in programmed cell death pathways often lead to tumor development and cancer-related mortality is projected to continue increasing despite the effort to develop more active and selective antitumoral compounds. In fact, tumor cell plasticity represents a major challenge in chemotherapy and improvement on anticancer therapies seems to rely on appropriate drug combinations. An overview of the current status regarding apoptotic pathways as well as available chemotherapeutic compounds provides a new perspective of possible future anticancer strategies

  9. Apoptotic gene expression in the neural tube during early human embryonic development

    Institute of Scientific and Technical Information of China (English)

    Guifang Chen; Tiandong Li; Peipei Ding; Ping Yang; Xiao Zhang

    2011-01-01

    Neural tube development comprises neural induction,neural epithelial cell proliferation,and apoptosis,as well as migration of nerve cells.Too much or too little apoptosis leads to abnormal nervous system development.The present study analyzed expression and distribution of apoptotic-related factors,including Fas,FasL,and caspase-3,during human embryonic neural tube development.Experimental results showed that increased caspase-3 expression promoted neural apoptosis via a mitochondriai-mediated intrinsic pathway at 4 weeks during early human embryonic neural tube development.Subsequently,Fas and FasL expression increased during embryonic development.The results suggest that neural cells influence neural apoptosis through synergistic effects of extrinsic pathways.Therefore,neural apoptosis during the early period of neural tube development in the human embryo might be regulated by the death receptor induced apoptotic extrinsic pathways.

  10. Cell-Centric View of Apoptosis and Apoptotic Cell Death-Inducing Antitumoral Strategies

    Directory of Open Access Journals (Sweden)

    Maria Dolores Boyano

    2011-03-01

    Full Text Available Programmed cell death and especially apoptotic cell death, occurs under physiological conditions and is also desirable under pathological circumstances. However, the more we learn about cellular signaling cascades, the less plausible it becomes to find restricted and well-limited signaling pathways. In this context, an extensive description of pathway-connections is necessary in order to point out the main regulatory molecules as well as to select the most appropriate therapeutic targets. On the other hand, irregularities in programmed cell death pathways often lead to tumor development and cancer-related mortality is projected to continue increasing despite the effort to develop more active and selective antitumoral compounds. In fact, tumor cell plasticity represents a major challenge in chemotherapy and improvement on anticancer therapies seems to rely on appropriate drug combinations. An overview of the current status regarding apoptotic pathways as well as available chemotherapeutic compounds provides a new perspective of possible future anticancer strategies.

  11. The nuclear γ-H2AX apoptotic ring: implications for cancers and autoimmune diseases.

    Science.gov (United States)

    Solier, Stéphanie; Pommier, Yves

    2014-06-01

    Apoptosis is a fundamental process for metazoan development. It is also relevant to the pathophysiology of immune diseases and cancers and to the outcome of cancer chemotherapies, as well as being a target for cancer therapies. Apoptosis involves intrinsic pathways typically initiated by DNA damaging agents and engaging mitochondria, and extrinsic pathways typically initiated by "death receptors" and their ligands TRAIL and TNF at the cell surface. Recently, we discovered the apoptotic ring, which microscopically looks like a nuclear annular staining early in apoptosis. This ring is, in three-dimensional space, a thick intranuclear shell consisting of epigenetic modifications including histone H2AX and DNA damage response (DDR) proteins. It excludes the DNA repair factors usually associated with γ-H2AX in the DDR nuclear foci. Here, we summarize our knowledge of the apoptotic ring, and discuss its biological and pathophysiological relevance, as well as its value as a potential pharmacodynamic biomarker for anticancer therapies. PMID:24448903

  12. Sulbutiamine counteracts trophic factor deprivation induced apoptotic cell death in transformed retinal ganglion cells.

    Science.gov (United States)

    Kang, Kui Dong; Majid, Aman Shah Abdul; Kim, Kyung-A; Kang, Kyungsu; Ahn, Hong Ryul; Nho, Chu Won; Jung, Sang Hoon

    2010-11-01

    Sulbutiamine is a highly lipid soluble synthetic analogue of vitamin B(1) and is used clinically for the treatment of asthenia. The aim of our study was to demonstrate whether sulbutiamine is able to attenuate trophic factor deprivation induced cell death to transformed retinal ganglion cells (RGC-5). Cells were subjected to serum deprivation for defined periods and sulbutiamine at different concentrations was added to the cultures. Various procedures (e.g. cell viability assays, apoptosis assay, reactive oxygen species analysis, Western blot analysis, flow cytometric analysis, glutathione (GSH) and glutathione-S-transferase (GST) measurement) were used to demonstrate the effect of sulbutiamine. Sulbutiamine dose-dependently attenuated apoptotic cell death induced by serum deprivation and stimulated GSH and GST activity. Moreover, sulbutiamine decreased the expression of cleaved caspase-3 and AIF. This study demonstrates for the first time that sulbutiamine is able to attenuate trophic factor deprivation induced apoptotic cell death in neuronal cells in culture. PMID:20809085

  13. Reemergence of apoptotic cells between fractionated doses in irradiated murine tumors

    International Nuclear Information System (INIS)

    The purpose of this investigation was to follow up our previous studies on the development of apoptosis in irradiated murine tumors by testing whether an apoptotic subpopulation of cells reemerges between fractionated exposures. Mice bearing a murine ovarian carcinoma, OCa-I, were treated in vivo with two fractionation protocols: two doses of 12.5 Gy separated by various times out to 5 days and multiple daily fractions of 2.5 Gy. Animals were killed 4 h after the last dose in each protocol, and the percent apoptosis was scored from stained histological sections made from the irradiated tumors according to the specific features characteristic of this mode of cell death. The 12.5+12.5 Gy protocol yielded a net total percent apoptosis of about 45% when the two doses were separated by 5 days (total dose = 25 Gy), whereas the 2.5 Gy per day protocol yielded about 50% net apoptotic cells when given for 5 days (total dose = 12.5 Gy). These values are to be compared to the value of 36% apoptotic cells that is yielded by large single doses (> 25 Gy). Thus, these results indicate that an apoptotic subpopulation of cells reemerged between the fractions in both protocols, but the kinetics appeared to be delayed in the 12.5+12.5 Gy vs. the multiple 2.5 Gy protocol. This reemergence of cells with the propensity for radiation-induced apoptosis between fractionated exposures is consistent with a role for this mode of cell death in the response of tumors to radiotherapy and may represent the priming of a new subpopulation of tumor cells for apoptosis as part of normal tumor homeostasis to counterbalance cell division. 25 refs., 3 figs., 1 tab

  14. Apoptotic Effect of Coix Polysaccharides on A549 Lung Cancer Cells in Vitro

    OpenAIRE

    Luo, Cheng; Liu, Wei; Lu, Xiangyi

    2012-01-01

    Background and objective Coix seeds are commonly used in Traditional Chinese Medicine and ingested through daily diet. The aim of this study is to analyze the apoptotic effect of coix polysaccharides on A549 cells. Methods A fraction of polysaccharides was isolated from coix seeds and extracted by ethanol precipitation. The extract was then purified by dialysis and DEAE-52 ion-exchange chromatography. Cell viability was determined by the MTT assay. Cell morphology was observed by scanning ele...

  15. Subcellular localization of PUMA regulates its pro-apoptotic activity in Burkitt's lymphoma B cells

    OpenAIRE

    Ambroise, Gorbatchev; Portier, Alain; Roders, Nathalie; Arnoult, Damien; Vazquez, Aimé

    2015-01-01

    The BH3-only protein PUMA (p53-upregulated modulator of apoptosis) is a major regulator of apoptosis. It belongs to the Bcl-2 family of proteins responsible for maintaining mitochondrial outer membrane integrity by controlling the intrinsic (mitochondrial) apoptotic pathway. We describe here a new pathway regulating PUMA activation through the control of its subcellular distribution. Surprisingly, neither PUMA upregulation in normal activated human B lymphocytes nor high levels of PUMA in Bur...

  16. Sculpting Skin Appendages Out of Epidermal Layers Via Temporally and Spatially Regulated Apoptotic Events

    OpenAIRE

    Chang, Chung-Hsing; Yu, Mingke; Wu, Ping; Jiang, Ting-Xin; Yu, Hsin-Su; Widelitz, Randall B.; Chuong, Cheng-Ming

    2004-01-01

    Complex skin appendages are built from the epidermal cells through induction, cell fate specification, proliferation, apoptosis, and differentiation, etc. Here we used the TUNEL assay and caspase-3 immuno-localization to examine apoptotic events in different stages of feather morphogenesis. We deduced three modes through which apoptosis may impact morphogenesis. In Mode 1A, apoptosis occurs within the localized growth zone to regulate growth as seen in growing buds. In Mode 1B, morphogen secr...

  17. Porcine parvovirus infection activates mitochondria-mediated apoptotic signaling pathway by inducing ROS accumulation

    OpenAIRE

    Zhao, Xiaomin; Xiang, Hailing; Bai, Xiaoyuan; Fei, Naijiao; Huang, Yong; Song, Xiangjun; Zhang, Hongling; Zhang, Liang; Tong, Dewen

    2016-01-01

    Background Porcine parvovirus (PPV) infection primarily causes reproductive failure of pregnant swine and results in host cell death. Boars, as an important disseminator, shed PPV to sows via semen. PPV infects and numerously replicates in boar testicle, which results in damage of swine testicle in vivo. Reactive oxygen species (ROS), a mediator of cell apoptosis, play a crucial role in the mitochondria apoptotic pathway. However, whether PPV infection induces ST cells apoptosis and ROS accum...

  18. Cocaine Causes Apoptotic Death in Rat Mesencephalon and Striatum Primary Cultures

    OpenAIRE

    Lepsch, Lucilia B; Planeta, Cleopatra S.; Critoforo Scavone

    2015-01-01

    To study cocaine’s toxic effects in vitro, we have used primary mesencephalic and striatal cultures from rat embryonic brain. Treatment with cocaine causes a dramatic increase in DNA fragmentation in both primary cultures. The toxicity induced by cocaine was paralleled with a concomitant decrease in the microtubule associated protein 2 (MAP2) and/or neuronal nucleus protein (NeuN) staining. We also observed in both cultures that the cell death caused by cocaine was induced by an apoptotic mec...

  19. Detection of apoptotic cells in horses with and without gastrointestinal disease.

    OpenAIRE

    Rowe, Emma L

    2003-01-01

    A study was performed to identify apoptotic cells in the equine intestine and to determine if the occurrence of apoptosis is affected by gastrointestinal disease and tissue layer of intestine. Samples of intestine were collected from 38 horses that underwent surgery or were humanely destroyed for small or large bowel obstruction, strangulation or distension. Samples were also taken from 9 horses which were humanely euthanized for reasons other than gastrointestinal disease or systemic disea...

  20. Mitochondrial Swelling and Incipient Outer Membrane Rupture in Preapoptotic and Apoptotic Cells

    OpenAIRE

    Sesso, A.; Belizário, JE; Marques, MM; Higuchi, ML; Schumacher, RI; Colquhoun, A; Ito, E.; Kawakami, J.

    2012-01-01

    Outer mitochondrial membrane (OMM) rupture was first noted in isolated mitochondria in which the inner mitochondrial membrane (IMM) had lost its selective permeability. This phenomenon referred to as mitochondrial permeability transition (MPT) refers to a permeabilized inner membrane that originates a large swelling in the mitochondrial matrix, which distends the outer membrane until it ruptures. Here, we have expanded previous electron microscopic observations that in apoptotic cells, OMM ru...

  1. Unexpected requirement for ELMO1 in apoptotic germ cell clearance in vivo

    OpenAIRE

    Elliott, Michael R.; Zheng, Shuqiu; Park, Daeho; Woodson, Robin I.; Reardon, Michael A.; Juncadella, Ignacio J.; Kinchen, Jason M.; Zhang, Jun; Lysiak, Jeffrey J.; Ravichandran, Kodi S.

    2010-01-01

    Apoptosis and the subsequent clearance of these dying cells occur throughout development and adult life in many tissues. Failure to promptly clear apoptotic cells has been linked to many diseases1-3. ELMO1 is an evolutionarily conserved cytoplasmic engulfment protein that functions downstream of the phosphatidylserine receptor BAI1, and, along with Dock180 and Rac1, promotes internalization of the dying cells4-7. Here, we generated ELMO1-deficient mice, and unexpectedly found them to be viabl...

  2. The Nuclear γ-H2AX Apoptotic Ring: Implications for Cancers and Autoimmune Diseases

    OpenAIRE

    Solier, Stéphanie; Pommier, Yves

    2014-01-01

    Apoptosis is a fundamental process for metazoan development. It is also relevant to the pathophysiology of immune diseases and cancers, and the outcome of cancer chemotherapies as well as being a target for cancer therapies. Apoptosis involves intrinsic pathways typically initiated by DNA damaging agents and engaging mitochondria, and extrinsic pathways typically initiated by “death receptors” and their ligands TRAIL and TNF at the cell surface. Recently, we discovered the apoptotic ring, whi...

  3. Fish oil supplementation reverses the effect of cholesterol on apoptotic gene expression in smooth muscle cells

    Directory of Open Access Journals (Sweden)

    Linares Ana

    2010-07-01

    Full Text Available Abstract Background Nutritional control of gene regulation guides the transformation of smooth muscle cells (SMC into foam cells in atherosclerosis. Oxidative stress has been reported in areas of lipid accumulation, activating proliferation genes. Suppression of oxidative stress by antioxidant administration reduces this activation and the progression of lesions. We hypothesized that fish oil consumption may protect against atherosclerotic vascular disease. The study objective was to determine the effects of dietary cholesterol and fish-oil intake on the apoptotic pathways induced by 25-hydroxycholesterol (25-HC in SMC cultures. Methods An in vivo/in vitro cell model was used, culturing SMC isolated from chicks exposed to an atherogenic cholesterol-rich diet with 5% of cholesterol (SMC-Ch alone or followed by an anti-atherogenic fish oil-rich diet with 10% of menhaden oil (SMC-Ch-FO and from chicks on standard diet (SMC-C. Cells were exposed to 25-HC, studying apoptosis levels by flow cytometry (Annexin V and expressions of caspase-3, c-myc, and p53 genes by quantitative real-time reverse transcriptase-polymerase chain reaction. Results: Exposure to 25-HC produced apoptosis in all three SMC cultures, which was mediated by increases in caspase-3, c-myc, and p53 gene expression. Changes were more marked in SMC-Ch than in SMC-C, indicating that dietary cholesterol makes SMC more susceptible to 25-HC-mediated apoptosis. Expression of p53 gene was elevated in SMC-Ch-FO. This supports the proposition that endogenous levels of p53 protect SMC against apoptosis and possibly against the development of atherosclerosis. Fish oil attenuated the increase in c-myc levels observed in SMC-C and SMC-Ch, possibly through its influence on the expression of antioxidant genes. Conclusion Replacement of a cholesterol-rich diet with a fish oil-rich diet produces some reversal of the cholesterol-induced changes, increasing the resistance of SMC to apoptosis.

  4. Apoptotic Effect of Coix Polysaccharides on A549 Lung Cancer Cells in Vitro

    Directory of Open Access Journals (Sweden)

    Cheng LUO

    2012-11-01

    Full Text Available Background and objective Coix seeds are commonly used in Traditional Chinese Medicine and ingested through daily diet. The aim of this study is to analyze the apoptotic effect of coix polysaccharides on A549 cells. Methods A fraction of polysaccharides was isolated from coix seeds and extracted by ethanol precipitation. The extract was then purified by dialysis and DEAE-52 ion-exchange chromatography. Cell viability was determined by the MTT assay. Cell morphology was observed by scanning electronic microscopy (SEM, and cell cycle was detected by flow cytometry (FCM. The relative quantities of caspase-3 and caspase-9 were determined by RT-PCR. Results Coix polysaccharides exerted remarkable inhibitory effects on A549 cell proliferation. Apoptotic bodies were observed by SEM. Apoptotic induction was also verified by DNA accumulation using propidium iodide nucleus staining in the S phase by flow cytometry, as well as by DNA fragmentation using the comet assay. Regarding the molecular mechanism of apoptosis induction, the gene expression of caspase-3 and caspase-9 increased after coix polysaccharide treatment. Conclusion Polysaccharide fraction CP-1 induced A549 cell apoptosis.

  5. Isolation of apoptotic mouse fetal oocytes by AnnexinV assay.

    Science.gov (United States)

    Lobascio, Anna-Maria; Klinger, Francesca-Gioia; De Felici, Massimo

    2007-01-01

    Expression of phosphotidylserine by fetal oocytes in culture renders significant numbers of such cells able to bind AnnexinV-coated microbeads and allows their separation from Annexin V-negative oocytes on a Magnetic Cell Separation (MACS) column in a magnetic field. The majority of oocytes (> or =75%) which bound Annexin V-coated microbeads were viable, as indicated by their propidium iodine (PI) negativity. However, they showed apoptotic morphologies and were found to be TUNEL-positive. On the other hand, AnnexinV-negative oocytes, besides being PI negative, appeared morphologically healthy and TUNEL negative. Moreover, AnnexinV-positive oocytes showed a marked lower ratio of Bcl-xL/Bax transcripts in comparison to AnnexinV-negative oocytes. We conclude that the present method is able to separate fetal oocytes in two distinct populations: AnnexinV-positive oocytes showing features typical of apoptotic cells and AnnexinV-negative oocytes comprising for the most part viable non-apoptotic cells. This procedure should greatly facilitate studies aimed to identify the currently poorly understood molecular pathways governing apoptosis in mammalian fetal oocytes. PMID:17294366

  6. Antitumor effects of traditional Chinese medicine targeting the cellular apoptotic pathway

    Directory of Open Access Journals (Sweden)

    Xu HL

    2015-05-01

    Full Text Available Huanli Xu,1 Xin Zhao,2 Xiaohui Liu,1 Pingxiang Xu,1 Keming Zhang,2 Xiukun Lin11Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, 2Department of Hepatobiliary Surgery, 302 Hospital of Chinese People’s Liberation Army, Beijing, People’s Republic of ChinaAbstract: Defects in apoptosis are common phenomena in many types of cancer and are also a critical step in tumorigenesis. Targeting the apoptotic pathway has been considered an intriguing strategy for cancer therapy. Traditional Chinese medicine (TCM has been used in the People’s Republic of China for thousands of years, and many of the medicines have been confirmed to be effective in the treatment of a number of tumors. With increasing cancer rates worldwide, the antitumor effects of TCMs have attracted more and more attention globally. Many of the TCMs have been shown to have antitumor activity through multiple targets, and apoptosis pathway-related targets have been extensively studied and defined to be promising. This review focuses on several antitumor TCMs, especially those with clinical efficacy, based on their effects on the apoptotic signaling pathway. The problems with and prospects of development of TCMs as anticancer agents are also presented.Keywords: traditional Chinese medicine, antitumor effects, apoptotic pathway

  7. Vitamin-C protect ethanol induced apoptotic neuro degeneration in postnatal rat brain

    International Nuclear Information System (INIS)

    Objective: To evaluate ethanol effects to induced activation of caspsae-3, and to observe the protective effects of Vitamin C (vit-C) on ethanol-induced apoptotic neuro degeneration in rat cortical area of brain. Methodology: Administration of a single dose of ethanol in 7-d postnatal (P7) rats triggers activation of caspase-3 and widespread apoptotic neuronal death. Western blot analysis, cells counting and Nissl staining were used to elucidate possible protective effect of vit-C against ethanol-induced apoptotic neuro degeneration in brain. Results: The results showed that ethanol significantly increased caspase-3 expression and neuronal apoptosis. Furthermore, the co-treatment of vit-C along with ethanol showed significantly decreased expression of caspase-3 as compare to control group. Conclusion: Our findings indicate that vit-C can prevent some of the deleterious effect of ethanol on developing rat brain when given after ethanol exposure and can be used as an effective protective agent for Fetal Alcohol Syndrome (FAS). (author)

  8. p53 dependent apoptotic cell death induces embryonic malformation in Carassius auratus under chronic hypoxia.

