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Sample records for ameliorate prepulse inhibition

  1. Prepulse inhibition deficits in women with PTSD.

    PubMed

    Pineles, Suzanne L; Blumenthal, Terry D; Curreri, Andrew J; Nillni, Yael I; Putnam, Katherine M; Resick, Patricia A; Rasmusson, Ann M; Orr, Scott P

    2016-09-01

    Prepulse inhibition (PPI) is an automatic and preattentive process, whereby a weak stimulus attenuates responding to a sudden and intense startle stimulus. PPI is a measure of sensorimotor filtering, which is conceptualized as a mechanism that facilitates processing of an initial stimulus and is protective from interruption by a later response. Impaired PPI has been found in (a) healthy women during the luteal phase of the menstrual cycle, and (b) individuals with types of psychopathology characterized by difficulty suppressing and filtering sensory, motor, or cognitive information. In the current study, 47 trauma-exposed women with or without posttraumatic stress disorder (PTSD) completed a PPI session during two different phases of the menstrual cycle: the early follicular phase, when estradiol and progesterone are both low, and the midluteal phase, when estradiol and progesterone are both high. Startle stimuli were 100 dB white noise bursts presented for 50 ms, and prepulses were 70 dB white noise bursts presented for 20 ms that preceded the startle stimuli by 120 ms. Women with PTSD showed deficits in PPI relative to the healthy trauma-exposed participants. Menstrual phase had no effect on PPI. These results provide empirical support for individuals with PTSD having difficulty with sensorimotor filtering. The potential utility of PPI as a Research Domain Criteria (RDoC) phenotype is discussed. PMID:27237725

  2. The effects of memantine on prepulse inhibition.

    PubMed

    Swerdlow, N R; van Bergeijk, D P; Bergsma, F; Weber, E; Talledo, J

    2009-06-01

    Reduced prepulse inhibition (PPI) of startle provides evidence of deficient sensorimotor gating in several disorders, including schizophrenia. The role of NMDA neurotransmission in the regulation of PPI is unclear, due to cross-species differences in the effects of NMDA antagonists on PPI. Recent reports suggest that drug effects on PPI differ in subgroups of normal humans that differ in the levels of baseline PPI or specific personality domains; here, we tested the effects of these variables on the sensitivity of PPI to the NMDA antagonist, memantine. PPI was measured in male Sprague-Dawley rats, after treatment with memantine (0, 10 or 20 mg/kg, s.c.). Baseline PPI was then measured in 37 healthy adult men. Next, subjects were tested twice, in a double-blind crossover design, comparing either (1) placebo vs 20 mg of the NMDA antagonist memantine (n=19) or (2) placebo vs 30 mg memantine (n=18). Tests included measures of acoustic startle amplitude, PPI, autonomic indices and subjective self-rating scales. Memantine had dose- and interval-dependent effects on PPI in rats. Compared with vehicle, 10 mg/kg increased short-interval (10-20 ms) PPI, and 20 mg/kg decreased long-interval (120 ms) PPI. In humans, memantine caused dose-dependent effects on psychological and somatic measures: 20 mg was associated with increased ratings of happiness, and 30 mg was associated with increased ratings of dizziness. PPI at the 120 ms prepulse interval was increased by 20 mg, but not 30 mg of memantine. Subgroups most sensitive to the PPI-enhancing effects of memantine were those with low baseline PPI, or with personality scale scores suggestive of high novelty seeking, high sensation seeking, or high disinhibition. NMDA blockade with memantine appears to have dose- and interval-dependent effects on sensorimotor gating in rats and humans, particularly among specific subgroups of normal human subjects. These findings are discussed as they relate to consistencies across other studies

  3. [The progress and prospect of prepulse inhibition in autism].

    PubMed

    Wu, Zhe-Meng; Lei, Ming; Wu, Xi-Hong; Li, Liang

    2014-12-25

    Prepulse inhibition (PPI) is suppression of the startle reflex when an intense startling stimulus is preceded by a weaker sensory stimulus (the prepulse). It is an operational measurement of sensorimotor gating mechanism to help human adapt to complex environment. This weak prepulse protect central cognitive processing by damping the effect of intense stimuli. Autistics cannot select out behaviorally important information from a lot of irrelevant resources and reflect abnormal gating mechanism and attentional abnormalities. Previous studies have not made agreement on whether autistic patients demonstrated deficits in PPI, because the results depend on age, sex, severity of the disease as well as the experimental parameters used. Moreover, these studies have not covered whether autistics have suffered deficits in higher-order processing. In this review, the "top-down" modulation of selective attention and subjective emotion are introduced into the PPI experiment. We also introduce fear conditioning and perceived spatial separation paradigm to further explore the interaction between autistic cognitive process and gating mechanism. PMID:25516523

  4. Motivated attention: Incentive effects on attentional modification of prepulse inhibition

    PubMed Central

    Ashare, Rebecca L.; Hawk, Larry W.; Mazzullo, Rebecca J.

    2008-01-01

    Prepulse inhibition (PPI) of startle is greater for attended compared to ignored prestimuli, and, consistent with theories of motivated attention, initial evidence suggests that this effect is greater among participants given performance-based incentives. The present study examined a within-subjects incentive manipulation. Participants (n = 41) completed two blocks of a tone discrimination task. During the incentive block, participants received trialwise feedback with small monetary incentives for task performance. Startle eyeblink EMG responses to auditory probes were assessed at 60-, 120-, and 180-ms tone-probe stimulus onset asynchronies (SOAs). As predicted, PPI was enhanced during attended compared to ignored prestimuli only at the 120-ms SOA in the incentive condition. There was no evidence of attentional modification in the no-incentive condition. These data suggest that attentional modification of PPI is sensitive to within-subjects manipulations of incentive, providing a useful tool for testing models of motivated attention in psychopathology and psychopharmacology. PMID:17640265

  5. Effects of Stimulus-Driven and Goal-Directed Attention on Prepulse Inhibition of Brain Oscillations

    PubMed Central

    Annic, Agnès; Bourriez, Jean-Louis; Delval, Arnaud; Bocquillon, Perrine; Trubert, Claire; Derambure, Philippe; Dujardin, Kathy

    2016-01-01

    Objective: Prepulse inhibition (PPI) is an operational measure of sensory gating. PPI of cortical response to a startling pulse is known to be modulated by attention. With a time-frequency analysis, we sought to determine whether goal-directed and stimulus-driven attention differentially modulate inhibition of cortical oscillations elicited by a startling pulse. Methods: An electroencephalogram (EEG) was recorded in 26 healthy controls performing an active acoustic PPI paradigm. Startling stimuli were presented alone or either 400 or 1000 ms after one of three types of visual prepulse: to-be-attended (goal-directed attention), unexpected (stimulus-driven attention) or to-be-ignored (non-focused attention). We calculated the percentage PPI for the auditory event-related spectral perturbation (ERSP) of theta (4–7 Hz), alpha (8–12 Hz), beta1 (13–20 Hz) and beta2 (20–30 Hz) oscillations and changes in inter-trial coherence (ITC), a measure of phase synchronization of electroencephalographic activity. Results: At 400 ms: (i) PPI of the ERSP of alpha, theta and beta1 oscillation was greater after an unexpected and a to-be-attended prepulse than after a to-be-ignored prepulse; and (ii) PPI of beta2 oscillations was greater after a to-be-attended than a to-be-ignored prepulse. At 1000 ms: (i) PPI of alpha oscillations was greater after an unexpected and a to-be-attended prepulse than after a to-be-ignored prepulse; and (ii) PPI of beta1 oscillations was greater after a to-be-attended than a to-be-ignored prepulse. The ITC values did not vary according to the type of prepulse. Conclusions: In an active PPI paradigm, stimulus-driven and goal-directed attention each have differential effects on the modulation of cortical oscillations. PMID:27524966

  6. Top-down modulation of prepulse inhibition of the startle reflex in humans and rats.

    PubMed

    Li, Liang; Du, Yi; Li, Nanxin; Wu, Xihong; Wu, Yanhong

    2009-09-01

    Prepulse inhibition (PPI) is the attenuation of the startle reflex when the sudden intense startling stimulus is shortly preceded by a weaker, non-startling sensory stimulus (prepulse). PPI reflects a protective function of reducing disruptive influences to the processing of prepulse signals and is recognized as a model of sensorimotor gating. In humans, PPI is modulated by both attentional and emotional responses to prepulse, indicating that this early-stage gating is top-down modulated by higher-order cognitive processes. Recent studies have confirmed top-down modulation of PPI in animals, because PPI in rats is enhanced by auditory fear conditioning and perceived separation between fear-conditioned prepulse and masker. This review summarizes recent studies of top-down modulation of PPI conducted in humans and those in rats. Since both baseline PPI and attentional modulation of PPI in patients with schizophrenia are impaired, and both baseline PPI and conditional modulation of PPI in rats with isolation rearing are impaired, this review emphasizes that investigation of top-down modulation of PPI is critical for establishing new animal models for studying both cognitive features and neural bases of schizophrenia. Deficits in either baseline PPI or attentional modulation of PPI in either patients with attention-deficit/hyperactivity disorder (ADHD) or ADHD-modeling rats are also discussed. PMID:19747594

  7. Stuttering and Sensory Gating: A Study of Acoustic Startle Prepulse Inhibition

    ERIC Educational Resources Information Center

    Alm, Per A.

