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Sample records for signaling suppressed cochlear

  1. Cochlear implantation for single-sided deafness and tinnitus suppression.

    Holder, Jourdan T; O'Connell, Brendan; Hedley-Williams, Andrea; Wanna, George

    To quantify the potential effectiveness of cochlear implantation for tinnitus suppression in patients with single-sided deafness using the Tinnitus Handicap Inventory. The study included 12 patients with unilateral tinnitus who were undergoing cochlear implantation for single-sided deafness. The Tinnitus Handicap Inventory was administered at the patient's cochlear implant candidacy evaluation appointment prior to implantation and every cochlear implant follow-up appointment, except activation, following implantation. Patient demographics and speech recognition scores were also retrospectively recorded using the electronic medical record. A significant reduction was found when comparing Tinnitus Handicap Inventory score preoperatively (61.2±27.5) to the Tinnitus Handicap Inventory score after three months of cochlear implant use (24.6±28.2, p=0.004) and the Tinnitus Handicap Inventory score beyond 6months of CI use (13.3±18.9, p=0.008). Further, 45% of patients reported total tinnitus suppression. Mean CNC word recognition score improved from 2.9% (SD 9.4) pre-operatively to 40.8% (SD 31.7) by 6months post-activation, which was significantly improved from pre-operative scores (p=0.008). The present data is in agreement with previously published studies that have shown an improvement in tinnitus following cochlear implantation for the large majority of patients with single-sided deafness. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Interaction of tinnitus suppression and hearing ability after cochlear implantation.

    Wang, Qian; Li, Jia-Nan; Lei, Guan-Xiong; Chen, Dai-Shi; Wang, Wei-Ze; Chen, Ai-Ting; Mong, Meng-Di; Li, Sun; Jiao, Qing-Shan; Yang, Shi-Ming

    2017-10-01

    To study the postoperative impact of cochlear implants (CIs) on tinnitus, as well as the impact of tinnitus on speech recognition with CI switched on. Fifty-two postlingual deafened CI recipients (21 males and 31 females) were assessed using an established Tinnitus Characteristics Questionnaire and Tinnitus Handicap Inventory (THI) before and after cochlear implantation. The tinnitus loudness was investigated when CI was switched on and off in CI recipients with persistent tinnitus. The relation between tinnitus loudness and recipients' satisfaction of cochlear implantation was analyzed by the visual analogue scale (VAS) score. With CI 'OFF', 42 CI recipients experienced tinnitus postimplant ipsilaterally and 44 contralaterally. Tinnitus was totally suppressed ipsilateral to the CI with CI 'ON' in 42.9%, partially suppressed in 42.9%, unchanged in 11.9% and aggravated in 2.4%. Tinnitus was totally suppressed contralaterally with CI 'ON' in 31.8% of CI recipients, partially suppressed in 47.7%, unchanged in 20.5%. Pearson correlation analysis showed that tinnitus loudness and the results of cochlear implant patients satisfaction was negatively correlated (r = .674, p tinnitus. The tinnitus loudness may affect patients' satisfaction with the use of CI.

  3. A software tool for analyzing multichannel cochlear implant signals.

    Lai, Wai Kong; Bögli, Hans; Dillier, Norbert

    2003-10-01

    A useful and convenient means to analyze the radio frequency (RF) signals being sent by a speech processor to a cochlear implant would be to actually capture and display them with appropriate software. This is particularly useful for development or diagnostic purposes. sCILab (Swiss Cochlear Implant Laboratory) is such a PC-based software tool intended for the Nucleus family of Multichannel Cochlear Implants. Its graphical user interface provides a convenient and intuitive means for visualizing and analyzing the signals encoding speech information. Both numerical and graphic displays are available for detailed examination of the captured CI signals, as well as an acoustic simulation of these CI signals. sCILab has been used in the design and verification of new speech coding strategies, and has also been applied as an analytical tool in studies of how different parameter settings of existing speech coding strategies affect speech perception. As a diagnostic tool, it is also useful for troubleshooting problems with the external equipment of the cochlear implant systems.

  4. The group delay and suppression pattern of the cochlear microphonic potential recorded at the round window.

    Wenxuan He

    Full Text Available BACKGROUND: It is commonly assumed that the cochlear microphonic potential (CM recorded from the round window (RW is generated at the cochlear base. Based on this assumption, the low-frequency RW CM has been measured for evaluating the integrity of mechanoelectrical transduction of outer hair cells at the cochlear base and for studying sound propagation inside the cochlea. However, the group delay and the origin of the low-frequency RW CM have not been demonstrated experimentally. METHODOLOGY/PRINCIPAL FINDINGS: This study quantified the intra-cochlear group delay of the RW CM by measuring RW CM and vibrations at the stapes and basilar membrane in gerbils. At low sound levels, the RW CM showed a significant group delay and a nonlinear growth at frequencies below 2 kHz. However, at high sound levels or at frequencies above 2 kHz, the RW CM magnitude increased proportionally with sound pressure, and the CM phase in respect to the stapes showed no significant group delay. After the local application of tetrodotoxin the RW CM below 2 kHz became linear and showed a negligible group delay. In contrast to RW CM phase, the BM vibration measured at location ∼2.5 mm from the base showed high sensitivity, sharp tuning, and nonlinearity with a frequency-dependent group delay. At low or intermediate sound levels, low-frequency RW CMs were suppressed by an additional tone near the probe-tone frequency while, at high sound levels, they were partially suppressed only at high frequencies. CONCLUSIONS/SIGNIFICANCE: We conclude that the group delay of the RW CM provides no temporal information on the wave propagation inside the cochlea, and that significant group delay of low-frequency CMs results from the auditory nerve neurophonic potential. Suppression data demonstrate that the generation site of the low-frequency RW CM shifts from apex to base as the probe-tone level increases.

  5. A Series of Case Studies of Tinnitus Suppression With Mixed Background Stimuli in a Cochlear Implant

    Keiner, A. J.; Walker, Kurt; Deshpande, Aniruddha K.; Witt, Shelley; Killian, Matthijs; Ji, Helena; Patrick, Jim; Dillier, Norbert; van Dijk, Pim; Lai, Wai Kong; Hansen, Marlan R.; Gantz, Bruce

    2015-01-01

    Purpose Background sounds provided by a wearable sound playback device were mixed with the acoustical input picked up by a cochlear implant speech processor in an attempt to suppress tinnitus. Method First, patients were allowed to listen to several sounds and to select up to 4 sounds that they thought might be effective. These stimuli were programmed to loop continuously in the wearable playback device. Second, subjects were instructed to use 1 background sound each day on the wearable device, and they sequenced the selected background sounds during a 28-day trial. Patients were instructed to go to a website at the end of each day and rate the loudness and annoyance of the tinnitus as well as the acceptability of the background sound. Patients completed the Tinnitus Primary Function Questionnaire (Tyler, Stocking, Secor, & Slattery, 2014) at the beginning of the trial. Results Results indicated that background sounds were very effective at suppressing tinnitus. There was considerable variability in sounds preferred by the subjects. Conclusion The study shows that a background sound mixed with the microphone input can be effective for suppressing tinnitus during daily use of the sound processor in selected cochlear implant users. PMID:26001407

  6. Benefit of a Contralateral Routing of Signal Device for Unilateral Cochlear Implant Users.

    Weder, Stefan; Kompis, Martin; Caversaccio, Marco; Stieger, Christof

    2014-01-01

    Objective: To investigate objective and subjective effects of an adjunctive contralateral routing of signal (CROS) device at the untreated ear in patients with a unilateral cochlear implant (CI). Design: Prospective study of 10 adult experienced unilateral CI users with bilateral severe-to-profound hearing loss. Speech in noise reception (SNR) and sound localization were measured with and without the additional CROS device. SNR was measured by applying speech signals at the untreated/CROS sid...

  7. Disproportionate Cochlear Length in Genus Homo Shows a High Phylogenetic Signal during Apes’ Hearing Evolution

    Braga, J.; Loubes, J-M.; Descouens, D.; Dumoncel, J.; Thackeray, J. F.; Kahn, J-L.; de Beer, F.; Riberon, A.; Hoffman, K.; Balaresque, P.; Gilissen, E.

    2015-01-01

    Changes in lifestyles and body weight affected mammal life-history evolution but little is known about how they shaped species’ sensory systems. Since auditory sensitivity impacts communication tasks and environmental acoustic awareness, it may have represented a deciding factor during mammal evolution, including apes. Here, we statistically measure the influence of phylogeny and allometry on the variation of five cochlear morphological features associated with hearing capacities across 22 living and 5 fossil catarrhine species. We find high phylogenetic signals for absolute and relative cochlear length only. Comparisons between fossil cochleae and reconstructed ape ancestral morphotypes show that Australopithecus absolute and relative cochlear lengths are explicable by phylogeny and concordant with the hypothetized ((Pan,Homo),Gorilla) and (Pan,Homo) most recent common ancestors. Conversely, deviations of the Paranthropus oval window area from these most recent common ancestors are not explicable by phylogeny and body weight alone, but suggest instead rapid evolutionary changes (directional selection) of its hearing organ. Premodern (Homo erectus) and modern human cochleae set apart from living non-human catarrhines and australopiths. They show cochlear relative lengths and oval window areas larger than expected for their body mass, two features corresponding to increased low-frequency sensitivity more recent than 2 million years ago. The uniqueness of the “hypertrophied” cochlea in the genus Homo (as opposed to the australopiths) and the significantly high phylogenetic signal of this organ among apes indicate its usefulness to identify homologies and monophyletic groups in the hominid fossil record. PMID:26083484

  8. Stronger efferent suppression of cochlear neural potentials by contralateral acoustic stimulation in awake than in anesthetized chinchilla

    Cristian eAedo

    2015-03-01

    Full Text Available There are two types of sensory cells in the mammalian cochlea, inner hair cells, which make synaptic contact with auditory-nerve afferent fibers, and outer hair cells that are innervated by crossed and uncrossed medial olivocochlear (MOC efferent fibers. Contralateral acoustic stimulation activates the uncrossed efferent MOC fibers reducing cochlear neural responses, thus modifying the input to the central auditory system. The chinchilla, among all studied mammals, displays the lowest percentage of uncrossed MOC fibers raising questions about the strength and frequency distribution of the contralateral-sound effect in this species. On the other hand, MOC effects on cochlear sensitivity have been mainly studied in anesthetized animals and since the MOC-neuron activity depends on the level of anesthesia, it is important to assess the influence of anesthesia in the strength of efferent effects. Seven adult chinchillas (Chinchilla laniger were chronically implanted with round-window electrodes in both cochleae. We compared the effect of contralateral sound in awake and anesthetized condition. Compound action potentials (CAP and cochlear microphonics (CM were measured in the ipsilateral cochlea in response to tones in absence and presence of contralateral sound. Control measurements performed after middle-ear muscles section in one animal discarded any possible middle-ear reflex activation. Contralateral sound produced CAP amplitude reductions in all chinchillas, with suppression effects greater by about 1-3 dB in awake than in anesthetized animals. In contrast, CM amplitude increases of up to 1.9 dB were found in only three awake chinchillas. In both conditions the strongest efferent effects were produced by contralateral tones at frequencies equal or close to those of ipsilateral tones. Contralateral CAP suppressions for 1-6 kHz ipsilateral tones corresponded to a span of uncrossed MOC fiber innervation reaching at least the central third of the

  9. Stronger efferent suppression of cochlear neural potentials by contralateral acoustic stimulation in awake than in anesthetized chinchilla.

    Aedo, Cristian; Tapia, Eduardo; Pavez, Elizabeth; Elgueda, Diego; Delano, Paul H; Robles, Luis

    2015-01-01

    There are two types of sensory cells in the mammalian cochlea, inner hair cells, which make synaptic contact with auditory-nerve afferent fibers, and outer hair cells that are innervated by crossed and uncrossed medial olivocochlear (MOC) efferent fibers. Contralateral acoustic stimulation activates the uncrossed efferent MOC fibers reducing cochlear neural responses, thus modifying the input to the central auditory system. The chinchilla, among all studied mammals, displays the lowest percentage of uncrossed MOC fibers raising questions about the strength and frequency distribution of the contralateral-sound effect in this species. On the other hand, MOC effects on cochlear sensitivity have been mainly studied in anesthetized animals and since the MOC-neuron activity depends on the level of anesthesia, it is important to assess the influence of anesthesia in the strength of efferent effects. Seven adult chinchillas (Chinchilla laniger) were chronically implanted with round-window electrodes in both cochleae. We compared the effect of contralateral sound in awake and anesthetized condition. Compound action potentials (CAP) and cochlear microphonics (CM) were measured in the ipsilateral cochlea in response to tones in absence and presence of contralateral sound. Control measurements performed after middle-ear muscles section in one animal discarded any possible middle-ear reflex activation. Contralateral sound produced CAP amplitude reductions in all chinchillas, with suppression effects greater by about 1-3 dB in awake than in anesthetized animals. In contrast, CM amplitude increases of up to 1.9 dB were found in only three awake chinchillas. In both conditions the strongest efferent effects were produced by contralateral tones at frequencies equal or close to those of ipsilateral tones. Contralateral CAP suppressions for 1-6 kHz ipsilateral tones corresponded to a span of uncrossed MOC fiber innervation reaching at least the central third of the chinchilla cochlea.

  10. [Digital signal processing of a novel neuron discharge model stimulation strategy for cochlear implants].

    Yang, Yiwei; Xu, Yuejin; Miu, Jichang; Zhou, Linghong; Xiao, Zhongju

    2012-10-01

    To apply the classic leakage integrate-and-fire models, based on the mechanism of the generation of physiological auditory stimulation, in the information processing coding of cochlear implants to improve the auditory result. The results of algorithm simulation in digital signal processor (DSP) were imported into Matlab for a comparative analysis. Compared with CIS coding, the algorithm of membrane potential integrate-and-fire (MPIF) allowed more natural pulse discharge in a pseudo-random manner to better fit the physiological structures. The MPIF algorithm can effectively solve the problem of the dynamic structure of the delivered auditory information sequence issued in the auditory center and allowed integration of the stimulating pulses and time coding to ensure the coherence and relevance of the stimulating pulse time.

  11. Suppression of Tinnitus in Chinese Patients Receiving Regular Cochlear Implant Programming.

    Liu, Ying; Wang, Hong; Han, Dong Xu; Li, Ming Hua; Wang, Yu; Xiao, Yu Li

    2016-04-01

    To assess the clinical effect of cochlear implant programming on tinnitus. Tinnitus patients (n = 234) were divided into 3 groups: (1) preoperative tinnitus (n = 108), (2) postoperative tinnitus occurring before implant switch-on at week 4 (n = 88), and (3) tinnitus occurring more than 1 year postoperatively (n = 44). Patients in each group were randomly allocated into a programming subgroup that received programming for 12 weeks postoperatively or after tinnitus occurrence or a control subgroup. Impedance testing and the Tinnitus Handicap Inventory (THI) were performed preoperatively and at 4, 6, 8, and 12 weeks postoperatively (groups 1 and 2) or after tinnitus occurrence (group 3). Comparisons were performed using t tests and chi-square tests. Impedance was significantly lower in the programming subgroup than in the control subgroup in groups 1 and 2 at 8 and 12 weeks and in group 3 at 12 weeks. The THI scores decreased in both programming and control subgroups in all groups. However, this decrease was pronounced in the programming subgroup, whereas in the control subgroup, it occurred slowly over time. Cochlear implant programming decreases impedance and improves tinnitus symptoms. © The Author(s) 2015.

  12. Intracochlear electrical stimulation suppresses apoptotic signaling in rat spiral ganglion neurons after deafening in vivo.

    Kopelovich, Jonathan C; Cagaanan, Alain P; Miller, Charles A; Abbas, Paul J; Green, Steven H

    2013-11-01

    To establish the intracellular consequences of electrical stimulation to spiral ganglion neurons after deafferentation. Here we use a rat model to determine the effect of both low and high pulse rate acute electrical stimulation on activation of the proapoptotic transcription factor Jun in deafferented spiral ganglion neurons in vivo. Experimental animal study. Hearing research laboratories of the University of Iowa Departments of Biology and Otolaryngology. A single electrode was implanted through the round window of kanamycin-deafened rats at either postnatal day 32 (P32, n = 24) or P60 (n = 22) for 4 hours of stimulation (monopolar, biphasic pulses, amplitude twice electrically evoked auditory brainstem response [eABR] threshold) at either 100 or 5000 Hz. Jun phosphorylation was assayed by immunofluorescence to quantitatively assess the effect of electrical stimulation on proapoptotic signaling. Jun phosphorylation was reliably suppressed by 100 Hz stimuli in deafened cochleae of P32 but not P60 rats. This effect was not significant in the basal cochlear turns. Stimulation frequency may be consequential: 100 Hz was significantly more effective than was 5 kHz stimulation in suppressing phospho-Jun. Suppression of Jun phosphorylation occurs in deafferented spiral ganglion neurons after only 4 hours of electrical stimulation. This finding is consistent with the hypothesis that electrical stimulation can decrease spiral ganglion neuron death after deafferentation.

  13. Coding of amplitude-modulated signals in the cochlear nucleus of a grass frog

    Bibikov, N. G.

    2002-07-01

    To study the mechanisms that govern the coding of temporal features of complex sound signals, responses of single neurons located in the dorsal nucleus of the medulla oblongata (the cochlear nucleus) of a curarized grass frog ( Rana temporaria) to pure tone bursts and amplitude modulated tone bursts with a modulation frequency of 20 Hz and modulation depths of 10 and 80% were recorded. The carrier frequency was equal to the characteristic frequency of a neuron, the average signal level was 20 30 dB above the threshold, and the signal duration was equal to ten full modulation periods. Of the 133 neurons studied, 129 neurons responded to 80% modulated tone bursts by discharges that were phase-locked with the envelope waveform. At this modulation depth, the best phase locking was observed for neurons with the phasic type of response to tone bursts. For tonic neurons with low characteristic frequencies, along with the reproduction of the modulation, phase locking with the carrier frequency of the signal was observed. At 10% amplitude modulation, phasic neurons usually responded to only the onset of a tone burst. Almost all tonic units showed a tendency to reproduce the envelope, although the efficiency of the reproduction was low, and for half of these neurons, it was below the reliability limit. Some neurons exhibited a more efficient reproduction of the weak modulation. For almost half of the neurons, a reliable improvement was observed in the phase locking of the response during the tone burst presentation (from the first to the tenth modulation period). The cooperative histogram of a set of neurons responding to 10% modulated tone bursts within narrow ranges of frequencies and intensities retains the information on the dynamics of the envelope variation. The data are compared with the results obtained from the study of the responses to similar signals in the acoustic midbrain center of the same object and also with the psychophysical effect of a differential

  14. Noise exposure immediately activates cochlear mitogen-activated protein kinase signaling

    Kumar N Alagramam

    2014-01-01

    Full Text Available Noise-induced hearing loss (NIHL is a major public health issue worldwide. Uncovering the early molecular events associated with NIHL would reveal mechanisms leading to the hearing loss. Our aim is to investigate the immediate molecular responses after different levels of noise exposure and identify the common and distinct pathways that mediate NIHL. Previous work showed mice exposed to 116 decibels sound pressure level (dB SPL broadband noise for 1 h had greater threshold shifts than the mice exposed to 110 dB SPL broadband noise, hence we used these two noise levels in this study. Groups of 4-8-week-old CBA/CaJ mice were exposed to no noise (control or to broadband noise for 1 h, followed by transcriptome analysis of total cochlear RNA isolated immediately after noise exposure. Previously identified and novel genes were found in all data sets. Following exposure to noise at 116 dB SPL, the earliest responses included up-regulation of 243 genes and down-regulation of 61 genes, while a similar exposure at 110 dB SPL up-regulated 155 genes and down-regulated 221 genes. Bioinformatics analysis indicated that mitogen-activated protein kinase (MAPK signaling was the major pathway in both levels of noise exposure. Nevertheless, both qualitative and quantitative differences were noticed in some MAPK signaling genes, after exposure to different noise levels. Cacna1b , Cacna1g , and Pla2g6 , related to calcium signaling were down-regulated after 110 dB SPL exposure, while the fold increase in the expression of Fos was relatively lower than what was observed after 116 dB SPL exposure. These subtle variations provide insight on the factors that may contribute to the differences in NIHL despite the activation of a common pathway.

  15. Analysis of Changes in Auditory Nerve Signals Following Simulated Tinnitus for the Verification of Cochlear Model

    Yi, Y

    2001-01-01

    For an interpretation of the tinnitus phenomenon, reticular lamina which transmits energy in a cochlear was assumed as a mass and the components for the stiffness and control were added to the model...

  16. BMP Suppresses PTEN Expression via RAS/ERK Signaling

    Beck, Stayce E.; Carethers, John M.

    2007-01-01

    Bone morphogenetic protein (BMP), a member of the transforming growth factor β family, classically utilizes the SMAD signaling pathway for its growth suppressive effects, and loss of this signaling cascade may accelerate cell growth. In the colon cancer predisposition syndrome Juvenile Polyposis, as well as in the late progression stages of nonsyndromic colorectal cancers, SMAD4 function is typically abrogated. Here, we utilized the SMAD4-null SW480 colon cancer cell line to examine BMPs effe...

  17. Suppressed visual looming stimuli are not integrated with auditory looming signals: Evidence from continuous flash suppression.

    Moors, Pieter; Huygelier, Hanne; Wagemans, Johan; de-Wit, Lee; van Ee, Raymond

    2015-01-01

    Previous studies using binocular rivalry have shown that signals in a modality other than the visual can bias dominance durations depending on their congruency with the rivaling stimuli. More recently, studies using continuous flash suppression (CFS) have reported that multisensory integration influences how long visual stimuli remain suppressed. In this study, using CFS, we examined whether the contrast thresholds for detecting visual looming stimuli are influenced by a congruent auditory stimulus. In Experiment 1, we show that a looming visual stimulus can result in lower detection thresholds compared to a static concentric grating, but that auditory tone pips congruent with the looming stimulus did not lower suppression thresholds any further. In Experiments 2, 3, and 4, we again observed no advantage for congruent multisensory stimuli. These results add to our understanding of the conditions under which multisensory integration is possible, and suggest that certain forms of multisensory integration are not evident when the visual stimulus is suppressed from awareness using CFS.

  18. VHF signal power suppression in stratiform and convective precipitation

    A. J. McDonald

    2006-03-01

    Full Text Available Previous studies have indicated that VHF clear-air radar return strengths are reduced during periods of precipitation. This study aims to examine whether the type of precipitation, stratiform and convective precipitation types are identified, has any impact on the relationships previously observed and to examine the possible mechanisms which produce this phenomenon. This study uses a combination of UHF and VHF wind-profiler data to define periods associated with stratiform and convective precipitation. This identification is achieved using an algorithm which examines the range squared corrected signal to noise ratio of the UHF returns for a bright band signature for stratiform precipitation. Regions associated with convective rainfall have been defined by identifying regions of enhanced range corrected signal to noise ratio that do not display a bright band structure and that are relatively uniform until a region above the melting layer. This study uses a total of 68 days, which incorporated significant periods of surface rainfall, between 31 August 2000 and 28 February 2002 inclusive from Aberystwyth (52.4° N, 4.1° W. Examination suggests that both precipitation types produce similar magnitude reductions in VHF signal power on average. However, the frequency of occurrence of statistically significant reductions in VHF signal power are very different. In the altitude range 2-4 km stratiform precipitation is related to VHF signal suppression approximately 50% of the time while in convective precipitation suppression is observed only 27% of the time. This statistical result suggests that evaporation, which occurs more often in stratiform precipitation, is important in reducing the small-scale irregularities in humidity and thereby the radio refractive index. A detailed case study presented also suggests that evaporation reducing small-scale irregularities in humidity may contribute to the observed VHF signal suppression.

  19. VHF signal power suppression in stratiform and convective precipitation

    A. J. McDonald

    2006-03-01

    Full Text Available Previous studies have indicated that VHF clear-air radar return strengths are reduced during periods of precipitation. This study aims to examine whether the type of precipitation, stratiform and convective precipitation types are identified, has any impact on the relationships previously observed and to examine the possible mechanisms which produce this phenomenon. This study uses a combination of UHF and VHF wind-profiler data to define periods associated with stratiform and convective precipitation. This identification is achieved using an algorithm which examines the range squared corrected signal to noise ratio of the UHF returns for a bright band signature for stratiform precipitation. Regions associated with convective rainfall have been defined by identifying regions of enhanced range corrected signal to noise ratio that do not display a bright band structure and that are relatively uniform until a region above the melting layer.

    This study uses a total of 68 days, which incorporated significant periods of surface rainfall, between 31 August 2000 and 28 February 2002 inclusive from Aberystwyth (52.4° N, 4.1° W. Examination suggests that both precipitation types produce similar magnitude reductions in VHF signal power on average. However, the frequency of occurrence of statistically significant reductions in VHF signal power are very different. In the altitude range 2-4 km stratiform precipitation is related to VHF signal suppression approximately 50% of the time while in convective precipitation suppression is observed only 27% of the time. This statistical result suggests that evaporation, which occurs more often in stratiform precipitation, is important in reducing the small-scale irregularities in humidity and thereby the radio refractive index. A detailed case study presented also suggests that evaporation reducing small-scale irregularities in humidity may contribute to the observed VHF signal

  20. Silymarin Suppresses Cellular Inflammation By Inducing Reparative Stress Signaling

    Lovelace, Erica S.; Wagoner, Jessica; MacDonald, James; Bammler, Theo; Bruckner, Jacob; Brownell, Jessica; Beyer, Richard; Zink, Erika M.; Kim, Young-Mo; Kyle, Jennifer E.; Webb-Robertson, Bobbie-Jo M.; Waters, Katrina M.; Metz, Thomas O.; Farin, Federico; Oberlies, Nicholas H.; Polyak, Steve

    2015-08-28

    Silymarin (SM), a natural product, is touted as a liver protectant and preventer of both chronic inflammation and diseases. To define how SM elicits these effects at a systems level, we performed transcriptional profiling, metabolomics, and signaling studies in human liver and T cell lines. Multiple pathways associated with cellular stress and metabolism were modulated by SM treatment within 0.5 to four hours: activation of Activating Transcription Factor 4 (ATF-4) and adenosine monophosphate protein kinase (AMPK) and inhibition of mammalian target of rapamycin (mTOR) signaling, the latter being associated with induction of DNA-damage-inducible transcript 4 (DDIT4). Metabolomics analyses revealed suppression of glycolytic, TCA cycle, and amino acid metabolism by SM treatment. Antiinflammatory effects arose with prolonged (i.e. 24 hours) SM exposure, with suppression of multiple proinflammatory mRNAs and nuclear factor kappa B (NF-κB) and forkhead box O (FOXO) signaling. Studies with murine knock out cells revealed that SM inhibition of both mTOR and NF-κB was partially AMPK dependent, while SM inhibition of the mTOR pathway in part required DDIT4. Thus, SM activates stress and repair responses that culminate in an anti-inflammatory phenotype. Other natural products induced similar stress responses, which correlated with their ability to suppress inflammation. Therefore, natural products like SM may be useful as tools to define how metabolic, stress, and repair pathways regulate cellular inflammation.

  1. BMP suppresses PTEN expression via RAS/ERK signaling.

    Beck, Stayce E; Carethers, John M

    2007-08-01

    Bone morphogenetic protein (BMP), a member of the transforming growth factor beta family, classically utilizes the SMAD signaling pathway for its growth suppressive effects,and loss of this signaling cascade may accelerate cell growth. In the colon cancer predisposition syndrome Juvenile Polyposis, as well as in the late progression stages of nonsyndromic colorectal cancers, SMAD4 function is typically abrogated. Here, we utilized the SMAD4-null SW480 colon cancer cell line to examine BMPs effect on a potential target gene, PTEN, and how its expression might be regulated. Initial treatment of the SMAD4-null cells with BMP resulted in mild growth suppression, but with prolonged exposure to BMP, the cells become growth stimulatory, which coincided with observed decreases in transcription and translation of PTEN, and with corresponding increases in phospho-AKT protein levels. BMP-induced PTEN suppression was mediated via the RAS/ERK pathway, as pharmacologic inhibition of RAS/ERK, or interference with protein function in the cytosol by DN-RAS prevented BMP-induced growth promotion and changes in PTEN levels, as did treatment with noggin, a BMP ligand inhibitor. Thus, BMP downregulates PTEN via RAS/ERK in a SMAD4-null environment that contributes to cell growth, and constitutes a SMAD4-independent but BMP-responsive signaling pathway.

  2. Lumican alleviates hypertrophic scarring by suppressing integrin-FAK signaling

    Zhao, Yuqian; Li, Xueyong; Xu, Xiaoli; He, Zhi; Cui, Lei; Lv, Xiaoxing

    2016-01-01

    Hypertrophic scarring (HS) is an overcompensation of wound healing that increases the risk of cosmetic disfigurement and functional impairment. No gold standard has been established for the treatment or prevention of HS. Our study aims to elucidate the expression and function of lumican in the pathogenesis of HS as well as the underlying mechanism involved in this procedure. An animal model of HS (rabbit ear) was established, and the Ad-lumican vectors were locally injected. Primary fibroblasts isolated from patients with hypertrophic burn scars were used in vitro. Histological and molecular changes in HS pathogenesis were evaluated. The results showed that lumican is significantly reduced in HS tissues and fibroblasts from HS patients as compared to normal skin or cells. Lumican levels were further suppressed in response to TGF-β stimulation. However, lumican upregulation effectively thinned the scar area and inhibited fibroblast proliferation and the cell cycle. Meanwhile, Ad-lumican administration suppressed the deposition of extracellular matrix, such as collagen and CTGF. Ad-lumican injected animals or fibroblasts presented comparable integrin α 2 β 1 expression while greatly reduced phosphorylation of FAK compared to the negative control. Moreover, Ad-lumican administration largely enhanced the binding of lumican to integrin α 2 β 1 and may thus inhibit the signaling propagation of collagen-integrin α 2 β 1 . Overall, the restoration of lumican levels contributed to suppressing the HS progression by inhibiting collagen-integrin α 2 β 1 -FAK signaling. - Highlights: • Lumican is downregulated during hypertrophic scar formation. • Lumican inhibits fibroblast proliferation. • Lumican inhibits extracellular matrix deposition. • Lumican suppresses collagen-integrin-FAK signaling.

  3. Trends in cochlear implants.

    Zeng, Fan-Gang

    2004-01-01

    More than 60,000 people worldwide use cochlear implants as a means to restore functional hearing. Although individual performance variability is still high, an average implant user can talk on the phone in a quiet environment. Cochlear-implant research has also matured as a field, as evidenced by the exponential growth in both the patient population and scientific publication. The present report examines current issues related to audiologic, clinical, engineering, anatomic, and physiologic aspects of cochlear implants, focusing on their psychophysical, speech, music, and cognitive performance. This report also forecasts clinical and research trends related to presurgical evaluation, fitting protocols, signal processing, and postsurgical rehabilitation in cochlear implants. Finally, a future landscape in amplification is presented that requires a unique, yet complementary, contribution from hearing aids, middle ear implants, and cochlear implants to achieve a total solution to the entire spectrum of hearing loss treatment and management.

  4. Artifact suppression and analysis of brain activities with electroencephalography signals.

    Rashed-Al-Mahfuz, Md; Islam, Md Rabiul; Hirose, Keikichi; Molla, Md Khademul Islam

    2013-06-05

    Brain-computer interface is a communication system that connects the brain with computer (or other devices) but is not dependent on the normal output of the brain (i.e., peripheral nerve and muscle). Electro-oculogram is a dominant artifact which has a significant negative influence on further analysis of real electroencephalography data. This paper presented a data adaptive technique for artifact suppression and brain wave extraction from electroencephalography signals to detect regional brain activities. Empirical mode decomposition based adaptive thresholding approach was employed here to suppress the electro-oculogram artifact. Fractional Gaussian noise was used to determine the threshold level derived from the analysis data without any training. The purified electroencephalography signal was composed of the brain waves also called rhythmic components which represent the brain activities. The rhythmic components were extracted from each electroencephalography channel using adaptive wiener filter with the original scale. The regional brain activities were mapped on the basis of the spatial distribution of rhythmic components, and the results showed that different regions of the brain are activated in response to different stimuli. This research analyzed the activities of a single rhythmic component, alpha with respect to different motor imaginations. The experimental results showed that the proposed method is very efficient in artifact suppression and identifying individual motor imagery based on the activities of alpha component.

  5. Brain signal complexity rises with repetition suppression in visual learning.

    Lafontaine, Marc Philippe; Lacourse, Karine; Lina, Jean-Marc; McIntosh, Anthony R; Gosselin, Frédéric; Théoret, Hugo; Lippé, Sarah

    2016-06-21

    Neuronal activity associated with visual processing of an unfamiliar face gradually diminishes when it is viewed repeatedly. This process, known as repetition suppression (RS), is involved in the acquisition of familiarity. Current models suggest that RS results from interactions between visual information processing areas located in the occipito-temporal cortex and higher order areas, such as the dorsolateral prefrontal cortex (DLPFC). Brain signal complexity, which reflects information dynamics of cortical networks, has been shown to increase as unfamiliar faces become familiar. However, the complementarity of RS and increases in brain signal complexity have yet to be demonstrated within the same measurements. We hypothesized that RS and brain signal complexity increase occur simultaneously during learning of unfamiliar faces. Further, we expected alteration of DLPFC function by transcranial direct current stimulation (tDCS) to modulate RS and brain signal complexity over the occipito-temporal cortex. Participants underwent three tDCS conditions in random order: right anodal/left cathodal, right cathodal/left anodal and sham. Following tDCS, participants learned unfamiliar faces, while an electroencephalogram (EEG) was recorded. Results revealed RS over occipito-temporal electrode sites during learning, reflected by a decrease in signal energy, a measure of amplitude. Simultaneously, as signal energy decreased, brain signal complexity, as estimated with multiscale entropy (MSE), increased. In addition, prefrontal tDCS modulated brain signal complexity over the right occipito-temporal cortex during the first presentation of faces. These results suggest that although RS may reflect a brain mechanism essential to learning, complementary processes reflected by increases in brain signal complexity, may be instrumental in the acquisition of novel visual information. Such processes likely involve long-range coordinated activity between prefrontal and lower order visual

  6. Epigenetic suppression of EGFR signaling in G-CIMP+ glioblastomas.

    Li, Jie; Taich, Zachary J; Goyal, Amit; Gonda, David; Akers, Johnny; Adhikari, Bandita; Patel, Kunal; Vandenberg, Scott; Yan, Wei; Bao, Zhaoshi; Carter, Bob S; Wang, Renzhi; Mao, Ying; Jiang, Tao; Chen, Clark C

    2014-09-15

    The intrinsic signaling cascades and cell states associated with the Glioma CpG Island Methylator Phenotype (G-CIMP) remain poorly understood. Using published mRNA signatures associated with EGFR activation, we demonstrate that G-CIMP+ tumors harbor decreased EGFR signaling using three independent datasets, including the Chinese Glioma Genome Atlas(CGGA; n=155), the REMBRANDT dataset (n=288), and The Cancer Genome Atlas (TCGA; n=406). Additionally, an independent collection of 25 fresh-frozen glioblastomas confirmed lowered pERK levels in G-CIMP+ specimens (pCIMP+ glioblastomas harbored lowered mRNA levels for EGFR and H-Ras. Induction of G-CIMP+ state by exogenous expression of a mutated isocitrate dehydrogenase 1, IDH1-R132H, suppressed EGFR and H-Ras protein expression as well as pERK accumulation in independent glioblastoma models. These suppressions were associated with increased deposition of the repressive histone markers, H3K9me3 and H3K27me3, in the EGFR and H-Ras promoter regions. The IDH1-R132H expression-induced pERK suppression can be reversed by exogenous expression of H-RasG12V. Finally, the G-CIMP+ Ink4a-Arf-/- EGFRvIII glioblastoma line was more resistant to the EGFR inhibitor, Gefitinib, relative to its isogenic G-CIMP- counterpart. These results suggest that G-CIMP epigenetically regulates EGFR signaling and serves as a predictive biomarker for EGFR inhibitors in glioblastoma patients.

  7. Feeding by whiteflies suppresses downstream jasmonic acid signaling by eliciting salicylic acid signaling.

    Zhang, Peng-Jun; Li, Wei-Di; Huang, Fang; Zhang, Jin-Ming; Xu, Fang-Cheng; Lu, Yao-Bin

    2013-05-01

    Phloem-feeding whiteflies in the species complex Bemisia tabaci cause extensive crop damage worldwide. One of the reasons for their "success" is their ability to suppress the effectual jasmonic acid (JA) defenses of the host plant. However, little is understood about the mechanisms underlying whitefly suppression of JA-regulated defenses. Here, we showed that the expression of salicylic acid (SA)-responsive genes (EDS1 and PR1) in Arabidopsis thaliana was significantly enhanced during feeding by whitefly nymphs. Whereas upstream JA-responsive genes (LOX2 and OPR3) also were induced, the downstream JA-responsive gene (VSP1) was repressed, i.e., whiteflies only suppressed downstream JA signaling. Gene-expression analyses with various Arabidopsis mutants, including NahG, npr-1, ein2-1, and dde2-2, revealed that SA signaling plays a key role in the suppression of downstream JA defenses by whitefly feeding. Assays confirmed that SA activation enhanced whitefly performance by suppressing downstream JA defenses.

  8. STATIC AND DYNAMIC POSTURE CONTROL IN POSTLINGUAL COCHLEAR IMPLANTED PATIENTS: Effects of dual-tasking, visual and auditory inputs suppression

    BERNARD DEMANZE eLaurence

    2014-01-01

    Full Text Available Posture control is based on central integration of multisensory inputs, and on internal representation of body orientation in space. This multisensory feedback regulates posture control and continuously updates the internal model of body’s position which in turn forwards motor commands adapted to the environmental context and constraints. The peripheral localization of the vestibular system, close to the cochlea, makes vestibular damage possible following cochlear implant (CI surgery. Impaired vestibular function in CI patients, if any, may have a strong impact on posture stability. The simple postural task of quiet standing is generally paired with cognitive activity in most day life conditions, leading therefore to competition for attentional resources in dual-tasking, and increased risk of fall particularly in patients with impaired vestibular function. This study was aimed at evaluating the effects of post-lingual cochlear implantation on posture control in adult deaf patients. Possible impairment of vestibular function was assessed by comparing the postural performance of patients to that of age-matched healthy subjects during a simple postural task performed in static and dynamic conditions, and during dual-tasking with a visual or auditory memory task. Postural tests were done in eyes open (EO and eyes closed (EC conditions, with the cochlear implant activated (ON or not (OFF. Results showed that the CI patients significantly reduced limits of stability and increased postural instability in static conditions. In dynamic conditions, they spent considerably more energy to maintain equilibrium, and their head was stabilized neither in space nor on trunk while the controls showed a whole body rigidification strategy. Hearing (prosthesis on as well as dual-tasking did not really improve the dynamic postural performance of the CI patients. We conclude that CI patients become strongly visual dependent mainly in challenging postural conditions.

  9. The design and validation of a hybrid digital-signal-processing plug-in for traditional cochlear implant speech processors.

    Hajiaghababa, Fatemeh; Marateb, Hamid R; Kermani, Saeed

    2018-06-01

    Cochlear implants (CIs) are electronic devices restoring partial hearing to deaf individuals with profound hearing loss. In this paper, a new plug-in for traditional IIR filter-banks (FBs) is presented for cochlear implants based on wavelet neural networks (WNNs). Having provided such a plug-in for commercially available CIs, it is possible not only to use available hardware in the market but also to optimize their performance compared with the-state-of-the-art. An online database of Dutch diphone perception was used in our study. The weights of the WNNs were tuned using particle swarm optimization (PSO) on a training set (speech-shaped noise (SSN) of 2 dB SNR), while its performance was assessed on a test set in terms of objective and composite measures in the hold-out validation framework. The cost function was defined based on the combination of mean square error (MSE), short‑time objective intelligibility (STOI) criteria on the training set. Variety of performance indices were used including segmental signal- to -noise ratio (SNRseg), MSE, STOI, log-likelihood ratio (LLR), weighted spectral slope (WSS), and composite measures C sig , C bak and C ovl . Meanwhile, the following CI speech processing techniques were used for comparison: traditional FBs, dual resonance nonlinear (DRNL) and simple dual path nonlinear (SPDN) models. The average SNRseg, MSE, and LLR values for the WNN in the entire data set were 2.496 ± 2.794, 0.086 ± 0.025 and 2.323 ± 0.281, respectively. The proposed method significantly improved MSE, SNR, SNRseg, LLR, C sig C bak and C ovl compared with the other three methods (repeated-measures analysis of variance (ANOVA); P < 0.05). The average running time of the proposed algorithm (written in Matlab R2013a) on the training and test sets for each consonant or vowel on an Intel dual-core 2.10 GHz CPU with 2GB of RAM was 9.91 ± 0.87 (s) and 0.19 ± 0.01 (s), respectively. The proposed algorithm is accurate and

  10. 4-aminopyridine in scala media reversibly alters the cochlear potentials and suppresses electrically evoked oto-acoustic emissions.

    Kirk, D L; Yates, G K

    1998-01-01

    Iontophoresis of 4-aminopyridine into scala media of the guinea pig cochlea caused elevation of the thresholds of the compound action potential of the auditory nerve, loss of amplitude of the extracellular cochlear microphonic response (CM), increase in the endocochlear potential (EP) and reduction in the amplitude of electrically evoked oto-acoustic emissions (EEOAEs). These changes were reversible over 10-20 min. The reciprocity of the changes in the CM and the EP was consistent with an interruption of both DC and AC currents through outer hair cells (OHCs), probably by blockade of mechano-electrical transduction (MET) channels in OHCs. Reductions in EEOAEs were consistent with the extrinsically applied generating current entering the OHC via the MET channels. Implications for the activation of OHC electromotility in vivo are discussed.

  11. Static and dynamic posture control in postlingual cochlear implanted patients: effects of dual-tasking, visual and auditory inputs suppression.

    Bernard-Demanze, Laurence; Léonard, Jacques; Dumitrescu, Michel; Meller, Renaud; Magnan, Jacques; Lacour, Michel

    2013-01-01

    Posture control is based on central integration of multisensory inputs, and on internal representation of body orientation in space. This multisensory feedback regulates posture control and continuously updates the internal model of body's position which in turn forwards motor commands adapted to the environmental context and constraints. The peripheral localization of the vestibular system, close to the cochlea, makes vestibular damage possible following cochlear implant (CI) surgery. Impaired vestibular function in CI patients, if any, may have a strong impact on posture stability. The simple postural task of quiet standing is generally paired with cognitive activity in most day life conditions, leading therefore to competition for attentional resources in dual-tasking, and increased risk of fall particularly in patients with impaired vestibular function. This study was aimed at evaluating the effects of postlingual cochlear implantation on posture control in adult deaf patients. Possible impairment of vestibular function was assessed by comparing the postural performance of patients to that of age-matched healthy subjects during a simple postural task performed in static (stable platform) and dynamic (platform in translation) conditions, and during dual-tasking with a visual or auditory memory task. Postural tests were done in eyes open (EO) and eyes closed (EC) conditions, with the CI activated (ON) or not (OFF). Results showed that the postural performance of the CI patients strongly differed from the controls, mainly in the EC condition. The CI patients showed significantly reduced limits of stability and increased postural instability in static conditions. In dynamic conditions, they spent considerably more energy to maintain equilibrium, and their head was stabilized neither in space nor on trunk: they behaved dynamically without vision like an inverted pendulum while the controls showed a whole body rigidification strategy. Hearing (prosthesis on) as well

  12. Robust suppression of nonstationary power-line interference in electrocardiogram signals

    Li, Guojun; Zeng, Xiaopin; Zhou, Yu; Liu, Guojin; Zhou, Xichuan; Zhou, Xiaona

    2012-01-01

    It is a challenge to suppress time-varying power-line interference (PLI) with various levels in electrocardiogram (ECG) signals. Most previous attempts of tracking and suppressing the nonstationary PLI signal are based on the least-squares (LS) algorithm. This makes these methods susceptible to QRS complex in suppressing a low-level PLI signal which is frequently coupled in battery-operated ECG equipment. To address the limitation of LS-based methods, this study presents a robust PLI suppression system based on a robust extension of the Kalman filter. In addition, we used an improved version of empirical mode decomposition to further attenuate the QRS complex. Experiments show that our system could effectively suppress the PLI while preserving meaningful ECG components at various interference levels. (paper)

  13. Suppression of Subsequent N1m Amplitude When the Masker Frequency is Different from the Signal

    Yuka Uratani

    2014-01-01

    Full Text Available When two tones are presented in a short interval of time, the presentation of the preceding tone (masker suppresses the response evoked by the subsequent tone (signal. To address the processing in forward suppression, we applied 2- and 4-kHz maskers, followed by a 1-kHz signal at varying signal delays (0 to 320 ms and measured the signal-evoked N1m. A two-way analysis of variance revealed a statistically significant effect for signal delay in both masker presentation conditions. The N1m peak amplitude at the signal delay of 320 ms was significantly larger than those of 10, 20, 40, and 80 ms ( p < 0.05. No significant enhancement for the very short signal delay was observed. The results suggest that the enhancement of N1m peak amplitude for short signal delay conditions is maximized when the frequency of the masker is identical to that of the signal.

  14. Cochlear Implants

    ... NIDCD A cochlear implant is a small, complex electronic device that can help to provide a sense ... Hearing Aids Retinitis Pigmentosa - National Eye Institute Telecommunications Relay Services Usher Syndrome Your Baby's Hearing Screening News ...

  15. A novel method for device-related electroencephalography artifact suppression to explore cochlear implant-related cortical changes in single-sided deafness.

    Kim, Kyungsoo; Punte, Andrea Kleine; Mertens, Griet; Van de Heyning, Paul; Park, Kyung-Joon; Choi, Hongsoo; Choi, Ji-Woong; Song, Jae-Jin

    2015-11-30

    Quantitative electroencephalography (qEEG) is effective when used to analyze ongoing cortical oscillations in cochlear implant (CI) users. However, localization of cortical activity in such users via qEEG is confounded by the presence of artifacts produced by the device itself. Typically, independent component analysis (ICA) is used to remove CI artifacts in auditory evoked EEG signals collected upon brief stimulation and it is effective for auditory evoked potentials (AEPs). However, AEPs do not reflect the daily environments of patients, and thus, continuous EEG data that are closer to such environments are desirable. In this case, device-related artifacts in EEG data are difficult to remove selectively via ICA due to over-completion of EEG data removal in the absence of preprocessing. EEGs were recorded for a long time under conditions of continuous auditory stimulation. To obviate the over-completion problem, we limited the frequency of CI artifacts to a significant characteristic peak and apply ICA artifact removal. Topographic brain mapping results analyzed via band-limited (BL)-ICA exhibited a better energy distribution, matched to the CI location, than data obtained using conventional ICA. Also, source localization data verified that BL-ICA effectively removed CI artifacts. The proposed method selectively removes CI artifacts from continuous EEG recordings, while ICA removal method shows residual peak and removes important brain activity signals. CI artifacts in EEG data obtained during continuous passive listening can be effectively removed with the aid of BL-ICA, opening up new EEG research possibilities in subjects with CIs. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. LC-MS/MS signal suppression effects in the analysis of pesticides in complex environmental matrices.

    Choi, B K; Hercules, D M; Gusev, A I

    2001-02-01

    The application of LC separation and mobile phase additives in addressing LC-MS/MS matrix signal suppression effects for the analysis of pesticides in a complex environmental matrix was investigated. It was shown that signal suppression is most significant for analytes eluting early in the LC-MS analysis. Introduction of different buffers (e.g. ammonium formate, ammonium hydroxide, formic acid) into the LC mobile phase was effective in improving signal correlation between the matrix and standard samples. The signal improvement is dependent on buffer concentration as well as LC separation of the matrix components. The application of LC separation alone was not effective in addressing suppression effects when characterizing complex matrix samples. Overloading of the LC column by matrix components was found to significantly contribute to analyte-matrix co-elution and suppression of signal. This signal suppression effect can be efficiently compensated by 2D LC (LC-LC) separation techniques. The effectiveness of buffers and LC separation in improving signal correlation between standard and matrix samples is discussed.

  17. Ethylene signaling renders the jasmonate response of Arabidopsis insensitive to future suppression by salicylic Acid.

    Leon-Reyes, Antonio; Du, Yujuan; Koornneef, Annemart; Proietti, Silvia; Körbes, Ana P; Memelink, Johan; Pieterse, Corné M J; Ritsema, Tita

    2010-02-01

    Cross-talk between jasmonate (JA), ethylene (ET), and Salicylic acid (SA) signaling is thought to operate as a mechanism to fine-tune induced defenses that are activated in response to multiple attackers. Here, 43 Arabidopsis genotypes impaired in hormone signaling or defense-related processes were screened for their ability to express SA-mediated suppression of JA-responsive gene expression. Mutant cev1, which displays constitutive expression of JA and ET responses, appeared to be insensitive to SA-mediated suppression of the JA-responsive marker genes PDF1.2 and VSP2. Accordingly, strong activation of JA and ET responses by the necrotrophic pathogens Botrytis cinerea and Alternaria brassicicola prior to SA treatment counteracted the ability of SA to suppress the JA response. Pharmacological assays, mutant analysis, and studies with the ET-signaling inhibitor 1-methylcyclopropene revealed that ET signaling renders the JA response insensitive to subsequent suppression by SA. The APETALA2/ETHYLENE RESPONSE FACTOR transcription factor ORA59, which regulates JA/ET-responsive genes such as PDF1.2, emerged as a potential mediator in this process. Collectively, our results point to a model in which simultaneous induction of the JA and ET pathway renders the plant insensitive to future SA-mediated suppression of JA-dependent defenses, which may prioritize the JA/ET pathway over the SA pathway during multi-attacker interactions.

  18. Modelling Cochlear Mechanics

    Guangjian Ni

    2014-01-01

    Full Text Available The cochlea plays a crucial role in mammal hearing. The basic function of the cochlea is to map sounds of different frequencies onto corresponding characteristic positions on the basilar membrane (BM. Sounds enter the fluid-filled cochlea and cause deflection of the BM due to pressure differences between the cochlear fluid chambers. These deflections travel along the cochlea, increasing in amplitude, until a frequency-dependent characteristic position and then decay away rapidly. The hair cells can detect these deflections and encode them as neural signals. Modelling the mechanics of the cochlea is of help in interpreting experimental observations and also can provide predictions of the results of experiments that cannot currently be performed due to technical limitations. This paper focuses on reviewing the numerical modelling of the mechanical and electrical processes in the cochlea, which include fluid coupling, micromechanics, the cochlear amplifier, nonlinearity, and electrical coupling.

  19. Cross-Term Suppression in Time Order Distribution for AWGN Signal

    WAQAS MAHMOOD

    2017-04-01

    Full Text Available A technique of cross-term suppression in WD (Wigner Distribution for a multi-component signal that is embedded WGN (White Gaussian Noise is proposed. In this technique, an optimized algorithm is developed for time-varying noisy signal and a CAD (Computer Aided Design simulator is designed for Numerical simulations of synthetic signal. In proposed technique, signal components are localized in tf (time frequency plane by STFT (Short Time Fourier Transform. Rectified STFT is computed and Spectral Kurtosis is used to separate a signal components from noise in t-f plane. The t-f plane is segmented and then signal components are filtered out by FFT (Fractional Fourier Transform. Finally, WD (free of cross terms of isolated signal component is computed to obtain high resolution in t-f plane.

  20. Ethylene signaling renders the jasmonate response of Arabidopsis insensitive to future suppression by salicylic acid

    Leon Reyes, H.A.; Du, Y.; Koornneef, A.; Proietti, S.; Körbes, A.P.; Memelink, J.; Pieterse, C.M.J.; Ritsema, T.

    2010-01-01

    Cross-talk between jasmonate (JA), ethylene (ET), and Salicylic acid (SA) signaling is thought to operate as a mechanism to fine-tune induced defenses that are activated in response to multiple attackers. Here, 43 Arabidopsis genotypes impaired in hormone signaling or defense-related processes were screened for their ability to express SA-mediated suppression of JA-responsive gene expression. Mutant cev1, which displays constitutive expression of JA and ET responses, appeared to be insensitiv...

  1. Gambogic acid inhibits multiple myeloma mediated osteoclastogenesis through suppression of chemokine receptor CXCR4 signaling pathways.

    Pandey, Manoj K; Kale, Vijay P; Song, Chunhua; Sung, Shen-shu; Sharma, Arun K; Talamo, Giampaolo; Dovat, Sinisa; Amin, Shantu G

    2014-10-01

    Bone disease, characterized by the presence of lytic lesions and osteoporosis is the hallmark of multiple myeloma (MM). Stromal cell-derived factor 1α (SDF-1α) and its receptor, CXC chemokine receptor 4 (CXCR4), has been implicated as a regulator of bone resorption, suggesting that agents that can suppress SDF1α/CXCR4 signaling might inhibit osteoclastogenesis, a process closely linked to bone resorption. We, therefore, investigated whether gambogic acid (GA), a xanthone, could inhibit CXCR4 signaling and suppress osteoclastogenesis induced by MM cells. Through docking studies we predicted that GA directly interacts with CXCR4. This xanthone down-regulates the expression of CXCR4 on MM cells in a dose- and time-dependent manner. The down-regulation of CXCR4 was not due to proteolytic degradation, but rather GA suppresses CXCR4 mRNA expression by inhibiting nuclear factor-kappa B (NF-κB) DNA binding. This was further confirmed by quantitative chromatin immunoprecipitation assay, as GA inhibits p65 binding at the CXCR4 promoter. GA suppressed SDF-1α-induced chemotaxis of MM cells and downstream signaling of CXCR4 by inhibiting phosphorylation of Akt, p38, and Erk1/2 in MM cells. GA abrogated the RANKL-induced differentiation of macrophages to osteoclasts in a dose- and time-dependent manner. In addition, we found that MM cells induced differentiation of macrophages to osteoclasts, and that GA suppressed this process. Importantly, suppression of osteoclastogenesis by GA was mediated through IL-6 inhibition. Overall, our results show that GA is a novel inhibitor of CXCR4 expression and has a strong potential to suppress osteoclastogenesis mediated by MM cells. Published by Elsevier Inc.

  2. Assessment of the Speech Intelligibility Performance of Post Lingual Cochlear Implant Users at Different Signal-to-Noise Ratios Using the Turkish Matrix Test

    Zahra Polat

    2016-10-01

    Full Text Available Background: Spoken word recognition and speech perception tests in quiet are being used as a routine in assessment of the benefit which children and adult cochlear implant users receive from their devices. Cochlear implant users generally demonstrate high level performances in these test materials as they are able to achieve high level speech perception ability in quiet situations. Although these test materials provide valuable information regarding Cochlear Implant (CI users’ performances in optimal listening conditions, they do not give realistic information regarding performances in adverse listening conditions, which is the case in the everyday environment. Aims: The aim of this study was to assess the speech intelligibility performance of post lingual CI users in the presence of noise at different signal-to-noise ratio with the Matrix Test developed for Turkish language. Study Design: Cross-sectional study. Methods: The thirty post lingual implant user adult subjects, who had been using implants for a minimum of one year, were evaluated with Turkish Matrix test. Subjects’ speech intelligibility was measured using the adaptive and non-adaptive Matrix Test in quiet and noisy environments. Results: The results of the study show a correlation between Pure Tone Average (PTA values of the subjects and Matrix test Speech Reception Threshold (SRT values in the quiet. Hence, it is possible to asses PTA values of CI users using the Matrix Test also. However, no correlations were found between Matrix SRT values in the quiet and Matrix SRT values in noise. Similarly, the correlation between PTA values and intelligibility scores in noise was also not significant. Therefore, it may not be possible to assess the intelligibility performance of CI users using test batteries performed in quiet conditions. Conclusion: The Matrix Test can be used to assess the benefit of CI users from their systems in everyday life, since it is possible to perform

  3. Kurarinol induces hepatocellular carcinoma cell apoptosis through suppressing cellular signal transducer and activator of transcription 3 signaling

    Shu, Guangwen; Yang, Jing; Zhao, Wenhao; Xu, Chan; Hong, Zongguo; Mei, Zhinan; Yang, Xinzhou

    2014-01-01

    Kurarinol is a flavonoid isolated from roots of the medical plant Sophora flavescens. However, its cytotoxic activity against hepatocellular carcinoma (HCC) cells and toxic effects on mammalians remain largely unexplored. Here, the pro-apoptotic activities of kurarinol on HCC cells and its toxic impacts on tumor-bearing mice were evaluated. The molecular mechanisms underlying kurarinol-induced HCC cell apoptosis were also investigated. We found that kurarinol dose-dependently provoked HepG2, Huh-7 and H22 HCC cell apoptosis. In addition, kurarinol gave rise to a considerable decrease in the transcriptional activity of signal transducer and activator of transcription 3 (STAT3) in HCC cells. Suppression of STAT3 signaling is involved in kurarinol-induced HCC cell apoptosis. In vivo studies showed that kurarinol injection substantially induced transplanted H22 cell apoptosis with low toxic impacts on tumor-bearing mice. Similarly, the transcriptional activity of STAT3 in transplanted tumor tissues was significantly suppressed after kurarinol treatment. Collectively, our current research demonstrated that kurarinol has the capacity of inducing HCC cell apoptosis both in vitro and in vivo with undetectable toxic impacts on the host. Suppressing STAT3 signaling is implicated in kurarinol-mediated HCC cell apoptosis. - Highlights: • Kurarinol induces hepatocellular carcinoma (HCC) cell apoptosis. • Kurarinol induces HCC cell apoptosis via inhibiting STAT3. • Kurarinol exhibits low toxic effects on tumor-bearing animals

  4. Noise Suppression in ECG Signals through Efficient One-Step Wavelet Processing Techniques

    E. Castillo

    2013-01-01

    Full Text Available This paper illustrates the application of the discrete wavelet transform (DWT for wandering and noise suppression in electrocardiographic (ECG signals. A novel one-step implementation is presented, which allows improving the overall denoising process. In addition an exhaustive study is carried out, defining threshold limits and thresholding rules for optimal wavelet denoising using this presented technique. The system has been tested using synthetic ECG signals, which allow accurately measuring the effect of the proposed processing. Moreover, results from real abdominal ECG signals acquired from pregnant women are presented in order to validate the presented approach.

  5. Schisantherin A suppresses osteoclast formation and wear particle-induced osteolysis via modulating RANKL signaling pathways

    He, Yi; Zhang, Qing; Shen, Yi; Chen, Xia; Zhou, Feng; Peng, Dan, E-mail: xyeypd@163.com

    2014-07-04

    Highlights: • Schisantherin A suppresses osteoclasts formation and function in vitro. • Schisantherin A impairs RANKL signaling pathway. • Schisantherin A suppresses osteolysis in vivo. • Schisantherin A may be used for treating osteoclast related diseases. - Abstract: Receptor activator of NF-κB ligand (RANKL) plays critical role in osteoclastogenesis. Targeting RANKL signaling pathways has been a promising strategy for treating osteoclast related bone diseases such as osteoporosis and aseptic prosthetic loosening. Schisantherin A (SA), a dibenzocyclooctadiene lignan isolated from the fruit of Schisandra sphenanthera, has been used as an antitussive, tonic, and sedative agent, but its effect on osteoclasts has been hitherto unknown. In the present study, SA was found to inhibit RANKL-induced osteoclast formation and bone resorption. The osteoclastic specific marker genes induced by RANKL including c-Src, SA inhibited OSCAR, cathepsin K and TRAP in a dose dependent manner. Further signal transduction studies revealed that SA down-regulate RANKL-induced nuclear factor-kappaB (NF-κB) signaling activation by suppressing the phosphorylation and degradation of IκBα, and subsequently preventing the NF-κB transcriptional activity. Moreover, SA also decreased the RANKL-induced MAPKs signaling pathway, including JNK and ERK1/2 posphorylation while had no obvious effects on p38 activation. Finally, SA suppressed the NF-κB and MAPKs subsequent gene expression of NFATc1 and c-Fos. In vivo studies, SA inhibited osteoclast function and exhibited bone protection effect in wear-particle-induced bone erosion model. Taken together, SA could attenuate osteoclast formation and wear particle-induced osteolysis by mediating RANKL signaling pathways. These data indicated that SA is a promising therapeutic natural compound for the treatment of osteoclast-related prosthesis loosening.

  6. Calorie-induced ER stress suppresses uroguanylin satiety signaling in diet-induced obesity.

    Kim, G W; Lin, J E; Snook, A E; Aing, A S; Merlino, D J; Li, P; Waldman, S A

    2016-05-23

    The uroguanylin-GUCY2C gut-brain axis has emerged as one component regulating feeding, energy homeostasis, body mass and metabolism. Here, we explore a role for this axis in mechanisms underlying diet-induced obesity (DIO). Intestinal uroguanylin expression and secretion, and hypothalamic GUCY2C expression and anorexigenic signaling, were quantified in mice on high-calorie diets for 14 weeks. The role of endoplasmic reticulum (ER) stress in suppressing uroguanylin in DIO was explored using tunicamycin, an inducer of ER stress, and tauroursodeoxycholic acid (TUDCA), a chemical chaperone that inhibits ER stress. The impact of consumed calories on uroguanylin expression was explored by dietary manipulation. The role of uroguanylin in mechanisms underlying obesity was examined using Camk2a-Cre-ER(T2)-Rosa-STOP(loxP/loxP)-Guca2b mice in which tamoxifen induces transgenic hormone expression in brain. DIO suppressed intestinal uroguanylin expression and eliminated its postprandial secretion into the circulation. DIO suppressed uroguanylin through ER stress, an effect mimicked by tunicamycin and blocked by TUDCA. Hormone suppression by DIO reflected consumed calories, rather than the pathophysiological milieu of obesity, as a diet high in calories from carbohydrates suppressed uroguanylin in lean mice, whereas calorie restriction restored uroguanylin in obese mice. However, hypothalamic GUCY2C, enriched in the arcuate nucleus, produced anorexigenic signals mediating satiety upon exogenous agonist administration, and DIO did not impair these responses. Uroguanylin replacement by transgenic expression in brain repaired the hormone insufficiency and reconstituted satiety responses opposing DIO and its associated comorbidities, including visceral adiposity, glucose intolerance and hepatic steatosis. These studies reveal a novel pathophysiological mechanism contributing to obesity in which calorie-induced suppression of intestinal uroguanylin impairs hypothalamic mechanisms

  7. Improving Multi Access Interference Suppression in Optical CDMA by using all-Optical Signal Processing

    T. B. Osadola

    2013-06-01

    Full Text Available This paper presents the study of a novel all-optical method for processing optical CDMA signals towards improving suppression of multi access interference. The main focus is on incoherent OCDMA systems using multiwavelength 2D-WH/TS codes generated using FBG based encoders and decoders. The MAI suppression capabilities based on its ability to eliminate selective wavelength pulse processing have been shown. A novel transmitter architecture that achieves up to 3dB power saving was also presented. As a result of hardware savings, processing cost will be significantly reduced and power budget improvement resulted in improved performance.

  8. A Two-Microphone Noise Reduction System for Cochlear Implant Users with Nearby Microphones—Part I: Signal Processing Algorithm Design and Development

    Marco Pelizzone

    2008-06-01

    Full Text Available Users of cochlear implant systems, that is, of auditory aids which stimulate the auditory nerve at the cochlea electrically, often complain about poor speech understanding in noisy environments. Despite the proven advantages of multimicrophone directional noise reduction systems for conventional hearing aids, only one major manufacturer has so far implemented such a system in a product, presumably because of the added power consumption and size. We present a physically small (intermicrophone distance 7 mm and computationally inexpensive adaptive noise reduction system suitable for behind-the-ear cochlear implant speech processors. Supporting algorithms, which allow the adjustment of the opening angle and the maximum noise suppression, are proposed and evaluated. A portable real-time device for test in real acoustic environments is presented.

  9. Suppression of choriocarcinoma invasion and metastasis following blockade of BDNF/TrkB signaling

    Kawamura, Kazuhiro; Kawamura, Nanami; Okamoto, Naoki; Manabe, Motomu

    2013-01-01

    Brain-derived neurotrophic factor (BDNF) acts through its cognate receptor tyrosine kinase-B (TrkB) to regulate diverse physiological functions in reproductive and other tissues. In normal and malignant trophoblastic cells, the BDNF/TrkB signaling promotes cell growth. Due to the highly malignant nature of choriocarcinoma, we investigated possible involvement of this system in choriocarcinoma cell invasion and metastasis. We demonstrated that treatment of cultured choriocarcinoma cells, known to express both BDNF and TrkB, with a soluble TrkB ectodomain or a Trk receptor inhibitor K252a suppressed cell invasion accompanied with decreased expression of matrix metalloproteinase-2, a cell invasion marker. In vivo studies using a tumor xenograft model in athymic nude mice further showed inhibition of cell invasion from tumors to surrounding tissues following the suppression of endogenous TrkB signaling. For an in vivo model of choriocarcinoma metastasis, we performed intravenous injections of JAR cells expressing firefly luciferase into severe combined immunodeficiency (SCID) mice. Treatment with K252a inhibited metastasis of tumors to distant organs. In vivo K252a treatment also suppressed metastatic tumor growth as reflected by decreased cell proliferation and increased apoptosis and caspases-3/7 activities, together with reduced tissue levels of a tumor marker, human chorionic gonadotropin-β. In vivo suppression of TrkB signaling also led to decreased expression of angiogenic markers in metastatic tumor, including cluster of differentiation 31 and vascular endothelial growth factor A. Our findings suggested essential autocrine/paracrine roles of the BDNF/TrkB signaling system in choriocarcinoma invasion and metastasis. Inhibition of this signaling could serve as the basis to develop a novel therapy for patients with choriocarcinoma

  10. J/Ψ suppression as a signal for the quark-gluon plasma

    Wong, C.Y.

    1997-01-01

    The authors review the search for the quark-gluon plasma using the signal of the suppression of J/ψ production in high-energy heavy-ion collisions. Recent anomalous J/ψ suppression in high-energy Pb-Pb collisions observed by the NA50 Collaboration are examined and compared with earlier results from pA and nucleus-nucleus collisions with heavy ions of smaller mass numbers. The anomalous suppression of J/ψ production in Pb-Pb collisions can be explained as due to the occurrence of a new phase of strong J/ψ absorption, which sets in when the number of nucleon-nucleon collisions at a spatial point exceeds about 4 and corresponds to a local energy density of about 3.4 GeV/fm 3

  11. Cochlear Implant

    Mehrnaz Karimi

    1992-04-01

    Full Text Available People with profound hearing loss are not able to use some kinds of conventional amplifiers due to the nature of their loss . In these people, hearing sense is stimulated only when the auditory nerve is activated via electrical stimulation. This stimulation is possible through cochlear implant. In fact, for the deaf people who have good mental health and can not use surgical and medical treatment and also can not benefit from air and bone conduction hearing aids, this device is used if they have normal central auditory system. The basic parts of the device included: Microphone, speech processor, transmitter, stimulator and receiver, and electrode array.

  12. miR-612 suppresses the stemness of liver cancer via Wnt/β-catenin signaling

    Tang, Jun [Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032 (China); Tao, Zhong-Hua [Department of Medical Oncology, Shanghai Cancer Center, Fudan University, Shanghai 200032 (China); Wen, Duo; Wan, Jin-Liang; Liu, Dong-Li; Zhang, Shu; Cui, Jie-Feng; Sun, Hui-Chuan; Wang, Lu [Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032 (China); Zhou, Jian; Fan, Jia [Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032 (China); Institute of Biomedical Sciences of Fudan University, Shanghai 200032 (China); Wu, Wei-Zhong, E-mail: wu.weizhong@zs-hospital.sh.cn [Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032 (China)

    2014-04-25

    Highlights: • miR-612 suppresses tumorsphere and clone formation of HCC cells. • miR-612 reduces drug resistance of HCC cells. • miR-612 suppresses tumorigenesis of HCC in NOD/SCID mice. • miR-612 inhibits an invasive frontier of HCC xenografts. • miR-612 suppresses Wnt/β-catenin signaling. - Abstract: Previous research showed that microRNA-612 (miR-612) has inhibitory effects on cell proliferation, migration, invasion, and metastasis of hepatocellular carcinoma (HCC). AKT2 was confirmed to be a direct target of miR-612, through which the epithelial–mesenchymal transition (EMT) and metastasis of HCC were inhibited. Our present findings reveal that miR-612 is able to suppress the stemness of HCC by reducing the number and size of tumorspheres as well as clone formation in soft agar, and to relieve drug resistance to cisplatin and 5-fluorouracil. In addition, miR-612 hampered the capacity of tumorigenesis in NOD/SCID mice and redistributed the tumor invasive frontier of miR-612-modulating cells. Finally, our findings suggest that Wnt/β-catenin signaling is required in the regulation of EMT-associated stem cell-like traits by miR-612.

  13. Salidroside Suppresses HUVECs Cell Injury Induced by Oxidative Stress through Activating the Nrf2 Signaling Pathway

    Yao Zhu

    2016-08-01

    Full Text Available Oxidative stress plays an important role in the pathogenesis of cardiovascular diseases. Salidroside (SAL, one of the main effective constituents of Rhodiola rosea, has been reported to suppress oxidative stress-induced cardiomyocyte injury and necrosis by promoting transcription of nuclear factor E2-related factor 2 (Nrf2-regulated genes such as heme oxygenase-1 (HO-1 and NAD(PH dehydrogenase (quinone1 (NQO1. However, it has not been indicated whether SAL might ameliorate endothelial injury induced by oxidative stress. Here, our study demonstrated that SAL might suppress HUVEC cell injury induced by oxidative stress through activating the Nrf2 signaling pathway. The results of our study indicated that SAL decreased the levels of intercellular reactive oxygen species (ROS and malondialdehyde (MDA, and improved the activities of superoxide dismutase (SOD and catalase (CAT, resulting in protective effects against oxidative stress-induced cell damage in HUVECs. It suppressed oxidative stress damage by inducing Nrf2 nuclear translocation and activating the expression of Nrf2-regulated antioxidant enzyme genes such as HO-1 and NQO1 in HUVECs. Knockdown of Nrf2 with siRNA abolished the cytoprotective effects against oxidative stress, decreased the expression of Nrf2, HO-1, and NQO1, and inhibited the nucleus translocation of Nrf2 in HUVECs. This study is the first to demonstrate that SAL suppresses HUVECs cell injury induced by oxidative stress through activating the Nrf2 signaling pathway.

  14. MicroRNA-145 suppresses hepatocellular carcinoma by targeting IRS1 and its downstream Akt signaling

    Wang, Yelin [Department of Anesthesiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou (China); Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou (China); Hu, Chen; Cheng, Jun [Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou (China); Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou (China); Chen, Binquan [Department of Anesthesiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou (China); Ke, Qinghong; Lv, Zhen; Wu, Jian [Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou (China); Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou (China); Zhou, Yanfeng, E-mail: zyfhdj@yahoo.com [Department of Anesthesiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou (China)

    2014-04-18

    Highlights: • MiR-145 expression is down-regulated in HCC tissues and inversely related with IRS1 levels. • MiR-145 directly targets IRS1 in HCC cells. • Restored expression of miR-145 suppressed HCC cell proliferation and growth. • MiR-145 induced IRS1 under-expression potentially reduced downstream AKT signaling. - Abstract: Accumulating evidences have proved that dysregulation of microRNAs (miRNAs) is involved in cancer initiation and progression. In this study, we showed that miRNA-145 level was significantly decreased in hepatocellular cancer (HCC) tissues and cell lines, and its low expression was inversely associated with the abundance of insulin receptor substrate 1 (IRS1), a key mediator in oncogenic insulin-like growth factor (IGF) signaling. We verified IRS1 as a direct target of miR-145 using Western blotting and luciferase reporter assay. Further, the restoration of miR-145 in HCC cell lines suppressed cancer cell growth, owing to down-regulated IRS1 expression and its downstream Akt/FOXO1 signaling. Our results demonstrated that miR-145 could inhibit HCC through targeting IRS1 and its downstream signaling, implicating the loss of miR-145 regulation may be a potential molecular mechanism causing aberrant oncogenic signaling in HCC.

  15. Pulsed arterial spin labeling using TurboFLASH with suppression of intravascular signal.

    Pell, Gaby S; Lewis, David P; Branch, Craig A

    2003-02-01

    Accurate quantification of perfusion with the ADC techniques requires the suppression of the majority of the intravascular signal. This is normally achieved with the use of diffusion gradients. The TurboFLASH sequence with its ultrashort repetition times is not readily amenable to this scheme. This report demonstrates the implementation of a modified TurboFLASH sequence for FAIR imaging. Intravascular suppression is achieved with a modified preparation period that includes a driven equilibrium Fourier transform (DEFT) combination of 90 degrees-180 degrees-90 degrees hard RF pulses subsequent to the inversion delay. These pulses rotate the perfusion-prepared magnetization into the transverse plane where it can experience the suitably placed diffusion gradients before being returned to the longitudinal direction by the second 90 degrees pulse. A value of b = 20-30 s/mm(2) was thereby found to suppress the majority of the intravascular signal. For single-slice perfusion imaging, quantification is only slightly modified. The technique can be readily extended to multislice acquisition if the evolving flow signal after the DEFT preparation is considered. An advantage of the modified preparation scheme is evident in the multislice FAIR images by the preservation of the sign of the magnetization difference. Copyright 2003 Wiley-Liss, Inc.

  16. Autonomous rexinoid death signaling is suppressed by converging signaling pathways in immature leukemia cells.

    Benoit, G R; Flexor, M; Besançon, F; Altucci, L; Rossin, A; Hillion, J; Balajthy, Z; Legres, L; Ségal-Bendirdjian, E; Gronemeyer, H; Lanotte, M

    2001-07-01

    On their own, retinoid X receptor (RXR)-selective ligands (rexinoids) are silent in retinoic acid receptor (RAR)-RXR heterodimers, and no selective rexinoid program has been described as yet in cellular systems. We report here on the rexinoid signaling capacity that triggers apoptosis of immature promyelocytic NB4 cells as a default pathway in the absence of survival factors. Rexinoid-induced apoptosis displays all features of bona fide programmed cell death and is inhibited by RXR, but not RAR antagonists. Several types of survival signals block rexinoid-induced apoptosis. RARalpha agonists switch the cellular response toward differentiation and induce the expression of antiapoptosis factors. Activation of the protein kinase A pathway in the presence of rexinoid agonists induces maturation and blocks immature cell apoptosis. Addition of nonretinoid serum factors also blocks cell death but does not induce cell differentiation. Rexinoid-induced apoptosis is linked to neither the presence nor stability of the promyelocytic leukemia-RARalpha fusion protein and operates also in non-acute promyelocytic leukemia cells. Together our results support a model according to which rexinoids activate in certain leukemia cells a default death pathway onto which several other signaling paradigms converge. This pathway is entirely distinct from that triggered by RAR agonists, which control cell maturation and postmaturation apoptosis.

  17. Curcumol suppresses RANKL-induced osteoclast formation by attenuating the JNK signaling pathway

    Yu, Mingxiang; Chen, Xianying; Lv, Chaoyang; Yi, Xilu; Zhang, Yao; Xue, Mengjuan; He, Shunmei; Zhu, Guoying; Wang, Hongfu

    2014-01-01

    Highlights: • Curcumol suppresses osteoclasts differentiation in vitro. • Curcumol impairs JNK/AP-1 signaling pathway. • Curcumol may be used for treating osteoclast related diseases. - Abstract: Osteoclasts, derived from hemopoietic progenitors of the monocyte/macrophage lineage, have a unique role in bone resorption, and are considered a potential therapeutic target in the treatment of such pathologic bone diseases as osteoporosis, rheumatoid arthritis, and periodontitis. In the present study, we demonstrate that curcumol, one of the major components of the essential oil of Rhizoma Curcumae, exhibits an inhibitory effect on receptor activator of nuclear factor kappaB ligand (RANKL)-induced osteoclast differentiation with both bone marrow-derived macrophages and RAW264.7 cells in a dose-dependent manner. In addition, RANKL-induced mRNA expression of osteoclast-specific genes, such as tartrate-resistant acid phosphatase, calcitonin receptor, and cathepsin K, is prominently reduced in the presence of curcumol. Furthermore, the molecular mechanism of action was investigated, and curcumol inhibited osteoclastogenesis by specifically impairing RANKL-induced c-Jun N-terminal kinase (JNK)/activator protein-1 (AP-1) signaling, which was further identified in rescue studies by means of anisomycin, a JNK signaling-specific activator. Taken together, these findings suggest that curcumol suppresses RANKL-induced osteoclast differentiation through the JNK/AP-1 signaling pathway, and may be useful as a therapeutic treatment for bone resorption-associated diseases

  18. Curcumol suppresses RANKL-induced osteoclast formation by attenuating the JNK signaling pathway

    Yu, Mingxiang, E-mail: yu.mingxiang@zs-hospital.sh.cn [Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai (China); Chen, Xianying [Department of Endocrinology and Metabolism, Hainan Provincial Nong Ken Hospital, Hainan (China); Lv, Chaoyang [Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai (China); Yi, Xilu [Department of Endocrinology and Metabolism, Shanghai Songjiang District Central Hospital, Shanghai (China); Zhang, Yao; Xue, Mengjuan; He, Shunmei [Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai (China); Zhu, Guoying [Institute of Radiation Medicine, Fudan University, Shanghai (China); Wang, Hongfu, E-mail: hfwang@shmu.edu.cn [Institute of Radiation Medicine, Fudan University, Shanghai (China)

    2014-05-02

    Highlights: • Curcumol suppresses osteoclasts differentiation in vitro. • Curcumol impairs JNK/AP-1 signaling pathway. • Curcumol may be used for treating osteoclast related diseases. - Abstract: Osteoclasts, derived from hemopoietic progenitors of the monocyte/macrophage lineage, have a unique role in bone resorption, and are considered a potential therapeutic target in the treatment of such pathologic bone diseases as osteoporosis, rheumatoid arthritis, and periodontitis. In the present study, we demonstrate that curcumol, one of the major components of the essential oil of Rhizoma Curcumae, exhibits an inhibitory effect on receptor activator of nuclear factor kappaB ligand (RANKL)-induced osteoclast differentiation with both bone marrow-derived macrophages and RAW264.7 cells in a dose-dependent manner. In addition, RANKL-induced mRNA expression of osteoclast-specific genes, such as tartrate-resistant acid phosphatase, calcitonin receptor, and cathepsin K, is prominently reduced in the presence of curcumol. Furthermore, the molecular mechanism of action was investigated, and curcumol inhibited osteoclastogenesis by specifically impairing RANKL-induced c-Jun N-terminal kinase (JNK)/activator protein-1 (AP-1) signaling, which was further identified in rescue studies by means of anisomycin, a JNK signaling-specific activator. Taken together, these findings suggest that curcumol suppresses RANKL-induced osteoclast differentiation through the JNK/AP-1 signaling pathway, and may be useful as a therapeutic treatment for bone resorption-associated diseases.

  19. mTOR signaling promotes foam cell formation and inhibits foam cell egress through suppressing the SIRT1 signaling pathway.

    Zheng, Haixiang; Fu, Yucai; Huang, Yusheng; Zheng, Xinde; Yu, Wei; Wang, Wei

    2017-09-01

    Atherosclerosis (AS) is a chronic immuno‑inflammatory disease accompanied by dyslipidemia. The authors previously demonstrated that sirtuin 1 (SIRT1) may prevent atherogenesis through influencing the liver X receptor/C‑C chemokine receptor type 7/nuclear factor‑κB (LXR‑CCR7/NF‑κB) signaling pathway. Previous studies have suggested a role for mammalian target of rapamycin (mTOR) signaling in the pathogenesis of cardiovascular diseases. The present study investigated the potential association between mTOR signaling and SIRT1‑LXR‑CCR7/NF‑κB signaling (SIRT1 signaling) in AS pathogenesis. To induce foam cell formation, U937 cells were differentiated into macrophages by exposure to phorbol 12‑myristate 13‑acetate (PMA) for 24 h, followed by treatment with palmitate and oxidized low density lipoprotein for a further 24 h. Oil red O staining revealed a large accumulation of lipid droplets present in foam cells. Western blot analysis demonstrated increased protein levels of phosphorylated (p)‑mTOR and its downstream factor p‑ribosomal protein S6 kinase (p70S6K). Reverse transcription‑quantitative polymerase chain reaction and western blot analyses additionally revealed decreased expression of SIRT1, LXRα and CCR7 and increased expression of NF‑κB and its downstream factor tumor necrosis factor‑α (TNF‑α) in an atherogenetic condition induced by lysophosphatidic acid (LPA). In addition, abundant lipid droplets accumulated in U937‑LPA‑treated foam cells. Rapamycin, an mTOR inhibitor, suppressed the expression and activity of mTOR and p70S6K, however enhanced expression of SIRT1, LXRα, and CCR7. Conversely, rapamycin deceased TNF‑α and NF‑κB activity, the latter of which was further confirmed by immunofluorescence analysis demonstrating increased levels of NF‑κB present in the cytoplasm compared with the nucleus. The findings of the present study suggest that mTOR signaling promotes foam cell formation and inhibits foam

  20. Diphlorethohydroxycarmalol from Ishige okamurae Suppresses Osteoclast Differentiation by Downregulating the NF-κB Signaling Pathway

    Hye Jung Ihn

    2017-12-01

    Full Text Available Marine algae possess a variety of beneficial effects on human health. In this study, we investigated whether diphlorethohydroxycarmalol (DPHC, isolated from Ishige okamurae, a brown alga, suppresses receptor activator of nuclear factor-κB ligand (RANKL-induced osteoclast differentiation. DPHC significantly suppressed RANKL-induced osteoclast differentiation and macrophage-colony stimulating factor (M-CSF expression in a dose-dependent manner. In addition, it significantly inhibited actin ring formation, the expression of osteoclast marker genes, such as tartrate-resistant acid phosphatase (TRAP, nuclear factor of activated T-cells cytoplasmic 1 (Nfatc1, cathepsin K (Ctsk, and dendritic cell-specific transmembrane protein (Dcstamp, and osteoclast-induced bone resorption. Analysis of the RANKL-mediated signaling pathway showed that the phosphorylation of both IκB and p65 was specifically inhibited by DPHC. These results suggest that DPHC substantially suppresses osteoclastogenesis by downregulating the RANK-NF-κB signaling pathway. Thus, it holds significant potential for the treatment of skeletal diseases associated with an enhanced osteoclast activity.

  1. Procyanidins Mitigate Osteoarthritis Pathogenesis by, at Least in Part, Suppressing Vascular Endothelial Growth Factor Signaling

    Angela Wang

    2016-12-01

    Full Text Available Procyanidins are a family of plant metabolites that have been suggested to mitigate osteoarthritis pathogenesis in mice. However, the underlying mechanism is largely unknown. This study aimed to determine whether procyanidins mitigate traumatic injury-induced osteoarthritis (OA disease progression, and whether procyanidins exert a chondroprotective effect by, at least in part, suppressing vascular endothelial growth factor signaling. Procyanidins (extracts from pine bark, orally administered to mice subjected to surgery for destabilization of the medial meniscus, significantly slowed OA disease progression. Real-time polymerase chain reaction revealed that procyanidin treatment reduced expression of vascular endothelial growth factor and effectors in OA pathogenesis that are regulated by vascular endothelial growth factor. Procyanidin-suppressed vascular endothelial growth factor expression was correlated with reduced phosphorylation of vascular endothelial growth factor receptor 2 in human OA primary chondrocytes. Moreover, components of procyanidins, procyanidin B2 and procyanidin B3 exerted effects similar to those of total procyanidins in mitigating the OA-related gene expression profile in the primary culture of human OA chondrocytes in the presence of vascular endothelial growth factor. Together, these findings suggest procyanidins mitigate OA pathogenesis, which is mediated, at least in part, by suppressing vascular endothelial growth factor signaling.