    Directory of Open Access Journals (Sweden)

    Paramita Banerjee Sawant

    Full Text Available Hypoxia is a global phenomenon affecting recruitment as well as the embryonic development of aquatic fauna. The present study depicts hypoxia induced disruption of the intrinsic pathway of programmed cell death (PCD, leading to embryonic malformation in the goldfish, Carrasius auratus. Constant hypoxia induced the early expression of pro-apoptotic/tumor suppressor p53 and concomitant expression of the cell death molecule, caspase-3, leading to high level of DNA damage and cell death in hypoxic embryos, as compared to normoxic ones. As a result, the former showed delayed 4 and 64 celled stages and a delay in appearance of epiboly stage. Expression of p53 efficiently switched off expression of the anti-apoptotic Bcl-2 during the initial 12 hours post fertilization (hpf and caused embryonic cell death. However, after 12 hours, simultaneous downregulation of p53 and Caspase-3 and exponential increase of Bcl-2, caused uncontrolled cell proliferation and prevented essential programmed cell death (PCD, ultimately resulting in significant (p<0.05 embryonic malformation up to 144 hpf. Evidences suggest that uncontrolled cell proliferation after 12 hpf may have been due to downregulation of p53 abundance, which in turn has an influence on upregulation of anti-apoptotic Bcl-2. Therefore, we have been able to show for the first time and propose that hypoxia induced downregulation of p53 beyond 12 hpf, disrupts PCD and leads to failure in normal differentiation, causing malformation in gold fish embryos.

  9. Anti-apoptotic peptides protect against radiation-induced cell death.

    Science.gov (United States)

    McConnell, Kevin W; Muenzer, Jared T; Chang, Kathy C; Davis, Chris G; McDunn, Jonathan E; Coopersmith, Craig M; Hilliard, Carolyn A; Hotchkiss, Richard S; Grigsby, Perry W; Hunt, Clayton R

    2007-04-01

    The risk of terrorist attacks utilizing either nuclear or radiological weapons has raised concerns about the current lack of effective radioprotectants. Here it is demonstrated that the BH4 peptide domain of the anti-apoptotic protein Bcl-xL can be delivered to cells by covalent attachment to the TAT peptide transduction domain (TAT-BH4) and provide protection in vitro and in vivo from radiation-induced apoptotic cell death. Isolated human lymphocytes treated with TAT-BH4 were protected against apoptosis following exposure to 15Gy radiation. In mice exposed to 5Gy radiation, TAT-BH4 treatment protected splenocytes and thymocytes from radiation-induced apoptotic cell death. Most importantly, in vivo radiation protection was observed in mice whether TAT-BH4 treatment was given prior to or after irradiation. Thus, by targeting steps within the apoptosis signaling pathway it is possible to develop post-exposure treatments to protect radio-sensitive tissues. PMID:17307150

  10. Gene therapy for carcinoma of the breast: Pro-apoptotic gene therapy

    International Nuclear Information System (INIS)

    The dysregulation of apoptosis contributes in a variety of ways to the malignant phenotype. It is increasingly recognized that the alteration of pro-apoptotic and anti-apoptotic molecules determines not only escape from mechanisms that control cell cycle and DNA damage, but also endows the cancer cells with the capacity to survive in the presence of a metabolically adverse milieu, to resist the attack of the immune system, to locally invade and survive despite a lack of tissue anchorage, and to evade the otherwise lethal insults induced by drugs and radiotherapy. A multitude of apoptosis mediators has been identified in the past decade, and the roles of several of them in breast cancer have been delineated by studying the clinical correlates of pathologically documented abnormalities. Using this information, attempts are being made to correct the fundamental anomalies at the genetic level. Fundamental to this end are the design of more efficient and selective gene transfer systems, and the employment of complex interventions that are tailored to breast cancer and that are aimed concomitantly towards different components of the redundant regulatory pathways. The combination of such genetic modifications is most likely to be effective when combined with conventional treatments, thus robustly activating several pro-apoptotic pathways

  11. Apoptotic protein profile in Leishmania donovani after treatment with hexaazatrinaphthylenes derivatives.

    Science.gov (United States)

    López-Arencibia, Atteneri; Martín-Navarro, Carmen M; Sifaoui, Ines; Reyes-Batlle, María; Wagner, Carolina; Lorenzo-Morales, Jacob; Piñero, José E

    2016-07-01

    Two hexaazatrinaphthylene derivatives, DGV-B and DGV-C previously known to induce an apoptotic-like process in Leishmania donovani parasites were used in this study. For this purpose, two different human protein commercial arrays were used to determine the proteomic profile of the treated parasites compared to non-treated ones. One of the commercial arrays is able to detect the relative expression of 35 human apoptosis-related proteins and the other one is able to identify 9 different human kinases. The obtained results showed that the two tested molecules were able to activate a programmed cell death process by different pathways in the promastigote stage of the parasite. The present study reports the potential application of two commercialised human apoptotic arrays to evaluate the action mechanism of active compounds at least against Leishmania donovani. The obtained data would be useful to establish the putative activated apoptosis pathways in the treated parasites and to further support the use of hexaazatrinaphthylene derivatives for the treatment of leishmaniasis in the near future. Nevertheless, further molecular studies should be developed in order to design and evaluate specific apoptotic arrays for Leishmania genus. PMID:27060614

  12. Mitochondrial response and calcium ion change in apoptotic insect cells induced by SfaMNPV

    Institute of Scientific and Technical Information of China (English)

    XIU Meihong; PENG Jianxin; HONG Huazhu

    2005-01-01

    Mitochondrial responses and changes of calcium ions in apoptotic insect SL-1 cells induced by Syngrapha falcifera multiple nuclear polyhedrosis virus (SfaMNPV) are reported in this paper. By using Rhodamine 123 as a fluorescent labeling probe, flow cytometry analysis and confocal laser scanning microscope observation we observed that the mitochondrial transmembrane potential (△Ψm) began to decrease in SL-1 cells at 4 h post infection and △Ψm reduced continuously with the extension of virus infection. Western blotting indicated that the Bcl-2 level in the mitochondria gradually declined and was down- regulated. Cells undergoing apoptosis were found to have an elevation of cytochrome c in the cytosol and a corresponding decrease in the mitochondria, which indicated that cytochrome c was released from mitochondria into cytosol. These results suggest that mitochondrion-mediated apoptotic signal transduction pathway exists in apoptotic insect cell induced by SfaMNPV. Cytosolic free calcium ([Ca2+]i) concentration rapidly increased after SfaMNPV infection and the elevated calcium was tested to come partly from extracelllular calcium ion influx. Flow cytometry analysis indicated that the apoptosis in SL-1 cells was not influenced by established cytosolic calcium clamped conditions and the EGTA inhibiting calcium influx. Therefore, neither the elevation of cytosolic calcium ion nor extracellular calcium entry was the inducing factor of apoptosis, which hinted that the depletion of ER Ca2+ store contributed to SL-1 cell apoptosis induced by SfaMNPV.

  13. The proteasomal and apoptotic phenotype determine bortezomib sensitivity of non-small cell lung cancer cells

    Directory of Open Access Journals (Sweden)

    Chęcińska Agnieszka

    2007-11-01

    Full Text Available Abstract Bortezomib is a novel anti-cancer agent which has shown promising activity in non-small lung cancer (NSCLC patients. However, only a subset of patients respond to this treatment. We show that NSCLC cell lines are differentially sensitive to bortezomib, IC50 values ranging from 5 to 83 nM. The apoptosis-inducing potential of bortezomib in NSCLC cells was found to be dependent not only on the apoptotic phenotype but also on the proteasomal phenotype of individual cell lines. Upon effective proteasome inhibition, H460 cells were more susceptible to apoptosis induction by bortezomib than SW1573 cells, indicating a different apoptotic phenotype. However, exposure to a low dose of bortezomib did only result in SW1573 cells, and not in H460 cells, in inhibition of proteasome activity and subsequent apoptosis. This suggests a different proteasomal phenotype as well. Additionally, overexpression of anti-apoptotic protein Bcl-2 in H460 cells did not affect the proteasomal phenotype of H460 cells but did result in decreased bortezomib-induced apoptosis. In conclusion, successful proteasome-inhibitor based treatment strategies in NSCLC face the challenge of having to overcome apoptosis resistance as well as proteasomal resistance of individual lung cancer cells. Further studies in NSCLC are warranted to elucidate underlying mechanisms.

  14. Proliferative and apoptotic effects of andrographolide on the BGC-823 human gastric cancer cell line

    Institute of Scientific and Technical Information of China (English)

    LI Shu-guang; WANG Yuan-yu; YE Zai-yuan; SHAO Qing-shu; TAO Hou-quan; SHU Li-sha; ZHAO Yi-feng

    2013-01-01

    Background Andrographolide has been shown to have anticancer activity on diverse cancer cell lines representing different types of human cancers.The aim of this research was to investigate the anticancer and apoptotic effects of andrographolide on the BGC-823 human gastric cancer cell line.Methods Cell proliferation and IC50 were evaluated using MTT assay,cell-cycle analysis with flow cytometry apoptotic effects with Annexin-V/propidium iodide double-staining assay,and morphologic structure with transmission electron microscopy.Immunohistochemistry and reverse-transcription PCR was used to analyze Bcl-2,Bax,and caspase-3 expressions.Results Andrographolide showed a time-and concentration-dependent inhibitory effects on BGC-823 cell growth.Compared to controls,the number of cells in the G0-G1-phase increased significantly,S and G2-M-phase cells decreased after 48 hours of treatment with andrographolide,and both early and late apoptotic rates increased significantly compared to the controls,all in a concentration-dependent manner.Bax and caspase-3 expressions were markedly increased,and Bcl-2 expression was decreased.Conclusions Andrographolide inhibits BGC-823 cell growth and induces BGC-823 cell apoptosis by up-regulating Bax and caspase-3 expressions and down-regulating Bcl-2 expression.Andrographolide may be useful as a potent and selective agent in the treatment of human gastric cancers.

  15. Mimicry of a 21.5 kDa myelin basic protein peptide by a Maedi Visna virus polymerase peptide does not contribute to the pathogenesis of encephalitis in sheep.

    Science.gov (United States)

    Davies, J M; Watt, N J; Torsteinsdottir, S; Carnegie, P R

    1996-12-01

    Epitope mimicry is the theory that an infectious agent such as a virus causes pathological effects via mimicry of host proteins and thus elicits a cross-reactive immune response to host tissues. Weise and Carnegie (1988) found a region of sequence similarity between the pol gene of the Maedi Visna virus (MVV), which induces demyelinating encephalitis in sheep, and myelin basic protein (MBP), which is known to induce experimental allergic encephalitis (EAE) in laboratory animals. In this study, cross-reactions between sera raised in sheep against synthetic peptides of MVV (TGKIPWILLPGR) and 21.5 kDa MBP (SGKVPWLKPGR) were demonstrated using enzyme-linked immunosorbant assay (ELISA) and thin layer chromatography (TLC) immunoprobing. The antibody responses of MVV-infected sheep were investigated using ELISA against the peptides, and MBP protein, immunoprobing of the peptides on TLC plates and Western blotting against MBP. Slight significant reactions to the 21.5 kDa MBP peptide (P plates. On the Western blots, eight of the 23 sheep with Visna had serum reactivity to MBP. This slight reaction to MBP in MVV-infected sheep is of interest because of the immune responses to MBP evident in multiple sclerosis and EAE, but its relevance in Visna is limited since no correlation with disease severity was observed. The cell-mediated immune responses of MVV-infected sheep against similar peptides was assessed. The peptides did not stimulate proliferation of peripheral blood lymphocytes of MVV-infected sheep. Since the MVV peptide was not recognised by antibodies or T lymphocytes from MVV-infected and encephalic sheep, it was concluded that epitope mimicry of this 21.5 kDa MBP peptide by the similar MVV pol peptide was not contributing to the immunopathogensis of Visna. The slight antibody response to MBP and the MBP peptide can be attributed to by-stander effects of the immunopathology of MVV-induced encephalitis. PMID:9014312

  16. Synergistic cytotoxic effects of bortezomib and CK2 inhibitor CX-4945 in acute lymphoblastic leukemia: turning off the prosurvival ER chaperone BIP/Grp78 and turning on the pro-apoptotic NF-κB

    Science.gov (United States)

    Buontempo, Francesca; Orsini, Ester; Lonetti, Annalisa; Cappellini, Alessandra; Chiarini, Francesca; Evangelisti, Camilla; Evangelisti, Cecilia; Melchionda, Fraia; Pession, Andrea; Bertaina, Alice; Locatelli, Franco; Bertacchini, Jessika; Neri, Luca Maria; McCubrey, James A.; Martelli, Alberto Maria

    2016-01-01

    The proteasome inhibitor bortezomib is a new targeted treatment option for refractory or relapsed acute lymphoblastic leukemia (ALL) patients. However, a limited efficacy of bortezomib alone has been reported. A terminal pro-apoptotic endoplasmic reticulum (ER) stress/unfolded protein response (UPR) is one of the several mechanisms of bortezomib-induced apoptosis. Recently, it has been documented that UPR disruption could be considered a selective anti-leukemia therapy. CX-4945, a potent casein kinase (CK) 2 inhibitor, has been found to induce apoptotic cell death in T-ALL preclinical models, via perturbation of ER/UPR pathway. In this study, we analyzed in T- and B-ALL preclinical settings, the molecular mechanisms of synergistic apoptotic effects observed after bortezomib/CX-4945 combined treatment. We demonstrated that, adding CX-4945 after bortezomib treatment, prevented leukemic cells from engaging a functional UPR in order to buffer the bortezomib-mediated proteotoxic stress in ER lumen. We documented that the combined treatment decreased pro-survival ER chaperon BIP/Grp78 expression, via reduction of chaperoning activity of Hsp90. Bortezomib/CX-4945 treatment inhibited NF-κB signaling in T-ALL cell lines and primary cells from T-ALL patients, but, intriguingly, in B-ALL cells the drug combination activated NF-κB p65 pro-apoptotic functions. In fact in B-cells, the combined treatment induced p65-HDAC1 association with consequent repression of the anti-apoptotic target genes, Bcl-xL and XIAP. Exposure to NEMO (IKKγ)-binding domain inhibitor peptide reduced the cytotoxic effects of bortezomib/CX-4945 treatment. Overall, our findings demonstrated that CK2 inhibition could be useful in combination with bortezomib as a novel therapeutic strategy in both T- and B-ALL. PMID:26593250

  17. Increased ratio of anti-apoptotic to pro-apoptotic Bcl2 gene-family members in lithium-responders one month after treatment initiation

    Directory of Open Access Journals (Sweden)

    Lowthert Lori

    2012-09-01

    Full Text Available Abstract Background Lithium is considered by many as the gold standard medication in the management of bipolar disorder (BD. However, the clinical response to lithium is heterogeneous, and the molecular basis for this difference in response is unknown. In the present study, we sought to determine how the peripheral blood gene expression profiles of patients with bipolar disorder (BD changed over time following intitiation of treatment with lithium, and whether differences in those profiles over time were related to the clinical response. Methods Illumina Sentrix Beadchip (Human-6v2 microarrays containing > 48,000 transcript probes were used to measure levels of expression of gene-expression in peripheral blood from 20 depressed subjects with BD prior to and every two weeks during 8 weeks of open-label treatment with lithium. Changes in gene-expression were compared between treatment responders (defined as a decrease in the Hamilton Depression Rating Scale of 50% or more and non-responders. Pathway analysis was conducted using GeneGO Metacore software. Results 127 genes showed a differential response in responders vs. non-responders. Pathway analysis showed that regulation of apoptosis was the most significantly affected pathway among these genes. Closer examination of the time-course of changes among BCL2 related genes showed that in lithium-responders, one month after starting treatment with lithium, several anti-apoptotic genes including Bcl2 and insulin receptor substrate 2 (IRS2 were up-regulated, while pro-apoptotic genes, including BCL2-antagonist/killer 1 (BAK1 and BCL2-associated agonist of cell death (BAD, were down-regulated. In contrast, in lithium non-responders, BCL2 and IRS2 were down-regulated, while BAK1 and BAD up-regulated at the one-month time-point. Conclusions These results suggest that differential changes in the balance of pro- and anti- apoptotic gene-expression following treatment with lithium may explain some of

  18. Changes in proliferating and apoptotic markers in the oviductal magnum of chickens during sexual maturation.

    Science.gov (United States)

    Hrabia, Anna; Leśniak-Walentyn, Agnieszka; Ocłoń, Ewa; Sechman, Andrzej

    2016-06-01

    The avian oviduct is characterized by dynamic hormonal, biochemical, and cellular changes during its development. To better understand the molecular mechanisms regulating proper development of this organ in birds, the rate of cell proliferation and apoptosis as well as these processes-related gene expressions in the chicken oviduct during the sexual maturation were examined. The oviducts were isolated from Hy-Line Brown chickens at 2-week intervals from 10 to 16 weeks of age, and at 17 weeks, i.e. just after the onset of egg laying. In the tissue from the middle part of the oviduct (the magnum) the following parameters were tested: (1) proliferating (proliferating cell nuclear antigen [PCNA]-positive) and apoptotic (Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive) cells, (2) mRNA expression of bcl-2, caspases 2, 3, 8, and 9, PCNA, survivin-142, and ovalbumin by quantitative real-time polymerase chain reaction, (3) protein expression of Bcl-2, PCNA, and caspases 3 and 9 by Western blot, (4) activity of caspases 2, 3, 8, and 9 by fluorometric method, and (5) localization of Bcl-2 and caspases by immunohistochemistry. It was found that the number of proliferating cells per unit area did not change during the examined period. The number of apoptotic cells in the oviductal wall remained on the same level until 14 weeks of age followed by a gradual decrease, reaching the lowest number at 17 weeks. The mRNA expression of all caspases and Bcl-2 gradually decreased during maturation, and PCNA decreased after 14 weeks of age. Survivin-142 mRNA level increased in 14-week-old chickens and then diminished, whereas ovalbumin expression was dramatically elevated in birds 16 weeks old and older. Patterns of protein expression of Bcl-2, PCNA, and caspases and activity of caspases were similar to mRNA, although not as pronounced. In the wall of the magnum the apoptotic cells and examined proteins were localized predominantly in the mucosa

  19. Investigation of the apoptotic pathway induced by benzimidazole-oxindole conjugates against human breast cancer cells MCF-7.

    Science.gov (United States)

    Lakshma Nayak, Vadithe; Nagaseshadri, Bobburi; Vishnuvardhan, M V P S; Kamal, Ahmed

    2016-07-15

    In our previous studies, benzimidazole-oxindole conjugates were synthesized and evaluated by National Cancer Institute (NCI) for their cytotoxic activity and the new molecules like 5c and 5p were considered as potential leads. These conjugates arrested the cell cycle at G2/M phase and inhibited tubulin polymerization. These observations prompted us to investigate the apoptotic mechanism induced by these lead molecules against human breast cancer cells (MCF-7). Studies like measurement of mitochondrial membrane potential (ΔΨm), generation of reactive oxygen species (ROS) and Annexin V-FITC assay revealed that these compounds induced mitochondrial mediated (intrinsic apoptotic pathway) apoptosis in human breast cancer cells. It was further confirmed by western blot analysis of pro apoptotic protein Bax, anti apoptotic protein Bcl-2, cytochrome c release, caspase-9 activity and cleavage of PARP. PMID:27262596

  20. High apoptotic index correlates to p21 and p27 expression indicating a favorable outcome of primary breast cancer patients, but lacking prognostic significance in multivariate analysis.