    2006-01-01

    It was hypothesized that stuttering may be related to impaired sensory gating, leading to overflow of superfluous disturbing auditory feedback and breakdown of the speech sequence. This hypothesis was tested using the "acoustic startle prepulse inhibition" (PPI) paradigm. A group of 22 adults with developmental stuttering were compared with…

  8. Prepulse Inhibition of the Acoustic Startle Reflex in High Functioning Autism

    PubMed Central

    Gruendler, Theo O. J.; Vogeley, Kai; Klosterkötter, Joachim; Kuhn, Jens

    2014-01-01

    Background High functioning autism is an autism spectrum disorder that is characterized by deficits in social interaction and communication as well as repetitive and restrictive behavior while intelligence and general cognitive functioning are preserved. According to the weak central coherence account, individuals with autism tend to process information detail-focused at the expense of global form. This processing bias might be reflected by deficits in sensorimotor gating, a mechanism that prevents overstimulation during the transformation of sensory input into motor action. Prepulse inhibition is an operational measure of sensorimotor gating, which indicates an extensive attenuation of the startle reflex that occurs when a startling pulse is preceded by a weaker stimulus, the prepulse. Methods In the present study, prepulse inhibition of acoustic startle was compared between 17 adults with high functioning autism and 17 sex-, age-, and intelligence-matched controls by means of electromyography. Results Results indicate that participants with high functioning autism exhibited significantly higher startle amplitudes than the control group. However, groups did not differ with regard to PPI or habituation of startle. Discussion These findings challenge the results of two previous studies that reported prepulse inhibition deficits in high-functioning autism and suggest that sensorimotor gating is only impaired in certain subgroups with autism spectrum disorder. PMID:24643088

  9. Auditory sensitivity of larval zebrafish (Danio rerio) measured using a behavioral prepulse inhibition assay

    PubMed Central

    Bhandiwad, Ashwin A.; Zeddies, David G.; Raible, David W.; Rubel, Edwin W.; Sisneros, Joseph A.

    2013-01-01

    SUMMARY Zebrafish (Danio rerio) have become a valuable model for investigating the molecular genetics and development of the inner ear in vertebrates. In this study, we employed a prepulse inhibition (PPI) paradigm to assess hearing in larval wild-type (AB) zebrafish during early development at 5–6 days post-fertilization (d.p.f.). We measured the PPI of the acoustic startle response in zebrafish using a 1-dimensional shaker that simulated the particle motion component of sound along the fish's dorsoventral axis. The thresholds to startle-inducing stimuli were determined in 5–6 d.p.f. zebrafish, and their hearing sensitivity was then characterized using the thresholds of prepulse tone stimuli (90–1200 Hz) that inhibited the acoustic startle response to a reliable startle stimulus (820 Hz at 20 dB re. 1 m s−2). Hearing thresholds were defined as the minimum prepulse tone level required to significantly reduce the startle response probability compared with the baseline (no-prepulse) condition. Larval zebrafish showed greatest auditory sensitivity from 90 to 310 Hz with corresponding mean thresholds of −19 to −10 dB re. 1 m s−2, respectively. Hearing thresholds of prepulse tones were considerably lower than previously predicted by startle response assays. The PPI assay was also used to investigate the relative contribution of the lateral line to the detection of acoustic stimuli. After aminoglycoside-induced neuromast hair-cell ablation, we found no difference in PPI thresholds between treated and control fish. We propose that this PPI assay can be used to screen for novel zebrafish hearing mutants and to investigate the ontogeny of hearing in zebrafish and other fishes. PMID:23966590

  10. Differentially organized top-down modulation of prepulse inhibition of startle.

    PubMed

    Du, Yi; Wu, Xihong; Li, Liang

    2011-09-21

    Prepulse inhibition (PPI) of startle is the suppression of the startle reflex when a weaker sensory stimulus (the prepulse) shortly precedes the startling stimulus. PPI can be attentionally enhanced in both humans and laboratory animals. This study investigated whether the following three forebrain structures, which are critical for initial cortical processing of auditory signals, auditory fear conditioning/memories, and spatial attention, respectively, play a role in the top-down modulation of PPI in rats: the primary auditory cortex (A1), lateral nucleus of the amygdala (LA), and posterior parietal cortex (PPC). The results show that, under the noise-masking condition, PPI was enhanced by fear conditioning of the prepulse in a prepulse-specific manner, and the conditioning-induced PPI enhancement was further increased by perceptual separation between the conditioned prepulse and the noise masker. Reversibly blocking glutamate receptors in the A1 with 2 mm kynurenic acid eliminated both the conditioning-induced and perceptual separation-induced PPI enhancements. Blocking the LA eliminated the conditioning-induced but not the perceptual separation-induced PPI enhancement, and blocking the PPC specifically eliminated the perceptual separation-induced PPI enhancement. The two types of PPI enhancements were also eliminated by the extinction manipulation. Thus, the top-down modulation of PPI is differentially organized and depends on operations of various forebrain structures. Due to the fine-tuned modulation by higher-order cognitive processes, functions of PPI can be more flexible to complex environments. The top-down enhancements of PPI in rats are also useful for modeling some mental disorders, such as schizophrenia, attention deficit/hyperactivity disorder, and posttraumatic stress disorder. PMID:21940455

  11. Impaired Prepulse Inhibition and Prepulse-Elicited Reactivity but Intact Reflex Circuit Excitability in Unmedicated Schizophrenia Patients: a Comparison With Healthy Subjects and Medicated Schizophrenia Patients

    PubMed Central

    Csomor, Philipp A.; Yee, Benjamin K.; Feldon, Joram; Theodoridou, Anastasia; Studerus, Erich; Vollenweider, Franz X.

    2009-01-01

    Deficient sensorimotor gating as indexed by prepulse inhibition (PPI) of the startle response has been reported repeatedly in patients suffering from schizophrenia. According to the widely accepted “protective hypothesis,” PPI reflects the protection of ongoing information processing against interference by other stimuli. Alternatively, it has been proposed that PPI might be regulated by startle reflex circuit excitability. In the present study, we evaluated these 2 conceptually divergent approaches underlying the regulation of PPI. To this end, we assessed sensorimotor gating as indexed by PPI, the reactivity to the prepulse-alone stimulus indexed as prepulse-elicited reactivity (PPER), and acoustic blink reflex excitability in terms of paired pulse suppression (PPS) within a single recording session in 13 unmedicated and 24 medicated (11 first break) schizophrenia patients in comparison to 43 healthy control subjects. The results showed that PPI was significantly reduced in unmedicated, but not in medicated schizophrenia patients. Furthermore, unmedicated patients could be distinguished from the medicated patients and control subjects in terms of PPER. In contrast to PPI, PPS did not differ between patients and control subjects. These findings are in line with the “protective hypothesis” of PPI and indicate that reduced sensorimotor gating in schizophrenia patients might be based on a reduced perception and/or processing of the prepulse stimulus. The extent to which PPER may or may not be causally associated with sensorimotor gating in schizophrenia has to be further investigated in human and animal studies. PMID:18245063

  12. Dissociative identity disorder and prepulse inhibition of the acoustic startle reflex

    PubMed Central

    Dale, Karl Yngvar; Flaten, Magne Arve; Elden, Åke; Holte, Arne

    2008-01-01

    A group of persons with dissociative identity disorder (DID) was compared with a group of persons with other dissociative disorders, and a group of nondiagnosed controls with regard to prepulse inhibition (PPI) of the acoustic startle reflex. The findings suggest maladaptive attentional processes at a controlled level, but not at a preattentive automatic level, in persons with DID. The prepulse occupied more controlled attentional resources in the DID group compared with the other two groups. Preattentive automatic processing, on the other hand, was normal in the DID group. Moreover, startle reflexes did not habituate in the DID group. In conclusion, increased PPI and delayed habituation is consistent with increased vigilance in individuals with DID. The present findings of reduced habituation of startle reflexes and increased PPI in persons with DID suggest the operation of a voluntary process that directs attention away from unpleasant or threatening stimuli. Aberrant voluntary attentional processes may thus be a defining characteristic in DID. PMID:18830396

  13. Realistic expectations of prepulse inhibition in translational models for schizophrenia research

    PubMed Central

    Swerdlow, Neal R.; Weber, Martin; Qu, Ying; Light, Gregory A.; Braff, David L.

    2009-01-01

    Introduction Under specific conditions, a weak lead stimulus, or “prepulse”, can inhibit the startling effects of a subsequent intense abrupt stimulus. This startle-inhibiting effect of the prepulse, termed “prepulse inhibition” (PPI), is widely used in translational models to understand the biology of brain based inhibitory mechanisms and their deficiency in neuropsychiatric disorders. In 1981, four published reports with “prepulse inhibition” as an index term were listed on Medline; over the past 5 years, new published Medline reports with “prepulse inhibition” as an index term have appeared at a rate exceeding once every 2.7 days (n = 678). Most of these reports focus on the use of PPI in translational models of impaired sensorimotor gating in schizophrenia. This rapid expansion and broad application of PPI as a tool for understanding schizophrenia has, at times, outpaced critical thinking and falsifiable hypotheses about the relative strengths vs. limitations of this measure. Objectives This review enumerates the realistic expectations for PPI in translational models for schizophrenia research, and provides cautionary notes for the future applications of this important research tool. Conclusion In humans, PPI is not “diagnostic”; levels of PPI do not predict clinical course, specific symptoms, or individual medication responses. In preclinical studies, PPI is valuable for evaluating models or model organisms relevant to schizophrenia, “mapping” neural substrates of deficient PPI in schizophrenia, and advancing the discovery and development of novel therapeutics. Across species, PPI is a reliable, robust quantitative phenotype that is useful for probing the neurobiology and genetics of gating deficits in schizophrenia. PMID:18568339

  14. Effects of acute nicotine on prepulse inhibition of auditory change-related cortical responses.

    PubMed

    Kodaira, Minori; Tsuruhara, Aki; Motomura, Eishi; Tanii, Hisashi; Inui, Koji; Kakigi, Ryusuke

    2013-11-01

    Prepulse inhibition (PPI) of startle is a measure of inhibitory function in which a weak leading stimulus suppresses the startle response to an intense stimulus. Usually, startle blink reflexes to an intense sound are used for measuring PPI. A recent magnetoencephalographic study showed that a similar phenomenon is observed for auditory change-related cortical response (Change-N1m) to an abrupt change in sound features. It has been well established that nicotine enhances PPI of startle. Therefore, in the present magnetoencephalographic study, the effects of acute nicotine on PPI of the Change-N1m were studied in 12 healthy subjects (two females and 10 males) under a repeated measures and placebo-controlled design. Nicotine (4 mg) was given as nicotine gum. The test Change-N1m response was elicited with an abrupt increase in sound pressure by 6 dB in a continuous background sound of 65 dB. PPI was produced by an insertion of a prepulse with a 3-dB-louder or 6-dB-weaker sound pressure than the background 75 ms before the test stimulus. Results show that nicotine tended to enhance the test Change-N1m response and significantly enhanced PPI for both prepulses. Therefore, nicotine's enhancing effect on PPI of the Change-N1m was similar to that on PPI of the startle. The present results suggest that the two measures share at least some mechanisms. PMID:23933145