  2. Sangivamycin induces apoptosis by suppressing Erk signaling in primary effusion lymphoma cells

    Wakao, Kazufumi [Department of Biotechnology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Kofu-shi 400-8511 (Japan); Watanabe, Tadashi [Department of Cell Biology, Kyoto Pharmaceutical University, Misasagi-Shichonocho 1, Yamashinaku, Kyoto 607-8412 (Japan); Takadama, Tadatoshi; Ui, Sadaharu [Department of Biotechnology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Kofu-shi 400-8511 (Japan); Shigemi, Zenpei; Kagawa, Hiroki [Department of Cell Biology, Kyoto Pharmaceutical University, Misasagi-Shichonocho 1, Yamashinaku, Kyoto 607-8412 (Japan); Higashi, Chizuka; Ohga, Rie; Taira, Takahiro [Department of Molecular Cell Biology, Faculty of Medicine, University of Yamanashi, Chuoh-shi 409-3898 (Japan); Fujimuro, Masahiro, E-mail: fuji2@mb.kyoto-phu.ac.jp [Department of Cell Biology, Kyoto Pharmaceutical University, Misasagi-Shichonocho 1, Yamashinaku, Kyoto 607-8412 (Japan)

    2014-02-07

    Highlights: • Sangivamycin induces the apoptosis of B cell lymphoma PEL cells. • Sangivamycin suppresses Erk signaling by inhibiting Erk phosphorylation in PEL cells. • The activation of Erk signaling is essential for PEL cell survival. • Sangivamycin induces the apoptosis of PEL cells without production of progeny virus. • Sangivamycin may serve as a novel drug for the treatment of PEL. - Abstract: Sangivamycin, a structural analog of adenosine and antibiotic exhibiting antitumor and antivirus activities, inhibits protein kinase C and the synthesis of both DNA and RNA. Primary effusion lymphoma (PEL) is an aggressive neoplasm caused by Kaposi’s sarcoma-associated herpesvirus (KSHV) in immunosuppressed patients and HIV-infected homosexual males. PEL cells are derived from post-germinal center B cells, and are infected with KSHV. Herein, we asked if sangivamycin might be useful to treat PEL. We found that sangivamycin killed PEL cells, and we explored the underlying mechanism. Sangivamycin treatment drastically decreased the viability of PEL cell lines compared to KSHV-uninfected B lymphoma cell lines. Sangivamycin induced the apoptosis of PEL cells by activating caspase-7 and -9. Further, sangivamycin suppressed the phosphorylation of Erk1/2 and Akt, thus inhibiting activation of the proteins. Inhibitors of Akt and MEK suppressed the proliferation of PEL cells compared to KSHV-uninfected cells. It is known that activation of Erk and Akt signaling inhibits apoptosis and promotes proliferation in PEL cells. Our data therefore suggest that sangivamycin induces apoptosis by inhibiting Erk and Akt signaling in such cells. We next investigated whether sangivamycin, in combination with an HSP90 inhibitor geldanamycin (GA) or valproate (valproic acid), potentiated the cytotoxic effects of the latter drugs on PEL cells. Compared to treatment with GA or valproate alone, the addition of sangivamycin enhanced cytotoxic activity. Our data thus indicate that

  3. Sangivamycin induces apoptosis by suppressing Erk signaling in primary effusion lymphoma cells

    Wakao, Kazufumi; Watanabe, Tadashi; Takadama, Tadatoshi; Ui, Sadaharu; Shigemi, Zenpei; Kagawa, Hiroki; Higashi, Chizuka; Ohga, Rie; Taira, Takahiro; Fujimuro, Masahiro

    2014-01-01

    Highlights: • Sangivamycin induces the apoptosis of B cell lymphoma PEL cells. • Sangivamycin suppresses Erk signaling by inhibiting Erk phosphorylation in PEL cells. • The activation of Erk signaling is essential for PEL cell survival. • Sangivamycin induces the apoptosis of PEL cells without production of progeny virus. • Sangivamycin may serve as a novel drug for the treatment of PEL. - Abstract: Sangivamycin, a structural analog of adenosine and antibiotic exhibiting antitumor and antivirus activities, inhibits protein kinase C and the synthesis of both DNA and RNA. Primary effusion lymphoma (PEL) is an aggressive neoplasm caused by Kaposi’s sarcoma-associated herpesvirus (KSHV) in immunosuppressed patients and HIV-infected homosexual males. PEL cells are derived from post-germinal center B cells, and are infected with KSHV. Herein, we asked if sangivamycin might be useful to treat PEL. We found that sangivamycin killed PEL cells, and we explored the underlying mechanism. Sangivamycin treatment drastically decreased the viability of PEL cell lines compared to KSHV-uninfected B lymphoma cell lines. Sangivamycin induced the apoptosis of PEL cells by activating caspase-7 and -9. Further, sangivamycin suppressed the phosphorylation of Erk1/2 and Akt, thus inhibiting activation of the proteins. Inhibitors of Akt and MEK suppressed the proliferation of PEL cells compared to KSHV-uninfected cells. It is known that activation of Erk and Akt signaling inhibits apoptosis and promotes proliferation in PEL cells. Our data therefore suggest that sangivamycin induces apoptosis by inhibiting Erk and Akt signaling in such cells. We next investigated whether sangivamycin, in combination with an HSP90 inhibitor geldanamycin (GA) or valproate (valproic acid), potentiated the cytotoxic effects of the latter drugs on PEL cells. Compared to treatment with GA or valproate alone, the addition of sangivamycin enhanced cytotoxic activity. Our data thus indicate that

  4. Efficacy of Mesenchymal Stem Cells in Suppression of Hepatocarcinorigenesis in Rats: Possible Role of Wnt Signaling

    Abdel Aziz, Mohamed T

    2011-05-05

    Abstract Background The present study was conducted to evaluate the tumor suppressive effects of bone marrow derived mesenchymal stem cells (MSCs) in an experimental hepatocellular carcinoma (HCC) model in rats and to investigate the possible role of Wnt signaling in hepato-carcinogenesis. Methods Ninety rats were included in the study and were divided equally into: Control group, rats which received MSCs only, rats which received MSCs vehicle only, HCC group induced by diethylnitroseamine (DENA) and CCl 4 , rats which received MSCs after HCC induction, rats which received MSCs before HCC induction. Histopathological examination and gene expression of Wnt signaling target genes by real time, reverse transcription-polymerase chain reaction (RT-PCR) in rat liver tissue, in addition to serum levels of ALT, AST and alpha fetoprotein were performed in all groups. Results Histopathological examination of liver tissue from animals which received DENA-CCl4 only, revealed the presence of anaplastic carcinoma cells and macro-regenerative nodules type II with foci of large and small cell dysplasia. Administration of MSCs into rats after induction of experimental HCC improved the histopathological picture which showed minimal liver cell damage, reversible changes, areas of cell drop out filled with stem cells. Gene expression in rat liver tissue demonstrated that MSCs downregulated β-catenin, proliferating cell nuclear antigen (PCNA), cyclin D and survivin genes expression in liver tissues after HCC induction. Amelioration of the liver status after administration of MSCs has been inferred by the significant decrease of ALT, AST and Alpha fetoprotein serum levels. Administration of MSCs before HCC induction did not show any tumor suppressive or protective effect. Conclusions Administration of MSCs in chemically induced HCC has tumor suppressive effects as evidenced by down regulation of Wnt signaling target genes concerned with antiapoptosis, mitogenesis, cell proliferation

  5. A paradoxical signal intensity increase in fatty livers using opposed-phase gradient echo imaging with fat-suppression pulses

    Mulkern, Robert V.; Voss, Stephan; Loeb Salsberg, Sandra; Krauel, Marta Ramon; Ludwig, David S.

    2008-01-01

    With the increase in obese and overweight children, nonalcoholic fatty liver disease has become more prevalent in the pediatric population. Appreciating subtleties of magnetic resonance (MR) signal intensity behavior from fatty livers under different imaging conditions thus becomes important to pediatric radiologists. We report an initially confusing signal behavior - increased signal from fatty livers when fat-suppression pulses are applied in an opposed-phase gradient echo imaging sequence - and seek to explain the physical mechanisms for this paradoxical signal intensity behavior. Abdominal MR imaging at 3 T with a 3-D volumetric interpolated breath-hold (VIBE) sequence in the opposed-phase condition (TR/TE 3.3/1.3 ms) was performed in five obese boys (14±2 years of age, body mass index >95th percentile for age and sex) with spectroscopically confirmed fatty livers. Two VIBE acquisitions were performed, one with and one without the use of chemical shift selective (CHESS) pulse fat suppression. The ratios of fat-suppressed over non-fat-suppressed signal intensities were assessed in regions-of-interest (ROIs) in five tissues: subcutaneous fat, liver, vertebral marrow, muscle and spleen. The boys had spectroscopically estimated hepatic fat levels between 17% and 48%. CHESS pulse fat suppression decreased subcutaneous fat signals dramatically, by more than 85% within regions of optimal fat suppression. Fatty liver signals, in contrast, were elevated by an average of 87% with CHESS pulse fat suppression. Vertebral marrow signal was also significantly elevated with CHESS pulse fat suppression, while spleen and muscle signals demonstrated only small signal increases on the order of 10%. We demonstrated that CHESS pulse fat suppression actually increases the signal intensity from fatty livers in opposed-phase gradient echo imaging conditions. The increase can be attributed to suppression of one partner of the opposed-phase pair that normally contributes to the

  6. A paradoxical signal intensity increase in fatty livers using opposed-phase gradient echo imaging with fat-suppression pulses

    Mulkern, Robert V.; Voss, Stephan [Harvard Medical School, Department of Radiology, Children' s Hospital Boston, Boston, MA (United States); Loeb Salsberg, Sandra; Krauel, Marta Ramon; Ludwig, David S. [Harvard Medical School, Department of Medicine, Children' s Hospital Boston, Boston, MA (United States)

    2008-10-15

    With the increase in obese and overweight children, nonalcoholic fatty liver disease has become more prevalent in the pediatric population. Appreciating subtleties of magnetic resonance (MR) signal intensity behavior from fatty livers under different imaging conditions thus becomes important to pediatric radiologists. We report an initially confusing signal behavior - increased signal from fatty livers when fat-suppression pulses are applied in an opposed-phase gradient echo imaging sequence - and seek to explain the physical mechanisms for this paradoxical signal intensity behavior. Abdominal MR imaging at 3 T with a 3-D volumetric interpolated breath-hold (VIBE) sequence in the opposed-phase condition (TR/TE 3.3/1.3 ms) was performed in five obese boys (14{+-}2 years of age, body mass index >95th percentile for age and sex) with spectroscopically confirmed fatty livers. Two VIBE acquisitions were performed, one with and one without the use of chemical shift selective (CHESS) pulse fat suppression. The ratios of fat-suppressed over non-fat-suppressed signal intensities were assessed in regions-of-interest (ROIs) in five tissues: subcutaneous fat, liver, vertebral marrow, muscle and spleen. The boys had spectroscopically estimated hepatic fat levels between 17% and 48%. CHESS pulse fat suppression decreased subcutaneous fat signals dramatically, by more than 85% within regions of optimal fat suppression. Fatty liver signals, in contrast, were elevated by an average of 87% with CHESS pulse fat suppression. Vertebral marrow signal was also significantly elevated with CHESS pulse fat suppression, while spleen and muscle signals demonstrated only small signal increases on the order of 10%. We demonstrated that CHESS pulse fat suppression actually increases the signal intensity from fatty livers in opposed-phase gradient echo imaging conditions. The increase can be attributed to suppression of one partner of the opposed-phase pair that normally contributes to the

  7. BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling.

    He, Xi C; Zhang, Jiwang; Tong, Wei-Gang; Tawfik, Ossama; Ross, Jason; Scoville, David H; Tian, Qiang; Zeng, Xin; He, Xi; Wiedemann, Leanne M; Mishina, Yuji; Li, Linheng

    2004-10-01

    In humans, mutations in BMPR1A, SMAD4 and PTEN are responsible for juvenile polyposis syndrome, juvenile intestinal polyposis and Cowden disease, respectively. The development of polyposis is a common feature of these diseases, suggesting that there is an association between BMP and PTEN pathways. The mechanistic link between BMP and PTEN pathways and the related etiology of juvenile polyposis is unresolved. Here we show that conditional inactivation of Bmpr1a in mice disturbs homeostasis of intestinal epithelial regeneration with an expansion of the stem and progenitor cell populations, eventually leading to intestinal polyposis resembling human juvenile polyposis syndrome. We show that BMP signaling suppresses Wnt signaling to ensure a balanced control of stem cell self-renewal. Mechanistically, PTEN, through phosphatidylinosital-3 kinase-Akt, mediates the convergence of the BMP and Wnt pathways on control of beta-catenin. Thus, BMP signaling may control the duplication of intestinal stem cells, thereby preventing crypt fission and the subsequent increase in crypt number.

  8. Simultaneous transmission of wired and wireless signals based on double sideband carrier suppression

    Bitew, Mekuanint Agegnehu; Shiu, Run-Kai; Peng, Peng-Chun; Wang, Cheng-Hao; Chen, Yan-Ming

    2017-11-01

    In this paper, we proposed and experimentally demonstrated simultaneous transmission of wired and wireless signals based on double sideband optical carrier suppression. By properly adjusting the bias point of the dual-output mach-zehnder modulator (MZM), a central carrier in one output port and a pair of first-order sidebands in another output port are generated. The pair of first-order sidebands are fed into a second MZM to generate second-order order sidebands. A wired signal is embedded on the central carrier while a wireless signal is embedded on the second-order sidebands. Unlike other schemes, we did not use optical filter to separate the carrier from the optical sidebands. The measured bit error rate (BER) and eye-diagrams after a 25 km single-mode-fiber (SMF) transmission proved that the proposed scheme is successful for both wired and wireless signals transmission. Moreover, the power penalty at the BER of 10-9 is 0.3 and 0.7 dB for wired and wireless signals, respectively.

  9. Suppression of Quasiparticle Scattering Signals in Bilayer Graphene Due to Layer Polarization and Destructive Interference.

    Jolie, Wouter; Lux, Jonathan; Pörtner, Mathias; Dombrowski, Daniela; Herbig, Charlotte; Knispel, Timo; Simon, Sabina; Michely, Thomas; Rosch, Achim; Busse, Carsten

    2018-03-09

    We study chemically gated bilayer graphene using scanning tunneling microscopy and spectroscopy complemented by tight-binding calculations. Gating is achieved by intercalating Cs between bilayer graphene and Ir(111), thereby shifting the conduction band minima below the chemical potential. Scattering between electronic states (both intraband and interband) is detected via quasiparticle interference. However, not all expected processes are visible in our experiment. We uncover two general effects causing this suppression: first, intercalation leads to an asymmetrical distribution of the states within the two layers, which significantly reduces the scanning tunneling spectroscopy signal of standing waves mainly present in the lower layer; second, forward scattering processes, connecting points on the constant energy contours with parallel velocities, do not produce pronounced standing waves due to destructive interference. We present a theory to describe the interference signal for a general n-band material.

  10. Suppression of Quasiparticle Scattering Signals in Bilayer Graphene Due to Layer Polarization and Destructive Interference

    Jolie, Wouter; Lux, Jonathan; Pörtner, Mathias; Dombrowski, Daniela; Herbig, Charlotte; Knispel, Timo; Simon, Sabina; Michely, Thomas; Rosch, Achim; Busse, Carsten

    2018-03-01

    We study chemically gated bilayer graphene using scanning tunneling microscopy and spectroscopy complemented by tight-binding calculations. Gating is achieved by intercalating Cs between bilayer graphene and Ir(111), thereby shifting the conduction band minima below the chemical potential. Scattering between electronic states (both intraband and interband) is detected via quasiparticle interference. However, not all expected processes are visible in our experiment. We uncover two general effects causing this suppression: first, intercalation leads to an asymmetrical distribution of the states within the two layers, which significantly reduces the scanning tunneling spectroscopy signal of standing waves mainly present in the lower layer; second, forward scattering processes, connecting points on the constant energy contours with parallel velocities, do not produce pronounced standing waves due to destructive interference. We present a theory to describe the interference signal for a general n -band material.

  11. Suppression of AC railway power-line interference in ECG signals recorded by public access defibrillators

    Dotsinsky Ivan

    2005-11-01

    Full Text Available Abstract Background Public access defibrillators (PADs are now available for more efficient and rapid treatment of out-of-hospital sudden cardiac arrest. PADs are used normally by untrained people on the streets and in sports centers, airports, and other public areas. Therefore, automated detection of ventricular fibrillation, or its exclusion, is of high importance. A special case exists at railway stations, where electric power-line frequency interference is significant. Many countries, especially in Europe, use 16.7 Hz AC power, which introduces high level frequency-varying interference that may compromise fibrillation detection. Method Moving signal averaging is often used for 50/60 Hz interference suppression if its effect on the ECG spectrum has little importance (no morphological analysis is performed. This approach may be also applied to the railway situation, if the interference frequency is continuously detected so as to synchronize the analog-to-digital conversion (ADC for introducing variable inter-sample intervals. A better solution consists of rated ADC, software frequency measuring, internal irregular re-sampling according to the interference frequency, and a moving average over a constant sample number, followed by regular back re-sampling. Results The proposed method leads to a total railway interference cancellation, together with suppression of inherent noise, while the peak amplitudes of some sharp complexes are reduced. This reduction has negligible effect on accurate fibrillation detection. Conclusion The method is developed in the MATLAB environment and represents a useful tool for real time railway interference suppression.

  12. Suppression of AC railway power-line interference in ECG signals recorded by public access defibrillators.

    Dotsinsky, Ivan

    2005-11-26

    Public access defibrillators (PADs) are now available for more efficient and rapid treatment of out-of-hospital sudden cardiac arrest. PADs are used normally by untrained people on the streets and in sports centers, airports, and other public areas. Therefore, automated detection of ventricular fibrillation, or its exclusion, is of high importance. A special case exists at railway stations, where electric power-line frequency interference is significant. Many countries, especially in Europe, use 16.7 Hz AC power, which introduces high level frequency-varying interference that may compromise fibrillation detection. Moving signal averaging is often used for 50/60 Hz interference suppression if its effect on the ECG spectrum has little importance (no morphological analysis is performed). This approach may be also applied to the railway situation, if the interference frequency is continuously detected so as to synchronize the analog-to-digital conversion (ADC) for introducing variable inter-sample intervals. A better solution consists of rated ADC, software frequency measuring, internal irregular re-sampling according to the interference frequency, and a moving average over a constant sample number, followed by regular back re-sampling. The proposed method leads to a total railway interference cancellation, together with suppression of inherent noise, while the peak amplitudes of some sharp complexes are reduced. This reduction has negligible effect on accurate fibrillation detection. The method is developed in the MATLAB environment and represents a useful tool for real time railway interference suppression.

  13. Piperlongumine inhibits atherosclerotic plaque formation and vascular smooth muscle cell proliferation by suppressing PDGF receptor signaling

    Son, Dong Ju [Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA (United States); Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA (United States); Kim, Soo Yeon [Division of Life Science, Korea Basic Science Institute, Daejeon (Korea, Republic of); Han, Seong Su [University of Iowa Carver College of Medicine, Department of Pathology, Iowa City, IA (United States); Kim, Chan Woo [Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA (United States); Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA (United States); Department of Bioinspired Science, Ehwa Womans University, Seoul (Korea, Republic of); Kumar, Sandeep [Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA (United States); Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA (United States); Park, Byeoung Soo [Nanotoxtech Co., Ansan (Korea, Republic of); Lee, Sung Eun [Division of Applied Biology and Chemistry, Kyungpook National University, Daegu (Korea, Republic of); Yun, Yeo Pyo [College of Pharmacy, Chungbuk National University, Cheongju (Korea, Republic of); Jo, Hanjoong, E-mail: hjo@emory.edu [Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA (United States); Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA (United States); Department of Bioinspired Science, Ehwa Womans University, Seoul (Korea, Republic of); Park, Young Hyun, E-mail: pyh012@sch.ac.kr [Department of Food Science and Nutrition, College of Natural Sciences, Soonchunhyang University, Asan (Korea, Republic of)

    2012-10-19

    Highlights: Black-Right-Pointing-Pointer Anti-atherogenic effect of PL was examined using partial carotid ligation model in ApoE KO mice. Black-Right-Pointing-Pointer PL prevented atherosclerotic plaque development, VSMCs proliferation, and NF-{kappa}B activation. Black-Right-Pointing-Pointer Piperlongumine reduced vascular smooth muscle cell activation through PDGF-R{beta} and NF-{kappa}B-signaling. Black-Right-Pointing-Pointer PL may serve as a new therapeutic molecule for atherosclerosis treatment. -- Abstract: Piperlongumine (piplartine, PL) is an alkaloid found in the long pepper (Piper longum L.) and has well-documented anti-platelet aggregation, anti-inflammatory, and anti-cancer properties; however, the role of PL in prevention of atherosclerosis is unknown. We evaluated the anti-atherosclerotic potential of PL in an in vivo murine model of accelerated atherosclerosis and defined its mechanism of action in aortic vascular smooth muscle cells (VSMCs) in vitro. Local treatment with PL significantly reduced atherosclerotic plaque formation as well as proliferation and nuclear factor-kappa B (NF-{kappa}B) activation in an in vivo setting. PL treatment in VSMCs in vitro showed inhibition of migration and platelet-derived growth factor BB (PDGF-BB)-induced proliferation to the in vivo findings. We further identified that PL inhibited PDGF-BB-induced PDGF receptor beta activation and suppressed downstream signaling molecules such as phospholipase C{gamma}1, extracellular signal-regulated kinases 1 and 2 and Akt. Lastly, PL significantly attenuated activation of NF-{kappa}B-a downstream transcriptional regulator in PDGF receptor signaling, in response to PDGF-BB stimulation. In conclusion, our findings demonstrate a novel, therapeutic mechanism by which PL suppresses atherosclerosis plaque formation in vivo.

  14. Andrographolide suppresses TRIF-dependent signaling of toll-like receptors by targeting TBK1.

    Kim, Ah-Yeon; Shim, Hyun-Jin; Shin, Hyeon-Myeong; Lee, Yoo Jung; Nam, Hyeonjeong; Kim, Su Yeon; Youn, Hyung-Sun

    2018-04-01

    Toll-like receptors (TLRs) play a crucial role in danger recognition and induction of innate immune response against bacterial and viral infections. The TLR adaptor molecule, toll-interleukin-1 receptor domain-containing adapter inducing interferon-β (TRIF), facilitates TLR3 and TLR4 signaling, leading to the activation of the transcription factor, NF-κB and interferon regulatory factor 3 (IRF3). Andrographolide, the active component of Andrographis paniculata, exerts anti-inflammatory effects; however, the principal molecular mechanisms remain unclear. The objective of this study was to investigate the role of andrographolide in TLR signaling pathways. Andrographolide suppressed NF-κB activation as well as COX-2 expression induced by TLR3 or TLR4 agonists. Andrographolide also suppressed the activation of IRF3 and the expression of interferon inducible protein-10 (IP-10) induced by TLR3 or TLR4 agonists. Andrographolide attenuated ligand-independent activation of IRF3 following overexpression of TRIF, TBK1, or IRF3. Furthermore, andrographolide inhibited TBK1 kinase activity in vitro. These results indicate that andrographolide modulates the TRIF-dependent pathway of TLRs by targeting TBK1 and represents a potential new anti-inflammatory candidate. Copyright © 2018 Elsevier B.V. All rights reserved.

  15. Dectin-1 Regulates Hepatic Fibrosis and Hepatocarcinogenesis by Suppressing TLR4 Signaling Pathways

    Lena Seifert

    2015-12-01

    Full Text Available Dectin-1 is a C-type lectin receptor critical in anti-fungal immunity, but Dectin-1 has not been linked to regulation of sterile inflammation or oncogenesis. We found that Dectin-1 expression is upregulated in hepatic fibrosis and liver cancer. However, Dectin-1 deletion exacerbates liver fibro-inflammatory disease and accelerates hepatocarcinogenesis. Mechanistically, we found that Dectin-1 protects against chronic liver disease by suppressing TLR4 signaling in hepatic inflammatory and stellate cells. Accordingly, Dectin-1–/– mice exhibited augmented cytokine production and reduced survival in lipopolysaccharide (LPS-mediated sepsis, whereas Dectin-1 activation was protective. We showed that Dectin-1 inhibits TLR4 signaling by mitigating TLR4 and CD14 expression, which are regulated by Dectin-1-dependent macrophage colony stimulating factor (M-CSF expression. Our study suggests that Dectin-1 is an attractive target for experimental therapeutics in hepatic fibrosis and neoplastic transformation. More broadly, our work deciphers critical cross-talk between pattern recognition receptors and implicates a role for Dectin-1 in suppression of sterile inflammation, inflammation-induced oncogenesis, and LPS-mediated sepsis.

  16. Dectin-1 Regulates Hepatic Fibrosis and Hepatocarcinogenesis by Suppressing TLR4 Signaling Pathways.

    Seifert, Lena; Deutsch, Michael; Alothman, Sara; Alqunaibit, Dalia; Werba, Gregor; Pansari, Mridul; Pergamo, Matthew; Ochi, Atsuo; Torres-Hernandez, Alejandro; Levie, Elliot; Tippens, Daniel; Greco, Stephanie H; Tiwari, Shaun; Ly, Nancy Ngoc Giao; Eisenthal, Andrew; van Heerden, Eliza; Avanzi, Antonina; Barilla, Rocky; Zambirinis, Constantinos P; Rendon, Mauricio; Daley, Donnele; Pachter, H Leon; Hajdu, Cristina; Miller, George

    2015-12-01

    Dectin-1 is a C-type lectin receptor critical in anti-fungal immunity, but Dectin-1 has not been linked to regulation of sterile inflammation or oncogenesis. We found that Dectin-1 expression is upregulated in hepatic fibrosis and liver cancer. However, Dectin-1 deletion exacerbates liver fibro-inflammatory disease and accelerates hepatocarcinogenesis. Mechanistically, we found that Dectin-1 protects against chronic liver disease by suppressing TLR4 signaling in hepatic inflammatory and stellate cells. Accordingly, Dectin-1(-/-) mice exhibited augmented cytokine production and reduced survival in lipopolysaccharide (LPS)-mediated sepsis, whereas Dectin-1 activation was protective. We showed that Dectin-1 inhibits TLR4 signaling by mitigating TLR4 and CD14 expression, which are regulated by Dectin-1-dependent macrophage colony stimulating factor (M-CSF) expression. Our study suggests that Dectin-1 is an attractive target for experimental therapeutics in hepatic fibrosis and neoplastic transformation. More broadly, our work deciphers critical cross-talk between pattern recognition receptors and implicates a role for Dectin-1 in suppression of sterile inflammation, inflammation-induced oncogenesis, and LPS-mediated sepsis. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  17. Receptor for advanced glycation end products inhibits proliferation in osteoblast through suppression of Wnt, PI3K and ERK signaling

    Li, Guofeng; Xu, Jingren; Li, Zengchun

    2012-01-01

    Highlights: ► RAGE overexpression suppresses cell proliferation in MC3T3-E1 cells. ► RAGE overexpression decreases Wnt/β-catenin signaling. ► RAGE overexpression decreases ERK and PI3K signaling. ► Inhibition of Wnt signaling abolishes PI3K signaling restored by RAGE blockade. ► Inhibition of Wnt signaling abolishes ERK signaling restored by RAGE blockade. -- Abstract: Expression of receptor for advanced glycation end products (RAGE) plays a crucial role in bone metabolism. However, the role of RAGE in the control of osteoblast proliferation is not yet evaluated. In the present study, we demonstrate that RAGE overexpression inhibits osteoblast proliferation in vitro. The negative regulation of RAGE on cell proliferation results from suppression of Wnt, PI3K and ERK signaling, and is restored by RAGE neutralizing antibody. Prevention of Wnt signaling using Sfrp1 or DKK1 rescues RAGE-decreased PI3K and ERK signaling and cell proliferation, indicating that the altered cell growth in RAGE overexpressing cells is in part secondary to alterations in Wnt signaling. Consistently, RAGE overexpression inhibits the expression of Wnt targets cyclin D1 and c-myc, which is partially reversed by RAGE blockade. Overall, these results suggest that RAGE inhibits osteoblast proliferation via suppression of Wnt, PI3K and ERK signaling, which provides novel mechanisms by which RAGE regulates osteoblast growth.

  18. Receptor for advanced glycation end products inhibits proliferation in osteoblast through suppression of Wnt, PI3K and ERK signaling

    Li, Guofeng [Department of Emergency Surgery, East Hospital, Tongji University School of Medicine, Shanghai 200120 (China); Xu, Jingren [Department of Traditional Chinese Orthopaedics, East Hospital, Tongji University School of Medicine, Shanghai 200120 (China); Li, Zengchun, E-mail: lizc.2007@yahoo.com.cn [Department of Emergency Surgery, East Hospital, Tongji University School of Medicine, Shanghai 200120 (China)

    2012-07-13

    Highlights: Black-Right-Pointing-Pointer RAGE overexpression suppresses cell proliferation in MC3T3-E1 cells. Black-Right-Pointing-Pointer RAGE overexpression decreases Wnt/{beta}-catenin signaling. Black-Right-Pointing-Pointer RAGE overexpression decreases ERK and PI3K signaling. Black-Right-Pointing-Pointer Inhibition of Wnt signaling abolishes PI3K signaling restored by RAGE blockade. Black-Right-Pointing-Pointer Inhibition of Wnt signaling abolishes ERK signaling restored by RAGE blockade. -- Abstract: Expression of receptor for advanced glycation end products (RAGE) plays a crucial role in bone metabolism. However, the role of RAGE in the control of osteoblast proliferation is not yet evaluated. In the present study, we demonstrate that RAGE overexpression inhibits osteoblast proliferation in vitro. The negative regulation of RAGE on cell proliferation results from suppression of Wnt, PI3K and ERK signaling, and is restored by RAGE neutralizing antibody. Prevention of Wnt signaling using Sfrp1 or DKK1 rescues RAGE-decreased PI3K and ERK signaling and cell proliferation, indicating that the altered cell growth in RAGE overexpressing cells is in part secondary to alterations in Wnt signaling. Consistently, RAGE overexpression inhibits the expression of Wnt targets cyclin D1 and c-myc, which is partially reversed by RAGE blockade. Overall, these results suggest that RAGE inhibits osteoblast proliferation via suppression of Wnt, PI3K and ERK signaling, which provides novel mechanisms by which RAGE regulates osteoblast growth.

  19. Efficient retina formation requires suppression of both Activin and BMP signaling pathways in pluripotent cells

    Kimberly A. Wong

    2015-03-01

    Full Text Available Retina formation requires the correct spatiotemporal patterning of key regulatory factors. While it is known that repression of several signaling pathways lead to specification of retinal fates, addition of only Noggin, a known BMP antagonist, can convert pluripotent Xenopus laevis animal cap cells to functional retinal cells. The aim of this study is to determine the intracellular molecular events that occur during this conversion. Surprisingly, blocking BMP signaling alone failed to mimic Noggin treatment. Overexpressing Noggin in pluripotent cells resulted in a concentration-dependent suppression of both Smad1 and Smad2 phosphorylation, which act downstream of BMP and Activin signaling, respectively. This caused a decrease in downstream targets: endothelial marker, xk81, and mesodermal marker, xbra. We treated pluripotent cells with dominant-negative receptors or the chemical inhibitors, dorsomorphin and SB431542, which each target either the BMP or Activin signaling pathway. We determined the effect of these treatments on retina formation using the Animal Cap Transplant (ACT assay; in which treated pluripotent cells were transplanted into the eye field of host embryos. We found that inhibition of Activin signaling, in the presence of BMP signaling inhibition, promotes efficient retinal specification in Xenopus tissue, mimicking the affect of adding Noggin alone. In whole embryos, we found that the eye field marker, rax, expanded when adding both dominant-negative Smad1 and Smad2, as did treating the cells with both dorsomorphin and SB431542. Future studies could translate these findings to a mammalian culture assay, in order to more efficiently produce retinal cells in culture.

  20. Temporal suppression and augmentation of click-evoked otoacoustic emissions

    Verhulst, Sarah; Harte, James; Dau, Torsten

    2008-01-01

    This study investigates temporal suppression of click-evoked otoacoustic emissions (CEOAEs), occurring when a suppressor-click is presented close in time to a test-click (e.g. 0-8ms). Various temporal suppression methods for examining temporal changes in cochlear compression were evaluated and me...... under test. Temporal suppression was shown to be comparable for CEOAEs and SSOAEs, indicating similar underlying cochlear nonlinear mechanisms. This study contributes to a better understanding of the temporal properties of cochlear dynamics....

  1. Resveratrol suppresses IGF-1 induced human colon cancer cell proliferation and elevates apoptosis via suppression of IGF-1R/Wnt and activation of p53 signaling pathways

    Radhakrishnan Sridhar

    2010-05-01

    Full Text Available Abstract Background Obesity is a global phenomenon and is associated with various types of cancer, including colon cancer. There is a growing interest for safe and effective bioactive compounds that suppress the risk for obesity-promoted colon cancer. Resveratrol (trans-3, 4', 5,-trihydroxystilbene, a stilbenoid found in the skin of red grapes and peanuts suppresses many types of cancers by regulating cell proliferation and apoptosis through a variety of mechanisms, however, resveratrol effects on obesity-promoted colon cancer are not clearly established. Methods We investigated the anti-proliferative effects of resveratrol on HT-29 and SW480 human colon cancer cells in the presence and absence of insulin like growth factor-1 (IGF-1; elevated during obesity and elucidated the mechanisms of action using IGF-1R siRNA in HT-29 cells which represents advanced colon carcinogenesis. Results Resveratrol (100-150 μM exhibited anti-proliferative properties in HT-29 cells even after IGF-1 exposure by arresting G0/G1-S phase cell cycle progression through p27 stimulation and cyclin D1 suppression. Treatment with resveratrol suppressed IGF-1R protein levels and concurrently attenuated the downstream Akt/Wnt signaling pathways that play a critical role in cell proliferation. Targeted suppression of IGF-1R using IGF-1R siRNA also affected these signaling pathways in a similar manner. Resveratrol treatment induced apoptosis by activating tumor suppressor p53 protein, whereas IGF-1R siRNA treatment did not affect apoptosis. Our data suggests that resveratrol not only suppresses cell proliferation by inhibiting IGF-1R and its downstream signaling pathways similar to that of IGF-1R siRNA but also enhances apoptosis via activation of the p53 pathway. Conclusions For the first time, we report that resveratrol suppresses colon cancer cell proliferation and elevates apoptosis even in the presence of IGF-1 via suppression of IGF-1R/Akt/Wnt signaling pathways and

  2. Resveratrol suppresses IGF-1 induced human colon cancer cell proliferation and elevates apoptosis via suppression of IGF-1R/Wnt and activation of p53 signaling pathways

    Vanamala, Jairam; Reddivari, Lavanya; Radhakrishnan, Sridhar; Tarver, Chris

    2010-01-01

    Obesity is a global phenomenon and is associated with various types of cancer, including colon cancer. There is a growing interest for safe and effective bioactive compounds that suppress the risk for obesity-promoted colon cancer. Resveratrol (trans-3, 4', 5,-trihydroxystilbene), a stilbenoid found in the skin of red grapes and peanuts suppresses many types of cancers by regulating cell proliferation and apoptosis through a variety of mechanisms, however, resveratrol effects on obesity-promoted colon cancer are not clearly established. We investigated the anti-proliferative effects of resveratrol on HT-29 and SW480 human colon cancer cells in the presence and absence of insulin like growth factor-1 (IGF-1; elevated during obesity) and elucidated the mechanisms of action using IGF-1R siRNA in HT-29 cells which represents advanced colon carcinogenesis. Resveratrol (100-150 μM) exhibited anti-proliferative properties in HT-29 cells even after IGF-1 exposure by arresting G 0 /G 1 -S phase cell cycle progression through p27 stimulation and cyclin D1 suppression. Treatment with resveratrol suppressed IGF-1R protein levels and concurrently attenuated the downstream Akt/Wnt signaling pathways that play a critical role in cell proliferation. Targeted suppression of IGF-1R using IGF-1R siRNA also affected these signaling pathways in a similar manner. Resveratrol treatment induced apoptosis by activating tumor suppressor p53 protein, whereas IGF-1R siRNA treatment did not affect apoptosis. Our data suggests that resveratrol not only suppresses cell proliferation by inhibiting IGF-1R and its downstream signaling pathways similar to that of IGF-1R siRNA but also enhances apoptosis via activation of the p53 pathway. For the first time, we report that resveratrol suppresses colon cancer cell proliferation and elevates apoptosis even in the presence of IGF-1 via suppression of IGF-1R/Akt/Wnt signaling pathways and activation of p53, suggesting its potential role as a

  3. Suppression of STAT3 Signaling by Δ9-Tetrahydrocannabinol (THC) Induces Trophoblast Dysfunction.

    Chang, Xinwen; Bian, Yiding; He, Qizhi; Yao, Julei; Zhu, Jingping; Wu, Jinting; Wang, Kai; Duan, Tao

    2017-01-01

    Marijuana is a widely used illicit drug and its consumption during pregnancy has been associated with adverse reproductive outcomes. The purpose of this study was to determine the effects of chronic intake of Δ9-tetrahydrocannabinol (THC), the major component of marijuana, on trophoblast function, placental development, and birth outcomes. The pathological characteristics and distribution of cannabinoid receptors in placenta were observed by immunohistochemical (IHC) staining. Cell migration in response to THC was measured by transwell assays. The levels of cannabinoid receptors and Signal Transducer and Activator of Transcription 3 (STAT3) were detected by western blot. We found the placenta expressed two main cannabinoid receptors, suggesting that THC induced biological responses in placental cells. Supporting this hypothesis, we observed dramatic alterations of placental morphology in marijuana users. Using THC and inhibitors of cannabinoid receptors, we demonstrated that THC impaired trophoblast cell migration and invasion partly via cannabinoid receptors. Additionally, pregnant mice injected with THC showed adverse reproductive events including reduced number of fetuses, lower maternal and placental weights. Mechanistically, STAT3 signaling pathway was involved in the THC-induced suppression of trophoblast cell motility and pregnancy outcomes. Our study indicates that the STAT3 signaling pathway plays a critical role in THC-induced trophoblast dysfunction. © 2017 The Author(s). Published by S. Karger AG, Basel.

  4. Experimental verification of the fission chamber gamma signal suppression by the Campbelling mode

    Vermeeren, L.; Weber, M. [SCK-CEN, Boeretang 200, B-2400 Mol (Belgium); Oriol, L.; Breaud, S.; Filliatre, P.; Geslot, B.; Jammes, C. [CEA, Centre de Cadarache, F-13109 Saint-Paul-lez-Durance (France); Normand, S.; Lescop, B. [CEA, Centre de Saclay, F-91191 Gif sur Yvette Cedex (France)

    2009-07-01

    For the on-line monitoring of high fast neutron fluxes in the presence of a strong thermal neutron component, SCK-CEN and CEA are jointly developing a Fast Neutron Detector System, based on {sup 242}Pu fission chambers as sensors and including dedicated electronics and data processing systems. Irradiation tests in the BR2 reactor of {sup 242}Pu fission chambers operating in current mode showed that in typical MTR (Materials Test Reactors) conditions the fission chamber currents are dominated by the gamma contribution. In order to reduce the gamma contribution to the signal, it was proposed to use the fission chambers in Campbelling mode. An irradiation experiment in the BR2 reactor with a {sup 242}Pu and a {sup 235}U fission chamber, both equipped with a suitable cable for measurements in Campbelling mode, proved the effectiveness of the suppression of the gamma-induced signal component by the Campbelling mode: gamma contribution reduction factors of 26 for the {sup 235}U fission chamber and more than 80 for the {sup 242}Pu fission chamber were obtained. The experimental data also prove that photofission contributions are negligibly small. Consequently, in typical MTR conditions the gamma contribution to the fission chamber Campbelling signal can be neglected. (authors)

  5. Experimental Verification of the Fission Chamber Gamma Signal Suppression by the Campbelling Mode

    Vermeeren, L.; Weber, M.; Oriol, L.; Breaud, S.; Filliatre, P.; Geslot, B.; Jammes, C.; Normand, S.; Lescop, B.

    2011-01-01

    For the on-line monitoring of high fast neutron fluxes in the presence of a strong thermal neutron component, SCK-CEN and CEA are jointly developing a Fast Neutron Detector System, based on 242 Pu fission chambers as sensors and including dedicated electronics and data processing systems. Irradiation tests in the BR2 reactor of 242 Pu fission chambers operating in current mode showed that in typical MTR conditions the fission chamber currents are dominated by the gamma contribution. In order to reduce the gamma contribution to the signal, it was proposed to use the fission chambers in Campbelling mode. An irradiation experiment in the BR2 reactor with a 242 Pu and a 235 U fission chamber, both equipped with a suitable cable for measurements in Campbelling mode, proved the effectiveness of the suppression of the gamma-induced signal component by the Campbelling mode: gamma contribution reduction factors of 26 for the 235 U fission chamber and more than 80 for the 242 Pu fission chamber were obtained. The experimental data also prove that photofission contributions are negligibly small. Consequently, in typical MTR conditions the gamma contribution to the fission chamber Campbelling signal can be neglected. (authors)

  6. Suppression of STAT3 Signaling by Δ9-Tetrahydrocannabinol (THC Induces Trophoblast Dysfunction

    Xinwen Chang

    2017-06-01

    Full Text Available Aims: Marijuana is a widely used illicit drug and its consumption during pregnancy has been associated with adverse reproductive outcomes. The purpose of this study was to determine the effects of chronic intake of Δ9-tetrahydrocannabinol (THC, the major component of marijuana, on trophoblast function, placental development, and birth outcomes. Methods: The pathological characteristics and distribution of cannabinoid receptors in placenta were observed by immunohistochemical (IHC staining. Cell migration in response to THC was measured by transwell assays. The levels of cannabinoid receptors and Signal Transducer and Activator of Transcription 3 (STAT3 were detected by western blot. Results: We found the placenta expressed two main cannabinoid receptors, suggesting that THC induced biological responses in placental cells. Supporting this hypothesis, we observed dramatic alterations of placental morphology in marijuana users. Using THC and inhibitors of cannabinoid receptors, we demonstrated that THC impaired trophoblast cell migration and invasion partly via cannabinoid receptors. Additionally, pregnant mice injected with THC showed adverse reproductive events including reduced number of fetuses, lower maternal and placental weights. Mechanistically, STAT3 signaling pathway was involved in the THC-induced suppression of trophoblast cell motility and pregnancy outcomes. Conclusion: Our study indicates that the STAT3 signaling pathway plays a critical role in THC-induced trophoblast dysfunction.

  7. MR diffusion weighted imaging with background signal suppression in breast cancer

    Li Ming; Zhang Bing; Zhou Zhengyang; Yu Haiping; Yuan Lei; Zhu Bin

    2009-01-01

    Objective: To explore the feasibility of echo planar imaging with short time inversion recovery (STIR-EPI) diffusion weighted imaging with background signal (DWIBS) suppression in breast cancer. Methods: The diffusion weighted imaging (DWI)with background suppression (b=800 mm 2 /s) was performed in 26 patients with breast cancer. Apparent diffusion coefficient(ADC) of all lesions were measured and compared. 3D maximum intensity projection (3D-MIP)and reverse black and white technique were used to show the lesions. DWI and DWIBS were performed and compared for the detection of breast cancer. Randomized blocks analysis of variance was used for the ADC values in different breast tissues, the ADC values in breast cancer and benign lesion were compared using t test. The paired chi square test was used for the detection rate of breast cancer in two different imaging methods. Results: Most of the breast cancers were hyperintense on DWI (b=800 mm 2 /s). The ADC value of cancer tissue was (0.93±0.25) x 10 -3 mm 2 /s, tumor necrosis was (2.06±0.17) x 10 -3 mm 2 /s, normal breast tissue was (1.92±0.23) x 10 -3 mm 2 /s and metastatic lymph node was (1.10±0.14) x 10 -3 mm 2 /s and the differences were statistically significant between two structures (P 2 =8.307, P 2 = 12.235, P -3 mm 2 /s and benign lesion (2.15±0.53) x 10 -3 mm 2 /s had significant statistical differences (t=8.626,P<0.05). Conclusion: Diffusion weighted MRI with background suppression can detect more lesions than DWI and can be potentially applied for the detection of the breast cancer combining the ADC value. (authors)

  8. Comparison between coasting and bunched beams on optimum stochastic cooling and signal suppression

    Wei, J.

    1991-01-01

    A comparison has been performed between coasting and bunched particle beams pertaining to the mechanism of stochastic cooling. In the case that particles occupy the entire sinusoidal rf bucket, the optimum cooling rate for the bunched beam is shown to be the same as that predicted from the coasting-beam theory using local particle density. However, in the case that particles occupy only the center of the bucket, the optimum rate decreases in proportion to the ratio of the bunch area to the bucket area. Furthermore, it has been shown for both coasting and bunched beams that particle motion is stable upon signal suppression if the amplitude of the gain is less than twice the optimum value over the entire frequency bandwidth of the cooling system. 7 refs., 1 fig

  9. Microanatomy of the cochlear hook

    Kwan, Changyow Claire; Tan, Xiaodong; Stock, Stuart R.; Soriano, Carmen; Xiao, Xianghui; Richter, Claus-Peter

    2017-09-01

    Communication among humans occurs through coding and decoding of acoustic information. The inner ear or cochlea acts as a frequency analyzer and divides the acoustic signal into small frequency bands, which are processed at different sites along the cochlea. The mechano-electrical conversion is accomplished by the soft tissue structures in the cochlea. While the anatomy for most of the cochlea has been well described, a detailed description of the very high frequency and vulnerable cochlear hook region is missing. To study the cochlear hook, mice cochleae were imaged with synchrotron radiation and high-resolution reconstructions have been made from the tomographic scans. This is the first detailed description of the bony and soft tissues of the hook region of the mammalian cochlea.

  10. Lens regeneration from the cornea requires suppression of Wnt/β-catenin signaling.

    Hamilton, Paul W; Sun, Yu; Henry, Jonathan J

    2016-04-01

    regeneration. In contrast, inhibition of Wnt signaling using either the small molecule IWR-1, treatment with recombinant human Dickkopf-1 (rhDKK1) protein, or transgenic expression of Xenopus DKK1, did not significantly affect the percentage of successful regeneration. Together, these results suggest a model where Wnt/β-catenin signaling is active in the cornea epithelium and needs to be suppressed during early lens regeneration in order for these cornea cells to give rise to a new lentoid. While this finding differs from what has been described in the newt, it closely resembles the role of Wnt signaling during the initial formation of the lens placode from the surface ectoderm during early embryogenesis. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. Curcumin enhances the radiosensitivity of renal cancer cells by suppressing NF-κB signaling pathway.

    Li, Gang; Wang, Ziming; Chong, Tie; Yang, Jie; Li, Hongliang; Chen, Haiwen

    2017-10-01

    The radiation resistance of renal cell carcinoma (RCC) remains the primary obstacle to improve patient survival. This study aimed to investigate the effects of curcumin on the radiosensitivity of RCC cells. Human RCC cell (ACHN) was exposed to irradiation (IR) and/or curcumin treatment. Cell viability, DNA repair, cell cycle, and apoptosis, were evaluated by MTT, immunofluoresence staining and flow cytometry. Moreover, ACHN cells were xenografted into nude mice and subjected to IR and/or curcumin treatment. The expression of NF-κB signaling related proteins in ACHN cells and xenografts was detected by western blot analysis. The results showed that curcumin significantly increased radiosensitivity of ACHN cells by inhibiting the cell proliferation and DNA damage repair, causing cell cycle arrest at G2/M phase, inducing apoptosis in vitro, and suppressing the growth of xenografts in vivo. In addition, curcumin enhanced radiosensitivity was through markedly inhibiting IR-induced NF-κB signaling by modulating the related protein expressions including NF-κBP65, I-κB, VEGF, COX2, and Bcl-2 in ACHN cells, which was further strengthened by NF-κB inhibitor PDTC treatment. Thus, curcumin may confer radiosensitivity on RCC via inhibition of NF-κB activation and its downstream regulars, suggesting the potential application of curcumin as an adjuvant in radiotherapy of RCC. Copyright © 2017. Published by Elsevier Masson SAS.

  12. Entada phaseoloides extract suppresses hepatic gluconeogenesis via activation of the AMPK signaling pathway.

    Zheng, Tao; Hao, Xincai; Wang, Qibin; Chen, Li; Jin, Si; Bian, Fang

    2016-12-04

    The seed of Entada phaseoloides (L.) Merr. (Entada phaseoloides) has been long used as a folk medicine for the treatment of Diabetes mellitus by Chinese ethnic minorities. Recent reports have demonstrated that total saponins from Entada phaseoloides (TSEP) could reduce fasting blood glucose in type 2 diabetic rats. However, the mechanism has not been fully elucidated. The aim of this study was to explore the underlying mechanisms of TSEP on type 2 Diabetes mellitus (T2DM). Primary mouse hepatocytes and HepG2 cells were used to investigate the effects of TSEP on gluconeogenesis. After treatment with TSEP, glucose production, genes expression levels of Glucose-6-phosphatase (G6pase) and Phosphoenoylpyruvate carboxykinase (Pepck) were detected. The efficacy and underlying mechanism of TSEP on AMP-activated protein kinase (AMPK) signaling pathway were determinated. TSEP significantly inhibited glucose production and the gluconeogenic gene expression. Treatment with TSEP elevated the phosphorylation of AMPK, which in turn promoted the phosphorylation of acetyl coenzyme A (ACC) and Akt/glycogen synthase kinase 3β (GSK3β), respectively. Furthermore, TSEP reduced lipid accumulation and improved insulin sensitivity in hepatocytes. These findings provide evidence that TSEP exerts an antidiabetic effect by suppressing hepatic gluconeogenesis via the AMPK signaling pathway. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  13. PLZF mediates the PTEN/AKT/FOXO3a signaling in suppression of prostate tumorigenesis.

    JingPing Cao

    Full Text Available Promyelocytic leukemia zinc finger (PLZF protein expression is closely related to the progression of human cancers, including prostate cancer (PCa. However, the according context of a signaling pathway for PLZF to suppress prostate tumorigenesis remains greatly unknown. Here we report that PLZF is a downstream mediator of the PTEN signaling pathway in PCa. We found that PLZF expression is closely correlated with PTEN expression in a cohort of prostate cancer specimens. Interestingly, both PTEN rescue and phosphoinositide 3-kinase (PI3K inhibitor LY294002 treatment increase the PLZF expression in prostate cancer cell lines. Further, luciferase reporter assay and chromatin immunoprecipitation assay demonstrate that FOXO3a, a transcriptional factor phosphorylated by PI3K/AKT, could directly bind to the promoter of PLZF gene. These results indicate that PTEN regulates PLZF expression by AKT/FOXO3a. Moreover, our animal experiments also demonstrate that PLZF is capable of inhibiting prostate tumorigenesis in vivo. Taken together, our study defines a PTEN/PLZF pathway and would shed new lights for developing therapeutic strategy of prostate cancer.

  14. Colorectal cancer cells suppress CD4+ T cells immunity through canonical Wnt signaling.

    Sun, Xuan; Liu, Suoning; Wang, Daguang; Zhang, Yang; Li, Wei; Guo, Yuchen; Zhang, Hua; Suo, Jian

    2017-02-28

    Understanding how colorectal cancer escapes from immunosurveillance and immune attack is important for developing novel immunotherapies for colorectal cancer. In this study we evaluated the role of canonical Wnt signaling in the regulation of T cell function in a mouse colorectal cancer model. We found that colorectal cancer cells expressed abundant Wnt ligands, and intratumoral T cells expressed various Frizzled proteins. Meanwhile, both active β-catenin and total β-catenin were elevated in intratumoral T cells. In vitro study indicated that colorectal cancer cells suppressed IFN-γ expression and increased IL-17a expression in activated CD4+ T cells. However, the cytotoxic activity of CD8+ T cells was not altered by colorectal cancer cells. To further evaluate the importance of Wnt signaling for CD4+ T cell-mediated cancer immunity, β-catenin expression was enforced in CD4+ T cells using lentiviral transduction. In an adoptive transfer model, enforced expression of β-catenin in intratumoral CD4+ T cells increased IL-17a expression, enhanced proliferation and inhibited apoptosis of colorectal cancer cells. Taken together, our study disclosed a new mechanism by which colorectal cancer impairs T cell immunity.

  15. A silyl andrographolide analogue suppresses Wnt/β-catenin signaling pathway in colon cancer.

    Reabroi, Somrudee; Chairoungdua, Arthit; Saeeng, Rungnapha; Kasemsuk, Teerapich; Saengsawang, Witchuda; Zhu, Weiming; Piyachaturawat, Pawinee

    2018-05-01

    Hyperactivation of Wnt/β-catenin signaling implicated in oncogenesis of colorectal cancer (CRC) is a potential molecular target for chemotherapy. An andrographolide analogue, 3A.1 (19-tert-butyldiphenylsilyl-8, 17-epoxy andrographolide) has previously been reported to be potently cytotoxic toward cancer cells by unknown molecular mechanisms. The present study explored the anti-cancer activity of analogue 3A.1 on Wnt/β-catenin signaling in colon cancer cells (HT29 cells) which were more sensitive to the others (HCT116 and SW480 cells). Analogue 3A.1 inhibited viability of HT29 cells with IC 50 value of 11.1 ± 1.4 μM at 24 h, which was more potent than that of the parent andrographolide. Analogue 3A.1 also suppressed the proliferation of HT29 cells and induced cell apoptosis in a dose-dependent manner. Its apoptotic activity was accompanied with increased expressions of proteins related to DNA damages; PARP-1 and γ-H2AX. In addition, analogue 3A.1 significantly inhibited T-cell factor and lymphoid enhancer factor (TCF/LEF) promoter activity of Wnt/β-catenin signaling. Accordingly, the expressions of Wnt target genes and β-catenin protein were suppressed. Moreover, analogue 3A.1 increased the activity of GSK-3β kinase, which is a negative regulator responsible for degradation of intracellular β-catenin. This mode of action was further supported by the absence of the effects after treatment with a GSK-3β inhibitor, and over-expression of a mutant β-catenin (S33Y). Our findings reveal, for the first time, an insight into the molecular mechanism of the anti-cancer activity of analogue 3A.1 through the inhibition of Wnt/β-catenin/GSK-3β pathway and provide a therapeutic potential of the andrographolide analogue 3A.1 in CRC treatment. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  16. CT evaluation of preoperative cochlear implantation cochlear implantation

    Tan Xiuzhong; Zhong Lansheng; Lan Bowen; Huang Yaosheng; Du Baowen; Zhu Jian

    2004-01-01

    Objective: To evaluate CT scan as a preoperative evaluation for cochlear implantation candidates. Methods: Axial high-resolution temporal bone CT and three-dimensional reconstruction of inner ear were performed in 93 patients with sensorineural hearing loss. results: Among 81 patients with congenital sensorineural deafness, Mondini malformation was seen in 7 case (13 ears); large vestibular aqueduct syndrome (LVAS) was revealed in 5 cases (8 ears); and inner ear ossification was found in 1 case (2 ears). In 1 case (2 ears) of inner ear fibrosis, reduced cochlear signal was noted on MRI but no unremarkable findings was shown on CT scan, however, in the operation, the device could not inserted into the basal circle of the cochlea, due to fibrous obliteration. In 12 patients with post-speech deafness, chronic suppurative tympanitis was seen in 2 cases (4 ears), and inner ear ossification was revealed in 1 case (2 ears). Conclusion: CT plays an indispensable role in the pre-operative evaluation of cochlear implantation. T 2 -weighted FSE-MRI of the inner ear is a useful complementary to CT scan. (authors)

  17. mTOR signaling promotes stem cell activation via counterbalancing BMP-mediated suppression during hair regeneration.

    Deng, Zhili; Lei, Xiaohua; Zhang, Xudong; Zhang, Huishan; Liu, Shuang; Chen, Qi; Hu, Huimin; Wang, Xinyue; Ning, Lina; Cao, Yujing; Zhao, Tongbiao; Zhou, Jiaxi; Chen, Ting; Duan, Enkui

    2015-02-01

    Hair follicles (HFs) undergo cycles of degeneration (catagen), rest (telogen), and regeneration (anagen) phases. Anagen begins when the hair follicle stem cells (HFSCs) obtain sufficient activation cues to overcome suppressive signals, mainly the BMP pathway, from their niche cells. Here, we unveil that mTOR complex 1 (mTORC1) signaling is activated in HFSCs, which coincides with the HFSC activation at the telogen-to-anagen transition. By using both an inducible conditional gene targeting strategy and a pharmacological inhibition method to ablate or inhibit mTOR signaling in adult skin epithelium before anagen initiation, we demonstrate that HFs that cannot respond to mTOR signaling display significantly delayed HFSC activation and extended telogen. Unexpectedly, BMP signaling activity is dramatically prolonged in mTOR signaling-deficient HFs. Through both gain- and loss-of-function studies in vitro, we show that mTORC1 signaling negatively affects BMP signaling, which serves as a main mechanism whereby mTORC1 signaling facilitates HFSC activation. Indeed, in vivo suppression of BMP by its antagonist Noggin rescues the HFSC activation defect in mTORC1-null skin. Our findings reveal a critical role for mTOR signaling in regulating stem cell activation through counterbalancing BMP-mediated repression during hair regeneration. © The Author (2015). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.

  18. Cyclin G2 suppresses estrogen-mediated osteogenesis through inhibition of Wnt/β-catenin signaling.

    Jinlan Gao

    Full Text Available Estrogen plays an important role in the maintenance of bone formation, and deficiency in the production of estrogen is directly linked to postmenopausal osteoporosis. To date, the underlying mechanisms of estrogen-mediated osteogenic differentiation are not well understood. In this study, a pluripotent mesenchymal precursor cell line C2C12 was used to induce osteogenic differentiation and subjected to detection of gene expressions or to manipulation of cyclin G2 expressions. C57BL/6 mice were used to generate bilateral ovariectomized and sham-operated mice for analysis of bone mineral density and protein expression. We identified cyclin G2, an unconventional member of cyclin, is involved in osteoblast differentiation regulated by estrogen in vivo and in vitro. In addition, the data showed that ectopic expression of cyclin G2 suppressed expression of osteoblast transcription factor Runx2 and osteogenic differentiation marker genes, as well as ALP activity and in vitro extracellular matrix mineralization. Mechanistically, Wnt/β-catenin signaling pathway is essential for cyclin G2 to inhibit osteogenic differentiation. To the best of our knowledge, the current study presents the first evidence that cyclin G2 serves as a negative regulator of both osteogenesis and Wnt/β-catenin signaling. Most importantly, the basal and 17β-estradiol-induced osteogenic differentiation was restored by overexpression of cyclin G2. These results taken together suggest that cyclin G2 may function as an endogenous suppressor of estrogen-induced osteogenic differentiation through inhibition of Wnt/β-catenin signaling.

  19. A SELEX-screened aptamer of human hepatitis B virus RNA encapsidation signal suppresses viral replication.

    Hui Feng

    Full Text Available BACKGROUND: The specific interaction between hepatitis B virus (HBV polymerase (P protein and the ε RNA stem-loop on pregenomic (pg RNA is crucial for viral replication. It triggers both pgRNA packaging and reverse transcription and thus represents an attractive antiviral target. RNA decoys mimicking ε in P protein binding but not supporting replication might represent novel HBV inhibitors. However, because generation of recombinant enzymatically active HBV polymerase is notoriously difficult, such decoys have as yet not been identified. METHODOLOGY/PRINCIPAL FINDINGS: Here we used a SELEX approach, based on a new in vitro reconstitution system exploiting a recombinant truncated HBV P protein (miniP, to identify potential ε decoys in two large ε RNA pools with randomized upper stem. Selection of strongly P protein binding RNAs correlated with an unexpected strong enrichment of A residues. Two aptamers, S6 and S9, displayed particularly high affinity and specificity for miniP in vitro, yet did not support viral replication when part of a complete HBV genome. Introducing S9 RNA into transiently HBV producing HepG2 cells strongly suppressed pgRNA packaging and DNA synthesis, indicating the S9 RNA can indeed act as an ε decoy that competitively inhibits P protein binding to the authentic ε signal on pgRNA. CONCLUSIONS/SIGNIFICANCE: This study demonstrates the first successful identification of human HBV ε aptamers by an in vitro SELEX approach. Effective suppression of HBV replication by the S9 aptamer provides proof-of-principle for the ability of ε decoy RNAs to interfere with viral P-ε complex formation and suggests that S9-like RNAs may further be developed into useful therapeutics against chronic hepatitis B.

  20. Appetite suppressing effect of Spinacia oleracea in rats: Involvement of the short term satiety signal cholecystokinin.

    Panda, Vandana; Shinde, Priyanka

    2017-06-01

    Spinacia oleracea (spinach) is a green leafy vegetable rich in antioxidant phyto-constituents such as flavonoids, polyphenols, carotenoids and vitamins. Fruits and vegetables rich in flavonoids are known to prevent weight gain by inducing satiety. The present study evaluates the appetite suppressing effect of a flavonoid rich extract of the spinach leaf (SOE) in rats. HPTLC of SOE was performed for detecting flavonoids. Rats were administered SOE (200 mg/kg and 400 mg/kg, p. o) and fluoxetine (6 mg/kg i. p) as a pre-meal for 14 days. Food intake and weight gain was observed daily during the treatment period. Serum levels of the short term satiety signals cholecystokinin (CCK) and glucose were measured on the 7th and 14thdays at different time points after start of meal to study the satiety inducing effect of SOE. HPTLC showed the presence of 14 flavonoids in SOE. SOE and fluoxetine treated rats showed a significant reduction in food intake and weight gain when compared with the normal control rats. On the 7th day of treatment, peak CCK levels were reached in 30 min after start of meal in fluoxetine treated rats and in 60 min in the remaining rats. On the 14th day, CCK peaking was observed in 30 min after start of meal in the fluoxetine as well as SOE 400 mg/kg treated rats. Peak glucose levels in all treatment groups were obtained in 60 min after start of feeding on both days of the study. It maybe concluded that SOE exhibited a promising appetite suppressing effect by inducing a quicker than normal release of CCK, thus eliciting an early onset of satiety in rats. This effect may be due to its high flavonoid content. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Quercetin suppresses cyclooxygenase-2 expression and angiogenesis through inactivation of P300 signaling.

    Xiangsheng Xiao

    Full Text Available Quercetin, a polyphenolic bioflavonoid, possesses multiple pharmacological actions including anti-inflammatory and antitumor properties. However, the precise action mechanisms of quercetin remain unclear. Here, we reported the regulatory actions of quercetin on cyclooxygenase-2 (COX-2, an important mediator in inflammation and tumor promotion, and revealed the underlying mechanisms. Quercetin significantly suppressed COX-2 mRNA and protein expression and prostaglandin (PG E(2 production, as well as COX-2 promoter activation in breast cancer cells. Quercetin also significantly inhibited COX-2-mediated angiogenesis in human endothelial cells in a dose-dependent manner. The in vitro streptavidin-agarose pulldown assay and in vivo chromatin immunoprecipitation assay showed that quercetin considerably inhibited the binding of the transactivators CREB2, C-Jun, C/EBPβ and NF-κB and blocked the recruitment of the coactivator p300 to COX-2 promoter. Moreover, quercetin effectively inhibited p300 histone acetyltransferase (HAT activity, thereby attenuating the p300-mediated acetylation of NF-κB. Treatment of cells with p300 HAT inhibitor roscovitine was as effective as quercetin at inhibiting p300 HAT activity. Addition of quercetin to roscovitine-treated cells did not change the roscovitine-induced inhibition of p300 HAT activity. Conversely, gene delivery of constitutively active p300 significantly reversed the quercetin-mediated inhibition of endogenous HAT activity. These results indicate that quercetin suppresses COX-2 expression by inhibiting the p300 signaling and blocking the binding of multiple transactivators to COX-2 promoter. Our findings therefore reveal a novel mechanism of action of quercetin and suggest a potential use for quercetin in the treatment of COX-2-mediated diseases such as breast cancers.

  2. A two-microphone noise reduction system for cochlear implant users with nearby microphones. Part I: Signal processing algorithm design and development

    Kompis, Martin; Bertram, Matthias; François, Jacques; Pelizzone, Marco

    2008-01-01

    Users of cochlear implant systems, that is, of auditory aids which stimulate the auditory nerve at the cochlea electrically, often complain about poor speech understanding in noisy environments. Despite the proven advantages of multimicrophone directional noise reduction systems for conventional hearing aids, only one major manufacturer has so far implemented such a system in a product, presumably because of the added power consumption and size. We present a physically small (intermicrophone ...

  3. Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD.

    Jiao, Na; Baker, Susan S; Chapa-Rodriguez, Adrian; Liu, Wensheng; Nugent, Colleen A; Tsompana, Maria; Mastrandrea, Lucy; Buck, Michael J; Baker, Robert D; Genco, Robert J; Zhu, Ruixin; Zhu, Lixin

    2017-08-03

    Bile acids are regulators of lipid and glucose metabolism, and modulate inflammation in the liver and other tissues. Primary bile acids such as cholic acid and chenodeoxycholic acid (CDCA) are produced in the liver, and converted into secondary bile acids such as deoxycholic acid (DCA) and lithocholic acid by gut microbiota. Here we investigated the possible roles of bile acids in non-alcoholic fatty liver disease (NAFLD) pathogenesis and the impact of the gut microbiome on bile acid signalling in NAFLD. Serum bile acid levels and fibroblast growth factor 19 (FGF19), liver gene expression profiles and gut microbiome compositions were determined in patients with NAFLD, high-fat diet-fed rats and their controls. Serum concentrations of primary and secondary bile acids were increased in patients with NAFLD. In per cent, the farnesoid X receptor (FXR) antagonistic DCA was increased, while the agonistic CDCA was decreased in NAFLD. Increased mRNA expression for cytochrome P450 7A1, Na + -taurocholate cotransporting polypeptide and paraoxonase 1, no change in mRNA expression for small heterodimer partner and bile salt export pump, and reduced serum FGF19 were evidence of impaired FXR and fibroblast growth factor receptor 4 (FGFR4)-mediated signalling in NAFLD. Taurine and glycine metabolising bacteria were increased in the gut of patients with NAFLD, reflecting increased secondary bile acid production. Similar changes in liver gene expression and the gut microbiome were observed in high-fat diet-fed rats. The serum bile acid profile, the hepatic gene expression pattern and the gut microbiome composition consistently support an elevated bile acid production in NAFLD. The increased proportion of FXR antagonistic bile acid explains, at least in part, the suppression of hepatic FXR-mediated and FGFR4-mediated signalling. Our study suggests that future NAFLD intervention may target the components of FXR signalling, including the bile acid converting gut microbiome. © Article

  4. STEREOLOGICAL ANALYSIS OF THE COCHLEAR NUCLEI OF MONKEY (MACACA FASCICULARIS AFTER DEAFFERENTATION

    Ana M Insausti

    2011-05-01

    Full Text Available The cochlear nuclei (CN in the brainstem receive the input signals from the inner ear through the cochlear nerve, and transmit these signals to higher auditory centres. A variety of lesions of the cochlear nerve cause deafness. As reported in the literature, artificial removal of auditive input, or 'deafferentation', induces structural alterations in the CN. The purpose of this study was to estimate a number of relevant stereological parameters of the CN in control and deafferented Macaca fascicularis monkeys.

  5. Albizia lebbeck suppresses histamine signaling by the inhibition of histamine H1 receptor and histidine decarboxylase gene transcriptions.

    Nurul, Islam Mohammed; Mizuguchi, Hiroyuki; Shahriar, Masum; Venkatesh, Pichairajan; Maeyama, Kazutaka; Mukherjee, Pulok K; Hattori, Masashi; Choudhuri, Mohamed Sahabuddin Kabir; Takeda, Noriaki; Fukui, Hiroyuki

    2011-11-01

    Histamine plays major roles in allergic diseases and its action is mediated mainly by histamine H(1) receptor (H1R). We have demonstrated that histamine signaling-related H1R and histidine decarboxylase (HDC) genes are allergic diseases sensitive genes and their expression level affects severity of the allergic symptoms. Therefore, compounds that suppress histamine signaling should be promising candidates as anti-allergic drugs. Here, we investigated the effect of the extract from the bark of Albizia lebbeck (AL), one of the ingredients of Ayruvedic medicines, on H1R and HDC gene expression using toluene-2,4-diisocyanate (TDI) sensitized allergy model rats and HeLa cells expressing endogenous H1R. Administration of the AL extract significantly decreased the numbers of sneezing and nasal rubbing. Pretreatment with the AL extract suppressed TDI-induced H1R and HDC mRNA elevations as well as [(3)H]mepyramine binding, HDC activity, and histamine content in the nasal mucosa. AL extract also suppressed TDI-induced up-regulation of IL-4, IL-5, and IL-13 mRNA. In HeLa cells, AL extract suppressed phorbol-12-myristate-13-acetate- or histamine-induced up-regulation of H1R mRNA. Our data suggest that AL alleviated nasal symptoms by inhibiting histamine signaling in TDI-sensitized rats through suppression of H1R and HDC gene transcriptions. Suppression of Th2-cytokine signaling by AL also suggests that it could affect the histamine-cytokine network. Copyright © 2011 Elsevier B.V. All rights reserved.

  6. Calcineurin signaling and PGC-1alpha expression are suppressed during muscle atrophy due to diabetes.

    Roberts-Wilson, Tiffany K; Reddy, Ramesh N; Bailey, James L; Zheng, Bin; Ordas, Ronald; Gooch, Jennifer L; Price, S Russ

    2010-08-01

    PGC-1alpha is a transcriptional coactivator that controls energy homeostasis through regulation of glucose and oxidative metabolism. Both PGC-1alpha expression and oxidative capacity are decreased in skeletal muscle of patients and animals undergoing atrophy, suggesting that PGC-1alpha participates in the regulation of muscle mass. PGC-1alpha gene expression is controlled by calcium- and cAMP-sensitive pathways. However, the mechanism regulating PGC-1alpha in skeletal muscle during atrophy remains unclear. Therefore, we examined the mechanism responsible for decreased PGC-1alpha expression using a rodent streptozotocin (STZ) model of chronic diabetes and atrophy. After 21days, the levels of PGC-1alpha protein and mRNA were decreased. We examined the activation state of CREB, a potent activator of PGC-1alpha transcription, and found that phospho-CREB was paradoxically high in muscle of STZ-rats, suggesting that the cAMP pathway was not involved in PGC-1alpha regulation. In contrast, expression of calcineurin (Cn), a calcium-dependent phosphatase, was suppressed in the same muscles. PGC-1alpha expression is regulated by two Cn substrates, MEF2 and NFATc. Therefore, we examined MEF2 and NFATc activity in muscles from STZ-rats. Target genes MRF4 and MCIP1.4 mRNAs were both significantly reduced, consistent with reduced Cn signaling. Moreover, levels of MRF4, MCIP1.4, and PGC-1alpha were also decreased in muscles of CnAalpha-/- and CnAbeta-/- mice without diabetes indicating that decreased Cn signaling, rather than changes in other calcium- or cAMP-sensitive pathways, were responsible for decreased PGC-1alpha expression. These findings demonstrate that Cn activity is a major determinant of PGC-1alpha expression in skeletal muscle during diabetes and possibly other conditions associated with loss of muscle mass.

  7. Calcineurin signaling and PGC-1α expression are suppressed during muscle atrophy due to diabetes

    Roberts-Wilson, Tiffany K.; Reddy, Ramesh N.; Bailey, James L.; Zheng, Bin; Ordas, Ronald; Gooch, Jennifer L.; Price, S. Russ

    2010-01-01

    PGC-1α is a transcriptional coactivator that controls energy homeostasis through regulation of glucose and oxidative metabolism. Both PGC-1α expression and oxidative capacity are decreased in skeletal muscle of patients and animals undergoing atrophy, suggesting that PGC-1α participates in the regulation of muscle mass. PGC-1α gene expression is controlled by calcium- and cAMP-sensitive pathways. However, the mechanism regulating PGC-1α in skeletal muscle during atrophy remains unclear. Therefore, we examined the mechanism responsible for decreased PGC-1α expression using a rodent streptozotocin (STZ) model of chronic diabetes and atrophy. After 21d, the levels of PGC-1α protein and mRNA were decreased. We examined the activation state of CREB, a potent activator of PGC-1α transcription, and found that phospho-CREB was paradoxically high in muscle of STZ-rats, suggesting that the cAMP pathway was not involved in PGC-1α regulation. In contrast, expression of calcineurin (Cn), a calcium-dependent phosphatase, was suppressed in the same muscles. PGC-1α expression is regulated by two Cn substrates, MEF2 and NFATc. Therefore, we examined MEF2 and NFATc activity in muscles from STZ-rats. Target genes MRF4 and MCIP1.4 were both significantly reduced, consistent with reduced Cn signaling. Moreover, levels of MRF4, MCIP1.4, and PGC-1α were also decreased in muscles of CnAα-/- and CnAβ-/- mice without diabetes indicating that decreased Cn signaling, rather than changes in other calcium- or cAMP-sensitive pathways, were responsible for decreased PGC-1α expression. These findings demonstrate that Cn activity is a major determinant of PGC-1α expression in skeletal muscle during diabetes and possibly other conditions associated with loss of muscle mass. PMID:20359506

  8. The Adenovirus E1A C Terminus Suppresses a Delayed Antiviral Response and Modulates RAS Signaling.

    Zemke, Nathan R; Berk, Arnold J

    2017-12-13

    The N-terminal half of adenovirus e1a assembles multimeric complexes with host proteins that repress innate immune responses and force host cells into S-phase. In contrast, the functions of e1a's C-terminal interactions with FOXK, DCAF7, and CtBP are unknown. We found that these interactions modulate RAS signaling, and that a single e1a molecule must bind all three of these host proteins to suppress activation of a subset of IFN-stimulated genes (ISGs). These ISGs were otherwise induced in primary respiratory epithelial cells at 12 hr p.i. This delayed activation of ISGs required IRF3 and coincided with an ∼10-fold increase in IRF3 from protein stabilization. The induced IRF3 bound to chromatin and localized to the promoters of activated ISGs. While IRF3, STAT1/2, and IRF9 all greatly increased in concentration, there were no corresponding mRNA increases, suggesting that e1a regulates the stabilities of these key activators of innate immune responses, as shown directly for IRF3. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Pristimerin overcomes adriamycin resistance in breast cancer cells through suppressing Akt signaling

    XIE, GUI'E; YU, XINPEI; LIANG, HUICHAO; CHEN, JINGSONG; TANG, XUEWEI; WU, SHAOQING; LIAO, CAN

    2016-01-01

    Breast cancer remains a major public health problem worldwide. Chemotherapy serves an important role in the treatment of breast cancer. However, resistance to chemotherapeutic agents, in particular, multi-drug resistance (MDR), is a major cause of treatment failure in cancer. Agents that can either enhance the effects of chemotherapeutics or overcome chemoresistance are urgently needed for the treatment of breast cancer. Pristimerin, a quinonemethide triterpenoid compound isolated from Celastraceae and Hippocrateaceae, has been shown to possess antitumor, anti-inflammatory, antioxidant and insecticidal properties. The aim of the present study was to investigate whether pristimerin can override chemoresistance in MCF-7/adriamycin (ADR)-resistant human breast cancer cells. The results demonstrated that pristimerin indeed displayed potent cytocidal effect on multidrug-resistant MCF-7/ADR breast cancer cells, and that these effects occurred through the suppression of Akt signaling, which in turn led to the downregulation of antiapoptotic effectors and increased apoptosis. These findings indicate that use of pristimerin may represent a potentially promising approach for the treatment of ADR-resistant breast cancer. PMID:27123073

  10. The preliminary study of MR diffusion weighted imaging with background body signal suppression on pulmonary diseases

    Wu Huawei; Cheng Jiejun; Xu Jianrong; Lu Qing; Ge Xin; Li Lei

    2008-01-01

    Objective: To evaluate maximum intensity projection (MIP) images and apparent diffusion coefficient (ADC) values of MR diffusion weighted imaging with background body signal suppression (DWIBS) on pulmonary diseases. Methods: Sixty-one patients with pulmonary diseases underwent DWlBS. The findings in three dimensional(3D) MIP image were observed and the ADC values of diseased region were measured. The diagnostic value of DWIBS on pulmonary diseases was evaluated. Results: Lung cancer and inflammatory disease were all demonstrated as dense intensity area on DWIBS. The mean ADC value of central lung cancer was (1.05±0.23) x 10 -3 mm 2 /s. The mean ADC value of peripheral lung cancer was (1.10 ± 0.17) x 10 -3 mm 2 /s. The mean ADC value of the inflammatory disease was (1.69 ± 0.29) x 10 -3 mm 2 /s. The mean ADC value had significant difference between peripheral lung cancer and the inflammatory disease (P<0.05). The MR sensitivity, specificity and accuracy in diagnosing the pulmonary diseases with DWIBS (86.84%, 82.60%, 85.24%, respectively) was higher than conventional MRI(78.94%, 78.26%, and 78.68%, respectively). Conclusion: DWIBS can demonstrate clearly the lesion's shape with 3D display. The quantitative measurement of ADC values is feasible. DWIBS may be a potential diagnostic method for differentiation on pulmonary diseases. (authors)

  11. Benefits and Risks of Cochlear Implants

    ... and Medical Procedures Implants and Prosthetics Cochlear Implants Benefits and Risks of Cochlear Implants Share Tweet Linkedin ... the Use of Cochlear Implants What are the Benefits of Cochlear Implants? For people with implants: Hearing ...

  12. A new phase modulated binomial-like selective-inversion sequence for solvent signal suppression in NMR.

    Chen, Johnny; Zheng, Gang; Price, William S

    2017-02-01

    A new 8-pulse Phase Modulated binomial-like selective inversion pulse sequence, dubbed '8PM', was developed by optimizing the nutation and phase angles of the constituent radio-frequency pulses so that the inversion profile resembled a target profile. Suppression profiles were obtained for both the 8PM and W5 based excitation sculpting sequences with equal inter-pulse delays. Significant distortions were observed in both profiles because of the offset effect of the radio frequency pulses. These distortions were successfully reduced by adjusting the inter-pulse delays. With adjusted inter-pulse delays, the 8PM and W5 based excitation sculpting sequences were tested on an aqueous lysozyme solution. The 8 PM based sequence provided higher suppression selectivity than the W5 based sequence. Two-dimensional nuclear Overhauser effect spectroscopy experiments were also performed on the lysozyme sample with 8PM and W5 based water signal suppression. The 8PM based suppression provided a spectrum with significantly increased (~ doubled) cross-peak intensity around the suppressed water resonance compared to the W5 based suppression. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  13. hTERT peptide fragment GV1001 demonstrates radioprotective and antifibrotic effects through suppression of TGF‑β signaling.

    Chen, Wei; Shin, Ki-Hyuk; Kim, Sangjae; Shon, Won-Jun; Kim, Reuben H; Park, No-Hee; Kang, Mo K

    2018-06-01

    GV1001 is a 16‑amino acid peptide derived from the human telomerase reverse transcriptase (hTERT) protein (616‑626; EARPALLTSRLRFIPK), which lies within the reverse transcriptase domain. Originally developed as an anticancer vaccine, GV1001 demonstrates diverse cellular effects, including anti‑inflammatory, tumor suppressive and antiviral effects. In the present study, the radioprotective and antifibrotic effects of GV1001 were demonstrated through suppressing transforming growth factor‑β (TGF‑β) signaling. Proliferating human keratinocytes underwent premature senescence upon exposure to ionizing radiation (IR), however, treatment of cells with GV1001 allowed the cells to proliferate and showed a reduction in senescent phenotype. GV1001 treatment notably increased the levels of Grainyhead‑like 2 and phosphorylated (p‑)Akt (Ser473), and reduced the activation of p53 and the level of p21/WAF1 in irradiated keratinocytes. It also markedly suppressed the level of TGF‑β signaling molecules, including p‑small mothers against decapentaplegic (Smad)2/3 and Smad4, and TGF‑β target genes, including zinc finger E‑box binding homeobox 1, fibronectin, N‑cadharin and Snail, in irradiated keratinocytes. Furthermore, GV1001 suppressed TGF‑β signaling in primary human fibroblasts and inhibited myofibroblast differentiation. Chromatin immunoprecipitation revealed that GV1001 suppressed the binding of Smad2 on the promoter regions of collagen type III α1 chain (Col3a1) and Col1a1. In a dermal fibrosis model in vivo, GV1001 treatment notably reduced the thickness of fibrotic lesions and the synthesis of Col3a1. These data indicated that GV1001 ameliorated the IR‑induced senescence phenotype and tissue fibrosis by inhibiting TGF‑β signaling and may have therapeutic effects on radiation‑induced tissue damage.

  14. Knockdown of Heparanase Suppresses Invasion of Human Trophoblasts by Activating p38 MAPK Signaling Pathway

    Guanglu Che

    2018-01-01

    Full Text Available Preeclampsia is a pregnancy-related disease with increasing maternal and perinatal morbidity and mortality worldwide. Defective trophoblast invasion is considered to be a major factor in the pathophysiological mechanism of preeclampsia. Heparanase, the only endo-β-glucuronidase in mammalian cells, has been shown to be abnormally expressed in the placenta of preeclampsia patients in our previous study. The biological role and potential mechanism of heparanase in trophoblasts remain unclear. In the present study, stably transfected HTR8/SVneo cell lines with heparanase overexpression or knockdown were constructed. The effect of heparanase on cellular proliferation, apoptosis, invasion, tube formation, and potential pathways in trophoblasts was explored. Our results showed that overexpression of heparanase promoted proliferation and invasion. Knockdown of heparanase suppressed proliferation, invasion, and tube formation but induced apoptosis. These findings reveal that downregulation of heparanase may contribute to defective placentation and plays a crucial role in the pathogenesis of preeclampsia. Furthermore, increased activation of p38 MAPK in heparanase-knockdown HTR8/SVneo cell was shown by MAPK pathway phosphorylation array and Western blotting assay. After pretreatment with 3 specific p38 MAPK inhibitors (BMS582949, SB203580, or BIRB796, inadequate invasion in heparanase-knockdown HTR8/SVneo cell was rescued. That indicates that knockdown of heparanase decreases HTR8/SVneo cell invasion through excessive activation of the p38 MAPK signaling pathway. Our study suggests that heparanase can be a potential predictive biomarker for preeclampsia at an early stage of pregnancy and represents a promising therapeutic target for the treatment of preeclampsia.

  15. Suppression of beam-excited electron waves by an externally applied RF signal

    Fukumasa, Osamu; Itatani, Ryohei

    1980-11-01

    Suppression of the beam-excited electron wave in a bounded system is investigated in connection with the beam distribution function. Wave suppression has two different processes depending on whether injected beams are reflected at the other end or not. In the absence of reflected beam electrons, deformation of the beam distribution function is observed in relation to the suppression of the electron wave. However, when beam electrons are reflected, the external wave suppresses the electron wave but distribution function shows no appreciable change. These experimental results show that nonlinear behaviors of beam electrons, namely behaviors of reflected beams, are quite important for wave suppression. By using the method of partial simulation, interaction between two waves in the bounded system including nonlinear motions of beam electrons is studied numerically. Qualitative agreement between experimental and numerical results is obtained. (author)

  16. Sub-picosecond timing fluctuation suppression in laser-based atmospheric transfer of microwave signal using electronic phase compensation

    Chen, Shijun; Sun, Fuyu; Bai, Qingsong; Chen, Dawei; Chen, Qiang; Hou, Dong

    2017-10-01

    We demonstrated a timing fluctuation suppression in outdoor laser-based atmospheric radio-frequency transfer over a 110 m one-way free-space link using an electronic phase compensation technique. Timing fluctuations and Allan Deviation are both measured to characterize the instability of transferred frequency incurred during the transfer process. With transferring a 1 GHz microwave signal over a timing fluctuation suppressed transmission link, the total root-mean-square (rms) timing fluctuation was measured to be 920 femtoseconds in 5000 s, with fractional frequency instability on the order of 1 × 10-12 at 1 s, and order of 2 × 10-16 at 1000 s. This atmospheric frequency transfer scheme with the timing fluctuation suppression technique can be used to fast build an atomic clock-based frequency free-space transmission link since its stability is superior to a commercial Cs and Rb clock.

  17. Trends in Cochlear Implants

    Zeng, Fan-Gang

    2004-01-01

    More than 60,000 people worldwide use cochlear implants as a means to restore functional hearing. Although individual performance variability is still high, an average implant user can talk on the phone in a quiet environment. Cochlear-implant research has also matured as a field, as evidenced by the exponential growth in both the patient population and scientific publication. The present report examines current issues related to audiologic, clinical, engineering, anatomic, and physiologic as...