    Science.gov (United States)

    Schöndorf, Thomas; Göhring, Uwe-Jochen; Becker, Martina; Hoopmann, Markus; Schmidt, Torsten; Rützel, Sabine; Rein, Daniel T; Ulrich, Uwe; Fechteler, Roland; Bersch, Alexander; Mallmann, Peter; Valter, Markus M

    2004-01-01

    This study was performed in order to investigate the role of the apoptotic index (AI) as a prediction parameter for the prognosis of patients with primary breast cancer. AI was determined by DNA fragmentation on 298 primary breast cancer samples and compared to clinically established breast cancer parameters. Additionally, we determined the expression of functional parameters including proliferating cell nuclear antigen, p21waf and p27kip by immunohistochemistry. The mean AI was found to be 11.9% (range, 0-90%). 189 tumors (63.4%) were negative for apoptosis, while 109 tissue samples (36.6%) were apoptotic with >5% positive cells. Using univariate analysis (chi2 test), the AI did not show any significant correlation to one of the established prognostic parameters of primary breast cancer (p > 0.05). In contrast, we found a significant positive correlation to the expression of the cell cycle inhibitors p21waf (p = 0.04) and p27kip (p = 0.024). During the clinical follow-up (median observation time for disease-free survival 87 months), several clinically established prognostic parameters including menopausal status, nodal status, tumor size, tumor grade, and hormone receptor expression could be confirmed and were analyzed with respect to the AI in the tumor. Furthermore, AI displayed a significant positive correlation to disease-free survival using Kaplan-Meier survival analysis (log-rank test, p = 0.04). However, AI lost its prognostic significance in multivariate analysis based on the Cox proportional hazard model (relative risk 0.8, confidence interval 0.52-1.33, p = 0.44). Our data indicate that high apoptotic rates in cancer tissues are indicative of a favorable patient outcome. However, the AI was not an independent factor. The study provides indirect evidence that this process may involve cell cycle inhibitors physiologically. PMID:15263811

  1. Fatal outcome in bacteremia is characterized by high plasma cell free DNA concentration and apoptotic DNA fragmentation: a prospective cohort study.

    Directory of Open Access Journals (Sweden)

    Reetta Huttunen

    Full Text Available INTRODUCTION: Recent studies have shown that apoptosis plays a critical role in the pathogenesis of sepsis. High plasma cell free DNA (cf-DNA concentrations have been shown to be associated with sepsis outcome. The origin of cf-DNA is unclear. METHODS: Total plasma cf-DNA was quantified directly in plasma and the amplifiable cf-DNA assessed using quantitative PCR in 132 patients with bacteremia caused by Staphylococcus aureus, Streptococcus pneumoniae, ß-hemolytic streptococcae or Escherichia coli. The quality of cf-DNA was analyzed with a DNA Chip assay performed on 8 survivors and 8 nonsurvivors. Values were measured on days 1-4 after positive blood culture, on day 5-17 and on recovery. RESULTS: The maximum cf-DNA values on days 1-4 (n = 132 were markedly higher in nonsurvivors compared to survivors (2.03 vs 1.26 ug/ml, p1.52 ug/ml remained an independent risk factor for case fatality in a logistic regression model. Qualitative analysis of cf-DNA showed that cf-DNA displayed a predominating low-molecular-weight cf-DNA band (150-200 bp in nonsurvivors, corresponding to the size of the apoptotic nucleosomal DNA. cf-DNA concentration showed a significant positive correlation with visually graded apoptotic band intensity (R = 0.822, p<0.001. CONCLUSIONS: Plasma cf-DNA concentration proved to be a specific independent prognostic biomarker in bacteremia. cf-DNA displayed a predominating low-molecular-weight cf-DNA band in nonsurvivors corresponding to the size of apoptotic nucleosomal DNA.

  2. Structure of Human B12 Trafficking Protein CblD Reveals Molecular Mimicry and Identifies a New Subfamily of Nitro-FMN Reductases.

    Science.gov (United States)

    Yamada, Kazuhiro; Gherasim, Carmen; Banerjee, Ruma; Koutmos, Markos

    2015-12-01

    In mammals, B12 (or cobalamin) is an essential cofactor required by methionine synthase and methylmalonyl-CoA mutase. A complex intracellular pathway supports the assimilation of cobalamin into its active cofactor forms and delivery to its target enzymes. MMADHC (the methylmalonic aciduria and homocystinuria type D protein), commonly referred to as CblD, is a key chaperone involved in intracellular cobalamin trafficking, and mutations in CblD cause methylmalonic aciduria and/or homocystinuria. Herein, we report the first crystal structure of the globular C-terminal domain of human CblD, which is sufficient for its interaction with MMADHC (the methylmalonic aciduria and homocystinuria type C protein), or CblC, and for supporting the cytoplasmic cobalamin trafficking pathway. CblD contains an α+β fold that is structurally reminiscent of the nitro-FMN reductase superfamily. Two of the closest structural relatives of CblD are CblC, a multifunctional enzyme important for cobalamin trafficking, and the activation domain of methionine synthase. CblD, CblC, and the activation domain of methionine synthase share several distinguishing features and, together with two recently described corrinoid-dependent reductive dehalogenases, constitute a new subclass within the nitro-FMN reductase superfamily. We demonstrate that CblD enhances oxidation of cob(II)alamin bound to CblC and that disease-causing mutations in CblD impair the kinetics of this reaction. The striking structural similarity of CblD to CblC, believed to be contiguous in the cobalamin trafficking pathway, suggests the co-option of molecular mimicry as a strategy for achieving its function. PMID:26364851

  3. Complement protein C1q directs macrophage polarization and limits inflammasome activity during the uptake of apoptotic cells

    OpenAIRE

    Benoit, Marie E; Clarke, Elizabeth V.; Morgado, Pedro; Fraser, Deborah A.; Tenner, Andrea J.

    2012-01-01

    Deficiency in C1q, the recognition component of the classical complement cascade and a pattern recognition receptor involved in apoptotic cell clearance, leads to lupus-like auto-immune diseases characterized by auto-antibodies to self proteins and aberrant innate immune cell activation likely due to impaired clearance of apoptotic cells. Here, we developed an autologous system using primary human lymphocytes and monocyte-derived macrophages (HMDMs) to characterize the effect of C1q on macrop...

  4. Complement protein C1q directs macrophage polarization and limits inflammasome activity during the uptake of apoptotic cells.

    OpenAIRE

    Benoit, Marie E; Clarke, Elizabeth V.; Morgado, Pedro; Fraser, Deborah A.; Tenner, Andrea J.

    2012-01-01

    Deficiency in C1q, the recognition component of the classical complement cascade and a pattern recognition receptor involved in apoptotic cell clearance, leads to lupus-like autoimmune diseases characterized by auto-antibodies to self proteins and aberrant innate immune cell activation likely due to impaired clearance of apoptotic cells. In this study, we developed an autologous system using primary human lymphocytes and human monocyte-derived macrophages (HMDMs) to characterize the effect of...

  5. In silico analysis and DHPLC screening strategy identifies novel apoptotic gene targets of aberrant promoter hypermethylation in prostate cancer.

    LENUS (Irish Health Repository)

    Murphy, Therese M

    2011-01-01

    Aberrant DNA methylation has been implicated as a key survival mechanism in cancer, whereby promoter hypermethylation silences genes essential for many cellular processes including apoptosis. Limited data is available on the methylation profile of apoptotic genes in prostate cancer (CaP). The aim of this study was to profile methylation of apoptotic-related genes in CaP using denaturing high performance liquid chromatography (DHPLC).

  6. Altered expression of apoptotic genes in response to OCT4B1 suppression in human tumor cell lines.

    Science.gov (United States)

    Mirzaei, Mohammad Reza; Najafi, Ali; Arababadi, Mohammad Kazemi; Asadi, Malek Hosein; Mowla, Seyed Javad

    2014-10-01

    OCT4B1 is a newly discovered spliced variant of OCT4 which is primarily expressed in pluripotent and tumor cells. Based on our previous studies, OCT4B1 is significantly overexpressed in tumors, where it endows an anti-apoptotic property to tumor cells. However, the mechanism by which OCT4B1 regulates the apoptotic pathway is not yet elucidated. Here, we investigated the effects of OCT4B1 suppression on the expression alteration of 84 genes involved in apoptotic pathway. The AGS (gastric adenocarcinoma), 5637 (bladder tumor), and U-87MG (brain tumor) cell lines were transfected with OCT4B1 or irrelevant siRNAs. The expression level of apoptotic genes was then quantified using a human apoptosis panel-PCR kit. Our data revealed an almost similar pattern of alteration in the expression profile of apoptotic genes in all three studied cell lines, following OCT4B1 suppression. In general, the expression of more than 54 apoptotic genes (64 % of arrayed genes) showed significant changes. Among these, some up-regulated (CIDEA, CIDEB, TNFRSF1A, TNFRSF21, TNFRSF11B, TNFRSF10B, and CASP7) and down-regulated (BCL2, BCL2L11, TP73, TP53, BAD, TRAF3, TRAF2, BRAF, BNIP3L, BFAR, and BAX) genes had on average more than tenfold gene expression alteration in all three examined cell lines. With some minor exceptions, suppression of OCT4B1 caused upregulation of pro-apoptotic and down-regulation of anti-apoptotic genes in transfected tumor cells. Uncovering OCT4B1 down-stream targets could further elucidate its part in tumorigenesis, and could lead to finding a new approach to combat cancer, based on targeting OCT4B1. PMID:25008565

  7. Crataegus oxycantha extract attenuates apoptotic incidence in myocardial ischemia-reperfusion injury by regulating Akt and HIF-1 signaling pathways.

    Science.gov (United States)

    Jayachandran, Kesavan S; Khan, Mahmood; Selvendiran, Karuppaiyah; Devaraj, S Niranjali; Kuppusamy, Periannan

    2010-11-01

    The objective of the present study was to evaluate the efficacy and mechanism of Crataegus oxycantha (COC) extract in preventing ischemia-reperfusion (IR) injury in an in vivo rat model of acute myocardial infarction induced by a 30-minute regional ischemia followed by 72 hours of reperfusion. The COC extract [100 mg/(kg body weight)] was administered 12 hours after the surgical procedure and then at 24-hour intervals for 3 days. Animals treated with COC extract showed a significant decrease in creatine kinase activity and infarct size. At the molecular level, COC administration resulted in a significant attenuation of PTEN (phosphatase and tensin homolog deleted on chromosome 10) and upregulation of phospho-Akt and c-Raf levels in the heart. As a consequence, cleaved caspase-9 and cleaved caspase-7 levels were significantly downregulated, indicating negative regulation of apoptosis by COC extract. In part with the hypoxia-inducible factor (HIF) signaling pathway, COC extract administration significantly upregulated the prolyl hydroxylase-2 level. In contrast, other proapoptotic proteins such as nuclear factor-κB, cytochrome c, apoptosis-inducing factor, and cleaved poly(adenosine diphosphate-ribose) polymerase levels were significantly downregulated in the COC-treated group when compared with the untreated control group. The results suggested that COC extract attenuated apoptotic incidence in the experimental myocardial ischemia-reperfusion model by regulating Akt and HIF-1 signaling pathways. PMID:20729753

  8. Farnesylpyridinium, an analog of isoprenoid farnesol, induces apoptosis but suppresses apoptotic body formation in human promyelocytic leukemia cells.

    Science.gov (United States)

    Hamada, Masahiro; Nishio, Kyo-ichi; Doe, Matsumi; Usuki, Yoshinosuke; Tanaka, Toshio

    2002-03-13

    1-Farnesylpyridinium (FPy), an analog of isoprenoid farnesol, initially induced morphological changes similar to those of typical apoptosis in human leukemia HL-60 cells but FPy-treated cells were characterized by the absolute absence of final apoptotic events such as fragmentation into apoptotic bodies. FPy-induced cell death was considered to be apoptotic on the basis of the induction of DNA fragmentation and the protection against these events by the coaddition of a pan-caspase inhibitor. The increase in the cytoplasmic cytochrome c level supported the possibility that FPy-treated cells should have the ability to complete the entire apoptotic process ending in cell fragmentation and apoptotic body formation. At concentrations too low to induce apoptosis, FPy could suppress the induction of apoptotic body formation in HL-60 cells by typical inducers of apoptosis such as actinomycin D or anisomycin. FPy exhibited a cytochalasin-like effect on spatial arrangement of actin filament independent of its apoptosis-inducing activity. PMID:11943160

  9. When mirroring is both simple and “smart”: how mimicry can be embodied, adaptive, and non-representational

    OpenAIRE

    Evan Walker Carr; Piotr eWinkielman

    2014-01-01

    The concept of mirroring has become rather ubiquitous. One of the most fundamental empirical and theoretical debates within research on mirroring concerns the role of mental representations: while some models argue that higher-order representational mechanisms underpin most cases of mirroring, other models argue that they only moderate a primarily non-representational process. As such, even though research on mirroring—along with its neural substrates, including the putative mirror neuron sys...

  10. A study on apoptotic signaling pathway in HL-60 cells induced by radiation

    International Nuclear Information System (INIS)

    The mechanical insights of death at cancer cells by ionizing radiation are not yet clearly defined. Recent evidences have demonstrated that radiation therapy may induce cell death via activation of signaling pathway for apoptosis in target cells. This study is designed whether ionizing radiation may activate the signaling cascades of apoptosis including caspase family cysteine proteases, Bcl2/Bax, cytochrome c and Fas/Fas-L in target cells. HL-60 cells were irradiated in vitro with 6 MV X-ray at dose ranges from 2 Gy to 32 Gy. The cell viability was tested by MTT assay and the extent of apoptosis was determined using agarose gel electrophoresis. The activities of caspase proteases were measured by proteolytic cleavages of substrates. Western blot analysis was used to monitor PARP, caspase-3, Cytochrome-c, BcI-2, Bax, Fas and Fas-L. Ionizing radiation decreases the viability of HL -60 cells in a time and dose dependent manner. Ionizing radiation-induced death in HL- 60 cells is an apoptotic death which is revealed as characteristic ladder-pattern fragmentation at genomic DNA over 16 Gy at 4 hours. Ionizing radiation induces the activation of caspase-2, 3, 6, 8 and 9 of HL --60 cells in a time-dependent manner. The activation of caspase- 3 protease is also evidenced by the digestion of poly (ADP-ribose) polymerase and procaspase 3 with 16Gy ionizing irradiation. Anti-apoptotic Bcl2 expression is decreased but apoptotic Bax expression is increased with mitochondrial cytochrome c release in a time- dependent manner. In addition, expression of Fas and Fas-L is also increased in a time dependent manner. These data suggest that ionizing radiation-induced apoptosis is mediated by the activation of various signaling pathways including caspase family cysteine proteases, BcI2/Bax, Fas and Fas-L in a time and dose dependent manner

  11. Tip60-mediated acetylation activates transcription independent apoptotic activity of Abl

    Directory of Open Access Journals (Sweden)

    Pandita Tej K

    2011-07-01

    Full Text Available Abstract Background The proto-oncogene, c-Abl encodes a ubiquitously expressed tyrosine kinase that critically governs the cell death response induced by genotoxic agents such as ionizing radiation and cisplatin. The catalytic function of Abl, which is essential for executing DNA damage response (DDR, is normally tightly regulated but upregulated several folds upon IR exposure due to ATM-mediated phosphorylation on S465. However, the mechanism/s leading to activation of Abl's apoptotic activity is currently unknown. Results We investigated the role of acetyl modification in regulating apoptotic activity of Abl and the results showed that DNA strand break-inducing agents, ionizing radiation and bleomycin induced Abl acetylation. Using mass spectrophotometry and site-specific acetyl antibody, we identified Abl K921, located in the DNA binding domain, and conforming to one of the lysine residue in the consensus acetylation motif (KXXK--X3-5--SGS is acetylated following DNA damage. We further observed that the S465 phosphorylated Abl is acetyl modified during DNA damage. Signifying the modification, cells expressing the non acetylatable K921R mutant displayed attenuated apoptosis compared to wild-type in response to IR or bleomycin treatment. WT-Abl induced apoptosis irrespective of new protein synthesis. Furthermore, upon γ-irradiation K921R-Abl displayed reduced chromatin binding compared to wild type. Finally, loss of Abl K921 acetylation in Tip60-knocked down cells and co-precipitation of Abl with Tip60 in DNA damaged cells identified Tip60 as an Abl acetylase. Conclusion Collective data showed that DNA damage-induced K921 Abl acetylation, mediated by Tip60, stimulates transcriptional-independent apoptotic activity and chromatin-associative property thereby defining a new regulatory mechanism governing Abl's DDR function.

  12. Relationship of angiogenic and apoptotic activities in soft-tissue sarcoma

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    Thin Thin Win

    2014-01-01

    Full Text Available Introduction: Angiogenesis and apoptosis play an essential role in tumor development and progression. Previous studies on apoptosis and angiogenesis of soft-tissue sarcoma (STS were done separately. This is the first study of the relationship between apoptotic and angiogenic activity. Correlation of expression of anti-apoptotic protein (Bcl-2 and pro-apoptotic protein (Bax in the tumor cells (TCs with their expression in endothelial cell (EC of the tumor blood vessels in STS were also carried out. Materials and Methods: 101 cases of STS; consisting liposarcoma, malignant fibrous histiocytoma, synovial sarcoma, fibrosarcoma, leiomyosarcoma, rhabdomyosarcoma and malignant peripheral nerve sheath tumor; were collected and immunohistochemical reaction of vascular endothelial growth factor (VEGF, Bcl-2 and Bax were examined. Results: Higher Bax expression in TCs (54.5% was seen compared to Bcl-2 expression (44.6%. There was a significant association between Bcl-2 and Bax in TCs with ECs. Significant association was also seen between histological types of STS with Bcl-2 expression; however not with Bax expression. There was an association between VEGF and Bax with high VEGF expression and weak Bax expression. However, VEGF expression was not associated with Bcl-2 expression and histological types. Conclusion: This study supports the role of ECs of tumor blood vessels and apoptosis of TCs in tumor management. Increased angiogenesis may inhibit apoptosis of TCs and lead to tumor growth. Therefore, inhibition of ECs survival or activation of ECs death is promising prospect for tumor therapy. Immunohistochemical antibodies in this study might be potential useful marker for the prognosis of STS.

  13. Phosphoproteomic analysis of apoptotic hematopoietic stem cells from hemoglobin E/β-thalassemia

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    Roytrakul Sittiruk

    2011-06-01

    Full Text Available Abstract Background Hemoglobin E/β-thalassemia is particularly common in Southeast Asia and has variable symptoms ranging from mild to severe anemia. Previous investigations demonstrated the remarkable symptoms of β-thalassemia in terms of the acceleration of apoptotic cell death. Ineffective erythropoiesis has been studied in human hematopoietic stem cells, however the distinct apoptotic mechanism was unclear. Methods The phosphoproteome of bone marrow HSCs/CD34+ cells from HbE/β-thalassemic patients was analyzed using IMAC phosphoprotein isolation followed by LC-MS/MS detection. Decyder MS software was used to quantitate differentially expressed proteins in 3 patients and 2 normal donors. The differentially expressed proteins from HSCs/CD34+ cells were compared with HbE/β-thalassemia and normal HSCs. Results A significant change in abundance of 229 phosphoproteins was demonstrated. Importantly, the analysis of the candidate proteins revealed a high abundance of proteins that are commonly found in apoptotic cells including cytochrome C, caspase 6 and apoptosis inducing factors. Moreover, in the HSCs patients a significant increase was observed in a specific type of phosphoserine/threonine binding protein, which is known to act as an important signal mediator for the regulation of cell survival and apoptosis in HbE/β-thalassemia. Conclusions Our study used a novel method to investigate proteins that influence a particular pathway in a given disease or physiological condition. Ultimately, phosphoproteome profiling in HbE/β-thalassemic stem cells is an effective method to further investigate the cell death mechanism of ineffective erythropoiesis in β-thalassemia. Our report provides a comprehensive phosphoproteome, an important resource for the study of ineffective erythropoiesis and developing therapies for HbE/β-thalassemia.