  15. Finasteride administration potentiates the disruption of prepulse inhibition induced by forced swim stress.

    PubMed

    Pallarès, M; Llidó, A; Mòdol, L; Vallée, M; Darbra, S

    2015-08-01

    Acute stress has been demonstrated to alter sensory gating processes, measured by the prepulse inhibition of the startle response (PPI). It is well known that brain and plasma levels of the neurosteroid allopregnanolone (ALLO) increase after acute environmental stress, fact that has been considered a homeostatic mechanism in restoring normal function following stress. Thus, it is of great interest to study the contribution of stress-altered plasma ALLO levels on PPI function. For this purpose, animals were injected with finasteride, an ALLO synthesis inhibitor, and submitted to swim stress before PPI testing. In order to obtain ALLO plasma levels, a separate set of animals that followed the same experimental procedure was used. We hypothesize that the blockade of ALLO production in response to stress can increase the stress-induced PPI disruption. In accordance with other authors, our results indicate that acute swim stress disrupted the normal PPI evolution (increase) related to the increase in prepulse intensities, and also decreased PPI at the highest prepulse intensity level (15 db above background). Finasteride potentiated the PPI decrease induced by swim stress in the intermediate prepulse intensity (10 db above background). As expected, plasma ALLO levels were increased in stressed animals and this increase was neutralized by prior finasteride administration. These results indicate that the neutralization of the physiological plasma ALLO levels increase after acute stress potentiates stress-induced PPI disruption. This data suggests that alterations in homeostatic ALLO synthesis mechanism may be linked to some neuropsychiatric disorders related to stress, such as anxiety/depression disorders. PMID:25913832

  16. Standardized extract of Ficus platyphylla reverses apomorphine-induced changes in prepulse inhibition and locomotor activity in rats.

    PubMed

    Chindo, Ben A; Kahl, Evelyn; Trzeczak, Doris; Dehmel, Petra; Becker, Axel; Fendt, Markus

    2015-10-15

    Preparations of Ficus platyphylla are used in Nigeria's folk medicine to manage a plethora of diseases including, insomnia, psychoses, depression, epilepsy, pain and inflammation. In this study, we examined the effects of the standardized methanol extract of F. platyphylla stem bark (FP) on apomorphine-induced changes in prepulse inhibition and locomotor activity in rats, as well as on the retrieval of a conditioned reaction in one-way active avoidance in mice. FP did not affect basal prepulse inhibition, but significantly reduced locomotor activity. The apomorphine-induced prepulse inhibition deficit and hyperactivity were significantly reversed by co-administration of clozapine or FP. Furthermore, FP inhibited the retrieval of a conditioned avoidance reaction. Our results revealed that FP contains psychoactive ingredients with neuroleptic-like properties, thus supporting the isolation and development of the biologically active components of this medicinal plant as antipsychotic agents. PMID:26192913

  17. Chronic estrogen and progesterone treatment inhibits ketamine-induced disruption of prepulse inhibition in rats.

    PubMed

    van den Buuse, Maarten; Mingon, Rebecca L; Gogos, Andrea

    2015-10-21

    Ketamine is a dissociative anesthetic and antagonist of N-methyl-d-aspartate receptors (NMDAr). Hypofunction of NMDAr may underlie some schizophrenia symptoms and the psychotomimetic effects of ketamine have been used to model this hypofunction. Gender differences exist in the age of onset and symptom profile of schizophrenia and sex steroid hormones have been successfully trialed as adjunctive treatment in this illness; however, the mechanism of action of these hormone treatment strategies remains unclear. The aim of this study was therefore to investigate the effect of sex steroid hormones on ketamine-induced disruption of prepulse inhibition (PPI), an endophenotype of schizophrenia. Female ovariectomized (OVX) rats did not show altered effects of ketamine compared to intact rats. There were also no significant changes in the effect of ketamine on PPI in OVX rats implanted with a high dose of estrogen. In contrast, in OVX rats implanted with a low dose of estrogen plus progesterone, the effect of 10mg/kg ketamine was significantly reduced. There were no parallel changes in startle amplitude. These results differ from previous studies on the effect of sex steroid hormones on the disruption of PPI by treatment with the NMDAr antagonist, MK-801, or dopaminergic drugs, such as apomorphine. We speculate that this differential effect of sex steroids on the action of ketamine is mediated by mechanisms other than dopaminergic stimulation or NMDA receptor blockade, for example GABAA receptors. These results extend our understanding of the effects of sex steroid hormones on PPI and their use as potential treatments in schizophrenia. PMID:26391745

  18. Different effects of unexpected changes in environmental conditions on prepulse inhibition in rats and humans.

    PubMed

    De la Casa, L G; Fernandez, A; Larrauri, J; Mena, A; Puentes, A; Quintero, E; Schmajuk, N

    2012-06-25

    The reduction of the startle response to an auditory stimulus caused by the presentation of another stimulus of lower intensity closely preceding it, a phenomenon known as prepulse inhibition (PPI), can be modulated by changes in dopaminergic activity. Schmajuk, Larrauri, De la Casa, and Levin (2009) demonstrated that this dopaminergic modulation of PPI in rats can be influenced by manipulating the experimental context, specifically by introducing changes in the ambient lighting condition that include novel elements. In this paper we analyze the effects of introducing changes in context illumination on PPI in male rats (Experiment 1) and humans (Experiment 2). The results with rats showed a reduction of PPI when the illumination condition switched from dark to light, but not from light to dark. In the experiment with human participants the reduction of PPI occurred for both changes in illumination conditions. The animal experiment results are interpreted in terms of competing exploratory behavior that appear when the context is illuminated after the dark-light transition; while in the case of human participants a perceptual and/or attentional mechanism after both illumination transitions is proposed, which may result in a reduced processing of the prepulse and subsequent lower PPI. PMID:22504495

  19. Hypnotizability, Hypnosis and Prepulse Inhibition of the Startle Reflex in Healthy Women: An ERP Analysis

    PubMed Central

    De Pascalis, Vilfredo; Russo, Emanuela

    2013-01-01

    A working model of the neurophysiology of hypnosis suggests that highly hypnotizable individuals (HHs) have more effective frontal attentional systems implementing control, monitoring performance, and inhibiting unwanted stimuli from conscious awareness, than low hypnotizable individuals (LHs). Recent studies, using prepulse inhibition (PPI) of the auditory startle reflex (ASR), suggest that HHs, in the waking condition, may show reduced sensory gating although they may selectively attend and disattend different stimuli. Using a within subject design and a strict subject selection procedure, in waking and hypnosis conditions we tested whether HHs compared to LHs showed a significantly lower inhibition of the ASR and startle-related brain activity in both time and intracerebral source localization domains. HHs, as compared to LH participants, exhibited (a) longer latency of the eyeblink startle reflex, (b) reduced N100 responses to startle stimuli, and (c) higher PPI of eyeblink startle and of the P200 and P300 waves. Hypnosis yielded smaller N100 waves to startle stimuli and greater PPI of this component than in the waking condition. sLORETA analysis revealed that, for the N100 (107 msec) elicited during startle trials, HHs had a smaller activation in the left parietal lobe (BA2/40) than LHs. Auditory pulses of pulse-with prepulse trials in HHs yielded less activity of the P300 (280 msec) wave than LHs, in the cingulate and posterior cingulate gyrus (BA23/31). The present results, on the whole, are in the opposite direction to PPI findings on hypnotizability previously reported in the literature. These results provide support to the neuropsychophysiological model that HHs have more effective sensory integration and gating (or filtering) of irrelevant stimuli than LHs. PMID:24278150

  20. Methodological optimization of tinnitus assessment using prepulse inhibition of the acoustic startle reflex.

    PubMed

    Longenecker, R J; Galazyuk, A V

    2012-11-16

    Recently prepulse inhibition of the acoustic startle reflex (ASR) became a popular technique for tinnitus assessment in laboratory animals. This method confers a significant advantage over the previously used time-consuming behavioral approaches utilizing basic mechanisms of conditioning. Although this technique has been successfully used to assess tinnitus in different laboratory animals, many of the finer details of this methodology have not been described enough to be replicated, but are critical for tinnitus assessment. Here we provide detail description of key procedures and methodological issues that provide guidance for newcomers with the process of learning to correctly apply gap detection techniques for tinnitus assessment in laboratory animals. The major categories of these issues include: refinement of hardware for best performance, optimization of stimulus parameters, behavioral considerations, and identification of optimal strategies for data analysis. This article is part of a Special Issue entitled: Tinnitus Neuroscience. PMID:22513102

  1. Startle response and prepulse inhibition modulation by positive- and negative-induced affect.

    PubMed

    De la Casa, Luis Gonzalo; Mena, Auxiliadora; Puentes, Andrea

    2014-02-01

    The startle response, a set of reflex behaviours intended to prepare the organism to face a potentially threatening stimulus, can be modulated by several factors as, for example, changes in affective state, or previous presentation of a weak stimulus (a phenomenon termed Pre-Pulse Inhibition [PPI]). In this paper we analyse whether the induction of positive or negative affective states in the participants modulates the startle response and the PPI phenomenon. The results revealed a decrease of the startle response and an increase of the PPI effect when registered while the participants were exposed to pleasant images (Experiment 1), and an increase of the startle response and of the PPI effect when they were exposed to a video-clip of unpleasant content (Experiment 2). These data are interpreted considering that changes in affective states correlate with changes in the startle reflex intensity, but changes in PPI might be the result of an attentional process. PMID:24188916

  2. Fear conditioning facilitates rats gap detection measured by prepulse inhibition of the startle reflex

    NASA Astrophysics Data System (ADS)

    Zou, Dan; Wu, Xihong; Li, Liang

    2005-04-01

    A low-intensity acoustic event presented shortly before an intense startling sound can inhibit the acoustic startle reflex. This phenomenon is called prepulse inhibition (PPI), and is widely used as a model of sensorimotor gating in both humans and animals. Particularly, it has been used for evaluating the aging effect on the mouse's ability to detect a silent gap in otherwise continuous sounds. The present study extended this model to the emotional modulation of gap detection. The results show that a silent gap embedded in each of the two broadband noise sounds (55 dB SPL), which were delivered by two spatially separated loudspeakers, could inhibit the startle reflex that was induced by a loud sound presented from the third loudspeaker 50 ms after the gap. The inhibitory effect largely depended on the duration of the gap, with the mean duration threshold around 11 ms across 18 rats tested. Pairing the gap with foot shock in a temporally specific manner, but not in a temporally random manner, significantly reduced the duration threshold. Thus this study established a new animal behavioral model both for studying auditory temporal processing and for studying auditory signal-detection plasticity induced by emotional learning.