  18. Quercetin suppresses insulin receptor signaling through inhibition of the insulin ligand–receptor binding and therefore impairs cancer cell proliferation

    Wang, Feng [Department of Gastroenterology, The Tenth People’s Hospital of Shanghai, Tongji University, Shanghai 200072 (China); Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030 (United States); Yang, Yong, E-mail: yyang@houstonmethodist.org [Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030 (United States); Department of Medicine, Weill Cornell Medical College, New York, NY 10065 (United States)

    2014-10-03

    Graphical abstract: - Highlights: • Quercetin inhibits insulin ligand–receptor interactions. • Quercetin reduces downstream insulin receptor signaling. • Quercetin blocks insulin induced glucose uptake. • Quercetin suppresses insulin stimulated cancer cell proliferation and tumor growth. - Abstract: Although the flavonoid quercetin is known to inhibit activation of insulin receptor signaling, the inhibitory mechanism is largely unknown. In this study, we demonstrate that quercetin suppresses insulin induced dimerization of the insulin receptor (IR) through interfering with ligand–receptor interactions, which reduces the phosphorylation of IR and Akt. This inhibitory effect further inhibits insulin stimulated glucose uptake due to decreased cell membrane translocation of glucose transporter 4 (GLUT4), resulting in impaired cancer cell proliferation. The effect of quercetin in inhibiting tumor growth was also evident in an in vivo model, indicating a potential future application for quercetin in the treatment of cancers.

  19. Quercetin suppresses insulin receptor signaling through inhibition of the insulin ligand–receptor binding and therefore impairs cancer cell proliferation

    Wang, Feng; Yang, Yong

    2014-01-01

    Graphical abstract: - Highlights: • Quercetin inhibits insulin ligand–receptor interactions. • Quercetin reduces downstream insulin receptor signaling. • Quercetin blocks insulin induced glucose uptake. • Quercetin suppresses insulin stimulated cancer cell proliferation and tumor growth. - Abstract: Although the flavonoid quercetin is known to inhibit activation of insulin receptor signaling, the inhibitory mechanism is largely unknown. In this study, we demonstrate that quercetin suppresses insulin induced dimerization of the insulin receptor (IR) through interfering with ligand–receptor interactions, which reduces the phosphorylation of IR and Akt. This inhibitory effect further inhibits insulin stimulated glucose uptake due to decreased cell membrane translocation of glucose transporter 4 (GLUT4), resulting in impaired cancer cell proliferation. The effect of quercetin in inhibiting tumor growth was also evident in an in vivo model, indicating a potential future application for quercetin in the treatment of cancers

  20. Tinnitus and Sleep Difficulties After Cochlear Implantation.

    Pierzycki, Robert H; Edmondson-Jones, Mark; Dawes, Piers; Munro, Kevin J; Moore, David R; Kitterick, Pádraig T

    To estimate and compare the prevalence of and associations between tinnitus and sleep difficulties in a sample of UK adult cochlear implant users and those identified as potential candidates for cochlear implantation. The study was conducted using the UK Biobank resource, a population-based cohort of 40- to 69-year olds. Self-report data on hearing, tinnitus, sleep difficulties, and demographic variables were collected from cochlear implant users (n = 194) and individuals identified as potential candidates for cochlear implantation (n = 211). These "candidates" were selected based on (i) impaired hearing sensitivity, inferred from self-reported hearing aid use and (ii) impaired hearing function, inferred from an inability to report words accurately at negative signal to noise ratios on an unaided closed-set test of speech perception. Data on tinnitus (presence, persistence, and related distress) and on sleep difficulties were analyzed using logistic regression models controlling for gender, age, deprivation, and neuroticism. The prevalence of tinnitus was similar among implant users (50%) and candidates (52%; p = 0.39). However, implant users were less likely to report that their tinnitus was distressing at its worst (41%) compared with candidates (63%; p = 0.02). The logistic regression model suggested that this difference between the two groups could be explained by the fact that tinnitus was less persistent in implant users (46%) compared with candidates (72%; p reported difficulties with sleep were similar among implant users (75%) and candidates (82%; p = 0.28), but participants with tinnitus were more likely to report sleep difficulties than those without (p explanation is supported by the similar prevalence of sleep problems among implant users and potential candidates for cochlear implantation, despite differences between the groups in tinnitus persistence and related emotional distress. Cochlear implantation may therefore not be an appropriate intervention

  1. [Morphologic feature and cochlear implant surgical approach for cochlear modiolus deficiency].

    Zhang, Daoxing

    2014-09-01

    To review the classification of cochlear modiolus deficiency and decision on surgical approach for above case,in order to provide mastery for cochlear implant (CI) indication. Basing on temporal bone HRCT pre-operation, CI subjects with modiolus deficiency were defined as following groups: (1) deficiency caused by cochlear dysplasia (Mondini malformation); (2) deficiency caused by dysplasia of cochlear and vestibule (Common cavity malformation); (3) deficiency caused by absence of internal acoustic meatus fundus (IP-III malformation). Three types of surgical approach were utilized: type I, electrode array was introduced through facial recess, enlarged the round window, type II, opened the surface of chchlea, electrode array was introduced through facial recess, fenestration on posterior promontory and then inserted around lateral wall of inner-cochlear cavity. type III, electrode array was introduce through fenestration of lateral semicircular canal and then placed close to the bony wall of common cavity. One hundred and sixty-six cochlear modiolus deficiency cases were identified into 3 groups as following: 135 Mondini malformation cases into group a, 18 common cavity malformation cases into group b, and 13 IP-III malformation cases into group c. Surgical approach: type I were used in 136 cases (123 Mondini cases and 13 IP-III cases), while approach type II in 12 cases (12 Mondini cases), and approach type III in 18 cases (18 common cavity cases). Income post-operation of CI: For group a (Mondini malformation), post-activation mean hearing threshold in sound field was 65 dB, speech recognition score is 95% (single finals test) and 25% (signal initials test), while it was 80 dB, 60% and 0 for group b (Conmon cavity malformation), and it was 55 dB, 100% and 45% for group c (IP-III malformation). The income of speech recognition score for cochlear modiolus deficiency was relatively poor, group b was worst and group c was best, while group a moderate.

  2. Major signal suppression from metal ion clusters in SFC/ESI-MS - Cause and effects.

    Haglind, Alfred; Hedeland, Mikael; Arvidsson, Torbjörn; Pettersson, Curt E

    2018-05-01

    The widening application area of SFC-MS with polar analytes and water-containing samples facilitates the use of quick and simple sample preparation techniques such as "dilute and shoot" and protein precipitation. This has also introduced new polar interfering components such as alkali metal ions naturally abundant in e.g. blood plasma and urine, which have shown to be retained using screening conditions in SFC/ESI-TOF-MS and causing areas of major ion suppression. Analytes co-eluting with these clusters will have a decreased signal intensity, which might have a major effect on both quantification and identification. When investigating the composition of the alkali metal clusters using accurate mass and isotopic pattern, it could be concluded that they were previously not described in the literature. Using NaCl and KCl standards and different chromatographic conditions, varying e.g. column and modifier, the clusters proved to be formed from the alkali metal ions in combination with the alcohol modifier and make-up solvent. Their compositions were [(XOCH 3 ) n  + X] + , [(XOH) n  + X] + , [(X 2 CO 3 ) n  + X] + and [(XOOCOCH 3 ) n  + X] + for X = Na + or K + in ESI+. In ESI-, the clusters depended more on modifier, with [(XCl) n  + Cl] - and [(XOCH 3 ) n  + OCH 3 ] - mainly formed in pure methanol and [(XOOCH) n  + OOCH] - when 20 mM NH 4 Fa was added. To prevent the formation of the clusters by avoiding methanol as modifier might be difficult, as this is a widely used modifier providing good solubility when analyzing polar compounds in SFC. A sample preparation with e.g. LLE would remove the alkali ions, however also introducing a time consuming and discriminating step into the method. Since the alkali metal ions were retained and affected by chromatographic adjustments as e.g. mobile phase modifications, a way to avoid them could therefore be chromatographic tuning, when analyzing samples containing them. Copyright © 2018 Elsevier

  3. Coding strategies for cochlear implants under adverse environments

    Tahmina, Qudsia

    Cochlear implants are electronic prosthetic devices that restores partial hearing in patients with severe to profound hearing loss. Although most coding strategies have significantly improved the perception of speech in quite listening conditions, there remains limitations on speech perception under adverse environments such as in background noise, reverberation and band-limited channels, and we propose strategies that improve the intelligibility of speech transmitted over the telephone networks, reverberated speech and speech in the presence of background noise. For telephone processed speech, we propose to examine the effects of adding low-frequency and high- frequency information to the band-limited telephone speech. Four listening conditions were designed to simulate the receiving frequency characteristics of telephone handsets. Results indicated improvement in cochlear implant and bimodal listening when telephone speech was augmented with high frequency information and therefore this study provides support for design of algorithms to extend the bandwidth towards higher frequencies. The results also indicated added benefit from hearing aids for bimodal listeners in all four types of listening conditions. Speech understanding in acoustically reverberant environments is always a difficult task for hearing impaired listeners. Reverberated sounds consists of direct sound, early reflections and late reflections. Late reflections are known to be detrimental to speech intelligibility. In this study, we propose a reverberation suppression strategy based on spectral subtraction to suppress the reverberant energies from late reflections. Results from listening tests for two reverberant conditions (RT60 = 0.3s and 1.0s) indicated significant improvement when stimuli was processed with SS strategy. The proposed strategy operates with little to no prior information on the signal and the room characteristics and therefore, can potentially be implemented in real-time CI

  4. Signal alteration of the cochlear perilymph on 3 different sequences after intratympanic Gd-DTPA administration at 3 tesla. Comparison of 3D-FLAIR, 3D-T1-weighted imaging, and 3D-CISS

    Yamazaki, Masahiro; Naganawa, Shinji; Kawai, Hisashi; Nihashi, Takashi; Nakashima, Tsutomu

    2010-01-01

    Three-dimensional fluid-attenuated inversion recovery (3D-FLAIR) imaging after intratympanic gadolinium injection is useful for pathophysiologic and morphologic analysis of the inner ear. However, statistical analysis of differences in inner ear signal intensity among 3D-FLAIR and other sequences has not been reported. We evaluated the signal intensity of cochlear fluid on each of 3D-FLAIR, 3D-T 1 -weighted imaging (T 1 WI), and 3D-constructive interference in the steady state (CISS) to clarify the differences in contrast effect among these 3 sequences using intratympanic gadolinium injection. Twenty-one patients underwent 3D-FLAIR, 3D-T 1 WI, and 3D-CISS imaging at 3 tesla 24 hours after intratympanic injection of gadolinium. We determined regions of interest of the cochleae (C) and medulla oblongata (M) on each image, evaluated the signal intensity ratio between C and M (CM ratio), and determined the ratio of cochlear signal intensity of the injected side to that of the non-injected side (contrast value). The CM ratio of the injected side (3.00±1.31, range, 0.53 to 4.88, on 3D-FLAIR; 0.83±0.30, range, 0.36 to 1.58 on 3D-T 1 WI) was significantly higher than that of the non-injected side (0.52±0.14, range, 0.30 to 0.76 on 3D-FLAIR; 0.49±0.11, range, 0.30 to 0.71 on 3D-T 1 WI) on 3D-FLAIR and 3D-T 1 WI (P 1 WI (1.73±0.60 range, 0.98 to 3.09) (P<0.001). The 3D-FLAIR sequence is the most sensitive for observing alteration in inner ear fluid signal after intratympanic gadolinium injection. Our results warrant use of 3D-FLAIR as a sensitive imaging technique to clarify the pathological and morphological mechanisms of disorders of the inner ear. (author)

  5. Xenopus Zic3 controls notochord and organizer development through suppression of the Wnt/β-catenin signaling pathway.

    Fujimi, Takahiko J; Hatayama, Minoru; Aruga, Jun

    2012-01-15

    Zic3 controls neuroectodermal differentiation and left-right patterning in Xenopus laevis embryos. Here we demonstrate that Zic3 can suppress Wnt/β-catenin signaling and control development of the notochord and Spemann's organizer. When we overexpressed Zic3 by injecting its RNA into the dorsal marginal zone of 2-cell-stage embryos, the embryos lost mesodermal dorsal midline structures and showed reduced expression of organizer markers (Siamois and Goosecoid) and a notochord marker (Xnot). Co-injection of Siamois RNA partially rescued the reduction of Xnot expression caused by Zic3 overexpression. Because the expression of Siamois in the organizer region is controlled by Wnt/β-catenin signaling, we subsequently examined the functional interaction between Zic3 and Wnt signaling. Co-injection of Xenopus Zic RNAs and β-catenin RNA with a reporter responsive to the Wnt/β-catenin cascade indicated that Zic1, Zic2, Zic3, Zic4, and Zic5 can all suppress β-catenin-mediated transcriptional activation. In addition, co-injection of Zic3 RNA inhibited the secondary axis formation caused by ventral-side injection of β-catenin RNA in Xenopus embryos. Zic3-mediated Wnt/β-catenin signal suppression required the nuclear localization of Zic3, and involved the reduction of β-catenin nuclear transport and enhancement of β-catenin degradation. Furthermore, Zic3 co-precipitated with Tcf1 (a β-catenin co-factor) and XIC (I-mfa domain containing factor required for dorsoanterior development). The findings in this report produce a novel system for fine-tuning of Wnt/β-catenin signaling. Copyright © 2011. Published by Elsevier Inc.

  6. ASH1L Suppresses Matrix Metalloproteinase through Mitogen-activated Protein Kinase Signaling Pathway in Pulpitis.

    Bei, Yin; Tianqian, Hui; Fanyuan, Yu; Haiyun, Luo; Xueyang, Liao; Jing, Yang; Chenglin, Wang; Ling, Ye

    2017-02-01

    with in vitro results, ASH1L was found in increased quantities in experimental dental pulpitis tissue. ASH1L knockdown markedly up-regulated the occurrence of MMP-1, MMP-2, and MMP-13. It also exercised an impact on the enzymatic activity of MMP-2 in HDPCs that had been stimulated with TNF-α. ASH1L knockdown activated the MAPK signal pathway in TNF-α-triggered HDPCs, the inhibition of which reversed the induction of MMPs. Our research identifies a mechanism by which ASH1L suppresses the occurrence and operation of MMPs during pulpitis. It does this through the MAPK pathway. Copyright © 2016 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

  7. Molecular mechanisms involved in cochlear implantation trauma and the protection of hearing and auditory sensory cells by inhibition of c-Jun-N-terminal kinase signaling.

    Eshraghi, Adrien A; Gupta, Chhavi; Van De Water, Thomas R; Bohorquez, Jorge E; Garnham, Carolyn; Bas, Esperanza; Talamo, Victoria Maria

    2013-03-01

    To investigate the molecular mechanisms involved in electrode insertion trauma (EIT) and to test the otoprotective effect of locally delivered AM-111. An animal model of cochlear implantation. Guinea pigs' hearing thresholds were measured by auditory brainstem response (ABR) before and after cochlear implantation in four groups: EIT; pretreated with hyaluronate gel 30 minutes before EIT (EIT+Gel); pretreated with hyaluronate gel/AM-111 30 minutes before EIT (EIT+AM-111); and unoperated contralateral ears as controls. Neurofilament, synapsin, and fluorescein isothiocyanate (FITC)-phalloidin staining for hair cell counts were performed at 90 days post-EIT. Immunostaining for 4-hydroxy-2-nonenal (HNE), activated caspase-3, CellROX, and phospho-c-Jun were performed at 24 hours post-EIT. ABR thresholds increased post-EIT in the cochleae of EIT only and EIT+Gel treated animals. There was no significant increase in hearing thresholds in cochleae from either EIT+AM-111 treated or unoperated control ears. AM-111 protection of organ of Corti sensory elements (i.e., hair cells [HCs], supporting cells [SCs], nerve fibers, and synapses) was documented at 3 months post-EIT. Immunostaining of 24-hour post-EIT specimens demonstrated increased levels of HNE in HCs and SCs; increased levels of CellROX and activation of caspase-3 was observed only in SCs, and phosphorylation of c-Jun occurred only in HCs of the EIT-only and EIT+Gel specimens. There was no immunostaining for either HNE, CellROX, caspase-3, or phospho-c-Jun in the organ of Corti specimens from AM-111 treated cochleae. Molecular mechanisms involved in programmed cell death of HCs are different than the ones involved in programmed cell death of SCs. Local delivery of AM-111 provided a significant level of protection against EIT-induced hearing losses, HC losses, and damage to neural elements. Copyright © 2012 The American Laryngological, Rhinological, and Otological Society, Inc.

  8. Hyaluronan suppresses prostate tumor cell proliferation through diminished expression of N-cadherin and aberrant growth factor receptor signaling

    Bharadwaj, Alamelu G.; Goodrich, Nathaniel P.; McAtee, Caitlin O.; Haferbier, Katie; Oakley, Gregory G.; Wahl, James K.; Simpson, Melanie A.

    2011-01-01

    Hyaluronan (HA) production has been functionally implicated in prostate tumorigenesis and metastasis. We previously used prostate tumor cells overexpressing the HA synthesizing enzyme HAS3 or the clinically relevant hyaluronidase Hyal1 to show that excess HA production suppresses tumor growth, while HA turnover accelerates spontaneous metastasis from the prostate. Here, we examined pathways responsible for effects of HAS3 and Hyal1 on tumor cell phenotype. Detailed characterization of cell cycle progression revealed that expression of Hyal1 accelerated cell cycle re-entry following synchronization, whereas HAS3 alone delayed entry. Hyal1 expressing cells exhibited a significant reduction in their ability to sustain ERK phosphorylation upon stimulation by growth factors, and in their expression of the cyclin-dependent kinase inhibitor p21. In contrast, HAS3 expressing cells showed prolonged ERK phosphorylation and increased expression of both p21 and p27, in asynchronous and synchronized cultures. Changes in cell cycle regulatory proteins were accompanied by HA-induced suppression of N-cadherin, while E-cadherin expression and β-catenin expression and distribution remained unchanged. Our results are consistent with a model in which excess HA synthesis suppresses cell proliferation by promoting homotypic E-cadherin mediated cell-cell adhesion, consequently signaling to elevate cell cycle inhibitor expression and suppress G1- to S-phase transition.

  9. Neural Substrates of Social Emotion Regulation: A fMRI Study on Imitation and Expressive Suppression to Dynamic Facial Signals

    Pascal eVrticka

    2013-02-01

    Full Text Available Emotion regulation is crucial for successfully engaging in social interactions. Yet, little is known about the neural mechanisms controlling behavioral responses to emotional expressions perceived in the face of other people, which constitute a key element of interpersonal communication. Here, we investigated brain systems involved in social emotion perception and regulation, using functional magnetic resonance imaging (fMRI in 20 healthy participants who saw dynamic facial expressions of either happiness or sadness, and were asked to either imitate the expression or to suppress any expression on their own face (in addition to a gender judgment control task. fMRI results revealed higher activity in regions associated with emotion (e.g., the insula, motor function (e.g., motor cortex, and theory of mind during imitation. Activity in dorsal cingulate cortex was also increased during imitation, possibly reflecting greater action monitoring or conflict with own feeling states. In addition, premotor regions were more strongly activated during both imitation and suppression, suggesting a recruitment of motor control for both the production and inhibition of emotion expressions. Expressive suppression produced increases in dorsolateral and lateral prefrontal cortex typically related to cognitive control. These results suggest that voluntary imitation and expressive suppression modulate brain responses to emotional signals perceived from faces, by up- and down-regulating activity in distributed subcortical and cortical networks that are particularly involved in emotion, action monitoring, and cognitive control.

  10. Simultaneous Suppression of IMD3 and IMD5 in Space TWT by IMD3 and 2HD Signal Injection

    Dongming Zhao

    2017-01-01

    Full Text Available This paper presents a signal injection technology showing significant reductions in both 3rd-order and 5th-order intermodulation distortions (IMD3 and IMD5 in space traveling wave tube (STWT. By applying the IMD3 to the IMD5 ratio (TFR as measures of location, the simultaneous suppressions of IMD3 and IMD5 in TWT are achieved by second harmonic distortion (2HD and IMD3 injection. According to the research on theoretical analysis and computer simulation, the optimum amplitude and phase parameters of the injected signal for maximum simultaneous suppressions are obtained. Then an experiment system is established based on vector network analyzer, optimum TFR are 2.1 dB and 12.5 dB, respectively, by second harmonic and IM3 injection, and the output powers of IMD3 and IMD5 were decreased. TFR with IMD3 injection is smaller than that with second harmonic injection in STWT, and the experiment system is more straightforward and easy to operate. Thus, the IMD3 injection performs better than that of second harmonic injection to suppress IMD5s for the narrow-band STWT.

  11. Input signal shaping based on harmonic frequency response function for suppressing nonlinear optical frequency in frequency-scanning interferometry

    Zhu, Yu; Liu, Zhigang; Deng, Wen; Deng, Zhongwen

    2018-05-01

    Frequency-scanning interferometry (FSI) using an external cavity diode laser (ECDL) is essential for many applications of the absolute distance measurement. However, owing to the hysteresis and creep of the piezoelectric actuator inherent in the ECDL, the optical frequency scanning exhibits a nonlinearity that seriously affects the phase extraction accuracy of the interference signal and results in the reduction of the measurement accuracy. To suppress the optical frequency nonlinearity, a harmonic frequency synthesis method for shaping the desired input signal instead of the original triangular wave is presented. The effectiveness of the presented shaping method is demonstrated through the comparison of the experimental results. Compared with an incremental Renishaw interferometer, the standard deviation of the displacement measurement of the FSI system is less than 2.4 μm when driven by the shaped signal.

  12. CAPE suppresses migration and invasion of prostate cancer cells via activation of non-canonical Wnt signaling.

    Tseng, Jen-Chih; Lin, Ching-Yu; Su, Liang-Chen; Fu, Hsiao-Hui; Yang, Shiaw-Der; Chuu, Chih-Pin

    2016-06-21

    Prostate cancer (PCa) was the fifth most common cancer overall in the world. More than 80% of patients died from PCa developed bone metastases. Caffeic acid phenethyl ester (CAPE) is a main bioactive component of honeybee hive propolis. Transwell and wound healing assays demonstrated that CAPE treatment suppressed the migration and invasion of PC-3 and DU-145 PCa cells. Gelatin zymography and Western blotting indicated that CAPE treatment reduced the abundance and activity of MMP-9 and MMP-2. Analysis using Micro-Western Array (MWA), a high-throughput antibody-based proteomics platform with 264 antibodies detecting signaling proteins involved in important pathways indicated that CAPE treatment induced receptor tyrosine kinase-like orphan receptor 2 (ROR2) in non-canonical Wnt signaling pathway but suppressed abundance of β-catenin, NF-κB activity, PI3K-Akt signaling, and epithelial-mesenchymal transition (EMT). Overexpression or knockdown of ROR2 suppressed or enhanced cell migration of PC-3 cells, respectively. TCF-LEF promoter binding assay revealed that CAPE treatment reduced canonical Wnt signaling. Intraperitoneal injection of CAPE reduced the metastasis of PC-3 xenografts in tail vein injection nude mice model. Immunohistochemical staining demonstrated that CAPE treatment increased abundance of ROR2 and Wnt5a but decreased protein expression of Ki67, Frizzle 4, NF-κB p65, MMP-9, Snail, β-catenin, and phosphorylation of IκBα. Clinical evidences suggested that genes affected by CAPE treatment (CTNNB1, RELA, FZD5, DVL3, MAPK9, SNAl1, ROR2, SMAD4, NFKBIA, DUSP6, and PLCB3) correlate with the aggressiveness of PCa. Our study suggested that CAPE may be a potential therapeutic agent for patients with advanced PCa.

  13. The preoperative imaging evaluation for cochlear implantation

    Liu Zhonglin; Wang Zhenchang; Fu Lin; Li Yong; Xian Junfang; Yang Bentao; Lan Baosen; Li Yongxin; Zheng Jun; Song Yan; Liu Bo; Chen Xueqing; He Haili

    2006-01-01

    Objective: To analyze CT and MRI findings of temporal bone and to evaluate preoperative diagnostic value for cochlear implantation. Methods: One hundred and sixty candidates for cochlear implantation were examined with axial CT scan, 64 of them also with coronal CT scan, and 119 patients with MRI. Results: All of 320 ears were well-aerated, and 206 ears had mastoid cavities extended posteriorly to the sigmoid sinus. The length from posterior-lateral tympanic wall to the outer cortex was (2.34±0.42) mm (left side) and (2.25±0.40) mm (right side) (U=1.887, P 1 and T 2 signal on MRI. The congenital malformations of inner ear occurred in 67 ears, including complete dysplasia in 1 ear, cochlear hypodysplasia in 6 ears, Mondini deformation in 5 ears, enlarged vestibular aqueduct in 40 ears, dysplastic semicircular canal and the vestibulae in 10 ears, and narrowing of internal auditory canal in 5 ears. Conclusion: Preoperative imaging examinations can provide critical information to ensure successful cochlear' implantation. (authors)

  14. High intensity signal of the posterior pituitary. A study with horizontal direction of frequency-encoding and fat suppression MR techniques

    Arslan, A.

    1999-01-01

    Purpose: To evaluate the consistency of fat in the high intensity signals of the normal neurohypophysis and to differentiate the high signal of posterior pituitary from that of dorsum sella. Sagittal SE T1-weighted images with frequency encoding in the horizontal direction were used in order to differentiate the high signal of posterior pituitary and dorsum sella by the vertically-oriented chemical shift artifact. Material and methods: The sellae of 46 normal volunteers were imaged with a commercially available fat suppression technique and SE sequences with frequency encoding in vertical (25 cases) and horizontal (21 cases) axes. Results: The high signal intensity was absent in 9% of the normal volunteers with no predilection to any specific age group. None of the cases with posterior pituitary high intensity signals showed suppression of the signal with fat suppression technique. A fat suppression technique was helpful in documenting the hyperintensity in 7% of normal volunteers. Nineteen of the 21 (90%) cases with high signal intensity were detected by routine SE T1-weighted images, whereas 18 of the 19 (95%) cases were detected by imaging with frequency encoding in the horizontal direction. Conclusion: The high signal does not indicate the presence of fat. Fat suppression technique and a horizontal direction of frequency encoding help in differentiating the high signal of the neurohypophysis from that of dorsum sella. (orig.)

  15. First-order signals in compact QED with monopole suppressed boundaries

    Lippert, T.; Schilling, K.; Forschungszentrum Juelich GmbH

    1995-01-01

    Pure gauge compact QED on hypercubic lattices is considered with periodically closed monopole currents suppressed. We compute observables on sublattices which are nested around the centre of the lattice in order to locate regions where translation symmetry is approximately recovered. Our Monte Carlo simulations on 24 4 -lattices give indications for a first-order nature of the U(1) phase transition. ((orig.))

  16. Canonical TGF-β Signaling Negatively Regulates Neuronal Morphogenesis through TGIF/Smad Complex-Mediated CRMP2 Suppression.

    Nakashima, Hideyuki; Tsujimura, Keita; Irie, Koichiro; Ishizu, Masataka; Pan, Miao; Kameda, Tomonori; Nakashima, Kinichi

    2018-05-16

    Functional neuronal connectivity requires proper neuronal morphogenesis and its dysregulation causes neurodevelopmental diseases. Transforming growth factor-β (TGF-β) family cytokines play pivotal roles in development, but little is known about their contribution to morphological development of neurons. Here we show that the Smad-dependent canonical signaling of TGF-β family cytokines negatively regulates neuronal morphogenesis during brain development. Mechanistically, activated Smads form a complex with transcriptional repressor TG-interacting factor (TGIF), and downregulate the expression of a neuronal polarity regulator, collapsin response mediator protein 2. We also demonstrate that TGF-β family signaling inhibits neurite elongation of human induced pluripotent stem cell-derived neurons. Furthermore, the expression of TGF-β receptor 1, Smad4, or TGIF, which have mutations found in patients with neurodevelopmental disorders, disrupted neuronal morphogenesis in both mouse (male and female) and human (female) neurons. Together, these findings suggest that the regulation of neuronal morphogenesis by an evolutionarily conserved function of TGF-β signaling is involved in the pathogenesis of neurodevelopmental diseases. SIGNIFICANCE STATEMENT Canonical transforming growth factor-β (TGF-β) signaling plays a crucial role in multiple organ development, including brain, and mutations in components of the signaling pathway associated with several human developmental disorders. In this study, we found that Smads/TG-interacting factor-dependent canonical TGF-β signaling regulates neuronal morphogenesis through the suppression of collapsin response mediator protein-2 (CRMP2) expression during brain development, and that function of this signaling is evolutionarily conserved in the mammalian brain. Mutations in canonical TGF-β signaling factors identified in patients with neurodevelopmental disorders disrupt the morphological development of neurons. Thus, our

  17. Hotair mediates hepatocarcinogenesis through suppressing miRNA-218 expression and activating P14 and P16 signaling.

    Fu, Wei-Ming; Zhu, Xiao; Wang, Wei-Mao; Lu, Ying-Fei; Hu, Bao-Guang; Wang, Hua; Liang, Wei-Cheng; Wang, Shan-Shan; Ko, Chun-Hay; Waye, Mary Miu-Yee; Kung, Hsiang-Fu; Li, Gang; Zhang, Jin-Fang

    2015-10-01

    Long non-coding RNA Hotair has been considered as a pro-oncogene in multiple cancers. Although there is emerging evidence that reveals its biological function and the association with clinical prognosis, the precise mechanism remains largely elusive. We investigated the function and mechanism of Hotair in hepatocellular carcinoma (HCC) cell models and a xenograft mouse model. The regulatory network between miR-218 and Hotair was elucidated by RNA immunoprecipitation and luciferase reporter assays. Finally, the correlation between Hotair, miR-218 and the target gene Bmi-1 were evaluated in 52 paired HCC specimens. In this study, we reported that Hotair negatively regulated miR-218 expression in HCC, which might be mediated through an EZH2-targeting-miR-218-2 promoter regulatory axis. Further investigation revealed that Hotair knockdown dramatically inhibited cell viability and induced G1-phase arrest in vitro and suppressed tumorigenicity in vivo by promoting miR-218 expression. Oncogene Bmi-1 was shown to be a functional target of miR-218, and the main downstream targets signaling, P16(Ink4a) and P14(ARF), were activated in Hotair-suppressed tumorigenesis. In primary human HCC specimens, Hotair and Bmi-1 were concordantly upregulated whereas miR-218 was downregulated in these tissues. Furthermore, Hotair was inversely associated with miR-218 expression and positively correlated with Bmi-1 expression in these clinical tissues. Hotair silence activates P16(Ink4a) and P14(ARF) signaling by enhancing miR-218 expression and suppressing Bmi-1 expression, resulting in the suppression of tumorigenesis in HCC. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  18. Growth of Murine Splenic Tissue Is Suppressed by Lymphotoxin β-Receptor Signaling (LTβR) Originating from Splenic and Non-Splenic Tissues

    Milićević, Novica M; Nohroudi, Klaus; Schmidt, Friederike

    2016-01-01

    LTβR signaling. Two-dimensional differential gel electrophoresis and subsequent mass spectrometry of stromal splenic tissue was applied to screen for potential factors mediating the LTβR dependent suppressive activity. Thus, LTβR dependent growth suppression is involved in regulating the size...

  19. Picrasidine I from Picrasma Quassioides Suppresses Osteoclastogenesis via Inhibition of RANKL Induced Signaling Pathways and Attenuation of ROS Production

    Lingbo Kong

    2017-10-01

    Full Text Available Background/Aims: Osteoporosis is a metabolic bone disorder that tortures about millions of people worldwide. Recent study demonstrated agents derived from picrasma quassioides is a promising drug for targets multiple signaling pathways. However its potential in treatment of bone loss has not been fully understood. Methods: The bone marrow macrophages (BMMs were cultured and induced with M-CSF and RANKL followed by picrasidine I (PI treatment. Then the effects of PI on osteoclast formation were evaluated by counting tartrate-resistant acid phosphatase (TRAP-positive multinucleated cells. Moreover, effects of PI on bone resorption activity of mature osteoclast were studied through bone resorption pit counting and actin ring structure analysis. Further, the involved potential signaling pathways cross-talking were investigated by performed Western blotting and quantitative real-time PCR examination. Results: Results demonstrated PI strongly inhibited RANKL induced osteoclast formation from its precursors. Mechanistically, the inhibitory effect of PI on osteoclast differentiation was due to the suppression of osteoclastogenic transcription factors, c-Fos and NFATc1. Moreover, PI markedly blocked the RANKL-induced osteoclastogenesis by attenuating MAPKs and NF-κB signaling pathways. In addition, PI decreased the ROS generation in osteoclast and osteoblast. Conclusion: Taken together our data demonstrate that PI has antiosteoclastogenic effect by inhibiting inflammation induced activation of MAPKs, NF-κB and ROS generation followed by suppressing the gene expression of c-Fos and NFATc1 in osteoclast precursors.

  20. A robust multi-frequency mixing algorithm for suppression of rivet signal in GMR inspection of riveted structures

    Safdernejad, Morteza S.; Karpenko, Oleksii; Ye, Chaofeng; Udpa, Lalita; Udpa, Satish

    2016-02-01

    The advent of Giant Magneto-Resistive (GMR) technology permits development of novel highly sensitive array probes for Eddy Current (EC) inspection of multi-layer riveted structures. Multi-frequency GMR measurements with different EC pene-tration depths show promise for detection of bottom layer notches at fastener sites. However, the distortion of the induced magnetic field due to flaws is dominated by the strong fastener signal, which makes defect detection and classification a challenging prob-lem. This issue is more pronounced for ferromagnetic fasteners that concentrate most of the magnetic flux. In the present work, a novel multi-frequency mixing algorithm is proposed to suppress rivet signal response and enhance defect detection capability of the GMR array probe. The algorithm is baseline-free and does not require any assumptions about the sample geometry being inspected. Fastener signal suppression is based upon the random sample consensus (RANSAC) method, which iteratively estimates parameters of a mathematical model from a set of observed data with outliers. Bottom layer defects at fastener site are simulated as EDM notches of different length. Performance of the proposed multi-frequency mixing approach is evaluated on finite element data and experimental GMR measurements obtained with unidirectional planar current excitation. Initial results are promising demonstrating the feasibility of the approach.

  1. Matrine pretreatment improves cardiac function in rats with diabetic cardiomyopathy via suppressing ROS/TLR-4 signaling pathway.

    Liu, Zhong-wei; Wang, Jun-kui; Qiu, Chuan; Guan, Gong-chang; Liu, Xin-hong; Li, Shang-jian; Deng, Zheng-rong

    2015-03-01

    Matrine is an alkaloid from Sophora alopecuroides L, which has shown a variety of pharmacological activities and potential therapeutic value in cardiovascular diseases. In this study we examined the protective effects of matrine against diabetic cardiomyopathy (DCM) in rats. Male SD rats were injected with streptozotocin (STZ) to induce DCM. One group of DCM rats was pretreated with matrine (200 mg·kg(-1)·d(-1), po) for 10 consecutive days before STZ injection. Left ventricular function was evaluated using invasive hemodynamic examination, and myocardiac apoptosis was assessed. Primary rat myocytes were used for in vitro experiments. Intracellular ROS generation, MDA content and GPx activity were determined. Real-time PCR and Western blotting were performed to detect the expression of relevant mRNAs and proteins. DCM rats exhibited abnormally elevated non-fasting blood glucose levels at 4 weeks after STZ injection, and LV function impairment at 16 weeks. The cardiac tissues of DCM rats showed markedly increased apoptosis, excessive ROS production, and activation of TLR-4/MyD-88/caspase-8/caspase-3 signaling. Pretreatment with matrine significantly decreased non-fasting blood glucose levels and improved LV function in DCM rats, which were associated with reducing apoptosis and ROS production, and suppressing TLR-4/MyD-88/caspase-8/caspase-3 signaling in cardiac tissues. Incubation in a high-glucose medium induced oxidative stress and activation of TLR-4/MyD-88 signaling in cultured myocytes in vitro, which were significantly attenuated by pretreatment with N-acetylcysteine. Excessive ROS production in DCM activates the TLR-4/MyD-88 signaling, resulting in cardiomyocyte apoptosis, whereas pretreatment with matrine improves cardiac function via suppressing ROS/TLR-4 signaling pathway.

  2. Leaders in Interdependent Contexts Suppress Nonverbal Assertiveness: A Multilevel Analysis of Japanese University Club Leaders' and Members' Rank Signaling.

    Ito, Atsuki; Gobel, Matthias S; Uchida, Yukiko

    2018-01-01

    Previous research has shown that leadership is signaled through nonverbal assertiveness. However, those studies have been mostly conducted in individualistic cultural contexts, such as in the U.S. Here, we suggest that one important strategy for goal attainment in collectivistic cultures is for leaders to self-regulate their behaviors. Thus, contrary to the previous evidence from individualistic cultural contexts, in collectivistic cultural contexts, leaders might suppress nonverbal assertiveness. To test this possibility, we assessed nonverbal behaviors (NVB) of Japanese leaders and members, and how they were evaluated by observers. We recruited Japanese leaders and members of university clubs and video-recorded them while introducing their club. Then, we coded their nonverbal rank signaling behavior. Finally, we asked a new set of naïve observers to watch these video-clips and to judge targets' suitability for being possible club leaders. Results of a multilevel analysis (level 1: individual participants, level 2: clubs) suggested that the more the club culture focused on tasks (rather than relationships), the more likely were leaders (but not members) of those clubs to suppress their nonverbal assertiveness. Naïve observers judged individuals who restrained from emitting nonverbal assertiveness as being more suitable and worthy club leaders. Thus, our findings demonstrate the cultural fit between contextual effects at the collective level (i.e., cultural orientation of a group) and the signaling and perceiving of social ranks at the individual level (i.e., suppression of nonverbal assertiveness). We discuss the importance of studying the cultural fit between the collective reality that people inhabit and people's psychology for future research in cultural psychology.

  3. Leaders in Interdependent Contexts Suppress Nonverbal Assertiveness: A Multilevel Analysis of Japanese University Club Leaders' and Members' Rank Signaling

    Atsuki Ito

    2018-05-01

    Full Text Available Previous research has shown that leadership is signaled through nonverbal assertiveness. However, those studies have been mostly conducted in individualistic cultural contexts, such as in the U.S. Here, we suggest that one important strategy for goal attainment in collectivistic cultures is for leaders to self-regulate their behaviors. Thus, contrary to the previous evidence from individualistic cultural contexts, in collectivistic cultural contexts, leaders might suppress nonverbal assertiveness. To test this possibility, we assessed nonverbal behaviors (NVB of Japanese leaders and members, and how they were evaluated by observers. We recruited Japanese leaders and members of university clubs and video-recorded them while introducing their club. Then, we coded their nonverbal rank signaling behavior. Finally, we asked a new set of naïve observers to watch these video-clips and to judge targets' suitability for being possible club leaders. Results of a multilevel analysis (level 1: individual participants, level 2: clubs suggested that the more the club culture focused on tasks (rather than relationships, the more likely were leaders (but not members of those clubs to suppress their nonverbal assertiveness. Naïve observers judged individuals who restrained from emitting nonverbal assertiveness as being more suitable and worthy club leaders. Thus, our findings demonstrate the cultural fit between contextual effects at the collective level (i.e., cultural orientation of a group and the signaling and perceiving of social ranks at the individual level (i.e., suppression of nonverbal assertiveness. We discuss the importance of studying the cultural fit between the collective reality that people inhabit and people's psychology for future research in cultural psychology.

  4. Ethylene signaling renders the jasmonate response of Arabidopsis insensitive to future suppression by salicylic acid

    Leon Reyes, H.A.; Du, Y.; Koornneef, A.; Proietti, S.; Körbes, A.P.; Memelink, J.; Pieterse, C.M.J.; Ritsema, T.

    2010-01-01

    Cross-talk between jasmonate (JA), ethylene (ET), and Salicylic acid (SA) signaling is thought to operate as a mechanism to fine-tune induced defenses that are activated in response to multiple attackers. Here, 43 Arabidopsis genotypes impaired in hormone signaling or defense-related processes were

  5. Stem signal suppression in fiber-coupled Al2O3:C dosimetry for 192Ir brachytherapy

    Kertzscher Schwencke, Gustavo Adolfo Vladimir; Andersen, Claus Erik; Edmund, J.M.

    2011-01-01

    was adapted for on-line in-vivo dosimetry using fiber-coupled carbon doped aluminum oxide (Al2O3:C). The technique involved a two-channel optical filtration of the radioluminescence (RL) emitted from a pre-irradiated Al2O3:C crystal with enhanced sensitivity. The system responded linearly in the absorbed dose......The stem signal, composed of fluorescence and Čerenkov light, becomes a significant source of uncertainty in fiber-coupled afterloaded brachytherapy dosimetry when the source dwells near the fiber cable but far from the detector. A stem suppression technique originally developed for scintillators...

  6. Tribbles 3 inhibits brown adipocyte differentiation and function by suppressing insulin signaling

    Jeong, Ha-Won; Choi, Ran Hee; McClellan, Jamie L. [Division of Applied Physiology, Department of Exercise Science, University of South Carolina, Columbia, SC 29208 (United States); Piroli, Gerardo G.; Frizzell, Norma [Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, SC 29208 (United States); Tseng, Yu-Hua; Goodyear, Laurie J. [Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215 (United States); Koh, Ho-Jin, E-mail: kohh@mailbox.sc.edu [Division of Applied Physiology, Department of Exercise Science, University of South Carolina, Columbia, SC 29208 (United States)

    2016-02-19

    Recent studies have demonstrated that adult humans have substantial amounts of functioning brown adipose tissue (BAT). Since BAT has been implicated as an anti-obese and anti-diabetic tissue, it is important to understand the signaling molecules that regulate BAT function. There has been a link between insulin signaling and BAT metabolism as deletion or pharmaceutical inhibition of insulin signaling impairs BAT differentiation and function. Tribbles 3 (TRB3) is a pseudo kinase that has been shown to regulate metabolism and insulin signaling in multiple tissues but the role of TRB3 in BAT has not been studied. In this study, we found that TRB3 expression was present in BAT and overexpression of TRB3 in brown preadipocytes impaired differentiation and decreased expression of BAT markers. Furthermore, TRB3 overexpression resulted in significantly lower oxygen consumption rates for basal and proton leakage, indicating decreased BAT activity. Based on previous studies showing that deletion or pharmaceutical inhibition of insulin signaling impairs BAT differentiation and function, we assessed insulin signaling in brown preadipocytes and BAT in vivo. Overexpression of TRB3 in cells impaired insulin-stimulated IRS1 and Akt phosphorylation, whereas TRB3KO mice displayed improved IRS1 and Akt phosphorylation. Finally, deletion of IRS1 abolished the function of TRB3 to regulate BAT differentiation and metabolism. These data demonstrate that TRB3 inhibits insulin signaling in BAT, resulting in impaired differentiation and function. - Highlights: • TRB3 is expressed in brown adipose tissue and its expression is increased during differentiation. • Overexpression of TRB3 inhibits differentiation and its activity. • Overexpression of TRB3 in brown preadipocytes inhibits insulin signaling. • TRB3KO mice displays improved insulin signaling in brown adipose tissue. • Insulin signaling is required for the effects of TRB3 to regulate brown adipose tissue differentiation and

  7. Tribbles 3 inhibits brown adipocyte differentiation and function by suppressing insulin signaling

    Jeong, Ha-Won; Choi, Ran Hee; McClellan, Jamie L.; Piroli, Gerardo G.; Frizzell, Norma; Tseng, Yu-Hua; Goodyear, Laurie J.; Koh, Ho-Jin

    2016-01-01

    Recent studies have demonstrated that adult humans have substantial amounts of functioning brown adipose tissue (BAT). Since BAT has been implicated as an anti-obese and anti-diabetic tissue, it is important to understand the signaling molecules that regulate BAT function. There has been a link between insulin signaling and BAT metabolism as deletion or pharmaceutical inhibition of insulin signaling impairs BAT differentiation and function. Tribbles 3 (TRB3) is a pseudo kinase that has been shown to regulate metabolism and insulin signaling in multiple tissues but the role of TRB3 in BAT has not been studied. In this study, we found that TRB3 expression was present in BAT and overexpression of TRB3 in brown preadipocytes impaired differentiation and decreased expression of BAT markers. Furthermore, TRB3 overexpression resulted in significantly lower oxygen consumption rates for basal and proton leakage, indicating decreased BAT activity. Based on previous studies showing that deletion or pharmaceutical inhibition of insulin signaling impairs BAT differentiation and function, we assessed insulin signaling in brown preadipocytes and BAT in vivo. Overexpression of TRB3 in cells impaired insulin-stimulated IRS1 and Akt phosphorylation, whereas TRB3KO mice displayed improved IRS1 and Akt phosphorylation. Finally, deletion of IRS1 abolished the function of TRB3 to regulate BAT differentiation and metabolism. These data demonstrate that TRB3 inhibits insulin signaling in BAT, resulting in impaired differentiation and function. - Highlights: • TRB3 is expressed in brown adipose tissue and its expression is increased during differentiation. • Overexpression of TRB3 inhibits differentiation and its activity. • Overexpression of TRB3 in brown preadipocytes inhibits insulin signaling. • TRB3KO mice displays improved insulin signaling in brown adipose tissue. • Insulin signaling is required for the effects of TRB3 to regulate brown adipose tissue differentiation and

  8. Effect of cochlear nerve electrocautery on the adult cochlear nucleus.

    Iseli, Claire E; Merwin, William H; Klatt-Cromwell, Cristine; Hutson, Kendall A; Ewend, Matthew G; Adunka, Oliver F; Fitzpatrick, Douglas C; Buchman, Craig A

    2015-04-01

    Electrocauterization and subsequent transection of the cochlear nerve induce greater injury to the cochlear nucleus than sharp transection alone. Some studies show that neurofibromatosis Type 2 (NF2) patients fit with auditory brainstem implants (ABIs) fail to achieve speech perception abilities similar to ABI recipients without NF2. Reasons for these differences remain speculative. One hypothesis posits poorer performance to surgically induced trauma to the cochlear nucleus from electrocautery. Sustained electrosurgical depolarization of the cochlear nerve may cause excitotoxic-induced postsynaptic nuclear injury. Equally plausible is that cautery in the vicinity of the cochlear nucleus induces necrosis. The cochlear nerve was transected in anesthetized adult gerbils sharply with or without bipolar electrocautery at varying intensities. Gerbils were perfused at 1, 3, 5, and 7 days postoperatively; their brainstem and cochleas were embedded in paraffin and sectioned at 10 μm. Alternate sections were stained with flourescent markers for neuronal injury or Nissl substance. In additional experiments, anterograde tracers were applied directly to a sectioned eighth nerve to verify that fluorescent-labeled profiles seen were terminating auditory nerve fibers. Cochlear nerve injury was observed from 72 hours postoperatively and was identical across cases regardless of surgical technique. Postsynaptic cochlear nucleus injury was not seen after distal transection of the nerve. By contrast, proximal transection was associated with trauma to the cochlear nucleus. Distal application of bipolar electrocautery seems safe for the cochlear nucleus. Application near the root entry zone must be used cautiously because this may compromise nuclear viability needed to support ABI stimulation.

  9. NANOS2 acts downstream of glial cell line-derived neurotrophic factor signaling to suppress differentiation of spermatogonial stem cells.

    Sada, Aiko; Hasegawa, Kazuteru; Pin, Pui Han; Saga, Yumiko

    2012-02-01

    Stem cells are maintained by both stem cell-extrinsic niche signals and stem cell-intrinsic factors. During murine spermatogenesis, glial cell line-derived neurotrophic factor (GDNF) signal emanated from Sertoli cells and germ cell-intrinsic factor NANOS2 represent key regulators for the maintenance of spermatogonial stem cells. However, it remains unclear how these factors intersect in stem cells to control their cellular state. Here, we show that GDNF signaling is essential to maintain NANOS2 expression, and overexpression of Nanos2 can alleviate the stem cell loss phenotype caused by the depletion of Gfra1, a receptor for GDNF. By using an inducible Cre-loxP system, we show that NANOS2 expression is downregulated upon the conditional knockout (cKO) of Gfra1, while ectopic expression of Nanos2 in GFRA1-negative spermatogonia does not induce de novo GFRA1 expression. Furthermore, overexpression of Nanos2 in the Gfra1-cKO testes prevents precocious differentiation of the Gfra1-knockout stem cells and partially rescues the stem cell loss phenotypes of Gfra1-deficient mice, indicating that the stem cell differentiation can be suppressed by NANOS2 even in the absence of GDNF signaling. Taken together, we suggest that NANOS2 acts downstream of GDNF signaling to maintain undifferentiated state of spermatogonial stem cells. Copyright © 2011 AlphaMed Press.

  10. A simple predistortion technique for suppression of nonlinear effects in periodic signals generated by nonlinear transducers

    Novak, A.; Simon, L.; Lotton, P.

    2018-04-01

    Mechanical transducers, such as shakers, loudspeakers and compression drivers that are used as excitation devices to excite acoustical or mechanical nonlinear systems under test are imperfect. Due to their nonlinear behaviour, unwanted contributions appear at their output besides the wanted part of the signal. Since these devices are used to study nonlinear systems, it should be required to measure properly the systems under test by overcoming the influence of the nonlinear excitation device. In this paper, a simple method that corrects distorted output signal of the excitation device by means of predistortion of its input signal is presented. A periodic signal is applied to the input of the excitation device and, from analysing the output signal of the device, the input signal is modified in such a way that the undesirable spectral components in the output of the excitation device are cancelled out after few iterations of real-time processing. The experimental results provided on an electrodynamic shaker show that the spectral purity of the generated acceleration output approaches 100 dB after few iterations (1 s). This output signal, applied to the system under test, is thus cleaned from the undesirable components produced by the excitation device; this is an important condition to ensure a correct measurement of the nonlinear system under test.

  11. Recent Progress on Liver Kinase B1 (LKB1: Expression, Regulation, Downstream Signaling and Cancer Suppressive Function

    Ren-You Gan

    2014-09-01

    Full Text Available Liver kinase B1 (LKB1, known as a serine/threonine kinase, has been identified as a critical cancer suppressor in many cancer cells. It is a master upstream kinase of 13 AMP-activated protein kinase (AMPK-related protein kinases, and possesses versatile biological functions. LKB1 gene is mutated in many cancers, and its protein can form different protein complexes with different cellular localizations in various cell types. The expression of LKB1 can be regulated through epigenetic modification, transcriptional regulation and post-translational modification. LKB1 dowcnstream pathways mainly include AMPK, microtubule affinity regulating kinase (MARK, salt-inducible kinase (SIK, sucrose non-fermenting protein-related kinase (SNRK and brain selective kinase (BRSK signalings, etc. This review, therefore, mainly discusses recent studies about the expression, regulation, downstream signaling and cancer suppressive function of LKB1, which can be helpful for better understanding of this molecular and its significance in cancers.

  12. Suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models of retinal degeneration

    Ma, Hongwei; Thapa, Arjun; Morris, Lynsie; Redmond, T. Michael; Baehr, Wolfgang; Ding, Xi-Qin

    2014-01-01

    Photoreceptors degenerate in a wide array of hereditary retinal diseases and age-related macular degeneration. There is currently no treatment available for retinal degenerations. While outnumbered roughly 20:1 by rods in the human retina, it is the cones that mediate color vision and visual acuity, and their survival is critical for vision. In this communication, we investigate whether thyroid hormone (TH) signaling affects cone viability in retinal degeneration mouse models. TH signaling is...

  13. G-Protein Gαs controls medulloblastoma initiation by suppressing sonic hedgehog signaling.

    He, Xuelian; Lu, Q Richard

    2015-01-01

    We identify Gαs as a novel tumor suppressor in medulloblastoma that functions principally by inhibition of sonic hedgehog signaling. Gαs not only stimulates cyclic adenosine monophosphate (cAMP)-dependent signaling but also inhibits ciliary trafficking of hedgehog components. Elevation of cAMP inhibits medulloblastoma growth and augments inhibition of smoothened to decrease tumor cell proliferation, thus highlighting Gαs as a potential therapeutic target.

  14. High signal in bone marrow at diffusion-weighted imaging with body background suppression (DWIBS) in healthy children

    Ording Mueller, Lil-Sofie; Avenarius, Derk [University Hospital North Norway, Department of Radiology, Tromsoe (Norway); Olsen, Oeystein E. [Great Ormond Street Hospital for Children, Department of Radiology, London (United Kingdom)

    2011-02-15

    In our experience, diffusion-weighted imaging with body background suppression (DWIBS) is hard to interpret in children who commonly have foci of restricted diffusion in their skeletons unrelated to pathology, sometimes in an asymmetrical pattern. This raises serious concern about the accuracy of DWIBS in cancer staging in children. To describe the signal distribution at DWIBS in the normal developing lumbar spine and pelvic skeleton. Forty-two healthy children underwent an MR DWIBS sequence of the abdomen and pelvis. An axial short-tau inversion-recovery (STIR) echo-planar imaging (EPI) pulse sequence was used. Two radiologists did a primary review of the images and based on these preliminary observations, separate scoring systems for the lumbar spine, pelvis and proximal femoral epiphyses/femoral heads were devised. Visual evaluation of the images was then performed by the two radiologists in consensus. The scoring was repeated separately 2 months later by a third radiologist. Restricted diffusion was defined as areas of high signal compared to the background. Coronal maximum intensity projection (MIP) reformats were used to assess the vertebral bodies. For the pelvis, the extension of high signal for each bone was given a score of 0 to 4. Cohen's Kappa interobserver agreement coefficients of signal distribution and asymmetry were calculated. All children had areas of high signal, both within the lumbar vertebral bodies and within the pelvic skeleton. Three patterns of signal distribution were seen in the lumbar spine, but no specific pattern was seen in the pelvis. There was a tendency toward a reduction of relative area of high signal within each bone with age, but also a widespread interindividual variation. Restricted diffusion is a normal finding in the pelvic skeleton and lumbar spine in children with an asymmetrical distribution seen in 48% of normal children in this study. DWIBS should be used with caution for cancer staging in children as this could

  15. High signal in bone marrow at diffusion-weighted imaging with body background suppression (DWIBS) in healthy children

    Ording Mueller, Lil-Sofie; Avenarius, Derk; Olsen, Oeystein E.

    2011-01-01

    In our experience, diffusion-weighted imaging with body background suppression (DWIBS) is hard to interpret in children who commonly have foci of restricted diffusion in their skeletons unrelated to pathology, sometimes in an asymmetrical pattern. This raises serious concern about the accuracy of DWIBS in cancer staging in children. To describe the signal distribution at DWIBS in the normal developing lumbar spine and pelvic skeleton. Forty-two healthy children underwent an MR DWIBS sequence of the abdomen and pelvis. An axial short-tau inversion-recovery (STIR) echo-planar imaging (EPI) pulse sequence was used. Two radiologists did a primary review of the images and based on these preliminary observations, separate scoring systems for the lumbar spine, pelvis and proximal femoral epiphyses/femoral heads were devised. Visual evaluation of the images was then performed by the two radiologists in consensus. The scoring was repeated separately 2 months later by a third radiologist. Restricted diffusion was defined as areas of high signal compared to the background. Coronal maximum intensity projection (MIP) reformats were used to assess the vertebral bodies. For the pelvis, the extension of high signal for each bone was given a score of 0 to 4. Cohen's Kappa interobserver agreement coefficients of signal distribution and asymmetry were calculated. All children had areas of high signal, both within the lumbar vertebral bodies and within the pelvic skeleton. Three patterns of signal distribution were seen in the lumbar spine, but no specific pattern was seen in the pelvis. There was a tendency toward a reduction of relative area of high signal within each bone with age, but also a widespread interindividual variation. Restricted diffusion is a normal finding in the pelvic skeleton and lumbar spine in children with an asymmetrical distribution seen in 48% of normal children in this study. DWIBS should be used with caution for cancer staging in children as this could lead

  16. Cyclopamine tartrate, an inhibitor of Hedgehog signaling, strongly interferes with mitochondrial function and suppresses aerobic respiration in lung cancer cells

    Alam, Md Maksudul; Sohoni, Sagar; Kalainayakan, Sarada Preeta; Garrossian, Massoud; Zhang, Li

    2016-01-01

    Aberrant Hedgehog (Hh) signaling is associated with the development of many cancers including prostate cancer, gastrointestinal cancer, lung cancer, pancreatic cancer, ovarian cancer, and basal cell carcinoma. The Hh signaling pathway has been one of the most intensely investigated targets for cancer therapy, and a number of compounds inhibiting Hh signaling are being tested clinically for treating many cancers. Lung cancer causes more deaths than the next three most common cancers (colon, breast, and prostate) combined. Cyclopamine was the first compound found to inhibit Hh signaling and has been invaluable for understanding the function of Hh signaling in development and cancer. To find novel strategies for combating lung cancer, we decided to characterize the effect of cyclopamine tartrate (CycT), an improved analogue of cyclopamine, on lung cancer cells and its mechanism of action. The effect of CycT on oxygen consumption and proliferation of non-small-cell lung cancer (NSCLC) cell lines was quantified by using an Oxygraph system and live cell counting, respectively. Apoptosis was detected by using Annexin V and Propidium Iodide staining. CycT’s impact on ROS generation, mitochondrial membrane potential, and mitochondrial morphology in NSCLC cells was monitored by using fluorometry and fluorescent microscopy. Western blotting and fluorescent microscopy were used to detect the levels and localization of Hh signaling targets, mitochondrial fission protein Drp1, and heme-related proteins in various NSCLC cells. Our findings identified a novel function of CycT, as well as another Hh inhibitor SANT1, to disrupt mitochondrial function and aerobic respiration. Our results showed that CycT, like glutamine depletion, caused a substantial decrease in oxygen consumption in a number of NSCLC cell lines, suppressed NSCLC cell proliferation, and induced apoptosis. Further, we found that CycT increased ROS generation, mitochondrial membrane hyperpolarization, and

  17. Ganoderma lucidum suppresses growth of breast cancer cells through the inhibition of Akt/NF-kappaB signaling.

    Jiang, Jiahua; Slivova, Veronika; Harvey, Kevin; Valachovicova, Tatiana; Sliva, Daniel

    2004-01-01

    Ganoderma lucidum (Reishi, Lingzhi) is a popular Asian mushroom that has been used for more than 2 millennia for the general promotion of health and was therefore called the "Mushroom of Immortality." Ganoderma lucidum was also used in traditional Chinese medicine to prevent or treat a variety of diseases, including cancer. We previously demonstrated that Ganoderma lucidum suppresses the invasive behavior of breast cancer cells by inhibiting the transcription factor NF-kappaB. However, the molecular mechanisms responsible for the inhibitory effects of Ganoderma lucidum on the growth of highly invasive and metastatic breast cancer cells has not been fully elucidated. Here, we show that Ganoderma lucidum inhibits proliferation of breast cancer MDA-MB-231 cells by downregulating Akt/NF-kappaB signaling. Ganoderma lucidum suppresses phosphorylation of Akt on Ser473 and downregulates the expression of Akt, which results in the inhibition of NF-kappaB activity in MDA-MB-231 cells. The biological effect of Ganoderma lucidum was demonstrated by cell cycle arrest at G0/G1, which was the result of the downregulation of expression of NF-kappaB-regulated cyclin D1, followed by the inhibition of cdk4. Our results suggest that Ganoderma lucidum inhibits the growth of MDA-MB-231 breast cancer cells by modulating Akt/NF-kappaB signaling and could have potential therapeutic use for the treatment of breast cancer.

  18. Wnt/β-catenin signaling mediates the suppressive effects of diallyl trisulfide on colorectal cancer stem cells.

    Zhang, Qi; Li, Xiao-Ting; Chen, Yue; Chen, Jia-Qi; Zhu, Jian-Yun; Meng, Yu; Wang, Xiao-Qian; Li, Yuan; Geng, Shan-Shan; Xie, Chun-Feng; Wu, Jie-Shu; Zhong, Cai-Yun; Han, Hong-Yu

    2018-06-01

    Cancer stem cells (CSCs) are responsible for colorectal cancer (CRC) initiation, growth, and metastasis. Garlic-derived organosulfur compound diallyl trisulfide (DATS) possesses cancer suppressive properties. Wnt/β-catenin signaling is a key target for CSCs inhibition. However, the interventional effect of DATS on colorectal CSCs has not been clarified. We aimed to illustrate the regulation of Wnt/β-catenin in DATS-induced colorectal CSCs inhibition. Serum-free medium culture was used to enrich colorectal CSCs. SW480 and DLD-1 sphere-forming cells were treated with different concentrations of DATS for 5 days; LiCl and β-catenin plasmids were used to stimulate the activity of Wnt/β-catenin pathway. The size and number of colonspheres were detected by tumorsphere formation assay; the expression of colorectal CSCs-related genes was detected by Western blotting and qRT-PCR; the capacities of colorectal CSCs proliferation and apoptosis were detected by Cell Counting Kit-8, Hoechst 33258 cell staining and flow cytometry, respectively. The levels of colorectal CSCs markers were elevated in the tumorspheres cells. DATS efficiently suppressed the activity of colorectal CSCs, as evidenced by reducing the size and number of colonspheres, decreasing the expression of colorectal CSCs markers, promoting apoptosis and inhibiting the proliferation of colorectal CSCs. Moreover, DATS suppressed the activity of Wnt/β-catenin pathway, while upregulation of Wnt/β-catenin diminished the inhibitory effect of DATS on colorectal CSCs. Wnt/β-catenin pathway mediates DATS-induced colorectal CSCs suppression. These findings support the use of DATS for targeting colorectal CSCs.

  19. RYBP Inhibits Progression and Metastasis of Lung Cancer by Suppressing EGFR Signaling and Epithelial-Mesenchymal Transition

    Xiaoxiao Dinglin

    2017-04-01

    Full Text Available Lung cancer (LC is a common lethal malignancy with rapid progression and metastasis, and Ring1 and YY1 binding protein (RYBP has been shown to suppress cell growth in human cancers. This study aimed to investigate the role of RYBP in LC progression and metastasis. In this study, a total of 149 LC patients were recruited, and the clinical stage of their tumors, metastasis status, survival time, presence of epidermal growth factor receptor (EGFR mutation, and RYBP expression levels were measured. RYBP silencing and overexpression were experimentally performed in LC cell lines and in nude mice, and the expressions of genes in EGFR-related signaling pathways and epithelial-mesenchymal transition (EMT were detected. The results showed that RYBP was downregulated in LC compared with adjacent normal tissues, and low RYBP expression was associated with a more severe clinical stage, high mortality, high metastasis risk, and poor survival. Cell proliferation and xenograft growth were inhibited by RYBP overexpression, whereas proliferation and xenograft growth were accelerated by RYBP silencing. EGFR and phosphorylated-EGFR levels were upregulated when RYBP was silenced, whereas EGFR, p-EGFR, p-AKT, and p-ERK were downregulated when RYBP was overexpressed. Low RYBP expression was related to a high metastasis risk, and metastasized tumors showed low RYBP levels. Cell migration and invasion were promoted by silencing RYBP but were inhibited by overexpressed RYBP. In addition, the EMT marker vimentin showed diminished expression, and E-cadherin was promoted by the overexpression of RYBP. In conclusion, our data suggest that RYBP suppresses cell proliferation and LC progression by impeding the EGFR-ERK and EGFR-AKT signaling pathways and thereby inhibiting cell migration and invasion and LC metastasis through the suppression of EMT.

  20. Emodin suppresses TGF-β1-induced epithelial-mesenchymal transition in alveolar epithelial cells through Notch signaling pathway

    Gao, Rundi; Chen, Ruilin; Cao, Yu; Wang, Yuan; Song, Kang; Zhang, Ya; Yang, Junchao

    2017-01-01

    Pulmonary fibrosis is characterized by the destruction of lung tissue architecture and the formation of fibrous foci, currently has no satisfactory treatment. Emodin is a component of Chinese herb that has been reported to be medicament on pancreatic fibrosis and liver fibrosis. However, its role in pulmonary fibrosis has not been established yet. In the present study, we investigated the hypothesis that Emodin plays an inhibitory role in TGF-β1 induced epithelial-mesenchymal transition (EMT) of alveolar epithelial cell, and Emodin exerts its effect through the Notch signaling pathway. Emodin inhibits the proliferation of Rat alveolar type II epithelial cells RLE-6TN in a concentration-dependent manner; reduces the expression of Collagen I, α-SMA and Vimentin, promotes the expression of E-cadherin. Moreover, Emodin could regulate the expression patterns of the Notch signaling pathway-related factors and reduce the Notch-1 nucleus translocation. Knockdown of Notch-1 enhances the inhibitory effect of Emodin on TGF-β1-induced EMT in RLE-6TN cells. In conclusion, the data of the present study suggests that Emodin suppresses TGF-β1-induced EMT in alveolar epithelial cells through Notch signaling pathway and shows the potential to be effective in the treatment of pulmonary fibrosis. - Highlights: • Emodin inhibits TGF-β1-induced EMT in alveolar epithelial cells. • Emodin regulates the expression patterns of the Notch signaling pathway-related factors. • Emodin inhibits TGF-β1-induced Notch-1 nucleus translocation and activation.

  1. Triptolide inhibits TGF-β1-induced cell proliferation in rat airway smooth muscle cells by suppressing Smad signaling

    Chen, Ming; Lv, Zhiqiang; Huang, Linjie [Department of Respiratory Medicine, Sun Yat-Sen Memorial Hospital, Institute for Respiratory disease of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong Province 510120 (China); Zhang, Wei [Department of Geratology, the Second People' s Hospital of Shenzhen, Shenzhen 518000 (China); Lin, Xiaoling; Shi, Jianting; Zhang, Wei; Liang, Ruiyun [Department of Respiratory Medicine, Sun Yat-Sen Memorial Hospital, Institute for Respiratory disease of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong Province 510120 (China); Jiang, Shanping, E-mail: shanpingjiang@126.com [Department of Respiratory Medicine, Sun Yat-Sen Memorial Hospital, Institute for Respiratory disease of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong Province 510120 (China)

    2015-02-15

    Background: We have reported that triptolide can inhibit airway remodeling in a murine model of asthma via TGF-β1/Smad signaling. In the present study, we aimed to investigate the effect of triptolide on airway smooth muscle cells (ASMCs) proliferation and the possible mechanism. Methods: Rat airway smooth muscle cells were cultured and made synchronized, then pretreated with different concentration of triptolide before stimulated by TGF-β1. Cell proliferation was evaluated by MTT assay. Flow cytometry was used to study the influence of triptolide on cell cycle and apoptosis. Signal proteins (Smad2, Smad3 and Smad7) were detected by western blotting analysis. Results: Triptolide significantly inhibited TGF-β1-induced ASMC proliferation (P<0.05). The cell cycle was blocked at G1/S-interphase by triptolide dose dependently. No pro-apoptotic effects were detected under the concentration of triptolide we used. Western blotting analysis showed TGF-β1 induced Smad2 and Smad3 phosphorylation was inhibited by triptolide pretreatment, and the level of Smad7 was increased by triptolide pretreatment. Conclusions: Triptolide may function as an inhibitor of asthma airway remodeling by suppressing ASMCs proliferation via negative regulation of Smad signaling pathway. - Highlights: • In this study, rat airway smooth muscle cells were cultured and made synchronized. • Triptolide inhibited TGF-β1-induced airway smooth muscle cells proliferation. • Triptolide inhibited ASMCs proliferation via negative regulation of Smad signaling pathway.

  2. Emodin suppresses TGF-β1-induced epithelial-mesenchymal transition in alveolar epithelial cells through Notch signaling pathway

    Gao, Rundi; Chen, Ruilin; Cao, Yu [Department of Respiration, The First Affiliated Hospital of Zhejiang Chinese Medicine University, NO. 56, Youdian Road, Shangcheng District, Hangzhou, Zhejiang Province 310006 (China); Wang, Yuan [Department of Pulmonary Function, The First Affiliated Hospital of Zhejiang Chinese Medicine University, NO. 56, Youdian Road, Shangcheng District, Hangzhou, Zhejiang Province 310006 (China); Song, Kang [Department of Respiration, The First Affiliated Hospital of Zhejiang Chinese Medicine University, NO. 56, Youdian Road, Shangcheng District, Hangzhou, Zhejiang Province 310006 (China); Zhang, Ya [Zhejiang Chinese Medicine University, No. 548, Binwen Road, Binjiang District, Hangzhou, Zhejiang Province 310006 (China); Yang, Junchao, E-mail: yangjunchaozj@zcmu.edu.cn [Department of Respiration, The First Affiliated Hospital of Zhejiang Chinese Medicine University, NO. 56, Youdian Road, Shangcheng District, Hangzhou, Zhejiang Province 310006 (China)

    2017-03-01

    Pulmonary fibrosis is characterized by the destruction of lung tissue architecture and the formation of fibrous foci, currently has no satisfactory treatment. Emodin is a component of Chinese herb that has been reported to be medicament on pancreatic fibrosis and liver fibrosis. However, its role in pulmonary fibrosis has not been established yet. In the present study, we investigated the hypothesis that Emodin plays an inhibitory role in TGF-β1 induced epithelial-mesenchymal transition (EMT) of alveolar epithelial cell, and Emodin exerts its effect through the Notch signaling pathway. Emodin inhibits the proliferation of Rat alveolar type II epithelial cells RLE-6TN in a concentration-dependent manner; reduces the expression of Collagen I, α-SMA and Vimentin, promotes the expression of E-cadherin. Moreover, Emodin could regulate the expression patterns of the Notch signaling pathway-related factors and reduce the Notch-1 nucleus translocation. Knockdown of Notch-1 enhances the inhibitory effect of Emodin on TGF-β1-induced EMT in RLE-6TN cells. In conclusion, the data of the present study suggests that Emodin suppresses TGF-β1-induced EMT in alveolar epithelial cells through Notch signaling pathway and shows the potential to be effective in the treatment of pulmonary fibrosis. - Highlights: • Emodin inhibits TGF-β1-induced EMT in alveolar epithelial cells. • Emodin regulates the expression patterns of the Notch signaling pathway-related factors. • Emodin inhibits TGF-β1-induced Notch-1 nucleus translocation and activation.

  3. Luteolin suppresses angiogenesis and vasculogenic mimicry formation through inhibiting Notch1-VEGF signaling in gastric cancer.

    Zang, Mingde; Hu, Lei; Zhang, Baogui; Zhu, Zhenglun; Li, Jianfang; Zhu, Zhenggang; Yan, Min; Liu, Bingya

    2017-08-26

    Gastric cancer is a great threat to the health of the people worldwide and lacks effective therapeutic regimens. Luteolin is one of Chinese herbs and presents in many fruits and green plants. In our previous study, we observed that luteolin inhibited cell migration and promoted cell apoptosis in gastric cancer. In the present study, luteolin significantly inhibited tube formation of human umbilical vein endothelial cells (HUVECs) through decreasing cell migration and proliferation of HUVECs in a dose-dependent manner. Vasculogenic mimicry (VM) tubes formed by gastric cancer cells were also inhibited with luteolin treatment. To explore how luteolin inhibited tubes formation, ELISA assay for VEGF was performed. Both of the VEGF secretion from Hs-746T cells and HUVECs were significantly decreased subsequent to luteolin treatment. In addition, cell migration was increased with the interaction between gastric cancer cells and HUVECs in co-culture assays. However, the promoting effects were abolished subsequent to luteolin treatment. Furthermore, luteolin inhibited VEGF secretion through suppressing Notch1 expression in gastric cancer. Overexpression of Notch1 in gastric cancer cells partially rescued the effects on cell migration, proliferation, HUVECs tube formation, and VM formation induced by luteolin treatment. In conclusion, luteolin inhibits angiogenesis and VM formation in gastric cancer through suppressing VEGF secretion dependent on Notch1 expression. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Signal enhancement, not active suppression, follows the contingent capture of visual attention.

    Livingstone, Ashley C; Christie, Gregory J; Wright, Richard D; McDonald, John J

    2017-02-01

    Irrelevant visual cues capture attention when they possess a task-relevant feature. Electrophysiologically, this contingent capture of attention is evidenced by the N2pc component of the visual event-related potential (ERP) and an enlarged ERP positivity over the occipital hemisphere contralateral to the cued location. The N2pc reflects an early stage of attentional selection, but presently it is unclear what the contralateral ERP positivity reflects. One hypothesis is that it reflects the perceptual enhancement of the cued search-array item; another hypothesis is that it is time-locked to the preceding cue display and reflects active suppression of the cue itself. Here, we varied the time interval between a cue display and a subsequent target display to evaluate these competing hypotheses. The results demonstrated that the contralateral ERP positivity is tightly time-locked to the appearance of the search display rather than the cue display, thereby supporting the perceptual enhancement hypothesis and disconfirming the cue-suppression hypothesis. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  5. Insulin-like growth factor-1 suppresses the Myostatin signaling pathway during myogenic differentiation

    Retamales, A.; Zuloaga, R.; Valenzuela, C.A.; Gallardo-Escarate, C.; Molina, A.; Valdés, J.A.

    2015-01-01

    Myogenic differentiation is a complex and well-coordinated process for generating mature skeletal muscle fibers. This event is autocrine/paracrine regulated by growth factors, principally Myostatin (MSTN) and Insulin-like Growth Factor-1 (IGF-1). Myostatin, a member of the transforming growth factor-β superfamily, is a negative regulator of skeletal muscle growth in vertebrates that exerts its inhibitory function by activating Smad transcription factors. In contrast, IGF-1 promotes the differentiation of skeletal myoblasts by activating the PI3K/Akt signaling pathway. This study reports on a novel functional crosstalk between the IGF-1 and MSTN signaling pathways, as mediated through interaction between PI3K/Akt and Smad3. Stimulation of skeletal myoblasts with MSTN resulted in a transient increase in the pSmad3:Smad3 ratio and Smad-dependent transcription. Moreover, MSTN inhibited myod gene expression and myoblast fusion in an Activin receptor-like kinase/Smad3-dependent manner. Preincubation of skeletal myoblasts with IGF-1 blocked MSTN-induced Smad3 activation, promoting myod expression and myoblast differentiation. This inhibitory effect of IGF-1 on the MSTN signaling pathway was dependent on IGF-1 receptor, PI3K, and Akt activities. Finally, immunoprecipitation assay analysis determined that IGF-1 pretreatment increased Akt and Smad3 interaction. These results demonstrate that the IGF-1/PI3K/Akt pathway may inhibit MSTN signaling during myoblast differentiation, providing new insight to existing knowledge on the complex crosstalk between both growth factors. - Highlights: • IGF-1 inhibits Myostatin canonical signaling pathway through IGF-1R/PI3K/Akt pathway. • IGF-1 promotes myoblast differentiation through a direct blocking of Myostatin signaling pathway. • IGF-1 induces the interaction of Akt with Smad3 in skeletal myoblast

  6. Insulin-like growth factor-1 suppresses the Myostatin signaling pathway during myogenic differentiation

    Retamales, A.; Zuloaga, R.; Valenzuela, C.A. [Laboratorio de Biotecnología Molecular, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Santiago (Chile); Gallardo-Escarate, C. [Laboratory of Biotechnology and Aquatic Genomics, Universidad de Concepción, Concepción (Chile); Interdisciplinary Center for Aquaculture Research (INCAR), P.O. Box 160-C, Concepción (Chile); Molina, A. [Laboratorio de Biotecnología Molecular, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Santiago (Chile); Interdisciplinary Center for Aquaculture Research (INCAR), P.O. Box 160-C, Concepción (Chile); Valdés, J.A., E-mail: jvaldes@unab.cl [Laboratorio de Biotecnología Molecular, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Santiago (Chile); Interdisciplinary Center for Aquaculture Research (INCAR), P.O. Box 160-C, Concepción (Chile)

    2015-08-21

    Myogenic differentiation is a complex and well-coordinated process for generating mature skeletal muscle fibers. This event is autocrine/paracrine regulated by growth factors, principally Myostatin (MSTN) and Insulin-like Growth Factor-1 (IGF-1). Myostatin, a member of the transforming growth factor-β superfamily, is a negative regulator of skeletal muscle growth in vertebrates that exerts its inhibitory function by activating Smad transcription factors. In contrast, IGF-1 promotes the differentiation of skeletal myoblasts by activating the PI3K/Akt signaling pathway. This study reports on a novel functional crosstalk between the IGF-1 and MSTN signaling pathways, as mediated through interaction between PI3K/Akt and Smad3. Stimulation of skeletal myoblasts with MSTN resulted in a transient increase in the pSmad3:Smad3 ratio and Smad-dependent transcription. Moreover, MSTN inhibited myod gene expression and myoblast fusion in an Activin receptor-like kinase/Smad3-dependent manner. Preincubation of skeletal myoblasts with IGF-1 blocked MSTN-induced Smad3 activation, promoting myod expression and myoblast differentiation. This inhibitory effect of IGF-1 on the MSTN signaling pathway was dependent on IGF-1 receptor, PI3K, and Akt activities. Finally, immunoprecipitation assay analysis determined that IGF-1 pretreatment increased Akt and Smad3 interaction. These results demonstrate that the IGF-1/PI3K/Akt pathway may inhibit MSTN signaling during myoblast differentiation, providing new insight to existing knowledge on the complex crosstalk between both growth factors. - Highlights: • IGF-1 inhibits Myostatin canonical signaling pathway through IGF-1R/PI3K/Akt pathway. • IGF-1 promotes myoblast differentiation through a direct blocking of Myostatin signaling pathway. • IGF-1 induces the interaction of Akt with Smad3 in skeletal myoblast.

  7. Activated protein synthesis and suppressed protein breakdown signaling in skeletal muscle of critically ill patients

    Jespersen, Jakob G; Nedergaard, Anders; Reitelseder, Søren

    2011-01-01

    Skeletal muscle mass is controlled by myostatin and Akt-dependent signaling on mammalian target of rapamycin (mTOR), glycogen synthase kinase 3β (GSK3β) and forkhead box O (FoxO) pathways, but it is unknown how these pathways are regulated in critically ill human muscle. To describe factors invol...... involved in muscle mass regulation, we investigated the phosphorylation and expression of key factors in these protein synthesis and breakdown signaling pathways in thigh skeletal muscle of critically ill intensive care unit (ICU) patients compared with healthy controls....

  8. Activated protein synthesis and suppressed protein breakdown signaling in skeletal muscle of critically ill patients

    Jespersen, Jakob G; Nedergaard, Anders; Reitelseder, Søren

    2011-01-01

    Skeletal muscle mass is controlled by myostatin and Akt-dependent signaling on mammalian target of rapamycin (mTOR), glycogen synthase kinase 3ß (GSK3ß) and forkhead box O (FoxO) pathways, but it is unknown how these pathways are regulated in critically ill human muscle. To describe factors invol...... involved in muscle mass regulation, we investigated the phosphorylation and expression of key factors in these protein synthesis and breakdown signaling pathways in thigh skeletal muscle of critically ill intensive care unit (ICU) patients compared with healthy controls....

  9. MicroRNA-200a suppresses the Wnt/β-catenin signaling pathway by interacting with β-catenin.

    Su, Juan; Zhang, Anling; Shi, Zhendong; Ma, Feifei; Pu, Peiyu; Wang, Tao; Zhang, Jie; Kang, Chunsheng; Zhang, Qingyu

    2012-04-01

    The Wnt/β-catenin signaling pathway is crucial for human organ development and is involved in tumor progression of many cancers. Accumulating evidence suggests that the expression of β-catenin is, in part, regulated by specific microRNAs (miRNAs). The purpose of this study was to determine the expression of a recently identified epithelial to mesenchymal transition (EMT)-associated tumor suppressor microRNA (miR)-200a, in cancer cells. We also aimed to identify specific miR-200a target genes and to investigate the antitumor effects of miR-200a on the Wnt/β-catenin signaling pathway. We employed TOP/FOP flash luciferase assays to identify the effect of miR-200a on the Wnt/β-catenin pathway and we confirmed our observations using fluorescence microscopy. To determine target genes of miR-200a, a 3' untranslated region (3' UTR) luciferase assay was performed. Cell viability, invasion and wound healing assays were carried out for functional analysis after miRNA transfection. We further investigated the role of miR-200a in EMT by Western blot analysis. We found fluctuation in the expression of miR-200a that was accompanied by changes in the expression of members of the Wnt/β-catenin signaling pathway. We also determined that miR-200a can directly interact with the 3' UTR of CTNNB1 (the gene that encodes β-catenin) to suppress Wnt/β-catenin signaling. MiR-200a could also influence the biological activities of SGC790 and U251 cells. Our results demonstrate that miR-200a is a new tumor suppressor that can regulate the activity of the Wnt/β-catenin signaling pathway via two mechanisms. MiR-200a is a candidate target for tumor treatment via its regulation of the Wnt/β-catenin signaling pathway.

  10. Cartilage Intermediate Layer Protein 1 Suppresses TGF-β Signaling in Cardiac Fibroblasts

    Kazuhiro Shindo

    2017-06-01

    Conclusion: We identified CILP1 as a potential regulator of cardiac fibrosis by inhibiting TGF-β signaling, and these results suggest the promise of CILP1 as a novel therapeutic target for preventing cardiac fibrosis and heart failure in MI patients.

  11. Erk signaling suppresses embryonic stem cell self-renewal to specify endoderm

    Hamilton, William B; Brickman, Joshua M

    2014-01-01

    Fgf signaling via Erk activation has been associated with both neural induction and the generation of a primed state for the differentiation of embryonic stem cells (ESCs) to all somatic lineages. To dissect the role of Erk in both ESC self-renewal and lineage specification, we explored...

  12. Chemical Suppression of the Reactivated Androgen Signaling Pathway in Androgen-Independent Prostate Cancer

    2011-07-01

    when it is ingested during pregnancy [20,21]. Aside from its role in development, Hh signaling also supports stem cells in adult tissues [22-24]. However...For the mo.~t commonly uti - lized human prostate cancer cell lines (LNCaP and derivatives, DUI45, PC3 or CWR22rvl) grown in culture, Shh, Glil/2 and

  13. Tick saliva suppresses IFN signalling in dendritic cells upon Borrelia afzelii infection

    Lieskovská, Jaroslava; Kopecký, Jan

    2012-01-01

    Roč. 34, č. 1 (2012), s. 32-39 ISSN 0141-9838 R&D Projects: GA MŠk(CZ) LC06009 Institutional support: RVO:60077344 Keywords : Borrelia * dendritic cells * interferon signalling * tick saliva Subject RIV: EC - Immunology Impact factor: 2.208, year: 2012

  14. The aryl hydrocarbon receptor suppresses osteoblast proliferation and differentiation through the activation of the ERK signaling pathway

    Yu, Haitao; Du, Yuxuan; Zhang, Xulong; Sun, Ying; Li, Shentao; Dou, Yunpeng [Department of Immunology, School of Basic Medical Sciences, Capital Medical University, No. 10 Xitoutiao, You An Men, Beijing 100069 (China); Li, Zhanguo [Department of Rheumatology and Immunology, Clinical Immunology Center, Peking University People' s Hospital, No. 11 Xizhimen South Street, Beijing 100044 (China); Yuan, Huihui, E-mail: huihui_yuan@163.com [Department of Immunology, School of Basic Medical Sciences, Capital Medical University, No. 10 Xitoutiao, You An Men, Beijing 100069 (China); Zhao, Wenming, E-mail: zhao-wenming@163.com [Department of Immunology, School of Basic Medical Sciences, Capital Medical University, No. 10 Xitoutiao, You An Men, Beijing 100069 (China)

    2014-11-01

    Ahr activation is known to be associated with synovitis and exacerbated rheumatoid arthritis (RA), but its contributions to bone loss have not been completely elucidated. Osteoblast proliferation and differentiation are abnormal at the erosion site in RA. Here, we reported that the expression of Ahr was increased in the hind paws' bone upon collagen-induced arthritis (CIA) in mice, and the levels of Ahr were negatively correlated with bone mineral density (BMD). In addition, immunofluorescent staining showed that the high expression of Ahr was mainly localized in osteoblasts from the CIA mice compared to normal controls. Moreover, the luciferase intensity of Ahr in the nucleus increased by 12.5% in CIA osteoblasts compared to that in normal controls. In addition, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) activation of the Ahr inhibited pre-osteoblast MC3T3-E1 cellular proliferation and differentiation in a dose-dependent manner. Interestingly, the levels of alkaline phosphatase (ALP) mRNA expression in the osteoblasts of CIA mice were reduced compared to normal controls. In contrast, decreased ALP expression by activated Ahr was completely reversed after pretreatment with an Ahr inhibitor (CH-223191) in MC3T3-E1 cell lines and primary osteoblasts on day 5. Our data further showed that activation of Ahr promoted the phosphorylation of ERK after 5 days. Moreover, Ahr-dependent activation of the ERK signaling pathway decreased the levels of proliferation cells and inhibited ALP activity in MC3T3-E1 cells. These results demonstrated that the high expression of Ahr may suppress osteoblast proliferation and differentiation through activation of the ERK signaling pathway, further enabling bone erosion in CIA mice. - Highlights: • The upregulation of Ahr was localized in osteoblasts of CIA mice. • The overexpression of Ahr suppressed osteoblast development. • The Ahr activated ERK signaling pathway to exacerbate bone erosion.