  14. Autoantibodies against complement C1q specifically target C1q bound on early apoptotic cells.

    Science.gov (United States)

    Bigler, Cornelia; Schaller, Monica; Perahud, Iryna; Osthoff, Michael; Trendelenburg, Marten

    2009-09-01

    Autoantibodies against complement C1q (anti-C1q) are frequently found in patients with systemic lupus erythematosus (SLE). They strongly correlate with the occurrence of severe lupus nephritis, suggesting a pathogenic role in SLE. Because anti-C1q are known to recognize a neoepitope on bound C1q, but not on fluid-phase C1q, the aim of this study was to clarify the origin of anti-C1q by determining the mechanism that renders C1q antigenic. We investigated anti-C1q from serum and purified total IgG of patients with SLE and hypocomplementemic urticarial vasculitis as well as two monoclonal human anti-C1q Fab from a SLE patient generated by phage display. Binding characteristics, such as their ability to recognize C1q bound on different classes of Igs, on immune complexes, and on cells undergoing apoptosis, were analyzed. Interestingly, anti-C1q did not bind to C1q bound on Igs or immune complexes. Neither did we observe specific binding of anti-C1q to C1q bound on late apoptotic/necrotic cells when compared with binding in the absence of C1q. However, as shown by FACS analysis and confocal microscopy, anti-C1q specifically targeted C1q bound on early apoptotic cells. Anti-C1q were found to specifically target C1q bound on cells undergoing apoptosis. Our observations suggest that early apoptotic cells are a major target of the autoimmune response in SLE and provide a direct link between human SLE, apoptosis, and C1q. PMID:19648280

  15. HSP70 mediates survival in apoptotic cells – Boolean network prediction and experimental validation

    Directory of Open Access Journals (Sweden)

    Suhas Vasaikar

    2015-08-01

    Full Text Available Neuronal stress or injury results in the activation of proteins, which regulate the balance between survival and apoptosis. However, the complex mechanism of cell signalling involving cell death and survival, activated in response to cellular stress is not yet completely understood. To bring more clarity about these mechanisms, a Boolean network was constructed that represented the apoptotic pathway in neuronal cells. FasL and neurotrophic growth factor (NGF were considered as inputs in the absence and presence of heat shock proteins known to shift the balance towards survival by rescuing pro-apoptotic cells. The probabilities of survival, DNA repair and apoptosis as cellular fates, in the presence of either the growth factor or FasL, revealed a survival bias encoded in the network. Boolean predictions tested by measuring the mRNA expression level of caspase-3, caspase-8 and BAX in neuronal Neuro2a (N2a cell line with NGF and FasL as external input, showed positive correlation with the observed experimental results for survival and apoptotic states. It was observed that HSP70 contributed more towards rescuing cells from apoptosis in comparison to HSP27, HSP40 and HSP90. Overexpression of HSP70 in N2a transfected cells showed reversal of cellular fate from FasL-induced apoptosis to survival. Further, the pro-survival role of the proteins BCL2, IAP, cFLIP and NFκB determined by vertex perturbation analysis was experimentally validated through protein inhibition experiments using EM20-25, Embelin and Wedelolactone, which resulted in 1.27-fold, 1.26-fold and 1.46-fold increase in apoptosis of N2a cells. The existence of a one-to-one correspondence between cellular fates and attractor states shows that Boolean networks may be employed with confidence in qualitative analytical studies of biological networks.

  16. Stimulating basal mitochondrial respiration decreases doxorubicin apoptotic signaling in H9c2 cardiomyoblasts.

    Science.gov (United States)

    Deus, Cláudia M; Zehowski, Cheryl; Nordgren, Kendra; Wallace, Kendall B; Skildum, Andrew; Oliveira, Paulo J

    2015-08-01

    Doxorubicin (DOX) is currently used in cancer chemotherapy, however, its use often results in adverse effects highlighted by the development of cardiomyopathy and ultimately heart failure. Interestingly, DOX cardiotoxicity is decreased by resveratrol or by physical activity, suggesting that increased mitochondrial activity may be protective. Conversely, recent studies showed that troglitazone, a PPARγ agonist, increases the cytotoxicity of DOX against breast cancer cells by up-regulating mitochondrial biogenesis. The hypothesis for the current investigation was that DOX cytotoxicity in H9c2 cardiomyoblasts is decreased when mitochondrial capacity is increased. We focused on several end-points for DOX cytotoxicity, including loss of cell mass, apoptotic signaling and alterations of autophagic-related proteins. Our results show that a galactose-based, modified cell culture medium increased H9c2 basal mitochondrial respiration, protein content, and mtDNA copy number without increasing maximal or spare respiratory capacity. H9c2 cardiomyoblasts cultured in the galactose-modified media showed lower DOX-induced activation of the apoptotic pathway, measured by decreased caspase-3 and -9 activation, and lower p53 expression, although ultimately loss of cells was not prevented. Treatment with the PPARγ agonist troglitazone had no effect on DOX toxicity in this cardiac cell line, which agrees with the fact that troglitazone did not increase mitochondrial DNA content or capacity at the concentrations and duration of exposure used in this investigation. Our results show that mitochondrial remodeling caused by stimulating basal rates of oxidative phosphorylation decreased DOX-induced apoptotic signaling and increased DOX-induced autophagy in H9c2 cardiomyoblasts. The differential effect on cytotoxicity in cardiac versus breast cancer cell lines suggests a possible overall improvement in the clinical efficacy for doxorubicin in treating cancer. PMID:25997894

  17. Peptide screening to knockdown Bcl-2's anti-apoptotic activity: implications in cancer treatment.

    Science.gov (United States)

    Raghav, Pawan Kumar; Verma, Yogesh Kumar; Gangenahalli, Gurudutta U

    2012-04-01

    Bcl-2 (B cell lymphoma-2) is an anti-apoptotic member of Bcl-2 family and its overexpression causes development of several types of cancer. The BH3 domain of pro-apoptotic and BH3-only proteins is capable of binding to Bcl-2 protein to induce apoptosis. This binding is the basis for the development of novel anticancer drug which would likely antagonize Bcl-2 overexpression. In this study we have identified BH3 domain of Bax (Bax BH3) as potentially the best Bcl-2 antagonist by performing docking of BH3 peptides (peptides representing BH3 domain of pro-apoptotic and BH3-only proteins) into the Bcl-2 hydrophobic groove formed by BH3, BH1 and BH2 domains (also referred as BH3 cleft). To predict the best small antagonist for Bcl-2, three groups of small peptides (pentapeptide, tetrapeptide and tripeptide) were designed and screened against Bcl-2 which revealed the structural importance of a set of residues playing a vital role in interaction with Bcl-2. The docking and scoring function identified KRIG and KRI as specific peptides among the screened small peptides responsible for Bcl-2 neutralization and would induce apoptosis. The applied pharmacokinetic and pharmacological filters to all small peptides signify that only IGD has drug-like properties and displayed good oral bioavailability. However, the obtained binding affinity of IGD to Bcl-2 was diminutive. Hence deprotonation, amidation, acetylation, benzoylation, benzylation, and addition of phenyl, deoxyglucose and glucose fragments were performed to increase the binding affinity and to prevent its rapid degradation. Benzoylated IGD tripeptide (IGD(bzo)) was observed to have increased binding affinity than IGD with acceptable pharmacokinetic filters. In addition, stability of Bcl-2/IGD(bzo) complex was validated by Molecular Dynamics (MD) simulations revealing improved binding energy, salt bridges and strong interaction energies. This study suggests a new molecule that inhibits Bcl-2 associated cancer

  18. Methane attenuates retinal ischemia/reperfusion injury via anti-oxidative and anti-apoptotic pathways.

    Science.gov (United States)

    Liu, Lin; Sun, Qinglei; Wang, Ruobing; Chen, Zeli; Wu, Jiangchun; Xia, Fangzhou; Fan, Xian-Qun

    2016-09-01

    Retinal ischemia/reperfusion injury (IRI) may cause incurable visual impairment due to neural regeneration limits. Methane was shown to exert a protective effect against IRI in many organs. This study aims to explore the possible protective effects of methane-rich saline against retinal IRI in rat. Retinal IRI was performed on the right eyes of male Sprague-Dawley rats, which were immediately injected intraperitoneally with methane-saturated saline (25ml/kg). At one week after surgery, the number of retinal ganglion cells (RGCs), total retinal thickness, visual function were measured by hematoxylin and eosin staining, FluoroGold anterograde labeling and flash visual evoked potentials. The levels of 8-hydroxy-2-deoxyguanosine (8-OHdG), 4-Hydroxy-2-nonenal (4-HNE), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), caspase-3, caspase-9, B cell lymphoma/leukemia-2 (Bcl-2) and Bcl-2 associated X protein (Bax) in retinas were assessed by immunofluorescence staining, enzyme-linked immunosorbent assay and quantitative polymerase chain reaction. As expected, methane treatment significantly improved the retinal IRI-induced RGC loss, total retinal layer thinning and visual dysfunction. Moreover, methane treatment significantly reduced the levels of oxidative stress biomarkers (8-OHdG, 4-HNE, MDA) and increased the antioxidant enzyme activities (SOD, CAT, GPx) in the retinas with IRI. Meanwhile, methane treatment significantly increased the anti-apoptotic gene (Bcl-2) expression and decreased the pro-apoptotic gene (Bax) expression, accompanied by the suppression of caspase-3 and caspase-9 activity. Thus, these data demonstrated that methane can exert a neuroprotective role against retinal IRI through anti-oxidative and anti-apoptotic pathways. PMID:27208496

  19. Detection of apoptotic cells by selective precipitation of [3H]thymidine-labelled DNA.

    OpenAIRE

    Patki, A H; Lederman, M M

    1996-01-01

    Apoptosis is characterized by systematic fragmentation of high-molecular-weight DNA into oligonucleosome fragments. A sensitive method for detection of apoptotic cells involving [3H]thymidine-labelled DNA is presented. Cells from mid-log-phase cultures were labelled with [3H]thymidine for 15 to 18 h and then exposed to gamma irradiation to induce apoptosis. A modified Hirt method was used to separate low-molecular-weight DNA from high-molecular-weight DNA. The percentage of fragmented DNA and...

  20. Sesquiterpene lactones from Inula britannica and their cytotoxic and apoptotic effects on human cancer cell lines.

    Science.gov (United States)

    Bai, Naisheng; Lai, Ching-Shu; He, Kan; Zhou, Zhu; Zhang, Li; Quan, Zheng; Zhu, Nanqun; Zheng, Qun Yi; Pan, Min-Hsiung; Ho, Chi-Tang

    2006-04-01

    Three new sesquiterpenes (1-3), together with four known sesquiterpene lactones, were isolated from the flowers of Inula britannica var. chinensis. Structures were established on the basis of high-field 1D and 2D NMR methods supported by HRMS. All sesquiterpene lactones were tested for cytotoxicity as well as apoptotic ratio in human COLO 205, HT 29, HL-60, and AGS cancer cells. Compounds 3 and 4, two alpha-methylene gamma-lactone-bearing sesquiterpenes, were modestly active in these assays. PMID:16643020

  1. Anti-apoptotic effects of aspirin following cerebral ischemia-reperfusion injury in rats

    Institute of Scientific and Technical Information of China (English)

    Liying Qiu; Bin Du; Ying Li; Hongbin Fan; Zhiyong Yang

    2008-01-01

    BACKGROUND: The pharmacological effects of aspirin on apoptosis are complex. The underlying mechanisms have not been properly defined. OBJECTIVE: To observe the effect of different doses of aspirin on brain cell apoptosis following focal cerebral ischemia-reperfusion injury (CIRI) in rats. DESING, TIME AND SETTING: A randomized, controlled, animal experiment, performed at the School of Medicine and Pharmaceutics, Jiangnan University between June and October 2006. MATERIALS: Twenty-six male, adult, Sprague Dawley rats (grade II), weighing 240-290 g, were obtained from Shanghai Experimental Animal Center, Chinese Academy of Sciences. Aspirin was provided by Sigma (USA). METHODS: The rats were randomly divided into four groups: sham-operation (SO), CIRI+ vehicle, CIRI+ aspirin (6 mg/kg), and CIRI + aspirin (60 mg/kg). Rats in the lesion groups were intragastrically administrated saline, aspirin (6 mg/kg), or aspirin (60 mg/kg), respectively. MAIN OUTCOME MEASURES: The number of pyramidal neurons with normal appearance in the cerebral cortex at 2-4 mm from the midline; apoptotic cell death as measured by TUNEL; Bcl-2 and Bax protein localization was determined by immunohistochemistry; maiondiaidehyde (MDA) and super oxidation (SOD) content were determined by biochemistry method; adenosine triphosphate (ATP) content measured by capillary electrophoresis. RESULTS: Following CIRI, the following parameters were altered compared with sham-operated animals: the number of neurons with normal appearance was significantly reduced in the cerebral cortex; the number of apoptotic cells increased; Bax protein expression was enhanced; and the ratio between Bcl-2 and Bax decreased. In addition, MDA content increased significantly, whereas ATP content decreased (P < 0.01 ). Aspirin ameliorated the loss of healthy pyramidal neurons. Both 6 and 60 mg/kg aspirin increased the ratio between Bcl-2 and Bax, with no significant difference between the treatment groups. In addition, 60 mg

  2. Anti-Apoptotic Gene Delivery with cyclo-(d-Trp-Tyr Peptide Nanotube via Eye Drop Following Corneal Epithelial Debridement

    Directory of Open Access Journals (Sweden)

    Yu-Hsing Lee

    2015-07-01

    Full Text Available Corneal keratocyte apoptosis triggered by cornel debridement is one mechanism of corneal disorders. In this study, the feasibility of cyclo-(d-Trp-Tyr peptide nanotubes (PNTs as carriers of caspase 3 silence shRNA delivery was assessed. A model of epithelial injury by epithelial debridement was applied to investigate the feasibility of PNTs as gene delivery carriers on corneal injury. First, the PNTs were found within 2 μm in length and 300 nm in width by an atomic force microscope and confocal laser microscope system. Plasmid DNAs were observed to be associated with PNTs by atomic force microscope and confocal laser scanning microscope. The plasmids were associated with tyrosine of PNTs with a binding constant of 2.7 × 108 M−1. The stability of plasmid DNA with PNTs against the DNase was found at 60 min. Using thioflavin T pre-stained PNTs on the corneal eye drop delivery, the distribution of PNTs was in the epithelial and stroma regions. After corneal debridement, the rhodamine-labeled plasmid DNA and thioflavin T pre-stained PNTs were also delivered and could be observed in the stroma of cornea. PNTs complexed with anti-apoptotic plasmid caspase 3 silencing shRNA eye drop delivery decreased 41% of caspase 3 activity after the first dose by caspase 3 activity and Western blot analysis.

  3. Anti-inflammatory and anti-apoptotic effects of Crataegus oxyacantha on isoproterenol-induced myocardial damage.

    Science.gov (United States)

    Vijayan, Navin Alukkathara; Thiruchenduran, Mohana; Devaraj, Sivasitamparam Niranjali

    2012-08-01

    This study was designed to evaluate the anti-inflammatory and anti-apoptotic effects of the alcoholic extract of the berries of Crataegus oxyacantha (AEC), a medicinal herb, on isoproterenol-induced myocardial infarction (MI) in a rat model. Three groups of Wistar albino rats, each comprising six animals, were selected for this study. Group I rats served as control. Group II rats were given isoproterenol (85 mg/kg body weight) subcutaneously on 59th and 60th days. Group III rats were given AEC (0.5 ml/100 g body weight/day), orally on a daily basis for 60 days, and isoproterenol (85 mg/kg body weight, subcutaneously) was given on 59th and 60th days. On the 61st day, the animals were sacrificed, and marker enzymes like lactate dehydrogenase (LDH) and creatine kinase (CK) were estimated in serum. In the heart tissue sample, antioxidant status, lipid peroxidation and anti-inflammatory properties of AEC were determined. Isoproterenol significantly increased the release of LDH, CK in serum, decreased the antioxidant status in the heart along with an increase in lipid peroxidation. Nitritive stress and apoptosis were seen in isoproterenol-induced rat heart. Pre-treatment with the AEC for 60 days had a significant effect on all the above factors and maintained near normal status. The study confirms the protective effect of AEC against isoproterenol-induced inflammation and apoptosis-associated MI in rats. PMID:22350754

  4. Soluble VEGF receptor 1 (sFLT1) induces non-apoptotic death in ovarian and colorectal cancer cells

    Science.gov (United States)

    Miyake, Tatsuya; Kumasawa, Keiichi; Sato, Noriko; Takiuchi, Tsuyoshi; Nakamura, Hitomi; Kimura, Tadashi

    2016-01-01

    Soluble Vascular Endothelial Growth Factor Receptor 1 (sVEGFR1/sFLT1) is an angiogenesis inhibitor that competes with angiogenic factors such as VEGF and Placental Growth Factor (PlGF). Imbalances of VEGF and sFLT1 levels can cause pathological conditions such as tumour growth or preeclampsia. We observed direct damage caused by sFLT1 in tumour cells. We exposed several kinds of cells derived from ovarian and colorectal cancers as well as HEK293T cells to sFLT1 in two ways, transfection and exogenous application. The cell morphology and an LDH assay revealed cytotoxicity. Additional experiments were performed to clarify how sFLT1 injured cells. In this study, non-apoptotic cell damage was found to be induced by sFLT1. Moreover, sFLT1 showed an anti-tumour effect in a mouse model of ovarian cancer. Our results suggest that sFLT1 has potential as a cancer therapeutic candidate. PMID:27103202

  5. Emodin Induces Apoptotic Death in Murine Myelomonocytic Leukemia WEHI-3 Cells In Vitro and Enhances Phagocytosis in Leukemia Mice In Vivo

    Directory of Open Access Journals (Sweden)

    Yuan-Chang Chang

    2011-01-01

    Full Text Available Emodin is one of major compounds in rhubarb (Rheum palmatum L., a plant used as herbal medicine in Chinese population. Although many reports have shown that emodin exhibits anticancer activity in many tumor cell types, there is no available information addressing emodin-affected apoptotic responses in the murine leukemia cell line (WEHI-3 and modulation of the immune response in leukemia mice. We investigated that emodin induced cytotoxic effects in vitro and affected WEHI-3 cells in vivo. This study showed that emodin decreased viability and induced DNA fragmentation in WEHI-3 cells. Cells after exposure to emodin for 24 h have shown chromatin condensation and DNA damage. Emodin stimulated the productions of ROS and Ca2+ and reduced the level of ΔΨm by flow cytometry. Our results from Western blotting suggest that emodin triggered apoptosis of WEHI-3 cells through the endoplasmic reticulum (ER stress, caspase cascade-dependent and -independent mitochondrial pathways. In in vivo study, emodin enhanced the levels of B cells and monocytes, and it also reduced the weights of liver and spleen compared with leukemia mice. Emodin promoted phagocytic activity by monocytes and macrophages in comparison to the leukemia mice group. In conclusions, emodin induced apoptotic death in murine leukemia WEHI-3 cells and enhanced phagocytosis in the leukemia animal model.

  6. Protective effects of melittin on transforming growth factor-β1 injury to hepatocytes via anti-apoptotic mechanism

    International Nuclear Information System (INIS)

    Melittin is a cationic, hemolytic peptide that is the main toxic component in the venom of the honey bee (Apis mellifera). Melittin has multiple effects, including anti-bacterial, anti-viral and anti-inflammatory, in various cell types. However, the anti-apoptotic mechanisms of melittin have not been fully elucidated in hepatocytes. Apoptosis contributes to liver inflammation and fibrosis. Knowledge of the apoptotic mechanisms is important to develop new and effective therapies for treatment of cirrhosis, portal hypertension, liver cancer, and other liver diseases. In the present study, we investigated the anti-apoptotic effect of melittin on transforming growth factor (TGF)-β1-induced apoptosis in hepatocytes. TGF-β1-treated hepatocytes were exposed to low doses (0.5 and 1 μg/mL) and high dose (2 μg/mL) of melittin. The low doses significantly protected these cells from DNA damage in TGF-β1-induced apoptosis compared to the high dose. Also, melittin suppressed TGF-β1-induced apoptotic activation of the Bcl-2 family and caspase family of proteins, which resulted in the inhibition of poly-ADP-ribose polymerase (PARP) cleavage. These results demonstrate that TGF-β1 induces hepatocyte apoptosis and that an optimal dose of melittin exerts anti-apoptotic effects against TGF-β1-induced injury to hepatocytes via the mitochondrial pathway. These results suggest that an optimal dose of melittin can serve to protect cells against TGF-β1-mediated injury. - Highlights: → We investigated the anti-apoptotic effect of melittin on TGF-β1-induced hepatocyte. → TGF-β1 induces hepatocyte apoptosis. → TGF-β1-treated hepatocytes were exposed to low doses and high dose of melittin. → Optimal dose of melittin exerts anti-apoptotic effects to hepatocytes.