  3. Gap prepulse inhibition of the auditory late response in healthy subjects.

    PubMed

    Ku, Yunseo; Ahn, Joong Woo; Kwon, Chiheon; Suh, Myung-Whan; Lee, Jun Ho; Oh, Seung Ha; Kim, Hee Chan

    2015-11-01

    The gap-startle paradigm has been used as a behavioral method for tinnitus screening in animal studies. This study aimed to investigate gap prepulse inhibition (GPI) of the auditory late response (ALR) as the objective response of the gap-intense sound paradigm in humans. ALRs were recorded in response to gap-intense and no-gap-intense sound stimuli in 27 healthy subjects. The amplitudes of the baseline-to-peak (N1, P2, and N2) and the peak-to-peak (N1P2 and P2N2) were compared between two averaged ALRs. The variations in the inhibition ratios of N1P2 and P2N2 during the experiment were analyzed by increasing stimuli repetitions. The effect of stimulus parameter adjustments on GPI ratios was evaluated. No-gap-intense sound stimuli elicited greater peak amplitudes than gap-intense sound stimuli, and significant differences were found across all peaks. The overall mean inhibition ratios were significantly lower than 1.0, where the value 1.0 indicates that there were no differences between gap-intense and no-gap-intense sound responses. The initial decline in GPI ratios was shown in N1P2 and P2N2 complexes, and this reduction was nearly complete after 100 stimulus repetitions. Significant effects of gap length and interstimulus interval on GPI ratios were observed. We found significant inhibition of ALR peak amplitudes in performing the gap-intense sound paradigm in healthy subjects. The N1P2 complex represented GPI well in terms of suppression degree and test-retest reliability. Our findings offer practical information for the comparative study of healthy subjects and tinnitus patients using the gap-intense sound paradigm with the ALR. PMID:26272085

  4. Differential involvement of 5-HT projections within the amygdala in prepulse inhibition but not in psychotomimetic drug-induced hyperlocomotion.

    PubMed

    Kusljic, Snezana; van den Buuse, Maarten

    2006-03-15

    While there is abundant evidence for a role of 5-HT and the amygdala in anxiety and depression, the role of 5-HT in this brain region in schizophrenia is less well understood. We therefore examined the effects of local 5-HT depletion in the amygdala on psychotomimetic drug-induced locomotor hyperactivity and prepulse inhibition, two animal model of aspects of schizophrenia. Pentobarbital-anaesthetized (60 mg/kg, i.p.) male Sprague-Dawley rats were stereotaxically micro-injected with 0.5 microl of a 5 microg/mul solution of the 5-HT neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) into either the basolateral (BLA) or central nucleus of amygdala (CeN). Two weeks after the surgery, rats with BLA lesions did not show changes in either psychotomimetic drug-induced locomotor hyperactivity or prepulse inhibition. In contrast, rats with CeN lesions showed significant disruption of prepulse inhibition, but no changes in psychotomimetic drug-induced locomotor hyperactivity. Neurochemical analysis and autoradiographic labelling of 5-HT transporter sites showed that a good degree of anatomical selectivity was obtained. Following administration of 5,7-DHT into the amygdala, the concentration of 5-HT was significantly reduced. Similarly, 5-HT transporter autoradiographs showed differential and selective lesions of 5-HT innervation in targeted subregions of the amygdala. These results provide evidence for differential involvement of 5-HT projections within the amygdala in prepulse inhibition but not locomotor hyperactivity. Thus, the present study supports the view that 5-HT in the amygdala may be involved in aspects of schizophrenia and a target for antipsychotic drug action. PMID:16303186

  5. Alterations to prepulse inhibition magnitude and latency in adult rats following neonatal treatment with domoic acid and social isolation rearing.

    PubMed

    Marriott, Amber L; Tasker, R Andrew; Ryan, Catherine L; Doucette, Tracy A

    2016-02-01

    Deficits in perceptual, informational, and attentional processing are consistently identified as a core feature in schizophrenia and related neuropsychiatric disorders. Neonatal injections of low doses of the AMPA/kainate agonist domoic acid (DOM) have previously been shown to alter various aspects of perceptual and attentional processing in adult rats. The current study investigated the effects of combined neonatal DOM treatment with isolation rearing on prepulse inhibition behaviour and relevant neurochemical measures, to assess the usefulness of these paradigms in modeling neurodevelopmental disorders. Daily subcutaneous injections of DOM (20 μg/kg) or saline were administered to male and female rat pups from postnatal days (PND) 8-14. After weaning, rats were either housed alone or in groups of 4. Both the magnitude and latency of prepulse inhibition were determined in adulthood (approximately 4.5 months of age) and post-mortem brain tissue was assayed using Western blot. Social isolation alone significantly lowered PPI magnitude in male (but not female) rats while DOM treatment appeared to make animals refractory to this effect. Combining social isolation and DOM treatment caused an additive decrease in PPI startle latency. No statistically significant differences were found in the expression of D1, D2, TH, GAD65 or GAD67 protein in either the prefrontal cortex or hippocampus, although some tendencies toward differences were noted. We conclude that both neonatal low-dose DOM and social isolation affect prepulse inhibition in rats but that each paradigm exerts these effects through different neuronal signalling systems. PMID:26590368

  6. Deficit in Prepulse Inhibition in Mice Caused by Dietary n-3 Fatty Acid Deficiency

    PubMed Central

    Fedorova, Irina; Alvheim, Anita R.; Hussein, Nahed; Salem, Norman

    2010-01-01

    Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) may be biosynthesized from a precursor α-linolenic acid (LNA) or obtained preformed in the diet. Dams were fed four diets with different levels of the various n-3 fatty acids during pregnancy and lactation, and their offspring were weaned to the same diets: “n-3 Deficient”, containing (as % total fatty acids) 0.07% of LNA; “Low LNA” (0.4%); “High LNA” (4.8%); and a “DHA+EPA” diet, containing 0.4% of LNA, 2% DHA and 2% EPA. Sensorimotor gating was measured by prepulse inhibition (PPI) of the acoustic startle response in C57Bl6 mice. The n-3 Deficient and Low LNA diets caused a substantial deficit in PPI compared to the DHA+EPA diet, whereas the High LNA diet induced a less pronounced, but significant reduction of PPI. These are the first data that demonstrate a deficit in sensorimotor gating in rodents caused by an inadequate amount of the n-3 fatty acids in the diet. Our results differentiate the effects of a High LNA diet from one with added EPA and DHA even though the difference in brain DHA content is only 12% between these dietary groups. PMID:20001105

  7. Behavioral and pharmacological validation of an integrated fear-potentiated startle and prepulse inhibition paradigm.

    PubMed

    Zhang, Mengjiao; Li, Ming

    2016-07-01

    Fear-potentiated startle (FPS) and prepulse inhibition (PPI) of acoustic startle are two widely used paradigms specifically designed to capture the impact of negative emotion (e.g. fear) and preattentive function on startle response. Currently, there is no single paradigm that incorporates both FPS and PPI, making it impossible to examine the potential interactions between fear and attention in the regulation of startle response. In this study, we developed an integrated FPS and PPI test protocol and validated it with psychoactive drugs. In Experiment 1, male Sprague-Dawley rats were randomly assigned to one of five groups, receiving either Light -Shock conditioning trials, non-overlapping Lights and Shocks, Light alone, Shock alone, or no Light and Shock. They were then tested for startle response and PPI concurrently, under the Light or No Light. FPS was observed only in rats subjected to fear conditioning, whereas all rats showed PPI and startle habituation. Experiment 2 used this paradigm and demonstrated a dissociative effect between diazepam (an anxiolytic drug) and phencyclidine (a nonselective NMDA receptor antagonist) on FPS and PPI. Diazepam suppressed both FPS and PPI, while PCP selectively disrupted PPI but not FPS. The diazepam's anxiolytic effect on FPS was further confirmed in the elevated plus maze test. Together, our findings indicate that our paradigm combines FPS and PPI into a single paradigm, and that is useful to examine potential interactions between multiple psychological processes, to identify the common neural substrates and to screen new drugs with multiple psychoactive effects. PMID:27059335

  8. Acoustic startle and prepulse inhibition predict smoking lapse in posttraumatic stress disorder.

    PubMed

    Vrana, Scott R; Calhoun, Patrick S; Dennis, Michelle F; Kirby, Angela C; Beckham, Jean C

    2015-10-01

    Most smokers who attempt to quit lapse within the first week and are ultimately unsuccessful in their quit attempt. Nicotine withdrawal exacerbates cognitive and attentional problems and may be one factor in smoking relapse. The startle reflex response and prepulse inhibition (PPI) of the response are sensitive to arousal and early attentional dysregulation. The current study examined whether startle response and PPI are related to early smoking lapse, and if this differs in people with and without posttraumatic stress disorder (PTSD). Participants with (N = 34) and without (N = 57) PTSD completed a startle reflex and PPI assessment during (1) ad lib smoking (2) on the first day of abstinence during a quit attempt. Most (88%) participants lapsed within the first week of the quit attempt. PTSD status predicted shorter time to lapse. Larger startle magnitude and greater PPI predicted a longer duration before smoking lapse. When diagnostic groups were examined separately, greater PPI predicted a longer successful quit attempt only in participants with a PTSD diagnosis. The startle reflex response and PPI may provide an objective, neurophysiological evaluation of regulation of arousal and early attentional processes by nicotine, which are important factors in smoking cessation success. PMID:26253620

  9. Effects of Intravenous Nicotine on Prepulse Inhibition in Smokers and Nonsmokers: Relationship with Familial Smoking

    PubMed Central

    Drobes, David J.; MacQueen, David A.; Blank, Melissa D.; Saladin, Michael E.; Malcolm, Robert J.