  15. Xanomeline suppresses excessive pro-inflammatory cytokine responses through neural signal-mediated pathways and improves survival in lethal inflammation

    Rosas-Ballina, Mauricio; Ferrer, Sergio Valdés; Dancho, Meghan; Ochani, Mahendar; Katz, David; Cheng, Kai Fan; Olofsson, Peder S.; Chavan, Sangeeta S.; Al-Abed, Yousef; Tracey, Kevin J.; Pavlov, Valentin A.

    2014-01-01

    Inflammatory conditions characterized by excessive immune cell activation and cytokine release, are associated with bidirectional immune system-brain communication, underlying sickness behavior and other physiological responses. The vagus nerve has an important role in this communication by conveying sensory information to the brain, and brain-derived immunoregulatory signals that suppress peripheral cytokine levels and inflammation. Brain muscarinic acetylcholine receptor (mAChR)-mediated cholinergic signaling has been implicated in this regulation. However, the possibility of controlling inflammation by peripheral administration of centrally-acting mAChR agonists is unexplored. To provide insight we used the centrally-acting M1 mAChR agonist xanomeline, previously developed in the context of Alzheimer’s disease and schizophrenia. Intraperitoneal administration of xanomeline significantly suppressed serum and splenic TNF levels, alleviated sickness behavior, and increased survival during lethal murine endotoxemia. The anti-inflammatory effects of xanomeline were brain mAChR-mediated and required intact vagus nerve and splenic nerve signaling. The anti-inflammatory efficacy of xanomeline was retained for at least 20h, associated with alterations in splenic lymphocyte, and dendritic cell proportions, and decreased splenocyte responsiveness to endotoxin. These results highlight an important role of the M1 mAChR in a neural circuitry to spleen in which brain cholinergic activation lowers peripheral pro-inflammatory cytokines to levels favoring survival. The therapeutic efficacy of xanomeline was also manifested by significantly improved survival in preclinical settings of severe sepsis. These findings are of interest for strategizing novel therapeutic approaches in inflammatory diseases. PMID:25063706

  16. Activated protein synthesis and suppressed protein breakdown signaling in skeletal muscle of critically ill patients.

    Jakob G Jespersen

    Full Text Available BACKGROUND: Skeletal muscle mass is controlled by myostatin and Akt-dependent signaling on mammalian target of rapamycin (mTOR, glycogen synthase kinase 3β (GSK3β and forkhead box O (FoxO pathways, but it is unknown how these pathways are regulated in critically ill human muscle. To describe factors involved in muscle mass regulation, we investigated the phosphorylation and expression of key factors in these protein synthesis and breakdown signaling pathways in thigh skeletal muscle of critically ill intensive care unit (ICU patients compared with healthy controls. METHODOLOGY/PRINCIPAL FINDINGS: ICU patients were systemically inflamed, moderately hyperglycemic, received insulin therapy, and showed a tendency to lower plasma branched chain amino acids compared with controls. Using Western blotting we measured Akt, GSK3β, mTOR, ribosomal protein S6 kinase (S6k, eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1, and muscle ring finger protein 1 (MuRF1; and by RT-PCR we determined mRNA expression of, among others, insulin-like growth factor 1 (IGF-1, FoxO 1, 3 and 4, atrogin1, MuRF1, interleukin-6 (IL-6, tumor necrosis factor α (TNF-α and myostatin. Unexpectedly, in critically ill ICU patients Akt-mTOR-S6k signaling was substantially higher compared with controls. FoxO1 mRNA was higher in patients, whereas FoxO3, atrogin1 and myostatin mRNAs and MuRF1 protein were lower compared with controls. A moderate correlation (r2=0.36, p<0.05 between insulin infusion dose and phosphorylated Akt was demonstrated. CONCLUSIONS/SIGNIFICANCE: We present for the first time muscle protein turnover signaling in critically ill ICU patients, and we show signaling pathway activity towards a stimulation of muscle protein synthesis and a somewhat inhibited proteolysis.

  17. Research on the range side lobe suppression method for modulated stepped frequency radar signals

    Liu, Yinkai; Shan, Tao; Feng, Yuan

    2018-05-01

    The magnitude of time-domain range sidelobe of modulated stepped frequency radar affects the imaging quality of inverse synthetic aperture radar (ISAR). In this paper, the cause of high sidelobe in modulated stepped frequency radar imaging is analyzed first in real environment. Then, the chaos particle swarm optimization (CPSO) is used to select the amplitude and phase compensation factors according to the minimum sidelobe criterion. Finally, the compensated one-dimensional range images are obtained. Experimental results show that the amplitude-phase compensation method based on CPSO algorithm can effectively reduce the sidelobe peak value of one-dimensional range images, which outperforms the common sidelobe suppression methods and avoids the coverage of weak scattering points by strong scattering points due to the high sidelobes.

  18. Defining the therapeutic time window for suppressing the inflammatory prostaglandin E2 signaling after status epilepticus

    Du, Yifeng; Kemper, Timothy; Qiu, Jiange; Jiang, Jianxiong

    2016-01-01

    Neuroinflammation is a common feature in nearly all neurological and some psychiatric disorders. Resembling its extraneural counterpart, neuroinflammation can be both beneficial and detrimental depending on the responding molecules. The overall effect of inflammation on disease progression is highly dependent on the extent of inflammatory mediator production and the duration of inflammatory induction. The time-dependent aspect of inflammatory responses suggests that the therapeutic time window for quelling neuroinflammation might vary with molecular targets and injury types. Therefore, it is important to define the therapeutic time window for anti-inflammatory therapeutics, as contradicting or negative results might arise when different treatment regimens are utilized even in similar animal models. Herein, we discuss a few critical factors that can help define the therapeutic time window and optimize treatment paradigm for suppressing the cyclooxygenase-2/prostaglandin-mediated inflammation after status epilepticus. These determinants should also be relevant to other anti-inflammatory therapeutic strategies for the CNS diseases. PMID:26689339

  19. Suppression of ERβ signaling via ERβ knockout or antagonist protects against bladder cancer development.

    Hsu, Iawen; Chuang, Kun-Lung; Slavin, Spencer; Da, Jun; Lim, Wei-Xun; Pang, See-Tong; O'Brien, Jeanne H; Yeh, Shuyuan

    2014-03-01

    Epidemiological studies showed that women have a lower bladder cancer (BCa) incidence, yet higher muscle-invasive rates than men, suggesting that estrogen and the estrogen receptors, estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ), may play critical roles in BCa progression. Using in vitro cell lines and an in vivo carcinogen N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced mouse BCa model, we found that ERβ plays a positive role in promoting BCa progression. Knockdown of ERβ with ERβ-shRNA in ERβ-positive human BCa J82, 647v and T24 cell lines led to suppressed cell growth and invasion. Mice lacking ERβ have less cancer incidence with reduced expression of the proliferation marker Ki67 in BBN-induced BCa. Consistently, our results show that non-malignant urothelial cells with ERβ knockdown are more resistant to carcinogen-induced malignant transformation. Mechanism dissection found that targeting ERβ suppressed the expression of minichromosome maintenance complex component 5 (MCM5), a DNA replication licensing factor that is involved in tumor cell growth. Restoring MCM5 expression can partially reverse ERβ knockdown-mediated growth reduction. Supportively, treating cells with the ERβ-specific antagonist, 4-[2-Phenyl-5,7-bis(trifluoromethyl) pyrazolo[1,5-a]pyrimidin-3-yl]phenol (PHTPP), reduced BCa cell growth and invasion, as well as MCM5 expression. Furthermore, we provide the first evidence that BCa burden and mortality can be controlled by PHTPP treatment in the carcinogen-induced BCa model. Together, these results demonstrate that ERβ could play positive roles in promoting BCa progression via MCM5 regulation. Targeting ERβ through ERβ-shRNA, PHTPP or via downstream targets, such as MCM5, could serve as potential therapeutic approaches to battle BCa.

  20. LIM-domain protein AJUBA suppresses malignant mesothelioma cell proliferation via Hippo signaling cascade.

    Tanaka, I; Osada, H; Fujii, M; Fukatsu, A; Hida, T; Horio, Y; Kondo, Y; Sato, A; Hasegawa, Y; Tsujimura, T; Sekido, Y

    2015-01-02

    Malignant mesothelioma (MM) is one of the most aggressive neoplasms usually associated with asbestos exposure and is highly refractory to current therapeutic modalities. MMs show frequent activation of a transcriptional coactivator Yes-associated protein (YAP), which is attributed to the neurofibromatosis type 2 (NF2)-Hippo pathway dysfunction, leading to deregulated cell proliferation and acquisition of a malignant phenotype. However, the whole mechanism of disordered YAP activation in MMs has not yet been well clarified. In the present study, we investigated various components of the NF2-Hippo pathway, and eventually found that MM cells frequently showed downregulation of LIM-domain protein AJUBA, a binding partner of large tumor suppressor type 2 (LATS2), which is one of the last-step kinases of the NF2-Hippo pathway. Although loss of AJUBA expression was independent of the alteration status of other Hippo pathway components, MM cell lines with AJUBA inactivation showed a more dephosphorylated (activated) level of YAP. Immunohistochemical analysis showed frequent downregulation of AJUBA in primary MMs, which was associated with YAP constitutive activation. We found that AJUBA transduction into MM cells significantly suppressed promoter activities of YAP-target genes, and the suppression of YAP activity by AJUBA was remarkably canceled by knockdown of LATS2. In connection with these results, transduction of AJUBA-expressing lentivirus significantly inhibited the proliferation and anchorage-independent growth of the MM cells that harbored ordinary LATS family expression. Taken together, our findings indicate that AJUBA negatively regulates YAP activity through the LATS family, and inactivation of AJUBA is a novel key mechanism in MM cell proliferation.

  1. Aspirin suppresses the abnormal lipid metabolism in liver cancer cells via disrupting an NFκB-ACSL1 signaling

    Yang, Guang; Wang, Yuan; Feng, Jinyan; Liu, Yunxia; Wang, Tianjiao; Zhao, Man; Ye, Lihong; Zhang, Xiaodong

    2017-01-01

    Abnormal lipid metabolism is a hallmark of tumorigenesis. Hence, the alterations of metabolism enhance the development of hepatocellular carcinoma (HCC). Aspirin is able to inhibit the growth of cancers through targeting nuclear factor κB (NF-κB). However, the role of aspirin in disrupting abnormal lipid metabolism in HCC remains poorly understood. In this study, we report that aspirin can suppress the abnormal lipid metabolism of HCC cells through inhibiting acyl-CoA synthetase long-chain family member 1 (ACSL1), a lipid metabolism-related enzyme. Interestingly, oil red O staining showed that aspirin suppressed lipogenesis in HepG2 cells and Huh7 cells in a dose-dependent manner. In addition, aspirin attenuated the levels of triglyceride and cholesterol in the cells, respectively. Strikingly, we identified that aspirin was able to down-regulate ACSL1 at the levels of mRNA and protein. Moreover, we validated that aspirin decreased the nuclear levels of NF-κB in HepG2 cells. Mechanically, PDTC, an inhibitor of NF-κB, could down-regulate ACSL1 at the levels of mRNA and protein in the cells. Functionally, PDTC reduced the levels of lipid droplets, triglyceride and cholesterol in HepG2 cells. Thus, we conclude that aspirin suppresses the abnormal lipid metabolism in HCC cells via disrupting an NFκB-ACSL1 signaling. Our finding provides new insights into the mechanism by which aspirin inhibits abnormal lipid metabolism of HCC. Therapeutically, aspirin is potentially available for HCC through controlling abnormal lipid metabolism. - Highlights: • Aspirin inhibits the levels of liquid droplets, triglyceride and cholesterol in HCC cells. • Aspirin is able to down-regulate ACSL1 in HCC cells. • NF-κB inhibitor PDTC can down-regulate ACSL1 and reduces lipogenesis in HCC cells. • Aspirin suppresses the abnormal lipid metabolism in HCC cells via disrupting an NFκB-ACSL1 signaling.

  2. Cochlear implantation in Mondini dysplasia.

    Daneshi, Ahmad; Hassanzadeh, Saeid; Abasalipour, Parvaneh; Emamdjomeh, Hessamaddin; Farhadi, Mohammad

    2003-01-01

    The use of cochlear implantation to treat patients with inner ear malformations such as Mondini dysplasia has been increasingly successful. Until now, conventional hearing aids in these patients have not performed well. Consequently, the hearing problem for patients with this condition has been somewhat improved with the use of cochlear implants. Various results of cochlear implantation have been reported in these patients so far. This is a report of 5 patients with Mondini malformation who have undergone cochlear implant surgery. Copyright 2003 S. Karger AG, Basel

  3. Concurrent inhibition of kit- and FcepsilonRI-mediated signaling: coordinated suppression of mast cell activation

    Jensen, Bettina M; Beaven, Michael A; Iwaki, Shoko

    2008-01-01

    Although primarily required for the growth, differentiation, and survival of mast cells, Kit ligand (stem cell factor) is also required for optimal antigen-mediated mast cell activation. Therefore, concurrent inhibition of Kit- and FcepsilonRI-mediated signaling would be an attractive approach...... characterized Kit inhibitor imatinib mesylate (imatinib). In contrast to imatinib, however, hypothemycin also effectively inhibited FcepsilonRI-mediated degranulation and cytokine production in addition to the potentiation of these responses via Kit. The effect of hypothemycin on Kit-mediated responses could...... be explained by its inhibition of Kit kinase activity, whereas the inhibitory effects on FcepsilonRI-dependent signaling were at the level of Btk activation. Because hypothemycin also significantly reduced the mouse passive cutaneous anaphylaxis response in vivo, these data provide proof of principle...

  4. Dietary gossypol suppressed postprandial TOR signaling and elevated ER stress pathways in turbot (Scophthalmus maximus L.).

    Bian, Fuyun; Jiang, Haowen; Man, Mingsan; Mai, Kangsen; Zhou, Huihui; Xu, Wei; He, Gen

    2017-01-01

    Gossypol is known to be a polyphenolic compound toxic to animals. However, its molecular targets are far from fully characterized. To evaluate the physiological and molecular effects of gossypol, we chose turbot (Scophthalmus maximus L.), a carnivorous fish, as our model species. Juvenile turbots (7.83 ± 0.02 g) were fed diets containing gradient levels of gossypol at 0 (G0), 600 (G1), and 1,200 (G2) mg/kg diets for 11 wk. After the feeding trial, fish growth, body protein, and fat contents were significantly reduced in the G2 group compared with those of the G0 group (P TOR) signaling and induced endoplasmic reticulum (ER) stress pathway in both the feeding experiment and cell cultures. Our results demonstrated that gossypol inhibited TOR signaling and elevated ER stress pathways both in vivo and in vitro, thus providing new mechanism of action of gossypol in nutritional physiology. Copyright © 2017 the American Physiological Society.

  5. Activation of Brain Somatostatin Signaling Suppresses CRF Receptor-Mediated Stress Response

    Andreas Stengel; Yvette F. Taché; Yvette F. Taché

    2017-01-01

    Corticotropin-releasing factor (CRF) is the hallmark brain peptide triggering the response to stress and mediates—in addition to the stimulation of the hypothalamus-pituitary-adrenal (HPA) axis—other hormonal, behavioral, autonomic and visceral components. Earlier reports indicate that somatostatin-28 injected intracerebroventricularly counteracts the acute stress-induced ACTH and catecholamine release. Mounting evidence now supports that activation of brain somatostatin signaling exerts a br...

  6. Suppression of Instability on Sensing Signal of Optical Pulse Correlation Measurement in Remote Fiber Sensing

    Hirokazu Kobayashi

    2012-01-01

    response and improve the accuracy of signals at the focused sensing regions. We also experimentally demonstrate remote temperature monitoring over a 30 km-long distance using a remote reference technique, and we estimate the resolution and the measurable span of the temperature variation as (1.1/L∘C and (5.9×10/L°C, respectively, where L is the length of the fiber in the sensing region.

  7. Sonic Hedgehog Signaling Drives Mitochondrial Fragmentation by Suppressing Mitofusins in Cerebellar Granule Neuron Precursors and Medulloblastoma.

    Malhotra, Anshu; Dey, Abhinav; Prasad, Niyathi; Kenney, Anna Marie

    2016-01-01

    Sonic hedgehog (Shh) signaling is closely coupled with bioenergetics of medulloblastoma, the most common malignant pediatric brain tumor. Shh-associated medulloblastoma arises from cerebellar granule neuron precursors (CGNP), a neural progenitor whose developmental expansion requires signaling by Shh, a ligand secreted by the neighboring Purkinje neurons. Previous observations show that Shh signaling inhibits fatty acid oxidation although driving increased fatty acid synthesis. Proliferating CGNPs and mouse Shh medulloblastomas feature high levels of glycolytic enzymes in vivo and in vitro. Because both of these metabolic processes are closely linked to mitochondrial bioenergetics, the role of Shh signaling in mitochondrial biogenesis was investigated. This report uncovers a surprising decrease in mitochondrial membrane potential (MMP) and overall ATP production in CGNPs exposed to Shh, consistent with increased glycolysis resulting in high intracellular acidity, leading to mitochondrial fragmentation. Ultrastructural examination of mitochondria revealed a spherical shape in Shh-treated cells, in contrast to the elongated appearance in vehicle-treated postmitotic cells. Expression of mitofusin 1 and 2 was reduced in these cells, although their ectopic expression restored the MMP to the nonproliferating state and the morphology to a fused, interconnected state. Mouse Shh medulloblastoma cells featured drastically impaired mitochondrial morphology, restoration of which by ectopic mitofusin expression was also associated with a decrease in the expression of Cyclin D2 protein, a marker for proliferation. This report exposes a novel role for Shh in regulating mitochondrial dynamics and rescue of the metabolic profile of tumor cells to that of nontransformed, nonproliferating cells and represents a potential avenue for development of medulloblastoma therapeutics. ©2015 American Association for Cancer Research.

  8. A20 restricts wnt signaling in intestinal epithelial cells and suppresses colon carcinogenesis.

    Ling Shao

    Full Text Available Colon carcinogenesis consists of a multistep process during which a series of genetic and epigenetic adaptations occur that lead to malignant transformation. Here, we have studied the role of A20 (also known as TNFAIP3, a ubiquitin-editing enzyme that restricts NFκB and cell death signaling, in intestinal homeostasis and tumorigenesis. We have found that A20 expression is consistently reduced in human colonic adenomas than in normal colonic tissues. To further investigate A20's potential roles in regulating colon carcinogenesis, we have generated mice lacking A20 specifically in intestinal epithelial cells and interbred these with mice harboring a mutation in the adenomatous polyposis coli gene (APC(min. While A20(FL/FL villin-Cre mice exhibit uninflamed intestines without polyps, A20(FL/FL villin-Cre APC(min/+ mice contain far greater numbers and larger colonic polyps than control APC(min mice. We find that A20 binds to the β-catenin destruction complex and restricts canonical wnt signaling by supporting ubiquitination and degradation of β-catenin in intestinal epithelial cells. Moreover, acute deletion of A20 from intestinal epithelial cells in vivo leads to enhanced expression of the β-catenin dependent genes cyclinD1 and c-myc, known promoters of colon cancer. Taken together, these findings demonstrate new roles for A20 in restricting β-catenin signaling and preventing colon tumorigenesis.

  9. Gamabufotalin, a major derivative of bufadienolide, inhibits VEGF-induced angiogenesis by suppressing VEGFR-2 signaling pathway.

    Tang, Ning; Shi, Lei; Yu, Zhenlong; Dong, Peipei; Wang, Chao; Huo, Xiaokui; Zhang, Baojing; Huang, Shanshan; Deng, Sa; Liu, Kexin; Ma, Tonghui; Wang, Xiaobo; Wu, Lijun; Ma, Xiao-Chi

    2016-01-19

    Gamabufotalin (CS-6), a main active compound isolated from Chinese medicine Chansu, has been shown to strongly inhibit cancer cell growth and inflammatory response. However, its effects on angiogenesis have not been known yet. Here, we sought to determine the biological effects of CS-6 on signaling mechanisms during angiogenesis. Our present results fully demonstrate that CS-6 could significantly inhibit VEGF triggered HUVECs proliferation, migration, invasion and tubulogenesis in vitro and blocked vascularization in Matrigel plugs impregnated in C57/BL6 mice as well as reduced vessel density in human lung tumor xenograft implanted in nude mice. Computer simulations revealed that CS-6 interacted with the ATP-binding sites of VEGFR-2 using molecular docking. Furthermore, western blot analysis indicated that CS-6 inhibited VEGF-induced phosphorylation of VEGFR-2 kinase and suppressed the activity of VEGFR-2-mediated signaling cascades. Therefore, our studies demonstrated that CS-6 inhibited angiogenesis by inhibiting the activation of VEGFR-2 signaling pathways and CS-6 could be a potential candidate in angiogenesis-related disease therapy.

  10. High levels of pigment epithelium-derived factor in diabetes impair wound healing through suppression of Wnt signaling.

    Qi, Weiwei; Yang, Chuan; Dai, Zhiyu; Che, Di; Feng, Juan; Mao, Yuling; Cheng, Rui; Wang, Zhongxiao; He, Xuemin; Zhou, Ti; Gu, Xiaoqiong; Yan, Li; Yang, Xia; Ma, Jian-Xing; Gao, Guoquan

    2015-04-01

    Diabetic foot ulcer (DFU) caused by impaired wound healing is a common vascular complication of diabetes. The current study revealed that plasma levels of pigment epithelium-derived factor (PEDF) were elevated in type 2 diabetic patients with DFU and in db/db mice. To test whether elevated PEDF levels contribute to skin wound-healing delay in diabetes, endogenous PEDF was neutralized with an anti-PEDF antibody in db/db mice. Our results showed that neutralization of PEDF accelerated wound healing, increased angiogenesis in the wound skin, and improved the functions and numbers of endothelial progenitor cells (EPCs) in the diabetic mice. Further, PEDF-deficient mice showed higher baseline blood flow in the skin, higher density of cutaneous microvessels, increased skin thickness, improved numbers and functions of circulating EPCs, and accelerated wound healing compared with wild-type mice. Overexpression of PEDF suppressed the Wnt signaling pathway in the wound skin. Lithium chloride-induced Wnt signaling activation downstream of the PEDF interaction site attenuated the inhibitory effect of PEDF on EPCs and rescued the wound-healing deficiency in diabetic mice. Taken together, these results suggest that elevated circulating PEDF levels contribute to impaired wound healing in the process of angiogenesis and vasculogenesis through the inhibition of Wnt/β-catenin signaling. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  11. Aspirin suppresses the abnormal lipid metabolism in liver cancer cells via disrupting an NFκB-ACSL1 signaling.

    Yang, Guang; Wang, Yuan; Feng, Jinyan; Liu, Yunxia; Wang, Tianjiao; Zhao, Man; Ye, Lihong; Zhang, Xiaodong

    2017-05-06

    Abnormal lipid metabolism is a hallmark of tumorigenesis. Hence, the alterations of metabolism enhance the development of hepatocellular carcinoma (HCC). Aspirin is able to inhibit the growth of cancers through targeting nuclear factor κB (NF-κB). However, the role of aspirin in disrupting abnormal lipid metabolism in HCC remains poorly understood. In this study, we report that aspirin can suppress the abnormal lipid metabolism of HCC cells through inhibiting acyl-CoA synthetase long-chain family member 1 (ACSL1), a lipid metabolism-related enzyme. Interestingly, oil red O staining showed that aspirin suppressed lipogenesis in HepG2 cells and Huh7 cells in a dose-dependent manner. In addition, aspirin attenuated the levels of triglyceride and cholesterol in the cells, respectively. Strikingly, we identified that aspirin was able to down-regulate ACSL1 at the levels of mRNA and protein. Moreover, we validated that aspirin decreased the nuclear levels of NF-κB in HepG2 cells. Mechanically, PDTC, an inhibitor of NF-κB, could down-regulate ACSL1 at the levels of mRNA and protein in the cells. Functionally, PDTC reduced the levels of lipid droplets, triglyceride and cholesterol in HepG2 cells. Thus, we conclude that aspirin suppresses the abnormal lipid metabolism in HCC cells via disrupting an NFκB-ACSL1 signaling. Our finding provides new insights into the mechanism by which aspirin inhibits abnormal lipid metabolism of HCC. Therapeutically, aspirin is potentially available for HCC through controlling abnormal lipid metabolism. Copyright © 2017. Published by Elsevier Inc.

  12. Apatinib Inhibits Angiogenesis Via Suppressing Akt/GSK3β/ANG Signaling Pathway in Anaplastic Thyroid Cancer

    Zhijian Jin

    2017-12-01

    Full Text Available Background/Aims: Anaplastic thyroid carcinoma (ATC is one of the most lethal human malignancies, and there is no efficient method to slow its process. Apatinib, a novel tyrosine kinase inhibitor (TKI, has been confirmed for its efficacy and safety in the treatment of advanced gastric carcinoma patients. However, the effects of Apatinib in ATC are still unknown. Methods: In this study, we explored the effects and mechanisms of Apatinib on tumor growth and angiogenesis in vitro and in vitro in ATC cells. Angiogenesis antibodies array was utilized to detect the expression of angiogenesis-related genes after Apatinib treatment in ATC cells. In addition, we used Akt activator, Akt inhibitor and GSK3β inhibitor to further study the mechanism for how Apatinib suppressed angiogenesis. Results: Apatinib treatment could suppress the growth of ATC cells in a dose- and time-dependent manner via inducing apoptosis and blocking cell cycle progression at G0/G1 phase. Moreover, Apatinib treatment decreased the expression of angiogenin (ANG and inhibited angiogenesis of ATC cells in vitro and in vitro. We further confirmed that recombinant human ANG (rhANG significantly abrogated Apatinib-mediated anti-angiogenic ability in ATC cells. Additionally, Apatinib treatment decreased the level of p-Akt and p-GSK3β. Moreover, the Apatinib-mediated decrease of ANG and anti-angiogenic ability were partly reversed when an Akt activator, SC79, was administered. Furthermore, the anti-angiogenic ability of Apatinib can be enhanced in the presence of Akt inhibitor, and the inhibition of GSK3β attenuated the anti-angiogenic ability of Apatinib. Conclusion: Our results demonstrated that Apatinib treatment inhibited tumor growth, and Apatinib-induced suppression of Akt/GSK3β/ANG signaling pathway may play an important role in the inhibition of angiogenesis in ATC, supporting a potential therapeutic approach for using Apatinib in the treatment of ATC.

  13. Ginkgolide C Suppresses Adipogenesis in 3T3-L1 Adipocytes via the AMPK Signaling Pathway

    Chian-Jiun Liou

    2015-01-01

    Full Text Available Ginkgolide C, isolated from Ginkgo biloba leaves, is a flavone reported to have multiple biological functions, from decreased platelet aggregation to ameliorating Alzheimer disease. The study aim was to evaluate the antiadipogenic effect of ginkgolide C in 3T3-L1 adipocytes. Ginkgolide C was used to treat differentiated 3T3-L1 cells. Cell supernatant was collected to assay glycerol release, and cells were lysed to measure protein and gene expression related to adipogenesis and lipolysis by western blot and real-time PCR, respectively. Ginkgolide C significantly suppressed lipid accumulation in differentiated adipocytes. It also decreased adipogenesis-related transcription factor expression, including peroxisome proliferator-activated receptor and CCAAT/enhancer-binding protein. Furthermore, ginkgolide C enhanced adipose triglyceride lipase and hormone-sensitive lipase production for lipolysis and increased phosphorylation of AMP-activated protein kinase (AMPK, resulting in decreased activity of acetyl-CoA carboxylase for fatty acid synthesis. In coculture with an AMPK inhibitor (compound C, ginkgolide C also improved activation of sirtuin 1 and phosphorylation of AMPK in differentiated 3T3-L1 cells. The results suggest that ginkgolide C is an effective flavone for increasing lipolysis and inhibiting adipogenesis in adipocytes through the activated AMPK pathway.

  14. Efter cochlear implant

    Højen, Anders

    Dit barn har netop fået et cochlear implant. Hvad nu? Skal barnet fokusere udelukkende på at lære talt sprog, eller skal det også lære/fortsætte med tegnsprog eller støttetegn? Det er et vanskeligt spørgsmål, og før valget foretages, er det vigtigt at vurdere hvilke konsekvenser valget har, dels...... for den sproglige udvikling isoleret set, og dels for barnets udvikling ud fra en helhedsbetragtning. Dette indlæg fokuserer på, hvilke forventninger man kan have til cochlear implant-brugeres sproglige udvikling med talt sprog alene, hhv. med to sprog (tale og tegn). Disse forventninger er baseret på...

  15. Chronic social isolation suppresses proplastic response and promotes proapoptotic signalling in prefrontal cortex of Wistar rats.

    Djordjevic, Ana; Adzic, Miroslav; Djordjevic, Jelena; Radojcic, Marija B

    2010-08-15

    Successful adaptation to stress involves synergized actions of glucocorticoids and catecholamines at several levels of the CNS, including the prefrontal cortex (PFC). Inside the PFC, hormonal signals trigger concerted actions of transcriptional factors, such as glucocorticoid receptor (GR) and nuclear factor kappa B (NFkappaB), culminating in a balanced, proadaptive expression of their common genes, such as proplastic NCAM and/or apoptotic Bax and Bcl-2. In the present study, we hypothesized that chronic stress may compromise the balance between GR and NFkappaB signals and lead to an altered/maladaptive expression of their cognate genes in the PFC. Our results obtained with Wistar rats exposed to chronic social isolation indicated alterations of the GR relative to the NFkappaB, in favor of the GR, in both the cytoplasmic and the nuclear compartments of the PFC. Although these alterations did not affect the induction of proplastic NCAM gene, they decreased the NCAM sialylation necessary for plastic response and caused marked relocation of the mitochondrial membrane antiapoptotic Bcl-2 protein to its cytoplasmic form. Moreover, the compromised PSA-NCAM plastic response found under chronic stress was sustained after exposure of animals to the subsequent acute stress, whereas the proapoptotic signals were further emphasized. It is concluded that chronic social isolation of Wistar animals leads to a maladaptive response of the PFC, considering the diminishment of its plastic potential and potentiating of apoptosis. Such conditions in the PFC are likely to compromise its ability to interact with other CNS structures, such as the hippocampus, which is necessary for successful adaptation to stress. (c) 2010 Wiley-Liss, Inc.

  16. Celastrol inhibits chondrosarcoma proliferation, migration and invasion through suppression CIP2A/c-MYC signaling pathway

    Jinhui Wu

    2017-05-01

    Full Text Available Chondrosarcomas (CS is the second most frequent tumors of cartilage origin. A small compound extracted from Thunder God Vine (Tripterygium wilfordii Hook. F. called celastrol can directly bound CIP2A protein and effectively inhibit cell proliferation and induce apoptosis in several cancer cells. However, little knowledge is concern about the important role of CIP2A in CS patients and the therapeutic value of celastrol on CS. Our results showed that CIP2A and c-MYC were verified to be oncoproteins by detecting their mRNA and protein expression in 10 human CS tissues by qRT-PCR and Western blots. After treatment of celastrol, the proliferation, migration and invasion were significantly inhibited; whereas the apoptosis was largely induced in human CS cell lines. In addition, celastrol inhibited the expression of CIP2A, c-MYC, and suppressed apoptotic proteins BAX and caspase-8 in human CS cells, on the other hand, it induced the expression of antiapoptotic protein Bcl-2. Finally, knockdown of CIP2A also inhibited the migration and invasion and induced apoptosis of human CS cells. To sum up, we found that celastrol had effects on inhibiting proliferation, migration, invasion and inducing apoptosis through suppression CIP2A/c-MYC signaling pathway in vitro, which may provide a new therapeutic regimen for CS.

  17. Cochlear implantation in patients with bilateral cochlear trauma.

    Serin, Gediz Murat; Derinsu, Ufuk; Sari, Murat; Gergin, Ozgül; Ciprut, Ayça; Akdaş, Ferda; Batman, Cağlar

    2010-01-01

    Temporal bone fracture, which involves the otic capsule, can lead to complete loss of auditory and vestibular functions, whereas the patients without fractures may experience profound sensorineural hearing loss due to cochlear concussion. Cochlear implant is indicated in profound sensorineural hearing loss due to cochlear trauma but who still have an intact auditory nerve. This is a retrospective review study. We report 5 cases of postlingually deafened patients caused by cochlear trauma, who underwent cochlear implantation. Preoperative and postoperative hearing performance will be presented. These patients are cochlear implanted after the cochlear trauma in our department between 2001 and 2006. All patients performed very well with their implants, obtained open-set speech understanding. They all became good telephone users after implantation. Their performance in speech understanding was comparable to standard postlingual adult patients implanted. Cochlear implantation is an effective aural rehabilitation in profound sensorineural hearing loss caused by temporal bone trauma. Preoperative temporal bone computed tomography, magnetic resonance imaging, and promontorium stimulation testing are necessary to make decision for the surgery and to determine the side to be implanted. Surgery could be challenging and complicated because of anatomical irregularity. Moreover, fibrosis and partial or total ossification within the cochlea must be expected. Copyright 2010. Published by Elsevier Inc.

  18. Activation of Brain Somatostatin Signaling Suppresses CRF Receptor-Mediated Stress Response

    Andreas Stengel

    2017-04-01

    Full Text Available Corticotropin-releasing factor (CRF is the hallmark brain peptide triggering the response to stress and mediates—in addition to the stimulation of the hypothalamus-pituitary-adrenal (HPA axis—other hormonal, behavioral, autonomic and visceral components. Earlier reports indicate that somatostatin-28 injected intracerebroventricularly counteracts the acute stress-induced ACTH and catecholamine release. Mounting evidence now supports that activation of brain somatostatin signaling exerts a broader anti-stress effect by blunting the endocrine, autonomic, behavioral (with a focus on food intake and visceral gastrointestinal motor responses through the involvement of distinct somatostatin receptor subtypes.

  19. Activation of Brain Somatostatin Signaling Suppresses CRF Receptor-Mediated Stress Response.

    Stengel, Andreas; Taché, Yvette F

    2017-01-01

    Corticotropin-releasing factor (CRF) is the hallmark brain peptide triggering the response to stress and mediates-in addition to the stimulation of the hypothalamus-pituitary-adrenal (HPA) axis-other hormonal, behavioral, autonomic and visceral components. Earlier reports indicate that somatostatin-28 injected intracerebroventricularly counteracts the acute stress-induced ACTH and catecholamine release. Mounting evidence now supports that activation of brain somatostatin signaling exerts a broader anti-stress effect by blunting the endocrine, autonomic, behavioral (with a focus on food intake) and visceral gastrointestinal motor responses through the involvement of distinct somatostatin receptor subtypes.

  20. MicroRNA-200a suppresses the Wnt/?-catenin signaling pathway by interacting with ?-catenin

    SU, JUAN; ZHANG, ANLING; SHI, ZHENDONG; MA, FEIFEI; PU, PEIYU; WANG, TAO; ZHANG, JIE; KANG, CHUNSHENG; ZHANG, QINGYU

    2011-01-01

    The Wnt/?-catenin signaling pathway is crucial for human organ development and is involved in tumor progression of many cancers. Accumulating evidence suggests that the expression of ?-catenin is, in part, regulated by specific microRNAs (miRNAs). The purpose of this study was to determine the expression of a recently identified epithelial to mesenchymal transition (EMT)-associated tumor suppressor microRNA (miR)-200a, in cancer cells. We also aimed to identify specific miR-200a target genes ...

  1. Andrographolide Suppress Tumor Growth by Inhibiting TLR4/NF-κB Signaling Activation in Insulinoma

    Zhang, Qian-Qian; Ding, Yi; Lei, Yan; Qi, Cui-Ling; He, Xiao-Dong; Lan, Tian; Li, Jiang-Chao; Gong, Ping; Yang, Xuesong; Geng, Jian-Guo; Wang, Li-Jing

    2014-01-01

    Insulinomas are rare tumors, and approximately 10% of insulinomas are malignant. Accumulating evidence has implicated that we still lack effective therapy to treat the patients who are diagnosed with rare malignant insulinoma. Previous studies have reported that Andrographolide (Andro) could inhibit cell cycle progression, reduce cell invasion and induce cell apoptosis in many common cancer cells. However, the effects of andro are cell type-dependent. So we emplored the β-TC-6 cells and the RIP1-Tag2 transgenic mouse model of endogenously growing insulinoma model to elucidate the possible anti-cancer effect of Andro on insulinoma, an uncommon type of malignant cancers in this study. Our experiments revealed that Andro significantly inhibited tumor growth at both the early-stage and the advanced-stage of insulinoma through targeting the TLR4/NF-κB signaling pathway. This work initially provides the evidence that the TLR4/NF-κB signaling pathway might be vital as a potential therapeutic target, and also indispensable in Andro-mediated anti-cancer effect in insulinoma. PMID:24719558

  2. Leptin Suppresses the Rewarding Effects of Running via STAT3 Signaling in Dopamine Neurons.

    Fernandes, Maria Fernanda A; Matthys, Dominique; Hryhorczuk, Cécile; Sharma, Sandeep; Mogra, Shabana; Alquier, Thierry; Fulton, Stephanie

    2015-10-06

    The adipose hormone leptin potently influences physical activity. Leptin can decrease locomotion and running, yet the mechanisms involved and the influence of leptin on the rewarding effects of running ("runner's high") are unknown. Leptin receptor (LepR) signaling involves activation of signal transducer and activator of transcription-3 (STAT3), including in dopamine neurons of the ventral tegmental area (VTA) that are essential for reward-relevant behavior. We found that mice lacking STAT3 in dopamine neurons exhibit greater voluntary running, an effect reversed by viral-mediated STAT3 restoration. STAT3 deletion increased the rewarding effects of running whereas intra-VTA leptin blocked it in a STAT3-dependent manner. Finally, STAT3 loss-of-function reduced mesolimbic dopamine overflow and function. Findings suggest that leptin influences the motivational effects of running via LepR-STAT3 modulation of dopamine tone. Falling leptin is hypothesized to increase stamina and the rewarding effects of running as an adaptive means to enhance the pursuit and procurement of food. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. ZNF383, a novel KRAB-containing zinc finger protein, suppresses MAPK signaling pathway

    Cao Lei; Wang Zhi; Zhu Chuanbing; Zhao Yulian; Yuan Wuzhou; Li Jing; Wang Yuequn; Ying Zhaochu; Li Yongqing; Yu Weishi; Wu Xiushan; Liu Mingyao

    2005-01-01

    Mitogen-activated protein kinases (MAPKs) are major components of pathways controlling embryogenesis, cell differentiation, cell proliferation, and cell death. One of the most explored functions of MAPK signaling is the regulation of gene expression by direct or indirect phosphorylation and subsequent activation of transcription factors. In this article, we isolated a novel KRAB-related zinc finger gene named ZNF383 from an early embryo heart cDNA library. The cDNA of ZNF383 is 2220 bp, encoding a protein of 475 amino acids. The protein is conserved in evolution across different species. Northern blot analysis indicates that a 2.2 kb transcript specific for ZNF383 is detected in most of the examined human adult and embryonic tissues with a higher level in skeletal muscle. In COS-7 cells, ZNF383 protein is localized to nucleus and cytoplasm. ZNF383 is a transcription repressor when fused to Gal-4 DNA-binding domain and cotransfected with VP-16. Deletion analysis indicates that the KRAB box of ZNF383 is responsible for the transcriptional repressor activity. Overexpression of ZNF383 in cells inhibits the transcriptional activities of AP-1 and SRE, suggesting that ZNF383 may act as a negative regulator in MAPK-mediated signaling pathways

  4. Andrographolide Inhibits Ovariectomy-Induced Bone Loss via the Suppression of RANKL Signaling Pathways

    Wang, Tao; Liu, Qian; Zhou, Lin; Yuan, Jin Bo; Lin, Xixi; Zeng, Rong; Liang, Xiaonan; Zhao, Jinmin; Xu, Jiake

    2015-01-01

    Osteoporosis is a debilitating skeletal disorder with an increased risk of low-energy fracture, which commonly occurs among postmenopausal women. Andrographolide (AP), a natural product isolated from Andrographis paniculata, has been found to have anti-inflammatory, anti-cancer, anti-asthmatic, and neuro-protective properties. However, its therapeutic effect on osteoporosis is unknown. In this study, an ovariectomy (OVX) mouse model was used to evaluate the therapeutic effects of AP on post-menopausal osteoporosis by using micro-computed tomography (micro-CT). Bone marrow-derived osteoclast culture was used to examine the inhibitory effect of AP on osteoclastogenesis. Real time PCR was employed to examine the effect of AP on the expression of osteoclast marker genes. The activities of transcriptional factors NF-κB and NFATc1 were evaluated using a luciferase reporter assay, and the IκBα protein level was analyzed by Western blot. We found that OVX mice treated with AP have greater bone volume (BV/TV), trabecular thickness (Tb.Th), and trabecular number (Tb.N) compared to vehicle-treated OVX mice. AP inhibited RANKL-induced osteoclastogenesis, the expression of osteoclast marker genes including cathepsin K (Ctsk), TRACP (Acp5), and NFATc1, as well as the transcriptional activities of NF-κB and NFATc1. In conclusion, our results suggest that AP inhibits estrogen deficiency-induced bone loss in mice via the suppression of RANKL-induced osteoclastogensis and NF-κB and NFATc1 activities and, thus, might have therapeutic potential for osteoporosis. PMID:26593901

  5. Andrographolide Inhibits Ovariectomy-Induced Bone Loss via the Suppression of RANKL Signaling Pathways

    Tao Wang

    2015-11-01

    Full Text Available Osteoporosis is a debilitating skeletal disorder with an increased risk of low-energy fracture, which commonly occurs among postmenopausal women. Andrographolide (AP, a natural product isolated from Andrographis paniculata, has been found to have anti-inflammatory, anti-cancer, anti-asthmatic, and neuro-protective properties. However, its therapeutic effect on osteoporosis is unknown. In this study, an ovariectomy (OVX mouse model was used to evaluate the therapeutic effects of AP on post-menopausal osteoporosis by using micro-computed tomography (micro-CT. Bone marrow-derived osteoclast culture was used to examine the inhibitory effect of AP on osteoclastogenesis. Real time PCR was employed to examine the effect of AP on the expression of osteoclast marker genes. The activities of transcriptional factors NF-κB and NFATc1 were evaluated using a luciferase reporter assay, and the IκBα protein level was analyzed by Western blot. We found that OVX mice treated with AP have greater bone volume (BV/TV, trabecular thickness (Tb.Th, and trabecular number (Tb.N compared to vehicle-treated OVX mice. AP inhibited RANKL-induced osteoclastogenesis, the expression of osteoclast marker genes including cathepsin K (Ctsk, TRACP (Acp5, and NFATc1, as well as the transcriptional activities of NF-κB and NFATc1. In conclusion, our results suggest that AP inhibits estrogen deficiency-induced bone loss in mice via the suppression of RANKL-induced osteoclastogensis and NF-κB and NFATc1 activities and, thus, might have therapeutic potential for osteoporosis.

  6. Andrographolide Inhibits Ovariectomy-Induced Bone Loss via the Suppression of RANKL Signaling Pathways.

    Wang, Tao; Liu, Qian; Zhou, Lin; Yuan, Jin Bo; Lin, Xixi; Zeng, Rong; Liang, Xiaonan; Zhao, Jinmin; Xu, Jiake

    2015-11-17

    Osteoporosis is a debilitating skeletal disorder with an increased risk of low-energy fracture, which commonly occurs among postmenopausal women. Andrographolide (AP), a natural product isolated from Andrographis paniculata, has been found to have anti-inflammatory, anti-cancer, anti-asthmatic, and neuro-protective properties. However, its therapeutic effect on osteoporosis is unknown. In this study, an ovariectomy (OVX) mouse model was used to evaluate the therapeutic effects of AP on post-menopausal osteoporosis by using micro-computed tomography (micro-CT). Bone marrow-derived osteoclast culture was used to examine the inhibitory effect of AP on osteoclastogenesis. Real time PCR was employed to examine the effect of AP on the expression of osteoclast marker genes. The activities of transcriptional factors NF-κB and NFATc1 were evaluated using a luciferase reporter assay, and the IκBα protein level was analyzed by Western blot. We found that OVX mice treated with AP have greater bone volume (BV/TV), trabecular thickness (Tb.Th), and trabecular number (Tb.N) compared to vehicle-treated OVX mice. AP inhibited RANKL-induced osteoclastogenesis, the expression of osteoclast marker genes including cathepsin K (Ctsk), TRACP (Acp5), and NFATc1, as well as the transcriptional activities of NF-κB and NFATc1. In conclusion, our results suggest that AP inhibits estrogen deficiency-induced bone loss in mice via the suppression of RANKL-induced osteoclastogensis and NF-κB and NFATc1 activities and, thus, might have therapeutic potential for osteoporosis.

  7. Andrographolide suppresses melanin synthesis through Akt/GSK3β/β-catenin signal pathway.

    Zhu, Ping-Ya; Yin, Wei-Han; Wang, Meng-Ran; Dang, Yong-Yan; Ye, Xi-Yun

    2015-07-01

    Tyrosinase (TYR) is the key enzyme controlling the production of melanin. Very few papers have reported that andrographolide can inhibit melanin content. To investigate the effects of andrographolide on melanin synthesis. Cell viability, melanin content, TYR activity, transcriptional and protein expression levels of TYR family and other kinds of proteins involved in melanogenesis were measured after the treatments of andrographolide. It was found that andrographolide decreased melanin content, TYR activity and transcriptional and protein expression of TYR family and microphthalmia-associated transcription factor (MITF) in B16F10 melanoma cells. Data showed andrographolide also decreased melanin content and TYR content in ultraviolet B (UVB) irradiation induced brown guinea pigs. Moreover, we found that melanin content and TYR activity were effectively inhibited in Human Epidermis Melanocyte (HEM) treated with andrographolide at the medium concentrations without apparent effect on cell viability. Results in experiments treated with MG-132 or cycloheximide (CHX) showed that andrographolide lowered the content of β-catenin in cell nucleus resulting from accelerating the degradation of β-catenin. Phosphorylation of glycogen synthase kinase 3β (GSK3β) and Akt decreased simultaneously. 6-Bromoindirubin-3'-oxime (BIO, inhibitor of GSK3β) and insulin-like growth factors-1 (IGF-1, activator of Akt) could reverse the decline of β-catenin in B16F10 cells induced by andrographolide. These results demonstrate that andrographolide can effectively suppress melanin content and TYR activity in B16F10 cells, HEM cells and UVB-induced brown guinea pig skin by decreasing phosphorylation of GSK3β dependent on Akt, promoting the degradation of β-catenin, inhibiting β-catenin into the nucleus and decreasing the expression of MITF and TYR family. Data indicate that andrographolide may be a potential whiting agent which can have great market in cosmetics and in clinical such as

  8. Nanostructure Secondary-Mirror Apodizing Mask for Transmitter Signal Suppression in a Duplex Telescope

    Hagopian, John; Livas, Jeffrey; Shiri, Shahram; Getty, Stephanie; Tveekrem, June; Butler, James

    2012-01-01

    A document discusses a nanostructure apodizing mask, made of multi-walled carbon nanotubes, that is applied to the centers (or in and around the holes) of the secondary mirrors of telescopes that are used to interferometrically measure the strain of space-time in response to gravitational waves. The shape of this ultra-black mask can be adjusted to provide a smooth transition to the clear aperture of the secondary mirror to minimize diffracted light. Carbon nanotubes grown on silicon are a viable telescope mirror substrate, and can absorb significantly more light than other black treatments. The hemispherical reflectance of multi-walled carbon nanotubes grown at GSFC is approximately 3 to 10 times better than a standard aerospace paint used for stray light control. At the LISA (Laser Interferometer Space Antenna) wavelength of 1 micron, the advantage over paint is a factor of 10. Primarily, in the center of the secondary mirror (in the region of central obscuration, where no received light is lost) a black mask is applied to absorb transmitted light that could be reflected back into the receiver. In the LISA telescope, this is in the center couple of millimeters. The shape of this absorber is critical to suppress diffraction at the edge. By using the correct shape, the stray light can be reduced by approximately 10 to the 9 orders of magnitude versus no center mask. The effect of the nanotubes has been simulated in a stray-light model. The effect of the apodizing mask has been simulated in a near-field diffraction model. Specifications are geometry-dependent, but the baseline design for the LISA telescope has been modeled as well. The coatings are somewhat fragile, but work is continuing to enhance adhesion.

  9. Lithium Suppresses Hedgehog Signaling via Promoting ITCH E3 Ligase Activity and Gli1–SUFU Interaction in PDA Cells

    Xinshuo Wang

    2017-11-01

    Full Text Available Dysregulation of Hedgehog (Hh signaling pathway is one of the hallmarks of pancreatic ductal adenocarcinoma (PDA. Lithium, a clinical mood stabilizer for the treatment of mental disorders, is known to suppress tumorigenic potential of PDA cells by targeting the Hh/Gli signaling pathway. In this study, we investigated the molecular mechanism of lithium induced down-regulation of Hh/Gli1. Our data show that lithium promotes the poly-ubiquitination and proteasome-mediated degradation of Gli1 through activating E3 ligase ITCH. Additionally, lithium enhances interaction between Gli1 and SUFU via suppressing GSK3β, which phosphorylates SUFU and destabilizes the SUFU-Gli1 inhibitory complex. Our studies illustrate a novel mechanism by which lithium suppresses Hh signaling via simultaneously promoting ITCH-dependent Gli1 ubiquitination/degradation and SUFU-mediated Gli1 inhibition.

  10. Bmi-1-targeting suppresses osteosarcoma aggressiveness through the NF-κB signaling pathway

    Liu, Jiaguo; Luo, Bin; Zhao, Meng

    2017-01-01

    Bone cancer is one of the most lethal malignancies and the specific causes of tumor initiation are not well understood. B-cell-specific Moloney murine leukemia virus integration site 1 protein (Bmi-1) has been reported to be associated with the initiation and progression of osteosarcoma, and as a prognostic indicator in the clinic. In the current study, a full-length antibody targeting Bmi-1 (AbBmi-1) was produced and the preclinical value of Bmi-1-targeted therapy was evaluated in bone carcinoma cells and tumor xenograft mice. The results indicated that the Bmi-1 expression level was markedly upregulated in bone cancer cell lines, and inhibition of Bmi-1 by AbBmi-1 reduced the invasiveness and migration of osteosarcoma cells. Overexpression of Bmi-1 promoted proliferation and angiogenesis, and increased apoptosis resistance induced by cisplatin via the nuclear factor-κB (NF-κB) signal pathway. In addition, AbBmi-1 treatment inhibited the tumorigenicity of osteosarcoma cells in vivo. Furthermore, AbBmi-1 blocked NF-κB signaling and reduced MMP-9 expression. Furthermore, Bmi-1 promoted osteosarcoma tumor growth, whereas AbBmi-1 significantly inhibited osteosarcoma tumor growth in vitro and in vivo. Notably, AbBmi-1 decreased the percentages of Ki67-positive cells and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells in tumors compared with Bmi-1-treated and PBS controls. Notably, MMP-9 and NF-κB expression were downregulated by treatment with AbBmi-1 in MG-63 osteosarcoma cells. In conclusion, the data provides evidence that AbBmi-1 inhibited the progression of osteosarcoma, suggesting that AbBmi-1 may be a novel anti-cancer agent through the inhibition of Bmi-1 via activating the NF-κB pathway in osteosarcoma. PMID:28983587

  11. Chronic stress accelerates ligature-induced periodontitis by suppressing glucocorticoid receptor-α signaling.

    Lu, Huaixiu; Xu, Minguang; Wang, Feng; Liu, Shisen; Gu, Jing; Lin, Songshan; Zhao, Lisheng

    2016-03-25

    Periodontitis is a common chronic inflammatory disease. Recent studies have shown that chronic stress (CS) might modulate periodontal disease, but there are few models of CS-induced periodontitis, and the underlying mechanisms are unclear. The present study established a rat model of periodontitis associated with CS induced by nylon thread ligatures. The severity of periodontitis was evaluated in this model by radiographic and pathological examination. The inflammatory reaction indicated by the elevated serum levels of interleukin (IL)-1β, IL-6 and IL-8 was assessed by enzyme-linked immunosorbent assay. Toll-like receptor-4 (TLR4) and glucocorticoid receptor-α (GR-α) expressions were detected by reverse transcriptase-PCR and western blotting. Open-field tests and serum corticosterone were used to evaluate CS. The results showed that CS induced behavioral changes and increased corticosterone levels of the animals with periodontitis. CS stimulation markedly increased alveolar bone loss, periodontal pocket depth and the number of plaques. It also enhanced the inflammatory reaction. These results suggest that CS accelerated the ligature-induced pathological changes associated with periodontitis. Further analysis of the mechanisms involved showed that GR-α expression was significantly downregulated in periodontal tissues of the animals undergoing CS. Blocking GR-α signaling in lipopolysaccharide and corticosteroid-treated human periodontal ligament fibroblast cells in vitro significantly upregulated the expression of p-Akt (protein kinase B) and TLR4, promoted nuclear factor-κB activity and increased levels of IL-1β, IL-6 and IL-8. This research suggests that CS might accelerate the pathological progression of periodontitis by a GR-α signaling-mediated inflammatory response and that this may be a potential therapeutic target for the treatment of periodontal disease, particularly in patients with CS.

  12. Evaluation of dual-source parallel RF excitation for diffusion-weighted whole-body MR imaging with background body signal suppression at 3.0 T.

    Mürtz, Petra; Kaschner, Marius; Träber, Frank; Kukuk, Guido M; Büdenbender, Sarah M; Skowasch, Dirk; Gieseke, Jürgen; Schild, Hans H; Willinek, Winfried A

    2012-11-01

    To evaluate the use of dual-source parallel RF excitation (TX) for diffusion-weighted whole-body MRI with background body signal suppression (DWIBS) at 3.0 T. Forty consecutive patients were examined on a clinical 3.0-T MRI system using a diffusion-weighted (DW) spin-echo echo-planar imaging sequence with a combination of short TI inversion recovery and slice-selective gradient reversal fat suppression. DWIBS of the neck (n=5), thorax (n=8), abdomen (n=6) and pelvis (n=21) was performed both with TX (2:56 min) and with standard single-source RF excitation (4:37 min). The quality of DW images and reconstructed inverted maximum intensity projections was visually judged by two readers (blinded to acquisition technique). Signal homogeneity and fat suppression were scored as "improved", "equal", "worse" or "ambiguous". Moreover, the apparent diffusion coefficient (ADC) values were measured in muscles, urinary bladder, lymph nodes and lesions. By the use of TX, signal homogeneity was "improved" in 25/40 and "equal" in 15/40 cases. Fat suppression was "improved" in 17/40 and "equal" in 23/40 cases. These improvements were statistically significant (p3.0 T with respect to signal homogeneity and fat suppression, reduced scan time by approximately one-third, and did not influence the measured ADC values. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  13. SKLB188 inhibits the growth of head and neck squamous cell carcinoma by suppressing EGFR signalling.

    Barzegar, Mansoureh; Ma, Shuang; Zhang, Chao; Chen, Xin; Gu, Ying; Shang, Chaowei; Jiang, Xiaojuan; Yang, Jiao; Nathan, Cherie-Ann; Yang, Shengyong; Huang, Shile

    2017-10-10

    Overexpression of epidermal growth factor receptor (EGFR) occurs in approximately 90% of head and neck squamous cell carcinoma (HNSCC), and is correlated with poor prognosis. Thus, targeting EGFR is a promising strategy for treatment of HNSCC. Several small molecule EGFR inhibitors have been tested in clinical trials for treatment of HNSCC, but none of them are more effective than the current chemotherapeutic drugs. Thus, it is urgently needed to develop novel EGFR inhibitors for HNSCC treatment. By screening an in-house focused library containing approximately 650 000 known kinase inhibitors and kinase inhibitor-like compounds containing common kinase inhibitor core scaffolds, we identified SKLB188 as a lead compound for inhibition of EGFR. The anticancer effects of SKLB188 on HNSCC cells were investigated by in vitro cell growth, cell cycle and apoptosis assays, as well as in vivo FaDu xenograft mouse model. Molecular docking, in vitro kinase profiling and western blotting were performed to characterise EGFR as the molecular target. SKLB188 inhibited HNSCC cell proliferation by inducing G 1 cell cycle arrest, which was associated with downregulating the expression of Cdc25A, cyclins D1/A and cyclin-dependent kinases (CDK2/4), and upregulating the expression of cyclin-dependent kinase (CDK) inhibitors (p21 Cip1 and p27 Kip1 ), leading to decreased phosphorylation of Rb. SKLB188 also induced caspase-dependent apoptosis of HNSCC cells by downregulating the expression of Mcl-1 and survivin. Molecular docking revealed that SKLB188 could bind to the kinase domain of EGFR through hydrogen bonds and hydrophobic interactions. In vitro kinase assay showed that SKLB188 inhibited the activity of a recombinant human EGFR very potently (IC 50 =5 nM). Western blot analysis demonstrated that SKLB188 inhibited the phosphorylation of EGFR and its downstream targets, extracellular signal-regulated protein kinases 1 and 2 (Erk1/2) and Akt in the cells. In addition, SKLB188 dose

  14. Edaravone attenuates neuronal apoptosis in hypoxic-ischemic brain damage rat model via suppression of TRAIL signaling pathway.

    Li, Chunyi; Mo, Zhihuai; Lei, Junjie; Li, Huiqing; Fu, Ruying; Huang, Yanxia; Luo, Shijian; Zhang, Lei

    2018-06-01

    Edaravone is a new type of oxygen free radical scavenger and able to attenuate various brain damage including hypoxic-ischemic brain damage (HIBD). This study was aimed at investigating the neuroprotective mechanism of edaravone in rat hypoxic-ischemic brain damage model and its correlation with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling pathway. 75 seven-day-old Sprague-Dawley neonatal rats were equally divided into three groups: sham-operated group (sham), HIBD group and HIBD rats injected with edaravone (HIBD + EDA) group. Neurological severity and space cognitive ability of rats in each group were evaluated using Longa neurological severity score and Morris water maze testing. TUNEL assay and flow cytometry were used to determine brain cell apoptosis. Western blot was used to estimate the expression level of death receptor-5 (DR5), Fas-associated protein with death domain (FADD), caspase 8, B-cell lymphoma-2 (Bcl-2) and Bcl-2 associated X protein (Bax). In addition, immunofluorescence was performed to detect caspase 3. Edaravone reduced neurofunctional damage caused by HIBD and improved the cognitive capability of rats. The above experiment results suggested that edaravone could down-regulate the expression of active caspase 3 protein, thereby relieving neuronal apoptosis. Taken together, edaravone could attenuate neuronal apoptosis in rat hypoxic-ischemic brain damage model via suppression of TRAIL signaling pathway, which also suggested that edaravone might be an effective therapeutic strategy for HIBD clinical treatment. Copyright © 2018 Elsevier Ltd. All rights reserved.

  15. Mind Bomb Regulates Cell Death during TNF Signaling by Suppressing RIPK1’s Cytotoxic Potential

    Rebecca Feltham

    2018-04-01

    Full Text Available Summary: Tumor necrosis factor (TNF is an inflammatory cytokine that can signal cell survival or cell death. The mechanisms that switch between these distinct outcomes remain poorly defined. Here, we show that the E3 ubiquitin ligase Mind Bomb-2 (MIB2 regulates TNF-induced cell death by inactivating RIPK1 via inhibitory ubiquitylation. Although depletion of MIB2 has little effect on NF-κB activation, it sensitizes cells to RIPK1- and caspase-8-dependent cell death. We find that MIB2 represses the cytotoxic potential of RIPK1 by ubiquitylating lysine residues in the C-terminal portion of RIPK1. Our data suggest that ubiquitin conjugation of RIPK1 interferes with RIPK1 oligomerization and RIPK1-FADD association. Disruption of MIB2-mediated ubiquitylation, either by mutation of MIB2’s E3 activity or RIPK1’s ubiquitin-acceptor lysines, sensitizes cells to RIPK1-mediated cell death. Together, our findings demonstrate that Mind Bomb E3 ubiquitin ligases can function as additional checkpoint of cytokine-induced cell death, selectively protecting cells from the cytotoxic effects of TNF. : Feltham et al. show that MIB2 directly ubiquitylates RIPK1 upon TNF stimulation, suppressing the cytotoxic potential of RIPK1 and acting as a checkpoint within the TNF signaling pathway. Keywords: MIB2, RIPK1, TNF, cell death, caspase-8, IAPs, ubiquitin

  16. Secreted Clusterin protein inhibits osteoblast differentiation of bone marrow mesenchymal stem cells by suppressing ERK1/2 signaling pathway.

    Abdallah, Basem M; Alzahrani, Abdullah M; Kassem, Moustapha

    2018-05-01

    Secreted Clusterin (sCLU, also known as Apolipoprotein J) is an anti-apoptotic glycoprotein involved in the regulation of cell proliferation, lipid transport, extracellular tissue remodeling and apoptosis. sCLU is expressed and secreted by mouse bone marrow-derived skeletal (stromal or mesenchymal) stem cells (mBMSCs), but its functional role in MSC biology is not known. In this study, we demonstrated that Clusterin mRNA expression and protein secretion in conditioned medium increased during adipocyte differentiation and decreased during osteoblast differentiation of mBMSCs. Treatment of mBMSC cultures with recombinant sCLU protein increased cell proliferation and exerted an inhibitory effect on the osteoblast differentiation while stimulated adipocyte differentiation in a dose-dependent manner. siRNA-mediated silencing of Clu expression in mBMSCs reduced adipocyte differentiation and stimulated osteoblast differentiation of mBMSCs. Furthermore, the inhibitory effect of sCLU on the osteoblast differentiation of mBMSCs was mediated by the suppression of extracellular signal-regulated kinase (ERK1/2) phosphorylation. In conclusion, we identified sCLU as a regulator of mBMSCs lineage commitment to osteoblasts versus adipocytes through a mechanism mediated by ERK1/2 signaling. Inhibiting sCLU is a possible therapeutic approach for enhancing osteoblast differentiation and consequently bone formation. Copyright © 2018 Elsevier Inc. All rights reserved.

  17. Notch4 Signaling Induces a Mesenchymal–Epithelial–like Transition in Melanoma Cells to Suppress Malignant Behaviors

    Rad, Ehsan Bonyadi; Hammerlindl, Heinz; Wels, Christian; Popper, Ulrich; Menon, Dinoop Ravindran; Breiteneder, Heimo; Kitzwoegerer, Melitta; Hafner, Christine; Herlyn, Meenhard; Bergler, Helmut; Schaider, Helmut

    2016-01-01

    The effects of Notch signaling are context-dependent and both oncogenic and tumor-suppressive functions have been described. Notch signaling in melanoma is considered oncogenic, but clinical trials testing Notch inhibition in this malignancy have not proved successful. Here, we report that expression of the constitutively active intracellular domain of Notch4 (N4ICD) in melanoma cells triggered a switch from a mesenchymal-like parental phenotype to an epithelial-like phenotype. The epithelial-like morphology was accompanied by strongly reduced invasive, migratory, and proliferative properties concomitant with the downregulation of epithelial–mesenchymal transition markers Snail2 (SNAI2), Twist1, vimentin (VIM), and MMP2 and the reexpression of E-cadherin (CDH1). The N4ICD-induced phenotypic switch also resulted in significantly reduced tumor growth in vivo. Immunohistochemical analysis of primary human melanomas and cutaneous metastases revealed a significant correlation between Notch4 and E-cadherin expression. Mechanistically, we demonstrate that N4ICD induced the expression of the transcription factors Hey1 and Hey2, which bound directly to the promoter regions of Snail2 and Twist1 and repressed gene transcription, as determined by EMSA and luciferase assays. Taken together, our findings indicate a role for Notch4 as a tumor suppressor in melanoma, uncovering a potential explanation for the poor clinical efficacy of Notch inhibitors observed in this setting. PMID:26801977

  18. Andrographolide suppresses epithelial mesenchymal transition by inhibition of MAPK signalling pathway in lens epithelial cells.

    Kayastha, Forum; Johar, Kaid; Gajjar, Devarshi; Arora, Anshul; Madhu, Hardik; Ganatra, Darshini; Vasavada, Abhay

    2015-06-01

    Epithelial mesenchymal transition (EMT) of lens epithelial cells (LECs) may contribute to the development of posterior capsular opacification (PCO), which leads to visual impairment. Andrographolide has been shown to have therapeutic potential against various cancers. However, its effect on human LECs is still unknown. The purpose of this study is to evaluate the effect of andrographolide on EMT induced by growth factors in the fetal human lens epithelial cell line (FHL 124). Initially the LECs were treated with growth factors (TGF-beta 2 and bFGF) to induce EMT. Subsequently these EMT-induced cells were treated with andrographolide at 100 and 500 nM concentrations for 24 h. Our results showed that FHL 124 cells treated with growth factors had a significant decrease in protein and m-RNA levels of epithelial markers pax6 and E-Cadherin. After administering andrographolide, these levels significantly increased. It was noticed that EMT markers alpha-SMA, fibronectin and collagen IV significantly decreased after treatment with andrographolide when compared to the other group. Treatment with andrographolide significantly inhibited phosphorylation of ERK and JNK. Cell cycle analysis showed that andrographolide did not arrest cells at G0/G1 or G2/M at tested concentrations. Our findings suggest that andrographolide helps sustain epithelial characteristics by modulating EMT markers and inhibiting the mitogen-activated protein kinase (MAPK) signalling pathway in LECs. Hence it can prove to be useful in curbing EMT-mediated PCO.

  19. Suppression of Rac1 Signaling by Influenza A Virus NS1 Facilitates Viral Replication

    Jiang, Wei; Sheng, Chunjie; Gu, Xiuling; Liu, Dong; Yao, Chen; Gao, Shijuan; Chen, Shuai; Huang, Yinghui; Huang, Wenlin; Fang, Min

    2016-01-01

    Influenza A virus (IAV) is a major human pathogen with the potential to become pandemic. IAV contains only eight RNA segments; thus, the virus must fully exploit the host cellular machinery to facilitate its own replication. In an effort to comprehensively characterize the host machinery taken over by IAV in mammalian cells, we generated stable A549 cell lines with over-expression of the viral non-structural protein (NS1) to investigate the potential host factors that might be modulated by the NS1 protein. We found that the viral NS1 protein directly interacted with cellular Rac1 and facilitated viral replication. Further research revealed that NS1 down-regulated Rac1 activity via post-translational modifications. Therefore, our results demonstrated that IAV blocked Rac1-mediated host cell signal transduction through the NS1 protein to facilitate its own replication. Our findings provide a novel insight into the mechanism of IAV replication and indicate new avenues for the development of potential therapeutic targets. PMID:27869202

  20. Dusuqing granules (DSQ) suppress inflammation in Klebsiella pneumonia rat via NF-κB/MAPK signaling.

    Mei, Xue; Wang, Hao-Xun; Li, Jian-Sheng; Liu, Xiao-Hui; Lu, Xiao-Fan; Li, Ya; Zhang, Wei-Yu; Tian, Yan-Ge

    2017-04-17

    Dusuqing granules (DSQ) have been used in the treatment of bacterial pneumonia clinically, with remarkable benefits. This study was initiated to explore the effects of DSQ on pulmonary inflammation by regulating nuclear factor (NF)-κB/mitogen-activated protein kinase (MAPK) signaling in bacterial pneumonia rats. Rat model was duplicated with Klebsiella pneumonia by a one-time intratracheal injection. Rats were randomized into control, model, DSQ and levofloxacin (LVX) groups. After administrated with appropriate medicines for 7 days, lung tissues were harvested and prepared for pathological analysis, and interleukin (IL)-1, IL-6, monocyte chemotactic protein (MCP)-1and macrophage inflammatory protein (MIP)-2 detections. NF-κB mRNA was measured by real-time qPCR, and the phosphorylation and total proteins of P38MAPK, JNK46/54, ERK42/44 were determined by Western blotting. Marked pathological impairments were observed in model rats, whereas were improved in DSQ group. The cytokines levels, NF-κB mRNA expression and the phosphorylation of P38MAPK, JNK46/54 and ERK42/44 proteins were significantly higher in model group, and were significantly depressed in DSQ group. The protective effects of DSQ on Klebsiella pneumonia might be attributed to its inactivative effects of NF-κB/ MAPK pathway.

  1. The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis

    Boyle, D L; Soma, K; Hodge, J; Kavanaugh, A; Mandel, D; Mease, P; Shurmur, R; Singhal, A K; Wei, N; Rosengren, S; Kaplan, I; Krishnaswami, S; Luo, Z; Bradley, J; Firestein, G S

    2015-01-01

    Objective Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The pathways affected by tofacitinib and the effects on gene expression in situ are unknown. Therefore, tofacitinib effects on synovial pathobiology were investigated. Methods A randomised, double-blind, phase II serial synovial biopsy study (A3921073; NCT00976599) in patients with RA with an inadequate methotrexate response. Patients on background methotrexate received tofacitinib 10 mg twice daily or placebo for 28 days. Synovial biopsies were performed on Days -7 and 28 and analysed by immunoassay or quantitative PCR. Clinical response was determined by disease activity score and European League Against Rheumatism (EULAR) response on Day 28 in A3921073, and at Month 3 in a long-term extension study (A3921024; NCT00413699). Results Tofacitinib exposure led to EULAR moderate to good responses (11/14 patients), while placebo was ineffective (1/14 patients) on Day 28. Tofacitinib treatment significantly reduced synovial mRNA expression of matrix metalloproteinase (MMP)-1 and MMP-3 (pTofacitinib significantly decreased plasma CXCL10 (pTofacitinib reduces metalloproteinase and interferon-regulated gene expression in rheumatoid synovium, and clinical improvement correlates with reductions in STAT1 and STAT3 phosphorylation. JAK1-mediated interferon and interleukin-6 signalling likely play a key role in the synovial response. Trial registration number NCT00976599. PMID:25398374

  2. Lemur Tyrosine Kinase-3 Suppresses Growth of Prostate Cancer Via the AKT and MAPK Signaling Pathways

    Pengcheng Sun

    2017-08-01

    Full Text Available Background/Aims: Lemur tyrosine kinase (LMTK-3 is a member of the receptor tyrosine kinase (RTK family. Abnormal expression of LMTK-3 exists in various types of cancers, especially in endocrine-resistant breast cancers; however, the precise level of expression and the biological function in prostate cancer are poorly understood. Methods: In the present study, we determined the expression of LMTK-3 in prostate cancer using immunohistochemistry and Western blotting. We infected PC3 and LNCaP cells with lentivirus-LMTK-3 and observed the biologic characteristics of the PC3 and LNCaP cells in vitro with TUNEL, and migration and invasion assays, respectively. We also established a transplant tumor model of human prostate cancer with infected cells in 15 BALB/c-nu/nu nude mice. Results: LMTK-3 was expressed in prostate epithelial cells. There was a significant decline in the level of LMTK-3 expression in prostate cancers compared to normal tissues. LMTK-3 inhibited PC3 and LNCaP cell growth, migration, and invasion, and induced cell apoptosis in vitro. We also observed that LMTK-3 induced PC3 cell apoptosis in vivo. Further study showed that LMTK-3 inhibited phosphorylation of AKT and ERK, and promoted phosphorylation and activation of p38 kinase and Jun kinase (JNK. Conclusion: Recombinant lentivirus with enhanced expression of LMTK-3 inhibited prostate cancer cell growth and induced apoptosis in vitro and in vivo. AKT and MAPK signaling pathways may contribute to the process.

  3. Hyperbaric oxygen upregulates cochlear constitutive nitric oxide synthase

    Kao Ming-Ching

    2011-02-01

    Full Text Available Abstract Background Hyperbaric oxygen therapy (HBOT is a known adjuvant for treating ischemia-related inner ear diseases. Controversies still exist in the role of HBOT in cochlear diseases. Few studies to date have investigated the cellular changes that occur in inner ears after HBOT. Nitric oxide, which is synthesized by nitric oxide synthase (NOS, is an important signaling molecule in cochlear physiology and pathology. Here we investigated the effects of hyperbaric oxygen on eardrum morphology, cochlear function and expression of NOS isoforms in cochlear substructures after repetitive HBOT in guinea pigs. Results Minor changes in the eardrum were observed after repetitive HBOT, which did not result in a significant hearing threshold shift by tone burst auditory brainstem responses. A differential effect of HBOT on the expression of NOS isoforms was identified. Upregulation of constitutive NOS (nNOS and eNOS was found in the substructures of the cochlea after HBOT, but inducible NOS was not found in normal or HBOT animals, as shown by immunohistochemistry. There was no obvious DNA fragmentation present in this HBOT animal model. Conclusions The present evidence indicates that the customary HBOT protocol may increase constitutive NOS expression but such upregulation did not cause cell death in the treated cochlea. The cochlear morphology and auditory function are consequently not changed through the protocol.

  4. Verbal Working Memory in Children With Cochlear Implants

    Caldwell-Tarr, Amanda; Low, Keri E.; Lowenstein, Joanna H.

    2017-01-01

    Purpose Verbal working memory in children with cochlear implants and children with normal hearing was examined. Participants Ninety-three fourth graders (47 with normal hearing, 46 with cochlear implants) participated, all of whom were in a longitudinal study and had working memory assessed 2 years earlier. Method A dual-component model of working memory was adopted, and a serial recall task measured storage and processing. Potential predictor variables were phonological awareness, vocabulary knowledge, nonverbal IQ, and several treatment variables. Potential dependent functions were literacy, expressive language, and speech-in-noise recognition. Results Children with cochlear implants showed deficits in storage and processing, similar in size to those at second grade. Predictors of verbal working memory differed across groups: Phonological awareness explained the most variance in children with normal hearing; vocabulary explained the most variance in children with cochlear implants. Treatment variables explained little of the variance. Where potentially dependent functions were concerned, verbal working memory accounted for little variance once the variance explained by other predictors was removed. Conclusions The verbal working memory deficits of children with cochlear implants arise due to signal degradation, which limits their abilities to acquire phonological awareness. That hinders their abilities to store items using a phonological code. PMID:29075747

  5. 4-1BB Signaling in Conventional T Cells Drives IL-2 Production That Overcomes CD4+CD25+FoxP3+ T Regulatory Cell Suppression.

    Hampartsoum B Barsoumian

    Full Text Available Costimulation with the recombinant SA-4-1BBL agonist of 4-1BB receptor on conventional CD4+ T cells (Tconvs overcomes the suppression mediated by naturally occurring CD4+CD25+FoxP3+ T regulatory cells (Tregs. The mechanistic basis of this observation has remained largely unknown. Herein we show that Tconvs, but not Tregs, are the direct target of SA-4-1BBL-mediated evasion of Treg suppression. IL-2 produced by Tconvs in response to 4-1BB signaling is both necessary and sufficient for overcoming Treg suppression. Supernatant from Tconvs stimulated with SA-4-1BBL contains high levels of IL-2 and overcomes Treg suppression in ex vivo Tconv:Treg cocultures. Removal of IL-2 from such supernatant restores Treg suppression and repletion of Tconv:Treg cocultures with exogenous recombinant IL-2 overcomes suppression. This study establishes 4-1BB signaling as a key circuit that regulates physical and functional equilibrium between Tregs and Tconvs with important implications for immunotherapy for indications where a fine balance between Tregs and Teffs plays a decisive role.

  6. BMI-1 suppression increases the radiosensitivity of oesophageal carcinoma via the PI3K/Akt signaling pathway.

    Yang, Xing-Xiao; Ma, Ming; Sang, Mei-Xiang; Zhang, Xue-Yuan; Liu, Zhi-Kun; Song, Heng; Zhu, Shu-Chai

    2018-02-01

    BMI-1 knockdown, while the kinase agonist IGF-1 reversed the effects of BMI-1 knockdown on cell viability and radiosensitivity. Taken together, BMI-1 knockdown induces radiosensitivity in ESCC and significantly inhibits cell viability, which may contribute to an increased proportion of cells in the G0/G1 phase and cell apoptosis via suppression of the PI3K/Akt signalling pathway.

  7. Cochlear implant magnet retrofit.

    Cohen, N L; Breda, S D; Hoffman, R A

    1988-06-01

    An implantable magnet is now available for patients who have received the standard Nucleus 22-channel cochlear implant and who are not able to wear the headband satisfactorily. This magnet is attached in piggy-back fashion to the previously implanted receiver/stimulator by means of a brief operation under local anesthesia. Two patients have received this magnet retrofit, and are now wearing the headset with greater comfort and satisfaction. It is felt that the availability of this magnet will increase patient compliance in regard to hours of implant usage.

  8. Cochlear implants in Waardenburg syndrome.

    Cullen, Robert D; Zdanski, Carlton; Roush, Patricia; Brown, Carolyn; Teagle, Holly; Pillsbury, Harold C; Buchman, Craig

    2006-07-01

    Waardenburg syndrome is an autosomal-dominant syndrome characterized by dystopia canthorum, hyperplasia of the eyebrows, heterochromia irides, a white forelock, and sensorineural hearing loss in 20% to 55% of patients. This patient population accounts for approximately 2% of congenitally deaf children. The purpose of this retrospective case review was to describe the outcomes for those children with Waardenburg syndrome who have undergone cochlear implantation. Pediatric cochlear implant recipients with documented evidence of Waardenburg syndrome underwent retrospective case review. All patients received their cochlear implants at the study institution followed by outpatient auditory habilitation. Charts were reviewed for etiology and duration of deafness, age at time of cochlear implantation, perioperative complications, duration of use, and performance outcomes. Results of standard tests batteries for speech perception and production administered as a part of the patients' auditory habilitation were reviewed. Seven patients with Waardenburg syndrome and cochlear implants were identified. The average age at implantation was 37 months (range, 18-64 months) and the average duration of use was 69 months (range, 12-143 months). All of these patients are active users of their devices and perform very well after implantation. There were no major complications in this small group of patients. Children with congenital sensorineural hearing loss without other comorbidities (e.g., developmental delay, inner ear malformations) perform well when they receive cochlear implantation and auditory habilitation. Patients with Waardenburg syndrome can be expected to have above-average performance after cochlear implantation.

  9. Herbal Extract SH003 Suppresses Tumor Growth and Metastasis of MDA-MB-231 Breast Cancer Cells by Inhibiting STAT3-IL-6 Signaling

    Youn Kyung Choi

    2014-01-01

    Full Text Available Cancer inflammation promotes cancer progression, resulting in a high risk of cancer. Here, we demonstrate that our new herbal extract, SH003, suppresses both tumor growth and metastasis of MDA-MB-231 breast cancer cells via inhibiting STAT3-IL-6 signaling path. Our new herbal formula, SH003, mixed extract from Astragalus membranaceus, Angelica gigas, and Trichosanthes kirilowii Maximowicz, suppressed MDA-MB-231 tumor growth and lung metastasis in vivo and reduced the viability and metastatic abilities of MDA-MB-231 cells in vitro. Furthermore, SH003 inhibited STAT3 activation, which resulted in a reduction of IL-6 production. Therefore, we conclude that SH003 suppresses highly metastatic breast cancer growth and metastasis by inhibiting STAT3-IL-6 signaling path.

  10. COCHLEAR IMPLANTATION PREVALENCE IN ELDERLY

    A. V. Starokha

    2014-01-01

    Full Text Available Current paper describes an experience of cochlear implantation in elderly. Cochlear implantation has become a widely accepted intervention in the treatment of individuals with severe-to-profound sensorineural hearing loss. Cochlear implants are now accepted as a standard of care to optimize hearing and subsequent speech development in children and adults with deafness. But cochlear implantation affects not only hearing abilities, speech perception and speech production; it also has an outstanding impact on the social life, activities and self-esteem of each patient. The aim of this study was to evaluate the cochlear implantation efficacy in elderly with severe to profound sensorineural hearing loss. There were 5 patients under our observation. Surgery was performed according to traditional posterior tympanotomy and cochleostomy for cochlear implant electrode insertion for all observed patients. The study was conducted in two stages: before speech processor’s activation and 3 months later. Pure tone free field audiometry was performed to each patient to assess the efficiency of cochlear implantation in dynamics. The aim of the study was also to evaluate quality of life in elderly with severe to profound sensorineural hearing loss after unilateral cochlear implantation. Each patient underwent questioning with 36 Item Short Form Health Survey (SF-36. SF-36 is a set of generic, coherent, and easily administered quality-of-life measures. The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The eight sections are: physical functioning; physical role functioning; emotional role functioning; vitality; emotional well-being; social role functioning; bodily pain; general health perceptions. Our results demonstrate that cochlear implantation in elderly consistently improved quality of life

  11. Salicylic acid suppresses jasmonic acid signaling downstream of SCFCOI1-JAZ by targeting GCC promoter motifs via transcription factor ORA59

    Does, D. van der; Leon-Reyes, A.; Koornneef, A.; Verk, M.C. van; Rodenburg, N.; Pauwels, L.; Goossens, A.; Körbes, A.P.; Memelink, J.; Ritsema, T.; Wees, S.C.M. van; Pieterse, C.M.J.

    2013-01-01

    Antagonism between the defense hormones salicylic acid (SA) and jasmonic acid (JA) plays a central role in the modulation of the plant immune signaling network, but the molecular mechanisms underlying this phenomenon are largely unknown. Here, we demonstrate that suppression of the JA pathway by SA

  12. Metformin-mediated growth inhibition involves suppression of the IGF-I receptor signalling pathway in human pancreatic cancer cells

    Karnevi, Emelie; Said, Katarzyna; Andersson, Roland; Rosendahl, Ann H

    2013-01-01

    Epidemiological studies have shown direct associations between type 2 diabetes and obesity, both conditions associated with hyperglycaemia and hyperinsulinemia, and the risk of pancreatic cancer. Up to 80% of pancreatic cancer patients present with either new-onset type 2 diabetes or impaired glucose tolerance at the time of diagnosis. Recent population studies indicate that the incidence of pancreatic cancer is reduced among diabetics taking metformin. In this study, the effects of exposure of pancreatic cancer cells to high glucose levels on their growth and response to metformin were investigated. The human pancreatic cancer cell lines AsPC-1, BxPC-3, PANC-1 and MIAPaCa-2 were grown in normal (5 mM) or high (25 mM) glucose conditions, with or without metformin. The influence by metformin on proliferation, apoptosis and the AMPK and IGF-IR signalling pathways were evaluated in vitro. Metformin significantly reduced the proliferation of pancreatic cancer cells under normal glucose conditions. Hyperglycaemia however, protected against the metformin-induced growth inhibition. The anti-proliferative actions of metformin were associated with an activation of AMP-activated protein kinase AMPK Thr172 together with an inhibition of the insulin/insulin-like growth factor-I (IGF-I) receptor activation and downstream signalling mediators IRS-1 and phosphorylated Akt. Furthermore, exposure to metformin during normal glucose conditions led to increased apoptosis as measured by poly(ADP-ribose) polymerase (PARP) cleavage. In contrast, exposure to high glucose levels promoted a more robust IGF-I response and Akt activation which correlated to stimulated AMPK Ser485 phosphorylation and impaired AMPK Thr172 phosphorylation, resulting in reduced anti-proliferative and apoptotic effects by metformin. Our results indicate that metformin has direct anti-tumour activities in pancreatic cancer cells involving AMPK Thr172 activation and suppression of the insulin/IGF signalling pathways

  13. Cochlear Implantation and Single-sided Deafness: A Systematic Review of the Literature

    Cabral Junior, Francisco

    2015-07-01

    Full Text Available Introduction Current data show that binaural hearing is superior to unilateral hearing, specifically in the understanding of speech in noisy environments. Furthermore, unilateral hearing reduce onés ability to localize sound. Objectives This study provides a systematic review of recent studies to evaluate the outcomes of cochlear implantation in patients with single-sided deafness (SSD with regards to speech discrimination, sound localization and tinnitus suppression. Data Synthesis We performed a search in the PubMed, Cochrane Library and Lilacs databases to assess studies related to cochlear implantation in patients with unilateral deafness. After critical appraisal, eleven studies were selected for data extraction and analysis of demographic, study design and outcome data. Conclusion Although some studies have shown encouraging results on cochlear implantation and SSD, all fail to provide a high level of evidence. Larger studies are necessary to define the tangible benefits of cochlear implantation in patients with SSD.