  7. Integrin α PAT-2/CDC-42 signaling is required for muscle-mediated clearance of apoptotic cells in Caenorhabditis elegans.

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    Hsiao-Han Hsieh

    Full Text Available Clearance of apoptotic cells by engulfment plays an important role in the homeostasis and development of multicellular organisms. Despite the fact that the recognition of apoptotic cells by engulfment receptors is critical in inducing the engulfment process, the molecular mechanisms are still poorly understood. Here, we characterize a novel cell corpse engulfment pathway mediated by the integrin α subunit PAT-2 in Caenorhabditis elegans and show that it specifically functions in muscle-mediated engulfment during embryogenesis. Inactivation of pat-2 results in a defect in apoptotic cell internalization. The PAT-2 extracellular region binds to the surface of apoptotic cells in vivo, and the intracellular region may mediate signaling for engulfment. We identify essential roles of small GTPase CDC-42 and its activator UIG-1, a guanine-nucleotide exchange factor, in PAT-2-mediated cell corpse removal. PAT-2 and CDC-42 both function in muscle cells for apoptotic cell removal and are co-localized in growing muscle pseudopods around apoptotic cells. Our data suggest that PAT-2 functions through UIG-1 for CDC-42 activation, which in turn leads to cytoskeletal rearrangement and apoptotic cell internalization by muscle cells. Moreover, in contrast to PAT-2, the other integrin α subunit INA-1 and the engulfment receptor CED-1, which signal through the conserved signaling molecules CED-5 (DOCK180/CED-12 (ELMO or CED-6 (GULP respectively, preferentially act in epithelial cells to mediate cell corpse removal during mid-embryogenesis. Our results show that different engulfing cells utilize distinct repertoires of receptors for engulfment at the whole organism level.

  8. Norcantharidin inhibits tumor growth and vasculogenic mimicry of human gallbladder carcinomas by suppression of the PI3-K/MMPs/Ln-5γ2 signaling pathway

    International Nuclear Information System (INIS)

    Vasculogenic mimicry (VM) is a novel tumor blood supply in some highly aggressive malignant tumors. Recently, we reported VM existed in gallbladder carcinomas (GBCs) and the formation of the special passage through the activation of the PI3K/MMPs/Ln-5γ2 signaling pathway. GBC is a highly aggressive malignant tumor with disappointing treatments and a poor prognosis. Norcantharidin (NCTD) has shown to have multiple antitumor activities against GBCs, etc; however the exact mechanism is not thoroughly elucidated. In this study, we firstly investigated the anti-VM activity of NCTD as a VM inhibitor for GBCs and its underlying mechanisms. In vitro and in vivo experiments to determine the effects of NCTD on proliferation, invasion, migration, VM formation, hemodynamic and tumor growth of GBC-SD cells and xenografts were respectively done by proliferation, invasion, migration assays, H&E staining and CD31-PAS double stainings, optic/electron microscopy, tumor assay, and dynamic micro-MRA. Further, immunohistochemistry, immunofluorescence, Western blotting and RT-PCR were respectively used to examine expression of VM signaling-related markers PI3-K, MMP-2, MT1-MMP and Ln-5γ2 in GBC-SD cells and xenografts in vitro and in vivo. After treatment with NCTD, proliferation, invasion, migration of GBC-SD cells were inhibited; GBC-SD cells and xenografts were unable to form VM-like structures; tumor center-VM region of the xenografts exhibited a decreased signal in intensity; then cell or xenograft growth was inhibited. Whereas all of untreated GBC-SD cells and xenografts formed VM-like structures with the same conditions; the xenograft center-VM region exhibited a gradually increased signal; and facilitated cell or xenograft growth. Furthermore, expression of MMP-2 and MT1-MMP products from sections/supernates of 3-D matrices and the xenografts, and expression of PI3-K, MMP-2, MM1-MMP and Ln-5γ2 proteins/mRNAs of the xenografts were all decreased in NCTD or TIMP-2 group; (all P

  9. Expression of CD82/KAI1 and HIF-1α in Non-small Cell Lung Cancer 
and Their Relationship to Vasculogenic Mimicry

    Directory of Open Access Journals (Sweden)

    Shiwu WU

    2011-12-01

    Full Text Available Background and objective Vasculogenic mimicry (VM, found in many high invasive ability tumors, is associated with tumor invasion and metastasis. Many genes exhibit abnormal levels of expression in these tumors. This study aims to find good markers for predicting the invasion and metastasis of non-small cell lung cancer (NSCLC. Methods VM and expression of CD82/KAI1 and HIF-1α were examined via immunohistochemistry and histochemistry of 160 NSCLC and 20 normal lung tissue specimens. Results In NSCLC, positive rates of 37.5%, 48.8%, and 36.9% were obtained for CD82/KAI1, HIF-1α, and VM, respectively. In normal lung tissue, positive rates of 95.0%, 0, and 0 were obtained for CD82/KAI1, HIF-1α, and VM, respectively. A significant difference was found between the NSCLC and normal lung groups (P<0.01. VM and the expression levels of CD82/KAI1 and HIF-1α were significantly related to tumor differentiation, lymph node metastasis, clinical staging, and postoperative survival time (P<0.01 for all. A negative correlation was found between the expression levels of CD82/KAI1 and HIF-1α; a similar relationship was observed between CD82/KAI1 and VM. A positive relationship between the expression of HIF-1α and VM was revealed; there was a significant relationship between microvessel density (MVD and the expression of CD82/KAI1 or HIF-1α or VM. VM and overexpression of HIF-1α were related to poor prognosis: the survival rates were significantly lower in positive patients than in negative patients (both P<0.01. The survival rates of the CD82/KAI1-positive and CD82/KAI1-negative groups were significantly different (P<0.01. The five-year survival rate was significantly different between the group with MVD≥22 and the group with MVD<22 (P<0.01. pTNM stage, positive expressions of CD82/KAI1 and HIF-1α, and VM were independent prognostic factors of NSCLC (P<0.01. Conclusion VM and the expressions of CD82/KAI1 and HIF-1α in NSCLC are related to

  10. Pärimus ja jäljendus. Postkolonialistlik katse mõista rahvatantsu olukorda Eesti NSV-s ja pärast seda. Tradition and Mimicry

    Directory of Open Access Journals (Sweden)

    Sille Kapper

    2012-04-01

    Full Text Available Estonian dance history and traditions can in some respects be viewed as colonised culture. Folk dance research can help clarify which period or periods in our history could be discussed within the framework of colonialism. In this article, I analyse a style of staged folk dance, posing the question if a colonial situation came into being in Soviet-occupied Estonia in 1940 – 1991, and whether or not any colonial traits can be observed in Soviet Estonian cultural life and arts. The limits for what constitutes folk dance became extremely wide during the course of the 20th century, and came to encompass traditional as well as staged folk dances. The creation and performance of the latter became particularly popular in the days of the Estonian SSR. Looking at stylised dances performed at dance festivals or amateur concerts through the prism of post-colonialism could help find markers pointing to the colonial situation within the Soviet-era compositions. Stage and stadium performances at times share more similarities with classical ballet and character dance than with traditional dance – a situation which inspires to interpretations through Homi Bhabha’s notion of mimicry (Estonian: jäliendus; Annus 2003: 138–139. The style based on homogenization and other canons of classical dance has even after the re-independence of Estonia preserved the characteristics which came into being during the colonial period; out of the colonial interference, a new tradition has been born (for comparison, see Bhabha’s ’English book’. In post-colonial Estonia, the tradition of staged folk dances has little in common with folklore and a lot in common with performance arts. The hybrid art form which came into being mimicring a colonialising culture has its own – and if dance festivals are also taken into account – rather broad following of amateurs and spectators, in certain respects representing or wishing to represent the entire nation. At the same time

  11. Unc93b Induces Apoptotic Cell Death and Is Cleaved by Host and Enteroviral Proteases.

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    Katharine G Harris

    Full Text Available Unc93b is an endoplasmic reticulum (ER-resident transmembrane protein that serves to bind and traffic toll-like receptors (TLRs from the ER to their appropriate subcellular locations for ligand sensing. Because of its role in TLR trafficking, Unc93b is necessary for an effective innate immune response to coxsackievirus B3 (CVB, a positive-sense single stranded RNA virus belonging to the enterovirus family. Here, we show that Unc93b is cleaved by a CVB-encoded cysteine protease (3Cpro during viral replication. Further, we define a role for Unc93b in the induction of apoptotic cell death and show that expression of wild-type Unc93b, but not a mutant incapable of binding TLRs or exiting the ER (H412R, induces apoptosis. Furthermore, we show that cellular caspases activated during apoptosis directly cleave Unc93b. Interestingly, we show that the 3Cpro- and caspase-mediated cleavage of Unc93b both occur within ten amino acids in the distal N-terminus of Unc93b. Mechanistically, neither caspase-mediated nor 3Cpro-mediated cleavage of Unc93b altered its trafficking function, inhibited its role in facilitating TLR3 or TLR8 signaling, or altered its apoptosis-inducing effects. Taken together, our studies show that Unc93b is targeted by both viral- and host cell-specific proteases and identify a function of Unc93b in the induction of apoptotic cell death.

  12. Lactadherin inhibits secretory phospholipase A2 activity on pre-apoptotic leukemia cells.

    Directory of Open Access Journals (Sweden)

    Steffen Nyegaard

    Full Text Available Secretory phospholipase A2 (sPLA2 is a critical component of insect and snake venoms and is secreted by mammalian leukocytes during inflammation. Elevated secretory PLA2 concentrations are associated with autoimmune diseases and septic shock. Many sPLA2's do not bind to plasma membranes of quiescent cells but bind and digest phospholipids on the membranes of stimulated or apoptotic cells. The capacity of these phospholipases to digest membranes of stimulated or apoptotic cells correlates to the exposure of phosphatidylserine. In the present study, the ability of the phosphatidyl-L-serine-binding protein, lactadherin to inhibit phospholipase enzyme activity has been assessed. Inhibition of human secretory phospholipase A2-V on phospholipid vesicles exceeded 90%, whereas inhibition of Naja mossambica sPLA2 plateaued at 50-60%. Lactadherin inhibited 45% of activity of Naja mossambica sPLA2 and >70% of human secretory phospholipase A2-V on the membranes of human NB4 leukemia cells treated with calcium ionophore A23187. The data indicate that lactadherin may decrease inflammation by inhibiting sPLA2.

  13. [Effect of lidamycin on mitochondria initiated apoptotic pathway in human cancer cells].

    Science.gov (United States)

    Qiu, Qiang; Wang, Zhen; Jiang, Jian-ming; Li, Dian-dong

    2007-02-01

    Although enediyne antibiotic lidamycin ( LDM) is a potent inducer of apoptosis, the underlying mechanisms of its apoptotic functions remain to be explored. Here, we aim to elucidate its possible mechanisms in mitochondria initiated apoptotic pathway involved in human BEL-7402 and MCF-7 cells. Cytochrome c released from mitchondria to cytosol fraction was detected by Western blotting. p53 and Bax, Bcl-2 expressions were detected by Western blotting and RT-PCR. MTT assay was used to detect cytotoxicity of LDM with or without caspase inhibitor z-VAD-fmk. After the BEL-7402 cells were exposed to 0. 1 micromol x L(-1) LDM within 6 h, the increase of cytochrome c in the cytosol and decrease in the mitochondria were observed when compared with untreated cells. The expression of Bax, an important proapoptotic member of the Bcl-2 family, increased gradually in the BEL-7402 cells after exposure to LDM of 0. 1 micromol x L (-1) for 2, 6, and 9 h, separately, while Bcl-2 increased at 2 and 6 h, and decreased at 9 h after LDM treatment. Enhanced protein expressions were parallel with respective increased mRNA level for Bax only, but not p53. Caspase inhibitor may inhibit partially the killing effects induced by LDM. Therefore we conclude that the rapid activation of mitochondrial pathway induced by LDM in tumor cells might contribute to its highly potent cytotoxicities. PMID:17518039

  14. Para-Phenylenediamine Induces Apoptotic Death of Melanoma Cells and Reduces Melanoma Tumour Growth in Mice

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    Debajit Bhowmick

    2016-01-01

    Full Text Available Melanoma is one of the most aggressive forms of cancer, usually resistant to standard chemotherapeutics. Despite a huge number of clinical trials, any success to find a chemotherapeutic agent that can effectively destroy melanoma is yet to be achieved. Para-phenylenediamine (p-PD in the hair dyes is reported to purely serve as an external dyeing agent. Very little is known about whether p-PD has any effect on the melanin producing cells. We have demonstrated p-PD mediated apoptotic death of both human and mouse melanoma cells in vitro. Mouse melanoma tumour growth was also arrested by the apoptotic activity of intraperitoneal administration of p-PD with almost no side effects. This apoptosis is shown to occur primarily via loss of mitochondrial membrane potential (MMP, generation of reactive oxygen species (ROS, and caspase 8 activation. p-PD mediated apoptosis was also confirmed by the increase in sub-G0/G1 cell number. Thus, our experimental observation suggests that p-PD can be a potential less expensive candidate to be developed as a chemotherapeutic agent for melanoma.

  15. Para-Phenylenediamine Induces Apoptotic Death of Melanoma Cells and Reduces Melanoma Tumour Growth in Mice.

    Science.gov (United States)

    Bhowmick, Debajit; Bhar, Kaushik; Mallick, Sanjaya K; Das, Subhadip; Chatterjee, Nabanita; Sarkar, Tuhin Subhra; Chakrabarti, Rajarshi; Das Saha, Krishna; Siddhanta, Anirban

    2016-01-01

    Melanoma is one of the most aggressive forms of cancer, usually resistant to standard chemotherapeutics. Despite a huge number of clinical trials, any success to find a chemotherapeutic agent that can effectively destroy melanoma is yet to be achieved. Para-phenylenediamine (p-PD) in the hair dyes is reported to purely serve as an external dyeing agent. Very little is known about whether p-PD has any effect on the melanin producing cells. We have demonstrated p-PD mediated apoptotic death of both human and mouse melanoma cells in vitro. Mouse melanoma tumour growth was also arrested by the apoptotic activity of intraperitoneal administration of p-PD with almost no side effects. This apoptosis is shown to occur primarily via loss of mitochondrial membrane potential (MMP), generation of reactive oxygen species (ROS), and caspase 8 activation. p-PD mediated apoptosis was also confirmed by the increase in sub-G0/G1 cell number. Thus, our experimental observation suggests that p-PD can be a potential less expensive candidate to be developed as a chemotherapeutic agent for melanoma. PMID:27293892

  16. Manganese induces mitochondrial dynamics impairment and apoptotic cell death: a study in human Gli36 cells.

    Science.gov (United States)

    Alaimo, Agustina; Gorojod, Roxana M; Miglietta, Esteban A; Villarreal, Alejandro; Ramos, Alberto J; Kotler, Mónica L

    2013-10-25

    Manganese (Mn) is an essential trace element due to its participation in many physiological processes. However, overexposure to this metal leads to a neurological disorder known as Manganism whose clinical manifestations and molecular mechanisms resemble Parkinson's disease. Several lines of evidence implicate astrocytes as an early target of Mn neurotoxicity being the mitochondria the most affected organelles. The aim of this study was to investigate the possible mitochondrial dynamics alterations in Mn-exposed human astrocytes. Therefore, we employed Gli36 cells which express the astrocytic markers GFAP and S100B. We demonstrated that Mn triggers the mitochondrial apoptotic pathway revealed by increased Bax/Bcl-2 ratio, by the loss of mitochondrial membrane potential and by caspase-9 activation. This apoptotic program may be in turn responsible of caspase-3/7 activation, PARP-1 cleavage, chromatin condensation and fragmentation. In addition, we determined that Mn induces deregulation in mitochondria-shaping proteins (Opa-1, Mfn-2 and Drp-1) expression levels in parallel with the disruption of the mitochondrial network toward to an exacerbated fragmentation. Since mitochondrial dynamics is altered in several neurodegenerative diseases, these proteins could become future targets to be considered in Manganism treatment. PMID:24021799

  17. Activation of intrinsic apoptotic signaling pathway in cancer cells by Cymbopogon citratus polysaccharide fractions.

    Science.gov (United States)

    Thangam, Ramar; Sathuvan, Malairaj; Poongodi, Arasu; Suresh, Veeraperumal; Pazhanichamy, Kalailingam; Sivasubramanian, Srinivasan; Kanipandian, Nagarajan; Ganesan, Nalini; Rengasamy, Ramasamy; Thirumurugan, Ramasamy; Kannan, Soundarapandian

    2014-07-17

    Essential oils of Cymbopogon citratus were already reported to have wide ranging medical and industrial applications. However, information on polysaccharides from the plant and their anticancer activities are limited. In the present study, polysaccharides from C. citratus were extracted and fractionated by anion exchange and gel filtration chromatography. Two different polysaccharide fractions such as F1 and F2 were obtained, and these fractions were found to have distinct acidic polysaccharides as characterized by their molecular weight and sugar content. NMR spectral analysis revealed the presence of (1→4) linked b-d-Xylofuranose moiety in these polysaccharides. Using these polysaccharide fractions F1 and F2, anti-inflammatory and anticancer activities were evaluated against cancer cells in vitro and the mechanism of action of the polysaccharides in inducing apoptosis in cancer cells via intrinsic pathway was also proposed. Two different reproductive cancer cells such as Siha and LNCap were employed for in vitro studies on cytotoxicity, induction of apoptosis and apoptotic DNA fragmentation, changes in mitochondrial membrane potential, and profiles of gene and protein expression in response to treatment of cells by the polysaccharide fractions. These polysaccharide fractions exhibited potential cytotoxic and apoptotic effects on carcinoma cells, and they induced apoptosis in these cells through the events of up-regulation of caspase 3, down-regulation of bcl-2 family genes followed by cytochrome c release. PMID:24702929

  18. Apoptotic effects of non-edible parts of Punica granatum on human multiple myeloma cells.

    Science.gov (United States)

    Kiraz, Yağmur; Neergheen-Bhujun, Vidushi S; Rummun, Nawraj; Baran, Yusuf

    2016-02-01

    Multiple myeloma is of great concern since existing therapies are unable to cure this clinical condition. Alternative therapeutic approaches are mandatory, and the use of plant extracts is considered interesting. Punica granatum and its derived products were suggested as potential anticancer agents due to the presence of bioactive compounds. Thus, polypenolic-rich extracts of the non-edible parts of P. granatum were investigated for their antiproliferative and apoptotic effects on U266 multiple myeloma cells. We demonstrated that there were dose-dependent decreases in the proliferation of U266 cells in response to P. granatum extracts. Also, exposure to the extracts triggered apoptosis with significant increases in loss of mitochondrial membrane potential in U266 cells exposed to the leaves and stem extracts, while the flower extract resulted in slight increases in loss of MMP. These results were confirmed by Annexin-V analysis. These results documented the cytotoxic and apoptotic effects of P. granatum extracts on human U266 multiple myeloma cells via disruption of mitochondrial membrane potential and increasing cell cycle arrest. The data suggest that the extracts can be envisaged in cancer chemoprevention and call for further exploration into the potential application of these plant parts. PMID:26318303

  19. Possible involvement of protein kinase C in apoptotic cell death of macrophages infected with Actinobacillus actinomycetemcomitans.