    2013-01-01

    Rationale The reinforcing properties of nicotine may be, in part, derived from its ability to enhance certain forms of cognitive processing. Several animal and human studies have shown that nicotine increases prepulse inhibition (PPI) of the startle reflex. However, it remains unclear whether these effects are related to smoking susceptibility. Objectives The current study examined the effects of intravenously delivered nicotine on PPI in smokers and nonsmokers, as well as its association with a quantitative index of familial smoking. Methods The sample consisted of 30 non-smokers and 16 smokers, who completed an initial assessment, followed on a separate day by a laboratory assessment of PPI prior to and following each of two intravenous nicotine infusions. Separate doses were used in smoker and non-smoker samples. Results Analyses indicated that both nicotine infusions acutely enhanced PPI among non-smokers, and this enhancement was positively related to the degree of smoking among first and second-degree relatives. Smokers also displayed PPI enhancement after receiving the first infusion, but this effect was unrelated to familial smoking. Conclusions These data suggest that the PPI paradigm may have utility as an endophenotype for cognitive processes which contribute to smoking risk. PMID:23624809

  10. Sleep duration, depression, and oxytocinergic genotype influence prepulse inhibition of the startle reflex in postpartum women.

    PubMed

    Comasco, Erika; Gulinello, Maria; Hellgren, Charlotte; Skalkidou, Alkistis; Sylven, Sara; Sundström-Poromaa, Inger

    2016-04-01

    The postpartum period is characterized by a post-withdrawal hormonal status, sleep deprivation, and susceptibility to affective disorders. Postpartum mothering involves automatic and attentional processes to screen out new external as well as internal stimuli. The present study investigated sensorimotor gating in relation to sleep duration, depression, as well as catecholaminergic and oxytocinergic genotypes in postpartum women. Prepulse inhibition (PPI) of the startle reflex and startle reactivity were assessed two months postpartum in 141 healthy and 29 depressed women. The catechol-O-methyltransferase (COMT) Val158Met, and oxytocin receptor (OXTR) rs237885 and rs53576 polymorphisms were genotyped, and data on sleep duration were collected. Short sleep duration (less than four hours in the preceding night) and postpartum depression were independently associated with lower PPI. Also, women with postpartum depression had higher startle reactivity in comparison with controls. The OXTR rs237885 genotype was related to PPI in an allele dose-dependent mode, with T/T healthy postpartum women carriers displaying the lowest PPI. Reduced sensorimotor gating was associated with sleep deprivation and depressive symptoms during the postpartum period. Individual neurophysiological vulnerability might be mediated by oxytocinergic genotype which relates to bonding and stress response. These findings implicate the putative relevance of lower PPI of the startle response as an objective physiological correlate of liability to postpartum depression. PMID:26857197

  11. Spontaneously Hypertensive Rats (SHR) present deficits in prepulse inhibition of startle specifically reverted by clozapine.

    PubMed

    Levin, Raquel; Calzavara, Mariana Bendlin; Santos, Camila Maurício; Medrano, Wladimir Agostini; Niigaki, Suzy Tamie; Abílio, Vanessa Costhek

    2011-08-15

    Deficits in an operational measure of sensorimotor gating - the prepulse inhibition of startle (PPI) - are presented in psychiatric disorders such as schizophrenia, bipolar disorder, and attention deficit/hyperactivity disorder (ADHD). Some previous studies showed that the spontaneously hypertensive rats (SHR) present PPI deficit. Although SHR is suggested as an animal model to study ADHD, we have suggested that the behavioral phenotype of this strain mimics some aspects of schizophrenia. The aim of this study was to characterize the PPI response in SHR. Pharmacological characterization consisted in the evaluation of the effects of the following drugs administered to adult Wistar rats (WR) and SHR previously to the PPI test: amphetamine (used for ADHD and also a psychotomimetic drug), haloperidol and clozapine (antipsychotic drugs), metoclopramide (dopamine antagonist without antipsychotic properties) and carbamazepine (mood stabilizer). Our results showed that SHR presented reduced PPI. This deficit was similar to that induced by amphetamine in WR. Only the atypical antipsychotic clozapine improved the PPI deficit observed in SHR. These findings reinforce the SHR strain as an animal model to study several aspects of schizophrenia, including the abnormalities in sensorimotor gating associated with this disease. PMID:21693159

  12. Prepulse inhibition of the acoustic startle reflex vs. auditory brainstem response for hearing assessment.

    PubMed

    Longenecker, R J; Alghamdi, F; Rosen, M J; Galazyuk, A V

    2016-09-01

    The high prevalence of noise-induced and age-related hearing loss in the general population has warranted the use of animal models to study the etiology of these pathologies. Quick and accurate auditory threshold determination is a prerequisite for experimental manipulations targeting hearing loss in animal models. The standard auditory brainstem response (ABR) measurement is fairly quick and translational across species, but is limited by the need for anesthesia and a lack of perceptual assessment. The goal of this study was to develop a new method of hearing assessment utilizing prepulse inhibition (PPI) of the acoustic startle reflex, a commonly used tool that measures detection thresholds in awake animals, and can be performed on multiple animals simultaneously. We found that in control mice PPI audiometric functions are similar to both ABR and traditional operant conditioning audiograms. The hearing thresholds assessed with PPI audiometry in sound exposed mice were also similar to those detected by ABR thresholds one day after exposure. However, three months after exposure PPI threshold shifts were still evident at and near the frequency of exposure whereas ABR thresholds recovered to the pre-exposed level. In contrast, PPI audiometry and ABR wave one amplitudes detected similar losses. PPI audiometry provides a high throughput automated behavioral screening tool of hearing in awake animals. Overall, PPI audiometry and ABR assessments of the auditory system are robust techniques with distinct advantages and limitations, which when combined, can provide ample information about the functionality of the auditory system. PMID:27349914

  13. Combined prenatal and chronic postnatal vitamin D deficiency in rats impairs prepulse inhibition of acoustic startle.

    PubMed

    Burne, Thomas H J; Féron, François; Brown, Jillanne; Eyles, Darryl W; McGrath, John J; Mackay-Sim, Alan

    2004-06-01

    There is growing evidence that 1,25-dihydroxyvitamin D3 is involved in normal brain development. The aim of this study was to examine the impact of prenatal and postnatal hypovitaminosis D on prepulse inhibition (PPI) of acoustic startle in adult rats. We compared six groups of rats: control rats with normal vitamin D throughout life and normal litter size (Litter); control rats with normal vitamin D but with a reduced litter size of two (Control); offspring from reduced litters of vitamin D deplete mothers who were repleted at birth (Birth), repleted at weaning (Weaning) or remained on a deplete diet until 10 weeks of age (Life); or control rats that were placed on a vitamin D-deficient diet from 5 to 10 weeks of age (Adult). All rats were tested in acoustic startle chambers at 5 and 10 weeks of age for acoustic startle responses and for PPI. There were no significant group differences at 5 weeks of age on the acoustic startle response or on PPI. At 10 weeks of age, rats in the Life group only had impaired PPI despite having normal acoustic startle responses. We conclude that combined prenatal and chronic postnatal hypovitaminosis D, but not early life hypovitaminosis D, alters PPI. PMID:15178159

  14. Differential effect of clomipramine on habituation and prepulse inhibition in dominant versus subordinate rats.

    PubMed

    Yang, Alvin; Daya, Tahira; Carlton, Karen; Yan, Jin Hui; Schmid, Susanne

    2016-03-01

    Many patients with depression have comorbidities associated with an impairment of sensorimotor gating, such as e.g. schizophrenia, Parkinson Disease, or Alzheimer disease. Anti-depressants like clomipramine that modulate serotonergic or norepinephrinergic neurotransmission have been shown to impact sensorimotor gating, it is therefore important to study potential effects of clomipramine in order to rule out an exacerbation of sensorimotor gating impairment. Prior studies in animals and humans have been inconclusive. Since serotonin and norepinephrine levels are closely related to anxiety and stress levels and therefore to the social status of an animal, we tested the hypothesis that acute and chronic effects of clomipramine on sensorimotor gating are different in dominant versus subordinate rats, which might be responsible for conflicting results in past animal studies. We used habituation and prepulse inhibition (PPI) of the acoustic startle response as operational measures of sensorimotor gating. After establishing the dominant animal in pair-housed male rats, we injected clomipramine for two weeks and measured acute effects on baseline startle, habituation and PPI after the first injection and chronic effects at the end of the two weeks. Chronic treatment with clomipramine significantly increased habituation in subordinate rats, but had no effect on habituation in dominant animals. Furthermore, PPI was slightly enhanced in subordinate rats upon chronic treatment while no changes occurred in dominant animals. We conclude that the social status of an animal, and therefore the basic anxiety/stress level determines whether or not clomipramine has a beneficial effect on sensorimotor gating and discuss possible underlying mechanisms. PMID:26754403

  15. Effects of deep brain stimulation on prepulse inhibition in obsessive-compulsive disorder.

    PubMed

    Kohl, S; Gruendler, T O J; Huys, D; Sildatke, E; Dembek, T A; Hellmich, M; Vorderwulbecke, M; Timmermann, L; Ahmari, S E; Klosterkoetter, J; Jessen, F; Sturm, V; Visser-Vandewalle, V; Kuhn, J

    2015-01-01

    Owing to a high response rate, deep brain stimulation (DBS) of the ventral striatal area has been approved for treatment-refractory obsessive-compulsive disorder (tr-OCD). Many basic issues regarding DBS for tr-OCD are still not understood, in particular, the mechanisms of action and the origin of side effects. We measured prepulse inhibition (PPI) in treatment-refractory OCD patients undergoing DBS of the nucleus accumbens (NAcc) and matched controls. As PPI has been used in animal DBS studies, it is highly suitable for translational research. Eight patients receiving DBS, eight patients with pharmacological treatment and eight age-matched healthy controls participated in our study. PPI was measured twice in the DBS group: one session with the stimulator switched on and one session with the stimulator switched off. OCD patients in the pharmacologic group took part in a single session. Controls were tested twice, to ensure stability of data. Statistical analysis revealed significant differences between controls and (1) patients with pharmacological treatment and (2) OCD DBS patients when the stimulation was switched off. Switching the stimulator on led to an increase in PPI at a stimulus-onset asynchrony of 200 ms. There was no significant difference in PPI between OCD patients being stimulated and the control group. This study shows that NAcc-DBS leads to an increase in PPI in tr-OCD patients towards a level seen in healthy controls. Assuming that PPI impairments partially reflect the neurobiological substrates of OCD, our results show that DBS of the NAcc may improve sensorimotor gating via correction of dysfunctional neural substrates. Bearing in mind that PPI is based on a complex and multilayered network, our data confirm that DBS most likely takes effect via network modulation. PMID:26556284