  14. Tinnitus after Simultaneous and Sequential Bilateral Cochlear Implantation.

    Ramakers, Geerte G J; Kraaijenga, Véronique J C; Smulders, Yvette E; van Zon, Alice; Stegeman, Inge; Stokroos, Robert J; Free, Rolien H; Frijns, Johan H M; Huinck, Wendy J; Van Zanten, Gijsbert A; Grolman, Wilko

    2017-01-01

    suppression of tinnitus compared with their unilateral situation. While bilateral cochlear implantation can have a positive effect on preoperative tinnitus complaints, the induction of (temporary or permanent) tinnitus was also reported. Dutch Trial Register NTR1722.

  15. Tinnitus after Simultaneous and Sequential Bilateral Cochlear Implantation

    Geerte G. J. Ramakers

    2017-11-01

    , four patients had an additional benefit of the second CI: a total suppression of tinnitus compared with their unilateral situation.ConclusionWhile bilateral cochlear implantation can have a positive effect on preoperative tinnitus complaints, the induction of (temporary or permanent tinnitus was also reported.Clinical Trial RegistrationDutch Trial Register NTR1722.

  16. Labyrinthectomy with cochlear implantation.

    Zwolan, T A; Shepard, N T; Niparko, J K

    1993-05-01

    Numerous reports indicate that the cochlea remains responsive to electrical stimulation following labyrinthectomy. We report a case of a 47-year-old woman with a severe to profound sensorineural hearing loss from birth, who developed episodic vertigo with symptoms suggestive of delayed onset endolymphatic hydrops. Following 8 months of failed medical and vestibular rehabilitation management, a right-sided labyrinthectomy combined with cochlear implantation was performed without complication. Postoperatively the patient was free of vertigo. Attempts to activate the patient's device between 4 to 12 weeks after surgery were unsuccessful as stimulation of the electrodes resulted in discomfort. However, all 20 electrodes elicited comfortable hearing sensations 16 weeks postsurgery. One year after the successful activation, the patient demonstrated improved sound awareness and speech recognition with the implant when compared with preoperative performance with a hearing aid. This case study suggests that electrical detection thresholds with prosthetic stimulation may be unstable in the recently labyrinthectomized ear but supports and extends prior observations of preserved cochlear responsiveness after labyrinthectomy.

  17. Valsartan attenuates pulmonary hypertension via suppression of mitogen activated protein kinase signaling and matrix metalloproteinase expression in rodents.

    Lu, Yuyan; Guo, Haipeng; Sun, Yuxi; Pan, Xin; Dong, Jia; Gao, Di; Chen, Wei; Xu, Yawei; Xu, Dachun

    2017-08-01

    It has previously been demonstrated that the renin-angiotensin system is involved in the pathogenesis and development of pulmonary hypertension (PH). However, the efficacy of angiotensin II type I (AT1) receptor blockers in the treatment of PH is variable. The present study examined the effects of the AT1 receptor blocker valsartan on monocrotaline (MCT)‑induced PH in rats and chronic hypoxia‑induced PH in mice. The results demonstrated that valsartan markedly attenuated development of PH in rats and mice, as indicated by reduced right ventricular systolic pressure, diminished lung vascular remodeling and decreased right ventricular hypertrophy, compared with vehicle treated animals. Immunohistochemical analyses of proliferating cell nuclear antigen expression revealed that valsartan suppressed smooth muscle cell proliferation. Western blot analysis demonstrated that valsartan limited activation of p38, c‑Jun N‑terminal kinase 1/2 and extracellular signal‑regulated kinase 1/2 signaling pathways and significantly reduced MCT‑induced upregulation of pulmonary matrix metalloproteinases‑2 and ‑9, and transforming growth factor‑β1 expression. The results suggested that valsartan attenuates development of PH in rodents by reducing expression of extracellular matrix remodeling factors and limiting smooth muscle cell proliferation to decrease pathological vascular remodeling. Therefore, valsartan may be a valuable future therapeutic approach for the treatment of PH.

  18. Bone morphogenetic protein-9 suppresses growth of myeloma cells by signaling through ALK2 but is inhibited by endoglin

    Olsen, O E; Wader, K F; Misund, K; Våtsveen, T K; Rø, T B; Mylin, A K; Turesson, I; Størdal, B F; Moen, S H; Standal, T; Waage, A; Sundan, A; Holien, T

    2014-01-01

    Multiple myeloma is a malignancy of plasma cells predominantly located in the bone marrow. A number of bone morphogenetic proteins (BMPs) induce apoptosis in myeloma cells in vitro, and with this study we add BMP-9 to the list. BMP-9 has been found in human serum at concentrations that inhibit cancer cell growth in vitro. We here show that the level of BMP-9 in serum was elevated in myeloma patients (median 176 pg/ml, range 8–809) compared with healthy controls (median 110 pg/ml, range 8–359). BMP-9 was also present in the bone marrow and was able to induce apoptosis in 4 out of 11 primary myeloma cell samples by signaling through ALK2. BMP-9-induced apoptosis in myeloma cells was associated with c-MYC downregulation. The effects of BMP-9 were counteracted by membrane-bound (CD105) or soluble endoglin present in the bone marrow microenvironment, suggesting a mechanism for how myeloma cells can evade the tumor suppressing activity of BMP-9 in multiple myeloma

  19. Complex-enhanced chaotic signals with time-delay signature suppression based on vertical-cavity surface-emitting lasers subject to chaotic optical injection

    Chen, Jianjun; Duan, Yingni; Zhong, Zhuqiang

    2018-03-01

    A chaotic system is constructed on the basis of vertical-cavity surface-emitting lasers (VCSELs), where a slave VCSEL subject to chaotic optical injection (COI) from a master VCSEL with the external feedback. The complex degree (CD) and time-delay signature (TDS) of chaotic signals generated by this chaotic system are investigated numerically via permutation entropy (PE) and self-correlation function (SF) methods, respectively. The results show that, compared with master VCSEL subject to optical feedback, complex-enhanced chaotic signals with TDS suppression can be achieved for S-VCSEL subject to COI. Meanwhile, the influences of several controllable parameters on the evolution maps of CD of chaotic signals are carefully considered. It is shown that the CD of chaotic signals for S-VCSEL is always higher than that for M-VCSEL due to the CIO effect. The TDS of chaotic signals can be significantly suppressed by choosing the reasonable parameters in this system. Furthermore, TDS suppression and high CD chaos can be obtained simultaneously in the specific parameter ranges. The results confirm that this chaotic system may effectively improve the security of a chaos-based communication scheme.

  20. Puerarin suppresses proliferation of endometriotic stromal cells partly via the MAPK signaling pathway induced by 17ß-estradiol-BSA.

    Wen Cheng

    Full Text Available BACKGROUND: Puerarin is a major isoflavonoid compound extracted from Radix puerariae. It has a weak estrogenic action by binding to estrogen receptors (ERs. In our early clinical practice to treat endometriosis, a better therapeutic effect was achieved if the formula of traditional Chinese medicine included Radix puerariae. The genomic and non-genomic effects of puerarin were studied in our Lab. This study aims to investigate the ability of puerarin to bind competitively to ERs in human endometriotic stromal cells (ESCs, determine whether and how puerarin may influence phosphorylation of the non-genomic signaling pathway induced by 17ß-estradiol conjugated to BSA (E(2-BSA. METHODOLOGY: ESCs were successfully established. Binding of puerarin to ERs was assessed by a radioactive competitive binding assay in ESCs. Activation of the signaling pathway was screened by human phospho-kinase array, and was further confirmed by western blot. Cell proliferation was analyzed according to the protocol of CCK-8. The mRNA and protein levels of cyclin D1, Cox-2 and Cyp19 were determined by real-time PCR and western blotting. Inhibitor of MEK1/2 or ER antagonist was used to confirm the involved signal pathway. PRINCIPAL FINDINGS: Our data demonstrated that the total binding ability of puerarin to ERs on viable cells is around 1/3 that of 17ß-estradiol (E(2. E(2-BSA was able to trigger a rapid, non-genomic, membrane-mediated activation of ERK1/2 in ESCs and this phenomenon was associated with an increased proliferation of ESCs. Treating ESCs with puerarin abrogated the phosphorylation of ERK and significantly decreased cell proliferation, as well as related gene expression levels enhanced by E(2-BSA. CONCLUSIONS/SIGNIFICANCE: Puerarin suppresses proliferation of ESCs induced by E(2-BSA partly via impeding a rapid, non-genomic, membrane-initiated ERK pathway, and down-regulation of Cyclin D1, Cox-2 and Cyp19 are involved in the process. Our data further show

  1. M-COPA suppresses endolysosomal Kit-Akt oncogenic signalling through inhibiting the secretory pathway in neoplastic mast cells.

    Yasushi Hara

    Full Text Available Gain-of-function mutations in Kit receptor tyrosine kinase result in the development of a variety of cancers, such as mast cell tumours, gastrointestinal stromal tumours (GISTs, acute myeloid leukemia, and melanomas. The drug imatinib, a selective inhibitor of Kit, is used for treatment of mutant Kit-positive cancers. However, mutations in the Kit kinase domain, which are frequently found in neoplastic mast cells, confer an imatinib resistance, and cancers expressing the mutants can proliferate in the presence of imatinib. Recently, we showed that in neoplastic mast cells that endogenously express an imatinib-resistant Kit mutant, Kit causes oncogenic activation of the phosphatidylinositol 3-kinase-Akt (PI3K-Akt pathway and the signal transducer and activator of transcription 5 (STAT5 but only on endolysosomes and on the endoplasmic reticulum (ER, respectively. Here, we show a strategy for inhibition of the Kit-PI3K-Akt pathway in neoplastic mast cells by M-COPA (2-methylcoprophilinamide, an inhibitor of this secretory pathway. In M-COPA-treated cells, Kit localization in the ER is significantly increased, whereas endolysosomal Kit disappears, indicating that M-COPA blocks the biosynthetic transport of Kit from the ER. The drug greatly inhibits oncogenic Akt activation without affecting the association of Kit with PI3K, indicating that ER-localized Kit-PI3K complex is unable to activate Akt. Importantly, M-COPA but not imatinib suppresses neoplastic mast cell proliferation through inhibiting anti-apoptotic Akt activation. Results of our M-COPA treatment assay show that Kit can activate Erk not only on the ER but also on other compartments. Furthermore, Tyr568/570, Tyr703, Tyr721, and Tyr936 in Kit are phosphorylated on the ER, indicating that these five tyrosine residues are all phosphorylated before mutant Kit reaches the plasma membrane (PM. Our study provides evidence that Kit is tyrosine-phosphorylated soon after synthesis on the ER but is

  2. M-COPA suppresses endolysosomal Kit-Akt oncogenic signalling through inhibiting the secretory pathway in neoplastic mast cells.

    Hara, Yasushi; Obata, Yuuki; Horikawa, Keita; Tasaki, Yasutaka; Suzuki, Kyohei; Murata, Takatsugu; Shiina, Isamu; Abe, Ryo

    2017-01-01

    Gain-of-function mutations in Kit receptor tyrosine kinase result in the development of a variety of cancers, such as mast cell tumours, gastrointestinal stromal tumours (GISTs), acute myeloid leukemia, and melanomas. The drug imatinib, a selective inhibitor of Kit, is used for treatment of mutant Kit-positive cancers. However, mutations in the Kit kinase domain, which are frequently found in neoplastic mast cells, confer an imatinib resistance, and cancers expressing the mutants can proliferate in the presence of imatinib. Recently, we showed that in neoplastic mast cells that endogenously express an imatinib-resistant Kit mutant, Kit causes oncogenic activation of the phosphatidylinositol 3-kinase-Akt (PI3K-Akt) pathway and the signal transducer and activator of transcription 5 (STAT5) but only on endolysosomes and on the endoplasmic reticulum (ER), respectively. Here, we show a strategy for inhibition of the Kit-PI3K-Akt pathway in neoplastic mast cells by M-COPA (2-methylcoprophilinamide), an inhibitor of this secretory pathway. In M-COPA-treated cells, Kit localization in the ER is significantly increased, whereas endolysosomal Kit disappears, indicating that M-COPA blocks the biosynthetic transport of Kit from the ER. The drug greatly inhibits oncogenic Akt activation without affecting the association of Kit with PI3K, indicating that ER-localized Kit-PI3K complex is unable to activate Akt. Importantly, M-COPA but not imatinib suppresses neoplastic mast cell proliferation through inhibiting anti-apoptotic Akt activation. Results of our M-COPA treatment assay show that Kit can activate Erk not only on the ER but also on other compartments. Furthermore, Tyr568/570, Tyr703, Tyr721, and Tyr936 in Kit are phosphorylated on the ER, indicating that these five tyrosine residues are all phosphorylated before mutant Kit reaches the plasma membrane (PM). Our study provides evidence that Kit is tyrosine-phosphorylated soon after synthesis on the ER but is unable to

  3. Evaluation of dual-source parallel RF excitation for diffusion-weighted whole-body MR imaging with background body signal suppression at 3.0 T

    Muertz, Petra, E-mail: petra.muertz@ukb.uni-bonn.de [Department of Radiology, University of Bonn (Germany); Kaschner, Marius, E-mail: marius.kaschner@ukb.uni-bonn.de [Department of Radiology, University of Bonn (Germany); Traeber, Frank, E-mail: frank.traeber@ukb.uni-bonn.de [Department of Radiology, University of Bonn (Germany); Kukuk, Guido M., E-mail: guido.kukuk@ukb.uni-bonn.de [Department of Radiology, University of Bonn (Germany); Buedenbender, Sarah M., E-mail: sarah_m_buedenbender@yahoo.de [Department of Radiology, University of Bonn (Germany); Skowasch, Dirk, E-mail: dirk.skowasch@ukb.uni-bonn.de [Department of Medicine, University of Bonn (Germany); Gieseke, Juergen, E-mail: juergen.gieseke@philips.com [Philips Healthcare, Best (Netherlands); Department of Radiology, University of Bonn (Germany); Schild, Hans H., E-mail: hans.schild@ukb.uni-bonn.de [Department of Radiology, University of Bonn (Germany); Willinek, Winfried A., E-mail: winfried.willinek@ukb.uni-bonn.de [Department of Radiology, University of Bonn (Germany)

    2012-11-15

    Purpose: To evaluate the use of dual-source parallel RF excitation (TX) for diffusion-weighted whole-body MRI with background body signal suppression (DWIBS) at 3.0 T. Materials and methods: Forty consecutive patients were examined on a clinical 3.0-T MRI system using a diffusion-weighted (DW) spin-echo echo-planar imaging sequence with a combination of short TI inversion recovery and slice-selective gradient reversal fat suppression. DWIBS of the neck (n = 5), thorax (n = 8), abdomen (n = 6) and pelvis (n = 21) was performed both with TX (2:56 min) and with standard single-source RF excitation (4:37 min). The quality of DW images and reconstructed inverted maximum intensity projections was visually judged by two readers (blinded to acquisition technique). Signal homogeneity and fat suppression were scored as 'improved', 'equal', 'worse' or 'ambiguous'. Moreover, the apparent diffusion coefficient (ADC) values were measured in muscles, urinary bladder, lymph nodes and lesions. Results: By the use of TX, signal homogeneity was 'improved' in 25/40 and 'equal' in 15/40 cases. Fat suppression was 'improved' in 17/40 and 'equal' in 23/40 cases. These improvements were statistically significant (p < 0.001, Wilcoxon signed-rank test). In five patients, fluid-related dielectric shading was present, which improved remarkably. The ADC values did not significantly differ for the two RF excitation methods (p = 0.630 over all data, pairwise Student's t-test). Conclusion: Dual-source parallel RF excitation improved image quality of DWIBS at 3.0 T with respect to signal homogeneity and fat suppression, reduced scan time by approximately one-third, and did not influence the measured ADC values.

  4. Cochlear implants and medical tourism.

    McKinnon, Brian J; Bhatt, Nishant

    2010-09-01

    To compare the costs of medical tourism in cochlear implant surgery performed in India as compared to the United States. In addition, the cost savings of obtaining cochlear implant surgery in India were compare d to those of other surgical interventions obtained as a medical tourist. Searches were conducted on Medline and Google using the search terms: 'medical tourism', 'medical offshoring', 'medical outsourcing', 'cochlear implants' and 'cochlear implantation'. The information regarding cost of medical treatment was obtained from personal communication with individuals familiar with India's cochlear implantation medical tourism industry. The range of cost depended on length of stay as well as the device chosen. Generally the cost, inclusive of travel, surgery and device, was in the range of $21,000-30,000, as compared to a cost range of $40,000-$60,000 in the US. With the escalating cost of healthcare in the United States, it is not surprising that some patients would seek to obtain surgical care overseas at a fraction of the cost. Participants in medical tourism often have financial resources, but lack health insurance coverage. While cardiovascular and orthopedic surgery performed outside the United States in India at centers that cater to medical tourists are often performed at one-quarter to one-third of the cost that would have been paid in the United States, the cost differential for cochlear implants is not nearly as favorable.

  5. Fenofibrate suppresses cellular metabolic memory of high glucose in diabetic retinopathy via a sirtuin 1-dependent signalling pathway.

    Zhao, Shuzhi; Li, Jun; Wang, Na; Zheng, Bingqing; Li, Tao; Gu, Qing; Xu, Xun; Zheng, Zhi

    2015-10-01

    Inflammation is a major contributing factor in the development of diabetic microvascular complications, regardless of whether improved glycaemic control is achieved. Studies have increasingly indicated that fenofibrate, a lipid‑lowering therapeutic agent in clinical use, exerts a potential anti‑inflammatory effect, which is mediated by sirtuin 1 (SIRT1; an NAD+‑dependent deacetylase) in endothelial cells. The aim of the present study was to investigate the inhibitory effect of fenofibrate on metabolic memory (via the regulation of SIRT1), and inflammatory responses in cell and animal models of diabetic retinopathy (DR). The data demonstrated that high glucose treatment in human retinal endothelial cells (HRECs) inhibited the expression and deacetylase activity of SIRT1. The reduction of SIRT1 expression and deacetylase activity persisted following a return to normal glucose levels. Furthermore, nuclear factor‑κB expression was observed to be negatively correlated with SIRT1 expression and activity in HRECs under high glucose levels and the subsequent return to normal glucose levels. Fenofibrate treatment abrogated these changes. Knockdown of SIRT1 attenuated the effect of fenofibrate on high glucose‑induced NF‑κB expression. In addition, fenofibrate upregulated SIRT1 expression through peroxisome proliferator‑activated receptor α in high glucose‑induced metabolic memory. These findings indicate that fenofibrate is important in anti‑inflammatory processes and suppresses the cellular metabolic memory of high glucose‑induced stress via the SIRT1‑dependent signalling pathway. Thus, treatment with fenofibrate may offer a promising therapeutic strategy for halting the development of DR and other complications of diabetes.

  6. NLRP3 and ASC suppress lupus-like autoimmunity by driving the immunosuppressive effects of TGF-β receptor signalling.

    Lech, Maciej; Lorenz, Georg; Kulkarni, Onkar P; Grosser, Marian O O; Stigrot, Nora; Darisipudi, Murthy N; Günthner, Roman; Wintergerst, Maximilian W M; Anz, David; Susanti, Heni Eka; Anders, Hans-Joachim

    2015-12-01

    The NLRP3/ASC inflammasome drives host defence and autoinflammatory disorders by activating caspase-1 to trigger the secretion of mature interleukin (IL)-1β/IL-18, but its potential role in autoimmunity is speculative. We generated and phenotyped Nlrp3-deficient, Asc-deficient, Il-1r-deficient and Il-18-deficient C57BL/6-lpr/lpr mice, the latter being a mild model of spontaneous lupus-like autoimmunity. While lack of IL-1R or IL-18 did not affect the C57BL/6-lpr/lpr phenotype, lack of NLRP3 or ASC triggered massive lymphoproliferation, lung T cell infiltrates and severe proliferative lupus nephritis within 6 months, which were all absent in age-matched C57BL/6-lpr/lpr controls. Lack of NLRP3 or ASC increased dendritic cell and macrophage activation, the expression of numerous proinflammatory mediators, lymphocyte necrosis and the expansion of most T cell and B cell subsets. In contrast, plasma cells and autoantibody production were hardly affected. This unexpected immunosuppressive effect of NLRP3 and ASC may relate to their known role in SMAD2/3 phosphorylation during tumour growth factor (TGF)-β receptor signalling, for example, Nlrp3-deficiency and Asc-deficiency significantly suppressed the expression of numerous TGF-β target genes in C57BL/6-lpr/lpr mice and partially recapitulated the known autoimmune phenotype of Tgf-β1-deficient mice. These data identify a novel non-canonical immunoregulatory function of NLRP3 and ASC in autoimmunity. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  7. Prolonged activation of S6K1 does not suppress IRS or PI-3 kinase signaling during muscle cell differentiation

    MacKenzie Matthew G

    2010-05-01

    Full Text Available Abstract Background Myogenesis in C2C12 cells requires the activation of the PI3K/mTOR signaling pathways. Since mTOR signaling can feedback through S6K1 to inhibit the activation of PI3K, the aim of this work was to assess whether feedback from S6K1 played a role in myogenesis and determine whether siRNA mediated knockdown of S6K1 would lead to an increased rate of myotube formation. Results S6K1 activity increased in a linear fashion following plating and was more than 3-fold higher after Day 3 of differentiation (subconfluent = 11.09 ± 3.05, Day 3 = 29.34 ± 3.58. IRS-1 levels tended to increase upon serum withdrawal but decreased approximately 2-fold (subconfluent = 0.88 ± 0.10, Day 3 = 0.42 ± 0.06 3 days following differentiation whereas IRS-2 protein remained stable. IRS-1 associated p85 was significantly reduced upon serum withdrawal (subconfluent = 0.86 ± 0.07, Day 0 = 0.31 ± 0.05, remaining low through day 1. IRS-2 associated p85 decreased following serum withdrawal (subconfluent = 0.96 ± 0.05, Day 1 = 0.56 ± 0.08 and remained suppressed up to Day 3 following differentiation (0.56 ± 0.05. Phospho-tyrosine associated p85 increased significantly from subconfluent to Day 0 and remained elevated throughout differentiation. siRNA directed against S6K1 and S6K2 did not result in changes in IRS-1 levels after either 48 or 96 hrs. Furthermore, neither 48 nor 96 hrs of S6K1 knockdown caused a change in myotube formation. Conclusions Even though S6K1 activity increases throughout muscle cell differentiation and IRS-1 levels decrease over this period, siRNA suggests that S6K1 is not mediating the decrease in IRS-1. The decrease in IRS-1/2 associated p85 together with the increase in phospho-tyrosine associated p85 suggests that PI3K associates primarily with scaffolds other than IRS-1/2 during muscle cell differentiation.

  8. 7-Dehydrocholesterol (7-DHC), But Not Cholesterol, Causes Suppression of Canonical TGF-β Signaling and Is Likely Involved in the Development of Atherosclerotic Cardiovascular Disease (ASCVD).

    Huang, Shuan Shian; Liu, I-Hua; Chen, Chun-Lin; Chang, Jia-Ming; Johnson, Frank E; Huang, Jung San

    2017-06-01

    For several decades, cholesterol has been thought to cause ASCVD. Limiting dietary cholesterol intake has been recommended to reduce the risk of the disease. However, several recent epidemiological studies do not support a relationship between dietary cholesterol and/or blood cholesterol and ASCVD. Consequently, the role of cholesterol in atherogenesis is now uncertain. Much evidence indicates that TGF-β, an anti-inflammatory cytokine, protects against ASCVD and that suppression of canonical TGF-β signaling (Smad2-dependent) is involved in atherogenesis. We had hypothesized that cholesterol causes ASCVD by suppressing canonical TGF-β signaling in vascular endothelium. To test this hypothesis, we determine the effects of cholesterol, 7-dehydrocholesterol (7-DHC; the biosynthetic precursor of cholesterol), and other sterols on canonical TGF-β signaling. We use Mv1Lu cells (a model cell system for studying TGF-β activity) stably expressing the Smad2-dependent luciferase reporter gene. We demonstrate that 7-DHC (but not cholesterol or other sterols) effectively suppresses the TGF-β-stimulated luciferase activity. We also demonstrate that 7-DHC suppresses TGF-β-stimulated luciferase activity by promoting lipid raft/caveolae formation and subsequently recruiting cell-surface TGF-β receptors from non-lipid raft microdomains to lipid rafts/caveolae where TGF-β receptors become inactive in transducing canonical signaling and undergo rapid degradation upon TGF-β binding. We determine this by cell-surface 125 I-TGF-β-cross-linking and sucrose density gradient ultracentrifugation. We further demonstrate that methyl-β-cyclodextrin (MβCD), a sterol-chelating agent, reverses 7-DHC-induced suppression of TGF-β-stimulated luciferase activity by extrusion of 7-DHC from resident lipid rafts/caveolae. These results suggest that 7-DHC, but not cholesterol, promotes lipid raft/caveolae formation, leading to suppression of canonical TGF-β signaling and atherogenesis. J

  9. Cochlear implantation in a bilateral Mondini dysplasia.

    Turrini, M; Orzan, E; Gabana, M; Genovese, E; Arslan, E; Fisch, U

    1997-01-01

    We report the speech perception progress and programming procedures of a case of congenital profound deafness and bilateral Mondini dysplasia implanted with a Nucleus 20 + 2 cochlear implant at the age of six. Unclear relations between electrodes array and cochlear partition made implant programming difficult and non-standard procedures were set. Cochlear implantation may give excellent rehabilitative results also in cochleae with malformation.

  10. Delphinidin, a specific inhibitor of histone acetyltransferase, suppresses inflammatory signaling via prevention of NF-κB acetylation in fibroblast-like synoviocyte MH7A cells

    Seong, Ah-Reum; Yoo, Jung-Yoon; Choi, KyungChul; Lee, Mee-Hee; Lee, Yoo-Hyun; Lee, Jeongmin; Jun, Woojin; Kim, Sunoh; Yoon, Ho-Geun

    2011-01-01

    Highlights: → Delphinidin is a novel inhibitor of p300/CBP histone acetyltransferase. → Delphinidin prevents the hyperacetylation of p65 by inhibiting the HAT activity of p300/CBP. → Delphinidin efficiently suppresses the expression of inflammatory cytokines in MH7A cells via hypoacetylation of NF-κB. → Delphinidin inhibits cytokine release in the Jurkat T lymphocyte cell line. -- Abstract: Histone acetyltransferase (HAT) inhibitors (HATi) isolated from dietary compounds have been shown to suppress inflammatory signaling, which contributes to rheumatoid arthritis. Here, we identified a novel HATi in Punica granatum L. known as delphinidin (DP). DP did not affect the activity of other epigenetic enzymes (histone deacetylase, histone methyltransferase, or sirtuin1). DP specifically inhibited the HAT activities of p300/CBP. It also inhibited p65 acetylation in MH7A cells, a human rheumatoid arthritis synovial cell line. DP-induced hypoacetylation was accompanied by cytosolic accumulation of p65 and nuclear localization of IKBα. Accordingly, DP treatment inhibited TNFα-stimulated increases in NF-κB function and expression of NF-κB target genes in these cells. Importantly, DP suppressed lipopolysaccharide-induced pro-inflammatory cytokine expression in Jurkat T lymphocytes, demonstrating that HATi efficiently suppresses cytokine-mediated immune responses. Together, these results show that the HATi activity of DP counters anti-inflammatory signaling by blocking p65 acetylation and that this compound may be useful in preventing inflammatory arthritis.

  11. Delphinidin, a specific inhibitor of histone acetyltransferase, suppresses inflammatory signaling via prevention of NF-{kappa}B acetylation in fibroblast-like synoviocyte MH7A cells

    Seong, Ah-Reum; Yoo, Jung-Yoon; Choi, KyungChul [Department of Biochemistry and Molecular Biology, Center for Chronic Metabolic Disease Research, College of Medicine, Yonsei University, Seoul (Korea, Republic of); Lee, Mee-Hee [Department of Biochemistry and Molecular Biology, Center for Chronic Metabolic Disease Research, College of Medicine, Yonsei University, Seoul (Korea, Republic of); Brain Korea 21 Project for Medical Sciences, Yonsei University, College of Medicine, Seoul (Korea, Republic of); Lee, Yoo-Hyun [Department of Food Science and Nutrition, The University of Suwon, Kyunggi-do (Korea, Republic of); Lee, Jeongmin [Department of Medical Nutrition, Kyung Hee University, Kyunggi-do (Korea, Republic of); Jun, Woojin [Department of Food and Nutrition, Chonnam National University, Gwangju (Korea, Republic of); Kim, Sunoh, E-mail: sunoh@korea.ac.kr [Jeollanamdo Institute of Natural Resources Research, Jeonnam (Korea, Republic of); Yoon, Ho-Geun, E-mail: yhgeun@yuhs.ac [Department of Biochemistry and Molecular Biology, Center for Chronic Metabolic Disease Research, College of Medicine, Yonsei University, Seoul (Korea, Republic of); Brain Korea 21 Project for Medical Sciences, Yonsei University, College of Medicine, Seoul (Korea, Republic of)

    2011-07-08

    Highlights: {yields} Delphinidin is a novel inhibitor of p300/CBP histone acetyltransferase. {yields} Delphinidin prevents the hyperacetylation of p65 by inhibiting the HAT activity of p300/CBP. {yields} Delphinidin efficiently suppresses the expression of inflammatory cytokines in MH7A cells via hypoacetylation of NF-{kappa}B. {yields} Delphinidin inhibits cytokine release in the Jurkat T lymphocyte cell line. -- Abstract: Histone acetyltransferase (HAT) inhibitors (HATi) isolated from dietary compounds have been shown to suppress inflammatory signaling, which contributes to rheumatoid arthritis. Here, we identified a novel HATi in Punica granatum L. known as delphinidin (DP). DP did not affect the activity of other epigenetic enzymes (histone deacetylase, histone methyltransferase, or sirtuin1). DP specifically inhibited the HAT activities of p300/CBP. It also inhibited p65 acetylation in MH7A cells, a human rheumatoid arthritis synovial cell line. DP-induced hypoacetylation was accompanied by cytosolic accumulation of p65 and nuclear localization of IKB{alpha}. Accordingly, DP treatment inhibited TNF{alpha}-stimulated increases in NF-{kappa}B function and expression of NF-{kappa}B target genes in these cells. Importantly, DP suppressed lipopolysaccharide-induced pro-inflammatory cytokine expression in Jurkat T lymphocytes, demonstrating that HATi efficiently suppresses cytokine-mediated immune responses. Together, these results show that the HATi activity of DP counters anti-inflammatory signaling by blocking p65 acetylation and that this compound may be useful in preventing inflammatory arthritis.

  12. Minocycline suppresses interleukine-6, its receptor system and signaling pathways and impairs migration, invasion and adhesion capacity of ovarian cancer cells: in vitro and in vivo studies.

    Parvin Ataie-Kachoie

    Full Text Available Interleukin (IL-6 has been shown to be a major contributing factor in growth and progression of ovarian cancer. The cytokine exerts pro-tumorigenic activity through activation of several signaling pathways in particular signal transducer and activator of transcription (STAT3 and extracellular signal-regulated kinase (ERK1/2. Hence, targeting IL-6 is becoming increasingly attractive as a treatment option in ovarian cancer. Here, we investigated the effects of minocycline on IL-6 and its signaling pathways in ovarian cancer. In vitro, minocycline was found to significantly suppress both constitutive and IL-1β or 4-hydroxyestradiol (4-OH-E2-stimulated IL-6 expression in human ovarian cancer cells; OVCAR-3, SKOV-3 and CAOV-3. Moreover, minocycline down-regulated two major components of IL-6 receptor system (IL-6Rα and gp130 and blocked the activation of STAT3 and ERK1/2 pathways leading to suppression of the downstream product MCL-1. In female nude mice bearing intraperitoneal OVCAR-3 tumors, acute administration (4 and 24 h of minocycline (30 mg/kg led to suppression of IL-6. Even single dose of minocycline was effective at significantly lowering plasma and tumor IL-6 levels. In line with this, tumoral expression of p-STAT3, p-ERK1/2 and MCL-1 were decreased in minocycline-treated mice. Evaluation of the functional implication of minocycline on metastatic activity revealed the capacity of minocycline to inhibit cellular migration, invasion and adhesion associated with down-regulation of matrix metalloproteinases (MMP-2 and 9. Thus, the data suggest a potential role for minocycline in suppressing IL-6 expression and activity. These effects may prove to be an important attribute to the upcoming clinical trials of minocycline in ovarian cancer.

  13. Minocycline Suppresses Interleukine-6, Its Receptor System and Signaling Pathways and Impairs Migration, Invasion and Adhesion Capacity of Ovarian Cancer Cells: In Vitro and In Vivo Studies

    Ataie-Kachoie, Parvin; Morris, David L.; Pourgholami, Mohammad H.

    2013-01-01

    Interleukin (IL)-6 has been shown to be a major contributing factor in growth and progression of ovarian cancer. The cytokine exerts pro-tumorigenic activity through activation of several signaling pathways in particular signal transducer and activator of transcription (STAT3) and extracellular signal-regulated kinase (ERK)1/2. Hence, targeting IL-6 is becoming increasingly attractive as a treatment option in ovarian cancer. Here, we investigated the effects of minocycline on IL-6 and its signaling pathways in ovarian cancer. In vitro, minocycline was found to significantly suppress both constitutive and IL-1β or 4-hydroxyestradiol (4-OH-E2)-stimulated IL-6 expression in human ovarian cancer cells; OVCAR-3, SKOV-3 and CAOV-3. Moreover, minocycline down-regulated two major components of IL-6 receptor system (IL-6Rα and gp130) and blocked the activation of STAT3 and ERK1/2 pathways leading to suppression of the downstream product MCL-1. In female nude mice bearing intraperitoneal OVCAR-3 tumors, acute administration (4 and 24 h) of minocycline (30 mg/kg) led to suppression of IL-6. Even single dose of minocycline was effective at significantly lowering plasma and tumor IL-6 levels. In line with this, tumoral expression of p-STAT3, p-ERK1/2 and MCL-1 were decreased in minocycline-treated mice. Evaluation of the functional implication of minocycline on metastatic activity revealed the capacity of minocycline to inhibit cellular migration, invasion and adhesion associated with down-regulation of matrix metalloproteinases (MMP)-2 and 9. Thus, the data suggest a potential role for minocycline in suppressing IL-6 expression and activity. These effects may prove to be an important attribute to the upcoming clinical trials of minocycline in ovarian cancer. PMID:23593315

  14. Matrine suppresses airway inflammation by downregulating SOCS3 expression via inhibition of NF-κB signaling in airway epithelial cells and asthmatic mice

    Sun, Daqing [Department of Respiration, Xi’an Children’s Hospital, Xi’an 710003 (China); Wang, Jing [Department of Neonatology, Xi’an Children’s Hospital, Xi’an 710003 (China); Yang, Niandi [Outpatient Department, School of Aerospace Engineering, Air Force Engineering University, Xi’an 710038 (China); Ma, Haixin, E-mail: drhaixinma@163.com [Department of Quality Control, Xi’an Children’s Hospital, Xi’an 710003 (China)

    2016-08-12

    Matrine has been demonstrated to attenuate allergic airway inflammation. Elevated suppressor of cytokine signaling 3 (SOCS3) was correlated with the severity of asthma. The aim of this study was to investigate the effect of matrine on SOCS3 expression in airway inflammation. In this study, we found that matrine significantly inhibited OVA-induced AHR, inflammatory cell infiltration, goblet cell differentiation, and mucous production in a dose-dependent manner in mice. Matrine also abrogated the level of interleukin (IL)-4 and IL-13, but enhanced interferon (IFN)-γ expression, both in BALF and in lung homogenates. Furthermore, matrine impeded TNF-α-induced the expression of IL-6 and adhesion molecules in airway epithelial cells (BEAS-2B and MLE-12). Additionally, we found that matrine inhibited SOCS3 expression, both in asthmatic mice and TNF-α-stimulated epithelial cells via suppression of the NF-κB signaling pathway by using pcDNA3.1-SOCS3 plasmid, SOCS3 siRNA, or nuclear factor kappa-B (NF-κB) inhibitor PDTC. Conclusions: Matrine suppresses airway inflammation by downregulating SOCS3 expression via inhibition of NF-κB signaling in airway epithelial cells and asthmatic mice. - Highlights: • Matrine attenuates asthmatic symptoms and regulates Th1/Th2 balance in vivo. • Matrine suppresses inflammation responses in vitro. • Matrine decreases SOCS3 expression both in vivo and in vitro. • Matrine inhibits SOCS3 expression by suppressing NF-κB signaling.

  15. Curcumin inhibits urothelial tumor development by suppressing IGF2 and IGF2-mediated PI3K/AKT/mTOR signaling pathway.

    Tian, Binqiang; Zhao, Yingmei; Liang, Tao; Ye, Xuxiao; Li, Zuowei; Yan, Dongliang; Fu, Qiang; Li, Yonghui

    2017-08-01

    We have previously reported that curcumin inhibits urothelial tumor development in a rat bladder carcinogenesis model. In this study, we report that curcumin inhibits urothelial tumor development by suppressing IGF2 and IGF2-mediated PI3K/AKT/mTOR signaling pathway. Curcumin inhibits IGF2 expression at the transcriptional level and decreases the phosphorylation levels of IGF1R and IRS-1 in bladder cancer cells and N-methyl-N-nitrosourea (MNU)-induced urothelial tumor tissue. Ectopic expression of IGF2 and IGF1R, but not IGF1, in bladder cancer cells restored this process, suggesting that IGF2 is a target of curcumin. Moreover, introduction of constitutively active AKT1 abolished the inhibitory effect of curcumin on cell proliferation, migration, and restored the phosphorylation levels of 4E-BP1 and S6K1, suggesting that curcumin functions via suppressing IGF2-mediated AKT/mTOR signaling pathway. In summary, our results reveal that suppressing IGF2 and IGF2-mediated PI3K/AKT/mTOR signaling pathway is one of the mechanisms of action of curcumin. Our findings suggest a new therapeutic strategy against human bladder cancer caused by aberrant activation of IGF2, which are useful for translational application of curcumin.

  16. Effect of gadolinium injection on diffusion-weighted imaging with background body signal suppression (DWIBS) imaging of breast lesions.

    Moschetta, Marco; Telegrafo, Michele; Rella, Leonarda; Stabile Ianora, Amato Antonio; Angelelli, Giuseppe

    2014-12-01

    Diffusion-weighted imaging with background body signal suppression (DWIBS) provides both qualitative and quantitative imaging of breast lesions and are usually performed before contrast material injection (CMI). This study aims to assess whether the administration of gadolinium significantly affects DWIBS imaging. 200 patients were prospectively evaluated by MRI with STIR, TSE-T2, pre-CMI DWIBS, contrast enhanced THRIVE-T1 and post-CMI DWIBS sequences. Pre and post-CMI DWIBS were analyzed searching for the presence of breast lesions and calculating the ADC value. ADC values of ≤1.44×10(-3) mm(2)/s were considered suspicious for malignancy. This analysis was then compared with the histological findings. Sensitivity, specificity, diagnostic accuracy (DA), positive predictive value (PPV) and negative (NPV) were calculated for both sequences and represented by ROC analysis. Pre and post-CMI ADC values were compared by using the paired t test. In 150/200 (59%) patients, pre and post-CMI DWIBS indicated the presence of breast lesions, 53 (35%) with ADC values of >1.44×10(-3) mm(2)/s and 97 (65%) with ADC≤1.44×10(-3) mm(2)/s. Pre-CMI and post-DWIBS sequences obtained the same sensitivity, specificity, DA, PPV and NPV values of 97%, 83%, 89%, 79% and 98%. The mean ADC value of benign lesions was 1.831±0.18×10(-3) mm(2)/s before and 1.828±0.18×10(-3) mm(2)/s after CMI. The mean ADC value of the malignant lesions was 1.146±0.16×10(-3) mm(2)/s before and 1.144±0.16×10(-3) mm(2)/s after CMI. No significant difference was found between pre and post CMI ADC values (p>0.05). DWIBS imaging is not influenced by CMI. Breast MR protocol could be modified by placing DWIBS after dynamic contrast enhanced sequences in order to maximize patient cooperation. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. Inositol Hexaphosphate Inhibits Proliferation and Induces Apoptosis of Colon Cancer Cells by Suppressing the AKT/mTOR Signaling Pathway

    Małgorzata Kapral

    2017-10-01

    Full Text Available Abstract: AKT, a serine/threonine protein kinase and mammalian target of rapamycin (mTOR plays a critical role in the proliferation and resistance to apoptosis that are essential to the development and progression of colon cancer. Therefore, AKT/mTOR signaling pathway has been recognized as an attractive target for anticancer therapy. Inositol hexaphosphate (InsP6, a natural occurring phytochemical, has been shown to have both preventive and therapeutic effects against various cancers, however, its exact molecular mechanisms of action are not fully understood. The aim of the in vitro study was to investigate the anticancer activity of InsP6 on colon cancer with the focus on inhibiting the AKT1 kinase and p70S6K1 as mTOR effector, in relation to proliferation and apoptosis of cells. The colon cancer Caco-2 cells were cultured using standard techniques and exposed to InsP6 at different concentrations (1 mM, 2.5 mM and 5 mM. Cellular proliferative activity was monitored by 5-bromo-2′-deoxyuridine (BrdU incorporation into cellular DNA. Flow cytometric analysis was performed for cell cycle progression and apoptosis studies. Real-time RT-qPCR was used to validate mRNA levels of CDNK1A, CDNK1B, CASP3, CASP9, AKT1 and S6K1 genes. The concentration of p21 protein as well as the activities of caspase 3, AKT1 and p70S6K1 were determined by the ELISA method. The results revealed that IP6 inhibited proliferation and stimulated apoptosis of colon cancer cells. This effect was mediated by an increase in the expression of genes encoding p21, p27, caspase 3, caspase 9 as well a decrease in transcription of AKT1 and S6K1. InsP6 suppressed phosphorylation of AKT1 and p70S6K1, downstream effector of mTOR. Based on these studies it may be concluded that InsP6 can reduce proliferation and induce apoptosis through inhibition of the AKT/mTOR pathway and mTOR effector followed by modulation of the expression and activity of several key components of these pathways in

  18. MRI of the labyrinth with volume rendering for cochlear implants candidates

    Sakata, Motomichi; Harada, Kuniaki; Shirase, Ryuji; Suzuki, Junpei; Nagahama, Hiroshi

    2009-01-01

    We demonstrated three-dimensional models of the labyrinth by volume rendering (VR) in preoperative assessment for cochlear implantation. MRI data sets were acquired in selected subjects using three-dimensional-fast spin echo sequences (3D-FSE). We produced the three-dimensional models of the labyrinth from axial heavily T2-weighted images. The three-dimensional models distinguished the scala tympani and scala vestibuli and provided multidirectional images. The optimal threshold three-dimensional models clearly showed the focal region of signal loss in the cochlear turns (47.1%) and the presence of inner ear anomalies (17.3%) in our series of patients. This study was concluded that these three-dimensional models by VR provide the oto-surgeon with precise, detailed, and easily interpreted information about the cochlear turns for cochlear implants candidates. (author)

  19. A phone-assistive device based on Bluetooth technology for cochlear implant users.

    Qian, Haifeng; Loizou, Philipos C; Dorman, Michael F

    2003-09-01

    Hearing-impaired people, and particularly hearing-aid and cochlear-implant users, often have difficulty communicating over the telephone. The intelligibility of telephone speech is considerably lower than the intelligibility of face-to-face speech. This is partly because of lack of visual cues, limited telephone bandwidth, and background noise. In addition, cellphones may cause interference with the hearing aid or cochlear implant. To address these problems that hearing-impaired people experience with telephones, this paper proposes a wireless phone adapter that can be used to route the audio signal directly to the hearing aid or cochlear implant processor. This adapter is based on Bluetooth technology. The favorable features of this new wireless technology make the adapter superior to traditional assistive listening devices. A hardware prototype was built and software programs were written to implement the headset profile in the Bluetooth specification. Three cochlear implant users were tested with the proposed phone-adapter and reported good speech quality.

  20. Deriving cochlear delays in humans using otoacoustic emissions and auditory evoked potentials

    Pigasse, Gilles

    A great deal of the processing of incoming sounds to the auditory system occurs within the cochlear. The organ of Corti within the cochlea has differing mechanical properties along its length that broadly gives rise to frequency selectivity. Its stiffness is at maximum at the base and decreases...... relation between frequency and travel time in the cochlea defines the cochlear delay. This delay is directly associated with the signal analysis occurring in the inner ear and is therefore of primary interest to get a better knowledge of this organ. It is possible to estimate the cochlear delay by direct...... and invasive techniques, but these disrupt the normal functioning of the cochlea and are usually conducted in animals. In order to obtain an estimate of the cochlear delay that is closer to the normally functioning human cochlea, the present project investigates non-invasive methods in normal hearing adults...

  1. Congenitally Deafblind Children and Cochlear Implants

    Dammeyer, Jesper Herup

    2008-01-01

    There has been much research conducted demonstrating the positive benefits of cochlear implantation (CI) in children who are deaf. Research on cochlear implantation in children who are both deaf and blind, however, is lacking. The purpose of this article is to present a study of 5 congenitally...... deafblind children who received cochlear implants between 2.2 and 4.2 years of age.  Ratings of video observations were used to measure the children's early communication development with and without the use of their cochlear implants. In addition, parental interviews were used to assess the benefits...... parents perceived regarding their children's cochlear implants. Two examples are included in this article to illustrate the parents' perspectives about cochlear implantation in their deafblind children. Benefits of cochlear implantation in this cohort of children included improved attention and emotional...

  2. [Bilateral cochlear implants].

    Müller, J

    2017-07-01

    Cochlear implants (CI) are standard for the hearing rehabilitation of severe to profound deafness. Nowadays, if bilaterally indicated, bilateral implantation is usually recommended (in accordance with German guidelines). Bilateral implantation enables better speech discrimination in quiet and in noise, and restores directional and spatial hearing. Children with bilateral CI are able to undergo hearing-based hearing and speech development. Within the scope of their individual possibilities, bilaterally implanted children develop faster than children with unilateral CI and attain, e.g., a larger vocabulary within a certain time interval. Only bilateral implantation allows "binaural hearing," with all the benefits that people with normal hearing profit from, namely: better speech discrimination in quiet and in noise, as well as directional and spatial hearing. Naturally, the developments take time. Binaural CI users benefit from the same effects as normal hearing persons: head shadow effect, squelch effect, and summation and redundancy effects. Sequential CI fitting is not necessarily disadvantageous-both simultaneously and sequentially fitted patients benefit in a similar way. For children, earliest possible fitting and shortest possible interval between the two surgeries seems to positively influence the outcome if bilateral CI are indicated.

  3. Astragaloside IV suppresses transforming growth factor-β1 induced fibrosis of cultured mouse renal fibroblasts via inhibition of the MAPK and NF-κB signaling pathways

    Che, Xiajing; Wang, Qin; Xie, Yuanyuan; Xu, Weijia; Shao, Xinghua; Mou, Shan, E-mail: shan_mou@126.com; Ni, Zhaohui, E-mail: doctor_nzh@126.com

    2015-09-04

    Renal fibrosis, a progressive process characterized by the accumulation of extracellular matrix (ECM) leading to organ dysfunction, is a characteristic of chronic kidney diseases. Among fibrogenic factors known to regulate the renal fibrotic process, transforming growth factor-β (TGF-β) plays a central role. In the present study, we examined the effect of Astragaloside IV (AS-IV), a component of the traditional Chinese medicinal plant Astragalus membranaceus, on the processes associated with renal fibrosis in cultured mouse renal fibroblasts treated with TGF-β1. RT-PCR, western blotting, immunofluorescence staining and collagen assays showed that AS-IV suppressed TGF-β1 induced fibroblast proliferation, transdifferentiation, and ECM production in a dose-dependent manner. Examination of the underlying mechanisms showed that the effect of AS-IV on the inhibition of fibroblast differentiation and ECM formation were mediated by its modulation of the activity of the MAPK and NF-κB signaling pathways. Taken together, our results indicate that AS-IV alleviates renal interstitial fibrosis via a mechanism involving the MAPK and NF-κB signaling pathways and demonstrate the therapeutic potential of AS-IV for the treatment of chronic kidney diseases. - Highlights: • AS-IV suppressed TGF-β1 induced renal fibroblast proliferation. • AS-IV suppressed TGF-β1 induced renal fibroblast transdifferentiation. • AS-IV suppressed TGF-β1 induced ECM production. • AS-IV alleviates renal fibrosis via the MAPK and NF-κB signaling pathways.

  4. A novel insulinotropic mechanism of whole grain-derived γ-oryzanol via the suppression of local dopamine D2 receptor signalling in mouse islet.

    Kozuka, Chisayo; Sunagawa, Sumito; Ueda, Rei; Higa, Moritake; Ohshiro, Yuzuru; Tanaka, Hideaki; Shimizu-Okabe, Chigusa; Takayama, Chitoshi; Matsushita, Masayuki; Tsutsui, Masato; Ishiuchi, Shogo; Nakata, Masanori; Yada, Toshihiko; Miyazaki, Jun-Ichi; Oyadomari, Seiichi; Shimabukuro, Michio; Masuzaki, Hiroaki

    2015-07-03

    γ-Oryzanol, derived from unrefined rice, attenuated the preference for dietary fat in mice, by decreasing hypothalamic endoplasmic reticulum stress. However, no peripheral mechanisms, whereby γ-oryzanol could ameliorate glucose dyshomeostasis were explored. Dopamine D 2 receptor signalling locally attenuates insulin secretion in pancreatic islets, presumably via decreased levels of intracellular cAMP. We therefore hypothesized that γ-oryzanol would improve high-fat diet (HFD)-induced dysfunction of islets through the suppression of local D 2 receptor signalling. Glucose metabolism and regulation of molecules involved in D 2 receptor signalling in pancreatic islets were investigated in male C57BL/6J mice, fed HFD and treated with γ-oryzanol . In isolated murine islets and the beta cell line, MIN6 , the effects of γ-oryzanol on glucose-stimulated insulin secretion (GSIS) was analysed using siRNA for D 2 receptors and a variety of compounds which alter D 2 receptor signalling. In islets, γ-oryzanol enhanced GSIS via the activation of the cAMP/PKA pathway. Expression of molecules involved in D 2 receptor signalling was increased in islets from HFD-fed mice, which were reciprocally decreased by γ-oryzanol. Experiments with siRNA for D 2 receptors and D 2 receptor ligands in vitro suggest that γ-oryzanol suppressed D 2 receptor signalling and augmented GSIS. γ-Oryzanol exhibited unique anti-diabetic properties. The unexpected effects of γ-oryzanol on D 2 receptor signalling in islets may provide a novel; natural food-based, approach to anti-diabetic therapy. © 2015 The British Pharmacological Society.

  5. Caloric Restriction Mimetic 2-Deoxyglucose Alleviated Inflammatory Lung Injury via Suppressing Nuclear Pyruvate Kinase M2–Signal Transducer and Activator of Transcription 3 Pathway

    Kai Hu

    2018-03-01

    Full Text Available Inflammation is an energy-intensive process, and caloric restriction (CR could provide anti-inflammatory benefits. CR mimetics (CRM, such as the glycolytic inhibitor 2-deoxyglucose (2-DG, mimic the beneficial effects of CR without inducing CR-related physiologic disturbance. This study investigated the potential anti-inflammatory benefits of 2-DG and the underlying mechanisms in mice with lipopolysaccharide (LPS-induced lethal endotoxemia. The results indicated that pretreatment with 2-DG suppressed LPS-induced elevation of tumor necrosis factor alpha and interleukin 6. It also suppressed the upregulation of myeloperoxidase, attenuated Evans blue leakage, alleviated histological abnormalities in the lung, and improved the survival of LPS-challenged mice. Treatment with 2-DG had no obvious effects on the total level of pyruvate kinase M2 (PKM2, but it significantly suppressed LPS-induced elevation of PKM2 in the nuclei. Prevention of PKM2 nuclear accumulation by ML265 mimicked the anti-inflammatory benefits of 2-DG. In addition, treatment with 2-DG or ML265 suppressed the phosphorylation of nuclear signal transducer and activator of transcription 3 (STAT3. Inhibition of STAT3 by stattic suppressed LPS-induced inflammatory injury. Interestingly, posttreatment with 2-DG at the early stage post-LPS challenge also improved the survival of the experimental animals. This study found that treatment with 2-DG, a representative CRM, provided anti-inflammatory benefits in lethal inflammation. The underlying mechanisms included suppressed nuclear PKM2-STAT3 pathway. These data suggest that 2-DG might have potential value in the early intervention of lethal inflammation.

  6. Caloric Restriction Mimetic 2-Deoxyglucose Alleviated Inflammatory Lung Injury via Suppressing Nuclear Pyruvate Kinase M2-Signal Transducer and Activator of Transcription 3 Pathway.

    Hu, Kai; Yang, Yongqiang; Lin, Ling; Ai, Qing; Dai, Jie; Fan, Kerui; Ge, Pu; Jiang, Rong; Wan, Jingyuan; Zhang, Li

    2018-01-01

    Inflammation is an energy-intensive process, and caloric restriction (CR) could provide anti-inflammatory benefits. CR mimetics (CRM), such as the glycolytic inhibitor 2-deoxyglucose (2-DG), mimic the beneficial effects of CR without inducing CR-related physiologic disturbance. This study investigated the potential anti-inflammatory benefits of 2-DG and the underlying mechanisms in mice with lipopolysaccharide (LPS)-induced lethal endotoxemia. The results indicated that pretreatment with 2-DG suppressed LPS-induced elevation of tumor necrosis factor alpha and interleukin 6. It also suppressed the upregulation of myeloperoxidase, attenuated Evans blue leakage, alleviated histological abnormalities in the lung, and improved the survival of LPS-challenged mice. Treatment with 2-DG had no obvious effects on the total level of pyruvate kinase M2 (PKM2), but it significantly suppressed LPS-induced elevation of PKM2 in the nuclei. Prevention of PKM2 nuclear accumulation by ML265 mimicked the anti-inflammatory benefits of 2-DG. In addition, treatment with 2-DG or ML265 suppressed the phosphorylation of nuclear signal transducer and activator of transcription 3 (STAT3). Inhibition of STAT3 by stattic suppressed LPS-induced inflammatory injury. Interestingly, posttreatment with 2-DG at the early stage post-LPS challenge also improved the survival of the experimental animals. This study found that treatment with 2-DG, a representative CRM, provided anti-inflammatory benefits in lethal inflammation. The underlying mechanisms included suppressed nuclear PKM2-STAT3 pathway. These data suggest that 2-DG might have potential value in the early intervention of lethal inflammation.

  7. Baicalein suppresses 17-β-estradiol-induced migration, adhesion and invasion of breast cancer cells via the G protein-coupled receptor 30 signaling pathway.

    Shang, Dandan; Li, Zheng; Zhu, Zhuxia; Chen, Huamei; Zhao, Lujun; Wang, Xudong; Chen, Yan

    2015-04-01

    Flavonoids are structurally similar to steroid hormones, particularly estrogens, and therefore have been studied for their potential effects on hormone-dependent cancers. Baicalein is the primary flavonoid derived from the root of Scutellaria baicalensis Georgi. In the present study, we investigated the effects of baicalein on 17β-estradiol (E2)-induced migration, adhesion and invasion of MCF-7 and SK-BR-3 breast cancer cells. The results demonstrated that baicalein suppressed E2-stimulated wound-healing migration and cell‑Matrigel adhesion, and ameliorated E2-promoted invasion across a Matrigel-coated Transwell membrane. Furthermore, baicalein interfered with E2-induced novel G protein-coupled estrogen receptor (GPR30)-related signaling, including a decrease in tyrosine phosphorylation of epidermal growth factor receptor (EGFR) as well as phosphorylation of extracellular signal-regulated kinase (ERK) and serine/threonine kinase Akt, without affecting GPR30 expression. The results also showed that baicalein suppressed the expression of GPR30 target genes, cysteine-rich 61 (CYR61) and connective tissue growth factor (CTGF) induced by E2. Furthermore, baicalein prevented GPR30-related signaling activation and upregulation of CYR61 and CTGF mRNA levels induced by G1, a specific GPR 30 agonist. The results suggest that baicalein inhibits E2-induced migration, adhesion and invasion through interfering with GPR30 signaling pathway activation, which indicates that it may act as a therapeutic candidate for the treatment of GPR30-positive breast cancer metastasis.

  8. Catechol Groups Enable Reactive Oxygen Species Scavenging-Mediated Suppression of PKD-NFkappaB-IL-8 Signaling Pathway by Chlorogenic and Caffeic Acids in Human Intestinal Cells

    Hee Soon Shin

    2017-02-01

    Full Text Available Chlorogenic acid (CHA and caffeic acid (CA are phenolic compounds found in coffee, which inhibit oxidative stress-induced interleukin (IL-8 production in intestinal epithelial cells, thereby suppressing serious cellular injury and inflammatory intestinal diseases. Therefore, we investigated the anti-inflammatory mechanism of CHA and CA, both of which inhibited hydrogen peroxide (H2O2-induced IL-8 transcriptional activity. They also significantly suppressed nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB transcriptional activity, nuclear translocation of the p65 subunit, and phosphorylation of IκB kinase (IKK. Additionally, upstream of IKK, protein kinase D (PKD was also suppressed. Finally, we found that they scavenged H2O2-induced reactive oxygen species (ROS and the functional moiety responsible for the anti-inflammatory effects of CHA and CA was the catechol group. Therefore, we conclude that the presence of catechol groups in CHA and CA allows scavenging of intracellular ROS, thereby inhibiting H2O2-induced IL-8 production via suppression of PKD-NF-κB signaling in human intestinal epithelial cells.

  9. Aqueous fraction from Cuscuta japonica seed suppresses melanin synthesis through inhibition of the p38 mitogen-activated protein kinase signaling pathway in B16F10 cells.

    Jang, Ji Yeon; Kim, Ha Neui; Kim, Yu Ri; Choi, Yung Hyun; Kim, Byung Woo; Shin, Hwa Kyoung; Choi, Byung Tae

    2012-05-07

    Semen cuscutae has been used traditionally to treat pimples and alleviate freckles and melasma in Korea. The present study aimed to investigate the inhibitory effect of Cuscuta japonica Choisy seeds on alpha-melanocyte-stimulating hormone (α-MSH)-induced melanogenesis. The aqueous fraction from Semen cuscutae (AFSC) was used to determine anti-melanogenic effects by examination of cellular melanin contents, tyrosinase activity assay, cAMP assay and Western blot analysis for melanin synthesis-related signaling proteins in B16F10 mouse melanoma cells. AFSC markedly inhibited α-MSH-induced melanin synthesis and tyrosinase activity, and also decreased α-MSH-induced expression of microphthalmia-associated transcription factor (MITF) and tyrosinase-related proteins (TRPs). Moreover, AFSC significantly decreased the level of phosphorylated p38 mitogen-activated protein kinase (MAPK) signaling through the down-regulation of α-MSH-induced cAMP. Furthermore, we confirmed that the specific inhibitor of p38 MAPK (SB203580)-mediated suppressed melanin synthesis and tyrosinase activity was further attenuated by AFSC. AFSC also further decreased SB203580-mediated suppression of MITF and TRP expression. These results indicate that AFSC inhibits p38 MAPK phosphorylation with suppressed cAMP levels and subsequently down-regulate MITF and TRP expression, which results in a marked reduction of melanin synthesis and tyrosinase activity in α-MSH-stimulated B16F10 cells. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  10. Diffusion-weighted whole-body MR imaging with background body signal suppression: a feasibility study at 3.0 Tesla

    Muertz, Petra; Krautmacher, Carsten; Traeber, Frank; Schild, Hans H.; Willinek, Winfried A.; Gieseke, Juergen

    2007-01-01

    The purpose was to provide a diffusion-weighted whole-body magnetic resonance (MR) imaging sequence with background body signal suppression (DWIBS) at 3.0 Tesla. A diffusion-weighted spin-echo echo-planar imaging sequence was combined with the following methods of fat suppression: short TI inversion recovery (STIR), spectral attenuated inversion recovery (SPAIR), and spectral presaturation by inversion recovery (SPIR). Optimized sequences were implemented on a 3.0- and a 1.5-Tesla system and evaluated in three healthy volunteers and six patients with various lesions in the neck, chest, and abdomen on the basis of reconstructed maximum intensity projection images. In one patient with metastases of malignant melanoma, DWIBS was compared with 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET). Good fat suppression for all regions and diagnostic image quality in all cases could be obtained at 3.0 Tesla with the STIR method. In comparison with 1.5 Tesla, DWIBS images at 3.0 Tesla were judged to provide a better lesion-to-bone tissue contrast. However, larger susceptibility-induced image distortions and signal intensity losses, stronger blurring artifacts, and more pronounced motion artifacts degraded the image quality at 3.0 Tesla. A good correlation was found between the metastases as depicted by DWIBS and those as visualized by FDG-PET. DWIBS is feasible at 3.0 Tesla with diagnostic image quality. (orig.)

  11. Suppression of type I and type III IFN signalling by NSs protein of severe fever with thrombocytopenia syndrome virus through inhibition of STAT1 phosphorylation and activation.

    Chaudhary, Vidyanath; Zhang, Shuo; Yuen, Kit-San; Li, Chuan; Lui, Pak-Yin; Fung, Sin-Yee; Wang, Pei-Hui; Chan, Chi-Ping; Li, Dexin; Kok, Kin-Hang; Liang, Mifang; Jin, Dong-Yan

    2015-11-01

    Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne pathogen causing significant morbidity and mortality in Asia. NSs protein of SFTSV is known to perturb type I IFN induction and signalling, but the mechanism remains to be fully understood. Here, we showed the suppression of both type I and type III IFN signalling by SFTSV NSs protein is mediated through inhibition of STAT1 phosphorylation and activation. Infection with live SFTSV or expression of NSs potently suppressed IFN-stimulated genes but not NFkB activation. NSs was capable of counteracting the activity of IFN-α1, IFN-β, IFN-λ1 and IFN-λ2. Mechanistically, NSs associated with STAT1 and STAT2, mitigated IFN-β-induced phosphorylation of STAT1 at S727, and reduced the expression and activity of STAT1 protein in IFN-β-treated cells, resulting in the inhibition of STAT1 and STAT2 recruitment to IFNstimulated promoters. Taken together, SFTSV NSs protein is an IFN antagonist that suppresses phosphorylation and activation of STAT1.

  12. Suppression of skeletal muscle signal using a crusher coil: A human cardiac (31) p-MR spectroscopy study at 7 tesla.

    Schaller, Benoit; Clarke, William T; Neubauer, Stefan; Robson, Matthew D; Rodgers, Christopher T

    2016-03-01

    The translation of sophisticated phosphorus MR spectroscopy ((31)P-MRS) protocols to 7 Tesla (T) is particularly challenged by the issue of radiofrequency (RF) heating. Legal limits on RF heating make it hard to reliably suppress signals from skeletal muscle that can contaminate human cardiac (31)P spectra at 7T. We introduce the first surface-spoiling crusher coil for human cardiac (31)P-MRS at 7T. A planar crusher coil design was optimized with simulations and its performance was validated in phantoms. Crusher gradient pulses (100 μs) were then applied during human cardiac (31)P-MRS at 7T. In a phantom, residual signals were 50 ± 10% with BISTRO (B1 -insensitive train to obliterate signal), and 34 ± 8% with the crusher coil. In vivo, residual signals in skeletal muscle were 49 ± 4% using BISTRO, and 24 ± 5% using the crusher coil. Meanwhile, in the interventricular septum, spectral quality and metabolite quantification did not differ significantly between BISTRO (phosphocreatine/adenosine triphosphate [PCr/ATP] = 2.1 ± 0.4) and the crusher coil (PCr/ATP = 1.8 ± 0.4). However, the specific absorption rate (SAR) decreased from 96 ± 1% of the limit (BISTRO) to 16 ± 1% (crusher coil). A crusher coil is an SAR-efficient alternative for selectively suppressing skeletal muscle during cardiac (31)P-MRS at 7T. A crusher coil allows the use of sequence modules that would have been SAR-prohibitive, without compromising skeletal muscle suppression. © 2015 The Authors. Magnetic Resonance in Medicine Published by Wiley Periodicals, Inc. on behalf of International Society of Medicine in Resonance.

  13. Suppression of skeletal muscle signal using a crusher coil: A human cardiac 31p‐MR spectroscopy study at 7 tesla

    Clarke, William T.; Neubauer, Stefan; Robson, Matthew D.; Rodgers, Christopher T.

    2015-01-01

    Purpose The translation of sophisticated phosphorus MR spectroscopy (31P‐MRS) protocols to 7 Tesla (T) is particularly challenged by the issue of radiofrequency (RF) heating. Legal limits on RF heating make it hard to reliably suppress signals from skeletal muscle that can contaminate human cardiac 31P spectra at 7T. We introduce the first surface‐spoiling crusher coil for human cardiac 31P‐MRS at 7T. Methods A planar crusher coil design was optimized with simulations and its performance was validated in phantoms. Crusher gradient pulses (100 μs) were then applied during human cardiac 31P‐MRS at 7T. Results In a phantom, residual signals were 50 ± 10% with BISTRO (B1‐insensitive train to obliterate signal), and 34 ± 8% with the crusher coil. In vivo, residual signals in skeletal muscle were 49 ± 4% using BISTRO, and 24 ± 5% using the crusher coil. Meanwhile, in the interventricular septum, spectral quality and metabolite quantification did not differ significantly between BISTRO (phosphocreatine/adenosine triphosphate [PCr/ATP] = 2.1 ± 0.4) and the crusher coil (PCr/ATP = 1.8 ± 0.4). However, the specific absorption rate (SAR) decreased from 96 ± 1% of the limit (BISTRO) to 16 ± 1% (crusher coil). Conclusion A crusher coil is an SAR‐efficient alternative for selectively suppressing skeletal muscle during cardiac 31P‐MRS at 7T. A crusher coil allows the use of sequence modules that would have been SAR‐prohibitive, without compromising skeletal muscle suppression. Magn Reson Med 75:962–972, 2016. © 2015 The Authors. Magnetic Resonance in Medicine Published by Wiley Periodicals, Inc. on behalf of International Society of Medicine in Resonance. PMID:25924813

  14. Identification of a regulatory T cell specific cell surface molecule that mediates suppressive signals and induces Foxp3 expression.

    Wang, Rui; Wan, Qi; Kozhaya, Lina; Fujii, Hodaka; Unutmaz, Derya

    2008-07-16

    Regulatory T (T(reg)) cells control immune activation and maintain tolerance. How T(regs) mediate their suppressive function is unclear. Here we identified a cell surface molecule, called GARP, (or LRRC32), which within T cells is specifically expressed in T(regs) activated through the T cell receptor (TCR). Ectopic expression of GARP in human naïve T (T(N)) cells inhibited their proliferation and cytokine secretion upon TCR activation. Remarkably, GARP over-expression in T(N) cells induced expression of T(reg) master transcription factor Foxp3 and endowed them with a partial suppressive function. The extracellular but not the cytoplasmic region of GARP, was necessary for these functions. Silencing Foxp3 in human T(reg) cells reduced expression of GARP and attenuated their suppressive function. However, GARP function was not affected when Foxp3 was downregulated in GARP-overexpressing cells, while silencing GARP in Foxp3-overexpressing cells reduced their suppressive activity. These findings reveal a novel cell surface molecule-mediated regulatory mechanism, with implications for modulating aberrant immune responses.

  15. Identification of a regulatory T cell specific cell surface molecule that mediates suppressive signals and induces Foxp3 expression.

    Rui Wang

    2008-07-01

    Full Text Available Regulatory T (T(reg cells control immune activation and maintain tolerance. How T(regs mediate their suppressive function is unclear. Here we identified a cell surface molecule, called GARP, (or LRRC32, which within T cells is specifically expressed in T(regs activated through the T cell receptor (TCR. Ectopic expression of GARP in human naïve T (T(N cells inhibited their proliferation and cytokine secretion upon TCR activation. Remarkably, GARP over-expression in T(N cells induced expression of T(reg master transcription factor Foxp3 and endowed them with a partial suppressive function. The extracellular but not the cytoplasmic region of GARP, was necessary for these functions. Silencing Foxp3 in human T(reg cells reduced expression of GARP and attenuated their suppressive function. However, GARP function was not affected when Foxp3 was downregulated in GARP-overexpressing cells, while silencing GARP in Foxp3-overexpressing cells reduced their suppressive activity. These findings reveal a novel cell surface molecule-mediated regulatory mechanism, with implications for modulating aberrant immune responses.

  16. Glycolipids from spinach suppress LPS-induced vascular inflammation through eNOS and NK-κB signaling.

    Ishii, Masakazu; Nakahara, Tatsuo; Araho, Daisuke; Murakami, Juri; Nishimura, Masahiro

    2017-07-01

    Glycolipids are the major constituent of the thylakoid membrane of higher plants and have a variety of biological and pharmacological activities. However, anti-inflammatory effects of glycolipids on vascular endothelial cells have not been elucidated. Here, we investigated the effect of glycolipids extracted from spinach on lipopolysaccharides (LPS)-induced endothelial inflammation and evaluated the underlying molecular mechanisms. Treatment with glycolipids from spinach had no cytotoxic effects on cultured human umbilical vein endothelial cells (HUVECs) and significantly blocked the expression of LPS-induced interleukin (IL)-6, monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), and intracellular adhesion molecule-1 (ICAM-1) in them. Glycolipids treatment also effectively suppressed monocyte adhesion to HUVECs. Treatment with glycolipids inhibited LPS-induced NF-κB phosphorylation and nuclear translocation. In addition, glycolipids treatment significantly promoted endothelial nitric oxide synthase (eNOS) activation and nitric oxide (NO) production in HUVECs. Furthermore, glycolipids treatment blocked LPS-induced inducible NOS (iNOS) expression in HUVECs. Pretreatment with a NOS inhibitor attenuated glycolipids-induced suppression of NF-κB activation and adhesion molecule expression, and abolished the glycolipids-mediated suppression of monocyte adhesion to HUVECs. These results indicate that glycolipids suppress LPS-induced vascular inflammation through attenuation of the NF-κB pathway by increasing NO production in endothelial cells. These findings suggest that glycolipids from spinach may have a potential therapeutic use for inflammatory vascular diseases. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  17. Nonstructural 5A Protein of Hepatitis C Virus Interferes with Toll-Like Receptor Signaling and Suppresses the Interferon Response in Mouse Liver.

    Takeya Tsutsumi

    Full Text Available The hepatitis C virus nonstructural protein NS5A is involved in resistance to the host immune response, as well as the viral lifecycle such as replication and maturation. Here, we established transgenic mice expressing NS5A protein in the liver and examined innate immune responses against lipopolysaccharide (LPS in vivo. Intrahepatic gene expression levels of cytokines such as interleukin-6, tumor necrosis factor-α, and interferon-γ were significantly suppressed after LPS injection in the transgenic mouse liver. Induction of the C-C motif chemokine ligand 2, 4, and 5 was also suppressed. Phosphorylation of the signal transducer and activator of transcription 3, which is activated by cytokines, was also reduced, and expression levels of interferon-stimulated genes, 2'-5' oligoadenylate synthase, interferon-inducible double-stranded RNA-activated protein kinase, and myxovirus resistance 1 were similarly suppressed. Since LPS binds to toll-like receptor 4 and stimulates the downstream pathway leading to induction of these genes, we examined the extracellular signal-regulated kinase and IκB-α. The phosphorylation levels of these molecules were reduced in transgenic mouse liver, indicating that the pathway upstream of the molecules was disrupted by NS5A. Further analyses revealed that the interaction between interleukin-1 receptor-associated kinase-1 and tumor necrosis factor receptor associated factor-6 was dispersed in transgenic mice, suggesting that NS5A may interfere with this interaction via myeloid differentiation primary response gene 88, which was shown to interact with NS5A. Since the gut microbiota, a source of LPS, is known to be associated with pathological conditions in liver diseases, our results suggest the involvement of NS5A in the pathogenesis of HCV infected-liver via the suppression of innate immunity.

  18. Reading skills after cochlear implantation

    Vermeulen, A.M.

    2007-01-01

    It has frequently been found that profoundly deaf children with conventional hearing aids have difficulties with the comprehension of written text. Cochlear Implants (CIs) were expected to enhance the reading comprehension of these profoundly deaf children because they provide auditory access to

  19. Advancing Binaural Cochlear Implant Technology

    Mathias Dietz

    2015-12-01

    Full Text Available This special issue contains a collection of 13 papers highlighting the collaborative research and engineering project entitled Advancing Binaural Cochlear Implant Technology—ABCIT—as well as research spin-offs from the project. In this introductory editorial, a brief history of the project is provided, alongside an overview of the studies.

  20. Radiotherapy Suppresses Bone Cancer Pain through Inhibiting Activation of cAMP Signaling in Rat Dorsal Root Ganglion and Spinal Cord

    Guiqin Zhu

    2016-01-01

    Full Text Available Radiotherapy is one of the major clinical approaches for treatment of bone cancer pain. Activation of cAMP-PKA signaling pathway plays important roles in bone cancer pain. Here, we examined the effects of radiotherapy on bone cancer pain and accompanying abnormal activation of cAMP-PKA signaling. Female Sprague-Dawley rats were used and received tumor cell implantation (TCI in rat tibia (TCI cancer pain model. Some of the rats that previously received TCI treatment were treated with X-ray radiation (radiotherapy. Thermal hyperalgesia and mechanical allodynia were measured and used for evaluating level of pain caused by TCI treatment. PKA mRNA expression in dorsal root ganglion (DRG was detected by RT-PCR. Concentrations of cAMP, IL-1β, and TNF-α as well as PKA activity in DRG and the spinal cord were measured by ELISA. The results showed that radiotherapy significantly suppressed TCI-induced thermal hyperalgesia and mechanical allodynia. The level of PKA mRNA in DRG, cAMP concentration and PKA activity in DRG and in the spinal cord, and concentrations of IL-1β and TNF-α in the spinal cord were significantly reduced by radiotherapy. In addition, radiotherapy also reduced TCI-induced bone loss. These findings suggest that radiotherapy may suppress bone cancer pain through inhibition of activation of cAMP-PKA signaling pathway in DRG and the spinal cord.

  1. Erythropoietin suppresses epithelial to mesenchymal transition and intercepts Smad signal transduction through a MEK-dependent mechanism in pig kidney (LLC-PK1) cell lines

    Chen, Chien-Liang; Chou, Kang-Ju; Lee, Po-Tsang; Chen, Ying-Shou; Chang, Tsu-Yuan; Hsu, Chih-Yang; Huang, Wei-Chieh; Chung, Hsiao-Min; Fang, Hua-Chang

    2010-01-01

    Purpose: Tumor growth factor-β1 (TGF-β1) plays a pivotal role in processes like kidney epithelial-mesenchymal transition (EMT) and interstitial fibrosis, which correlate well with progression of renal disease. Little is known about underlying mechanisms that regulate EMT. Based on the anatomical relationship between erythropoietin (EPO)-producing interstitial fibroblasts and adjacent tubular cells, we investigated the role of EPO in TGF-β1-mediated EMT and fibrosis in kidney injury. Methods: We examined apoptosis and EMT in TGF-β1-treated LLC-PK1 cells in the presence or absence of EPO. We examined the effect of EPO on TGF-β1-mediated Smad signaling. Apoptosis and cell proliferation were assessed with flow cytometry and hemocytometry. We used Western blotting and indirect immunofluorescence to evaluate expression levels of TGF-β1 signal pathway proteins and EMT markers. Results: We demonstrated that ZVAD-FMK (a caspase inhibitor) inhibited TGF-β1-induced apoptosis but did not inhibit EMT. In contrast, EPO reversed TGF-β1-mediated apoptosis and also partially inhibited TGF-β1-mediated EMT. We showed that EPO treatment suppressed TGF-β1-mediated signaling by inhibiting the phosphorylation and nuclear translocation of Smad 3. Inhibition of mitogen-activated protein kinase kinase 1 (MEK 1) either directly with PD98059 or with MEK 1 siRNA resulted in inhibition of EPO-mediated suppression of EMT and Smad signal transduction in TGF-β1-treated cells. Conclusions: EPO inhibited apoptosis and EMT in TGF-β1-treated LLC-PK1 cells. This effect of EPO was partially mediated by a mitogen-activated protein kinase-dependent inhibition of Smad signal transduction.

  2. [Cochlear implant treatment in Germany].

    Jacob, R; Stelzig, Y

    2013-01-01

    Restoration of impaired auditory function through cochlear implant is possible, with high reliably and great success. Nevertheless, there are regular disputes between patients and insurance companies due to high costs. In Germany, approx. 1.9 Mio. people are severely hearing impaired. It can be estimated that for adequate hearing rehabilitation about 30,000 cochlear implants/year are necessary. Currently, less than 10% of those affected are offered cochlear implant. A handicap is defined if there is deviation from normal hearing for more than 6 months. This sets a time frame for the supply with cochlear implant after sudden deafness. The professional code requires to advice all medical options to a person seeking help for hearing loss. This includes benefit-risk consideration. At this point, the economic aspect plays no role. The indication for medical treatment is only subject to the treating physician and should not be modified by non-physicians or organizations. It should be noted that a supply of hearing aids is qualitatively different to the help from a cochlear implant, which provides a restoration of lost function. In social law (SGB V and IX) doctors are requested to advise and recommend all measures which contribute to normal hearing (both sides). This indicates that doctors may be prosecuted for not offering help when medically possible, just because health insurance employees did not approve the cost balance. The current situation, with insufficient medical care for the hearing impaired, needs clarifying. To do this, patients, health insurance companies, the political institutions, legislation and professional societies need to accept their responsibilities.

  3. Andrographolide suppresses proliferation of human colon cancer SW620 cells through the TLR4/NF-κB/MMP-9 signaling pathway.

    Zhang, Rui; Zhao, Jian; Xu, Jian; Jiao, De-Xin; Wang, Jian; Gong, Zhi-Qiang; Jia, Jian-Hui

    2017-10-01

    Modern pharmacological research has revealed that andrographolide has various functions, including anti-bacterial, anti-inflammatory and anti-viral effects, immunoregulation, treating cardiovascular and cerebrovascular diseases, and prevention and treatment of alcoholic liver injury. The present study investigated whether andrographolide suppresses the proliferation of human colon cancer cell through the Toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB/matrix metalloproteinase-9 (MMP-9) signaling pathway. The MTT assay and lactate dehydrogenase assay were used to evaluate the anticancer effects of andrographolide on cell proliferation and cytotoxicity in human colon cancer SW620 cells. Flow cytometry was used to analyze the anticancer effects of andrographolide on apoptosis by Annexin V-fluorescein isothiocyanate/propidium iodide kit. The effects of andrographolide on the activity of caspase-3/9 were measured using ELISA. Western blot analysis was also used to analyze the protein expression of TLR4, myeloid differentiation primary response gene 88 (MyD88), NF-κB-p65 and MMP-9. In the present study, it was found that andrographolide suppressed the cell proliferation, augmented cytotoxicity, evoked cell apoptosis and activated caspase-3/9 activities in human colon cancer SW620 cells. The results revealed that the anti-proliferation effects of andrographolide on the SW620 cells was associated with the inhibition of TLR4, MyD88, NF-κB-p65 and MMP-9 signaling activation. The results suggest that andrographolide is a promising drug for treatment of human colon cancer via suppression of the TLR4/NF-κB/MMP-9 signaling pathway.

  4. Comparison of facet joint activity on 99mTc-MDP SPECT/CT with facet joint signal change on MRI with fat suppression.

    Lehman, Vance T; Murphy, Robert C; Schenck, Louis A; Carter, Rickey E; Johnson, Geoffrey B; Kotsenas, Amy L; Morris, Jonathan M; Nathan, Mark A; Wald, John T; Maus, Timothy P

    2016-01-01

    We compared signal change on magnetic resonance imaging (MRI) with fat suppression and bone scan activity of lumbar facet joints to determine if these two imaging findings are correlated. We retrospectively identified all patients who underwent imaging of the lumbar spine for pain evaluation using both technetium-99m methylene disphosphonate single-photon emission computed tomography/computed tomography (99mTc-MDP SPECT/CT) and MRI with at least one fat-suppressed T2- or T1-weighted sequence with gadolinium enhancement within a 180-day interval, at our institution between 1 January 2008 and 19 February 2013. Facet joint activity on 99mTc-MDP SPECT/CT and peri-facet signal change on MRI were rated as normal or increased. Agreement between the two examination types were determined with the κ and prevalence-adjusted bias-adjusted κ (PABAK) statistics. This study included 60 patients (28 male, 47%), with a mean age of 49±19.7 years (range, 12-93 years). The κ value indicated no agreement between 99mTc-MDP SPECT/CT and MRI (κ=-0.026; 95% confidence interval: -0.051, 0.000). The PABAK values were fair to high at each spinal level, which suggests that relatively low disease prevalence lowered the κ values. Together, the κ and PABAK values indicate that there is some degree of intermodality agreement, but that it is not consistent. Overall, facet joint signal change on fat-suppressed MRI did not always correlate with increased 99mTc-MDP SPECT/CT activity. MRI and 99mTc-MDP SPECT/CT for facet joint evaluation should not be considered interchangeable examinations in clinical practice or research.

  5. Honokiol inhibits sphere formation and xenograft growth of oral cancer side population cells accompanied with JAK/STAT signaling pathway suppression and apoptosis induction

    Huang, Jhy-Shrian; Yao, Chih-Jung; Chuang, Shuang-En; Yeh, Chi-Tai; Lee, Liang-Ming; Chen, Ruei-Ming; Chao, Wan-Ju; Whang-Peng, Jacqueline; Lai, Gi-Ming

    2016-01-01

    Eliminating cancer stem cells (CSCs) has been suggested for prevention of tumor recurrence and metastasis. Honokiol, an active compound of Magnolia officinalis, had been proposed to be a potential candidate drug for cancer treatment. We explored its effects on the elimination of oral CSCs both in vitro and in vivo. By using the Hoechst side population (SP) technique, CSCs-like SP cells were isolated from human oral squamous cell carcinoma (OSCC) cell lines, SAS and OECM-1. Effects of honokiol on the apoptosis and signaling pathways of SP-derived spheres were examined by Annexin V/Propidium iodide staining and Western blotting, respectively. The in vivo effectiveness was examined by xenograft mouse model and immunohistochemical tissue staining. The SP cells possessed higher stemness marker expression (ABCG2, Ep-CAM, Oct-4 and Nestin), clonogenicity, sphere formation capacity as well as tumorigenicity when compared to the parental cells. Treatment of these SP-derived spheres with honokiol resulted in apoptosis induction via Bax/Bcl-2 and caspase-3-dependent pathway. This apoptosis induction was associated with marked suppression of JAK2/STAT3, Akt and Erk signaling pathways in honokiol-treated SAS spheres. Consistent with its effect on JAK2/STAT3 suppression, honokiol also markedly inhibited IL-6-mediated migration of SAS cells. Accordingly, honokiol dose-dependently inhibited the growth of SAS SP xenograft and markedly reduced the immunohistochemical staining of PCNA and endothelial marker CD31 in the xenograft tumor. Honokiol suppressed the sphere formation and xenograft growth of oral CSC-like cells in association with apoptosis induction and inhibition of survival/proliferation signaling pathways as well as angiogenesis. These results suggest its potential as an integrative medicine for combating oral cancer through targeting on CSCs. The online version of this article (doi:10.1186/s12885-016-2265-6) contains supplementary material, which is available to

  6. Diversity in cochlear morphology and its influence on cochlear implant electrode position

    Marel, K.S. van der; Briaire, J.J.; Wolterbeek, R..; Snel-Bongers, J.; Verbist, B.M.; Frijns, J.H.