    Science.gov (United States)

    Nonaka, K; Ishisaki, A; Muro, M; Kato, S; Oido, M; Nakashima, K; Kowashi, Y; Nishihara, T

    1998-02-15

    We have previously reported the evidence for apoptosis in the mouse macrophage cell line J774.1 by the periodontopathic bacterium Actinobacillus actinomycetemcomitans. In this study, we examined the role of protein kinases in the induction of apoptosis in A. actinomycetemcomitans-infected J774.1 cells by the MTT assay, fluorescence microscopy and flow cytometric analysis. After J774.1 cells were precultured with protein kinase C (PKC) activator, phorbol 12-myristate 13-acetate (PMA), J774.1 cells infected with A. actinomycetemcomitans showed the increased percentage of apoptotic cells. On the contrary, protein kinase A (PKA) activators, such as forskolin and dibutyryl cAMP, do not mimic the effect of PMA. PKC inhibitors, such as staurosporine, calphostin C, chelerythrine chloride, and H7 were found to suppress apoptotic cell death in J774.1 cells infected with A. actinomycetemcomitans. However, HA1004, known as PKA inhibitor, had no effect on apoptosis in infected macrophages. The results presented here suggest that the signals through PKC may play crucial roles in the modulation of apoptosis in macrophages infected with A. actinomycetemcomitans. PMID:9503618

  20. Design and Synthesis of Pro-Apoptotic Compounds Inspired by Diatom Oxylipins

    Directory of Open Access Journals (Sweden)

    Giovanna Romano

    2013-11-01

    Full Text Available Oxylipins are a large and diverse family of fatty acid derivatives exhibiting different levels of oxidation of the carbon chain. They are involved in many biological functions in mammals, plants and diatoms. In this last group of organisms, they are suggested to play a role in the reproductive failure of copepod predators, showing clear pro-apoptotic effects on newborn nauplii. In this work, these compounds were tested for the ability to induce mitotic arrest in sea urchin embryos. We show for the first time that oxylipins have an increased efficacy in their corresponding methylated form. Natural oxylipins were also used as an inspiration for the rational design and synthesis of stable chemical analogs with apoptotic activity against tumor cell lines. This approach led to the synthesis of the linear C15-ketol (22 that was shown to induce apoptosis in human leukemia U-937 cells. These results are proof of the concept of the use of eco-physiological considerations as a platform to guide the search for novel drug candidates.

  1. Potential for Modulation of the Fas Apoptotic Pathway by Epidermal Growth Factor in Sarcomas

    Directory of Open Access Journals (Sweden)

    David E. Joyner

    2011-01-01

    Full Text Available One important mechanism by which cancer cells parasitize their host is by escaping apoptosis. Thus, selectively facilitating apoptosis is a therapeutic mechanism by which oncotherapy may prove highly advantageous. One major apoptotic pathway is mediated by Fas ligand (FasL. The death-inducing signaling Ccmplex (DISC and subsequent death-domain aggregations are created when FasL is bound by its receptor thereby enabling programmed cell death. Conceptually, if a better understanding of the Fas pathway can be garnered, an oncoselective prodeath therapeutic approach can be tailored. Herein, we propose that EGF and CTGF play essential roles in the regulation of the Fas apoptotic pathway in sarcomas. Tumor and in vitro data suggest viable cells counter the prodeath signal induced by FasL by activating EGF, which in turn induces prosurvival CTGF. The prosurvival attributes of CTGF ultimately predominate over the death-inducing FasL. Cells destined for elimination inhibit this prosurvival response via a presently undefined pathway. This scenario represents a novel role for EGF and CTGF as regulators of the Fas pathway in sarcomas.

  2. Role of p53 gene in apoptotic repair of genotoxic tissue damage in mice

    Energy Technology Data Exchange (ETDEWEB)

    Kato, Fumio; Kakihara, Hiroyo; Kunugita, Naoki; Ootsuyama, Akira; Norimura, Toshiyuki [Univ. of Occupational and Environmental Health, Kitakyushu, Fukuoka (Japan)

    2002-12-01

    When DNA is damaged by exposure to a small amount of radiation, it is repaired efficiently by innate mechanisms. However, if cellular damage is more extensive, DNA repair cannot be adequately completed. To clarify the role of the p53 gene in apoptotic tissue repair, the incidence of in-vivo radiation-induced somatic mutation was evaluated by measuring the T cell receptor (TCR) gene expression in p53(+/+) and p53(-/-) mice. After {gamma}-irradiation with 3 Gy,the TCR mutation frequency (MF) was higher in p53(+/+) mice than in the controls. However, when the mice were exposed to 3 Gy at a low dose rate, the TCR MF did not increase in the p53(+/+) mice, whereas it increased and remained elevated in p53(-/-) mice, which are unable to induce apoptosis. In p53(+/+) mice, the TCR MF peaked 9 days after {gamma}-irradiation with 3 Gy at a high dose rate, and then gradually decreased with a half-life of about 13 days. However, in p53(-/-) mice, the peak level of the TCR MF did not decline significantly with time. Hence, complete repair of mutagenic damage in irradiated tissues requires the integration of DNA repair and p53-dependent apoptotic tissue repair. (author)

  3. GalNAc-T14 may be involved in regulating the apoptotic action of IGFBP-3

    Indian Academy of Sciences (India)

    Chen Wu; Yaojun Shan; Xinxia Liu; Wenqian Song; Jiali Wang; Minji Zou; Min Wang; Donggang Xu

    2009-09-01

    Insulin-like growth factor binding protein-3 (IGFBP-3) is known to induce apoptosis in an insulin-like growth factor (IGF)-dependent and IGF-independent manner, but the mechanism underlying the IGF-independent effects remains unclear. Polypeptide -acetylgalactosaminyltransferase 14 (GalNAc-T14) is a novel IGFBP-3 binding partner. In this paper, small interference RNA (siRNA) targeting GalNAc-T14 was used to examine whether GalNAc-T14 affects the apoptotic action of IGFBP-3. Using semi-quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) and western blot analysis, we determined that GalNAc-T14 expression was downregulated by the siRNA directed against GalNAc-T14. Apoptosis analysis of IGFBP-3-overexpressing cells treated with siRNA against GalNAc-T14 was performed to determine if GalNAc-T14 was specifically involved in IGFBP-3 signalling. The results, as determined by flow cytometric analysis and caspase-3 assay, showed that the extent of apoptosis induced by IGFBP-3 increased with RNA interference (RNAi) knockdown of GalNAc-T14. Our data suggest that GalNAc-T14 influences the apoptotic action of IGFBP-3 and might mediate the signalling pathway of IGFBP-3. Experiments to determine the role of GalNAc-T14 in the regulation of apoptosis induced by IGFBP-3 are under way.

  4. ORF3 of duck circovirus: a novel protein with apoptotic activity.

    Science.gov (United States)

    Xiang, Qi-Wang; Wang, Xin; Xie, Zhi-Jing; Sun, Ya-Ni; Zhu, Yan-Li; Wang, Shu-Jing; Liu, Hong-Jie; Jiang, Shi-Jin

    2012-09-14

    Duck circovirus (DuCV) is classified in the genus Circovirus of the Circoviridae family. Two major open reading frames (ORFs), encoding the replicase (ORF1/rep) and the capsid protein (ORF2/cap), have been recognized for DuCV. Sequence analysis show that another major conserved ORF (named ORF3) is located in the complementary strand of ORF1/rep of DuCV, and its function remains to be investigated. In this study, the ORF3 of DuCV was expressed in recombinant baculovirus-infected Sf9 cells. By IFA and Western blot analysis, the ORF3 protein was positive for the sera from ducks infected with DuCV. The percentages of apoptotic cells of the Sf9 cells infected with the recombinant baculovirus encoding ORF3 of DuCV were significantly higher than (Pbaculovirus at 24, 48 and 72 h postinfection. Based on our knowledge, we deduced that the ORF3 protein of DuCV might play an important role in viral pathogenesis via its apoptotic activity. PMID:22537707

  5. Local Augmented Angiotensinogen Secreted from Apoptotic Vascular Endothelial Cells Is a Vital Mediator of Vascular Remodelling.

    Directory of Open Access Journals (Sweden)

    Shyh-Jong Wu

    Full Text Available Vascular remodelling is a critical vasculopathy found in atheromatous diseases and allograft failures. The local renin angiotensin system (RAS has been implicated in vascular remodelling. However, the mechanisms by which the augmented local RAS is associated with the initial event of endothelial cell apoptosis in injured vasculature remain undefined. We induced the apoptosis of human umbilical vein endothelial cells (HUVECs and vascular smooth muscle cells (VSMCs through serum starvation (SS. After the cells were subjected to SS, we found that the mRNA expression of angiotensinogen (AGT was increased by >3-fold in HUVECs and by approximately 2.5-fold in VSMCs. In addition, the expression of angiotensin-converting enzyme (ACE mRNA was increased in VSMCs but decreased to 50% in HUVECs during the same apoptotic process. Increases in the expression of AGT protein and angiotensin II (Ang II were found in a serum-free medium conditioned by HUVECs (SSC. The increased Ang II was suppressed using lisinopril (an ACE inhibitor treatment. Moreover, the activation of ERK1/2 induced by the SSC in VSMCs was also suppressed by losartan. In conclusion, we first demonstrated that the augmented AGT released from apoptotic endothelial cells acts as a vital progenitor of Ang II to accelerate vascular remodelling, and we suggest that blocking local augmented Ang II might be an effective strategy for restraining intimal hyperplasia.

  6. In vitro anti-proliferative and apoptotic activity of different fractions of Artemisia armeniaca

    Directory of Open Access Journals (Sweden)

    Mahdi Mojarrab

    2013-10-01

    Full Text Available Anti-proliferative properties have been reported for certain species of the genus Artemisia.In this study, we investigated the cytotoxic and apoptotic effects of n-hexane, CH2Cl2, EtOAc, n-BuOH and H2O fractions obtained from a crude methanol extract of A. armeniaca on two myeloid cell lines, apoptosis-proficient HL60 cells and apoptosis-resistant K562 cells; in addition, J774 cells were used as a control. Among the solvent fractions of A. armeniaca, the CH2Cl2 fraction was found to have the largest anti-proliferative effect on cancer cells. The IC50 values obtained using an MTS assay for the CH2Cl2 fraction were 75 and 130 µg/ml for HL-60 cells and K562, respectively. The control cells were not significantly affected by this fraction. A flow cytometry histogram of cells treated with the CH2Cl2 fraction of A. armeniacarevealed a sub-G1 peak. DNA fragmentation, increased protein levels of Bax and cleavage of the poly (ADP-ribose polymerase (PARP protein confirmed the induction of apoptosis in cells after a 48-h exposure to the CH2Cl2 fraction. Our results corroborate the cytotoxic and apoptotic effects of the CH2Cl2 fraction of A. armeniaca on K562 and HL-60 cancer cell lines.

  7. Gene Expression Profiling in Apoptotic K562 Cells Treated by Homoharringtonine

    Institute of Scientific and Technical Information of China (English)

    Wei JIN; Jiong WU; Zhigang ZHUANG; Junjie Li; Fei FEI; Genhong DI; Ying CHEN; Ming YAO; Zhimin SHAO

    2007-01-01

    Gene chip technology was used to determine the gene expression profiles in apoptotic K562 cells induced by homoharringtonine. The expression of forty-four mRNAs was found to be changed significantly were identified after screening with a gene chip capable of detecting 14,218 different human mRNA species simultaneously. Of these genes, 17 were up-regulated and 27 were down-regulated.Most of them were found to be related to apoptosis, oncogenes, or tumor suppression. Several genes with altered gene expression, such as human transforming growth factor-beta inducible early protein gene (TIEG), vitamin D3 upregulated protein 1 gene (VDUP1), RNA binding motif protein 4 gene (RBM4) and v-myc myelocytomatosis viral oncogene homolog (C-MYC), were confirmed by Northern blot analysis.According to the dynamic gene expression pattern in these apoptotic cells, the activated transforming growth factor-β and tumor necrosis factor signaling pathways play an important role in homoharringtonine-induced apoptosis. TIEG was significantly altered after apoptosis induction, it should be critical for apoptosis signal transmission.

  8. Role of p53 gene in apoptotic repair of genotoxic tissue damage in mice

    International Nuclear Information System (INIS)

    When DNA is damaged by exposure to a small amount of radiation, it is repaired efficiently by innate mechanisms. However, if cellular damage is more extensive, DNA repair cannot be adequately completed. To clarify the role of the p53 gene in apoptotic tissue repair, the incidence of in-vivo radiation-induced somatic mutation was evaluated by measuring the T cell receptor (TCR) gene expression in p53(+/+) and p53(-/-) mice. After γ-irradiation with 3 Gy,the TCR mutation frequency (MF) was higher in p53(+/+) mice than in the controls. However, when the mice were exposed to 3 Gy at a low dose rate, the TCR MF did not increase in the p53(+/+) mice, whereas it increased and remained elevated in p53(-/-) mice, which are unable to induce apoptosis. In p53(+/+) mice, the TCR MF peaked 9 days after γ-irradiation with 3 Gy at a high dose rate, and then gradually decreased with a half-life of about 13 days. However, in p53(-/-) mice, the peak level of the TCR MF did not decline significantly with time. Hence, complete repair of mutagenic damage in irradiated tissues requires the integration of DNA repair and p53-dependent apoptotic tissue repair. (author)

  9. Sam68 is cleaved by caspases under apoptotic cell death induced by ionizing radiation

    International Nuclear Information System (INIS)

    The RNA-binding protein Sam68, a mitotic substrate of tyrosine kinases, has been reported to participate in the cell cycle, apoptosis, and signaling. In particular, overexpression of Sam68 protein is known to suppress cell growth and cell cycle progression in NIH3T3 cells. Although Sam68 is involved in many cellular activities, the function of Sam68, especially in response to apoptotic stimulation, is not well understood. In this study, we found that Sam68 protein is cleaved in immune cells undergoing apoptosis induced by γ-radiation. Moreover, we found that Sam68 cleavage was induced by apoptotic stimuli containing γ-radiation in a caspase-dependent manner. In particular, we showed that activated casepase-3, 7, 8 and 9 can directly cleave Sam68 protein through in vitro protease cleavage assay. Finally, we found that the knockdown of Sam68 attenuated γ-radiation-induced cell death and growth suppression. Conclusively, the cleavage of Sam68 is a new indicator for the cell damaging effects of ionizing radiation. (author)

  10. Cathepsin B launches an apoptotic exit effort upon cell death-associated disruption of lysosomes.

    Science.gov (United States)

    de Castro, M A G; Bunt, G; Wouters, F S

    2016-01-01

    The release of cathepsin proteases from disrupted lysosomes results in lethal cellular autodigestion. Lysosomal disruption-related cell death is highly variable, showing both apoptotic and necrotic outcomes. As the substrate spectrum of lysosomal proteases encompasses the apoptosis-regulating proteins of the Bcl-2 family, their degradation could influence the cell death outcome upon lysosomal disruption. We used Förster resonance energy transfer (FRET)-based biosensors to image the real-time degradation of the Bcl-2-family members, Bcl-xl, Bax and Bid, in living cells undergoing lysosomal lysis and identified an early chain of proteolytic events, initiated by the release of cathepsin B, which directs cells toward apoptosis. In this apoptotic exit strategy, cathepsin B's proteolytic activity results in apoptosis-inducing Bid and removes apoptosis-preventing Bcl-xl. Cathepsin B furthermore appears to degrade a cystein protease that would otherwise have eliminated apoptosis-supporting Bax, indirectly keeping cellular levels of the Bax protein up. The concerted effort of these three early events shifts the balance of cell fate away from necrosis and toward apoptosis. PMID:27551506

  11. Bioactive compounds from crocodile (Crocodylus siamensis) white blood cells induced apoptotic cell death in hela cells.

    Science.gov (United States)

    Patathananone, Supawadee; Thammasirirak, Sompong; Daduang, Jureerut; Chung, Jing Gung; Temsiripong, Yosapong; Daduang, Sakda

    2016-08-01

    Crocodile (Crocodylus siamensis) white blood cell extracts (WBCex) were examined for anticancer activity in HeLa cell lines using the MTT assay. The percentage viability of HeLa cells significantly deceased after treatment with WBCex in a dose- and time-dependent manner. The IC50 dose was suggested to be approximately 225 μg/mL protein. Apoptotic cell death occurred in a time-dependent manner based on investigation by flow cytometry using annexin V-FITC and PI staining. DAPI nucleic acid staining indicated increased chromatin condensation. Caspase-3, -8 and -9 activities also increased, suggesting the induction of the caspase-dependent apoptotic pathway. Furthermore, the mitochondrial membrane potential (ΔΨm ) of HeLa cells was lost as a result of increasing levels of Bax and reduced levels of Bcl-2, Bcl-XL, Bcl-Xs, and XIAP. The decreased ΔΨm led to the release of cytochrome c and the activation of caspase-9 and -3. Apoptosis-inducing factor translocated into the nuclei, and endonuclease G (Endo G) was released from the mitochondria. These results suggest that anticancer agents in WBCex can induce apoptosis in HeLa cells via both caspase-dependent and -independent pathways. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 986-997, 2016. PMID:25691005

  12. Anti-apoptotic role of retinoic acid in the inner ear of noise-exposed mice

    International Nuclear Information System (INIS)

    Exposure to loud noise can induce temporary or permanent hearing loss, and acoustic trauma is the major cause of hearing impairment in industrial nations. However, the mechanisms underlying the death of hair cells after acoustic trauma remain unclear. In addition to its involvement in cellular stress and apoptosis, the c-Jun N-terminal kinase (JNK), a member of the mitogen-activated protein kinase family, is involved in cell survival, transformation, embryonic morphogenesis, and differentiation. JNK is primarily activated by various environmental stresses including noise, and the phenotypic result appears be to cell death. All-trans retinoic acid (ATRA) is an active metabolite of vitamin A that regulates a wide range of biological processes, including cell proliferation, differentiation, and morphogenesis. We evaluated the role of ATRA in preserving hearing in mice exposed to noise that can induce permanent hearing loss. Mice fed with ATRA before and during 3 consecutive days of noise exposure had a more preserved hearing threshold than mice fed sesame oil or saline. Histological and TUNEL staining of the cochlea showed significantly enhanced preservation of the organ of Corti, including outer hair cells and relatively low apoptotic nuclei, in mice-fed ATRA than in mice-fed sesame oil or saline. Phospho-JNK immunohistochemistry showed that ATRA inhibited the activation of JNK. These results suggest that ATRA has an anti-apoptotic effect on cochleae exposed to noise

  13. Functional interaction between the pro-apoptotic DAP3 and the glucocorticoid receptor.

    Science.gov (United States)

    Hulkko, Sanna M; Zilliacus, Johanna

    2002-07-19

    Apoptosis is an essential process for functions such as organ development and the immune response, and glucocorticoids are one of the important regulators of the cellular functions underlying these events. We have previously shown that the pro-apoptotic death-associated protein 3 (DAP3) directly interacts with the glucocorticoid receptor (GR), leading to the enhancement of the activity of the ligand-induced receptor. Here, we show that coexpression of DAP3 and GR results in an increased amount of cellular GR, as well as in partial translocation of DAP3 to the nucleus. Although the N-terminal domain of DAP3 is sufficient for interaction with GR, the full-length DAP3 is needed to efficiently increase GR levels and enhance the transcriptional activity of GR. Since full-length DAP3 is also necessary for the pro-apoptotic effect, the interplay between the N- and C-termini of DAP3 is probably essential for its cellular function. PMID:12099703

  14. Para-Phenylenediamine Induces Apoptotic Death of Melanoma Cells and Reduces Melanoma Tumour Growth in Mice

    Science.gov (United States)

    Bhowmick, Debajit; Bhar, Kaushik; Mallick, Sanjaya K.; Das, Subhadip; Chatterjee, Nabanita; Sarkar, Tuhin Subhra; Chakrabarti, Rajarshi; Das Saha, Krishna; Siddhanta, Anirban

    2016-01-01

    Melanoma is one of the most aggressive forms of cancer, usually resistant to standard chemotherapeutics. Despite a huge number of clinical trials, any success to find a chemotherapeutic agent that can effectively destroy melanoma is yet to be achieved. Para-phenylenediamine (p-PD) in the hair dyes is reported to purely serve as an external dyeing agent. Very little is known about whether p-PD has any effect on the melanin producing cells. We have demonstrated p-PD mediated apoptotic death of both human and mouse melanoma cells in vitro. Mouse melanoma tumour growth was also arrested by the apoptotic activity of intraperitoneal administration of p-PD with almost no side effects. This apoptosis is shown to occur primarily via loss of mitochondrial membrane potential (MMP), generation of reactive oxygen species (ROS), and caspase 8 activation. p-PD mediated apoptosis was also confirmed by the increase in sub-G0/G1 cell number. Thus, our experimental observation suggests that p-PD can be a potential less expensive candidate to be developed as a chemotherapeutic agent for melanoma. PMID:27293892

  15. Homocysteine thiolactone induces apoptotic DNA damage mediated by increased intracellular hydrogen peroxide and caspase 3 activation in HL-60 cells.