  16. Cortical electroconvulsive stimulation alleviates breeding-induced prepulse inhibition deficit in rats.

    PubMed

    John, Nadine; Theilmann, Wiebke; Frieling, Helge; Krauss, Joachim K; Alam, Mesbah; Schwabe, Kerstin; Brandt, Claudia

    2016-01-01

    In patients with medical-refractory schizophrenia electroconvulsive therapy (ECT), i.e., the induction of therapeutic seizures via cortical surface electrodes, is effectively used. Electroconvulsive stimulation (ECS) in rodents simulates ECT in humans and is applied to investigate the mechanisms underlying this treatment. Experimentally-induced reduced prepulse inhibition (PPI) of the acoustic startle response (ASR), i.e., the reduction of the startle response to an intense acoustic stimulus when this stimulus is shortly preceded by a weaker not-startling stimulus, serves as an endophenotype for neuropsychiatric disorders that are accompanied by disturbed sensorimotor gating, such as schizophrenia. Here we used rats selectively bred for high and low PPI to evaluate whether bifrontal cortical ECS would affect PPI. For this purpose, cortical screw electrodes were stereotactically implanted above the frontal cortex. After recovery ECS was applied for five consecutive days with stimuli of 1 ms pulse-width, 100 pulses/s, 1 s duration, ranging from 5.5 mA to 10 mA. PPI of ASR was measured one day before ECS, and on days 1, 7, and 14 after the last ECS. In rats with breeding-induced low PPI ECS increased PPI one week after stimulation. In contrast, ECS decreased PPI in rats with high PPI on the first day after stimulation. The reaction to the startle impulse was reduced by ECS without difference between groups. This work provides evidence that rats with breeding-induced high or low PPI could be used to further investigate the underlying mechanisms of ECT in neuropsychiatric disorders with disturbed sensorimotor gating like schizophrenia. PMID:26476178

  17. Comparison of mouse minimum audible angle determined in prepulse inhibition and operant conditioning procedures.

    PubMed

    Behrens, Derik; Klump, Georg M

    2016-03-01

    Both reward based operant conditioning (OC) and reflex-based prepulse inhibition (PPI) procedures are used in sound localisation studies in mice. Since the results of both procedures are compared in the literature, it is important to assess whether they provide similar results if the same stimulus paradigm is applied. Here, we compare the sensitivity of C57BL/6 mice in OC and PPI procedures for detecting a switch in speaker location using broadband and narrowband noise stimuli and determined their minimum audible angle (MAA). In the OC procedure, we calculated d' values from the hit and false alarm rates. In the PPI procedure, we calculated the area under ROC curves from the startle response amplitudes and derived da values to obtain a sensitivity measure that corresponds to d'. For both procedures, the mean sensitivity to the speaker switch increased with an increase in angular separation. For broadband noise stimuli, a d' of up to 3.3 (OC) and a da of up to 1.1 (PPI) were observed at large speaker separations. Narrowband noise stimuli resulted in lower sensitivities in both procedures, resulting in a maximum d' of 2.0 (OC) and a maximum da of 0.3 (PPI). Using a sensitivity of 1.0 as the threshold criterion, broadband noise MAAs in the range from 32° to 46° were observed in the OC procedure whereas a broadband noise MAAs of 108° or higher were observed in the PPI procedure. In the OC procedure, narrowband noise MAAs in the range from 37° to 62° were observed. In the PPI procedure, no narrowband noise MAA could be determined since none of the subjects reached the threshold. Thus, OC procedures result in a better performance of the subjects in the sound localization task than PPI procedures, challenging the view that both procedures can be used interchangeably. PMID:26807797

  18. Deletion of striatal adenosine A(2A) receptor spares latent inhibition and prepulse inhibition but impairs active avoidance learning.

    PubMed

    Singer, Philipp; Wei, Catherine J; Chen, Jiang-Fan; Boison, Detlev; Yee, Benjamin K

    2013-04-01

    Following early clinical leads, the adenosine A(2A)R receptor (A(2A)R) has continued to attract attention as a potential novel target for treating schizophrenia, especially against the negative and cognitive symptoms of the disease because of A(2A)R's unique modulatory action over glutamatergic in addition to dopaminergic signaling. Through (i) the antagonistic interaction with the dopamine D(2) receptor, and (ii) the regulation of glutamate release and N-methyl-d-aspartate receptor function, striatal A(2A)R is ideally positioned to fine-tune the dopamine-glutamate balance, the disturbance of which is implicated in the pathophysiology of schizophrenia. However, the precise function of striatal A(2A)Rs in the regulation of schizophrenia-relevant behavior is poorly understood. Here, we tested the impact of conditional striatum-specific A(2A)R knockout (st-A(2A)R-KO) on latent inhibition (LI) and prepulse inhibition (PPI) - behavior that is tightly regulated by striatal dopamine and glutamate. These are two common cross-species translational tests for the assessment of selective attention and sensorimotor gating deficits reported in schizophrenia patients; and enhanced performance in these tests is associated with antipsychotic drug action. We found that neither LI nor PPI was significantly affected in st-A(2A)R-KO mice, although a deficit in active avoidance learning was identified in these animals. The latter phenotype, however, was not replicated in another form of aversive conditioning - namely, conditioned taste aversion. Hence, the present study shows that neither learned inattention (as measured by LI) nor sensory gating (as indexed by PPI) requires the integrity of striatal A(2A)Rs - a finding that may undermine the hypothesized importance of A(2A)R in the genesis and/or treatment of schizophrenia. PMID:23276608

  19. Orally active glutamate carboxypeptidase II inhibitor 2-MPPA attenuates dizocilpine-induced prepulse inhibition deficits in mice.

    PubMed

    Takatsu, Yuto; Fujita, Yuko; Tsukamoto, Takashi; Slusher, Barbara S; Hashimoto, Kenji

    2011-01-31

    Glutamate carboxypeptidase II (GCP II) is a glial enzyme responsible for the hydrolysis of N-acetylaspartylglutamate (NAAG) into glutamate and N-acetylaspartate (NAA). Abnormalities in glutamate neurotransmission are implicated in the pathophysiology of schizophrenia. In this study, we examined the effects of a novel, orally active GCP II inhibitor, 2-(3-mercaptopropyl)pentanedioic acid (2-MPPA), on the prepulse inhibition (PPI) deficits after administration of the N-methyl-d-aspartate (NMDA) receptor antagonist dizocilpine. Oral administration of 2-MPPA (10, 30 or 100mg/kg) significantly attenuated dizocilpine (0.1mg/kg)-induced PPI deficits in mice, in a dose dependent manner. Furthermore, the efficacy of 2-MPPA on dizocilpine-induced PPI deficits was significantly antagonized by pretreatment with the selective group II metabotropic glutamate receptor (mGluR) antagonist LY341495 (1.0mg/kg). In the same model, however, the selective group II mGluR agonist LY354740 (3, 10 or 30 mg/kg) significantly attenuated dizocilpine-induced PPI deficits at only one dose and prepulse intensity. Our findings suggest that GCP II inhibition may be useful therapeutic strategy for schizophrenia. From a mechanistic perspective, while increased NAAG and activation of group II mGluRs may contribute to the therapeutic efficacy of 2-MPPA, it is likely that additional pharmacological activities are also involved. PMID:21093418

  20. Effects of ADORA2A gene variation and caffeine on prepulse inhibition: a multi-level risk model of anxiety.

    PubMed

    Gajewska, Agnieszka; Blumenthal, Terry D; Winter, Bernward; Herrmann, Martin J; Conzelmann, Annette; Mühlberger, Andreas; Warrings, Bodo; Jacob, Christian; Arolt, Volker; Reif, Andreas; Zwanzger, Peter; Pauli, Paul; Deckert, Jürgen; Domschke, Katharina

    2013-01-10

    The complex pathogenesis of anxiety and panic disorder in particular has been suggested to be influenced by genetic factors such as the adenosine A2A receptor gene (ADORA2A) 1976T>C polymorphism (rs5751876) as well as neuropsychological factors such as early information processing deficits. In 114 healthy individuals (males=57, females=57) controlled for anxiety sensitivity (AS), a multi-level risk model of the development of anxiety was applied: Genetic (ADORA2A 1976T>C variant) and biochemical (300 mg of caffeine citrate vs. placebo) factors were hypothesized to influence early information processing as measured by the prepulse inhibition/facilitation paradigm (stimulus onset asynchronies (SOAs) of 60, 120, 240, 480 and 2000ms between prepulses and startle stimuli). A fourfold interaction of genotype, intervention, gender, and SOAs was discerned. Stratification by SOAs revealed that at 120 ms and 240 ms SOAs in the caffeine condition, PPI was impaired in female ADORA2A 1976TT risk genotype carriers as compared to male ADORA2A 1976TT homozygotes, while no significant effects were observed in the ADORA2A 1976CC/CT non-risk genotype or placebo group. Only in high anxiety sensitive probands, a significant intervention effect was discerned with impaired prepulse facilitation (PPF) due to caffeine. The present results point to an impaired ability to selectively process very early information and to gate irrelevant sensory information, respectively, in female ADORA2A 1976TT homozygotes in response to caffeine, providing further evidence for the adenosinergic system to be involved in the pathogenesis of anxiety. PMID:22940476

  1. The T-type calcium channel antagonist Z944 disrupts prepulse inhibition in both epileptic and non-epileptic rats.

    PubMed

    Marks, Wendie N; Greba, Quentin; Cain, Stuart M; Snutch, Terrance P; Howland, John G