    2014-01-01

    To define a minimal set of descriptive parameters for cochlear morphology and study its influence on the cochlear implant electrode position in relation to surgical insertion distance.Cochlear morphology and electrode position were analyzed using multiplanar reconstructions of the pre- and

  7. Benzoxathiol derivative BOT-4-one suppresses L540 lymphoma cell survival and proliferation via inhibition of JAK3/STAT3 signaling.

    Kim, Byung Hak; Min, Yun Sook; Choi, Jung Sook; Baeg, Gyeong Hun; Kim, Young Soo; Shin, Jong Wook; Kim, Tae Yoon; Ye, Sang Kyu

    2011-05-31

    Persistently activated JAK/STAT3 signaling pathway plays a pivotal role in various human cancers including major carcinomas and hematologic tumors, and is implicated in cancer cell survival and proliferation. Therefore, inhibition of JAK/STAT3 signaling may be a clinical application in cancer therapy. Here, we report that 2-cyclohexylimino-6-methyl-6,7-dihydro-5H-benzo [1,3]oxathiol-4-one (BOT-4-one), a small molecule inhibitor of JAK/STAT3 signaling, induces apoptosis through inhibition of STAT3 activation. BOT-4-one suppressed cytokine (upd)-induced tyrosine phosphorylation and transcriptional activity of STAT92E, the sole Drosophila STAT homolog. Consequently, BOT-4-one significantly inhibited STAT3 tyrosine phosphorylation and expression of STAT3 downstream target gene SOCS3 in various human cancer cell lines, and its effect was more potent in JAK3-activated Hodgkin's lymphoma cell line than in JAK2-activated breast cancer and prostate cancer cell lines. In addition, BOT-4-one-treated Hodgkin's lymphoma cells showed decreased cell survival and proliferation by inducing apoptosis through down-regulation of STAT3 downstream target anti-apoptotic gene expression. These results suggest that BOT-4-one is a novel small molecule inhibitor of JAK3/STAT3 signaling and may have therapeutic potential in the treatment of human cancers harboring aberrant JAK3/STAT3 signaling, specifically Hodgkin's lymphoma.

  8. Cochlear implant revision surgeries in children.

    Amaral, Maria Stella Arantes do; Reis, Ana Cláudia Mirândola B; Massuda, Eduardo T; Hyppolito, Miguel Angelo

    2018-02-16

    The surgery during which the cochlear implant internal device is implanted is not entirely free of risks and may produce problems that will require revision surgeries. To verify the indications for cochlear implantation revision surgery for the cochlear implant internal device, its effectiveness and its correlation with certain variables related to language and hearing. A retrospective study of patients under 18 years submitted to cochlear implant Surgery from 2004 to 2015 in a public hospital in Brazil. Data collected were: age at the time of implantation, gender, etiology of the hearing loss, audiological and oral language characteristics of each patient before and after Cochlear Implant surgery and any need for surgical revision and the reason for it. Two hundred and sixty-five surgeries were performed in 236 patients. Eight patients received a bilateral cochlear implant and 10 patients required revision surgery. Thirty-two surgeries were necessary for these 10 children (1 bilateral cochlear implant), of which 21 were revision surgeries. In 2 children, cochlear implant removal was necessary, without reimplantation, one with cochlear malformation due to incomplete partition type I and another due to trauma. With respect to the cause for revision surgery, of the 8 children who were successfully reimplanted, four had cochlear calcification following meningitis, one followed trauma, one exhibited a facial nerve malformation, one experienced a failure of the cochlear implant internal device and one revision surgery was necessary because the electrode was twisted. The incidence of the cochlear implant revision surgery was 4.23%. The period following the revision surgeries revealed an improvement in the subject's hearing and language performance, indicating that these surgeries are valid in most cases. Copyright © 2018 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

  9. Fetal ECG Extraction from Abdominal Signals: A Review on Suppression of Fundamental Power Line Interference Component and Its Harmonics

    Ţarălungă, Dragoş-Daniel; Ungureanu, Georgeta-Mihaela; Gussi, Ilinca; Strungaru, Rodica; Wolf, Werner

    2014-01-01

    Interference of power line (PLI) (fundamental frequency and its harmonics) is usually present in biopotential measurements. Despite all countermeasures, the PLI still corrupts physiological signals, for example, electromyograms (EMG), electroencephalograms (EEG), and electrocardiograms (ECG). When analyzing the fetal ECG (fECG) recorded on the maternal abdomen, the PLI represents a particular strong noise component, being sometimes 10 times greater than the fECG signal, and thus impairing the...

  10. Inhibition of canonical WNT signaling pathway by β-catenin/CBP inhibitor ICG-001 ameliorates liver fibrosis in vivo through suppression of stromal CXCL12.

    Akcora, Büsra Öztürk; Storm, Gert; Bansal, Ruchi

    2018-03-01

    Quiescent hepatic stellate cells (HSCs), in response to liver injury, undergo characteristic morphological transformation into proliferative, contractile and ECM-producing myofibroblasts. In this study, we investigated the implication of canonical Wnt signaling pathway in HSCs and liver fibrogenesis. Canonical Wnt signaling pathway activation and inhibition using β-catenin/CBP inhibitor ICG001 was examined in-vitro in TGFβ-activated 3T3, LX2, primary human HSCs, and in-vivo in CCl 4 -induced acute liver injury mouse model. Fibroblasts-conditioned medium studies were performed to assess the Wnt-regulated paracrine factors involved in crosstalk between HSCs-macrophages and HSCs-endothelial cells. Canonical Wnt signaling pathway components were significantly up-regulated in-vitro and in-vivo. In-vitro, ICG-001 significantly inhibited fibrotic parameters, 3D-collagen contractility and wound healing. Conditioned medium induced fibroblasts-mediated macrophage and endothelial cells activation was significantly inhibited by ICG-001. In-vivo, ICG-001 significantly attenuated collagen accumulation and HSC activation. Interestingly, ICG-001 drastically inhibited macrophage infiltration, intrahepatic inflammation and angiogenesis. We further analyzed the paracrine factors involved in Wnt-mediated effects and found CXCL12 was significantly suppressed both in-vitro and in-vivo following Wnt inhibition. Wnt-regulated CXCL12 secretion from activated HSCs potentiated macrophage infiltration and activation, and angiogenesis. Pharmacological inhibition of canonical Wnt signaling pathway via suppression of stromal CXCL12 suggests a potential therapeutic approach targeting activated HSCs in liver fibrosis. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

  11. Arctigenin inhibits lipopolysaccharide-induced iNOS expression in RAW264.7 cells through suppressing JAK-STAT signal pathway.

    Kou, Xianjuan; Qi, Shimei; Dai, Wuxing; Luo, Lan; Yin, Zhimin

    2011-08-01

    Arctigenin has been demonstrated to have an anti-inflammatory function, but the precise mechanisms of its action remain to be fully defined. In the present study, we determined the effects of arctigenin on lipopolysaccharide (LPS)-induced production of proinflammatory mediators and the underlying mechanisms involved in RAW264.7 cells. Our results indicated that arctigenin exerted its anti-inflammatory effect by inhibiting ROS-dependent STAT signaling through its antioxidant activity. Arctigenin also significantly reduced the phosphorylation of STAT1 and STAT 3 as well as JAK2 in LPS-stimulated RAW264.7 cells. The inhibitions of STAT1 and STAT 3 by arctigenin prevented their translocation to the nucleus and consequently inhibited expression of iNOS, thereby suppressing the expression of inflammation-associated genes, such as IL-1β, IL-6 and MCP-1, whose promoters contain STAT-binding elements. However, COX-2 expression was slightly inhibited at higher drug concentrations (50 μM). Our data demonstrate that arctigenin inhibits iNOS expression via suppressing JAK-STAT signaling pathway in macrophages. Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.

  12. Mangiferin inhibits lipopolysaccharide-induced production of interleukin-6 in human oral epithelial cells by suppressing toll-like receptor signaling.

    Li, Hao; Wang, Qi; Chen, Xinmin; Ding, Yi; Li, Wei

    2016-11-01

    Oral epithelial cells have currently been found to play an important role in inflammatory modulation in periodontitis. Mangiferin is a natural glucosylxanthone with anti-inflammatory activity. The aim of this study was to investigate the regulatory effect of mangiferin on lipopolysaccharide (LPS)-induced production of proinflammatory cytokine interleukin-6 (IL-6) in oral epithelial cells and the underlying mechanisms. The levels of LPS-induced IL-6 production in OKF6/TERT-2 oral keratinocytes were detected using enzyme-linked immunosorbent assay (ELISA). The expression of Toll-like receptor (TLR) 2 and TLR4 was determined using western blot analysis. And the phosphorylation of TLR downstream nuclear factor-κB (NF-κB), p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK) was examined using cell-based protein phosphorylation ELISA kits. We found that mangiferin reduced LPS-upregulated IL-6 production in OKF6/TERT-2 cells. Additionally, mangiferin inhibited LPS-induced TLR2 and TLR4 overexpression, and suppressed the phosphorylation of NF-κB, p38 MAPK and JNK. Moreover, mangiferin repressed IL-6 production and TLR signaling activation in a dose-dependent manner after 24h treatment. Mangiferin decreases LPS-induced production of IL-6 in human oral epithelial cells by suppressing TLR signaling, and this glucosylxanthone may have potential for the treatment of periodontitis. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Salicylic Acid Suppresses Jasmonic Acid Signaling Downstream of SCFCOI1-JAZ by Targeting GCC Promoter Motifs via Transcription Factor ORA59[C][W][OA

    Van der Does, Dieuwertje; Leon-Reyes, Antonio; Koornneef, Annemart; Van Verk, Marcel C.; Rodenburg, Nicole; Pauwels, Laurens; Goossens, Alain; Körbes, Ana P.; Memelink, Johan; Ritsema, Tita; Van Wees, Saskia C.M.; Pieterse, Corné M.J.

    2013-01-01

    Antagonism between the defense hormones salicylic acid (SA) and jasmonic acid (JA) plays a central role in the modulation of the plant immune signaling network, but the molecular mechanisms underlying this phenomenon are largely unknown. Here, we demonstrate that suppression of the JA pathway by SA functions downstream of the E3 ubiquitin-ligase Skip-Cullin-F-box complex SCFCOI1, which targets JASMONATE ZIM-domain transcriptional repressor proteins (JAZs) for proteasome-mediated degradation. In addition, neither the stability nor the JA-induced degradation of JAZs was affected by SA. In silico promoter analysis of the SA/JA crosstalk transcriptome revealed that the 1-kb promoter regions of JA-responsive genes that are suppressed by SA are significantly enriched in the JA-responsive GCC-box motifs. Using GCC:GUS lines carrying four copies of the GCC-box fused to the β-glucuronidase reporter gene, we showed that the GCC-box motif is sufficient for SA-mediated suppression of JA-responsive gene expression. Using plants overexpressing the GCC-box binding APETALA2/ETHYLENE RESPONSE FACTOR (AP2/ERF) transcription factors ERF1 or ORA59, we found that SA strongly reduces the accumulation of ORA59 but not that of ERF1. Collectively, these data indicate that the SA pathway inhibits JA signaling downstream of the SCFCOI1-JAZ complex by targeting GCC-box motifs in JA-responsive promoters via a negative effect on the transcriptional activator ORA59. PMID:23435661

  14. Salicylic acid suppresses jasmonic acid signaling downstream of SCFCOI1-JAZ by targeting GCC promoter motifs via transcription factor ORA59.

    Van der Does, Dieuwertje; Leon-Reyes, Antonio; Koornneef, Annemart; Van Verk, Marcel C; Rodenburg, Nicole; Pauwels, Laurens; Goossens, Alain; Körbes, Ana P; Memelink, Johan; Ritsema, Tita; Van Wees, Saskia C M; Pieterse, Corné M J

    2013-02-01

    Antagonism between the defense hormones salicylic acid (SA) and jasmonic acid (JA) plays a central role in the modulation of the plant immune signaling network, but the molecular mechanisms underlying this phenomenon are largely unknown. Here, we demonstrate that suppression of the JA pathway by SA functions downstream of the E3 ubiquitin-ligase Skip-Cullin-F-box complex SCF(COI1), which targets JASMONATE ZIM-domain transcriptional repressor proteins (JAZs) for proteasome-mediated degradation. In addition, neither the stability nor the JA-induced degradation of JAZs was affected by SA. In silico promoter analysis of the SA/JA crosstalk transcriptome revealed that the 1-kb promoter regions of JA-responsive genes that are suppressed by SA are significantly enriched in the JA-responsive GCC-box motifs. Using GCC:GUS lines carrying four copies of the GCC-box fused to the β-glucuronidase reporter gene, we showed that the GCC-box motif is sufficient for SA-mediated suppression of JA-responsive gene expression. Using plants overexpressing the GCC-box binding APETALA2/ETHYLENE RESPONSE FACTOR (AP2/ERF) transcription factors ERF1 or ORA59, we found that SA strongly reduces the accumulation of ORA59 but not that of ERF1. Collectively, these data indicate that the SA pathway inhibits JA signaling downstream of the SCF(COI1)-JAZ complex by targeting GCC-box motifs in JA-responsive promoters via a negative effect on the transcriptional activator ORA59.

  15. Tetherin Suppresses Type I Interferon Signaling by Targeting MAVS for NDP52-Mediated Selective Autophagic Degradation in Human Cells.

    Jin, Shouheng; Tian, Shuo; Luo, Man; Xie, Weihong; Liu, Tao; Duan, Tianhao; Wu, Yaoxing; Cui, Jun

    2017-10-19

    Tetherin (BST2/CD317) is an interferon-inducible antiviral factor known for its ability to block the release of enveloped viruses from infected cells. Yet its role in type I interferon (IFN) signaling remains poorly defined. Here, we demonstrate that Tetherin is a negative regulator of RIG-I like receptor (RLR)-mediated type I IFN signaling by targeting MAVS. The induction of Tetherin by type I IFN accelerates MAVS degradation via ubiquitin-dependent selective autophagy in human cells. Moreover, Tetherin recruits E3 ubiquitin ligase MARCH8 to catalyze K27-linked ubiquitin chains on MAVS at lysine 7, which serves as a recognition signal for NDP52-dependent autophagic degradation. Taken together, our findings reveal a negative feedback loop of RLR signaling generated by Tetherin-MARCH8-MAVS-NDP52 axis and provide insights into a better understanding of the crosstalk between selective autophagy and optimal deactivation of type I IFN signaling. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Ovatodiolide Targets β-Catenin Signaling in Suppressing Tumorigenesis and Overcoming Drug Resistance in Renal Cell Carcinoma

    Jar-Yi Ho

    2013-01-01

    Full Text Available Dysregulated β-catenin signaling is intricately involved in renal cell carcinoma (RCC carcinogenesis and progression. Determining potential β-catenin signaling inhibitors would be helpful in ameliorating drug resistance in advanced or metastatic RCC. Screening for β-catenin signaling inhibitors involved in silico inquiry of the PubChem Bioactivity database followed by TCF/LEF reporter assay. The biological effects of ovatodiolide were evaluated in 4 RCC cell lines in vitro and 2 RCC cell lines in a mouse xenograft model. The synergistic effects of ovatodiolide and sorafenib or sunitinib were examined in 2 TKI-resistant RCC cell lines. Ovatodiolide, a pure compound of Anisomeles indica, inhibited β-catenin signaling and reduced RCC cell viability, survival, migration/invasion, and in vitro cell or in vivo mouse tumorigenicity. Cytotoxicity was significantly reduced in a normal kidney epithelial cell line with the treatment. Ovatodiolide reduced phosphorylated β-catenin (S552 that inhibited β-catenin nuclear translocation. Moreover, ovatodiolide decreased β-catenin stability and impaired the association of β-catenin and transcription factor 4. Ovatodiolide combined with sorafenib or sunitinib overcame drug resistance in TKI-resistant RCC cells. Ovatodiolide may be a potent β-catenin signaling inhibitor, with synergistic effects with sorafenib or sunitinib, and therefore, a useful candidate for improving RCC therapy.

  17. Quantitative Phospho-proteomic Analysis of TNFα/NFκB Signaling Reveals a Role for RIPK1 Phosphorylation in Suppressing Necrotic Cell Death.

    Mohideen, Firaz; Paulo, Joao A; Ordureau, Alban; Gygi, Steve P; Harper, J Wade

    2017-07-01

    TNFα is a potent inducer of inflammation due to its ability to promote gene expression, in part via the NFκB pathway. Moreover, in some contexts, TNFα promotes Caspase-dependent apoptosis or RIPK1/RIPK3/MLKL-dependent necrosis. Engagement of the TNF Receptor Signaling Complex (TNF-RSC), which contains multiple kinase activities, promotes phosphorylation of several downstream components, including TAK1, IKKα/IKKβ, IκBα, and NFκB. However, immediate downstream phosphorylation events occurring in response to TNFα signaling are poorly understood at a proteome-wide level. Here we use Tandem Mass Tagging-based proteomics to quantitatively characterize acute TNFα-mediated alterations in the proteome and phosphoproteome with or without inhibition of the cIAP-dependent survival arm of the pathway with a SMAC mimetic. We identify and quantify over 8,000 phosphorylated peptides, among which are numerous known sites in the TNF-RSC, NFκB, and MAP kinase signaling systems, as well as numerous previously unrecognized phosphorylation events. Functional analysis of S320 phosphorylation in RIPK1 demonstrates a role for this event in suppressing its kinase activity, association with CASPASE-8 and FADD proteins, and subsequent necrotic cell death during inflammatory TNFα stimulation. This study provides a resource for further elucidation of TNFα-dependent signaling pathways. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  18. Polydatin inhibits cell proliferation and induces apoptosis in laryngeal cancer and HeLa cells via suppression of the PDGF/AKT signaling pathway.

    Li, Haixia; Shi, Baoyuan; Li, Yanyun; Yin, Fengfang

    2017-07-01

    Polydatin (PD), a stilbene compound extracted from Polygonum cuspidatum, is suggested to possess anti-cancer activities, including inhibition of cell proliferation, cell cycle arrest, and induction of apoptosis. The platelet-derived growth factor (PDGF)/AKT signaling pathway plays complex roles in tumor suppression. However, the effect of PD on the PDGF/AKT signaling pathway in laryngeal cancer and HeLa cells has not been explored. MTT assay and flow cytometry showed that PD inhibited cell proliferation and induced apoptosis in Hep-2 and AMC-HN-8 cells. Western blot analysis indicated that PD inhibited the expression levels of PDGF-B and phosphorylated AKT (p-AKT) in both cells. Treatment of PDGF-B siRNA or PDGFR inhibitor found that after the PDGF signaling was inactivated, p-AKT expression was significantly decreased in Hep-2 cells. Tumor xenograft experiment in nude mice indicated PD significantly inhibited the growth of Hep-2 cells in vivo. In conclusion, PD inhibited cell proliferation and induced apoptosis in laryngeal cancer and HeLa cells via inactivation of the PDGF/AKT signaling pathway. © 2017 Wiley Periodicals, Inc.

  19. Arctigenin Suppress Th17 Cells and Ameliorates Experimental Autoimmune Encephalomyelitis Through AMPK and PPAR-γ/ROR-γt Signaling.

    Li, Wen; Zhang, Zhihui; Zhang, Kai; Xue, Zhenyi; Li, Yan; Zhang, Zimu; Zhang, Lijuan; Gu, Chao; Zhang, Qi; Hao, Junwei; Da, Yurong; Yao, Zhi; Kong, Ying; Zhang, Rongxin

    2016-10-01

    Arctigenin is a herb compound extract from Arctium lappa and is reported to exhibit pharmacological properties, including neuronal protection and antidiabetic, antitumor, and antioxidant properties. However, the effects of arctigenin on autoimmune inflammatory diseases of the CNS, multiple sclerosis (MS), and its animal model experimental autoimmune encephalomyelitis (EAE) are still unclear. In this study, we demonstrated that arctigenin-treated mice are resistant to EAE; the clinical scores of arctigenin-treated mice are significantly reduced. Histochemical assays of spinal cord sections also showed that arctigenin reduces inflammation and demyelination in mice with EAE. Furthermore, the Th1 and Th17 cells in peripheral immune organs are inhibited by arctigenin in vivo. In addition, the Th1 cytokine IFN-γ and transcription factor T-bet, as well as the Th17 cytokines IL-17A, IL-17F, and transcription factor ROR-γt are significantly suppressed upon arctigenin treatment in vitro and in vivo. Interestedly, Th17 cells are obviously inhibited in CNS of mice with EAE, while Th1 cells do not significantly change. Besides, arctigenin significantly restrains the differentiation of Th17 cells. We further demonstrate that arctigenin activates AMPK and inhibits phosphorylated p38, in addition, upregulates PPAR-γ, and finally suppresses ROR-γt. These findings suggest that arctigenin may have anti-inflammatory and immunosuppressive properties via inhibiting Th17 cells, indicating that it could be a potential therapeutic drug for multiple sclerosis or other autoimmune inflammatory diseases.

  20. Chronic restraint stress impairs endocannabinoid mediated suppression of GABAergic signaling in the hippocampus of adult male rats.

    Hu, Wen; Zhang, Mingyue; Czéh, Boldizsár; Zhang, Weiqi; Flügge, Gabriele

    2011-07-15

    Chronic stress, a risk factor for the development of psychiatric disorders, is known to induce alterations in neuronal networks in many brain areas. Previous studies have shown that chronic stress changes the expression of the cannabinoid receptor 1 (CB1) in the brains of adult rats, but neurophysiological consequences of these changes remained unclear. Here we demonstrate that chronic restraint stress causes a dysfunction in CB1 mediated modulation of GABAergic transmission in the hippocampus. Using an established protocol, adult male Sprague Dawley rats were daily restrained for 21 days and whole-cell voltage clamp was performed at CA1 pyramidal neurons. When recording carbachol-evoked inhibitory postsynaptic currents (IPSCs) which presumably originate from CB1 expressing cholecystokinin (CCK) interneurons, we found that depolarization-induced suppression of inhibition (DSI) was impaired by the stress. DSI is a form of short-term plasticity at GABAergic synapses that is known to be CB1 mediated and has been suggested to be involved in hippocampal information encoding. Chronic stress attenuated the depolarization-induced suppression of the frequency of carbachol-evoked IPSCs. Incubation with a CB1 receptor antagonist prevented this DSI effect in control but not in chronically stressed animals. The stress-induced impairment of CB1-mediated short-term plasticity at GABAergic synapses may underlie cognitive deficits which are commonly observed in animal models of stress as well as in patients with stress-related psychiatric disorders. Copyright © 2011 Elsevier Inc. All rights reserved.

  1. Fetal ECG Extraction from Abdominal Signals: A Review on Suppression of Fundamental Power Line Interference Component and Its Harmonics

    Dragoş-Daniel Ţarălungă

    2014-01-01

    Full Text Available Interference of power line (PLI (fundamental frequency and its harmonics is usually present in biopotential measurements. Despite all countermeasures, the PLI still corrupts physiological signals, for example, electromyograms (EMG, electroencephalograms (EEG, and electrocardiograms (ECG. When analyzing the fetal ECG (fECG recorded on the maternal abdomen, the PLI represents a particular strong noise component, being sometimes 10 times greater than the fECG signal, and thus impairing the extraction of any useful information regarding the fetal health state. Many signal processing methods for cancelling the PLI from biopotentials are available in the literature. In this review study, six different principles are analyzed and discussed, and their performance is evaluated on simulated data (three different scenarios, based on five quantitative performance indices.

  2. Fetal ECG extraction from abdominal signals: a review on suppression of fundamental power line interference component and its harmonics.

    Ţarălungă, Dragoş-Daniel; Ungureanu, Georgeta-Mihaela; Gussi, Ilinca; Strungaru, Rodica; Wolf, Werner

    2014-01-01

    Interference of power line (PLI) (fundamental frequency and its harmonics) is usually present in biopotential measurements. Despite all countermeasures, the PLI still corrupts physiological signals, for example, electromyograms (EMG), electroencephalograms (EEG), and electrocardiograms (ECG). When analyzing the fetal ECG (fECG) recorded on the maternal abdomen, the PLI represents a particular strong noise component, being sometimes 10 times greater than the fECG signal, and thus impairing the extraction of any useful information regarding the fetal health state. Many signal processing methods for cancelling the PLI from biopotentials are available in the literature. In this review study, six different principles are analyzed and discussed, and their performance is evaluated on simulated data (three different scenarios), based on five quantitative performance indices.

  3. Suppression of Wnt signaling by the miR-29 family is mediated by demethylation of WIF-1 in non-small-cell lung cancer

    Tan, Min [Department of Respiratory Medicine, Shanghai Tenth People’s Hospital, Tongji University, Shanghai 200072 (China); Wu, Junjie, E-mail: wujunjiesh@126.com [Department of Pneumology, Changhai Hospital of Shanghai, Second Military Medical University, Shanghai 200433 (China); State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200433 (China); Cai, Yong, E-mail: dryongcai@126.com [Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433 (China)

    2013-09-06

    Highlights: •Dnmt3A and Dnmt3B are involved in the down-regulation of WIF-1 expression in non-small-cell lung cancer. •MiR-29 family members could restore WIF-1 expression through demethylation. •MiR-29s suppress Wnt/β-catenin signaling pathway and inhibit tumor growth. •The expression of miR-29a and miR-29b could be regulated partially in a positive feedback loop. -- Abstract: Wnt inhibitory factor-1 (WIF-1) silencing induced by promoter hypermethylation is a common mechanism of aberrant activation of the Wnt signaling pathway in non-small-cell lung cancer (NSCLC). However, the activity of regulators associated with the methylation of the WIF-1 gene remains unclear. Here, we investigated the role of three DNA methyltransferases (DNMT1, DNMT3A and DNMT3B) in the expression of WIF-1. The three DNMTs were up-regulated in NSCLC tumor tissues and suppression of DNMT3A and DNMT3B restored the expression of WIF-1 in NSCLC cells. The miR-29 family (miR-29a, -29b, and -29c), which negatively regulates DNMT3A and DNMT3B, was examined in association with the Wnt/β-catenin signaling pathway. A positive correlation between the expression of WIF-1 and that of MiR-29s was observed in NSCLC tissues. Methylation-specific PCR and Western blotting indicated that miR-29s positively regulate WIF-1 expression by inhibiting the methylation of its promoter. Furthermore, miR-29 overexpression downregulated β-catenin expression, inhibited cell proliferation and induced apoptosis. The expression of miR-29a and miR-29b was partially regulated by DNMT3A and DNMT3B in a positive feedback loop. Taken together, our findings show that miR-29s suppress the Wnt signaling pathway through demethylation of WIF-1 in NSCLC.

  4. Developmental exposure of aflatoxin B1 reversibly affects hippocampal neurogenesis targeting late-stage neural progenitor cells through suppression of cholinergic signaling in rats

    Tanaka, Takeshi; Mizukami, Sayaka; Hasegawa-Baba, Yasuko; Onda, Nobuhiko; Sugita-Konishi, Yoshiko; Yoshida, Toshinori; Shibutani, Makoto

    2015-01-01

    Highlights: • Maternal AFB 1 exposure effect on hippocampal neurogenesis was examined in rats. • AFB 1 reversibly reduced cell proliferation and type-3 progenitor cells in the SGZ. • Suppressed cholinergic signals to GABAergic interneurons may reduce type-3 cells. • Suppressed BDNF–TRKB signaling may contribute to aberration of neurogenesis. • The NOAEL for offspring was determined to be 0.1 ppm (7.1–13.6 μg/kg BW/day). - Abstract: To elucidate the maternal exposure effects of aflatoxin B 1 (AFB 1 ) and its metabolite aflatoxin M 1 , which is transferred into milk, on postnatal hippocampal neurogenesis, pregnant Sprague-Dawley rats were provided a diet containing AFB 1 at 0, 0.1, 0.3, or 1.0 ppm from gestational day 6 to day 21 after delivery on weaning. Offspring were maintained through postnatal day (PND) 77 without AFB 1 exposure. Following exposure to 1.0 ppm AFB 1 , offspring showed no apparent systemic toxicity at weaning, whereas dams showed increased liver weight and DNA repair gene upregulation in the liver. In the hippocampal dentate gyrus of male PND 21 offspring, the number of doublecortin + progenitor cells were decreased, which was associated with decreased proliferative cell population in the subgranular zone at ≥0.3 ppm, although T-box brain 2 + cells, tubulin beta III + cells, gamma-H2A histone family, member X + cells, and cyclin-dependent kinase inhibitor 1A + cells did not fluctuate in number. AFB 1 exposure examined at 1.0 ppm also resulted in transcript downregulation of the cholinergic receptor subunit Chrna7 and dopaminergic receptor Drd2 in the dentate gyrus, although there was no change in transcript levels of DNA repair genes. In the hippocampal dentate hilus, interneurons expressing CHRNA7 or phosphorylated tropomyosin receptor kinase B (TRKB) decreased at ≥0.3 ppm. On PND 77, there were no changes in neurogenesis-related parameters. These results suggested that maternal AFB 1 exposure reversibly affects hippocampal

  5. Morin ameliorates chemically induced liver fibrosis in vivo and inhibits stellate cell proliferation in vitro by suppressing Wnt/β-catenin signaling

    MadanKumar, Perumal; NaveenKumar, Perumal; Manikandan, Samidurai [Department of Biochemistry, University of Madras, Guindy Campus, Chennai 600 025, Tamil Nadu (India); Devaraj, Halagowder [Department of Zoology, University of Madras, Guindy Campus, Chennai 600 025, Tamil Nadu (India); NiranjaliDevaraj, Sivasithamparam, E-mail: niranjali@yahoo.com [Department of Biochemistry, University of Madras, Guindy Campus, Chennai 600 025, Tamil Nadu (India)

    2014-06-01

    The anti-fibrotic effect of morin was examined in LX-2 cells (culture-activated human hepatic stellate cells) and in diethylnitrosamine induced rat model of liver fibrosis. The in vitro study was designed to determine whether morin affects the survival of cultured LX-2 cells, while the in vivo study was designed to evaluate the antioxidant and anti-fibrotic efficacy of morin on diethylnitrosamine induced liver fibrosis in male albino Wistar rat. The activities of liver function enzymes in serum, liver lipid peroxide levels, activities of serum antioxidant enzymes and liver architecture were monitored to cast light on the antioxidant and hepatoprotective nature of morin. To establish the anti-fibrotic effects of morin, the levels of key Wnt signaling molecules which are strongly associated with the signal transduction pathway of HSC activation were measured. Overall, from the in vitro results, it was observed that morin at 50 μM concentration inhibited the proliferation of cultured LX-2 cells, inhibited Wnt signaling and induced G1 cell cycle arrest. The in vivo results further confirmed that morin by downregulating the expressions of GSK-3β, β-catenin and cyclin D1 ameliorated DEN-induced liver fibrosis. Hence morin could be employed as a promising chemopreventive natural supplement for liver fibrosis. - Highlights: • In vivo and in vitro results revealed the active participation of Wnt signaling. • Morin at 50 μM inhibited LX-2 cell proliferation by suppressing Wnt signaling. • Morin exhibited hepatoprotective effects against DEN induced liver fibrosis. • Morin inhibited HSC activation in vivo by downregulating Wnt/β-catenin signaling.

  6. Serotonin projection patterns to the cochlear nucleus.

    Thompson, A M; Thompson, G C

    2001-07-13

    The cochlear nucleus is well known as an obligatory relay center for primary auditory nerve fibers. Perhaps not so well known is the neural input to the cochlear nucleus from cells containing serotonin that reside near the midline in the midbrain raphe region. Although the specific locations of the main, if not sole, sources of serotonin within the dorsal cochlear nucleus subdivision are known to be the dorsal and median raphe nuclei, sources of serotonin located within other cochlear nucleus subdivisions are not currently known. Anterograde tract tracing was used to label fibers originating from the dorsal and median raphe nuclei while fluorescence immunohistochemistry was used to simultaneously label specific serotonin fibers in cat. Biotinylated dextran amine was injected into the dorsal and median raphe nuclei and was visualized with Texas Red, while serotonin was visualized with fluorescein. Thus, double-labeled fibers were unequivocally identified as serotoninergic and originating from one of the labeled neurons within the dorsal and median raphe nuclei. Double-labeled fiber segments, typically of fine caliber with oval varicosities, were observed in many areas of the cochlear nucleus. They were found in the molecular layer of the dorsal cochlear nucleus, in the small cell cap region, and in the granule cell and external regions of the cochlear nuclei, bilaterally, of all cats. However, the density of these double-labeled fiber segments varied considerably depending upon the exact region in which they were found. Fiber segments were most dense in the dorsal cochlear nucleus (especially in the molecular layer) and the large spherical cell area of the anteroventral cochlear nucleus; they were moderately dense in the small cell cap region; and fiber segments were least dense in the octopus and multipolar cell regions of the posteroventral cochlear nucleus. Because of the presence of labeled fiber segments in subdivisions of the cochlear nucleus other than the

  7. Ferulic acid suppresses activation of hepatic stellate cells through ERK1/2 and Smad signaling pathways in vitro.

    Xu, Tianjiao; Pan, Zhi; Dong, Miaoxian; Yu, Chunlei; Niu, Yingcai

    2015-01-01

    Hepatic stellate cells (HSCs) are the primary source of matrix components in hepatic fibrosis. Ferulic acid (FA) has antifibrotic potential in renal and cardiac disease. However, whether FA comprises inhibitive effects of HSCs activation remains to be clarified. This study aims at evaluating the hypothesis that FA inhibits extracellular matrix (ECM)-related gene expression by the interruption of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) or/and Smad signaling pathways in HSC-T6. Our results indicated that FA significantly inhibited both viability and activation of HSC-T6 cells in vitro. In addition, we demonstrated, for the first time, that FA dramatically inhibited the expression of α1(I) collagen (Col-I) and fibronectin at levels of transcription and translation. Moreover, FA treatment inhibited Smad transcriptional activity, as evaluated by transient transfection with a plasmid construction containing SMAD response element and the luciferase reporter gene. Furthermore, FA inhibition of HSCs activation involved in both focal adhesion kinase (FAK)-dependent ERK1/2 and Smad signaling pathways with independent manner. Blocking transforming growth factor-β by a neutralizing antibody caused a marked reduction in both ERK1/2 and Smad signaling. These results support FA as an effective therapeutic agent for the prevention and treatment of hepatic fibrosis. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. Long-Term Expansion, Enhanced Chondrogenic Potential, and Suppression of Endochondral Ossification of Adult Human MSCs via WNT Signaling Modulation

    Roberto Narcisi

    2015-03-01

    Full Text Available Mesenchymal stem cells (MSCs are a potential source of chondrogenic cells for the treatment of cartilage disorders, but loss of chondrogenic potential during in vitro expansion and the propensity of cartilage to undergo hypertrophic maturation impede their therapeutic application. Here we report that the signaling protein WNT3A, in combination with FGF2, supports long-term expansion of human bone marrow-derived MSCs. The cells retained their chondrogenic potential and other phenotypic and functional properties of multipotent MSCs, which were gradually lost in the absence of WNT3A. Moreover, we discovered that endogenous WNT signals are the main drivers of the hypertrophic maturation that follows chondrogenic differentiation. Inhibition of WNT signals during differentiation prevented calcification and maintained cartilage properties following implantation in a mouse model. By maintaining potency during expansion and preventing hypertrophic maturation following differentiation, the modulation of WNT signaling removes two major obstacles that impede the clinical application of MSCs in cartilage repair.

  9. Overexpression of HepaCAM inhibits cell viability and motility through suppressing nucleus translocation of androgen receptor and ERK signaling in prostate cancer.

    Song, Xuedong; Wang, Yin; Du, Hongfei; Fan, Yanru; Yang, Xue; Wang, Xiaorong; Wu, Xiaohou; Luo, Chunli

    2014-07-01

    HepaCAM is suppressed in a variety of human cancers, and involved in cell adhesion, growth, migration, invasion, and survival. However, the expression and function of HepaCAM in prostate cancer are still unknown. HepaCAM expression has been detected by RT-PCR, Western blotting and immunohistochemistry staining in prostate cell lines RWPE-1, LNCap, DU145, PC3, and in 75 human prostate tissue specimens, respectively. Meanwhile, the cell proliferation ability was detected by WST-8 assay. The role of HepaCAM in prostate cancer cell migration and invasion was examined by wound healing and transwell assay. And flow cytometry was used to observe the apoptosis of prostate cancer cells. Then we detected changes of Androgen Receptor translocation and ERK signaling using immunofluorescence staining and western blot after overexpression of HepaCAM. The HepaCAM expression was significantly down-regulated in prostate cancer tissues and undetected in prostate cancer cells. However, the low HepaCAM expression was not statistically associated with clinicopathological characteristics of prostate cancer. Overexpression of HepaCAM in prostate cancer cells decreased the cell proliferation, migration and invasion, and induced the cell apoptosis. Meanwhile, HepaCAM prevented the androgen receptor translocation from the cytoplasm to the nucleus and down-regulated the MAPK/ERK signaling. Our results suggested that HepaCAM acted as a tumor suppressor in prostate cancer. HepaCAM inhibited cell viability and motility which might be through suppressing the nuclear translocation of Androgen Receptor and down-regulating the ERK signaling. Therefore, it was indicated that HepaCAM may be a potential therapeutic target for prostate cancer. © 2014 Wiley Periodicals, Inc.

  10. Blockade of the IL-6 trans-signalling/STAT3 axis suppresses cachexia in Kras-induced lung adenocarcinoma.

    Miller, A; McLeod, L; Alhayyani, S; Szczepny, A; Watkins, D N; Chen, W; Enriori, P; Ferlin, W; Ruwanpura, S; Jenkins, B J

    2017-05-25

    Lung cancer is the leading cause of cancer death worldwide, and is frequently associated with the devastating paraneoplastic syndrome of cachexia. The potent immunomodulatory cytokine interleukin (IL)-6 has been linked with the development of lung cancer as well as cachexia; however, the mechanisms by which IL-6 promotes muscle wasting in lung cancer cachexia are ill-defined. In this study, we report that the gp130 F/F knock-in mouse model displaying hyperactivation of the latent transcription factor STAT3 via the common IL-6 cytokine family signalling receptor, gp130, develops cachexia during Kras-driven lung carcinogenesis. Specifically, exacerbated weight loss, early mortality and reduced muscle and adipose tissue mass were features of the gp130 F/F :Kras G12D model, but not parental Kras G12D mice in which STAT3 was not hyperactivated. Gene expression profiling of muscle tissue in cachectic gp130 F/F :Kras G12D mice revealed the upregulation of IL-6 and STAT3-target genes compared with Kras G12D muscle tissue. These cachectic features of gp130 F/F :Kras G12D mice were abrogated upon the genetic normalization of STAT3 activation or ablation of IL-6 in gp130 F/F :Kras G12D :Stat3 -/+ or gp130 F/F :Kras G12D :Il6 -/- mice, respectively. Furthermore, protein levels of the soluble IL-6 receptor (sIL-6R), which is the central facilitator of IL-6 trans-signalling, were elevated in cachectic muscle from gp130 F/F :Kras G12D mice, and the specific blockade of IL-6 trans-signalling, but not classical signalling, with an anti-IL-6R antibody ameliorated cachexia-related characteristics in gp130 F/F :Kras G12D mice. Collectively, these preclinical findings identify trans-signalling via STAT3 as the signalling modality by which IL-6 promotes muscle wasting in lung cancer cachexia, and therefore support the clinical evaluation of the IL-6 trans-signalling/STAT3 axis as a therapeutic target in advanced lung cancer patients presenting with cachexia.

  11. Oral administration of nano-emulsion curcumin in mice suppresses inflammatory-induced NFκB signaling and macrophage migration.

    Nicholas A Young

    Full Text Available Despite the widespread use of curcumin for centuries in Eastern medicine as an anti-inflammatory agent, its molecular actions and therapeutic viability have only recently been explored. While curcumin does have potential therapeutic efficacy, both solubility and bioavailability must be improved before it can be more successfully translated to clinical care. We have previously reported a novel formulation of nano-emulsion curcumin (NEC that achieves significantly greater plasma concentrations in mice after oral administration. Here, we confirm the immunosuppressive effects of NEC in vivo and further examine its molecular mechanisms to better understand therapeutic potential. Using transgenic mice harboring an NFκB-luciferase reporter gene, we demonstrate a novel application of this in vivo inflammatory model to test the efficacy of NEC administration by bioluminescent imaging and show that LPS-induced NFκB activity was suppressed with NEC compared to an equivalent amount of curcumin in aqueous suspension. Administration of NEC by oral gavage resulted in a reduction of blood monocytes, decreased levels of both TLR4 and RAGE expression, and inhibited secretion of MCP-1. Mechanistically, curcumin blocked LPS-induced phosphorylation of the p65 subunit of NFκB and IκBα in murine macrophages. In a mouse model of peritonitis, NEC significantly reduced macrophage recruitment, but not T-cell or B-cell levels. In addition, curcumin treatment of monocyte derived cell lines and primary human macrophages in vitro significantly inhibited cell migration. These data demonstrate that curcumin can suppress inflammation by inhibiting macrophage migration via NFκB and MCP-1 inhibition and establish that NEC is an effective therapeutic formulation to increase the bioavailability of curcumin in order to facilitate this response.

  12. Effusanin E suppresses nasopharyngeal carcinoma cell growth by inhibiting NF-κB and COX-2 signaling.

    Mingzhu Zhuang

    Full Text Available Rabdosia serra is well known for its antibacterial, anti-inflammatory and antitumor activities, but no information has been available for the active compounds derived from this plant in inhibiting human nasopharyngeal carcinoma (NPC cell growth. In this study, we isolated and purified a natural diterpenoid from Rabdosia serra and identified its chemical structure as effusanin E and elucidated its underlying mechanism of action in inhibiting NPC cell growth. Effusanin E significantly inhibited cell proliferation and induced apoptosis in NPC cells. Effusanin E also induced the cleavage of PARP, caspase-3 and -9 proteins and inhibited the nuclear translocation of p65 NF-κB proteins. Moreover, effusanin E abrogated the binding of NF-κB to the COX-2 promoter, thereby inhibiting the expression and promoter activity of COX-2. Pretreatment with a COX-2 or NF-κB-selective inhibitor (celecoxib or ammonium pyrrolidinedithiocarbamate had an additive effect on the effusanin E-mediated inhibition of proliferation, while pretreatment with an activator of NF-κB/COX-2 (lipopolysaccharides abrogated the effusanin E-mediated inhibition of proliferation. Effusanin E also significantly suppressed tumor growth in a xenograft mouse model without obvious toxicity, furthermore, the expression of p50 NF-κB and COX-2 were down-regulated in the tumors of nude mice. These data suggest that effusanin E suppresses p50/p65 proteins to down-regulate COX-2 expression, thereby inhibiting NPC cell growth. Our findings provide new insights into exploring effusanin E as a potential therapeutic compound for the treatment of human nasopharyngeal carcinoma.

  13. The TLR3/TICAM-1 signal constitutively controls spontaneous polyposis through suppression of c-Myc in Apc Min/+ mice.

    Ono, Junya; Shime, Hiroaki; Takaki, Hiromi; Takashima, Ken; Funami, Kenji; Yoshida, Sumito; Takeda, Yohei; Matsumoto, Misako; Kasahara, Masanori; Seya, Tsukasa

    2017-10-17

    Intestinal tumorigenesis is promoted by myeloid differentiation primary response gene 88 (MyD88) activation in response to the components of microbiota in Apc Min/+ mice. Microbiota also contains double-stranded RNA (dsRNA), a ligand for TLR3, which activates the toll-like receptor adaptor molecule 1 (TICAM-1, also known as TRIF) pathway. We established Apc Min/+ Ticam1 -/- mice and their survival was compared to survival of Apc Min/+ Myd88 -/- and wild-type (WT) mice. The properties of polyps were investigated using immunofluorescence staining and RT-PCR analysis. We demonstrate that TICAM-1 is essential for suppression of polyp formation in Apc Min/+ mice. TICAM-1 knockout resulted in shorter survival of mice compared to WT mice or mice with knockout of MyD88 in the Apc Min/+ background. Polyps were more frequently formed in the distal intestine of Apc Min/+ Ticam1 -/- mice than in Apc Min/+ mice. Infiltration of immune cells such as CD11b + and CD8α + cells into the polyps was detected histologically. CD11b and CD8α mRNAs were increased in polyps of Apc Min/+ Ticam1 -/- mice compared to Apc Min/+ mice. Gene expression of inducible nitric oxide synthase (iNOS), interferon (IFN)-γ, CXCL9 and IL-12p40 was increased in polyps of Apc Min/+ Ticam1 -/- mice. mRNA and protein expression of c-Myc, a critical transcription factor for inflammation-associated polyposis, were increased in polyps of Apc Min/+ Ticam1 -/- mice. A Lactobacillus strain producing dsRNA was detected in feces of Apc Min/+ mice. These results imply that the TLR3/TICAM-1 pathway inhibits polyposis through suppression of c-Myc expression and supports long survival in Apc Min/+ mice.

  14. miR-124 suppresses proliferation and invasion of nasopharyngeal carcinoma cells through the Wnt/β-catenin signaling pathway by targeting Capn4

    Hu H

    2017-05-01

    Full Text Available Haili Hu,1,* Guanghui Wang,1,* Congying Li2 1Department of Otorhinolaryngology, Huaihe Hospital of Henan University, 2Department of Otorhinolaryngology, School of Medicine, Kaifeng University, Kaifeng, People’s Republic of China *These authors contributed equally to this work Background: Recent studies have demonstrated that microRNA 124 (miR-124 acts as a tumor suppressor in nasopharyngeal carcinoma (NPC; however, the exact molecular mechanism by which miR-124 exerts tumor suppression has not been well elucidated.Materials and methods: We performed quantitative real-time PCR (qRT-PCR to measure the expression of metastasis associated lung adenocarcinoma transcript 1, miR-124, and calpain small subunit 1 (Capn4 mRNAs in NPC cell lines. We also performed western blot analysis to detect the levels of Capn4. Furthermore, we performed MTT assay and transwell invasion assay to determine the proliferation and invasion ability of two NPC cell lines, namely, HONE1 and CNE2 cells, respectively. The verification of targets of miR-124 was performed using prediction softwares and luciferase reporter analysis.Results: According to our results, the expression of Capn4 was found to be elevated, whereas the expression of miR-124 was lowered in NPC cell lines compared with normal nasopharyngeal cells. When we preformed overexpression of miR-124, it suppressed the proliferation and invasion of NPC cells. Moreover, miR-124 suppressed the expression of Capn4 by targeting Capn4 in HONE1 and CNE2 cells. When we preformed overexpression of Capn4, it reversed the inhibitory effect of miR-124 on the proliferation and invasion of NPC cells. Furthermore, miR-124–Capn4 axis decreased the levels of β-catenin, cyclin D1, and c-Myc, the components of the Wnt/β-catenin signaling pathway.Conclusion: The suppression of proliferation and invasion of NPC cells by miR-124 were achieved by the regulation of Wnt/β-catenin signaling pathway by targeting Capn4. The results of

  15. Deafblind People's Experiences of Cochlear Implantation

    Soper, Janet

    2006-01-01

    Cochlear implants are electronic devices that create the sensation of hearing in those who cannot obtain any benefit from conventional hearing aids. This article examines the experience of cochlear implantation in a select group of individuals with acquired deafblindness, focusing on three key themes: access to communication, information and…

  16. Preclinical evaluation of destruxin B as a novel Wnt signaling target suppressing proliferation and metastasis of colorectal cancer using non-invasive bioluminescence imaging

    Yeh, Chi-Tai [Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan (China); Center of Excellence for Cancer Research, Taipei Medical University, Taipei, Taiwan (China); Department of Surgery, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan (China); Rao, Yerra Koteswara [Institute of Biochemical Sciences and Technology, Chaoyang University of Technology, Taichung, Taiwan (China); Ye, Min [Department of Natural Medicine, School of Pharmaceutical Sciences, Peking University, Beijing (China); Wu, Wen-Shi [Department of Horticulture and Biotechnology, Chinese Culture University, Taipei, Taiwan (China); Chang, Tung-Chen [Department of Surgery, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan (China); Wang, Liang-Shun [Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan (China); Division of Thoracic Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan (China); Wu, Chih-Hsiung [Center of Excellence for Cancer Research, Taipei Medical University, Taipei, Taiwan (China); Department of Surgery, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan (China); Wu, Alexander T.H., E-mail: chaw1211@tmu.edu.tw [Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan (China); Department of Radiation Oncology, Taipei Medical University Hospital, Taipei, Taiwan (China); Tzeng, Yew-Min, E-mail: ymtzeng@cyut.edu.tw [Institute of Biochemical Sciences and Technology, Chaoyang University of Technology, Taichung, Taiwan (China)

    2012-05-15

    In continuation to our studies toward the identification of direct anti-cancer targets, here we showed that destruxin B (DB) from Metarhizium anisopliae suppressed the proliferation and induced cell cycle arrest in human colorectal cancer (CRC) HT29, SW480 and HCT116 cells. Additionally, DB induced apoptosis in HT29 cells by decreased expression level of anti-apoptotic proteins Bcl-2 and Bcl-xL while increased pro-apoptotic Bax. On the other hand, DB attenuated Wnt-signaling by downregulation of β-catenin, Tcf4 and β-catenin/Tcf4 transcriptional activity, concomitantly with decreased expression of β-catenin target genes cyclin D1, c-myc and survivin. Furthermore, DB affected the migratory and invasive ability of HT29 cells through suppressed MMPs-2 and -9 enzymatic activities. We also found that DB targeted the MAPK and/or PI3K/Akt pathway by reduced expression of Akt, IKK-α, JNK, NF-κB, c-Jun and c-Fos while increased that of IκBα. Finally, we demonstrated that DB inhibited tumorigenesis in HT29 xenograft mice using non-invasive bioluminescence technique. Consistently, tumor samples from DB-treated mice demonstrated suppressed expression of β-catenin, cyclin D1, survivin, and endothelial marker CD31 while increased caspase-3 expression. Collectively, our data supports DB as an inhibitor of Wnt/β-catenin/Tcf signaling pathway that may be beneficial in the CRC management. Highlights: ► Destruxin B (DB) inhibited colorectal cancer cells growth and induced apoptosis. ► MAPK and/or PI3K/Akt cascade cooperates in DB induced apoptosis. ► DB affected the migratory and invasive ability of HT29 cells through MMP-9. ► DB attenuated Wnt-signaling components β-catenin, Tcf4. ► DB attenuated cyclin D1, c-myc, survivin and tumorigenesis in HT29 xenograft mice.

  17. Lipo-PGE1 suppresses collagen production in human dermal fibroblasts via the ERK/Ets-1 signaling pathway.

    Yoolhee Yang

    Full Text Available Dysregulation of collagen production contributes to various pathological processes, including tissue fibrosis as well as impaired wound healing. Lipo-prostaglandin E1 (Lipo-PGE1, a lipid microsphere-incorporated prostaglandin E1, is used as a vasodilator for the treatment of peripheral vascular diseases. Lipo-PGE1 was recently shown to enhance human dermal fibroblast (HDF migration and in vivo wound healing. No published study has characterized the role of Lipo-PGE1 in collagen regulation in HDFs. Here, we investigated the cellular signaling mechanism by which Lipo-PGE1 regulates collagen in HDFs. Collagen production was evaluated by the Sircol collagen assay, Western blot analysis of type I collagen and real time PCR. Unexpectedly, Lipo-PGE1 decreased mRNA expression of collagen 1A1, 1A2, and 3A1. Lipo-PGE1 markedly inhibited type I collagen and total soluble collagen production. In addition, Lipo-PGE1 inhibited transforming growth factor-β-induced collagen expression via Smad2 phosphorylation. To further investigate whether extracellular signal-regulated kinase (ERK/Ets-1 signaling, a crucial pathway in collagen regulation, is involved in Lipo-PGE1-inhibited collagen production, cells were pretreated with an ERK-specific inhibitor, PD98059, prior to the addition of Lipo-PGE1. Lipo-PGE1-inhibited collagen mRNA expression and total soluble collagen production were recovered by pretreatment with PD98059. Moreover, Lipo-PGE1 directly induced the phosphorylation of ERK. Furthermore, silencing of Ets-1 recovered Lipo-PGE1-inhibited collagen production and PD98059 blocked Lipo-PGE1-enhanced Ets-1 expression. The present study reveals an important role for Lipo-PGE1 as a negative regulator of collagen gene expression and production via ERK/Ets-1 signaling. These results suggest that Lipo-PGE1 could potentially be a therapeutic target in diseases with deregulated collagen turnover.

  18. Activation of Nrf2 Signaling Augments Vesicular Stomatitis Virus Oncolysis via Autophagy-Driven Suppression of Antiviral Immunity.

    Olagnier, David; Lababidi, Rassin R; Hadj, Samar Bel; Sze, Alexandre; Liu, Yiliu; Naidu, Sharadha Dayalan; Ferrari, Matteo; Jiang, Yuan; Chiang, Cindy; Beljanski, Vladimir; Goulet, Marie-Line; Knatko, Elena V; Dinkova-Kostova, Albena T; Hiscott, John; Lin, Rongtuan

    2017-08-02

    Oncolytic viruses (OVs) offer a promising therapeutic approach to treat multiple types of cancer. In this study, we show that the manipulation of the antioxidant network via transcription factor Nrf2 augments vesicular stomatitis virus Δ51 (VSVΔ51) replication and sensitizes cancer cells to viral oncolysis. Activation of Nrf2 signaling by the antioxidant compound sulforaphane (SFN) leads to enhanced VSVΔ51 spread in OV-resistant cancer cells and improves the therapeutic outcome in different murine syngeneic and xenograft tumor models. Chemoresistant A549 lung cancer cells that display constitutive dominant hyperactivation of Nrf2 signaling are particularly vulnerable to VSVΔ51 oncolysis. Mechanistically, enhanced Nrf2 signaling stimulated viral replication in cancer cells and disrupted the type I IFN response via increased autophagy. This study reveals a previously unappreciated role for Nrf2 in the regulation of autophagy and the innate antiviral response that complements the therapeutic potential of VSV-directed oncolysis against multiple types of OV-resistant or chemoresistant cancer. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  19. Fisetin suppresses malignant proliferation in human oral squamous cell carcinoma through inhibition of Met/Src signaling pathways.

    Li, Yan-Shu; Qin, Xing-Jun; Dai, Wei

    2017-01-01

    Fisetin (3,7,3',4'-tetrahydroxyflavone) is a dietary flavonoid and has been indicated as a novel anti-cancer agent in several types of cancer cells. However, the mechanisms underlying the effect of fisetin in human oral squamous cell carcinoma (OSCC) remain unclear. Here, we report that fisetin significantly inhibits tumor cell proliferation and induces apoptosis in OSCC (UM-SCC-23 and Tca-8113) cancer cell lines. Further analysis demonstrates that fisetin also inhibits Met/Src signaling pathways using the PathScan ® receptor tyrosine kinases (RTK) Signaling Antibody Array Kit. Fisetin resulted in decreased basal expression of Met and Src protein in UM-SCC-23 cancer cell lines, which validated by western blot. A student's t -test (two-tailed) was used to compare differences between groups. Furthermore, fisetin significantly inhibited the expression of a disintegrin and metalloproteinase 9 (ADAM9) protein in OSCC cells. Taken together, these results provide novel insights into the mechanism of fisetin and suggest potential therapeutic strategies for human OSCC by blocking the Met/Src signaling pathways.

  20. Importance of cochlear health for implant function.

    Pfingst, Bryan E; Zhou, Ning; Colesa, Deborah J; Watts, Melissa M; Strahl, Stefan B; Garadat, Soha N; Schvartz-Leyzac, Kara C; Budenz, Cameron L; Raphael, Yehoash; Zwolan, Teresa A

    2015-04-01

    Amazing progress has been made in providing useful hearing to hearing-impaired individuals using cochlear implants, but challenges remain. One such challenge is understanding the effects of partial degeneration of the auditory nerve, the target of cochlear implant stimulation. Here we review studies from our human and animal laboratories aimed at characterizing the health of the implanted cochlea and the auditory nerve. We use the data on cochlear and neural health to guide rehabilitation strategies. The data also motivate the development of tissue-engineering procedures to preserve or build a healthy cochlea and improve performance obtained by cochlear implant recipients or eventually replace the need for a cochlear implant. This article is part of a Special Issue entitled . Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Roquin Suppresses the PI3K-mTOR Signaling Pathway to Inhibit T Helper Cell Differentiation and Conversion of Treg to Tfr Cells.

    Essig, Katharina; Hu, Desheng; Guimaraes, Joao C; Alterauge, Dominik; Edelmann, Stephanie; Raj, Timsse; Kranich, Jan; Behrens, Gesine; Heiseke, Alexander; Floess, Stefan; Klein, Juliane; Maiser, Andreas; Marschall, Susan; Hrabĕ de Angelis, Martin; Leonhardt, Heinrich; Calkhoven, Cornelis F; Noessner, Elfriede; Brocker, Thomas; Huehn, Jochen; Krug, Anne B; Zavolan, Mihaela; Baumjohann, Dirk; Heissmeyer, Vigo

    2017-12-19

    Roquin proteins preclude spontaneous T cell activation and aberrant differentiation of T follicular helper (Tfh) or T helper 17 (Th17) cells. Here we showed that deletion of Roquin-encoding alleles specifically in regulatory T (Treg) cells also caused the activation of conventional T cells. Roquin-deficient Treg cells downregulated CD25, acquired a follicular Treg (Tfr) cell phenotype, and suppressed germinal center reactions but could not protect from colitis. Roquin inhibited the PI3K-mTOR signaling pathway by upregulation of Pten through interfering with miR-17∼92 binding to an overlapping cis-element in the Pten 3' UTR, and downregulated the Foxo1-specific E3 ubiquitin ligase Itch. Loss of Roquin enhanced Akt-mTOR signaling and protein synthesis, whereas inhibition of PI3K or mTOR in Roquin-deficient T cells corrected enhanced Tfh and Th17 or reduced iTreg cell differentiation. Thereby, Roquin-mediated control of PI3K-mTOR signaling prevents autoimmunity by restraining activation and differentiation of conventional T cells and specialization of Treg cells. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. HMBA Enhances Prostratin-Induced Activation of Latent HIV-1 via Suppressing the Expression of Negative Feedback Regulator A20/TNFAIP3 in NF-κB Signaling

    Duchu Chen

    2016-01-01

    Full Text Available In the past decade, much emphasis has been put on the transcriptional activation of HIV-1, which is proposed as a promised strategy for eradicating latent HIV-1 provirus. Two drugs, prostratin and hexamethylene bisacetamide (HMBA, have shown potent effects as inducers for releasing HIV-1 latency when used alone or in combination, although their cellular target(s are currently not well understood, especially under drug combination. Here, we have shown that HMBA and prostratin synergistically release HIV-1 latency via different mechanisms. While prostratin strongly stimulates HMBA-induced HIV-1 transcription via improved P-TEFb activation, HMBA is capable of boosting NF-κB-dependent transcription initiation by suppressing prostratin-induced expression of the deubiquitinase A20, a negative feedback regulator in the NF-κB signaling pathway. In addition, HMBA was able to increase prostratin-induced phosphorylation and degradation of NF-κB inhibitor IκBα, thereby enhancing and prolonging prostratin-induced nuclear translocation of NF-κB, a prerequisite for stimulation of transcription initiation. Thus, by blocking the negative feedback circuit, HMBA functions as a signaling enhancer of the NF-κB signaling pathway.

  3. Comparison of Two Music Training Approaches on Music and Speech Perception in Cochlear Implant Users

    Fuller, Christina D; Galvin, John J; Maat, Bert; Başkent, Deniz; Free, Rolien H

    2018-01-01

    In normal-hearing (NH) adults, long-term music training may benefit music and speech perception, even when listening to spectro-temporally degraded signals as experienced by cochlear implant (CI) users. In this study, we compared two different music training approaches in CI users and their effects

  4. Speech Rate Normalization and Phonemic Boundary Perception in Cochlear-Implant Users

    Jaekel, Brittany N.; Newman, Rochelle S.; Goupell, Matthew J.

    2017-01-01

    Purpose: Normal-hearing (NH) listeners rate normalize, temporarily remapping phonemic category boundaries to account for a talker's speech rate. It is unknown if adults who use auditory prostheses called cochlear implants (CI) can rate normalize, as CIs transmit degraded speech signals to the auditory nerve. Ineffective adjustment to rate…

  5. Suppression of Virulence of Toxigenic Vibrio cholerae by Anethole through the Cyclic AMP (cAMP-cAMP Receptor Protein Signaling System.

    M Shamim Hasan Zahid

    Full Text Available Use of natural compounds as antivirulence drugs could be an alternative therapeutic approach to modify the outcome of bacterial infections, particularly in view of growing resistance to available antimicrobials. Here, we show that sub-bactericidal concentration of anethole, a component of sweet fennel seed, could suppress virulence potential in O1 El Tor biotype strains of toxigenic Vibrio cholerae, the causative agent of the ongoing 7th cholera pandemic. The expression of cholera toxin (CT and toxin coregulated pilus (TCP, the major virulence factors of V. cholerae, is controlled through a regulatory cascade involving activation of ToxT with synergistic coupling interaction of ToxR/ToxS with TcpP/TcpH. We present evidence that anethole inhibits in vitro expression of CT and TCP in a toxT-dependent but toxR/toxS-independent manner and through repression of tcpP/tcpH, by using bead-ELISA, western blotting and quantitative real-time RT-PCR assays. The cyclic AMP (cAMP-cAMP receptor protein (CRP is a well-studied global signaling system in bacterial pathogens, and this complex is known to suppress expression of tcpP/tcpH in V. cholerae. We find that anethole influences the virulence regulatory cascade by over-expressing cyaA and crp genes. Moreover, suppression of toxigenic V. cholerae-mediated fluid accumulation in ligated ileum of rabbit by anethole demonstrates its potentiality as an antivirulence drug candidate against the diseases caused by toxigenic V. cholerae. Taken altogether, these results revealing a mechanism of virulence inhibition in V. cholerae by the natural compound anethole, may have relevance in designing antivirulence compounds, particularly against multiple antibiotic resistant bacterial pathogens.

  6. Suppression of Virulence of Toxigenic Vibrio cholerae by Anethole through the Cyclic AMP (cAMP)-cAMP Receptor Protein Signaling System.

    Zahid, M Shamim Hasan; Awasthi, Sharda Prasad; Asakura, Masahiro; Chatterjee, Shruti; Hinenoya, Atsushi; Faruque, Shah M; Yamasaki, Shinji

    2015-01-01

    Use of natural compounds as antivirulence drugs could be an alternative therapeutic approach to modify the outcome of bacterial infections, particularly in view of growing resistance to available antimicrobials. Here, we show that sub-bactericidal concentration of anethole, a component of sweet fennel seed, could suppress virulence potential in O1 El Tor biotype strains of toxigenic Vibrio cholerae, the causative agent of the ongoing 7th cholera pandemic. The expression of cholera toxin (CT) and toxin coregulated pilus (TCP), the major virulence factors of V. cholerae, is controlled through a regulatory cascade involving activation of ToxT with synergistic coupling interaction of ToxR/ToxS with TcpP/TcpH. We present evidence that anethole inhibits in vitro expression of CT and TCP in a toxT-dependent but toxR/toxS-independent manner and through repression of tcpP/tcpH, by using bead-ELISA, western blotting and quantitative real-time RT-PCR assays. The cyclic AMP (cAMP)-cAMP receptor protein (CRP) is a well-studied global signaling system in bacterial pathogens, and this complex is known to suppress expression of tcpP/tcpH in V. cholerae. We find that anethole influences the virulence regulatory cascade by over-expressing cyaA and crp genes. Moreover, suppression of toxigenic V. cholerae-mediated fluid accumulation in ligated ileum of rabbit by anethole demonstrates its potentiality as an antivirulence drug candidate against the diseases caused by toxigenic V. cholerae. Taken altogether, these results revealing a mechanism of virulence inhibition in V. cholerae by the natural compound anethole, may have relevance in designing antivirulence compounds, particularly against multiple antibiotic resistant bacterial pathogens.

  7. Injury Signals Cooperate with Nf1 Loss to Relieve the Tumor-Suppressive Environment of Adult Peripheral Nerve

    Sara Ribeiro

    2013-10-01

    Full Text Available Schwann cells are highly plastic cells that dedifferentiate to a progenitor-like state following injury. However, deregulation of this plasticity, may be involved in the formation of neurofibromas, mixed-cell tumors of Schwann cell (SC origin that arise upon loss of NF1. Here, we show that adult myelinating SCs (mSCs are refractory to Nf1 loss. However, in the context of injury, Nf1-deficient cells display opposing behaviors along the wounded nerve; distal to the injury, Nf1−/− mSCs redifferentiate normally, whereas at the wound site Nf1−/− mSCs give rise to neurofibromas in both Nf1+/+ and Nf1+/− backgrounds. Tracing experiments showed that distinct cell types within the tumor derive from Nf1-deficient SCs. This model of neurofibroma formation demonstrates that neurofibromas can originate from adult SCs and that the nerve environment can switch from tumor suppressive to tumor promoting at a site of injury. These findings have implications for both the characterization and treatment of neurofibromas.

  8. Suppression of postmitochondrial signaling and delayed response to UV-induced nuclear apoptosis in HeLa cells

    Sasai, Kaori; Yajima, Hirohiko; Suzuki, Fumio

    2002-01-01

    Activation of postmitochondrial pathways by UV irradiation was examined using mouse lymphoma 3SB and human leukemic Jurkat cells and two human carcinoma cell lines (HeLa and MCF-7). Exposure of 3SB and Jurkat cells resulted in large amounts of cytochrome c and apoptosis-inducing factor (AIF) being released into the cytosol, and a clear laddering pattern of DNA fragments was observed within 3 h of incubation after irradiation. Simultaneously, activation of caspase-9 and its downstream caspases was detected. HeLa and MCF-7 cells also showed extensive release of mitochondrial factors and caspase-9 activation at 4 to 6 h after exposure, but apoptotic nuclear changes appeared much later. Compared with 3SB and Jurkat cells, these carcinoma cell lines exhibited reduced activation of caspase-9-like proteolytic activity by UV radiation, and levels of caspase-3-like activity in HeLa cells were extremely low, similar to those in caspase-3-deficient MCF-7 cells. These results suggest that the delayed response to UV-induced nuclear apoptosis in HeLa cells is due to a reduced activation of the caspase cascade downstream of cytochrome c release and suppression of caspase-3 activity. (author)

  9. Suppressive role of OGT-mediated O-GlcNAcylation of BAP1 in retinoic acid signaling.

    Moon, Seungtae; Lee, Yong-Kyu; Lee, Sang-Wang; Um, Soo-Jong

    2017-10-07

    BRCA1-associated protein 1 (BAP1) has been implicated in diverse biological functions, including tumor suppression. However, its regulation via glycosylation and its role in embryonic stem (ES) cells are poorly defined. BAP1 was recently reported to interact with O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT). Here, we confirmed the physical interaction and investigated its functional significance. The O-GlcNAcylation of BAP1, which requires OGT, was examined in vivo and in vitro, and was proven using alloxan, an OGT inhibitor. OGT promoted the BAP1-induced repression of retinoic acid (RA)-induced RA receptor (RAR) activation. The repressive activity of BAP1 was relieved by alloxan but exacerbated by PUGNAc, an O-GlcNAcase (OGA) inhibitor. Finally, we addressed the role of O-GlcNAcylation in the RA-induced differentiation of murine ES cells. Alkaline phosphatase staining revealed the cooperation of RA and alloxan for impairing the pluripotency of ES cells. This cooperation was also observed by measuring the size of embryonic bodies and the expression of Sox2, a pluripotency marker. Overall, our data suggest that OGT-mediated O-GlcNAcylation of BAP1 prefers the maintenance of pluripotency, whereas its inhibition facilitates RA-induced differentiation in ES cells. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. GATA-Dependent Glutaminolysis Drives Appressorium Formation in Magnaporthe oryzae by Suppressing TOR Inhibition of cAMP/PKA Signaling.

    Marroquin-Guzman, Margarita; Wilson, Richard A

    2015-04-01

    Fungal plant pathogens are persistent and global food security threats. To invade their hosts they often form highly specialized infection structures, known as appressoria. The cAMP/ PKA- and MAP kinase-signaling cascades have been functionally delineated as positive-acting pathways required for appressorium development. Negative-acting regulatory pathways that block appressorial development are not known. Here, we present the first detailed evidence that the conserved Target of Rapamycin (TOR) signaling pathway is a powerful inhibitor of appressorium formation by the rice blast fungus Magnaporthe oryzae. We determined TOR signaling was activated in an M. oryzae mutant strain lacking a functional copy of the GATA transcription factor-encoding gene ASD4. Δasd4 mutant strains could not form appressoria and expressed GLN1, a glutamine synthetase-encoding orthologue silenced in wild type. Inappropriate expression of GLN1 increased the intracellular steady-state levels of glutamine in Δasd4 mutant strains during axenic growth when compared to wild type. Deleting GLN1 lowered glutamine levels and promoted appressorium formation by Δasd4 strains. Furthermore, glutamine is an agonist of TOR. Treating Δasd4 mutant strains with the specific TOR kinase inhibitor rapamycin restored appressorium development. Rapamycin was also shown to induce appressorium formation by wild type and Δcpka mutant strains on non-inductive hydrophilic surfaces but had no effect on the MAP kinase mutant Δpmk1. When taken together, we implicate Asd4 in regulating intracellular glutamine levels in order to modulate TOR inhibition of appressorium formation downstream of cPKA. This study thus provides novel insight into the metabolic mechanisms that underpin the highly regulated process of appressorium development.

  11. GATA-Dependent Glutaminolysis Drives Appressorium Formation in Magnaporthe oryzae by Suppressing TOR Inhibition of cAMP/PKA Signaling.

    Margarita Marroquin-Guzman

    2015-04-01

    Full Text Available Fungal plant pathogens are persistent and global food security threats. To invade their hosts they often form highly specialized infection structures, known as appressoria. The cAMP/ PKA- and MAP kinase-signaling cascades have been functionally delineated as positive-acting pathways required for appressorium development. Negative-acting regulatory pathways that block appressorial development are not known. Here, we present the first detailed evidence that the conserved Target of Rapamycin (TOR signaling pathway is a powerful inhibitor of appressorium formation by the rice blast fungus Magnaporthe oryzae. We determined TOR signaling was activated in an M. oryzae mutant strain lacking a functional copy of the GATA transcription factor-encoding gene ASD4. Δasd4 mutant strains could not form appressoria and expressed GLN1, a glutamine synthetase-encoding orthologue silenced in wild type. Inappropriate expression of GLN1 increased the intracellular steady-state levels of glutamine in Δasd4 mutant strains during axenic growth when compared to wild type. Deleting GLN1 lowered glutamine levels and promoted appressorium formation by Δasd4 strains. Furthermore, glutamine is an agonist of TOR. Treating Δasd4 mutant strains with the specific TOR kinase inhibitor rapamycin restored appressorium development. Rapamycin was also shown to induce appressorium formation by wild type and Δcpka mutant strains on non-inductive hydrophilic surfaces but had no effect on the MAP kinase mutant Δpmk1. When taken together, we implicate Asd4 in regulating intracellular glutamine levels in order to modulate TOR inhibition of appressorium formation downstream of cPKA. This study thus provides novel insight into the metabolic mechanisms that underpin the highly regulated process of appressorium development.

  12. Wedelolactone enhances osteoblastogenesis by regulating Wnt/β-catenin signaling pathway but suppresses osteoclastogenesis by NF-κB/c-fos/NFATc1 pathway.

    Liu, Yan-Qiu; Hong, Zhi-Lai; Zhan, Li-Bin; Chu, Hui-Ying; Zhang, Xiao-Zhe; Li, Guo-Hui

    2016-08-25

    Bone homeostasis is maintained by formation and destruction of bone, which are two processes tightly coupled and controlled. Targeting both stimulation on bone formation and suppression on bone resorption becomes a promising strategy for treating osteoporosis. In this study, we examined the effect of wedelolactone, a natural product from Ecliptae herba, on osteoblastogenesis as well as osteoclastogenesis. In mouse bone marrow mesenchymal stem cells (BMSC), wedelolactone stimulated osteoblast differentiation and bone mineralization. At the molecular level, wedelolactone directly inhibited GSK3β activity and enhanced the phosphorylation of GSK3β, thereafter stimulated the nuclear translocation of β-catenin and runx2. The expression of osteoblastogenesis-related marker gene including osteorix, osteocalcin and runx2 increased. At the same concentration range, wedelolactone inhibited RANKL-induced preosteoclastic RAW264.7 actin-ring formation and bone resorption pits. Further, wedelolactone blocked NF-kB/p65 phosphorylation and abrogated the NFATc1 nuclear translocation. As a result, osteoclastogenesis-related marker gene expression decreased, including c-src, c-fos, and cathepsin K. In ovariectomized mice, administration of wedelolactone prevented ovariectomy-induced bone loss by enhancing osteoblast activity and inhibiting osteoclast activity. Together, these data demonstrated that wedelolactone facilitated osteoblastogenesis through Wnt/GSK3β/β-catenin signaling pathway and suppressed RANKL-induced osteoclastogenesis through NF-κB/c-fos/NFATc1 pathway. These results suggested that wedelolacone could be a novel dual functional therapeutic agent for osteoporosis.

  13. Neocryptotanshinone inhibits lipopolysaccharide-induced inflammation in RAW264.7 macrophages by suppression of NF-κB and iNOS signaling pathways

    Chuanhong Wu

    2015-07-01

    Full Text Available Neocryptotanshinone (NCTS is a natural product isolated from traditional Chinese herb Salvia miltiorrhiza Bunge. In this study, we investigated its anti-inflammatory effects in lipopolysaccharide (LPS-stimulated mouse macrophage (RAW264.7 cells. MTT results showed that NCTS partly reversed LPS-induced cytotoxicity. Real-time PCR results showed that NCTS suppressed LPS-induced mRNA expression of inflammatory cytokines, including tumor necrosis factor α (TNFα, interleukin-6 (IL-6 and interleukin-1β (IL-1β. Moreover, NCTS could decrease LPS-induced nitric oxide (NO production. Western blotting results showed that NCTS could down-regulate LPS-induced expression of inducible nitric oxide synthase (iNOS, p-IκBα, p-IKKβ and p-NF-κB p65 without affecting cyclooxygenase-2 (COX-2. In addition, NCTS inhibited LPS-induced p-NF-κB p65 nuclear translocation. In conclusion, these data demonstrated that NCTS showed anti-inflammatory effect by suppression of NF-κB and iNOS signaling pathways.

  14. Comparison of Social Interaction between Cochlear-Implanted Children with Normal Intelligence Undergoing Auditory Verbal Therapy and Normal-Hearing Children: A Pilot Study.

    Monshizadeh, Leila; Vameghi, Roshanak; Sajedi, Firoozeh; Yadegari, Fariba; Hashemi, Seyed Basir; Kirchem, Petra; Kasbi, Fatemeh

    2018-04-01

    A cochlear implant is a device that helps hearing-impaired children by transmitting sound signals to the brain and helping them improve their speech, language, and social interaction. Although various studies have investigated the different aspects of speech perception and language acquisition in cochlear-implanted children, little is known about their social skills, particularly Persian-speaking cochlear-implanted children. Considering the growing number of cochlear implants being performed in Iran and the increasing importance of developing near-normal social skills as one of the ultimate goals of cochlear implantation, this study was performed to compare the social interaction between Iranian cochlear-implanted children who have undergone rehabilitation (auditory verbal therapy) after surgery and normal-hearing children. This descriptive-analytical study compared the social interaction level of 30 children with normal hearing and 30 with cochlear implants who were conveniently selected. The Raven test was administered to the both groups to ensure normal intelligence quotient. The social interaction status of both groups was evaluated using the Vineland Adaptive Behavior Scale, and statistical analysis was performed using Statistical Package for Social Sciences (SPSS) version 21. After controlling age as a covariate variable, no significant difference was observed between the social interaction scores of both the groups (p > 0.05). In addition, social interaction had no correlation with sex in either group. Cochlear implantation followed by auditory verbal rehabilitation helps children with sensorineural hearing loss to have normal social interactions, regardless of their sex.

  15. Scandoside Exerts Anti-Inflammatory Effect Via Suppressing NF-κB and MAPK Signaling Pathways in LPS-Induced RAW 264.7 Macrophages

    Jingyu He

    2018-02-01

    Full Text Available The iridoids of Hedyotis diffusa Willd play an important role in the anti-inflammatory process, but the specific iridoid with anti-inflammatory effect and its mechanism has not be thoroughly studied. An iridoid compound named scandoside (SCA was isolated from H. diffusa and its anti-inflammatory effect was investigated in lipopolysaccharide (LPS-induced RAW 264.7 macrophages. Its anti-inflammatory mechanism was confirmed by in intro experiments and molecular docking analyses. As results, SCA significantly decreased the productions of nitric oxide (NO, prostaglandin E2 (PGE2, tumor necrosis factor-α (TNF-α and interleukin-6 (IL-6 and inhibited the levels of inducible nitric oxide synthase (iNOS, cyclooxygenase-2 (COX-2, TNF-α and IL-6 messenger RNA (mRNA expression in LPS-induced RAW 264.7 macrophages. SCA treatment suppressed the phosphorylation of inhibitor of nuclear transcription factor kappa-B alpaha (IκB-α, p38, extracellular signal-regulated kinase (ERK and c-Jun N-terminal kinase (JNK. The docking data suggested that SCA had great binding abilities to COX-2, iNOS and IκB. Taken together, the results indicated that the anti-inflammatory effect of SCA is due to inhibition of pro-inflammatory cytokines and mediators via suppressing the nuclear transcription factor kappa-B (NF-κB and mitogen-activated protein kinase (MAPK signaling pathways, which provided useful information for its application and development.

  16. [Cochlear implant in children: rational, indications and cost/efficacy].

    Martini, A; Bovo, R; Trevisi, P; Forli, F; Berrettini, S

    2013-06-01

    A cochlear implant (CI) is a partially implanted electronic device that can help to provide a sense of sound and support speech to severely to profoundly hearing impaired patients. It is constituted by an external portion, that usually sits behind the ear and an internal portion surgically placed under the skin. The external components include a microphone connected to a speech processor that selects and arranges sounds pucked up by the microphone. This is connected to a transmitter coil, worn on the side of the head, which transmits data to an internal receiver coil placed under the skin. The received data are delivered to an array of electrodes that are surgically implanted within the cochlea. The primary neural targets of the electrodes are the spiral ganglion cells which innervate fibers of the auditory nerve. When the electrodes are activated by the signal, they send a current along the auditory nerve and auditory pathways to the auditory cortex. Children and adults who are profoundly or severely hearing impaired can be fitted with cochlear implants. According to the Food and Drug Administration, approximately 188,000 people worldwide have received implants. In Italy it is extimated that there are about 6-7000 implanted patients, with an average of 700 CI surgeries per year. Cochlear implantation, followed by intensive postimplantation speech therapy, can help young children to acquire speech, language, and social skills. Early implantation provides exposure to sounds that can be helpful during the critical period when children learn speech and language skills. In 2000, the Food and Drug Administration lowered the age of eligibility to 12 months for one type of CI. With regard to the results after cochlear implantation in relation to early implantation, better linguistic results are reported in children implanted before 12 months of life, even if no sufficient data exist regarding the relation between this advantage and the duration of implant use and how long

  17. Signal amplification and leakage current suppression in amorphous silicon p-i-n diodes by field profile tailoring

    Hong, W.S.; Zhong, F.; Mireshghi, A.; Perez-Mendez, V.

    1999-01-01

    The performance of amorphous silicon p-i-n diodes as radiation detectors in terms of signal amplitude can be greatly improved when there is a built-in signal gain mechanism. The authors describe an avalanche gain mechanism which is achieved by introducing stacked intrinsic, p-type, and n-type layers into the diode structure. They replaced the intrinsic layer of the conventional p-i-n diode with i 1 -p-i 2 -n-i 3 multilayers. The i 2 layer (typically 1 ∼ 3 microm) achieves an electric field > 10 6 V/cm, while maintaining the p-i interfaces to the metallic contact at electric fields 4 V/cm, when the diode is fully depleted. For use in photo-diode applications the whole structure is less than 10 microm thick. Avalanche gains of 10 ∼ 50 can be obtained when the diode is biased to ∼ 500 V. Also, dividing the electrodes to strips of 2 microm width and 20 microm pitch reduced the leakage current up to an order of magnitude, and increased light transmission without creating inactive regions

  18. Chemoprevention of colon carcinogenesis by polyethylene glycol: suppression of epithelial proliferation via modulation of SNAIL/beta-catenin signaling.

    Roy, Hemant K; Kunte, Dhananjay P; Koetsier, Jennifer L; Hart, John; Kim, Young L; Liu, Yang; Bissonnette, Marc; Goldberg, Michael; Backman, Vadim; Wali, Ramesh K

    2006-08-01

    Polyethylene glycol (PEG) is one of the most potent chemopreventive agents against colorectal cancer; however, the mechanisms remain largely unexplored. In this study, we assessed the ability of PEG to target cyclin D1-beta-catenin-mediated hyperproliferation in the azoxymethane-treated rat model and the human colorectal cancer cell line, HT-29. Azoxymethane-treated rats were randomized to AIN-76A diet alone or supplemented with 5% PEG-8000. After 30 weeks, animals were euthanized and biopsies of aberrant crypt foci and uninvolved crypts were subjected to immunohistochemical and immunoblot analyses. PEG markedly suppressed both early and late markers of azoxymethane-induced colon carcinogenesis (fractal dimension by 80%, aberrant crypt foci by 64%, and tumors by 74%). In both azoxymethane-treated rats and HT-29 cells treated with 5% PEG-3350 for 24 hours, PEG decreased proliferation (45% and 52%, respectively) and cyclin D1 (78% and 56%, respectively). Because beta-catenin is the major regulator of cyclin D1 in colorectal cancer, we used the T-cell factor (Tcf)-TOPFLASH reporter assay to show that PEG markedly inhibited beta-catenin transcriptional activity. PEG did not alter total beta-catenin expression but rather its nuclear localization, leading us to assess E-cadherin expression (a major determinant of beta-catenin subcellular localization), which was increased by 73% and 71% in the azoxymethane-rat and HT-29 cells, respectively. We therefore investigated the effect of PEG treatment on levels of the negative regulator of E-cadherin, SNAIL, and observed a 50% and 75% decrease, respectively. In conclusion, we show, for the first time, a molecular mechanism through which PEG imparts its antiproliferative and hence profound chemopreventive effect.

  19. Suppression of Pax2 attenuates allodynia and hyperalgesia through ET-1-ETAR-NFAT5 signaling in a rat model of neuropathic pain.

    Tai, Lydia Wai; Pan, Zhiqiang; Sun, Liting; Li, Haobo; Gu, Pan; Wong, Stanley Sau Ching; Chung, Sookja K; Cheung, Chi Wai

    2018-05-27

    Endothelin-1 (ET-1) and its receptors (ETAR/ETBR) emerge to be a key signaling axis in neuropathic pain processing and are recognized as new therapeutic targets. Yet, little is known on the functional regulation of ET-1 axis during neuropathic pain. Bioinformatics analysis indicated that paired box gene 2 (Pax2) or nuclear factor of activated T-cells 5 (NFAT5), two transcription factors involved in the modulation of neurotransmission, may regulate ET-1. Therefore, we hypothesized that ET-1 axis may be regulated by Pax2 or NFAT5 in the development of neuropathic pain. After partial sciatic nerve ligation (pSNL), rats displayed allodynia and hyperalgesia, which was associated with increased mRNA and protein expressions of spinal Pax2, NFAT5, and mRNA levels of ET-1 and ETAR, but not ETBR. Knockdown of Pax2 or NFAT5 with siRNA, or inhibition of ETAR with BQ-123 attenuated pSNL-induced pain-like behaviors. At molecular level, Pax2 siRNA, but not NFAT5 siRNA, downregulated ET-1 and ETAR, while ETAR inhibitor reduced NFAT5, indicating Pax2 in the upstream of ET-1 axis with NFAT5 in the downstream. Further, suppression of Pax2 (inhibiting ET-1) or impairment of ET-1 signaling (inhibition of ETAR and/or decrease of NFAT5) deactivated mitogen-activated protein kinases (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways, supporting the significance of functional regulation of ET-1 axis in neuropathic pain signaling. These findings demonstrate that Pax2 targeting ET-1-ETAR-NFAT5 is a novel regulatory mechanism underlying neuropathic pain. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

  20. Focal adhesion kinase, a downstream mediator of Raf-1 signaling, suppresses cellular adhesion, migration, and neuroendocrine markers in BON carcinoid cells.