    Science.gov (United States)

    Huang, R F; Huang, S M; Lin, B S; Wei, J S; Liu, T Z

    2001-05-11

    The cytotoxicity of homocysteine derivatives on chromosomal damage in somatic cells is not well established. The present study used reactive homocysteine derivative of homocysteine thiolactone (Hcy) to investigate its causal effect on apoptotic DNA injury in human promyeloid HL-60 cells. Our results demonstrated that Hcy induced cell death and features of apoptosis including increased phosphotidylserine exposure on the membrane surface, increased apoptotic cells with hypoploid DNA contents, and internucleosomal DNA fragmentation, all of which occurred in a time- and concentration-dependent manner. Hcy treatment also significantly increased intracellular reactive oxygen species H2O2, which coincided with the elimination of caspase 3 proenzyme levels and increased caspase 3 activity at the time of the appearance of apoptotic DNA fragmentation. Preincubation of Hcy-treated HL-60 cells with catalase completely scavenged intracellular H2O2, thus inhibiting caspase 3 activity and protecting cells from apoptotic DNA damage. In contrast, superoxide dismutase failed to inhibit Hcy-induced DNA damage. Taken together, these results demonstrate that Hcy exerted its genotoxic effects on HL-60 cells through an apoptotic pathway, which is mediated by the activation of caspase 3 activity induced by an increase in intracellular hydrogen peroxide. PMID:11432446

  16. Protein C inhibitor (PCI binds to phosphatidylserine exposing cells with implications in the phagocytosis of apoptotic cells and activated platelets.

    Directory of Open Access Journals (Sweden)

    Daniela Rieger

    Full Text Available Protein C Inhibitor (PCI is a secreted serine protease inhibitor, belonging to the family of serpins. In addition to activated protein C PCI inactivates several other proteases of the coagulation and fibrinolytic systems, suggesting a regulatory role in hemostasis. Glycosaminoglycans and certain negatively charged phospholipids, like phosphatidylserine, bind to PCI and modulate its activity. Phosphatidylerine (PS is exposed on the surface of apoptotic cells and known as a phagocytosis marker. We hypothesized that PCI might bind to PS exposed on apoptotic cells and thereby influence their removal by phagocytosis. Using Jurkat T-lymphocytes and U937 myeloid cells, we show here that PCI binds to apoptotic cells to a similar extent at the same sites as Annexin V, but in a different manner as compared to live cells (defined spots on ∼10-30% of cells. PCI dose dependently decreased phagocytosis of apoptotic Jurkat cells by U937 macrophages. Moreover, the phagocytosis of PS exposing, activated platelets by human blood derived monocytes declined in the presence of PCI. In U937 cells the expression of PCI as well as the surface binding of PCI increased with time of phorbol ester treatment/macrophage differentiation. The results of this study suggest a role of PCI not only for the function and/or maturation of macrophages, but also as a negative regulator of apoptotic cell and activated platelets removal.

  17. Terminalia Chebula provides protection against dual modes of necroptotic and apoptotic cell death upon death receptor ligation

    Science.gov (United States)

    Lee, Yoonjung; Byun, Hee Sun; Seok, Jeong Ho; Park, Kyeong Ah; Won, Minho; Seo, Wonhyoung; Lee, So-Ra; Kang, Kidong; Sohn, Kyung-Cheol; Lee, Ill Young; Kim, Hyeong-Geug; Son, Chang Gue; Shen, Han-Ming; Hur, Gang Min

    2016-01-01

    Death receptor (DR) ligation elicits two different modes of cell death (necroptosis and apoptosis) depending on the cellular context. By screening a plant extract library from cells undergoing necroptosis or apoptosis, we identified a water extract of Terminalia chebula (WETC) as a novel and potent dual inhibitor of DR-mediated cell death. Investigation of the underlying mechanisms of its anti-necroptotic and anti-apoptotic action revealed that WETC or its constituents (e.g., gallic acid) protected against tumor necrosis factor-induced necroptosis via the suppression of TNF-induced ROS without affecting the upstream signaling events. Surprisingly, WETC also provided protection against DR-mediated apoptosis by inhibition of the caspase cascade. Furthermore, it activated the autophagy pathway via suppression of mTOR. Of the WETC constituents, punicalagin and geraniin appeared to possess the most potent anti-apoptotic and autophagy activation effect. Importantly, blockage of autophagy with pharmacological inhibitors or genetic silencing of Atg5 selectively abolished the anti-apoptotic function of WETC. These results suggest that WETC protects against dual modes of cell death upon DR ligation. Therefore, WETC might serve as a potential treatment for diseases characterized by aberrantly sensitized apoptotic or non-apoptotic signaling cascades. PMID:27117478

  18. Anti-apoptotic signature in thymic squamous cell carcinomas - functional relevance of anti-apoptotic BIRC3 expression in the thymic carcinoma cell line 1889c

    Directory of Open Access Journals (Sweden)

    AlexanderMarx

    2013-12-01

    Full Text Available The molecular pathogenesis of thymomas and thymic carcinomas (TCs is poorly understood and results of adjuvant therapy are unsatisfactory in case of metastatic disease and tumor recurrence. For these clinical settings, novel therapeutic strategies are urgently needed. Recently, limited sequencing efforts revealed that a broad spectrum of genes that play key roles in various common cancers are rarely affected in thymomas and thymic carcinomas, suggesting that other oncogenic principles might be important. This made us re-analyze historic expression data obtained in a spectrum of thymomas and thymic squamous cell carcinomas (TSCC with a custom made cDNA microarray. By cluster analysis, different anti-apoptotic signatures were detected in type B3 thymoma and TSCC, including overexpression of BIRC3 in TSCCs. This was confirmed by qRT-PCR in the original and an independent validation set of tumors. In contrast to several other cancer cell lines, the BIRC3-positive TSCC cell line, 1889c showed spontaneous apoptosis after BIRC3 knock-down. Targeting apoptosis genes is worth testing as therapeutic principle in TSCC.

  19. Supra-Additive apoptotic response in predominantly quiescent prostate tumors when treated with androgen ablation and radiotherapy

    International Nuclear Information System (INIS)

    Purpose: Several studies have documented that patients with high risk prostate cancer benefit from androgen ablation (AA) in conjunction with radiotherapy, as compared to those treated with androgen ablation or radiotherapy alone. The hypothesis is that a supra-additive effect is manifested when the treatments are given concomitantly as opposed to sequentially. However, the supra-additivity of this approach is difficult to prove in clinical trials due to tumor heterogeneity and because it takes over 6 years to obtain meaningful data on survival differences. Moreover, under certain conditions androgen ablation might induce quiescence (a more radioresistant state), resulting in a sub-additive interaction. For these reasons, we investigated the effects of androgen ablation and radiation using the androgen sensitive R3327-G Dunning rat prostate model. Materials and Methods: The R3327-G tumor line was used in the 23rd-24th in vivo transplant generations. The tumors were grown in the flanks of 250-300g male Copenhagen rats and were used when they reached approximately 1 cc. The growth fraction was determined by continuously labelling the tumors in vivo with chlorodeoxyuridine (CldUrd) via Alzet minipumps implanted in the opposite flank and measuring the incorporated CldUrd and DNA by flow cytometry. Pulse labelling with iododeoxyuridine (IdUrd) to determine the cell kinetic parameters of labelling index (LI), length of S-phase (Ts), and potential doubling time (Tpot) was accomplished by intraperitoneal injection; these parameters were also calculated from flow cytometric data. Apoptotic index was quantified using an immunohistochemical deoxynucleotidyl transferase (TUNEL) assay on formalin-fixed paraffin-embedded tissue; 2000 cells (20 or more high powered fields) were counted per tumor. Results: Tumor volume measurements revealed that the doubling time (Td) increased from an average of 10 d in intact rats to 37 d in castrates. The pulse labelling of tumors with IdUrd at

  20. In vitro assays for predicting tumor cell response to radiation by apoptotic pathways

    International Nuclear Information System (INIS)

    Purpose: We had previously shown that the rate of spontaneous and radiation-induced apoptosis was significantly greater in well-differentiated compared to anaplastic Dunning prostate carcinomas. The goal of this study was to define the most useful assay for quantifying radiation-induced apoptotic cell death and to determine if measured rates of radiation-induced apoptosis in tumor cell populations can predict treatment outcome. Materials and Methods: The time course and extent of radiation-induced apoptosis after single doses of Cesium-137 gamma-rays were measured by five different assays. These included gross DNA degradation, nucleosome ladder formation, labeling of 3'-OH ends in DNA with an immunofluorescence probe, immunofluorescence vital stains (LIVE/DEAD[reg] EUKOLIGHTTM) and trypan blue. The majority of these studies were performed with DU-145 human prostate cells. Data was analyzed to determine the component of cell inactivation resulting from apoptosis with the modified linear quadratic equation, -1n (SF) = (αa + αp) D + βpD2, were αa represents cell inactivation by radiation-induced apoptosis, αp and βp represent cell death by proliferative mechanisms and D represents radiation dose. Results: These studies indicated that DU-145 cell death after radiation occurs over two distinct time periods. The first phase of death begins shortly after irradiation and plateaus within 16-24 hr. This process of cell death has properties consistent with apoptosis as determined by 3'-OH DNA end-labeling and nucleosome ladder assays. The second phase of cell death (determined by viability staining) begins approximately 48 hr after irradiation and continues until the remainder of inactivated cells express their death. This longer phase of cell inactivation probably represents proliferative cell death and other non-apoptotic mechanisms. The five different assays were performed on DU-145 cells 24 hr after irradiation with 10 Gy. Significant nucleosome ladders were

  1. When mirroring is both simple and "smart": how mimicry can be embodied, adaptive, and non-representational.

    Science.gov (United States)

    Carr, Evan W; Winkielman, Piotr

    2014-01-01

    The concept of mirroring has become rather ubiquitous. One of the most fundamental empirical and theoretical debates within research on mirroring concerns the role of mental representations: while some models argue that higher-order representational mechanisms underpin most cases of mirroring, other models argue that they only moderate a primarily non-representational process. As such, even though research on mirroring-along with its neural substrates, including the putative mirror neuron system-has grown tremendously, so too has confusion about what it actually means to "mirror". Using recent research on spontaneous imitation, we argue that flexible mirroring effects can be fully embodied and dynamic-even in the absence of higher-order mental representations. We propose that mirroring can simply reflect an adaptive integration and utilization of cues obtained from the brain, body, and environment, which is especially evident within the social context. Such a view offers reconciliation among both representational and non-representational frameworks in cognitive neuroscience, which will facilitate revised interpretations of modern (and seemingly divergent) findings on when and how these embodied mirroring responses are employed. PMID:25071532

  2. When mirroring is both simple and smart: How mimicry can be embodied, adaptive, and non-representational

    Directory of Open Access Journals (Sweden)

    Evan Walker Carr

    2014-07-01

    Full Text Available The concept of mirroring has become rather ubiquitous. One of the most fundamental empirical and theoretical debates within research on mirroring concerns the role of mental representations: While some models argue that higher-order representational mechanisms underpin most cases of mirroring, other models argue that they only moderate a primarily non-representational process. As such, even though research on mirroring—along with its neural substrates, including the putative mirror neuron system—has grown tremendously, so too has confusion about what it actually means to mirror. Using recent research on spontaneous imitation, we argue that flexible mirroring effects can be fully embodied and dynamic—even in the absence of higher-order mental representations. We propose that mirroring can simply reflect an adaptive integration and utilization of cues obtained from the brain, body, and environment, which is especially evident within the social context. Such a view offers reconciliation among both representational and non-representational frameworks in cognitive neuroscience, which will facilitate revised interpretations of modern (and seemingly divergent findings on when and how these embodied mirroring responses are employed.

  3. Pannexin-1 and P2X7-Receptor Are Required for Apoptotic Osteocytes in Fatigued Bone to Trigger RANKL Production in Neighboring Bystander Osteocytes.

    Science.gov (United States)

    Cheung, Wing Yee; Fritton, J Christopher; Morgan, Stacy Ann; Seref-Ferlengez, Zeynep; Basta-Pljakic, Jelena; Thi, Mia M; Suadicani, Sylvia O; Spray, David C; Majeska, Robert J; Schaffler, Mitchell B

    2016-04-01

    Osteocyte apoptosis is required to induce intracortical bone remodeling after microdamage in animal models, but how apoptotic osteocytes signal neighboring "bystander" cells to initiate the remodeling process is unknown. Apoptosis has been shown to open pannexin-1 (Panx1) channels to release adenosine diphosphate (ATP) as a "find-me" signal for phagocytic cells. To address whether apoptotic osteocytes use this signaling mechanism, we adapted the rat ulnar fatigue-loading model to reproducibly introduce microdamage into mouse cortical bone and measured subsequent changes in osteocyte apoptosis, receptor activator of NF-κB ligand (RANKL) expression and osteoclastic bone resorption in wild-type (WT; C57Bl/6) mice and in mice genetically deficient in Panx1 (Panx1KO). Mouse ulnar loading produced linear microcracks comparable in number and location to the rat model. WT mice showed increased osteocyte apoptosis and RANKL expression at microdamage sites at 3 days after loading and increased intracortical remodeling and endocortical tunneling at day 14. With fatigue, Panx1KO mice exhibited levels of microdamage and osteocyte apoptosis identical to WT mice. However, they did not upregulate RANKL in bystander osteocytes or initiate resorption. Panx1 interacts with P2X7 R in ATP release; thus, we examined P2X7 R-deficient mice and WT mice treated with P2X7 R antagonist Brilliant Blue G (BBG) to test the possible role of ATP as a find-me signal. P2X7 RKO mice failed to upregulate RANKL in osteocytes or induce resorption despite normally elevated osteocyte apoptosis after fatigue loading. Similarly, treatment of fatigued C57Bl/6 mice with BBG mimicked behavior of both Panx1KO and P2X7 RKO mice; BBG had no effect on osteocyte apoptosis in fatigued bone but completely prevented increases in bystander osteocyte RANKL expression and attenuated activation of resorption by more than 50%. These results indicate that activation of Panx1 and P2X7 R are required for apoptotic osteocytes

  4. Evaluation of anti-apoptotic activity of different dietary antioxidants in renal cell carcinoma against hydrogen peroxide

    Institute of Scientific and Technical Information of China (English)

    Garg Neeraj K; Mangal Sharad; Sahu Tejram; Mehta Abhinav; Vyas Suresh P; Tyagi Rajeev K

    2011-01-01

    Objective: To evaluate the anti-apoptotic and radical scavenging activities of dietary phenolics, namely ascorbic acid, -tocopherol acetate, citric acid, salicylic acid, and estimate H2O2-induced apoptosis in renal cell carcinoma cells. Methods: The intracellular antioxidant potency of antioxidants was investigated. H2O2-induced apoptosis in RCC-26 was assayed with the following parameters: cell viability (% apoptosis), nucleosomal damage and DNA fragmentation, bcl-2 levels and flow cytometery analysis (ROS production evaluation). Results: The anticancer properties of antioxidants such as ascorbic acid, - tocopherol acetate, citric acid, salicylic acid with perdurable responses were investigated. It was observed that these antioxidants had protective effect (anti-apoptotic activity) against hydrogen peroxide (H2O2) in renal cell carcinoma (RCC-26) cell line. Conclusions: This study reveals and proves the anticancer properties. However, in cancer cell lines anti-apoptotic activity can indirectly reflect the cancer promoter activity through radicals scavenging, and significantly protect nucleus and bcl-2.

  5. Molecular and Computational Studies on Apoptotic Pathway Regulator, Bcl-2 Gene from Breast Cancer Cell Line MCF-7.

    Science.gov (United States)

    Tiwari, Pragya; Khan, M J

    2016-01-01

    Cancer is a dreadful disease constituting abnormal growth and proliferation of malignant cells in the body. Next to lung cancer, breast cancer is the most common form of cancer affecting women. The apoptotic pathway regulators, B cell lymphoma family of protein, play a key role in various malignancies defining cancer and their constitutive expression plays an integral role in breast cancer chemotherapy. The research work discusses the identification and molecular cloning of a B cell lymphoma like gene from human breast cancer cell line. The open reading frame of the gene consisted of 965 nucleotides, encoding a protein of 380 amino acids with a predicted molecular weight of 42.5 kilodalton. The predicted physiochemical properties of the gene were as follows: Isoelectric point - 9.49, molecular formula - C1893H3004N534O548S16, total number of negatively charged residues, (Aspartate+Glutamate) - 26, total number of positively charged residues, (Arginine+Lysine)-39, instability index-42.08 (unstable protein) and grand average of hydropathicity is -0.202. Additionally, phobius prediction suggested non-cytoplasmic localization of the putative protein. The presence of secondary structure in the protein was determined by Memsat program. A 3 dimensional protein homology model was generated using threading based method of protein modeling for structural and functional annotation of the putative protein. Future prospects accounts for the biochemical characterization of the enzyme including in vitro assays on breast cancer cell line would establish the functional characteristics of the protein and its physiological mechanisms in breast cancer development and its therapeutic-target role in future. PMID:27168686

  6. Apoptotic cell death during Drosophila oogenesis is differentially increased by electromagnetic radiation depending on modulation, intensity and duration of exposure.

    Science.gov (United States)

    Sagioglou, Niki E; Manta, Areti K; Giannarakis, Ioannis K; Skouroliakou, Aikaterini S; Margaritis, Lukas H

    2016-01-01

    Present generations are being repeatedly exposed to different types and doses of non-ionizing radiation (NIR) from wireless technologies (FM radio, TETRA and TV stations, GSM and UMTS phones/base stations, Wi-Fi networks, DECT phones). Although there is controversy on the published data regarding the non-thermal effects of NIR, studies have convincingly demonstrated bioeffects. Their results indicate that modulation, intensity, exposure duration and model system are important factors determining the biological response to irradiation. Attempting to address the dependence of NIR bioeffectiveness on these factors, apoptosis in the model biological system Drosophila melanogaster was studied under different exposure protocols. A signal generator was used operating alternatively under Continuous Wave (CW) or Frequency Modulation (FM) emission modes, at three power output values (10 dB, 0, -10 dB), under four carrier frequencies (100, 395, 682, 900 MHz). Newly emerged flies were exposed either acutely (6 min or 60 min on the 6th day), or repeatedly (6 min or 60 min daily for the first 6 days of their life). All exposure protocols resulted in an increase of apoptotic cell death (ACD) observed in egg chambers, even at very low electric field strengths. FM waves seem to have a stronger effect in ACD than continuous waves. Regarding intensity and temporal exposure pattern, EMF-biological tissue interaction is not linear in response. Intensity threshold for the induction of biological effects depends on frequency, modulation and temporal exposure pattern with unknown so far mechanisms. Given this complexity, translating such experimental data into possible human exposure guidelines is yet arbitrary. PMID:25333897

  7. Oxaliplatin immuno hybrid nanoparticles for active targeting: an approach for enhanced apoptotic activity and drug delivery to colorectal tumors.