    2016-09-22

    The role of T-type calcium channels in brain diseases such as absence epilepsy and neuropathic pain has been studied extensively. However, less is known regarding the involvement of T-type channels in cognition and behavior. Prepulse inhibition (PPI) is a measure of sensorimotor gating which is a basic process whereby the brain filters incoming stimuli to enable appropriate responding in sensory rich environments. The regulation of PPI involves a network of limbic, cortical, striatal, pallidal and pontine brain areas, many of which show high levels of T-type calcium channel expression. Therefore, we tested the effects of blocking T-type calcium channels on PPI with the potent and selective T-type antagonist Z944 (0.3, 1, 3, 10mg/kg; i.p.) in adult Wistar rats and two related strains, the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and Non-Epileptic Control (NEC). PPI was tested using a protocol that varied prepulse intensity (3, 6, and 12dB above background) and prepulse-pulse interval (30, 50, 80, 140ms). Z944 decreased startle in the Wistar strain at the highest dose relative to lower doses. Z944 dose-dependently disrupted PPI in the Wistar and GAERS strains with the most potent effect observed with the higher doses. These findings suggest that T-type calcium channels contribute to normal patterns of brain activity that regulate PPI. Given that PPI is disrupted in psychiatric disorders, future experiments that test the specific brain regions involved in the regulation of PPI by T-type calcium channels may help inform therapeutic development for those suffering from sensorimotor gating impairments. PMID:27365170

  2. The Functional Networks of Prepulse Inhibition: Neuronal Connectivity Analysis Based on FDG-PET in Awake and Unrestrained Rats.

    PubMed

    Rohleder, Cathrin; Wiedermann, Dirk; Neumaier, Bernd; Drzezga, Alexander; Timmermann, Lars; Graf, Rudolf; Leweke, F Markus; Endepols, Heike

    2016-01-01

    Prepulse inhibition (PPI) is a neuropsychological process during which a weak sensory stimulus ("prepulse") attenuates the motor response ("startle reaction") to a subsequent strong startling stimulus. It is measured as a surrogate marker of sensorimotor gating in patients suffering from neuropsychological diseases such as schizophrenia, as well as in corresponding animal models. A variety of studies has shown that PPI of the acoustical startle reaction comprises three brain circuitries for: (i) startle mediation, (ii) PPI mediation, and (iii) modulation of PPI mediation. While anatomical connections and information flow in the startle and PPI mediation pathways are well known, spatial and temporal interactions of the numerous regions involved in PPI modulation are incompletely understood. We therefore combined [(18)F]fluoro-2-deoxyglucose positron-emission-tomography (FDG-PET) with PPI and resting state control paradigms in awake rats. A battery of subtractive, correlative as well as seed-based functional connectivity analyses revealed a default mode-like network (DMN) active during resting state only. Furthermore, two functional networks were observed during PPI: Metabolic activity in the lateral circuitry was positively correlated with PPI effectiveness and involved the auditory system and emotional regions. The medial network was negatively correlated with PPI effectiveness, i.e., associated with startle, and recruited a spatial/cognitive network. Our study provides evidence for two distinct neuronal networks, whose continuous interplay determines PPI effectiveness in rats, probably by either protecting the prepulse or facilitating startle processing. Discovering similar networks affected in neuropsychological disorders may help to better understand mechanisms of sensorimotor gating deficits and provide new perspectives for therapeutic strategies. PMID:27493627

  3. Histamine H1 receptor involvement in prepulse inhibition and memory function: Relevance for the antipsychotic actions of clozapine

    PubMed Central

    Roegge, Cindy S.; Perraut, Charles; Hao, Xin; Levin, Edward D.

    2009-01-01

    Histamine H1 blockade is one of the more prominent actions of the multi-receptor acting antipsychotic clozapine. It is currently not known how much this H1 antagonism of clozapine contributes to the therapeutic or adverse side effects of clozapine. The current studies with Sprague-Dawley rats were conducted to determine the participation of histaminergic H1 receptor subtype in sensorimotor plasticity and memory function affected by clozapine using tests of prepulse inhibition (PPI) and radial-arm maze choice accuracy. The PPI impairment caused by the glutamate antagonist dizocilpine (MK-801) was significantly attenuated by clozapine. In the current project, we found that the selective H1 antagonist pyrilamine also reversed the dizocilpine-induced impairment in PPI of tactile startle with an auditory prepulse. In the radial-arm maze (RAM), pyrilamine, like clozapine, impaired working memory and caused a significant dose-related slowing of response. Pyrilamine, however, decreased the number of reference memory errors. We have previously shown that nicotine effectively attenuates the clozapine-induced working memory impairment, but in the current study, nicotine did not significantly alter the effects of pyrilamine on the RAM. In summary, the therapeutic effect of clozapine in reversing PPI impairment was mimicked by the H1 antagonist pyrilamine, while pyrilamine had a mixed effect on cognition. Pyrilamine impaired working memory but improved reference memory in rats. Thus, H1 antagonism seems to play a role in part of the beneficial actions of antipsychotics, such as clozapine. PMID:17382376

  4. Mice lacking collapsin response mediator protein 1 manifest hyperactivity, impaired learning and memory, and impaired prepulse inhibition.

    PubMed

    Yamashita, Naoya; Takahashi, Aoi; Takao, Keizo; Yamamoto, Toshifumi; Kolattukudy, Pappachan; Miyakawa, Tsuyoshi; Goshima, Yoshio

    2013-01-01

    Collapsin response mediator protein 1 (CRMP1) is one of the CRMP family members that are involved in various aspects of neuronal development such as axonal guidance and neuronal migration. Here we provide evidence that crmp1 (-/-) mice exhibited behavioral abnormalities related to schizophrenia. The crmp1 (-/-) mice exhibited hyperactivity and/or impaired emotional behavioral phenotype. These mice also exhibited impaired context-dependent memory and long-term memory retention. Furthermore, crmp1 (-/-) mice exhibited decreased prepulse inhibition, and this phenotype was rescued by administration of chlorpromazine, a typical antipsychotic drug. In addition, in vivo microdialysis revealed that the methamphetamine-induced release of dopamine in prefrontal cortex was exaggerated in crmp1 (-/-) mice, suggesting that enhanced mesocortical dopaminergic transmission contributes to their hyperactivity phenotype. These observations suggest that impairment of CRMP1 function may be involved in the pathogenesis of schizophrenia. We propose that crmp1 (-/-) mouse may model endophenotypes present in this neuropsychiatric disorder. PMID:24409129

  5. Glycine and GABAA receptors mediate tonic and phasic inhibitory processes that contribute to prepulse inhibition in the goldfish startle network

    PubMed Central

    Curtin, Paul C. P.; Preuss, Thomas

    2015-01-01

    Prepulse inhibition (PPI) is understood as a sensorimotor gating process that attenuates sensory flow to the startle pathway during early stages (20–1000 ms) of information processing. Here, we applied in vivo electrophysiology and pharmacology to determine if PPI is mediated by glycine receptors (GlyRs) and/or GABAA receptors (GABAARs) in the goldfish auditory startle circuit. Specifically, we used selective antagonists to dissect the contributions of target receptors on sound-evoked postsynaptic potentials (PSPs) recorded in the neurons that initiate startle, the Mauthner-cells (M-cell). We found that strychnine, a GlyR antagonist, disrupted a fast-activated (5 ms) and rapidly (<50 ms) decaying (feed-forward) inhibitory process that contributes to PPI at 20 ms prepulse/pulse inter-stimulus intervals (ISI). Additionally we observed increases of the evoked postsynaptic potential (PSP) peak amplitude (+87.43 ± 21.53%, N = 9) and duration (+204 ± 48.91%, N = 9). In contrast, treatment with bicuculline, a GABAAR antagonist, caused a general reduction in PPI across all tested interstimulus intervals (ISIs) (20–500 ms). Bicuculline also increased PSP peak amplitude (+133.8 ± 10.3%, N = 5) and PSP duration (+284.95 ± 65.64%, N = 5). Treatment with either antagonist also tonically increased post-synaptic excitability in the M-cells, reflected by an increase in the magnitude of antidromically-evoked action potentials (APs) by 15.07 ± 3.21%, N = 7 and 16.23 ± 7.08%, N = 5 for strychnine and bicuculline, respectively. These results suggest that GABAARs and GlyRs are functionally segregated to short- and longer-lasting sound-evoked (phasic) inhibitory processes that contribute to PPI, with the mediation of tonic inhibition by both receptor systems being critical for gain control within the M-cell startle circuit. PMID:25852486

  6. Modulation of Prepulse Inhibition and Startle Reflex by Emotions: A Comparison between Young and Older Adults

    PubMed Central

    Le Duc, Jolyanne; Fournier, Philippe; Hébert, Sylvie

    2016-01-01

    This study examined whether or not the acoustic startle response and sensorimotor gating may be modulated by emotions differentially between young and older adults. Two groups of participants (mean age Young: 24 years old; Elderly: 63.6 years old) were presented with three types of auditory stimuli (Startle alone, High or Low frequency Prepulse) while viewing pleasant, neutral, or unpleasant images. Electromyographic activity of the eyeblink response was measured. Results show that older adults displayed diminished eyeblink responses whereas younger adults displayed enhanced eyeblink responses when viewing negative images. Sensorimotor gating also differed between young and older adults, with enhanced sensorimotor gating abilities while viewing positive pictures in older adults and diminished abilities while viewing negative pictures among younger adults. These results argue in favor of a differential emotional influence on the sensorimotor abilities of young and older adults, with a positivity bias among the latter. PMID:26941643

  7. Assessment of Startle Response and Its Prepulse Inhibition Using Posturography: Pilot Study

    PubMed Central

    Polechoński, Jacek; Juras, Grzegorz; Słomka, Kajetan; Błaszczyk, Janusz; Małecki, Andrzej; Nawrocka, Agnieszka