    Ning, Li; Chen, Herbert; Kunnimalaiyaan, Muthusamy

    2010-05-01

    We have recently reported that activation of the Raf-1/mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase 1/2 (MEK1/2)/ERK1/2 signaling cascade in gastrointestinal carcinoid cell line (BON) alters cellular morphology and neuroendocrine phenotype. The mechanisms by which Raf-1 mediates these changes in carcinoid cells are unclear. Here, we report that activation of the Raf-1 signaling cascade in BON cells induced the expression of focal adhesion kinase (FAK) protein, suppressed the production of neuroendocrine markers, and resulted in significant decreases in cellular adhesion and migration. Importantly, inactivation of MEK1/2 by 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene or abolition of FAK induction in Raf-1-activated BON cells by targeted siRNA led to reversal of the Raf-1-mediated reduction in neuroendocrine markers and cellular adhesion and migration. Phosphorylation site-specific antibodies detected the phosphorylated FAK(Tyr407), but not FAK(Tyr397), in these Raf-1-activated cells, indicating that FAK(Tyr407) may be associated with changes in the neuroendocrine phenotype. Overexpression of constitutively active FAK plasmids (wild-type FAK or FAK(Tyr397) mutant) into BON cells reduced neuroendocrine markers, whereas the FAK(Tyr407) mutant plasmid did not show any decrease in the levels of neuroendocrine markers, indicating that phosphorylation of FAK at the Tyr(407) residue may be important for these effects. Our results showed for the first time that FAK is an essential downstream effector of the Raf-1/MEK1/2/ERK1/2 signaling cascade and negatively regulated the neuroendocrine and metastatic phenotype in BON cells. (c)2010 AACR.

  1. Activated factor X signaling via protease-activated receptor 2 suppresses pro-inflammatory cytokine production from LPS-stimulated myeloid cells.

    Gleeson, Eimear M

    2013-07-19

    Vitamin K-dependent proteases generated in response to vascular injury and infection enable fibrin clot formation, but also trigger distinct immuno-regulatory signaling pathways on myeloid cells. Factor Xa, a protease crucial for blood coagulation, also induces protease-activated receptor-dependent cell signaling. Factor Xa can bind both monocytes and macrophages, but whether factor Xa-dependent signaling stimulates or suppresses myeloid cell cytokine production in response to Toll-like receptor activation is not known. In this study, exposure to factor Xa significantly impaired pro-inflammatory cytokine production from lipopolysaccharide-treated peripheral blood mononuclear cells, THP-1 monocytic cells and murine macrophages. Furthermore, factor Xa inhibited nuclear factor-kappa B activation in THP-1 reporter cells, requiring phosphatidylinositide 3-kinase activity for its anti-inflammatory effect. Active-site blockade, γ-carboxyglutamic acid domain truncation and a peptide mimic of the factor Xa inter-epidermal growth factor-like region prevented factor Xa inhibition of lipopolysaccharide-induced tumour necrosis factor-α release. In addition, factor Xa anti-inflammatory activity was markedly attenuated by the presence of an antagonist of protease-activated receptor 2, but not protease-activated receptor 1. The key role of protease-activated receptor 2 in eliciting factor Xa-dependent anti-inflammatory signaling on macrophages was further underscored by the inability of factor Xa to mediate inhibition of tumour necrosis factor-α and interleukin-6 release from murine bone marrow-derived protease-activated receptor 2-deficient macrophages. We also show for the first time that, in addition to protease-activated receptor 2, factor Xa requires a receptor-associated protein-sensitive low-density lipoprotein receptor to inhibit lipopolysaccharide-induced cytokine production. Collectively, this study supports a novel function for factor Xa as an endogenous, receptor

  2. Fish oil suppresses cell growth and metastatic potential by regulating PTEN and NF-κB signaling in colorectal cancer.

    Shevali Kansal

    Full Text Available Homeostasis in eukaryotic tissues is tightly regulated by an intricate balance of the prosurvival and antisurvival signals. The tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10, a dual-specificity phosphatase, plays a functional role in cell cycle arrest and apoptosis. NF-κB and its downstream regulators (such as VEGF play a central role in prevention of apoptosis, promotion of inflammation and tumor growth. Therefore, we thought to estimate the expression of PTEN, Poly-ADP-ribose polymerase (PARP, NF-κBp50, NF-κBp65 and VEGF to evaluate the effect of supplementation of fish oil on apoptotic and inflammatory signaling in colon carcinoma. Male wistar rats in Group I received purified diet while Group II and III received modified diet supplemented with FO∶CO(1∶1&FO∶CO(2.5∶1 respectively. These were further subdivided into controls receiving ethylenediamine-tetra acetic-acid and treated groups received dimethylhydrazine-dihydrochloride (DMH/week for 4 weeks. Animals sacrificed 48 hours after last injection constituted initiation phase and that sacrificed after 16 weeks constituted post-initiation phase. We have analysed expression of PTEN, NF-κBp50, NF-κBp65 by flowcytometer and nuclear localization of NF-κB by immunofluorescence. PARP and VEGF were assessed by immunohistochemistry. In the initiation phase, animals receiving DMH have shown increased % of apoptotic cells, PTEN, PARP, NF-κBp50, NF-κBp65 and VEGF however in post-initiation phase no significant alteration in apoptosis with decreased PTEN and increased PARP, NF-κBp50, NF-κBp65 and VEGF were observed as compared to control animals. On treatment with both ratios of fish oil in both the phases, augmentation in % of apoptotic cells, decreased PTEN, PARP, NF-κBp50, NF-κBp65 and VEGF were documented with respect to DMH treated animals with effect being more exerted with higher ration in post-initiation phase. Hence, fish oil activates

  3. Newly synthesized quinazolinone HMJ-38 suppresses angiogenetic responses and triggers human umbilical vein endothelial cell apoptosis through p53-modulated Fas/death receptor signaling

    Chiang, Jo-Hua [Department of Life Sciences, National Chung Hsing University, 250, Kuo-Kuang Road, Taichung 402, Taiwan (China); Yang, Jai-Sing [Department of Pharmacology, China Medical University, Taichung 404, Taiwan (China); Lu, Chi-Cheng [Department of Life Sciences, National Chung Hsing University, 250, Kuo-Kuang Road, Taichung 402, Taiwan (China); Hour, Mann-Jen; Chang, Shu-Jen [School of Pharmacy, China Medical University, Taichung 40402, Taiwan (China); Lee, Tsung-Han, E-mail: thlee@email.nchu.edu.tw [Department of Life Sciences, National Chung Hsing University, 250, Kuo-Kuang Road, Taichung 402, Taiwan (China); Department of Biological Science and Technology, China Medical University, 91, Hsueh-Shih Road, Taichung 404, Taiwan (China); Chung, Jing-Gung, E-mail: jgchung@mail.cmu.edu.tw [Department of Biological Science and Technology, China Medical University, 91, Hsueh-Shih Road, Taichung 404, Taiwan (China); Department of Biotechnology, Asia University, Taichung 413, Taiwan (China)

    2013-06-01

    The current study aims to investigate the antiangiogenic responses and apoptotic death of human umbilical vein endothelial cells (HUVECs) by a newly synthesized compound named 2-(3′-methoxyphenyl)-6-pyrrolidinyl-4-quinazolinone (HMJ-38). This work attempted to not only explore the effects of angiogenesis on in vivo and ex vivo studies but also hypothesize the implications for HUVECs (an ideal cell model for angiogenesis in vitro) and further undermined apoptotic experiments to verify the underlying molecular signaling by HMJ-38. Our results demonstrated that HMJ-38 significantly inhibited blood vessel growth and microvessel formation by the mouse Matrigel plug assay of angiogenesis, and the suppression of microsprouting from the rat aortic ring assay was observed after HMJ-38 exposure. In addition, HMJ-38 disrupted the tube formation and blocked the ability of HUVECs to migrate in response to VEGF. We also found that HMJ-38 triggered cell apoptosis of HUVECs in vitro. HMJ-38 concentration-dependently suppressed viability and induced apoptotic damage in HUVECs. HMJ-38-influenced HUVECs were performed by determining the oxidative stress (ROS production) and ATM/p53-modulated Fas and DR4/DR5 signals that were examined by flow cytometry, Western blotting, siRNA and real-time RT-PCR analyses, respectively. Our findings demonstrate that p53-regulated extrinsic pathway might fully contribute to HMJ-38-provoked apoptotic death in HUVECs. In view of these observations, we conclude that HMJ-38 reduces angiogenesis in vivo and ex vivo as well as induces apoptosis of HUVECs in vitro. Overall, HMJ-38 has a potent anti-neovascularization effect and could warrant being a vascular targeting agent in the future. - Highlights: • HMJ-38 suppresses angiogenic actions in vivo and ex vivo. • Inhibitions of blood vessel and microvessel formation by HMJ-38 are acted. • Cytotoxic effects of HUVECs occur by HMJ-38 challenge. • p53-modulated extrinsic pathway contributes to HMJ-38

  4. Celecoxib Ameliorates Non-Alcoholic Steatohepatitis in Type 2 Diabetic Rats via Suppression of the Non-Canonical Wnt Signaling Pathway Expression

    Tian, Feng; Zhang, Ya Jie; Li, Yu; Xie, Ying

    2014-01-01

    Our aim was to test whether pharmacological inhibition of cycloxygenase-2 (COX-2) reverses non-alcoholic steatohepatitis (NASH) in type 2 diabetes mellitus (T2DM) rats via suppression of the non-canonical Wnt signaling pathway expression. Twenty-four male Sprague-Dawley rats were randomly distributed to two groups and were fed with a high fat and sucrose (HF-HS) diet or a normal chow diet, respectively. After four weeks, rats fed with a HF-HS diet were made diabetic with low-dose streptozotocin. At the 9th week the diabetic rats fed with a HF-HS diet or the non-diabetic rats fed with a normal chow diet were further divided into two subgroups treated with vehicle or celecoxib (a selective COX-2 inhibitor, 10 mg/Kg/day, gavage) for the last 4 weeks, respectively. At the end of the 12th week, rats were anesthetized. NASH was assessed by histology. Related cytokine expression was measured at both the protein and gene levels through immunohistochemistry (IHC), Western blot and real-time PCR. T2DM rats fed with a HF-HS diet developed steatohepatitis and insulin resistance associated with elevated serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), insulin levels and the non-alcoholic fatty liver disease (NAFLD) activity score (NAS). The expression of Wnt5a, JNK1, NF-κB p65, and COX-2 were all significantly increased in the T2DM-NASH group compared with the control and control-cele group. Hepatic injury was improved by celecoxib in T2DM-NASH-Cele group indicated by reduced serum ALT and AST levels and hepatic inflammation was reduced by celecoxib showed by histology and the NAFLD activity score (NAS). Serum related metabolic parameters, HOMA-IR and insulin sensitivity index were all improved by celecoxib. The expression of Wnt5a, JNK1, NF-κB p65, and COX-2 expression were all suppressed by celecoxib in T2DM-NASH-Cele group. The results of the present study indicated that celecoxib ameliorated NASH in T2DM rats via suppression of the non-canonical Wnt

  5. A novel shogaol analog suppresses cancer cell invasion and inflammation, and displays cytoprotective effects through modulation of NF-κB and Nrf2-Keap1 signaling pathways

    Gan, Fei-Fei; Ling, Hui; Ang, Xiaohui; Reddy, Shridhivya A.; Lee, Stephanie S-H.; Yang, Hong; Tan, Sock-Hoon [Department of Pharmacy, Faculty of Science, National University of Singapore (Singapore); Hayes, John D. [Jacqui Wood Cancer Centre, Division of Cancer Research, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland (United Kingdom); Chui, Wai-Keung [Department of Pharmacy, Faculty of Science, National University of Singapore (Singapore); Chew, Eng-Hui, E-mail: phaceh@nus.edu.sg [Department of Pharmacy, Faculty of Science, National University of Singapore (Singapore)

    2013-11-01

    Natural compounds containing vanilloid and Michael acceptor moieties appear to possess anti-cancer and chemopreventive properties. The ginger constituent shogaol represents one such compound. In this study, the anti-cancer potential of a synthetic novel shogaol analog 3-phenyl-3-shogaol (3-Ph-3-SG) was assessed by evaluating its effects on signaling pathways. At non-toxic concentrations, 3-Ph-3-SG suppressed cancer cell invasion in MDA-MB-231 and MCF-7 breast carcinoma cells through inhibition of PMA-activated MMP-9 expression. At similar concentrations, 3-Ph-3-SG reduced expression of the inflammatory mediators nitric oxide (NO), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and prostanglandin-E{sub 2} (PGE{sub 2}) in RAW 264.7 macrophage-like cells. Inhibition of cancer cell invasion and inflammation by 3-Ph-3-SG were mediated through suppression of the nuclear factor-kappaB (NF-κB) signaling pathway. The 3-Ph-3-SG also demonstrated cytoprotective effects by inducing the antioxidant response element (ARE)-driven genes NAD(P)H quinone oxidoreductase-1 (NQO1) and heme oxygenase-1 (HO-1). Cytoprotection by 3-Ph-3-SG was achieved at least partly through modification of cysteine residues in the E3 ubiquitin ligase substrate adaptor Kelch-like ECH-associated protein 1 (Keap1), which resulted in accumulation of transcription factor NF-E2 p45-related factor 2 (Nrf2). The activities of 3-Ph-3-SG were comparable to those of 6-shogaol, the most abundant naturally-occurring shogaol, and stronger than those of 4-hydroxyl-null deshydroxy-3-phenyl-3-shogaol, which attested the importance of the 4-hydroxy substituent in the vanilloid moiety for bioactivity. In summary, 3-Ph-3-SG is shown to possess activities that modulate stress-associated pathways relevant to multiple steps in carcinogenesis. Therefore, it warrants further investigation of this compound as a promising candidate for use in chemotherapeutic and chemopreventive strategies. - Highlights:

  6. The Sound Quality of Cochlear Implants: Studies With Single-sided Deaf Patients.

    Dorman, Michael F; Natale, Sarah Cook; Butts, Austin M; Zeitler, Daniel M; Carlson, Matthew L

    2017-09-01

    The goal of the present study was to assess the sound quality of a cochlear implant for single-sided deaf (SSD) patients fit with a cochlear implant (CI). One of the fundamental, unanswered questions in CI research is "what does an implant sound like?" Conventional CI patients must use the memory of a clean signal, often decades old, to judge the sound quality of their CIs. In contrast, SSD-CI patients can rate the similarity of a clean signal presented to the CI ear and candidate, CI-like signals presented to the ear with normal hearing. For Experiment 1 four types of stimuli were created for presentation to the normal hearing ear: noise vocoded signals, sine vocoded signals, frequency shifted, sine vocoded signals and band-pass filtered, natural speech signals. Listeners rated the similarity of these signals to unmodified signals sent to the CI on a scale of 0 to 10 with 10 being a complete match to the CI signal. For Experiment 2 multitrack signal mixing was used to create natural speech signals that varied along multiple dimensions. In Experiment 1 for eight adult SSD-CI listeners, the best median similarity rating to the sound of the CI for noise vocoded signals was 1.9; for sine vocoded signals 2.9; for frequency upshifted signals, 1.9; and for band pass filtered signals, 5.5. In Experiment 2 for three young listeners, combinations of band pass filtering and spectral smearing lead to ratings of 10. The sound quality of noise and sine vocoders does not generally correspond to the sound quality of cochlear implants fit to SSD patients. Our preliminary conclusion is that natural speech signals that have been muffled to one degree or another by band pass filtering and/or spectral smearing provide a close, but incomplete, match to CI sound quality for some patients.

  7. Bortezomib induces apoptosis and suppresses cell growth and metastasis by inactivation of Stat3 signaling in chondrosarcoma.

    Bao, Xing; Ren, Tingting; Huang, Yi; Ren, Chongmin; Yang, Kang; Zhang, Hongliang; Guo, Wei

    2017-02-01

    Bortezomib, formerly known as PS341, is a novel proteasome inhibitor with in vitro and in vivo antineoplastic effects in many malignancies. However, diverse antitumor mechanisms of bortezomib have been identified in many investigations and preclinical studies. Understanding the molecular and cellular mechanisms through which bortezomib acts will improve the therapeutic utility of this drug in different cancer types. In the present study, we investigated the in vitro and in vivo effects of bortezomib on chondrosarcoma. Bortezomib selectively inhibited cell growth in chondrosarcoma cells but not in normal articular cartilage cells. In addition to growth inhibition, apoptosis and cell cycle arrest, bortezomib triggered alleviation of migratory and invasive properties of chondrosarcoma cells. Mechanistically, signal transducer and activator of transcription 3 (Stat3) and its downstream targets Bcl-2, cyclin D1 and c-Myc was inactivated by bortezomib treatment. Accordingly, small interfering RNA (siRNA)-mediated Stat3 knockdown enhanced bortezomib-induced apoptosis, and concomitantly enhanced the inhibitory effect of bortezomib on cell viability, migration and invasion. Moreover, while Slug, MMP9, MMP2, CD44, N-cadherin and vimentin, the mesenchymal cell markers, were repressed by bortezomib concomitant increased expression of E-cadherin was observed. In vivo, bortezomib downregulated Stat3 activity and mesenchymal cell marker expression, induced apoptosis and inhibition of metastasis and tumor growth. Together, inactivation of Stat3 signaling contributes to bortezomib-induced inhibition of tumor growth, migration and invation on chondrosarcoma. Bortezomib demonstrates an antineoplastic role on chondrosarcoma both in vitro and in vivo. These beneficial effects can be explained by bortezomib-mediated Stat3 supression. The present study suggests a promising therapeutics target in chondrosarcoma and probably in other kinds of metastatic malignant tumors.

  8. Recombinant Human Endostatin Suppresses Mouse Osteoclast Formation by Inhibiting the NF-κB and MAPKs Signaling Pathways

    Non eChen

    2016-06-01

    Full Text Available Rheumatoid arthritis is an autoimmune disease characterized by synovial hyperplasia and progressive joint destruction. As reported previously, recombinant human endostatin (rhEndostatin is associated with inhibition of joint bone destruction present in rat adjuvant-induced arthritis; however, the effect of rhEndostatin on bone destruction is not known. This study was designed to assess the inhibitory effect and mechanisms of rhEndostatin on formation and function of osteoclasts in vitro, and to gain insight into the mechanism underlying the inhibitory effect of bone destruction. Bone marrow-derived macrophages isolated from BALB/c mice were stimulated with receptor activator of NF-κB ligand (RANKL and macrophage colony-stimulating factor to establish osteoclast formation. Osteoclast formation was determined by TRAP staining. Cell viability of BMMs affected by rhEndostatin was determined using a MTT assay. Bone resorption was examined with a bone resorption pits assay. The expression of osteoclast-specific markers was analyzed using quantitative real-time PCR. The related signaling pathways were examined using a Luciferase reporter assay and western blot analysis. Indeed, rhEndostatin showed a significant reduction in the number of osteoclast-like cells and early-stage bone resorption. Moreover, molecular analysis demonstrated that rhEndostatin attenuated RANKL-induced NF-κB signaling by inhibiting the phosphorylation of IκBα and NF-κB p65 nuclear translocation. Furthermore, rhEndostatin significantly inhibited the activation of RANKL-dependent mitogen-activated protein kinases (MAPKs, such as ERK1/2, JNK, and p38. Hence, we demonstrated for the first time that preventing the formation and function of osteoclasts is an important anti-bone destruction mechanism of rhEndostatin, which might be useful in the prevention and treatment of bone destruction in RA.

  9. [Responses of bat cochlear nucleus neurons to ultrasonic stimuli].

    Vasil'ev, A G; Grigor'eva, T I

    1977-01-01

    The responses of cochlear nuclei single units in Vespertilionidae and Rhinolophidae were studied by means of ultrasound stimuli of different frequencies. Most neurons were found to have one or two complementary response areas with best frequencies equal to 1/2 and 1/3 of the highest one (which we regard as the basic best frequency). In Vespertilionidae which emit frequency-modulated signals some neurons have complementary areas with upper thresholds. The latency of responses do not correlate with the stimulus frequency. This suggests that there is no correlative reception of echosignals at this level of auditory system in bats.

  10. Hydrogen sulfide-releasing naproxen suppresses colon cancer cell growth and inhibits NF-κB signaling

    Kodela R

    2015-08-01

    Full Text Available Ravinder Kodela,1 Niharika Nath,2 Mitali Chattopadhyay,1 Diandra E Nesbitt,1 Carlos A Velázquez-Martínez,3 Khosrow Kashfi11Department of Physiology, Pharmacology and Neuroscience, Sophie Davis School of Biomedical Education, City University of New York Medical School, 2Department of Life Sciences, New York Institute of Technology, New York, NY, USA; 3Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada Abstract: Colorectal cancer (CRC is the second leading cause of death due to cancer and the third most common cancer in men and women in the USA. Nuclear factor kappa B (NF-κB is known to be activated in CRC and is strongly implicated in its development and progression. Therefore, activated NF-κB constitutes a bona fide target for drug development in this type of malignancy. Many epidemiological and interventional studies have established nonsteroidal anti-inflammatory drugs (NSAIDs as a viable chemopreventive strategy against CRC. Our previous studies have shown that several novel hydrogen sulfide-releasing NSAIDs are promising anticancer agents and are safer derivatives of NSAIDs. In this study, we examined the growth inhibitory effect of a novel H2S-releasing naproxen (HS-NAP, which has a repertoire as a cardiovascular-safe NSAID, for its effects on cell proliferation, cell cycle phase transitions, and apoptosis using HT-29 human colon cancer cells. We also investigated its effect as a chemopreventive agent in a xenograft mouse model. HS-NAP suppressed the growth of HT-29 cells by induction of G0/G1 arrest and apoptosis and downregulated NF-κB. Tumor xenografts in mice were significantly reduced in volume. The decrease in tumor mass was associated with a reduction of cell proliferation, induction of apoptosis, and decreases in NF-κB levels in vivo. Therefore, HS-NAP demonstrates strong anticancer potential in CRC. Keywords: nonsteroidal anti-inflammatory drugs, cell cycle, apoptosis, xenograft, NF

  11. Audiovisual segregation in cochlear implant users.

    Simon Landry

    Full Text Available It has traditionally been assumed that cochlear implant users de facto perform atypically in audiovisual tasks. However, a recent study that combined an auditory task with visual distractors suggests that only those cochlear implant users that are not proficient at recognizing speech sounds might show abnormal audiovisual interactions. The present study aims at reinforcing this notion by investigating the audiovisual segregation abilities of cochlear implant users in a visual task with auditory distractors. Speechreading was assessed in two groups of cochlear implant users (proficient and non-proficient at sound recognition, as well as in normal controls. A visual speech recognition task (i.e. speechreading was administered either in silence or in combination with three types of auditory distractors: i noise ii reverse speech sound and iii non-altered speech sound. Cochlear implant users proficient at speech recognition performed like normal controls in all conditions, whereas non-proficient users showed significantly different audiovisual segregation patterns in both speech conditions. These results confirm that normal-like audiovisual segregation is possible in highly skilled cochlear implant users and, consequently, that proficient and non-proficient CI users cannot be lumped into a single group. This important feature must be taken into account in further studies of audiovisual interactions in cochlear implant users.

  12. Assessment of Cochlear Function during Cochlear Implantation by Extra- and Intracochlear Electrocochleography

    Dalbert, Adrian; Pfiffner, Flurin; Hoesli, Marco; Koka, Kanthaiah; Veraguth, Dorothe; Roosli, Christof; Huber, Alexander

    2018-01-01

    Objective: The aims of this study were: (1) To investigate the correlation between electrophysiological changes during cochlear implantation and postoperative hearing loss, and (2) to detect the time points that electrophysiological changes occur during cochlear implantation. Material and Methods: Extra- and intracochlear electrocochleography (ECoG) were used to detect electrophysiological changes during cochlear implantation. Extracochlear ECoG recordings were conducted through a needle elec...

  13. Norcantharidin inhibits tumor growth and vasculogenic mimicry of human gallbladder carcinomas by suppression of the PI3-K/MMPs/Ln-5γ2 signaling pathway

    Zhang, Jing-Tao; Sun, Wei; Zhang, Wen-Zhong; Ge, Chun-Yan; Liu, Zhong-Yan; Zhao, Ze-Ming; Lu, Xing-Sui; Fan, Yue-Zu

    2014-01-01

    < 0.01, vs. control group); NCTD down-regulated expression of these VM signaling-related markers in vitro and in vivo. NCTD inhibited tumor growth and VM of human GBCs in vitro and in vivo by suppression of the PI3-K/MMPs/Ln-5γ2 signaling pathway. It is firstly concluded that NCTD may be a potential anti-VM agent for human GBCs

  14. Tumour suppression in skin and other tissues via cross-talk between vitamin D- and p53-signalling

    Joerg eReichrath

    2014-06-01

    Full Text Available P53 and its family members have been implicated in the direct regulation of the vitamin D receptor (VDR. Vitamin D- and p53-signaling pathways have a significant impact on spontaneous or carcinogen-induced malignant transformation of cells, with VDR and p53 representing important tumour suppressors. VDR and the p53/p63/p73 proteins all function typically as receptors or sensors that turn into transcriptional regulators upon stimulus, with the main difference being that the nuclear VDR is activated as a transcription factor after binding its naturally occurring ligand 1,25-dihydroxyvitamin D with high affinity while the p53 family of transcription factors, mostly in the nucleoplasm, responds to a large number of alterations in cell homeostasis commonly referred to as stress. An increasing body of evidence now convincingly demonstrates a cross-talk between vitamin D- and p53-signaling that occurs at different levels, has genome-wide implications and that should be of high importance for many malignancies, including non-melanoma skin cancer. One interaction involves the ability of p53 to increase skin pigmentation via POMC derivatives including alpha-MSH and ACTH. Pigmentation protects the skin against UV-induced DNA damage and skin carcinogenesis, yet on the other hand reduces cutaneous synthesis of vitamin D. A second level of interaction may be through the ability of 1,25-dihydroxyvitamin D to increase the survival of skin cells after UV irradiation. UV irradiation-surviving cells show significant reductions in thymine dimers in the presence of 1,25-dihydroxyvitamin D that are associated with increased nuclear p53 protein expression, and significantly reduced NO products. A third level of interaction is documented by the ability of vitamin D compounds to regulate the expression of the murine double minute 2 (MDM2 gene in dependence of the presence of wild-type p53. MDM2 has a well established role as a key negative regulator of p53 activity

  15. Andrographolide Inhibits Inflammatory Cytokines Secretion in LPS-Stimulated RAW264.7 Cells through Suppression of NF-κB/MAPK Signaling Pathway.

    Li, Yu; He, Shengnan; Tang, Jishun; Ding, Nana; Chu, Xiaoyan; Cheng, Lianping; Ding, Xuedong; Liang, Ting; Feng, Shibin; Rahman, Sajid Ur; Wang, Xichun; Wu, Jinjie

    2017-01-01

    Andrographolide, the main active component extracted from Andrographis paniculata (Burm.f.) Wall. ex Nees, exerts anti-inflammatory effects; however, the principal molecular mechanisms remain unclear. The objective of this study was to investigate the molecular mechanisms of Andrographolide in modifying lipopolysaccharide- (LPS-) induced signaling pathway in RAW264.7 cells. An in vitro model of inflammation was induced by LPS in mouse RAW264.7 cells in the presence of Andrographolide. The concentration and expression levels of proinflammatory cytokines were determined by an enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. The nuclear level of NF- κ B was measured by an electrophoretic mobility shift assay (EMSA). The expression levels of NF- κ B, p38, ERK, and JNK were determined by western blot. Andrographolide dose-dependently inhibited the release and mRNA expression of TNF- α , IL-6, and IL-1 β in LPS-stimulated RAW264.7 cells. The nuclear level of p65 protein was decreased in Andrographolide treatment group. Western blot analysis showed that Andrographolide suppressed LPS-induced NF- κ B activation and the phosphorylation of IkBa, ERK1/2, JNK, and p38. These results suggest that Andrographolide exerts an anti-inflammatory effect by inhibiting the activation of NF- κ B/MAPK signaling pathway and the induction of proinflammatory cytokines.

  16. Andrographolide Inhibits Inflammatory Cytokines Secretion in LPS-Stimulated RAW264.7 Cells through Suppression of NF-κB/MAPK Signaling Pathway

    Yu Li

    2017-01-01

    Full Text Available Andrographolide, the main active component extracted from Andrographis paniculata (Burm.f. Wall. ex Nees, exerts anti-inflammatory effects; however, the principal molecular mechanisms remain unclear. The objective of this study was to investigate the molecular mechanisms of Andrographolide in modifying lipopolysaccharide- (LPS- induced signaling pathway in RAW264.7 cells. An in vitro model of inflammation was induced by LPS in mouse RAW264.7 cells in the presence of Andrographolide. The concentration and expression levels of proinflammatory cytokines were determined by an enzyme-linked immunosorbent assay (ELISA and quantitative real-time polymerase chain reaction (qRT-PCR, respectively. The nuclear level of NF-κB was measured by an electrophoretic mobility shift assay (EMSA. The expression levels of NF-κB, p38, ERK, and JNK were determined by western blot. Andrographolide dose-dependently inhibited the release and mRNA expression of TNF-α, IL-6, and IL-1β in LPS-stimulated RAW264.7 cells. The nuclear level of p65 protein was decreased in Andrographolide treatment group. Western blot analysis showed that Andrographolide suppressed LPS-induced NF-κB activation and the phosphorylation of IkBa, ERK1/2, JNK, and p38. These results suggest that Andrographolide exerts an anti-inflammatory effect by inhibiting the activation of NF-κB/MAPK signaling pathway and the induction of proinflammatory cytokines.

  17. Ectopic expression of miR-34a enhances radiosensitivity of non-small cell lung cancer cells, partly by suppressing the LyGDI signaling pathway

    Duan Weiming; Xu Yaxiang; Dong Yujin; Cao Lili; Tong Jian; Zhou Xinwen

    2013-01-01

    miR-34a is transcriptionally induced by the tumor suppressor gene p53, which is often downregulated in non-small cell lung cancer (NSCLC). To address whether the downstream signal of miR-34a is sufficient to induce apoptosis and to alter cellular radiosensitivity, a chemical synthetic miR-34a mimic was delivered into A549 and H1299 cells, with or without co-treatment of γ-irradiation. Results showed that ectopic expression of miR-34a induced dose-dependent cell growth inhibition and apoptosis in a p53-independent manner in both NSCLC cell lines. Interestingly, LyGDI was discovered as a new target gene of miR-34a, and downregulation of LyGDI promoted Rac1 activation and membrane translocation, resulting in cell apoptosis. Furthermore, restoration of miR-34a indirectly reduced cyclooxygenase-2 (COX-2) expression. Taken together, these results demonstrate that restoration of miR-34a expression enhances radiation-induced apoptosis, partly by suppressing the LyGDI signaling pathway, and miR-34a could possibly be used as a radiosensitizer for non-small cell lung cancer therapy. (author)

  18. Bee Venom Inhibits Porphyromonas gingivalis Lipopolysaccharides-Induced Pro-Inflammatory Cytokines through Suppression of NF-κB and AP-1 Signaling Pathways.

    Kim, Woon-Hae; An, Hyun-Jin; Kim, Jung-Yeon; Gwon, Mi-Gyeong; Gu, Hyemin; Park, Jae-Bok; Sung, Woo Jung; Kwon, Yong-Chul; Park, Kyung-Duck; Han, Sang Mi; Park, Kwan-Kyu

    2016-11-10

    Periodontitis is a chronic inflammatory disease that leads to destruction of tooth supporting tissues. Porphyromonas gingivalis ( P. gingivalis ), especially its lipopolysaccharides (LPS), is one of major pathogens that cause periodontitis. Bee venom (BV) has been widely used as a traditional medicine for various diseases. Previous studies have demonstrated the anti-inflammatory, anti-bacterial effects of BV. However, a direct role and cellular mechanism of BV on periodontitis-like human keratinocytes have not been explored. Therefore, we investigated the anti-inflammatory mechanism of BV against P. gingivalis LPS (PgLPS)-induced HaCaT human keratinocyte cell line. The anti-inflammatory effect of BV was demonstrated by various molecular biological methods. The results showed that PgLPS increased the expression of Toll-like receptor (TLR)-4 and pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-8, and interferon (IFN)-γ. In addition, PgLPS induced activation of the signaling pathways of inflammatory cytokines-related transcription factors, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activator protein 1 (AP-1). BV effectively inhibited those pro-inflammatory cytokines through suppression of NF-κB and AP-1 signaling pathways. These results suggest that administration of BV attenuates PgLPS-induced inflammatory responses. Furthermore, BV may be a useful treatment to anti-inflammatory therapy for periodontitis.

  19. Suppression of Hepatic Epithelial-to-Mesenchymal Transition by Melittin via Blocking of TGFβ/Smad and MAPK-JNK Signaling Pathways.

    Park, Ji-Hyun; Park, Byoungduck; Park, Kwan-Kyu

    2017-04-13

    Transforming growth factor (TGF)-β1 plays a crucial role in the epithelial-to-mesenchymal transition (EMT) in hepatocytes and hepatic stellate cells (HSC), which contributes to the pathogenesis of liver fibrosis. Melittin (MEL) is a major component of bee venom and is effective in rheumatoid arthritis, pain relief, cancer cell proliferation, fibrosis and immune modulating activity. In this study, we found that MEL inhibits hepatic EMT in vitro and in vivo, regulating the TGFβ/Smad and TGFβ/nonSmad signaling pathways. MEL significantly inhibited TGF-β1-induced expression of EMT markers (E-cadherin reduction and vimentin induction) in vitro. These results were confirmed in CCl₄-induced liver in vivo. Treatment with MEL almost completely blocked the phosphorylation of Smad2/3, translocation of Smad4 and phosphorylation of JNK in vitro and in vivo. Taken together, these results suggest that MEL suppresses EMT by inhibiting the TGFβ/Smad and TGFβ/nonSmad-c-Jun N-terminal kinase (JNK)/Mitogen-activated protein kinase (MAPK) signaling pathways. These results indicated that MEL possesses potent anti-fibrotic and anti-EMT properties, which may be responsible for its effects on liver diseases.

  20. Lycopene acts through inhibition of IκB kinase to suppress NF-κB signaling in human prostate and breast cancer cells.

    Assar, Emelia A; Vidalle, Magdalena Castellano; Chopra, Mridula; Hafizi, Sassan

    2016-07-01

    We studied the effect of the potent dietary antioxidant lycopene on multiple points along the nuclear factor kappa B (NF-κB) signaling pathway in prostate and breast cancer cells. Lycopene significantly inhibited prostate and breast cancer cell growth at physiologically relevant concentrations of ≥1.25 μM. Similar concentrations also caused a 30-40 % reduction in inhibitor of kappa B (IκB) phosphorylation in the cells, as determined by western blotting. Furthermore, the same degree of inhibition by lycopene was observed for NF-κB transcriptional activity, as determined by reporter gene assay. Concomitant with this, immunofluorescence staining of lycopene-treated cells showed a significant suppression (≥25 %) of TNF-induced NF-κB p65 subunit nuclear translocation. Further probing of lycopene's effects on upstream elements of the NF-κB pathway showed a 25 % inhibition of both activity of recombinant IκB kinase β (IKKβ) kinase in a cell-free in vitro assay, as well as activity of IKKβ immunoprecipitated from MDA-MB-231 cells treated with lycopene. In conclusion, the anticancer properties of lycopene may occur through inhibition of the NF-κB signaling pathway, beginning at the early stage of cytoplasmic IKK kinase activity, which then leads to reduced NF-κB-responsive gene regulation. Furthermore, these effects in cancer cells were observed at concentrations of lycopene that are relevant and achievable in vivo.

  1. Non-Water-Suppressed 1H MR Spectroscopy with Orientational Prior Knowledge Shows Potential for Separating Intra- and Extramyocellular Lipid Signals in Human Myocardium.

    Fillmer, Ariane; Hock, Andreas; Cameron, Donnie; Henning, Anke

    2017-12-04

    Conditions such as type II diabetes are linked with elevated lipid levels in the heart, and significantly increased risk of heart failure; however, metabolic processes underlying the development of cardiac disease in type II diabetes are not fully understood. Here we present a non-invasive method for in vivo investigation of cardiac lipid metabolism: namely, IVS-McPRESS. This technique uses metabolite-cycled, non-water suppressed 1 H cardiac magnetic resonance spectroscopy with prospective and retrospective motion correction. High-quality IVS-McPRESS data acquired from healthy volunteers allowed us to investigate the frequency shift of extramyocellular lipid signals, which depends on the myocardial fibre orientation. Assuming consistent voxel positioning relative to myofibres, the myofibre angle with the magnetic field was derived from the voxel orientation. For separation and individual analysis of intra- and extramyocellular lipid signals, the angle myocardial fibres in the spectroscopy voxel take with the magnetic field should be within ±24.5°. Metabolite and lipid concentrations were analysed with respect to BMI. Significant correlations between BMI and unsaturated fatty acids in intramyocellular lipids, and methylene groups in extramyocellular lipids were found. The proposed IVS-McPRESS technique enables non-invasive investigation of cardiac lipid metabolism and may thus be a useful tool to study healthy and pathological conditions.

  2. Ototoxicity of paclitaxel in rat cochlear organotypic cultures

    Dong, Yang; Ding, Dalian; Jiang, Haiyan; Shi, Jian-rong; Salvi, Richard; Roth, Jerome A.

    2014-01-01

    Paclitaxel (taxol) is a widely used antineoplastic drug employed alone or in combination to treat many forms of cancer. Paclitaxel blocks microtubule depolymerization thereby stabilizing microtubules and suppressing cell proliferation and other cellular processes. Previous reports indicate that paclitaxel can cause mild to moderate sensorineural hearing loss and some histopathologic changes in the mouse cochlea; however, damage to the neurons and the underlying cell death mechanisms are poorly understood. To evaluate the ototoxicity of paclitaxel in more detail, cochlear organotypic cultures from postnatal day 3 rats were treated with paclitaxel for 24 or 48 h with doses ranging from 1 to 30 μM. No obvious histopathologies were observed after 24 h treatment with any of the paclitaxel doses employed, but with 48 h treatment, paclitaxel damaged cochlear hair cells in a dose-dependent manner and also damaged auditory nerve fibers and spiral ganglion neurons (SGN) near the base of the cochlea. TUNEL labeling was negative in the organ of Corti, but positive in SGN with karyorrhexis 48 h after 30 μM paclitaxel treatment. In addition, caspase-6, caspase-8 and caspase-9 labeling was present in SGN treated with 30 μM paclitaxel for 48 h. These results suggest that caspase-dependent apoptotic pathways are involved in paclitaxel-induced damage of SGN, but not hair cells in cochlea. - Highlights: • Paclitaxel was toxic to cochlear hair cells and spiral ganglion neurons. • Paclitaxel-induced spiral ganglion degeneration was apoptotic. • Paclitaxel activated caspase-6, -8 and -8 in spiral ganglion neurons

  3. Ototoxicity of paclitaxel in rat cochlear organotypic cultures

    Dong, Yang [Shanghai University of Traditional Chinese Medicine, Shanghai 201203 (China); Center for Hearing and Deafness, University at Buffalo, NY 14214 (United States); Ding, Dalian; Jiang, Haiyan [Center for Hearing and Deafness, University at Buffalo, NY 14214 (United States); Shi, Jian-rong [Shanghai University of Traditional Chinese Medicine, Shanghai 201203 (China); Salvi, Richard [Center for Hearing and Deafness, University at Buffalo, NY 14214 (United States); Roth, Jerome A., E-mail: jaroth@buffalo.edu [Department of Pharmacology and Toxicology, University at Buffalo, NY 14214 (United States)

    2014-11-01

    Paclitaxel (taxol) is a widely used antineoplastic drug employed alone or in combination to treat many forms of cancer. Paclitaxel blocks microtubule depolymerization thereby stabilizing microtubules and suppressing cell proliferation and other cellular processes. Previous reports indicate that paclitaxel can cause mild to moderate sensorineural hearing loss and some histopathologic changes in the mouse cochlea; however, damage to the neurons and the underlying cell death mechanisms are poorly understood. To evaluate the ototoxicity of paclitaxel in more detail, cochlear organotypic cultures from postnatal day 3 rats were treated with paclitaxel for 24 or 48 h with doses ranging from 1 to 30 μM. No obvious histopathologies were observed after 24 h treatment with any of the paclitaxel doses employed, but with 48 h treatment, paclitaxel damaged cochlear hair cells in a dose-dependent manner and also damaged auditory nerve fibers and spiral ganglion neurons (SGN) near the base of the cochlea. TUNEL labeling was negative in the organ of Corti, but positive in SGN with karyorrhexis 48 h after 30 μM paclitaxel treatment. In addition, caspase-6, caspase-8 and caspase-9 labeling was present in SGN treated with 30 μM paclitaxel for 48 h. These results suggest that caspase-dependent apoptotic pathways are involved in paclitaxel-induced damage of SGN, but not hair cells in cochlea. - Highlights: • Paclitaxel was toxic to cochlear hair cells and spiral ganglion neurons. • Paclitaxel-induced spiral ganglion degeneration was apoptotic. • Paclitaxel activated caspase-6, -8 and -8 in spiral ganglion neurons.

  4. Rare sugar D-allose suppresses gibberellin signaling through hexokinase-dependent pathway in Oryza sativa L.

    Fukumoto, Takeshi; Kano, Akihito; Ohtani, Kouhei; Yamasaki-Kokudo, Yumiko; Kim, Bong-Gyu; Hosotani, Kouji; Saito, Miu; Shirakawa, Chikage; Tajima, Shigeyuki; Izumori, Ken; Ohara, Toshiaki; Shigematsu, Yoshio; Tanaka, Keiji; Ishida, Yutaka; Nishizawa, Yoko; Tada, Yasuomi; Ichimura, Kazuya; Gomi, Kenji; Akimitsu, Kazuya

    2011-12-01

    One of the rare sugars, D-allose, which is the epimer of D-glucose at C3, has an inhibitory effect on rice growth, but the molecular mechanisms of the growth inhibition by D-allose were unknown. The growth inhibition caused by D-allose was prevented by treatment with hexokinase inhibitors, D-mannoheptulose and N-acetyl-D-glucosamine. Furthermore, the Arabidopsis glucose-insensitive2 (gin2) mutant, which is a loss-of-function mutant of the glucose sensor AtHXK1, showed a D-allose-insensitive phenotype. D-Allose strongly inhibited the gibberellin-dependent responses such as elongation of the second leaf sheath and induction of α-amylase in embryo-less half rice seeds. The growth of the slender rice1 (slr1) mutant, which exhibits a constitutive gibberellin-responsive phenotype, was also inhibited by D-allose, and the growth inhibition of the slr1 mutant by D-allose was also prevented by D-mannoheptulose treatment. The expressions of gibberellin-responsive genes were down-regulated by D-allose treatment, and the down-regulations of gibberellin-responsive genes were also prevented by D-mannoheptulose treatment. These findings reveal that D-allose inhibits the gibberellin-signaling through a hexokinase-dependent pathway.

  5. AV-65, a novel Wnt/β-catenin signal inhibitor, successfully suppresses progression of multiple myeloma in a mouse model

    Yao, H; Ashihara, E; Strovel, J W; Nakagawa, Y; Kuroda, J; Nagao, R; Tanaka, R; Yokota, A; Takeuchi, M; Hayashi, Y; Shimazaki, C; Taniwaki, M; Strand, K; Padia, J; Hirai, H; Kimura, S; Maekawa, T

    2011-01-01

    Multiple myeloma (MM) is a malignant neoplasm of plasma cells. Although new molecular targeting agents against MM have been developed based on the better understanding of the underlying pathogenesis, MM still remains an incurable disease. We previously demonstrated that β-catenin, a downstream effector in the Wnt pathway, is a potential target in MM using RNA interference in an in vivo experimental mouse model. In this study, we have screened a library of more than 100 000 small-molecule chemical compounds for novel Wnt/β-catenin signaling inhibitors using a high-throughput transcriptional screening technology. We identified AV-65, which diminished β-catenin protein levels and T-cell factor transcriptional activity. AV-65 then decreased c-myc, cyclin D1 and survivin expression, resulting in the inhibition of MM cell proliferation through the apoptotic pathway. AV-65 treatment prolonged the survival of MM-bearing mice. These findings indicate that this compound represents a novel and attractive therapeutic agent against MM. This study also illustrates the potential of high-throughput transcriptional screening to identify candidates for anticancer drug discovery

  6. Insulin suppresses the AMPK signaling pathway to regulate lipid metabolism in primary cultured hepatocytes of dairy cows.

    Li, Xinwei; Li, Yu; Ding, Hongyan; Dong, Jihong; Zhang, Renhe; Huang, Dan; Lei, Lin; Wang, Zhe; Liu, Guowen; Li, Xiaobing

    2018-05-01

    Dairy cows with type II ketosis display hepatic fat accumulation and hyperinsulinemia, but the underlying mechanism is not completely clear. This study aimed to clarify the regulation of lipid metabolism by insulin in cow hepatocytes. In vitro, cow hepatocytes were treated with 0, 1, 10, or 100 nm insulin in the presence or absence of AICAR (an AMP-activated protein kinase alpha (AMPKα) activator). The results showed that insulin decreased AMPKα phosphorylation. This inactivation of AMPKα increased the gene and protein expression levels of carbohydrate responsive element-binding protein (ChREBP) and sterol regulatory element-binding protein-1c (SREBP-1c), which downregulated the expression of lipogenic genes, thereby decreasing lipid biosynthesis. Furthermore, AMPKα inactivation decreased the gene and protein expression levels of peroxisome proliferator-activated receptor-α (PPARα), which upregulated the expression of lipid oxidation genes, thereby increasing lipid oxidation. In addition, insulin decreased the very low density lipoprotein (VLDL) assembly. Consequently, triglyceride content was significantly increased in insulin treated hepatocytes. Activation of AMPKα induced by AICAR could reverse the effect of insulin on PPARα, SREBP-1c, and ChREBP, thereby decreasing triglyceride content. These results indicate that insulin inhibits the AMPKα signaling pathway to increase lipid synthesis and decrease lipid oxidation and VLDL assembly in cow hepatocytes, thereby inducing TG accumulation. This mechanism could partly explain the causal relationship between hepatic fat accumulation and hyperinsulinemia in dairy cows with type II ketosis.

  7. miR-150 suppresses the proliferation and tumorigenicity of leukemia stem cells by targeting the Nanog signaling pathway

    Dan-dan Xu

    2016-11-01

    Full Text Available Proliferation, a key feature of cancer cells, accounts for the majority of cancer-related diseases resulting in mortality. MicroRNAs (miRNAs plays important post-transcriptional modulation roles by acting on multiple signaling pathways, but the underlying mechanism in proliferation and tumorigenicity is unclear. Here, we identified the role of miR-150 in proliferation and tumorigenicity in leukemia stem cells (LSCs (CD34+CD38- cells. miR-150 expression was significantly down-regulated in LSCs from leukemia cell lines and clinical samples. Functional assays demonstrated that increased miR-150 expression inhibited proliferation and clonal and clonogenic growth, enhanced chemosensitivity, and attenuated tumorigenic activity of LSCs in vitro. Transplantation animal studies revealed that miR-150 overexpression progressively abrogates tumour growth. Immunohistochemistry assays demonstrated that miR-150 overexpression enhanced caspase-3 level and reduced Ki-67 level. Moreover, luciferase reporter assays indicated Nanog is a direct and functional target of miR-150. Nanog silencing using small interfering RNA recapitulated anti-proliferation and tumorigenicity inhibition effects. Furthermore, miR-150 directly down-regulated the expression of other cancer stem cell factors including Notch2 and CTNNB1. These results provide insights into the specific biological behaviour of miR-150 in regulating LSC proliferation and tumorigenicity. Targeting this miR-150/Nanog axis would be a helpful therapeutic strategy to treat acute myeloid leukemia.

  8. Prevention and management of cochlear implant infections.

    Gluth, Michael B; Singh, Rajesh; Atlas, Marcus D

    2011-11-01

    Understanding the issues of infection related to an implantable medical device is crucial to all cochlear implant teams. Furthermore, given the risk of central nervous system complications and the relatively high quantity of underlying resource investment associated with cochlear implantation, the stakes of infection are high. The optimal strategies to prevent and manage such infections are still evolving as good-quality prospective data to guide such management decisions are not yet abundant within the medical literature and many recommendations are based on retrospective reviews or anecdotal evidence. We will outline a general strategy to deal with cochlear implant-related infection based on both the authors' experience and the published literature.

  9. Saponin 1 Induces Apoptosis and Suppresses NF-κB-Mediated Survival Signaling in Glioblastoma Multiforme (GBM)

    Tang, Chi; Li, Bo; Wang, Yuangang; Gao, Zhenhui; Luo, Peng; Yin, Anan; Wang, Xiaoyang; Cheng, Guang; Fei, Zhou

    2013-01-01

    Saponin 1 is a triterpeniod saponin extracted from Anemone taipaiensis, a traditional Chinese medicine against rheumatism and phlebitis. It has also been shown to exhibit significant anti-tumor activity against human leukemia (HL-60 cells) and human hepatocellular carcinoma (Hep-G2 cells). Herein we investigated the effect of saponin 1 in human glioblastoma multiforme (GBM) U251MG and U87MG cells. Saponin 1 induced significant growth inhibition in both glioblastoma cell lines, with a 50% inhibitory concentration at 24 h of 7.4 µg/ml in U251MG cells and 8.6 µg/ml in U87MG cells, respectively. Nuclear fluorescent staining and electron microscopy showed that saponin 1 caused characteristic apoptotic morphological changes in the GBM cell lines. Saponin 1-induced apoptosis was also verified by DNA ladder electrophoresis and flow cytometry. Additionally, immunocytochemistry and western blotting analyses revealed a time-dependent decrease in the expression and nuclear location of NF-κB following saponin 1 treatment. Western blotting data indicated a significant decreased expression of inhibitors of apoptosis (IAP) family members,(e.g., survivin and XIAP) by saponin 1. Moreover, saponin 1 caused a decrease in the Bcl-2/Bax ratio and initiated apoptosis by activating caspase-9 and caspase-3 in the GBM cell lines. These findings indicate that saponin 1 inhibits cell growth of GBM cells at least partially by inducing apoptosis and inhibiting survival signaling mediated by NF-κB. In addition, in vivo study also demonstrated an obvious inhibition of saponin 1 treatment on the tumor growth of U251MG and U87MG cells-produced xenograft tumors in nude mice. Given the minimal toxicities of saponin 1 in non-neoplastic astrocytes, our results suggest that saponin 1 exhibits significant in vitro and in vivo anti-tumor efficacy and merits further investigation as a potential therapeutic agent for GBM. PMID:24278406

  10. Saponin 1 induces apoptosis and suppresses NF-κB-mediated survival signaling in glioblastoma multiforme (GBM.

    Juan Li

    Full Text Available Saponin 1 is a triterpeniod saponin extracted from Anemone taipaiensis, a traditional Chinese medicine against rheumatism and phlebitis. It has also been shown to exhibit significant anti-tumor activity against human leukemia (HL-60 cells and human hepatocellular carcinoma (Hep-G2 cells. Herein we investigated the effect of saponin 1 in human glioblastoma multiforme (GBM U251MG and U87MG cells. Saponin 1 induced significant growth inhibition in both glioblastoma cell lines, with a 50% inhibitory concentration at 24 h of 7.4 µg/ml in U251MG cells and 8.6 µg/ml in U87MG cells, respectively. Nuclear fluorescent staining and electron microscopy showed that saponin 1 caused characteristic apoptotic morphological changes in the GBM cell lines. Saponin 1-induced apoptosis was also verified by DNA ladder electrophoresis and flow cytometry. Additionally, immunocytochemistry and western blotting analyses revealed a time-dependent decrease in the expression and nuclear location of NF-κB following saponin 1 treatment. Western blotting data indicated a significant decreased expression of inhibitors of apoptosis (IAP family members,(e.g., survivin and XIAP by saponin 1. Moreover, saponin 1 caused a decrease in the Bcl-2/Bax ratio and initiated apoptosis by activating caspase-9 and caspase-3 in the GBM cell lines. These findings indicate that saponin 1 inhibits cell growth of GBM cells at least partially by inducing apoptosis and inhibiting survival signaling mediated by NF-κB. In addition, in vivo study also demonstrated an obvious inhibition of saponin 1 treatment on the tumor growth of U251MG and U87MG cells-produced xenograft tumors in nude mice. Given the minimal toxicities of saponin 1 in non-neoplastic astrocytes, our results suggest that saponin 1 exhibits significant in vitro and in vivo anti-tumor efficacy and merits further investigation as a potential therapeutic agent for GBM.

  11. TIM-3 Suppresses Anti-CD3/CD28-Induced TCR Activation and IL-2 Expression through the NFAT Signaling Pathway.

    Brian Tomkowicz

    Full Text Available TIM-3 (T cell immunoglobulin and mucin-domain containing protein 3 is a member of the TIM family of proteins that is preferentially expressed on Th1 polarized CD4+ and CD8+ T cells. Recent studies indicate that TIM-3 serves as a negative regulator of T cell function (i.e. T cell dependent immune responses, proliferation, tolerance, and exhaustion. Despite having no recognizable inhibitory signaling motifs, the intracellular tail of TIM-3 is apparently indispensable for function. Specifically, the conserved residues Y265/Y272 and surrounding amino acids appear to be critical for function. Mechanistically, several studies suggest that TIM-3 can associate with interleukin inducible T cell kinase (ITK, the Src kinases Fyn and Lck, and the p85 phosphatidylinositol 3-kinase (PI3K adaptor protein to positively or negatively regulate IL-2 production via NF-κB/NFAT signaling pathways. To begin to address this discrepancy, we examined the effect of TIM-3 in two model systems. First, we generated several Jurkat T cell lines stably expressing human TIM-3 or murine CD28-ECD/human TIM-3 intracellular tail chimeras and examined the effects that TIM-3 exerts on T cell Receptor (TCR-mediated activation, cytokine secretion, promoter activity, and protein kinase association. In this model, our results demonstrate that TIM-3 inhibits several TCR-mediated phenotypes: i NF-kB/NFAT activation, ii CD69 expression, and iii suppression of IL-2 secretion. To confirm our Jurkat cell observations we developed a primary human CD8+ cell system that expresses endogenous levels of TIM-3. Upon TCR ligation, we observed the loss of NFAT reporter activity and IL-2 secretion, and identified the association of Src kinase Lck, and PLC-γ with TIM-3. Taken together, our results support the conclusion that TIM-3 is a negative regulator of TCR-function by attenuating activation signals mediated by CD3/CD28 co-stimulation.

  12. Is All Human Hearing Cochlear?

    Seyede Faranak Emami

    2013-01-01

    Full Text Available The objective of this cross-sectional study was to investigate the possibility that the saccule may contribute to human hearing. The forty participants included twenty healthy people and twenty other subjects selected from patients who presented with benign paroxysmal positional vertigo to Audiology Department of Hazrat Rasoul Akram hospital (Tehran, Iran. Assessments comprised of audiological evaluations, cervical vestibular evoked myogenic potentials (cVEMPs, recognition of spoken phonemes in white noise (Rsp in wn, and auditory brainstem response to 500 Hz tone burst (ABR500 HZ. Twenty affected ears with decreased vestibular excitability as detected by abnormal cVEMPs revealed decreased scores of Rsp in wn and abnormal findings of ABR500 HZ. Both unaffected and normal ears had normal results. Multiple comparisons of mean values of cVEMPs and ABR500 HZ between three groups were significant (P<0.05, ANOVA. The correlation between RSP in wn and p13 latencies was significant. The peak-to-peak amplitudes showed significant correlation to RSP in wn. The correlation between RSP in wn and the latencies of n23 was significant. In high-level of noisy competing situations, healthy human saccular sensation can mediate the detection of low frequencies and possibly help in cochlear hearing for frequency and intensity discrimination. So, all human hearing is not cochlear.

  13. Cochlear implant: the family's perspective.

    Vieira, Sheila de Souza; Dupas, Giselle; Chiari, Brasilia Maria

    2018-07-01

    To understand the family's experience of a child who uses a cochlear implant (CI). Specifically, to identify the difficulties, changes, and feelings entailed by deafness and the use of the CI; the coping strategies; and to understand the role of the family for the child with a CI. Qualitative research, using Symbolic Interactionism and Straussian Grounded Theory as the theoretical and methodological frameworks, respectively. Data collection instrument: semi-structured interview. A total of 9 families (32 individuals) participated in the study. The children's ages ranged from 6 to 11 years old (mean = 8.9 years old). Their experience is described in the following categories: Having to fight for results, Coping with difficult situations, Recognizing that you are not alone, Learning to overcome, and Having one's life restored by the implant. Cochlear implantation changes the direction of the child and the family's life by restoring the child's opportunity to hear and to obtain good results in her personal, social, and academic development. Even after implantation, the child continues to experience difficulties and requires the family's mobilization in order to be successful. The family is the principal actor in the process of the child's rehabilitation.

  14. Investigation of Balance Function Using Dynamic Posturography under Electrical-Acoustic Stimulation in Cochlear Implant Recipients

    B. Schwab

    2010-01-01

    Full Text Available Introduction. The purpose of the present study is to investigate the effect of electrical-acoustic stimulation on vestibular function in CI patients by using the EquiTest and to help answer the question of whether electrically stimulating the inner ear using a cochlear implant influences the balance system in any way. Material and Methods. A test population (=50 was selected at random from among the cochlear implant recipients. Dynamic posturography (using the EquiTest was performed with the device switched off an switched on. Results. In summary, it can be said that an activated cochlear implant affects the function of the vestibular system and may, to an extent, even lead to a stabilization of balance function under the static conditions of dynamic posturography, but nevertheless also to a significant destabilization. Significant improvements in vestibular function were seen mainly in equilibrium scores under conditions 4 and 5, the composite equilibrium score, and the vestibular components as revealed by sensory analysis. Conclusions. Only under the static conditions are significantly poorer scores achieved when stimulation is applied. It may be that the explanation for any symptoms of dizziness lies precisely in the fact that they occur in supposedly noncritical situations, since, when the cochlear implant makes increased demands on the balance system, induced disturbances can be centrally suppressed.

  15. Berberine ameliorates chronic kidney injury caused by atherosclerotic renovascular disease through the suppression of NFκB signaling pathway in rats.

    Xin Wan

    chronic renal injury in rats with ARD, and that BBR can act against proinflammatory and profibrotic responses through suppression of the NFκB signaling pathway.

  16. Atorvastatin induces bile acid-synthetic enzyme Cyp7a1 by suppressing FXR signaling in both liver and intestine in mice[S

    Fu, Zidong Donna; Cui, Julia Yue; Klaassen, Curtis D.

    2014-01-01

    Statins are effective cholesterol-lowering drugs to treat CVDs. Bile acids (BAs), the end products of cholesterol metabolism in the liver, are important nutrient and energy regulators. The present study aims to investigate how statins affect BA homeostasis in the enterohepatic circulation. Male C57BL/6 mice were treated with atorvastatin (100 mg/kg/day po) for 1 week, followed by BA profiling by ultra-performance LC-MS/MS. Atorvastatin decreased BA pool size, mainly due to less BA in the intestine. Surprisingly, atorvastatin did not alter total BAs in the serum or liver. Atorvastatin increased the ratio of 12α-OH/non12α-OH BAs. Atorvastatin increased the mRNAs of the BA-synthetic enzymes cholesterol 7α-hydroxylase (Cyp7a1) (over 10-fold) and cytochrome P450 27a1, the BA uptake transporters Na+/taurocholate cotransporting polypeptide and organic anion transporting polypeptide 1b2, and the efflux transporter multidrug resistance-associated protein 2 in the liver. Noticeably, atorvastatin suppressed the expression of BA nuclear receptor farnesoid X receptor (FXR) target genes, namely small heterodimer partner (liver) and fibroblast growth factor 15 (ileum). Furthermore, atorvastatin increased the mRNAs of the organic cation uptake transporter 1 and cholesterol efflux transporters Abcg5 and Abcg8 in the liver. The increased expression of BA-synthetic enzymes and BA transporters appear to be a compensatory response to maintain BA homeostasis after atorvastatin treatment. The Cyp7a1 induction by atorvastatin appears to be due to suppressed FXR signaling in both the liver and intestine. PMID:25278499

  17. Curcumin inhibits osteoclastogenic potential in PBMCs from rheumatoid arthritis patients via the suppression of MAPK/RANK/c-Fos/NFATc1 signaling pathways.

    Shang, Wei; Zhao, Ling-Jie; Dong, Xiao-Lei; Zhao, Zhi-Ming; Li, Jing; Zhang, Bei-Bei; Cai, Hui

    2016-10-01

    The aim of the present study was to determine the effects of curcumin on the osteoclastogenic potential of peripheral blood mononuclear cells (PBMCs) obtained from patients with rheumatoid arthritis (RA), and to investigate the underlying molecular mechanisms. PBMCs from patients with RA (n=12) and healthy controls (n=10) were cultured to assess osteoclastogenic potential. The number of tartrate‑resistant acid phosphatase‑positive osteoclasts differentiated from PBMCs isolated from patients with RA was significantly increased compared with that of the healthy controls. In addition, the osteoclast number in patients with RA was correlated with the clinical indicators, Sharp score (r=0.810; P=0.001) and lumbar T‑score (r=‑0.685; P=0.014). Furthermore, the resorption area was increased in the RA group compared with the healthy controls. The mRNA and protein expression levels in PBMC‑derived osteoclasts treated with curcumin were measured by reverse transcription‑quantitative polymerase chain reaction and western blotting, respectively. Curcumin inhibited the osteoclastogenic potential of PBMCs, potentially by suppressing activation of extracellular signal‑regulated kinases 1 and 2, p38 and c‑Jun N‑terminal kinase, and inhibiting receptor activator of nuclear factor κB (RANK), c‑Fos and nuclear factor of activated T cells (NFATc1) expression. The results of the present study demonstrated that curcumin may inhibit the osteoclastogenic potential of PBMCs from patients with RA through the suppression of the mitogen‑activated protein kinase/RANK/c‑Fos/NFATc1 signaling pathways, and that curcumin may be a potential novel therapeutic agent for the treatment of bone deterioration in inflammatory diseases such as RA.

  18. Long noncoding RNA CASC2 predicts the prognosis of glioma patients and functions as a suppressor for gliomas by suppressing Wnt/β-catenin signaling pathway

    Wang R

    2017-07-01

    Full Text Available Ronglin Wang,1,* Yuqian Li,1,* Gang Zhu,1,* Bo Tian,1 Wen Zeng,1 Yang Yang,2 Zhihong Li1 1Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, 2Department of Neurosurgery, The 451th hospital of PLA, Xi’an, Shaanxi, People’s Republic of China *These authors contributed equally to this work Background: Previous studies have demonstrated that long noncoding RNA cancer susceptibility candidate 2 (lncRNA CASC2 is frequently downregulated in several types of tumors and functions as a tumor-suppressive factor. However, the clinical significance and function of CASC2 in human glioma remain largely unknown. The purpose of this study was to identify the clinical values of CASC2, as well as investigate the potential molecular mechanisms in glioma. Methods: This retrospective study first analyzed the expression levels of CASC2 using quantitative real-time polymerase chain reaction. Then, CASC2 expression levels were associated with various clinicopathologic characteristics and the survival rate of patients with glioma. Finally, the function and underlying molecular mechanisms of CASC2 in human glioma were investigated in U251 cell line. Results: By quantitative real-time polymerase chain reaction analysis, our data showed that CASC2 expression was significantly downregulated in glioma tissues and cell lines (U87 and U251 compared to adjacent normal brain tissues or normal human astrocytes. Moreover, its expression negatively correlated with tumor grade in glioma patients. Furthermore, Kaplan–Meier curves with log-rank analysis revealed a close correlation between downregulated CASC2 and shorter survival time in glioma patients. In addition, Cox regression analysis indicated that CASC2 could be considered as an independent risk factor for poor prognosis. Finally, in vitro experiment demonstrated that CASC2 overexpression remarkably suppressed glioma cell proliferation, migration, and invasion through suppressing Wnt

  19. Knockdown of human serine/threonine kinase 33 suppresses human small cell lung carcinoma by blocking RPS6/BAD signaling transduction.

    Sun, E L; Liu, C X; Ma, Z X; Mou, X Y; Mu, X A; Ni, Y H; Li, X L; Zhang, D; Ju, Y R

    2017-01-01

    Small cell lung cancer (SCLC) is characterized by rapid growth rate and a tendency to metastasize to distinct sites of patients' bodies. The human serine/threonine kinase 33 (STK33) gene has shown its potency as a therapeutic target for prevention of lung carcinomas including non-small cell lung cancer (NSCLC), but its function in the oncogenesis and development of SCLC remains unrevealed. In the current study, it was hypothesized that STK33 played a key role in the proliferation, survival, and invasion of SCLC cells. The expression of STK33 in human SCLC cell lines NCI-H466 and DMS153 was inhibited by specific shRNA. The cell proliferation, cell apoptosis, and cell invasion of the cells were assessed with a series of in vitro assays. To explore the mechanism through which STK33 gene exerted its function in the carcinogenesis of SCLC cells, the effect of STK33 knockdown on the activity of S6K1/RPS6/BAD signaling was detected. Then the results were further confirmed with STK33 inhibitor ML281 and in vivo assays. The results demonstrated that inhibition of STK33 in SCLC cells suppressed the cell proliferation and invasion while induced cell apoptosis. Associated with the change in the phenotypic features, knockdown of STK33 also decreased the phosphorylation of RPS6 and BAD while increased the expression of cleaved caspase 9, indicating that apoptosis induced by STK33 suppression was mediated via mitochondrial pathway. Similar to the results of STK33 knockdown, incubating NCI-H466 cells with STK33 inhibitor also reduced the cell viability by suppressing RPS6/BAD pathways. Additionally, STK33 knockdown also inhibited tumor growth and RPS6/BAD activity in mice models. Findings outlined in our study were different from that in NSCLC to some extent: knockdown of STK33 in SCLC cells induced the apoptosis through mitochondrial pathway but independent of S6K1 function, inferring that the function of STK33 might be cancer type specific.

  20. Cochlear implant: what the radiologist should know

    Gomes, Natalia Delage; Couto, Caroline Laurita Batista; Gaiotti, Juliana Oggioni; Costa, Ana Maria Doffemond; Ribeiro, Marcelo Almeida; Diniz, Renata Lopes Furletti Caldeira

    2013-01-01

    Cochlear implant is the method of choice in the treatment of deep sensorineural hypoacusis, particularly in patients where conventional amplification devices do not imply noticeable clinical improvement. Imaging findings are crucial in the indication or contraindication for such surgical procedure. In the assessment of the temporal bone, radiologists should be familiar with relative or absolute contraindication factors, as well as with factors that might significantly complicate the implantation. Some criteria such as cochlear nerve aplasia, labyrinthine and/or cochlear aplasia are still considered as absolute contraindications, in spite of studies bringing such criteria into question. Cochlear dysplasias constitute relative contraindications, among them labyrinthitis ossificans is highlighted. Other alterations may be mentioned as complicating agents in the temporal bone assessment, namely, hypoplasia of the mastoid process, aberrant facial nerve, otomastoiditis, otosclerosis, dehiscent jugular bulb, enlarged endolymphatic duct and sac. The experienced radiologist assumes an important role in the evaluation of this condition. (author)

  1. Cochlear implant: what the radiologist should know

    Natalia Delage Gomes

    2013-06-01

    Full Text Available Cochlear implant is the method of choice in the treatment of deep sensorineural hypoacusis, particularly in patients where conventional amplification devices do not imply noticeable clinical improvement. Imaging findings are crucial in the indication or contraindication for such surgical procedure. In the assessment of the temporal bone, radiologists should be familiar with relative or absolute contraindication factors, as well as with factors that might significantly complicate the implantation. Some criteria such as cochlear nerve aplasia, labyrinthine and/or cochlear aplasia are still considered as absolute contraindications, in spite of studies bringing such criteria into question. Cochlear dysplasias constitute relative contraindications, among them labyrinthitis ossificans is highlighted. Other alterations may be mentioned as complicating agents in the temporal bone assessment, namely, hypoplasia of the mastoid process, aberrant facial nerve, otomastoiditis, otosclerosis, dehiscent jugular bulb, enlarged endolymphatic duct and sac. The experienced radiologist assumes an important role in the evaluation of this condition.

  2. Cochlear anatomy: CT and MR imaging

    Martinez, Manuel; Bruno, Claudio; Martin, Eduardo; Canale, Nancy; De Luca, Laura; Spina, Juan C. h

    2002-01-01

    The authors present a brief overview of the normal cochlear anatomy with CT and MR images in order to allow a more complete identification of the pathological findings in patients with perceptive hipoacusia. (author)

  3. 3D-Flair sequence at 3T in cochlear otosclerosis

    Lombardo, Francesco; De Cori, Sara; Aghakhanyan, Gayane; Montanaro, Domenico; De Marchi, Daniele; Frijia, Francesca; Canapicchi, Raffaello [Fondazione CNR Regione Toscana ' ' G. Monasterio' ' , Neuroradiology Unit, Pisa (Italy); Fortunato, Susanna; Forli, Francesca; Berrettini, Stefano [University of Pisa, ENT Audiology Phoniatry Unit, Department of Neuroscience, Pisa (Italy); Chiappino, Dante [Fondazione CNR Regione Toscana ' ' G. Monasterio' ' , Department of Radiology, Massa (Italy)

    2016-10-15

    To assess the capability of three-dimensional fluid-attenuated inversion recovery (3D-FLAIR) sequences in detecting signal alterations of the endolabyrinthine fluid in patients with otosclerosis. 3D-FLAIR before and after (-/+) gadolinium (Gd) administration was added to the standard MR protocol and acquired in 13 patients with a clinical/audiological diagnosis of severe/profound hearing loss in otosclerosis who were candidates for cochlear implantation and in 11 control subjects using 3-T magnetic resonance imaging (MRI) equipment. The MRI signal of the fluid-filled cochlea was assessed both visually and calculating the signal intensity ratio (SIR = signal intensity cochlea/brainstem). We revealed no endocochlear signal abnormalities on T1-weighted -/+ Gd images for either group, while on 3D-FLAIR we found bilateral hyperintensity with enhancement after Gd administration in eight patients and bilateral hyperintensity without enhancement in one patient. No endocochlear signal abnormalities were detected in other patients or the control group. Using 3-T MRI equipment, the 3D-FLAIR -/+ Gd sequence is able to detect the blood-labyrinth barrier (BLB) breakdown responsible for alterations of the endolabyrinthine fluid in patients with cochlear otosclerosis. We believe that 3D-FLAIR +/- Gd is an excellent imaging modality to assess the intra-cochlear damage in otosclerosis patients. (orig.)

  4. 3D-Flair sequence at 3T in cochlear otosclerosis

    Lombardo, Francesco; De Cori, Sara; Aghakhanyan, Gayane; Montanaro, Domenico; De Marchi, Daniele; Frijia, Francesca; Canapicchi, Raffaello; Fortunato, Susanna; Forli, Francesca; Berrettini, Stefano; Chiappino, Dante

    2016-01-01

    To assess the capability of three-dimensional fluid-attenuated inversion recovery (3D-FLAIR) sequences in detecting signal alterations of the endolabyrinthine fluid in patients with otosclerosis. 3D-FLAIR before and after (-/+) gadolinium (Gd) administration was added to the standard MR protocol and acquired in 13 patients with a clinical/audiological diagnosis of severe/profound hearing loss in otosclerosis who were candidates for cochlear implantation and in 11 control subjects using 3-T magnetic resonance imaging (MRI) equipment. The MRI signal of the fluid-filled cochlea was assessed both visually and calculating the signal intensity ratio (SIR = signal intensity cochlea/brainstem). We revealed no endocochlear signal abnormalities on T1-weighted -/+ Gd images for either group, while on 3D-FLAIR we found bilateral hyperintensity with enhancement after Gd administration in eight patients and bilateral hyperintensity without enhancement in one patient. No endocochlear signal abnormalities were detected in other patients or the control group. Using 3-T MRI equipment, the 3D-FLAIR -/+ Gd sequence is able to detect the blood-labyrinth barrier (BLB) breakdown responsible for alterations of the endolabyrinthine fluid in patients with cochlear otosclerosis. We believe that 3D-FLAIR +/- Gd is an excellent imaging modality to assess the intra-cochlear damage in otosclerosis patients. (orig.)

  5. Suppression of NF-κB signaling and NLRP3 inflammasome activation in macrophages is responsible for the amelioration of experimental murine colitis by the natural compound fraxinellone

    Wu, Xue-Feng; Ouyang, Zi-Jun; Feng, Li-Li; Chen, Gong; Guo, Wen-Jie; Shen, Yan; Wu, Xu-Dong; Sun, Yang, E-mail: yangsun@nju.edu.cn; Xu, Qiang, E-mail: molpharm@163.com

    2014-11-15

    Inflammatory bowel disease (IBD) affects millions of people worldwide. Although the etiology of this disease is uncertain, accumulating evidence indicates a key role for the activated mucosal immune system. In the present study, we examined the effects of the natural compound fraxinellone on dextran sulfate sodium (DSS)-induced colitis in mice, an animal model that mimics IBD. Treatment with fraxinellone significantly reduced weight loss and diarrhea in mice and alleviated the macroscopic and microscopic signs of the disease. In addition, the activities of myeloperoxidase and alkaline phosphatase were markedly suppressed, while the levels of glutathione were increased in colitis tissues following fraxinellone treatment. This compound also decreased the colonic levels of interleukin (IL)-1β, IL-6, IL-18 and tumor necrosis factor (TNF)-α in a concentration-dependent manner. These effects of fraxinellone in mice with experimental colitis were attributed to its inhibition of CD11b{sup +} macrophage infiltration. The mRNA levels of macrophage-related molecules in the colon, including intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX2), were also markedly inhibited following fraxinellone treatment. The results from in vitro assays showed that fraxinellone significantly reduced lipopolysaccharide (LPS)-induced production of nitric oxide (NO), IL-1β and IL-18 as well as the activity of iNOS in both THP-1 cells and mouse primary peritoneal macrophages. The mechanisms responsible for these effects were attributed to the inhibitory role of fraxinellone in NF-κB signaling and NLRP3 inflammasome activation. Overall, our results support fraxinellone as a novel drug candidate in the treatment of colonic inflammation. - Highlights: • Fraxinellone, a lactone compound, alleviated DSS induced colitis. • The effects of fraxinellone were attributed to its inhibition on

  6. A DC-81-indole conjugate agent suppresses melanoma A375 cell migration partially via interrupting VEGF production and stromal cell-derived factor-1α-mediated signaling

    Hsieh, Ming-Chu; Hu, Wan-Ping; Yu, Hsin-Su; Wu, Wen-Chuan; Chang, Long-Sen; Kao, Ying-Hsien; Wang, Jeh-Jeng

    2011-01-01

    Pyrrolo[2,1-c][1,4]benzodiazepine (PBD) chemicals are antitumor antibiotics inhibiting nucleic acid synthesis. An indole carboxylate-PBD hybrid with six-carbon spacer structure (IN6CPBD) has been previously demonstrated to induce melanoma cell apoptosis and reduce metastasis in mouse lungs. This study aimed at investigating the efficacy of the other hybrid compound with four-carbon spacer (IN4CPBD) and elucidating its anti-metastatic mechanism. Human melanoma A375 cells with IN4CPBD treatment underwent cytotoxicity and apoptosis-associated assays. Transwell migration assay, Western blotting, and ELISA were used for mechanistic study. IN4CPBD exhibited potent melanoma cytotoxicity through interrupting G1/S cell cycle progression, increasing DNA fragmentation and hypodipoidic DNA contents, and reducing mitochondrial membrane potential. Caspase activity elevation suggested that both intrinsic and extrinsic pathways were involved in IN4CPBD-induced melanoma apoptosis. IN4CPBD up-regulated p53 and p21, thereby concomitantly derailing the equilibrium between Bcl-2 and Bax levels. Transwell migration assay demonstrated that stromal cell-derived factor-1α (SDF-1α) stimulated A375 cell motility, while kinase inhibitors treatment confirmed that Rho/ROCK, Akt, ERK1/2, and p38 MAPK pathways were involved in SDF-1α-enhanced melanoma migration. IN4CPBD not only abolished the SDF-1α-enhanced chemotactic motility but also suppressed constitutive MMP-9 and VEGF expression. Mechanistically, IN4CPBD down-regulated Akt, ERK1/2, and p38 MAPK total proteins and MYPT1 phosphorylation. In conclusion, beyond the fact that IN4CPBD induces melanoma cell apoptosis at cytotoxic dose, the interruption in the VEGF expression and the SDF-1α-related signaling at cytostatic dose may partially constitute the rationale for its in vivo anti-metastatic potency. - Research highlights: → A novel carboxylate-PBD hybrid as anti-melanoma drug. → IN4CPBD interrupts melanoma cell cycle progression

  7. The hearing benefit of cochlear implantation for individuals with unilateral hearing loss, but no tinnitus.

    Skarzynski, Henryk; Lorens, Artur; Kruszynska, Marika; Obrycka, Anita; Pastuszak, Dorota; Skarzynski, Piotr Henryk

    2017-07-01

    Cochlear implants improve the hearing abilities of individuals with unilateral hearing loss and no tinnitus. The benefit is no different from that seen in patients with unilateral hearing loss and incapacitating tinnitus. To evaluate hearing outcomes after cochlear implantation in individuals with unilateral hearing loss and no tinnitus and compare them to those obtained in a similar group who had incapacitating tinnitus. Six cases who did not experience tinnitus before operation and 15 subjects with pre-operative tinnitus were evaluated with a structured interview, a monosyllabic word test under difficult listening situations, a sound localization test, and an APHAB (abbreviated profile of hearing aid benefit) questionnaire. All subjects used their cochlear implant more than 8 hours a day, 7 days a week. In 'no tinnitus' patients, mean benefit of cochlear implantation was 19% for quiet speech, 15% for speech in noise (with the same signal-to-noise ratio in the implanted and non-implanted ear), and 16% for a more favourable signal-to-noise ratio at the implanted ear. Sound localization error improved by an average of 19°. The global score of APHAB improved by 16%. The benefits across all evaluations did not differ significantly between the 'no tinnitus' and 'tinnitus' groups.

  8. [Cochlear implantation through the middle fossa approach].

    Szyfter, W; Colletti, V; Pruszewicz, A; Kopeć, T; Szymiec, E; Kawczyński, M; Karlik, M

    2001-01-01

    The inner part of cochlear implant is inserted into inner ear during surgery through mastoid and middle ear. It is a classical method, used in the majority cochlear centers in the world. This is not a suitable method in case of chronic otitis media and middle ear malformation. In these cases Colletti proposed the middle fossa approach and cochlear implant insertion omitting middle ear structures. In patient with bilateral chronic otitis media underwent a few ears operations without obtaining dry postoperative cavity. Cochlear implantation through the middle fossa approach was performed in this patient. The bone fenster was cut, temporal lobe was bent and petrosus pyramid upper surface was exposed. When the superficial petrosal greater nerve, facial nerve and arcuate eminence were localised, the cochlear was open in the basal turn and electrode were inserted. The patient achieves good results in the postoperative speech rehabilitation. It confirmed Colletti tesis that deeper electrode insertion in the cochlear implantation through the middle fossa approach enable use of low and middle frequencies, which are very important in speech understanding.

  9. Suppression of NF-κB signal pathway by NLRC3-like protein in stony coral Acropora aculeus under heat stress.

    Zhou, Zhi; Wu, Yibo; Zhang, Chengkai; Li, Can; Chen, Guangmei; Yu, Xiaopeng; Shi, Xiaowei; Xu, Yanlai; Wang, Lingui; Huang, Bo

    2017-08-01

    Heat stress is the most common factor for coral bleaching, which has increased both in frequency and severity due to global warming. In the present study, the stony coral Acropora aculeus was subjected to acute heat stress and entire transcriptomes were sequenced via the next generation sequencing platform. Four paired-end libraries were constructed and sequenced in two groups, including a control and a heat stress group. A total of 120,319,751 paired-end reads with lengths of 2 × 100 bp were assembled and 55,021 coral-derived genes were obtained. After read mapping and abundance estimation, 9110 differentially expressed genes were obtained in the comparison between the control and heat stress group, including 4465 significantly upregulated and 4645 significantly downregulated genes. Twenty-three GO terms in the Biological Process category were overrepresented for significantly upregulated genes, and divided into six groups according to their relationship. These three groups were related to the NF-κB signal pathway, and the remaining three groups were relevant for pathogen response, immunocyte activation and protein ubiquitination. Forty-three common genes were found in four GO terms, which were directly related to the NF-κB signal pathway. These included 2 NACHT, LRR, PYD domains-containing protein, 5 nucleotide-binding oligomerization domain-containing protein, 29 NLRC3-like protein, 4 NLRC5-like protein, and 3 uncharacterized protein. For significantly downregulated genes, 27 overrepresented GO terms were found in the Biological Process category, which were relevant to protein ubiquitination and ATP metabolism. Our results indicate that heat stress suppressed the immune response level via the NLRC3-like protein, the fine-tuning of protein turnover activity, and ATP metabolism. This might disrupt the balance of coral-zooxanthellae symbiosis and result in the bleaching of the coral A. aculeus. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Chemoprevention by Quercetin of Oral Squamous Cell Carcinoma by Suppression of the NF-κB Signaling Pathway in DMBA-treated Hamsters.

    Zhang, Wen; Yin, Gang; Dai, Jianguo; Sun, Y U; Hoffman, Robert M; Yang, Zhijian; Fan, Yuan

    2017-08-01

    The aim of this study was to investigate the effects of the flavonoid quercetin on chemoprevention of oral squamous cell carcinoma (OSCC). The study involved molecular signaling pathways in 7,12-dimethylbenz(a) anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis. DMBA (0.5%) was painted at the right buccal pouches of hamsters for 14 weeks to induce carcinoma. DMBA-treated hamsters received simultaneous doses of quercetin. Animals without DMBA induction were used as normal controls. The incidence of OSCC and the severity of pre-malignant lesions were determined histologically. Apoptosis in the pouch tissue was determined by TUNEL staining. The mRNA and protein expression of NF-κB p50 and p65, as well as Bcl-2 and Bax genes were analyzed using RT-PCR and Western blotting, respectively. Quercetin, at various doses, significantly reduced OSCC incidence and severity of hyperplasia and dysplasia compared to the DMBA-induction-only group (p<0.01). Apoptosis was induced by quercetin treatment compared to the DMBA-induction-only group (p<0.01). mRNA and protein expression of NF-κB p50, p65 as well as Bcl-2 genes were significantly suppressed by quercetin at high doses compared to DMBA induction only (p<0.05). However, mRNA and protein expression of the Bax gene was increased by quercetin treatment at medium and high doses, compared to the DMBA-induction-only group (p<0.05). Quercetin significantly reduced body-weight loss compared to the DMBA-induction-only group (p<0.05). Quercetin reduced tumor incidence and induced apoptosis through modulation of NF-κB signaling and its target genes Bcl-2 and Bax in the DMBA-induced carcigenesis hamster model, suggesting the potential of quercetin as a candidate for OSCC chemoprevention. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  11. Cortical Plasticity after Cochlear Implantation

    Petersen, Bjørn; Gjedde, Albert; Wallentin, Mikkel

    2013-01-01

    recently implanted adult implant recipients listened to running speech or speech-like noise in four sequential PET sessions at each milestone. CI listeners with postlingual hearing loss showed differential activation of left superior temporal gyrus during speech and speech-like stimuli, unlike CI listeners...... with prelingual hearing loss. Furthermore, Broca's area was activated as an effect of time, but only in CI listeners with postlingual hearing loss. The study demonstrates that adaptation to the cochlear implant is highly related to the history of hearing loss. Speech processing in patients whose hearing loss...... occurred after the acquisition of language involves brain areas associated with speech comprehension, which is not the case for patients whose hearing loss occurred before the acquisition of language. Finally, the findings confirm the key role of Broca's area in restoration of speech perception, but only...