    Science.gov (United States)

    Tummala, Shashank; Gowthamarajan, K; Satish Kumar, M N; Wadhwani, Ashish

    2016-06-01

    Tumor necrosis factor related apoptosis inducing ligand (TRAIL) proved to be a promising new target for colorectal cancer treatment. Elevated expression of TRAIL protein in tumor cells distinguishes it from healthy cells, thereby delivering the drug at the specific site. Here, we formulated oxaliplatin immunohybrid nanoparticles (OIHNPs) to deliver oxaliplatin and anti-TRAIL for colorectal cancer treatment in xenograft tumor models. The polymeric chitosan layer binds to the lipid film with the mixture of phospholipids by an ultra sound method followed by conjugating with thiolated antibody using DSPE-PEG-mal3400, resulting in the formation of OIHNPs. The polymer layer helps in more encapsulation of the drug (71 ± 0.09%) with appreciable particle size (95 ± 0.01 nm), and lipid layer prevents degradation of the drug in serum by preventing nanoparticle aggregation. OIHNPs have shown a 4-fold decrease in the IC50 value compared to oxaliplatin in HT-29 cells by the MTT assay. These immuno-nanoparticles represent the successful uptake and internalization of oxaliplatin in HT-29 cells rather than in MCF-7 cells determined by triple fluorescence method. Apoptotic activity in vitro of OIHNPs was determined by the change in the mitochondria membrane potential that further elevates its anti-tumor property. Furthermore, the conjugated nanoparticles can effectively deliver the drug to the tumor sites, which can be attributed to its ability in reducing tumor mass and tumor volume in xenograft tumor models in vivo along with sustaining its release in vitro. These findings indicated that the oxaliplatin immuno-hybrid nanoparticles would be a promising nano-sized active targeted formulation for colorectal-tumor targeted therapy. PMID:26377238

  8. Molecular and computational studies on apoptotic pathway regulator, Bcl-2 gene from breast cancer cell line MCF-7

    Directory of Open Access Journals (Sweden)

    Pragya Tiwari

    2016-01-01

    Full Text Available Cancer is a dreadful disease constituting abnormal growth and proliferation of malignant cells in the body. Next to lung cancer, breast cancer is the most common form of cancer affecting women. The apoptotic pathway regulators, B cell lymphoma family of protein, play a key role in various malignancies defining cancer and their constitutive expression plays an integral role in breast cancer chemotherapy. The research work discusses the identification and molecular cloning of a B cell lymphoma like gene from human breast cancer cell line. The open reading frame of the gene consisted of 965 nucleotides, encoding a protein of 380 amino acids with a predicted molecular weight of 42.5 kilodalton. The predicted physiochemical properties of the gene were as follows: Isoelectric point - 9.49, molecular formula - C1893H3004N534O548S16, total number of negatively charged residues, (Aspartate+Glutamate - 26, total number of positively charged residues, (Arginine+Lysine-39, instability index-42.08 (unstable protein and grand average of hydropathicity is -0.202. Additionally, phobius prediction suggested non-cytoplasmic localization of the putative protein. The presence of secondary structure in the protein was determined by Memsat program. A 3 dimensional protein homology model was generated using threading based method of protein modeling for structural and functional annotation of the putative protein. Future prospects accounts for the biochemical characterization of the enzyme including in vitroassays on breast cancer cell line would establish the functional characteristics of the protein and its physiological mechanisms in breast cancer development and its therapeutic-target role in future.

  9. Molecular and Computational Studies on Apoptotic Pathway Regulator, Bcl-2 Gene from Breast Cancer Cell Line MCF-7

    Science.gov (United States)

    Tiwari, Pragya; Khan, M. J.

    2016-01-01

    Cancer is a dreadful disease constituting abnormal growth and proliferation of malignant cells in the body. Next to lung cancer, breast cancer is the most common form of cancer affecting women. The apoptotic pathway regulators, B cell lymphoma family of protein, play a key role in various malignancies defining cancer and their constitutive expression plays an integral role in breast cancer chemotherapy. The research work discusses the identification and molecular cloning of a B cell lymphoma like gene from human breast cancer cell line. The open reading frame of the gene consisted of 965 nucleotides, encoding a protein of 380 amino acids with a predicted molecular weight of 42.5 kilodalton. The predicted physiochemical properties of the gene were as follows: Isoelectric point - 9.49, molecular formula - C1893H3004N534O548S16, total number of negatively charged residues, (Aspartate+Glutamate) - 26, total number of positively charged residues, (Arginine+Lysine)-39, instability index-42.08 (unstable protein) and grand average of hydropathicity is -0.202. Additionally, phobius prediction suggested non-cytoplasmic localization of the putative protein. The presence of secondary structure in the protein was determined by Memsat program. A 3 dimensional protein homology model was generated using threading based method of protein modeling for structural and functional annotation of the putative protein. Future prospects accounts for the biochemical characterization of the enzyme including in vitro assays on breast cancer cell line would establish the functional characteristics of the protein and its physiological mechanisms in breast cancer development and its therapeutic-target role in future.

  10. Poncirin Induces Apoptosis in AGS Human Gastric Cancer Cells through Extrinsic Apoptotic Pathway by up-Regulation of Fas Ligand

    Directory of Open Access Journals (Sweden)

    Venu Venkatarame Gowda Saralamma

    2015-09-01

    Full Text Available Poncirin, a natural bitter flavanone glycoside abundantly present in many species of citrus fruits, has various biological benefits such as anti-oxidant, anti-microbial, anti-inflammatory and anti-cancer activities. The anti-cancer mechanism of Poncirin remains elusive to date. In this study, we investigated the anti-cancer effects of Poncirin in AGS human gastric cancer cells (gastric adenocarcinoma. The results revealed that Poncirin could inhibit the proliferation of AGS cells in a dose-dependent manner. It was observed Poncirin induced accumulation of sub-G1 DNA content, apoptotic cell population, apoptotic bodies, chromatin condensation, and DNA fragmentation in a dose-dependent manner in AGS cells. The expression of Fas Ligand (FasL protein was up-regulated dose dependently in Poncirin-treated AGS cells Moreover, Poncirin in AGS cells induced activation of Caspase-8 and -3, and subsequent cleavage of poly(ADP-ribose polymerase (PARP. Inhibitor studies’ results confirm that the induction of caspase-dependent apoptotic cell death in Poncirin-treated AGS cells was led by the Fas death receptor. Interestingly, Poncirin did not show any effect on mitochondrial membrane potential (ΔΨm, pro-apoptotic proteins (Bax and Bak and anti-apoptotic protein (Bcl-xL in AGS-treated cells followed by no activation in the mitochondrial apoptotic protein caspase-9. This result suggests that the mitochondrial-mediated pathway is not involved in Poncirin-induced cell death in gastric cancer. These findings suggest that Poncirin has a potential anti-cancer effect via extrinsic pathway-mediated apoptosis, possibly making it a strong therapeutic agent for human gastric cancer.

  11. Differential regulation of caspase-9 by ionizing radiation- and UV-induced apoptotic pathways in thymic cells

    International Nuclear Information System (INIS)

    In mouse thymic lymphoma 3SB cells bearing wild type p53, ionizing radiation (IR) and UV light are potent triggers of caspase-3-dependent apoptosis. Although cytochrome c was released from mitochondria as expected, caspase-9 activation was not observed in UV-exposed cells. Laser scanning confocal microscopy analysis showed that caspase-9 is localized in an unusual punctuated pattern in UV-induced apoptotic cells. In agreement with differences in the status of caspase-9 activation between IR and UV, subcellular protein fractionation experiments showed that pro-apoptotic apoptosis protease-activating factor 1 (Apaf-1), normally a part of the apoptosome assembled in response to the release of cytochrome c from mitochondria, and B-cell lymphoma extra long (Bcl-xL), an inhibitor of the change in mitochondrial membrane permeability, were redistributed by the IR-exposure but not by the UV-exposure. Instead of the sequestration of the capase-9/apoptosome activation in UV-induced apoptotic cells, the extrinsic apoptotic signaling generated by caspase-8 activation and consequent activation of B-cell lymphoma extra long (Bid) to release cytochrome c from mitochondria was observed. Thus, the post-mitochondrial apoptotic pathway downstream of cytochrome c release cannot operate the apoptosome function in UV-induced apoptosis in thymic 3SB cells. The intracellular redistribution and sequestration of apoptosis-related proteins upon mitochondrion-based apoptotic signaling was identified as a novel cellular mechanism to respond to DNA damage in an agent type-specific manner. This finding suggests that the kind of the critical ultimate apoptosis-inducing DNA lesion complex form resulting from the agent-specific DNA damage responses is important to determine which of apoptosis signals would be activated.

  12. Differential nitric oxide synthesis and host apoptotic events correlate with bleaching susceptibility in reef corals

    Science.gov (United States)

    Hawkins, T. D.; Krueger, T.; Becker, S.; Fisher, P. L.; Davy, S. K.

    2014-03-01

    Coral bleaching poses a threat to coral reefs worldwide. As a consequence of the temperature-induced breakdown in coral-dinoflagellate symbiosis, bleaching can have extensive effects on reef communities. However, our understanding of bleaching at a cellular level is limited, and this is particularly true regarding differential susceptibility among coral species. Recent work suggests that bleaching may represent a host innate immune-like response to symbiont dysfunction that involves synthesis of the signalling compound nitric oxide (NO) and the induction of host apoptotic-like cell death. In this study, we examined the activity of apoptosis-regulating enzymes alongside oxidised NO accumulation (a proxy for NO synthesis) in the reef corals Acropora millepora, Montipora digitata, and Pocillopora damicornis during experimental thermal stress. P. damicornis was the most sensitive species, suffering mortality (tissue sloughing) after 5 days at 33 °C but non-lethal bleaching after 9 days at 31.5 °C. A. millepora bleached at 33 °C but remained structurally intact, while M. digitata showed little evidence of bleaching. P. damicornis and A. millepora both exhibited evidence of temperature-induced NO synthesis and, after 5 days of heating, levels of oxidised NO in both species were fivefold higher than in controls maintained at 28.5 °C. These responses preceded bleaching by a number of days and may have occurred before symbiont dysfunction (measured as chlorophyll a degradation and oxidised NO accumulation). In A. millepora, apparent NO synthesis correlated with the induction of host apoptotic-like pathways, while in P. damicornis, the upregulation of apoptotic pathways occurred later. No evidence of elevated NO production or apoptosis was observed in M. digitata at 33 °C and baseline activity of apoptosis-regulating enzymes was negligible in this species. These findings provide important physiological data in the context of the responses of corals to global change and

  13. Neuroprotection with metformin and thymoquinone against ethanol-induced apoptotic neurodegeneration in prenatal rat cortical neurons

    Directory of Open Access Journals (Sweden)

    Ullah Ikram

    2012-01-01

    Full Text Available Abstract Background Exposure to ethanol during early development triggers severe neuronal death by activating multiple stress pathways and causes neurological disorders, such as fetal alcohol effects or fetal alcohol syndrome. This study investigated the effect of ethanol on intracellular events that predispose developing neurons for apoptosis via calcium-mediated signaling. Although the underlying molecular mechanisms of ethanol neurotoxicity are not completely determined, mitochondrial dysfunction, altered calcium homeostasis and apoptosis-related proteins have been implicated in ethanol neurotoxicity. The present study was designed to evaluate the neuroprotective mechanisms of metformin (Met and thymoquinone (TQ during ethanol toxicity in rat prenatal cortical neurons at gestational day (GD 17.5. Results We found that Met and TQ, separately and synergistically, increased cell viability after ethanol (100 mM exposure for 12 hours and attenuated the elevation of cytosolic free calcium [Ca2+]c. Furthermore, Met and TQ maintained normal physiological mitochondrial transmembrane potential (ΔψM, which is typically lowered by ethanol exposure. Increased cytosolic free [Ca2+]c and lowered mitochondrial transmembrane potential after ethanol exposure significantly decreased the expression of a key anti-apoptotic protein (Bcl-2, increased expression of Bax, and stimulated the release of cytochrome-c from mitochondria. Met and TQ treatment inhibited the apoptotic cascade by increasing Bcl-2 expression. These compounds also repressed the activation of caspase-9 and caspase-3 and reduced the cleavage of PARP-1. Morphological conformation of cell death was assessed by TUNEL, Fluoro-Jade-B, and PI staining. These staining methods demonstrated more cell death after ethanol treatment, while Met, TQ or Met plus TQ prevented ethanol-induced apoptotic cell death. Conclusion These findings suggested that Met and TQ are strong protective agents against ethanol

  14. Mycoplasma synoviae induces upregulation of apoptotic genes, secretion of nitric oxide and appearance of an apoptotic phenotype in infected chicken chondrocytes

    Directory of Open Access Journals (Sweden)

    Dusanic Daliborka

    2012-01-01

    Full Text Available Abstract The role of chondrocytes in the development of infectious arthritis is not well understood. Several examples of mycoplasma-induced arthritis in animals indicate that chondrocytes come into direct contact with bacteria. The objective of this study was to analyze the interaction of an arthrogenic Mycoplasma synoviae strain WVU 1853 with chicken chondrocytes. We found that M. synoviae significantly reduces chondrocyte respiration. This was accompanied by alterations in chondrocyte morphology, namely cell shrinkage and cytoplasm condensation, as well as nuclear condensation and formation of plasma membrane invaginations containing nuclear material, which appeared to cleave off the cell surface. In concordance with these apoptosis-like events in chondrocytes, transcription was increased in several pro-apoptotic genes. Twenty-four hours after infection, strong upregulation was assayed in NOS2, Mapk11, CASP8 and Casp3 genes. Twenty-four and 72 h incubation of chondrocytes with M. synoviae induced upregulation of AIFM1, NFκB1, htrA3 and BCL2. Casp3 and NOS2 remained upregulated, but upregulation ceased for Mapk11 and CASP8 genes. Increased production of nitric oxide was also confirmed in cell supernates. The data suggests that chicken chondrocytes infected with M. synoviae die by apoptosis involving production of nitric oxide, caspase 3 activation and mitochondrial inactivation. The results of this study show for the first time that mycoplasmas could cause chondrocyte apoptosis. This could contribute to tissue destruction and influence the development of arthritic conditions. Hence, the study gives new insights into the role of mycoplasma infection on chondrocyte biology and development of infectious arthritis in chickens and potentially in humans.

  15. Apoptotic cell death: its implications for imaging in the next millennium

    International Nuclear Information System (INIS)

    In this review the cellular phenomenon of apoptotic cell death and the imaging methods which can detect the process in vitro and in vivo are first discussed. Thereafter an outline is provided of the role of apoptosis in the pathophysiology of clinical disorders including stroke, neurodegenerative diseases, pulmonary inflammatory diseases, myocardial ischemia and inflammation, myelodysplastic disorders, organ transplantation, and oncology, in which imaging may play a critical role in diagnosis and patient management. Objective imaging markers of apoptosis may soon become measures of therapeutic success or failure in both current and future treatment paradigms. Since apoptosis is a major factor in many diseases, quantification and monitoring the process could become important in clinical decision making. (orig./MG) (orig.)

  16. Cell wall dynamics modulate acetic acid-induced apoptotic cell death of Saccharomyces cerevisiae

    Directory of Open Access Journals (Sweden)

    António Rego

    2014-08-01

    Full Text Available Acetic acid triggers apoptotic cell death in Saccharomyces cerevisiae, similar to mammalian apoptosis. To uncover novel regulators of this process, we analyzed whether impairing MAPK signaling affected acetic acid-induced apoptosis and found the mating-pheromone response and, especially, the cell wall integrity pathways were the major mediators, especially the latter, which we characterized further. Screening downstream effectors of this pathway, namely targets of the transcription factor Rlm1p, highlighted decreased cell wall remodeling as particularly important for acetic acid resistance. Modulation of cell surface dynamics therefore emerges as a powerful strategy to increase acetic acid resistance, with potential application in industrial fermentations using yeast, and in biomedicine to exploit the higher sensitivity of colorectal carcinoma cells to apoptosis induced by acetate produced by intestinal propionibacteria.

  17. Development of RI-based real-time display technology of apoptotic cell death

    Energy Technology Data Exchange (ETDEWEB)

    Park, Sang Hyun; Jagn, Beom Su; Hayu, Tyas Utami

    2012-01-15

    Apoptosis, or the programmed cell death, is the generally normal death of a cell in living organisms. Inappropriate apoptosis (either too little or too much) is a factor in many human disease including neurodegenerative diseases, autoimmune disorders and many types of cancer. Therefore, it is one of the most challenging and widely studied topics currently. Development of RI-based real-time display technology of apoptosis can be provided invaluable analysis data for diagnosis and treatment of various diseases. In this study, bifunctional chelator (BFC) for Tc-99m tricarbonyl was synthesized for ML-10 derivative radiolabeling. The formation of complexation of apoptotic cells was developed by combining the ML-10 moiety with the BFC for {sup 99m}Tc-tricarbonyl precursor. The results of this project will be utilized for the development of RI-Biomics Center-based Total Analysis System (TAS) through the optimization of equipment in the RI-Biomics Center.

  18. Apoptotic effects on cultured cells of atmospheric-pressure plasma produced using various gases

    Science.gov (United States)

    Tominami, Kanako; Kanetaka, Hiroyasu; Kudo, Tada-aki; Sasaki, Shota; Kaneko, Toshiro

    2016-01-01

    This study investigated the effects of low-temperature atmospheric-pressure plasma on various cells such as rat fibroblastic Rat-1 cell line, rat neuroblastoma-like PC12 cell line, and rat macrophage-like NR8383 cell line. The plasma was irradiated directly to a culture medium containing plated cells for 0-20 s. The applied voltage, excitation frequency, and argon or helium gas flow were, respectively, 3-6 kV, 10 kHz, and 3 L/min. Cell viability and apoptotic activity were evaluated using annexin-V/propidium iodide staining. Results showed that the low-temperature atmospheric-pressure plasma irradiation promoted cell death in a discharge-voltage-dependent and irradiation-time-dependent manner. Furthermore, different effects are produced depending on the cell type. Moreover, entirely different mechanisms might be responsible for the induction of apoptosis in cells by helium and argon plasma.

  19. Pro-apoptotic and anti-angiogenic properties of the α /β-thujone fraction from Thuja occidentalis on glioblastoma cells.

    Science.gov (United States)

    Torres, Angelo; Vargas, Yosselyn; Uribe, Daniel; Carrasco, Cristian; Torres, Cristian; Rocha, René; Oyarzún, Carlos; San Martín, Rody; Quezada, Claudia

    2016-05-01

    The most aggressive type of brain tumor is glioblastoma multiforme, which to date remains incurable. Thuja occidentalis is used in homeopathy for the treatment of cancer, however, its mechanism of action remains unknown. We set out to study the effects of thujone fractions of Thuja on glioblastoma using in vitro and in vivo models. We found that the α/ β-thujone fraction decrease the cell viability and exhibit a potent anti-proliferative, pro-apoptotic and anti-angiogenic effects in vitro. In vivo assays showed that α /β-thujone promotes the regression of neoplasia and inhibits the angiogenic markers VEGF, Ang-4 and CD31 into the tumor. PMID:26900077

  20. The calpain inhibitor MDL28170 induces the expression of apoptotic markers in Leishmania amazonensis promastigotes.

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    Fernanda A Marinho

    Full Text Available BACKGROUND: Human cutaneous leishmaniasis is caused by distinct species, including Leishmania amazonensis. Treatment of cutaneous leishmaniasis is far from satisfactory due to increases in drug resistance and relapses, and toxicity of compounds to the host. As a consequence for this situation, the development of new leishmanicidal drugs and the search of new targets in the parasite biology are important goals. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we investigated the mechanism of death pathway induced by the calpain inhibitor MDL28170 on Leishmania amazonensis promastigote forms. The combined use of different techniques was applied to contemplate this goal. MDL28170 treatment with IC50 (15 µM and two times the IC50 doses induced loss of parasite viability, as verified by resazurin assay, as well as depolarization of the mitochondrial membrane, which was quantified by JC-1 staining. Scanning and transmission electron microscopic images revealed drastic alterations on the parasite morphology, some of them resembling apoptotic-like death, including cell shrinking, surface membrane blebs and altered chromatin condensation pattern. The lipid rearrangement of the plasma membrane was detected by Annexin-V labeling. The inhibitor also induced a significant increase in the proportion of cells in the sub-G0/G1 phase, as quantified by propidium iodide staining, as well as genomic DNA fragmentation, detected by TUNEL assay. In cells treated with MDL28170 at two times the IC50 dose, it was also possible to observe an oligonucleossomal DNA fragmentation by agarose gel electrophoresis. CONCLUSIONS/SIGNIFICANCE: The data presented in the current study suggest that MDL28170 induces apoptotic marker expression in promastigotes of L. amazonensis. Altogether, the results described in the present work not only provide a rationale for further exploration of the mechanism of action of calpain inhibitors against trypanosomatids, but may also widen the