  12. Music enjoyment with cochlear implantation.

    Prevoteau, Charlotte; Chen, Stephanie Y; Lalwani, Anil K

    2018-10-01

    Since the advent of cochlear implant (CI) surgery in the 1960s, there have been remarkable technological and surgical advances enabling excellent speech perception in quiet with many CI users able to use the telephone. However, many CI users struggle with music perception, particularly with the pitch-based and melodic elements of music. Yet remarkably, despite poor music perception, many CI users enjoy listening to music based on self-report questionnaires, and prospective studies have suggested a disassociation between music perception and enjoyment. Music enjoyment is arguably a more functional measure of one's listening experience, and thus enhancing one's listening experience is a worthy goal. Recent studies have shown that re-engineering music to reduce its complexity may enhance enjoyment in CI users and also delineate differences in musical preferences from normal hearing listeners. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. A paraptosis-like cell death induced by δ-tocotrienol in human colon carcinoma SW620 cells is associated with the suppression of the Wnt signaling pathway

    Zhang, Jing-Shu; Li, Da-Ming; He, Ning; Liu, Ying-Hua; Wang, Chun-Hua; Jiang, Shu-Qing; Chen, Bing-Qing; Liu, Jia-Ren

    2011-01-01

    Tocotrienol is considered a beneficial effect agent on inhibition of tumor development. In this study, we focused on the effects of δ-tocotrienol and its possible mechanism on induction of death in human colon cancer SW620 cells. δ-Tocotrienol inhibited proliferation of SW620 cell in a dose-dependent manner. Our findings showed that δ-tocotrienol effectively induced paraptosis-like death in SW620 cells, correlated with the vacuolation that may be from welling and fusion of mitochondria and/or the endoplasmic reticulum (ER) as well as caspase-3 nonactivated. However, there were no changes in apoptosis based on flow cytometry analysis. Of being noted, δ-tocotrienol reduced the expression of β-catenin and wnt-1 proteins by about 50% at the highest dose (20 μmol/L). δ-Tocotrienol also decreased cyclin D1, c-jun and MMP-7 protein levels in SW620 cells. Altogether, these data indicate that δ-tocotrienol induces paraptosis-like cell death, which is associated with the suppression of the Wnt signaling pathway. Thus, our findings may provide a novel application in treatment of human colon carcinoma.

  14. MR evaluation of breast lesions obtained by diffusion-weighted imaging with background body signal suppression (DWIBS) and correlations with histological findings.

    Moschetta, Marco; Telegrafo, Michele; Rella, Leonarda; Capolongo, Arcangela; Stabile Ianora, Amato Antonio; Angelelli, Giuseppe

    2014-07-01

    Diffusion imaging represents a new imaging tool for the diagnosis of breast cancer. This study aims to investigate the role of diffusion-weighted MRI with background body signal suppression (DWIBS) for evaluating breast lesions. 90 patients were prospectively evaluated by MRI with STIR, TSE-T2, contrast enhanced THRIVE-T1 and DWIBS sequences. DWIBS were analyzed searching for the presence of breast lesions and calculating the ADC value. ADC values of ≤1.44×10(-3)mm(2)/s were considered suspicious for malignancy. This analysis was then compared with the histological findings. Sensitivity, specificity, diagnostic accuracy (DA), positive predictive value (PPV) and negative (NPV) were calculated. In 53/90 (59%) patients, DWIBS indicated the presence of breast lesions, 16 (30%) with ADC values of >1.44 and 37 (70%) with ADC≤1.44. The comparison with histology showed 25 malignant and 28 benign lesions. DWIBS sequences obtained sensitivity, specificity, DA, PPV and NPV values of 100, 82, 87, 68 and 100%, respectively. DWIBS can be proposed in the MRI breast protocol representing an accurate diagnostic complement. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. Apple Polyphenol Suppresses Indomethacin-Induced Gastric Damage in Experimental Animals by Lowering Oxidative Stress Status and Modulating the MAPK Signaling Pathway.

    Lee, Yi-Chen; Cheng, Chun-Wen; Lee, Huei-Jane; Chu, Huei-Chuien

    2017-11-01

    Indomethacin is a nonsteroid anti-inflammatory drug (NSAID) that is used to alleviate pain and inflammation in clinical medicine. Previous studies indicated that NSAIDs can cause gastrointestinal mucosal complications, and it is associated with mucosal lipid peroxidation and oxidative damage. Based on the evidences, decreasing oxidative stress may be an ideal therapeutic strategy for preventing gastrointestinal ulcer. Apple (Rosaceae Malus sp.) is one of the most commonly consumed fruits worldwide. The abundant polyphenolic constituents have received increasing attention for decades. In both in vivo and in vitro studies, the reports showed that apple polyphenol (AP) seems to provide an indirect antioxidant protection by activating cellular antioxidant enzymes to defend against oxidative stress. To address this issue and develop AP into a healthy improvement supplement, we studied the effect and potential mechanisms of AP in indomethacin-treated animal. The results showed AP can decelerate the gastric lesion, significantly suppress lipid peroxidation, increase the level of glutathione and the activity of catalase, and regulate the MAPK signaling proteins. These findings imply that AP protects the gastric mucosa from indomethacin-caused lesions and the protection is at least partially attributable to its antioxidative properties. This alternative medical function of AP may be a safe and effective intervention for preventing indomethacin-induced gastric complications.

  16. Saponins extracted from by-product of Asparagus officinalis L. suppress tumour cell migration and invasion through targeting Rho GTPase signalling pathway.

    Wang, Jieqiong; Liu, Yali; Zhao, Jingjing; Zhang, Wen; Pang, Xiufeng

    2013-04-01

    The inedible bottom part (~30-40%) of asparagus (Asparagus officinalis L.) spears is usually discarded as waste. However, since this by-product has been reported to be rich in many bioactive phytochemicals, it might be utilisable as a supplement in foods or natural drugs for its therapeutic effects. In this study it was identifed that saponins from old stems of asparagus (SSA) exerted potential inhibitory activity on tumour growth and metastasis. SSA suppressed cell viability of breast, colon and pancreatic cancers in a concentration-dependent manner, with half-maximum inhibitory concentrations ranging from 809.42 to 1829.96 µg mL(-1). However, SSA was more functional in blocking cell migration and invasion as compared with its cytotoxic effect, with an effective inhibitory concentration of 400 µg mL(-1). A mechanistic study showed that SSA markedly increased the activities of Cdc42 and Rac1 and decreased the activity of RhoA in cancer cells. SSA inhibits tumour cell motility through modulating the Rho GTPase signalling pathway, suggesting a promising use of SSA as a supplement in healthcare foods and natural drugs for cancer prevention and treatment. © 2012 Society of Chemical Industry.

  17. Maresin 1 Ameliorates Lung Ischemia/Reperfusion Injury by Suppressing Oxidative Stress via Activation of the Nrf-2-Mediated HO-1 Signaling Pathway

    Quanchao Sun

    2017-01-01

    Full Text Available Lung ischemia/reperfusion (I/R injury occurs in various clinical conditions and heavily damaged lung function. Oxidative stress reaction and antioxidant enzymes play a pivotal role in the etiopathogenesis of lung I/R injury. In the current study, we investigated the impact of Maresin 1 on lung I/R injury and explored the possible mechanism involved in this process. MaR 1 ameliorated I/R-induced lung injury score, wet/dry weight ratio, myeloperoxidase, tumor necrosis factor, bronchoalveolar lavage fluid (BALF leukocyte count, BALF neutrophil ratio, and pulmonary permeability index levels in lung tissue. MaR 1 significantly reduced ROS, methane dicarboxylic aldehyde, and 15-F2t-isoprostane generation and restored antioxidative enzyme (superoxide dismutase, glutathione peroxidase, and catalase activities. Administration of MaR 1 improved the expression of nuclear Nrf-2 and cytosolic HO-1 in I/R-treated lung tissue. Furthermore, we also found that the protective effects of MaR 1 on lung tissue injury and oxidative stress were reversed by HO-1 activity inhibitor, Znpp-IX. Nrf-2 transcription factor inhibitor, brusatol, significantly decreased MaR 1-induced nuclear Nrf-2 and cytosolic HO-1 expression. In conclusion, these results indicate that MaR 1 protects against lung I/R injury through suppressing oxidative stress. The mechanism is partially explained by activation of the Nrf-2-mediated HO-1 signaling pathway.

  18. Methyl Gallate Inhibits Osteoclast Formation and Function by Suppressing Akt and Btk-PLCγ2-Ca2+ Signaling and Prevents Lipopolysaccharide-Induced Bone Loss.

    Baek, Jong Min; Kim, Ju-Young; Lee, Chang Hoon; Yoon, Kwon-Ha; Lee, Myeung Su

    2017-03-07

    In the field of bone research, various natural derivatives have emerged as candidates for osteoporosis treatment by targeting abnormally elevated osteoclastic activity. Methyl gallate, a plant-derived phenolic compound, is known to have numerous pharmacological effects against inflammation, oxidation, and cancer. Our purpose was to explore the relation between methyl gallate and bone metabolism. Herein, we performed screening using methyl gallate by tartrate resistant acid phosphatase (TRAP) staining and revealed intracellular mechanisms responsible for methyl gallate-mediated regulation of osteoclastogenesis by Western blotting and quantitative reverse transcription polymerase chain reaction (RT-PCR). Furthermore, we assessed the effects of methyl gallate on the characteristics of mature osteoclasts. We found that methyl gallate significantly suppressed osteoclast formation through Akt and Btk-PLCγ2-Ca 2+ signaling. The blockade of these pathways was confirmed through transduction of cells with a CA-Akt retrovirus and evaluation of Ca 2+ influx intensity (staining with Fluo-3/AM). Indeed, methyl gallate downregulated the formation of actin ring-positive osteoclasts and resorption pit areas. In agreement with in vitro results, we found that administration of methyl gallate restored osteoporotic phenotype stimulated by acute systemic injection of lipopolysaccharide in vivo according to micro-computed tomography and histological analysis. Our data strongly indicate that methyl gallate may be useful for the development of a plant-based antiosteoporotic agent.

  19. Epothilones Suppress Neointimal Thickening in the Rat Carotid Balloon-Injury Model by Inducing Vascular Smooth Muscle Cell Apoptosis through p53-Dependent Signaling Pathway.

    Son, Dong Ju; Jung, Jae Chul; Hong, Jin Tae

    2016-01-01

    Microtubule stabilizing agents (MTSA) are known to inhibit vascular smooth muscle cell (VSMC) proliferation and migration, and effectively reduce neointimal hyperplasia and restenosis. Epothilones (EPOs), non-taxane MTSA, have been found to be effective in the inhibition of VSMC proliferation and neointimal formation by cell cycle arrest. However, effect of EPOs on apoptosis in hyper-proliferated VSMCs as a possible way to reduce neointimal formation and its action mechanism related to VSMC viability has not been suited yet. Thus, the purposes of the present study was to investigate whether EPOs are able to inhibit neointimal formation by inducing apoptosis within the region of neointimal hyperplasia in balloon-injured rat carotid artery, as well as underlying action mechanism. Treatment of EPO-B and EPO-D significantly induced apoptotic cell death and mitotic catastrophe in hyper-proliferated VSMCs, resulting in cell growth inhibition. Further, EPOs significantly suppressed VSMC proliferation and induced apoptosis by activation of p53-dependent apoptotic signaling pathway, Bax/cytochrome c/caspase-3. We further demonstrated that the local treatment of carotid arteries with EPOs potently inhibited neointimal lesion formation by induction of apoptosis in rat carotid injury model. Our findings demonstrate a potent anti-neointimal hyperplasia property of EPOs by inducing p53-depedent apoptosis in hyper-proliferated VSMCs.

  20. C/EBPα Short-Activating RNA Suppresses Metastasis of Hepatocellular Carcinoma through Inhibiting EGFR/β-Catenin Signaling Mediated EMT.

    Hongbo Huan

    Full Text Available Hepatocellular carcinoma is associated with high mortality, and tumor metastasis is an important reason for poor prognosis. However, metastasis has not been effectively prevented in clinical therapy and the mechanisms underlying metastasis have not been fully characterized. CCAAT/enhancer-binding protein-α (C/EBPα is a transcriptional regulator with an essential role in tumor metastasis. We used short-activating RNAs (saRNA to enhance expression of C/EBPα. Intravenous injection of C/EBPα-saRNA in a nude mouse liver orthotopic xenograft tumor model inhibited intrahepatic and distant metastasis. C/EBPα-saRNA-treated mice showed increased serum levels of albumin and decreased alanine aminotransferase (ALT, glutamic-oxalacetic transaminase (AST, indicating a role of C/EBPα in improving liver function. Migration and invasion were inhibited in hepatoma cell lines transfected with C/EBPα-saRNA. We also observed an inhibition of epithelial-mesenchymal transition (EMT and suppression of epidermal growth factor receptor (EGFR, EGFR phosphorylation, and β-catenin in C/EBPa-saRNA-transfected cells. Our results suggested that C/EBPα-saRNA successfully inhibited HCC metastasis by inhibiting EGFR/β-catenin signaling pathway mediated EMT in vitro and in vivo.

  1. Methyl Gallate Inhibits Osteoclast Formation and Function by Suppressing Akt and Btk-PLCγ2-Ca2+ Signaling and Prevents Lipopolysaccharide-Induced Bone Loss

    Jong Min Baek

    2017-03-01

    Full Text Available In the field of bone research, various natural derivatives have emerged as candidates for osteoporosis treatment by targeting abnormally elevated osteoclastic activity. Methyl gallate, a plant-derived phenolic compound, is known to have numerous pharmacological effects against inflammation, oxidation, and cancer. Our purpose was to explore the relation between methyl gallate and bone metabolism. Herein, we performed screening using methyl gallate by tartrate resistant acid phosphatase (TRAP staining and revealed intracellular mechanisms responsible for methyl gallate-mediated regulation of osteoclastogenesis by Western blotting and quantitative reverse transcription polymerase chain reaction (RT-PCR. Furthermore, we assessed the effects of methyl gallate on the characteristics of mature osteoclasts. We found that methyl gallate significantly suppressed osteoclast formation through Akt and Btk-PLCγ2-Ca2+ signaling. The blockade of these pathways was confirmed through transduction of cells with a CA-Akt retrovirus and evaluation of Ca2+ influx intensity (staining with Fluo-3/AM. Indeed, methyl gallate downregulated the formation of actin ring-positive osteoclasts and resorption pit areas. In agreement with in vitro results, we found that administration of methyl gallate restored osteoporotic phenotype stimulated by acute systemic injection of lipopolysaccharide in vivo according to micro-computed tomography and histological analysis. Our data strongly indicate that methyl gallate may be useful for the development of a plant-based antiosteoporotic agent.

  2. Caffeine suppresses exercise-enhanced long-term and location memory in middle-aged rats: Involvement of hippocampal Akt and CREB signaling.

    Cechella, José L; Leite, Marlon R; da Rocha, Juliana T; Dobrachinski, Fernando; Gai, Bibiana M; Soares, Félix A A; Bresciani, Guilherme; Royes, Luiz F F; Zeni, Gilson

    2014-11-05

    The cognitive function decline is closely related with brain changes generated by age. The ability of caffeine and exercise to prevent memory impairment has been reported in animal models and humans. The purpose of the present study was to investigate whether swimming exercise and caffeine administration enhance memory in middle-aged Wistar rats. Male Wistar rats (18months) received caffeine at a dose of 30mg/kg, 5days per week by a period of 4weeks. Animals were subjected to swimming training with a workload (3% of body weight, 20min per day for 4weeks). After 4weeks, the object recognition test (ORT) and the object location test (OLT) were performed. The results of this study demonstrated that caffeine suppressed exercise-enhanced long-term (ORT) and spatial (OLT) memory in middle-aged and this effect may be related to a decrease in hippocampal p-CREB signaling. This study also provided evidence that the effects of this protocol on memory were not accompanied by alterations in the levels of activated Akt. The [(3)H] glutamate uptake was reduced in hippocampus of rats administered with caffeine and submitted to swimming protocol. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  3. The Human Cochlear Mechanical Nonlinearity Inferred via Psychometric Functions

    Nizami Lance

    2013-12-01

    Extension of the model of Schairer and colleagues results in credible cochlear nonlinearities in man, suggesting that forward-masking provides a non-invasive way to infer the human mechanical cochlear nonlinearity.

  4. A speech processing study using an acoustic model of a multiple-channel cochlear implant

    Xu, Ying

    1998-10-01

    A cochlear implant is an electronic device designed to provide sound information for adults and children who have bilateral profound hearing loss. The task of representing speech signals as electrical stimuli is central to the design and performance of cochlear implants. Studies have shown that the current speech- processing strategies provide significant benefits to cochlear implant users. However, the evaluation and development of speech-processing strategies have been complicated by hardware limitations and large variability in user performance. To alleviate these problems, an acoustic model of a cochlear implant with the SPEAK strategy is implemented in this study, in which a set of acoustic stimuli whose psychophysical characteristics are as close as possible to those produced by a cochlear implant are presented on normal-hearing subjects. To test the effectiveness and feasibility of this acoustic model, a psychophysical experiment was conducted to match the performance of a normal-hearing listener using model- processed signals to that of a cochlear implant user. Good agreement was found between an implanted patient and an age-matched normal-hearing subject in a dynamic signal discrimination experiment, indicating that this acoustic model is a reasonably good approximation of a cochlear implant with the SPEAK strategy. The acoustic model was then used to examine the potential of the SPEAK strategy in terms of its temporal and frequency encoding of speech. It was hypothesized that better temporal and frequency encoding of speech can be accomplished by higher stimulation rates and a larger number of activated channels. Vowel and consonant recognition tests were conducted on normal-hearing subjects using speech tokens processed by the acoustic model, with different combinations of stimulation rate and number of activated channels. The results showed that vowel recognition was best at 600 pps and 8 activated channels, but further increases in stimulation rate and

  5. In-vitro characterization of a cochlear implant system for recording of evoked compound action potentials

    2012-01-01

    Background Modern cochlear implants have integrated recording systems for measuring electrically evoked compound action potentials of the auditory nerve. The characterization of such recording systems is important for establishing a reliable basis for the interpretation of signals acquired in vivo. In this study we investigated the characteristics of the recording system integrated into the MED-EL PULSARCI100 cochlear implant, especially its linearity and resolution, in order to develop a mathematical model describing the recording system. Methods In-vitro setup: The cochlear implant, including all attached electrodes, was fixed in a tank of physiologic saline solution. Sinusoidal signals of the same frequency but with different amplitudes were delivered via a signal generator for measuring and recording on a single electrode. Computer simulations: A basic mathematical model including the main elements of the recording system, i.e. amplification and digitalization stage, was developed. For this, digital output for sinusoidal input signals of different amplitudes were calculated using in-vitro recordings as reference. Results Using an averaging of 100 measurements the recording system behaved linearly down to approximately -60 dB of the input signal range. Using the same method, a system resolution of 10 μV was determined for sinusoidal signals. The simulation results were in very good agreement with the results obtained from in-vitro experiments. Conclusions The recording system implemented in the MED-EL PULSARCI100 cochlear implant for measuring the evoked compound action potential of the auditory nerve operates reliably. The developed mathematical model provides a good approximation of the recording system. PMID:22531599

  6. Suppression of the auxin response pathway enhances susceptibility to Phytophthora cinnamomi while phosphite-mediated resistance stimulates the auxin signalling pathway

    2014-01-01

    Background Phytophthora cinnamomi is a devastating pathogen worldwide and phosphite (Phi), an analogue of phosphate (Pi) is highly effective in the control of this pathogen. Phi also interferes with Pi starvation responses (PSR), of which auxin signalling is an integral component. In the current study, the involvement of Pi and the auxin signalling pathways in host and Phi-mediated resistance to P. cinnamomi was investigated by screening the Arabidopsis thaliana ecotype Col-0 and several mutants defective in PSR and the auxin response pathway for their susceptibility to this pathogen. The response to Phi treatment was also studied by monitoring its effect on Pi- and the auxin response pathways. Results Here we demonstrate that phr1-1 (phosphate starvation response 1), a mutant defective in response to Pi starvation was highly susceptible to P. cinnamomi compared to the parental background Col-0. Furthermore, the analysis of the Arabidopsis tir1-1 (transport inhibitor response 1) mutant, deficient in the auxin-stimulated SCF (Skp1 − Cullin − F-Box) ubiquitination pathway was also highly susceptible to P. cinnamomi and the susceptibility of the mutants rpn10 and pbe1 further supported a role for the 26S proteasome in resistance to P. cinnamomi. The role of auxin was also supported by a significant (P < 0.001) increase in susceptibility of blue lupin (Lupinus angustifolius) to P. cinnamomi following treatment with the inhibitor of auxin transport, TIBA (2,3,5-triiodobenzoic acid). Given the apparent involvement of auxin and PSR signalling in the resistance to P. cinnamomi, the possible involvement of these pathways in Phi mediated resistance was also investigated. Phi (especially at high concentrations) attenuates the response of some Pi starvation inducible genes such as AT4, AtACP5 and AtPT2 in Pi starved plants. However, Phi enhanced the transcript levels of PHR1 and the auxin responsive genes (AUX1, AXR1and AXR2), suppressed the primary root

  7. Spectral-Temporal Modulated Ripple Discrimination by Children With Cochlear Implants.

    Landsberger, David M; Padilla, Monica; Martinez, Amy S; Eisenberg, Laurie S

    observed for adults. An additional finding was that SMRT score was negatively correlated with age for adults with implants. Results from this study suggest that basic psychophysical capabilities of early implanted children and postlingually implanted adults differ when assessed in the sound field using their personal implant processors. Because spectral resolution does not improve with age for early implanted children, it seems likely that the sparse representation of the signal provided by a cochlear implant limits spectral resolution development. These results are supported by the finding that postlingually implanted adults, whose auditory systems matured before the onset of hearing loss, perform significantly better than early implanted children on the spectral resolution test.

  8. C-Type Lectin-Like Receptor 2 Suppresses AKT Signaling and Invasive Activities of Gastric Cancer Cells by Blocking Expression of Phosphoinositide 3-Kinase Subunits.

    Wang, Lan; Yin, Jie; Wang, Xuefei; Shao, Miaomiao; Duan, Fangfang; Wu, Weicheng; Peng, Peike; Jin, Jing; Tang, Yue; Ruan, Yuanyuan; Sun, Yihong; Gu, Jianxin

    2016-05-01

    markers; these tumor-suppressive effects of CLEC2 required SYK. CLEC2 and SYK interacted physically, and SYK maintained the stability of CLEC2 in cells. AGS cells with CLEC2 knockdown had increased levels of phosphorylated AKT and glycogen synthase kinase-3 beta, increased expression of Snail, reduced levels of E-cadherin, and formed more metastases in mice than AGS cells that expressed CLEC2; these knockdown changes were prevented by the PI3K inhibitor LY294002. Activation of CLEC2 in AGS cells reduced protein and messenger RNA levels of PI3K subunits p85 and p110; this effect was blocked by SYK inhibitor R406. Levels of CLEC2 and SYK proteins and messenger RNAs correlated in gastric tumor samples. CLEC2 suppresses metastasis of gastric cancer cells injected into mice, and prevents activation of AKT and glycogen synthase kinase-3 beta signaling, as well as invasiveness and expression of epithelial to mesenchymal transition markers in gastric cancer cell lines. CLEC2 prevents expression of PI3K subunits, in a SYK-dependent manner. Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.

  9. Microphone directionality, pre-emphasis filter, and wind noise in cochlear implants.

    Chung, King; McKibben, Nicholas

    2011-10-01

    Wind noise can be a nuisance or a debilitating masker for cochlear implant users in outdoor environments. Previous studies indicated that wind noise at the microphone/hearing aid output had high levels of low-frequency energy and the amount of noise generated is related to the microphone directionality. Currently, cochlear implants only offer either directional microphones or omnidirectional microphones for users at-large. As all cochlear implants utilize pre-emphasis filters to reduce low-frequency energy before the signal is encoded, effective wind noise reduction algorithms for hearing aids might not be applicable for cochlear implants. The purposes of this study were to investigate the effect of microphone directionality on speech recognition and perceived sound quality of cochlear implant users in wind noise and to derive effective wind noise reduction strategies for cochlear implants. A repeated-measure design was used to examine the effects of spectral and temporal masking created by wind noise recorded through directional and omnidirectional microphones and the effects of pre-emphasis filters on cochlear implant performance. A digital hearing aid was programmed to have linear amplification and relatively flat in-situ frequency responses for the directional and omnidirectional modes. The hearing aid output was then recorded from 0 to 360° at flow velocities of 4.5 and 13.5 m/sec in a quiet wind tunnel. Sixteen postlingually deafened adult cochlear implant listeners who reported to be able to communicate on the phone with friends and family without text messages participated in the study. Cochlear implant users listened to speech in wind noise recorded at locations that the directional and omnidirectional microphones yielded the lowest noise levels. Cochlear implant listeners repeated the sentences and rated the sound quality of the testing materials. Spectral and temporal characteristics of flow noise, as well as speech and/or noise characteristics before

  10. Ascorbic acid suppresses endotoxemia and NF-κB signaling cascade in alcoholic liver fibrosis in guinea pigs: A mechanistic approach

    Abhilash, P.A.; Harikrishnan, R.; Indira, M., E-mail: indiramadambath@gmail.com

    2014-01-15

    Alcohol consumption increases the small intestinal bacterial overgrowth (SIBO) and intestinal permeability of endotoxin. The endotoxin mediated inflammatory signaling plays a major role in alcoholic liver fibrosis. We evaluated the effect of ascorbic acid (AA), silymarin and alcohol abstention on the alcohol induced endotoxemia and NF-κB activation cascade pathway in guinea pigs (Cavia porcellus). Guinea pigs were administered ethanol at a daily dose of 4 g/kg b.wt for 90 days. After 90 days, ethanol administration was stopped. The ethanol treated animals were divided into abstention, silymarin (250 mg/kg b.wt) and AA (250 mg/kg b.wt) supplemented groups and maintained for 30 days. The SIBO, intestinal permeability and endotoxin were significantly increased in the ethanol group. The mRNA expressions of intestinal proteins claudin, occludin and zona occludens-1 were significantly decreased in ethanol group. The mRNA levels of inflammatory receptors, activity of IKKβ and the protein expressions of phospho-IκBα, NF-κB, TNF-α, TGF-β{sub 1} and IL-6 were also altered in ethanol group. The expressions of fibrosis markers α-SMA, α{sub 1} (I) collagen and sirius red staining in the liver revealed the induction of fibrosis. But the supplementation of AA could induce greater reduction of ethanol induced SIBO, intestinal barrier defects, NF-κB activation and liver fibrosis than silymarin. The possible mechanism may be the inhibitory effect of AA on SIBO, intestinal barrier defect and IKKβ, which decreased the activation of NF-κB and synthesis of cytokines. This might have led to suppression of HSCs activation and liver fibrosis. - Highlights: • Alcohol increases intestinal bacterial overgrowth and permeability of endotoxin. • Endotoxin mediated inflammation plays a major role in alcoholic liver fibrosis. • Ascorbic acid reduces endotoxemia, NF-κB activation and proinflammatory cytokines. • AA's action is by inhibition of SIBO, IKKβ and alteration of

  11. Ameliorating effect of TI-1-162, a hydroxyindenone derivative, against TNBS-induced rat colitis is mediated through suppression of RIP/ASK-1/MAPK signaling.

    Gurung, Pallavi; Banskota, Suhrid; Katila, Nikita; Gautam, Jaya; Kadayat, Tara Man; Choi, Dong-Young; Lee, Eung Seok; Jeong, Tae Cheon; Kim, Jung-Ae

    2018-05-15

    The pathogenesis of inflammatory bowel disease (IBD) is associated with production of immense pro-inflammatory cytokines including TNF-α. Once generated, TNF-α stimulates production of various pro-inflammatory cytokines and disrupts mucosal barrier by inducing inflamed mucosal epithelial cell death. In the present study, we investigated inhibitory effects of TI-1-162, a hydroxyindenone derivative, against TNF-α-induced and TNBS-induced colon inflammation. TI-1-162 showed inhibitory effect on the TNF-α-induced adhesion of U937 monocytic cells to HT-29 colonic epithelial cells (IC 50 = 0.83 ± 0.12 μM), which is an in vitro model representing the initial step of colitis. In addition, TI-1-162 suppressed TNF-α-stimulated caspase-3 activation and HT-29 cell apoptosis. These in vitro inhibitory activities of TI-1-162 correlated to recovery changes in in vivo colon tissues, such as downregulation of adhesion molecules (ICAM-1, VCAM-1) and chemokines (CCL11, CXCL1, CXCL2, CXCL3, CX3CL1) revealed by gene expression array and Western blot analyses. Such molecular recovery of colon epithelium from TNBS-treated rats corresponded to the recovery in body weight, colon weight/length, and myeloperoxidase level by TI-1-162 (10 and 30 mg/kg/day, orally). In relation to action mechanism, TI-1-162 did not disturb TNF-α binding to its receptor, but suppressed phosphorylation of RIP-1, ASK-1, JNK and p38, and nuclear translocation of NF-kB and AP-1, which corresponded to down regulation of inflammatory cytokines in TNF-α-treated cells (HT-29 and U937) and TNBS-treated rat colon tissues. Taken together, the results indicate that the protective effects of TI-1-162 against colon inflammation and epithelial cell death are associated with its inhibitory action in RIP/ASK-1/MAPK signaling pathway downstream to TNF receptor 1. Copyright © 2018 Elsevier B.V. All rights reserved.

  12. Deconstructing continuous flash suppression.

    Yang, Eunice; Blake, Randolph

    2012-03-08

    In this paper, we asked to what extent the depth of interocular suppression engendered by continuous flash suppression (CFS) varies depending on spatiotemporal properties of the suppressed stimulus and CFS suppressor. An answer to this question could have implications for interpreting the results in which CFS influences the processing of different categories of stimuli to different extents. In a series of experiments, we measured the selectivity and depth of suppression (i.e., elevation in contrast detection thresholds) as a function of the visual features of the stimulus being suppressed and the stimulus evoking suppression, namely, the popular "Mondrian" CFS stimulus (N. Tsuchiya & C. Koch, 2005). First, we found that CFS differentially suppresses the spatial components of the suppressed stimulus: Observers' sensitivity for stimuli of relatively low spatial frequency or cardinally oriented features was more strongly impaired in comparison to high spatial frequency or obliquely oriented stimuli. Second, we discovered that this feature-selective bias primarily arises from the spatiotemporal structure of the CFS stimulus, particularly within information residing in the low spatial frequency range and within the smooth rather than abrupt luminance changes over time. These results imply that this CFS stimulus operates by selectively attenuating certain classes of low-level signals while leaving others to be potentially encoded during suppression. These findings underscore the importance of considering the contribution of low-level features in stimulus-driven effects that are reported under CFS.

  13. Retrolabyrinthine approach for cochlear nerve preservation in neurofibromatosis type 2 and simultaneous cochlear implantation

    Bento, Ricardo Ferreira

    2014-01-01

    Full Text Available Introduction: Few cases of cochlear implantation (CI in neurofibromatosis type 2 (NF2 patients had been reported in the literature. The approaches described were translabyrinthine, retrosigmoid or middle cranial fossa. Objectives: To describe a case of a NF2- deafened-patient who underwent to vestibular schwannoma resection via RLA with cochlear nerve preservation and CI through the round window, at the same surgical time. Resumed Report: A 36-year-old woman with severe bilateral hearing loss due to NF2 was submitted to vestibular schwannoma resection and simultaneous CI. Functional assessment of cochlear nerve was performed by electrical promontory stimulation. Complete tumor removal was accomplishment via RLA with anatomic and functional cochlear and facial nerve preservation. Cochlear electrode array was partially inserted via round window. Sound field hearing threshold improvement was achieved. Mean tonal threshold was 46.2 dB HL. The patient could only detect environmental sounds and human voice but cannot discriminate vowels, words nor do sentences at 2 years of follow-up. Conclusion: Cochlear implantation is a feasible auditory restoration option in NF2 when cochlear anatomic and functional nerve preservation is achieved. The RLA is adequate for this purpose and features as an option for hearing preservation in NF2 patients.

  14. Fibro-vascular coupling in the control of cochlear blood flow.

    Min Dai

    Full Text Available Transduction of sound in the cochlea is metabolically demanding. The lateral wall and hair cells are critically vulnerable to hypoxia, especially at high sound levels, and tight control over cochlear blood flow (CBF is a physiological necessity. Yet despite the importance of CBF for hearing, consensus on what mechanisms are involved has not been obtained.We report on a local control mechanism for regulating inner ear blood flow involving fibrocyte signaling. Fibrocytes in the super-strial region are spatially distributed near pre-capillaries of the spiral ligament of the albino guinea pig cochlear lateral wall, as demonstrably shown in transmission electron microscope and confocal images. Immunohistochemical techniques reveal the inter-connected fibrocytes to be positive for Na+/K+ ATPase β1 and S100. The connected fibrocytes display more Ca(2+ signaling than other cells in the cochlear lateral wall as indicated by fluorescence of a Ca(2+ sensor, fluo-4. Elevation of Ca(2+ in fibrocytes, induced by photolytic uncaging of the divalent ion chelator o-nitrophenyl EGTA, results in propagation of a Ca(2+ signal to neighboring vascular cells and vasodilation in capillaries. Of more physiological significance, fibrocyte to vascular cell coupled signaling was found to mediate the sound stimulated increase in cochlear blood flow (CBF. Cyclooxygenase-1 (COX-1 was required for capillary dilation.The findings provide the first evidence that signaling between fibrocytes and vascular cells modulates CBF and is a key mechanism for meeting the cellular metabolic demand of increased sound activity.

  15. The cochlear implant as a tinnitus treatment.

    Vallés-Varela, Héctor; Royo-López, Juan; Carmen-Sampériz, Luis; Sebastián-Cortés, José M; Alfonso-Collado, Ignacio

    2013-01-01

    Tinnitus is a symptom of high prevalence in patients with cochlear pathology. We studied the evolution of tinnitus in patients undergoing unilateral cochlear implantation for treatment of profound hearing loss. This was a longitudinal, retrospective study of patients that underwent unilateral cochlear implantation and who had bilateral tinnitus. Tinnitus was assessed quantitatively and qualitatively before surgery and at 6 and 12 months after surgery. We evaluated 20 patients that underwent unilateral cochlear implantation with a Nucleus(®) CI24RE Contour Advance™ electrode device. During the periods in which the device was in operation, improvement or disappearance of tinnitus was evidenced in the ipsilateral ear in 65% of patients, and in the contralateral ear, in 50%. In periods in which the device was disconnected, improvement or disappearance of tinnitus was found in the ipsilateral ear in 50% of patients, and in the ear contralateral to the implant in 45% of the patients. In 10% of the patients, a new tinnitus appeared in the ipsilateral ear. The patients with profound hearing loss and bilateral tinnitus treated with unilateral cochlear implantation improved in a high percentage of cases, in the ipsilateral ear and in the contralateral ear. Copyright © 2012 Elsevier España, S.L. All rights reserved.

  16. Degradation of labial information modifies audiovisual speech perception in cochlear-implanted children.

    Huyse, Aurélie; Berthommier, Frédéric; Leybaert, Jacqueline

    2013-01-01

    The aim of the present study was to examine audiovisual speech integration in cochlear-implanted children and in normally hearing children exposed to degraded auditory stimuli. Previous studies have shown that speech perception in cochlear-implanted users is biased toward the visual modality when audition and vision provide conflicting information. Our main question was whether an experimentally designed degradation of the visual speech cue would increase the importance of audition in the response pattern. The impact of auditory proficiency was also investigated. A group of 31 children with cochlear implants and a group of 31 normally hearing children matched for chronological age were recruited. All children with cochlear implants had profound congenital deafness and had used their implants for at least 2 years. Participants had to perform an /aCa/ consonant-identification task in which stimuli were presented randomly in three conditions: auditory only, visual only, and audiovisual (congruent and incongruent McGurk stimuli). In half of the experiment, the visual speech cue was normal; in the other half (visual reduction) a degraded visual signal was presented, aimed at preventing lipreading of good quality. The normally hearing children received a spectrally reduced speech signal (simulating the input delivered by the cochlear implant). First, performance in visual-only and in congruent audiovisual modalities were decreased, showing that the visual reduction technique used here was efficient at degrading lipreading. Second, in the incongruent audiovisual trials, visual reduction led to a major increase in the number of auditory based responses in both groups. Differences between proficient and nonproficient children were found in both groups, with nonproficient children's responses being more visual and less auditory than those of proficient children. Further analysis revealed that differences between visually clear and visually reduced conditions and between

  17. Kaempferol Inhibits Angiogenesis by Suppressing HIF-1α and VEGFR2 Activation via ERK/p38 MAPK and PI3K/Akt/mTOR Signaling Pathways in Endothelial Cells.

    Kim, Gi Dae

    2017-12-01

    Kaempferol has been shown to inhibit vascular formation in endothelial cells. However, the underlying mechanisms are not fully understood. In the present study, we evaluated whether kaempferol exerts antiangiogenic effects by targeting extracellular signal-regulated kinase (ERK)/p38 mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling pathways in endothelial cells. Endothelial cells were treated with various concentrations of kaempferol for 24 h. Cell viability was determined by the 3- (4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay; vascular formation was analyzed by tube formation, wound healing, and mouse aortic ring assays. Activation of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor receptor 2 (VEGFR2), ERK/p38 MAPK, and PI3K/Akt/mTOR was analyzed by Western blotting. Kaempferol significantly inhibited cell migration and tube formation in endothelial cells, and suppressed microvessel sprouting in the mouse aortic ring assay. Moreover, kaempferol suppressed the activation of HIF-1α, VEGFR2, and other markers of ERK/p38 MAPK and PI3K/Akt/mTOR signaling pathways in endothelial cells. These results suggest that kaempferol inhibits angiogenesis by suppressing HIF-1α and VEGFR2 activation via ERK/p38 MAPK and PI3K/Akt/mTOR signaling in endothelial cells.

  18. Multisensory Integration in Cochlear Implant Recipients.

    Stevenson, Ryan A; Sheffield, Sterling W; Butera, Iliza M; Gifford, René H; Wallace, Mark T

    Speech perception is inherently a multisensory process involving integration of auditory and visual cues. Multisensory integration in cochlear implant (CI) recipients is a unique circumstance in that the integration occurs after auditory deprivation and the provision of hearing via the CI. Despite the clear importance of multisensory cues for perception, in general, and for speech intelligibility, specifically, the topic of multisensory perceptual benefits in CI users has only recently begun to emerge as an area of inquiry. We review the research that has been conducted on multisensory integration in CI users to date and suggest a number of areas needing further research. The overall pattern of results indicates that many CI recipients show at least some perceptual gain that can be attributable to multisensory integration. The extent of this gain, however, varies based on a number of factors, including age of implantation and specific task being assessed (e.g., stimulus detection, phoneme perception, word recognition). Although both children and adults with CIs obtain audiovisual benefits for phoneme, word, and sentence stimuli, neither group shows demonstrable gain for suprasegmental feature perception. Additionally, only early-implanted children and the highest performing adults obtain audiovisual integration benefits similar to individuals with normal hearing. Increasing age of implantation in children is associated with poorer gains resultant from audiovisual integration, suggesting a sensitive period in development for the brain networks that subserve these integrative functions, as well as length of auditory experience. This finding highlights the need for early detection of and intervention for hearing loss, not only in terms of auditory perception, but also in terms of the behavioral and perceptual benefits of audiovisual processing. Importantly, patterns of auditory, visual, and audiovisual responses suggest that underlying integrative processes may be

  19. Silibinin and its 2,3-dehydro-derivative inhibit basal cell carcinoma growth via suppression of mitogenic signaling and transcription factors activation.

    Tilley, Cynthia; Deep, Gagan; Agarwal, Chapla; Wempe, Michael F; Biedermann, David; Valentová, Kateřina; Kren, Vladimir; Agarwal, Rajesh

    2016-01-01

    Basal cell carcinoma (BCC) is the most common cancer worldwide, and its current treatment options are insufficient and toxic. Surprisingly, unlike several other malignancies, chemopreventive efforts against BCC are almost lacking. Silibinin, a natural agent from milk thistle seeds, has shown strong efficacy against several cancers including ultraviolet radiation-induced skin (squamous) cancer; however, its potential activity against BCC is not yet examined. Herein, for the first time, we report the efficacy of silibinin and its oxidation product 2,3-dehydrosilibinin (DHS) against BCC both in vitro and in vivo using ASZ (p53 mutated) and BSZ (p53 deleted) cell lines derived from murine BCC tumors. Both silibinin and DHS significantly inhibited cell growth and clonogenicity while inducing apoptosis in a dose- and time-dependent manner, with DHS showing higher activity at lower concentrations. Both agents also inhibited the mitogenic signaling by reducing EGFR, ERK1/2, Akt, and STAT3 phosphorylation and suppressed the activation of transcription factors NF-κB and AP-1. More importantly, in an ectopic allograft model, oral administration of silibinin and DHS (200 mg/kg body weight) strongly inhibited the ASZ tumor growth by 44% and 71% (P < 0.05), respectively, and decreased the expression of proliferation biomarkers (PCNA and cyclin D1) as well as NF-κB p50 and c-Fos in the tumor tissues. Taken together, these results provide the first evidence for the efficacy and usefulness of silibinin and its derivative DHS against BCC, and suggest the need for additional studies with these agents in pre-clinical and clinical BCC chemoprevention and therapy models. © 2014 Wiley Periodicals, Inc.

  20. Tanshinone IIA suppresses FcεRI-mediated mast cell signaling and anaphylaxis by activation of the Sirt1/LKB1/AMPK pathway.

    Li, Xian; Park, Soon Jin; Jin, Fansi; Deng, Yifeng; Yang, Ju Hye; Chang, Jae-Hoon; Kim, Dong-Young; Kim, Jung-Ae; Lee, Youn Ju; Murakami, Makoto; Son, Kun Ho; Chang, Hyeun Wook

    2018-06-01

    AMP-activated protein kinase (AMPK) and its upstream mediators liver kinase B1 (LKB1) and sirtuin 1 (Sirt1) are generally known as key regulators of metabolism. We have recently reported that the AMPK pathway negatively regulates mast cell activation and anaphylaxis. Tanshinone IIA (Tan IIA), an active component of Salvia miltiorrhiza extract that is currently used for the treatment of cardiovascular and cerebrovascular diseases, shows anti-diabetic activity and improves insulin resistance in db/db mice through activation of AMPK. The aim of this study was to evaluate the anti-allergic activity of Tan IIA in vivo and to investigate the underlying mechanism in vitro in the context of AMPK signaling. The anti-allergic effect of Tan IIA was evaluated using mouse bone marrow-derived mast cells (BMMCs) from AMPKα2 -/- or Sirt1 -/- mice, or BMMCs transfected with siRNAs specific for AMPKα2, LKB1, or Sirt1. AMPKα2 -/- and Sirt1 -/- mice were used to confirm the anti-allergic effect of Tan IIA in anaphylaxis in vivo. Tan IIA dose-dependently inhibited FcεRI-mediated degranulation and production of eicosanoids and cytokines in BMMCs. These inhibitory effects were diminished by siRNA-mediated knockdown or genetic deletion of AMPKα2 or Sirt1. Moreover, Tan IIA inhibited a mast cell-mediated local passive anaphylactic reaction in wild-type mice, but not in AMPKα2 -/- or Sirt1 -/- mice. In conclusion, Tan IIA suppresses FcεRI-mediated mast cell activation and anaphylaxis through activation of the inhibitory Sirt1-LKB1-AMPK pathway. Thus, Tan IIA may be useful as a new therapeutic agent for mast cell-mediated allergic diseases. Copyright © 2018 Elsevier Inc. All rights reserved.

  1. Usher syndrome and cochlear implantation.

    Loundon, Natalie; Marlin, Sandrine; Busquet, Denise; Denoyelle, Françoise; Roger, Gilles; Renaud, Francis; Garabedian, Erea Noel

    2003-03-01

    To evaluate the symptoms leading to diagnosis and the quality of rehabilitation after cochlear implantation in Usher syndrome. Retrospective cohort study. ENT department of a tertiary referral hospital. Among 210 patients given an implantation in the Ear, Nose, and Throat department, 185 were congenitally deaf and 13 had Usher syndrome (7.0%). Five had a family history of Usher, and eight were sporadic cases. Eleven cases were Usher type I, one was Usher type III, and one was not classified. The age at implantation ranged from 18 months to 44 years (mean, 6 years 1 month). The mean follow-up was 52 months (range, 9 months to 9 years). All patients had audiophonological and clinical examination, computed tomography scan of the temporal bones, ophthalmologic examination with fundoscopy, and an electroretinogram. Cerebral magnetic resonance imaging and vestibular examination were performed in 9 of 13 and 10 of 13 cases, respectively. Logopedic outcome measured preimplant and postimplant closed- and open-set word recognition and oral expression at follow-up. The most frequent initial sign of Usher syndrome was delayed walking, with a mean age of 20 months. Among the 172 other congenitally deaf children with implants, when deafness was not associated with other neurologic disorders, the mean age at walking was 14 months (p < 0.001). The fundoscopy was always abnormal after the age of 5 years, and the electroretinogram was abnormal in all cases. Vestibular function was abnormal in all but one case (nonclassified). The computed tomography scan and the magnetic resonance imaging were always normal. Logopedic results with cochlear implants showed good perception skills in all but one case. The best perceptive results were obtained in children implanted before the age of 9 years. Oral language had significantly progressed in 9 of 13 at follow-up. There was no relation between the visual acuity and the logopedic results. The earliest clinical sign associated with deafness

  2. Parental expectations and outcomes of pediatric cochlear implantation.

    Piazza, Elizabeth; Kandathil, Cherian; Carron, Jeffrey D

    2009-10-01

    Cochlear implants have been used with increasing frequency over the past twenty years, including very young patients. To determine if parents are satisfied with their children's performance after cochlear implantation. Survey mailed to parents of children receiving cochlear implants. 31 questionnaires were returned out of 69 mailed (45 %). The vast majority of responding parents felt that their children benefited substantially from cochlear implant surgery. Cochlear implantation is effective in helping children develop auditory-oral communication skills. Access to auditory/oral communication programs in this state remains an obstacle in postoperative habilitation.

  3. Do Adults with Cochlear Implants Rely on Different Acoustic Cues for Phoneme Perception than Adults with Normal Hearing?

    Moberly, Aaron C.; Lowenstein, Joanna H.; Tarr, Eric; Caldwell-Tarr, Amanda; Welling, D. Bradley; Shahin, Antoine J.; Nittrouer, Susan

    2014-01-01

    Purpose: Several acoustic cues specify any single phonemic contrast. Nonetheless, adult, native speakers of a language share weighting strategies, showing preferential attention to some properties over others. Cochlear implant (CI) signal processing disrupts the salience of some cues: In general, amplitude structure remains readily available, but…

  4. The effect of music on auditory perception in cochlear-implant users and normal-hearing listeners

    Fuller, Christina Diechina

    2016-01-01

    Cochlear implants (CIs) are auditory prostheses for severely deaf people that do not benefit from conventional hearing aids. Speech perception is reasonably good with CIs; other signals such as music perception are challenging. First, the perception of music and music related perception in CI users

  5. Effects of Semantic Context and Feedback on Perceptual Learning of Speech Processed through an Acoustic Simulation of a Cochlear Implant

    Loebach, Jeremy L.; Pisoni, David B.; Svirsky, Mario A.

    2010-01-01

    The effect of feedback and materials on perceptual learning was examined in listeners with normal hearing who were exposed to cochlear implant simulations. Generalization was most robust when feedback paired the spectrally degraded sentences with their written transcriptions, promoting mapping between the degraded signal and its acoustic-phonetic…

  6. Predicting effects of impaired cochlear processing on consonant discrimination in stationary noise

    Jepsen, Morten Løve; Dau, Torsten; Ghitza, Oded

    Cochlear hearing loss is typically associated with reduced sensitivity due to inner hair-cell (IHC) and outer hair-cell (OHC) dysfunction. OHC dysfunction also leads to supra-threshold deficits, such as reduced basilar-membrane (BM) compression as well as reduced frequency selectivity and temporal...... patterns from a Diagnostic Rhyme Test (DRT) were measured and analyzed in terms of acoustic-phonetic features. This was done for three listeners with cochlear hearing loss and at two signal-to-noise ratios. It is shown that the predicted errors patterns matched the measured patterns in most conditions......, such as the evaluation of hearing-instrument signal processing, where the effects of specific processing strategies can be simulated for individual hearing losses....

  7. Effects of training on recognition of musical instruments presented through cochlear implant simulations.

    Driscoll, Virginia D; Oleson, Jacob; Jiang, Dingfeng; Gfeller, Kate

    2009-01-01

    The simulation of the CI (cochlear implant) signal presents a degraded representation of each musical instrument, which makes recognition difficult. To examine the efficiency and effectiveness of three types of training on recognition of musical instruments as presented through simulations of the sounds transmitted through a CI. Participants were randomly assigned to one of three training conditions: repeated exposure, feedback, and direct instruction. Sixty-six adults with normal hearing. Each participant completed three training sessions per week, over a five-week time period, in which they listened to the CI simulations of eight different musical instruments. Analyses on percent of instruments identified correctly showed statistically significant differences between recognition accuracy of the three training conditions (p different types of training are differentially effective with regard to improving recognition of musical instruments presented through a degraded signal, which has practical implications for the auditory rehabilitation of persons who use cochlear implants.

  8. Cochlear implant after bacterial meningitis.

    Bille, Jesper; Ovesen, Therese

    2014-06-01

    The aim of this retrospective case study at a tertiary referral center was to investigate the outcome of cochlear implantation (CI) in children with sensorineural hearing loss due to meningitis compared to CI in children with deafness due to other reasons. This post-meningial group (PMG) consisted of 22 children undergoing CI due to deafness induced by meningitis, between December 1996 and January 2012. Five children had bilateral simultaneous implantation. None was excluded and the children were followed for at least 3 years. Operations were carried out by one of two surgeons using similar techniques in all cases. Each patient from the PMG was matched 2:1 with children having implantation for other reasons according to age and follow up (control group). Overall, the median category of auditory performance (CAP) and speech intelligibility rating (SIR) score were not statistically significantly different between the two groups. The presence of additional central nervous system (CNS) disorders (post-meningeal sequelae), however, correlated significantly with poorer outcome CI was a safe procedure without surgical complications in the present study. It is possible to restore auditory capacity and speech performance to a degree comparable to children undergoing implantation for other reasons. A statistically important variable is secondary CNS involvement. The rehabilitation program after CI should be adjusted according to these additional handicaps. It is recommended to screen meningitis patients as fast as possible to identify those with hearing loss and initiate treatment with hearing aids or CI. © 2013 The Authors. Pediatrics International © 2013 Japan Pediatric Society.

  9. Ipsilateral distortion product otoacoustic emission (2 f1-f2) suppression in children with sensorineural hearing loss

    Abdala, Carolina; Fitzgerald, Tracy S.

    2003-08-01

    Distortion product otoacoustic emission (DPOAE) ipsilateral suppression has been applied to study cochlear function and maturation in laboratory animals and humans. Although DPOAE suppression appears to be sensitive to regions of specialized cochlear function and to cochlear immaturity, it is not known whether it reflects permanent cochlear damage, i.e., sensorineural hearing loss (SNHL), in a reliable and systematic manner in humans. Eight school-aged children with mild-moderate SNHL and 20 normal-hearing children served as subjects in this study. DPOAE (2 f1-f2) suppression data were collected at four f2 frequencies (1500, 3000, 4000, and 6000 Hz) using moderate-level primary tones. Features of the DPOAE iso-suppression tuning curves and suppression growth were analyzed for both subject groups. Results show that DPOAE suppression tuning curves from hearing-impaired subjects can be reliably recorded. DPOAE suppression tuning curves were generally normal in appearance and shape for six out of eight hearing-impaired subjects but showed subtle abnormalities in at least one feature. There was not one single trend or pattern of abnormality that characterized all hearing-impaired subjects. The most prominent patterns of abnormality included: broadened tuning, elevated tip, and downward shift of tip frequency. The unique patterns of atypical DPOAE suppression in subjects with similar audiograms may suggest different patterns of underlying sensory cell damage. This speculation warrants further investigation.

  10. Music Therapy for Preschool Cochlear Implant Recipients

    Gfeller, Kate; Driscoll, Virginia; Kenworthy, Maura; Van Voorst, Tanya

    2010-01-01

    This paper provides research and clinical information relevant to music therapy for preschool children who use cochlear implants (CI). It consolidates information from various disciplinary sources regarding (a) cochlear implantation of young prelingually-deaf children (~age 2-5), (b) patterns of auditory and speech-language development, and (c) research regarding music perception of children with CIs. This information serves as a foundation for the final portion of the article, which describes typical music therapy goals and examples of interventions suitable for preschool children. PMID:23904691

  11. Activity patterns of cochlear ganglion neurones in the starling.

    Manley, G A; Gleich, O; Leppelsack, H J; Oeckinghaus, H

    1985-09-01

    Spontaneous activity and responses to simple tonal stimuli were studied in cochlear ganglion neurones of the starling. Both regular and irregular spontaneous activity were recorded. Non-auditory cells have their origin in the macula lagenae. Mean spontaneous rate for auditory cells (all irregularly spiking) was 45 spikes s-1. In half the units having characteristic frequencies (CFs) less than 1.5 kHz, time-interval histograms (TIHs) of spontaneous activity showed regularly-spaced peaks or 'preferred' intervals. The spacing of the peak intervals was, on average, 15% greater than the CF-period interval of the respective units. In TIH of lower-frequency cells without preferred intervals, the modal interval was also on average about 15% longer than the CF-period interval. Apparently, the resting oscillation frequency of these cells lies below their CF. Tuning curves (TCs) of neurones to short tone bursts show no systematic asymmetry as in mammals. Below CF 1 kHz, the low-frequency flanks of the TCs are, on average, steeper than the high-frequency flanks. Above CF 1 kHz, the reverse is true. The cochlear ganglion and nerve are tonotopically organized. Low-frequency fibres arise apically in the papilla basilaris and are found near non-auditory (lagenar) fibres. Discharge rates to short tones were monotonically related to sound pressure level. Saturation rates often exceeded 300 spikes s-1. 'On-off' responses and primary suppression of spontaneous activity were observed. A direct comparison of spontaneous activity and tuning-curve symmetry revealed that, apart from quantitative differences, fundamental qualitative differences exist between starling and guinea-pig primary afferents.

  12. Follow-up of cochlear implant use in patients who developed bacterial meningitis following cochlear implantation.

    Mancini, Patrizia; D'Elia, Chiara; Bosco, Ersilia; De Seta, Elio; Panebianco, Valeria; Vergari, Valeria; Filipo, Roberto

    2008-08-01

    The present study is a long-term follow-up of speech perception outcomes and cochlear implant use in three cases of meningitis that occurred after cochlear implantation. Case series study. Study was performed on three children implanted with different models of Clarion devices, two of them with positioner. Recognition and comprehension were assessed via the Italian adaptation of GASP (TAP) test, and phonetically balanced bi-syllabic words in open-set. High resolution computed tomography scan acquisition was performed to obtain axial coronal and oblique multiplanar reconstructions of the cochlea. Two patients were affected by enlarged cochlear acqueduct and Mondini malformation the first carrying positioner. One patient had a normal cochlea, and the positioner could have been the main cause of bacterial spread. As a consequence of meningitis the child with normal cochlea and the other with enlarged vestibular acqueduct developed cochlear ossification, increased M-level and worsening of hearing outcomes. The child with Mondini malformation developed facial nerve stimulation. Contralateral implantation was performed in the first two patients. Bacterial meningitis occurring after cochlear implantation may induce cochlear ossification, facial nerve stimulation, and permanent or temporary loss of implant use. Planned follow-up with high resolution computed tomography and evaluation of M-levels could be useful prognostic tools in the management of these patients.

  13. Silencing of B7-H4 suppresses the tumorigenicity of the MGC-803 human gastric cancer cell line and promotes cell apoptosis via the mitochondrial signaling pathway.

    Zhou, Donghui; Zhou, Yong; Li, Chao; Yang, Lina

    2018-04-01

    B7-H4 is a transmembrane protein which is a member of the B7 superfamily. It is overexpressed in various types of cancer, including gastric cancer. However, the effects of B7-H4 on the tumorigenicity of gastric cancer and the underlying mechanisms have not yet been fully explored. Thus, the aim of this study was to examine the effects of B7-H4 on the tumorigenicity of gastric cancer cells and to elucidate the underlying mechanisms. For this purpose, B7-H4 expression in gastric cancer tissues was detected by immunohistochemical staining. The effects of B7-H4 on the biological behavior of the MGC-803 human gastric cancer cell line were examined by Cell Counting kit-8 (CCK-8) assay, cell cycle analysis, wound healing assay, Annexin V/propidium iodide staining and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. Moreover, the expression levels of apoptotic markers, such as cleaved caspase‑3, cleaved caspase‑9, Bcl-2 and Bax were examined by western blot analysis. Immunohistochemical staining revealed that a high expression of B7-H4 was found in about 41.8% of tissues obtained from patients with gastric cancer. Comparative analysis revealed that B7-H4 expression significantly correlated with lymph node metastasis and the TNM stage. The results of CCK-8 assay, cell cycle analysis, wound healing assay, Annexin V/propidium iodide staining assay and TUNEL assay all demonstrated that the silencing of B7-H4 by small interfering RNA decreased cell proliferation, suppressed cell motility, and induced cell cycle arrest and the apoptosis of MGC-803 human gastric cancer cells. Furthermore, the results of western blot analysis indicated that the downregulation of B7-H4 induced the apoptosis of the MGC-803 cells via the mitochondrial signaling pathway through the activation of caspase‑3 and caspase‑9, and by altering the Bax/Bcl-2 ratio in a manner that favored apoptosis. Based on the findings on human gastric cancer cell line MGC-803, the

  14. Cochlear Implantation in Siblings With Refsum's Disease.

    Stähr, Kerstin; Kuechler, Alma; Gencik, Martin; Arnolds, Judith; Dendy, Meaghan; Lang, Stephan; Arweiler-Harbeck, Diana

    2017-08-01

    Whether the origin of severe hearing loss in Refsum's syndrome is caused by cochlear impairment or retrocochlear degeneration remains unclear. This case report aims to investigate hearing performance before and after cochlear implantation to shed light on this question. Also, identification of new mutations causing Refsum's syndrome would be helpful in generating additional means of diagnosis. A family of 4 individuals was subjected to genetic testing. Two siblings (56 and 61 years old) suffered from severe hearing and vision loss and received bilateral cochlear implants. Genetic analysis, audiological outcome, and clinical examinations were performed. One new mutation in the PHYH gene (c.768del63bp) causing Refsum's disease was found. Preoperative distortion product otoacoustic emissions (DPAOEs) were absent. Postoperative speech perception in Freiburger speech test was 100% for bisyllabic words and 85% (patient No. 1) and 65% (patient No. 2), respectively, for monosyllabic words. Five years after implantation, speech perception remained stable for bisyllabic words but showed decreasing capabilities for monosyllabic words. A new mutation causing Refsum's disease is presented. Cochlear implantation in case of severe hearing loss leads to an improvement in speech perception and should be recommended for patients with Refsum's disease, especially when the hearing loss is combined with a severe loss of vision. Decrease of speech perception in the long-term follow-up could indicate an additional retrocochlear degeneration.

  15. Libyan cochlear implant programme: achievements, difficulties, and ...

    Data relating to the patients who received cochlear implantation at Tripoli Medical Centre between October 2007 and February 2010 were analysed. Implant operations were performed on 37 patients. All patients received Med-El SONATATI100 devices. Thirty-four (91.9%) of these patients were children, whilst three (8.1%) ...

  16. Environmental Sound Training in Cochlear Implant Users

    Shafiro, Valeriy; Sheft, Stanley; Kuvadia, Sejal; Gygi, Brian

    2015-01-01

    Purpose: The study investigated the effect of a short computer-based environmental sound training regimen on the perception of environmental sounds and speech in experienced cochlear implant (CI) patients. Method: Fourteen CI patients with the average of 5 years of CI experience participated. The protocol consisted of 2 pretests, 1 week apart,…

  17. Multichannel cochlear implantation in the scala vestibuli.

    Lin, Karen; Marrinan, Michelle S; Waltzman, Susan B; Roland, J Thomas

    2006-08-01

    Sensorineural hearing loss resulting from otosclerosis, meningitis, chronic otitis media, autoimmune ear disease, and trauma can be associated with partial or total obstruction of the cochlear scalae. Multichannel cochlear implantation may be difficult in a cochlea with an obstructed scala tympani. The purpose of this study is to determine the safety and efficacy of scala tympani electrode insertion. Retrospective chart review. Academic medical center. Eight children and adults with profound sensorineural hearing loss who underwent cochlear implantation with known scala vestibuli electrode array insertion were subjects for this study. Eight study subjects underwent implantation: five with the Nucleus 24RCS (Contour) device and three with the Nucleus 24M device. Imaging findings, operative findings, and age-appropriate speech perception testing. All patients had full electrode insertion. Various obstructive patterns on computed tomography and magnetic resonance imaging were found, and there was a range of speech perception results. All but one patient improved based on age-appropriate monosyllabic word and sentence tests. Scala vestibuli multielectrode insertion is a viable alternative when scala tympani insertion is not possible because of abnormal anatomy or anatomical changes secondary to disease or previous implantation. We will also present an algorithm of options for decision making for implantation when encountering cochlear obstruction and difficult electrode insertion.

  18. Gender Categorization in Cochlear Implant Users

    Massida, Zoe; Marx, Mathieu; Belin, Pascal; James, Christopher; Fraysse, Bernard; Barone, Pascal; Deguine, Olivier

    2013-01-01

    Purpose: In this study, the authors examined the ability of subjects with cochlear implants (CIs) to discriminate voice gender and how this ability evolved as a function of CI experience. Method: The authors presented a continuum of voice samples created by voice morphing, with 9 intermediate acoustic parameter steps between a typical male and a…

  19. Simplifying cochlear implant speech processor fitting

    Willeboer, C.

    2008-01-01

    Conventional fittings of the speech processor of a cochlear implant (CI) rely to a large extent on the implant recipient's subjective responses. For each of the 22 intracochlear electrodes the recipient has to indicate the threshold level (T-level) and comfortable loudness level (C-level) while

  20. Listening Effort With Cochlear Implant Simulations

    Pals, Carina; Sarampalis, Anastasios; Başkent, Deniz

    2013-01-01

    Purpose: Fitting a cochlear implant (CI) for optimal speech perception does not necessarily optimize listening effort. This study aimed to show that listening effort may change between CI processing conditions for which speech intelligibility remains constant. Method: Nineteen normal-hearing

  1. Anomalous facial nerve canal with cochlear malformations.

    Romo, L V; Curtin, H D

    2001-05-01

    Anteromedial "migration" of the first segment of the facial nerve canal has been previously identified in a patient with a non-Mondini-type cochlear malformation. In this study, several patients with the same facial nerve canal anomaly were reviewed to assess for the association and type of cochlear malformation. CT scans of the temporal bone of 15 patients with anteromedial migration of the first segment of the facial nerve canal were collected from routine departmental examinations. In seven patients, the anomalous course was bilateral, for a total of 22 cases. The migration was graded relative to normal as either mild/moderate or pronounced. The cochlea in each of these cases was examined for the presence and size of the basilar, second, and apical turns. The turns were either absent, small, normal, or enlarged. The CT scans of five patients with eight Mondini malformations were examined for comparison. The degree of the facial nerve migration was pronounced in nine cases and mild/moderate in 13. All 22 of these cases had associated cochlear abnormalities of the non-Mondini variety. These included common cavity anomalies with lack of definition between the cochlea and vestibule (five cases), cochleae with enlarged basilar turns and absent second or third turns (five cases), and cochleae with small or normal basilar turns with small or absent second or third turns (12 cases). None of the patients with Mondini-type cochlear malformations had anteromedial migration of the facial nerve canal. Anteromedial migration of the facial nerve canal occurs in association with some cochlear malformations. It did not occur in association with the Mondini malformations. A cochlea with a Mondini malformation, being similar in size to a normal cochlea, may physically prohibit such a deviation in course.

  2. Transient-Switch-Signal Suppressor

    Bozeman, Richard J., Jr.

    1995-01-01

    Circuit delays transmission of switch-opening or switch-closing signal until after preset suppression time. Used to prevent transmission of undesired momentary switch signal. Basic mode of operation simple. Beginning of switch signal initiates timing sequence. If switch signal persists after preset suppression time, circuit transmits switch signal to external circuitry. If switch signal no longer present after suppression time, switch signal deemed transient, and circuit does not pass signal on to external circuitry, as though no transient switch signal. Suppression time preset at value large enough to allow for damping of underlying pressure wave or other mechanical transient.

  3. Comparison between bilateral cochlear implants and Neurelec Digisonic(®) SP Binaural cochlear implant: speech perception, sound localization and patient self-assessment.

    Bonnard, Damien; Lautissier, Sylvie; Bosset-Audoit, Amélie; Coriat, Géraldine; Beraha, Max; Maunoury, Antoine; Martel, Jacques; Darrouzet, Vincent; Bébéar, Jean-Pierre; Dauman, René

    2013-01-01

    An alternative to bilateral cochlear implantation is offered by the Neurelec Digisonic(®) SP Binaural cochlear implant, which allows stimulation of both cochleae within a single device. The purpose of this prospective study was to compare a group of Neurelec Digisonic(®) SP Binaural implant users (denoted BINAURAL group, n = 7) with a group of bilateral adult cochlear implant users (denoted BILATERAL group, n = 6) in terms of speech perception, sound localization, and self-assessment of health status and hearing disability. Speech perception was assessed using word recognition at 60 dB SPL in quiet and in a 'cocktail party' noise delivered through five loudspeakers in the hemi-sound field facing the patient (signal-to-noise ratio = +10 dB). The sound localization task was to determine the source of a sound stimulus among five speakers positioned between -90° and +90° from midline. Change in health status was assessed using the Glasgow Benefit Inventory and hearing disability was evaluated with the Abbreviated Profile of Hearing Aid Benefit. Speech perception was not statistically different between the two groups, even though there was a trend in favor of the BINAURAL group (mean percent word recognition in the BINAURAL and BILATERAL groups: 70 vs. 56.7% in quiet, 55.7 vs. 43.3% in noise). There was also no significant difference with regard to performance in sound localization and self-assessment of health status and hearing disability. On the basis of the BINAURAL group's performance in hearing tasks involving the detection of interaural differences, implantation with the Neurelec Digisonic(®) SP Binaural implant may be considered to restore effective binaural hearing. Based on these first comparative results, this device seems to provide benefits similar to those of traditional bilateral cochlear implantation, with a new approach to stimulate both auditory nerves. Copyright © 2013 S. Karger AG, Basel.

  4. Continued expression of GATA3 is necessary for cochlear neurosensory development.

    Jeremy S Duncan

    Full Text Available Hair cells of the developing mammalian inner ear are progressively defined through cell fate restriction. This process culminates in the expression of the bHLH transcription factor Atoh1, which is necessary for differentiation of hair cells, but not for their specification. Loss of several genes will disrupt ear morphogenesis or arrest of neurosensory epithelia development. We previously showed in null mutants that the loss of the transcription factor, Gata3, results specifically in the loss of all cochlear neurosensory development. Temporal expression of Gata3 is broad from the otic placode stage through the postnatal ear. It therefore remains unclear at which stage in development Gata3 exerts its effect. To better understand the stage specific effects of Gata3, we investigated the role of Gata3 in cochlear neurosensory specification and differentiation utilizing a LoxP targeted Gata3 line and two Cre lines. Foxg1(Cre∶Gata3(f/f mice show recombination of Gata3 around E8.5 but continue to develop a cochlear duct without differentiated hair cells and spiral ganglion neurons. qRT-PCR data show that Atoh1 was down-regulated but not absent in the duct whereas other hair cell specific genes such as Pou4f3 were completely absent. In addition, while Sox2 levels were lower in the Foxg1(Cre:Gata3(f/f cochlea, Eya1 levels remained normal. We conclude that Eya1 is unable to fully upregulate Atoh1 or Pou4f3, and drive differentiation of hair cells without Gata3. Pax2-Cre∶Gata3(f/f mice show a delayed recombination of Gata3 in the ear relative to Foxg1(Cre:Gata3(f/f . These mice exhibited a cochlear duct containing patches of partially differentiated hair cells and developed only few and incorrectly projecting spiral ganglion neurons. Our conditional deletion studies reveal a major role of Gata3 in the signaling of prosensory genes and in the differentiation of cochlear neurosenory cells. We suggest that Gata3 may act in combination with Eya1, Six1, and

  5. GYF-21, an Epoxide 2-(2-Phenethyl-Chromone Derivative, Suppresses Innate and Adaptive Immunity via Inhibiting STAT1/3 and NF-κB Signaling Pathways

    Ran Guo

    2017-05-01

    Full Text Available Multiple sclerosis is a chronic inflammatory autoimmune disease of the central nervous system characterized by demyelinating plaques and axonal loss. Inhibition on over activation of innate and adaptive immunity provides a rationale strategy for treatment of multiple sclerosis. In the present study, we investigated the inhibitory effects of GYF-21, an epoxide 2-(2-phenethyl-chromone derivative isolated from Chinese agarwood, on innate and adaptive immunity for revealing its potential to treat multiple sclerosis. The results showed that GYF-21 markedly inhibited the activation of microglia, and dendritic cells as well as neutrophils, all of which play important roles in innate immunity. Furthermore, GYF-21 significantly suppressed adaptive immunity via inhibiting the differentiation of naive CD4+ T cells into T helper 1 (Th1 and T helper 17 (Th17 cells, and suppressing the activation, proliferation, and IFN-γ secretion of CD8+ T cells. The mechanism study showed that GYF-21 evidently inhibited the activation of STAT1/3 and NF-κB signaling pathways in microglia. In conclusion, we demonstrated that GYF-21 can significantly inhibit innate and adaptive immunity via suppressing STAT1/3 and NF-κB signaling pathways, and has potential to be developed into therapeutic drug for multiple sclerosis.

  6. The Histone Deacetylase Inhibitors MS-275 and SAHA Suppress the p38 Mitogen-Activated Protein Kinase Signaling Pathway and Chemotaxis in Rheumatoid Arthritic Synovial Fibroblastic E11 Cells

    Hai-Shu Lin

    2013-11-01

    Full Text Available MS-275 (entinostat and SAHA (vorinostat, two histone deacetylase (HDAC inhibitors currently in oncological trials, have displayed potent anti-rheumatic activities in rodent models of rheumatoid arthritis (RA. To further elucidate their anti-inflammatory mechanisms, the impact of MS-275 and SAHA on the p38 mitogen-activated protein kinase (MAPK signaling pathway and chemotaxis was assessed in human rheumatoid arthritic synovial fibroblastic E11 cells. MS-275 and SAHA significantly suppressed the expression of p38α  MAPK, but induced the expression of MAPK phosphatase-1 (MKP-1, an endogenous suppressor of p38α  in E11 cells. At the same time, the association between p38α and MKP-1 was up-regulated and consequently, the activation (phosphorylation of p38α  was inhibited. Moreover, MS-275 and SAHA suppressed granulocyte chemotactic protein-2 (GCP-2, monocyte chemotactic protein-2 (MCP-2 and macrophage migration inhibitory factor (MIF in E11 cells in a concentration-dependent manner. Subsequently, E11-driven migration of THP-1 and U937 monocytes was inhibited. In summary, suppression of the p38 MAPK signaling pathway and chemotaxis appear to be important anti-rheumatic mechanisms of action of these HDAC inhibitors.

  7. Suppressed Belief

    Komarine Romdenh-Romluc

    2009-12-01

    Full Text Available Moran’s revised conception of conscious belief requires us to reconceptualise suppressed belief. The work of Merleau-Ponty offers a way to do this. His account of motor-skills allows us to understand suppressed beliefs as pre-reflective ways of dealing with the world.

  8. What Does Music Sound Like for a Cochlear Implant User?

    Jiam, Nicole T; Caldwell, Meredith T; Limb, Charles J

    2017-09-01

    Cochlear implant research and product development over the past 40 years have been heavily focused on speech comprehension with little emphasis on music listening and enjoyment. The relatively little understanding of how music sounds in a cochlear implant user stands in stark contrast to the overall degree of importance the public places on music and quality of life. The purpose of this article is to describe what music sounds like to cochlear implant users, using a combination of existing research studies and listener descriptions. We examined the published literature on music perception in cochlear implant users, particularly postlingual cochlear implant users, with an emphasis on the primary elements of music and recorded music. Additionally, we administered an informal survey to cochlear implant users to gather first-hand descriptions of music listening experience and satisfaction from the cochlear implant population. Limitations in cochlear implant technology lead to a music listening experience that is significantly distorted compared with that of normal hearing listeners. On the basis of many studies and sources, we describe how music is frequently perceived as out-of-tune, dissonant, indistinct, emotionless, and weak in bass frequencies, especially for postlingual cochlear implant users-which may in part explain why music enjoyment and participation levels are lower after implantation. Additionally, cochlear implant users report difficulty in specific musical contexts based on factors including but not limited to genre, presence of lyrics, timbres (woodwinds, brass, instrument families), and complexity of the perceived music. Future research and cochlear implant development should target these areas as parameters for improvement in cochlear implant-mediated music perception.

  9. CpG in Combination with an Inhibitor of Notch Signaling Suppresses Formalin-Inactivated Respiratory Syncytial Virus-Enhanced Airway Hyperresponsiveness and Inflammation by Inhibiting Th17 Memory Responses and Promoting Tissue-Resident Memory Cells in Lungs.

    Zhang, Lei; Li, Hongyong; Hai, Yan; Yin, Wei; Li, Wenjian; Zheng, Boyang; Du, Xiaomin; Li, Na; Zhang, Zhengzheng; Deng, Yuqing; Zeng, Ruihong; Wei, Lin

    2017-05-15

    Respiratory syncytial virus (RSV) is the leading cause of childhood hospitalizations. The formalin-inactivated RSV (FI-RSV) vaccine-enhanced respiratory disease (ERD) has been an obstacle to the development of a safe and effective killed RSV vaccine. Agonists of Toll-like receptor (TLR) have been shown to regulate immune responses induced by FI-RSV. Notch signaling plays critical roles during the differentiation and effector function phases of innate and adaptive immune responses. Cross talk between TLR and Notch signaling pathways results in fine-tuning of TLR-triggered innate inflammatory responses. We evaluated the impact of TLR and Notch signaling on ERD in a murine model by administering CpG, an agonist of TLR9, in combination with L685,458, an inhibitor of Notch signaling during FI-RSV immunization. Activation with CpG or deficiency of MyD88-dependent TLR signaling did not alleviate airway inflammation in FI-RSV-immunized mice. Activation or inhibition of Notch signaling with Dll4, one of the Notch ligands, or L685,458 did not suppress FI-RSV-enhanced airway inflammation either. However, the CpG together with L685,458 markedly inhibited FI-RSV-enhanced airway hyperresponsiveness, weight loss, and lung inflammation. Interestingly, CpG plus L685,458 completely inhibited FI-RSV-associated Th17 and Th17-associated proinflammatory chemokine responses in lungs following RSV challenge but not Th1 or Th2, memory responses. In addition, FI-RSV plus CpG plus L685,458 promoted protective CD8 + lung tissue-resident memory (TRM) cells. These results indicate that activation of TLR signaling combined with inhibition of Notch signaling prevent FI-RSV ERD, and the mechanism appears to involve suppressing proinflammatory Th17 memory responses and promoting protective TRM in lungs. IMPORTANCE RSV is the most important cause of lower respiratory tract infections in infants. The FI-RSV-enhanced respiratory disease (ERD) is a major impediment to the development of a safe and

  10. A Ca2+-calmodulin-eEF2K-eEF2 signalling cascade, but not AMPK, contributes to the suppression of skeletal muscle protein synthesis during contractions

    Rose, Adam John; Alsted, Thomas Junker; Jensen, Thomas Elbenhardt

    2009-01-01

    Skeletal muscle protein synthesis rate decreases during contractions but the underlying regulatory mechanisms are poorly understood. It was hypothesised that there would be a coordinated regulation of eukaryotic elongation factor 2 (eEF2) and eukaryotic initiation factor 4E-binding protein 1 (4EBP1......) phosphorylation by signalling cascades downstream of rises in intracellular [Ca(2+)] and decreased energy charge via AMP activated protein kinase (AMPK) in contracting skeletal muscle. When fast-twitch skeletal muscles were contracted ex vivo using different protocols, the suppression of protein synthesis...... correlated more closely with changes in eEF2 rather than 4EBP1 phosphorylation. Using a combination of Ca(2+) release agents and ATPase inhibitors it was shown that the 60-70% suppression of fast-twitch skeletal muscle protein synthesis during contraction was equally distributed between Ca(2+) and energy...

  11. [The development of musicality in children after cochlear implantation].

    Zheng, Yan; Liu, Bo; Dong, Ruijuan; Xu, Tianqiu; Chen, Jing; Chen, Xuejing; Zhong, Yan; Meng, Chao; Wang, Hong; Chen, Xueqing

    2014-08-01

    The purpose of this study is to analyze the development of musicality in children after cochlear implantation, and provide a clinical database for the evaluation of their musicality. Twenty-six children with cochlear implants (CI group) participated in this research. They received cochlear implants at the age of 11 to 68 months with a mean of 35.6 months. Seventy-six infants as a control group aged from 1 to 24 months with a mean of 6.1 months participated in this study, whose hearing were considered normal by passing the case history collection, high-risk registers for hearing loss and hearing screening using DPOAE. The music and young children with CIs: Musicality Rating Scale was used to evaluate their musicality. The evaluation was performed before cochlear implantation and 1, 3, 6, 9, 12, 24 months after cochlear implantation for children with cochlear implants. The evaluation was also performed at 1, 3, 6, 9, 12, 24 months for children with normal hearing. The mean scores of musicality showed significant improvements with time of CI use for CI group (Pmusicality also showed significant improvements with time for control group (P0.05). Significant difference was noted between the two groups at 24 months (Pmusicality of children with cochlear implants improved significantly with time after cochlear implantation. The most rapid growth was found in the first year after cochlear implantation.

  12. [Multi-channel cochlear implants in patients with Mondini malformation].

    Li, Yong-xin; Han, De-min; Zhao, Xiao-tian; Chen, Xue-qing; Kong, Ying; Zheng, Jun; Liu, Bo; Liu, Sha; Mo, Ling-yan; Zhang, Hua; Wang, Shuo

    2004-02-01

    To describe clinical experiences with multi-channel cochlear implantation in patients with Mondini malformation. Among 300 patients who received multi-channel cochlear implants from 1996 to 2002 in Beijing Tongren Hospital, 15 patients were diagnosed with Mondini malformation. A retrospective analysis was performed dealing with the surgical techniques, mapping and rehabilitations characteristics after surgery. 15 patients with normal cochlear structure are consider as control group. Gusher is found more common than the normal cochlear implantation, most of them are serious. The electrodes are inserted in the "cochleostomy" in full length of 13 Patients, 2 pairs of electrodes remains outside of "cochleostomy" in 2 patients. No serious complications occurred after implantation. All patients have auditory sensations. The impedance of the electrodes, the T level, C level and the hearing threshold are similar with the normal cochlear implantation group. The results have no significant difference in compare with normal cochlear group(P > 0.05). Multi-channel cochlear implantation could be performed safely in patients with Mondini malformation. The primary outcome for patients with Mondini malformation are similar to those with normal cochlear structure following the multi-channel cochlear implantation.

  13. Trichostatin A, a histone deacetylase inhibitor, suppresses JAK2/STAT3 signaling via inducing the promoter-associated histone acetylation of SOCS1 and SOCS3 in human colorectal cancer cells.

    Xiong, Hua; Du, Wan; Zhang, Yan-Jie; Hong, Jie; Su, Wen-Yu; Tang, Jie-Ting; Wang, Ying-Chao; Lu, Rong; Fang, Jing-Yuan

    2012-02-01

    Aberrant janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling is involved in the oncogenesis of several cancers. Suppressors of cytokine signaling (SOCS) genes and SH2-containing protein tyrosine phosphatase 1 (SHP1) proteins, which are negative regulators of JAK/STAT signaling, have been reported to have tumor suppressor functions. However, in colorectal cancer (CRC) cells, the mechanisms that regulate SOCS and SHP1 genes, and the cause of abnormalities in the JAK/STAT signaling pathway, remain largely unknown. The present study shows that trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, leads to the hyperacetylation of histones associated with the SOCS1 and SOCS3 promoters, but not the SHP1 promoter in CRC cells. This indicates that histone modifications are involved in the regulation of SOCS1 and SOCS3. Moreover, upregulation of SOCS1 and SOCS3 expression was achieved using TSA, which also significantly downregulated JAK2/STAT3 signaling in CRC cells. We also demonstrate that TSA suppresses the growth of CRC cells, and induces G1 cell cycle arrest and apoptosis through the regulation of downstream targets of JAK2/STAT3 signaling, including Bcl-2, survivin and p16(ink4a) . Therefore, our data demonstrate that TSA may induce SOCS1 and SOCS3 expression by inducing histone modifications and consequently inhibits JAK2/STAT3 signaling in CRC cells. These results also establish a mechanistic link between the inhibition of JAK2/STAT3 signaling and the anticancer action of TSA in CRC cells. Copyright © 2011 Wiley Periodicals, Inc.

  14. 4-Acetylantroquinonol B suppresses autophagic flux and improves cisplatin sensitivity in highly aggressive epithelial cancer through the PI3K/Akt/mTOR/p70S6K signaling pathway

    Liu, Mingche [Graduate Institute of Biomedical Materials and Tissue Engineering, College of biomedical engineering, Taipei Medical University, Taipei, Taiwan (China); Department of Urology, Taipei Medical University Hospital, Taipei, Taiwan (China); Department of Urology, School of Medicine, college of Medicine, Taipei Medical University, Taipei, Taiwan (China); Bamodu, Oluwaseun Adebayo [Department of Hematology and Oncology, Cancer Center, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan (China); Department of Medical Research & Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan (China); Huang, Wen-Chien [Institute of Traditional Medicine, School of Medicine, National Yang Ming University, Taipei, Taiwan (China); Department of Surgery, Division of Thoracic Surgery, MacKay Memorial Hospital, Taipei, Taiwan (China); Zucha, Muhammad Ary [Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan (China); Lin, Yen-Kuang [Biostatistics and Research Consultation Center, Taipei Medical University, Taipei 11031, Taiwan (China); Wu, Alexander T.H. [The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan (China); Huang, Chun-Chih [Center for General Education, National Taitung University, Taitung, Taiwan (China); Lee, Wei-Hwa [Department of Pathology, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan (China); Yuan, Chiou-Chung [Obstetrics and Gynecology Department, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan (China); Hsiao, M. [Genomics Research Center, Academia Sinica, Taipei, Taiwan (China); Deng, Li [Beijing Bioprocess Key Laboratory, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing (China); Amoy-BUCT Industrial Bio-technovation Institute, Amoy (China); and others

    2017-06-15

    Targeting residual self-renewing, chemoresistant cancerous cells may represent the key to overcoming therapy resistance. The entry of these quiescent cells into an activated state is associated with high metabolic demand and autophagic flux. Therefore, modulating the autophagy pathway in aggressive carcinomas may be beneficial as a therapeutic modality. In this study, we evaluated the anti-tumor activities of 4-acetylantroquinonol B (4-AAQB) in chemoresistant ovarian cancer cells, particularly its ability to modulate autophagy through autophagy-related genes (Atg). Atg-5 was overexpressed in invasive ovarian cancer cell lines and tissue (OR: 5.133; P = 0.027) and depleting Atg-5 in ES-2 cell lines significantly induced apoptosis. 4-AAQB effectively suppressed viability of various subtypes of ovarian cancer. Cells with higher cisplatin-resistance were more responsive to 4-AAQB. For the first time, we demonstrate that 4-AAQB significantly suppress Atg-5 and Atg-7 expression with decreased autophagic flux in ovarian cancer cells via inhibition of the PI3K/Akt/mTOR/p70S6K signaling pathway. Similar to Atg-5 silencing, 4-AAQB-induced autophagy inhibition significantly enhanced cell death in vitro. These results are comparable to those of hydroxychloroquine (HCQ). In addition, 4-AAQB/cisplatin synergistically induced apoptosis in ovarian cancer cells. In vivo, 4-AAQB/cisplatin also significantly induced apoptosis and autophagy in an ES-2 mouse xenografts model. This is the first report demonstrating the efficacy of 4-AAQ