    2016-01-01

    Purpose. The aim of this study was to evaluate the possibility of using static posturography in the assessment of sensorimotor gating. Subjects and Methods. Fourteen subjects took part in the experiment. The inhibitory mechanisms of startle reflex were used as the measure of sensorimotor gating. It was evoked by a strong acoustic stimulus (106 dB SPL, 40 ms) which was preceded by the weaker similar signal (80 dB SPL, 20 ms). A stabilographic platform was used to measure sensorimotor gating. Results. Results of static posturography show that the postural sway caused by the reaction to a strong acoustic stimulus is significantly smaller when this stimulus is preceded by the signal of lower intensity (prepulse). Such assessment is only possible in eyes open conditions. Conclusions. Static posturography can be simple and effective method used for diagnosis of sensorimotor gating in humans. PMID:27314041

  8. Modulation of Prepulse Inhibition and Startle Reflex by Emotions: A Comparison between Young and Older Adults.

    PubMed

    Le Duc, Jolyanne; Fournier, Philippe; Hébert, Sylvie

    2016-01-01

    This study examined whether or not the acoustic startle response and sensorimotor gating may be modulated by emotions differentially between young and older adults. Two groups of participants (mean age Young: 24 years old; Elderly: 63.6 years old) were presented with three types of auditory stimuli (Startle alone, High or Low frequency Prepulse) while viewing pleasant, neutral, or unpleasant images. Electromyographic activity of the eyeblink response was measured. Results show that older adults displayed diminished eyeblink responses whereas younger adults displayed enhanced eyeblink responses when viewing negative images. Sensorimotor gating also differed between young and older adults, with enhanced sensorimotor gating abilities while viewing positive pictures in older adults and diminished abilities while viewing negative pictures among younger adults. These results argue in favor of a differential emotional influence on the sensorimotor abilities of young and older adults, with a positivity bias among the latter. PMID:26941643

  9. The Functional Networks of Prepulse Inhibition: Neuronal Connectivity Analysis Based on FDG-PET in Awake and Unrestrained Rats

    PubMed Central

    Rohleder, Cathrin; Wiedermann, Dirk; Neumaier, Bernd; Drzezga, Alexander; Timmermann, Lars; Graf, Rudolf; Leweke, F. Markus; Endepols, Heike

    2016-01-01

    Prepulse inhibition (PPI) is a neuropsychological process during which a weak sensory stimulus (“prepulse”) attenuates the motor response (“startle reaction”) to a subsequent strong startling stimulus. It is measured as a surrogate marker of sensorimotor gating in patients suffering from neuropsychological diseases such as schizophrenia, as well as in corresponding animal models. A variety of studies has shown that PPI of the acoustical startle reaction comprises three brain circuitries for: (i) startle mediation, (ii) PPI mediation, and (iii) modulation of PPI mediation. While anatomical connections and information flow in the startle and PPI mediation pathways are well known, spatial and temporal interactions of the numerous regions involved in PPI modulation are incompletely understood. We therefore combined [18F]fluoro-2-deoxyglucose positron-emission-tomography (FDG-PET) with PPI and resting state control paradigms in awake rats. A battery of subtractive, correlative as well as seed-based functional connectivity analyses revealed a default mode-like network (DMN) active during resting state only. Furthermore, two functional networks were observed during PPI: Metabolic activity in the lateral circuitry was positively correlated with PPI effectiveness and involved the auditory system and emotional regions. The medial network was negatively correlated with PPI effectiveness, i.e., associated with startle, and recruited a spatial/cognitive network. Our study provides evidence for two distinct neuronal networks, whose continuous interplay determines PPI effectiveness in rats, probably by either protecting the prepulse or facilitating startle processing. Discovering similar networks affected in neuropsychological disorders may help to better understand mechanisms of sensorimotor gating deficits and provide new perspectives for therapeutic strategies. PMID:27493627

  10. Effects of acute ethanol or amphetamine administration on the acoustic startle response and prepulse inhibition in adolescent and adult rats

    PubMed Central

    Brunell, Steven Craig

    2007-01-01

    Rationale Adolescents differ from adults in their sensitivity to a variety of psychoactive drugs. For example, adolescent rats are less sensitive to locomotor stimulant and stereotypic effects of amphetamine as well as to motor-impairing and hypnotic effects of ethanol while more sensitive to ethanol-induced disruption of brain plasticity. Objective The current study further explored age differences in psychopharmacological sersitivity by examining the effects of d-amphetamine (1.0 and 4.0 mg/kg) or ethanol (0.5, 1.0 and 1.5 g/kg) given interperitoneally on the acoustic startle reposnse (ASR) and prepulse inhibition (PPI) in male adolescent and adult Sprague-Dawley rats. Materials and methods The animals were given five startle trials (120 dB for 40 ms) before semi-randomized presentation of 12 startle trials interspersed with ten trials at each prepulse intensity (40 ms pulse of 5, 10, or 20 dB above background; 100 ms before the startle stimulus). Results Adolescent controls showed significantly less PPI than adults, replicating previous ontogenetic findings. The higher dose of amphetamine disrupted PPI in adult but not in adolescent insensitivity to amphetamine to include this measure of sensorimotor gating. Ethanol exposure failed to alter PPI at either age, although both the 1.0 and 1.5 g/kg doses of ethanol significantly suppressed the magnitude of the ASR at both ages, potentially reflecting sedative or anxiolytic effects. Conclusion These data provide further evidence of the relative insensitivity of adolescent animals to amphetamine, although no age effects were found in terms of ethanol sensitivity using these measures of startle and sensorimotor gating. PMID:16758242

  11. Individual difference in prepulse inhibition does not predict spatial learning and memory performance in C57BL/6 mice.

    PubMed

    Peleg-Raibstein, Daria; Philipp, Singer; Feldon, Joram; Yee, Benjamin K

    2015-12-01

    The startle reflex to an intense acoustic pulse stimulus is attenuated if the pulse stimulus is shortly preceded by a weak non-startling prepulse stimulus. This attenuation of the startle reflex represents a form of pre-attentional sensory gating known as prepulse inhibition (PPI). Although PPI does not require learning, its expression is regulated by higher cognitive processes. PPI deficits have been detected in several psychiatric conditions including schizophrenia where they co-exist with cognitive deficits. A potential link between PPI expression and cognitive performance has therefore been suggested such that poor PPI may predict, or may be mechanistically linked to, overt cognitive impairments. A positive relationship between PPI and strategy formation, planning efficiency, and execution speed has been observed in healthy humans. However, parallel studies in healthy animals are rare. It thus remains unclear what cognitive domains may be associated with, or orthogonal to, sensory gating in the form of PPI in healthy animals. The present study evaluated a potential link between the magnitude of PPI and spatial memory performance by comparing two subgroups of animals differing substantially in baseline PPI expression (low-PPI vs high-PPI) within a homogenous cohort of 100 male adult C57BL/6 mice. Assessment of spatial reference memory in the Morris water maze and spatial recognition memory in the Y-maze failed to reveal any difference between low-PPI and high-PPI subjects. These negative findings contrast with our previous reports that individual difference in PPI correlated with sustained attention and working memory performance in C57BL/6 mice. PMID:25893564

  12. Update: Studies of prepulse inhibition of startle, with particular relevance to the pathophysiology or treatment of Tourette Syndrome

    PubMed Central

    Swerdlow, Neal R.

    2012-01-01

    Prepulse inhibition of the startle reflex (PPI) is an operational measure of sensorimotor gating, in which the motor response to an abrupt, intense stimulus is inhibited by a weak lead stimulus. PPI is reduced in several brain disorders, including Tourette Syndrome (TS); it is regulated by forebrain circuitry, including portions of the basal ganglia implicated in the pathophysiology of TS, and is also heritable and under strong genetic control. PPI has been the focus of numerous translational models, because it is expressed by most mammalian species, with remarkable conservation of response characteristics and underlying neural circuitry between rodents and primates. Several of these models have recently explored causative factors in TS – from genes to specific basal ganglia perturbations – as well as potential TS therapeutics, including novel pharmacological and neurosurgical interventions. With the focus on Comprehensive Behavioral Interventions for Tics (CBIT) in the evolving treatment model for TS, future studies might apply PPI as a predictive measure for CBIT response, or for identifying medications that might augment CBIT efficacy. In the end, a measure based on a simple pontine-based reflex will have limitations in its ability to explicate any complex behavioral phenotype. PMID:23017868

  13. Acetylcholinesterase inhibition ameliorates deficits in motivational drive

    PubMed Central

    2012-01-01

    Background Apathy is frequently observed in numerous neurological disorders, including Alzheimer's and Parkinson's, as well as neuropsychiatric disorders including schizophrenia. Apathy is defined as a lack of motivation characterized by diminished goal-oriented behavior and self-initiated activity. This study evaluated a chronic restraint stress (CRS) protocol in modeling apathetic behavior, and determined whether administration of an anticholinesterase had utility in attenuating CRS-induced phenotypes. Methods We assessed behavior as well as regional neuronal activity patterns using FosB immunohistochemistry after exposure to CRS for 6 h/d for a minimum of 21 d. Based on our FosB findings and recent clinical trials, we administered an anticholinesterase to evaluate attenuation of CRS-induced phenotypes. Results CRS resulted in behaviors that reflect motivational loss and diminished emotional responsiveness. CRS-exposed mice showed differences in FosB accumulation, including changes in the cholinergic basal forebrain system. Facilitating cholinergic signaling ameliorated CRS-induced deficits in initiation and motivational drive and rescued immediate early gene activation in the medial septum and nucleus accumbens. Conclusions Some CRS protocols may be useful for studying deficits in motivation and apathetic behavior. Amelioration of CRS-induced behaviors with an anticholinesterase supports a role for the cholinergic system in remediation of deficits in motivational drive. PMID:22433906

  14. Mice lacking collapsin response mediator protein 1 manifest hyperactivity, impaired learning and memory, and impaired prepulse inhibition

    PubMed Central

    Yamashita, Naoya; Takahashi, Aoi; Takao, Keizo; Yamamoto, Toshifumi; Kolattukudy, Pappachan; Miyakawa, Tsuyoshi; Goshima, Yoshio

    2013-01-01

    Collapsin response mediator protein 1 (CRMP1) is one of the CRMP family members that are involved in various aspects of neuronal development such as axonal guidance and neuronal migration. Here we provide evidence that crmp1−/− mice exhibited behavioral abnormalities related to schizophrenia. The crmp1−/− mice exhibited hyperactivity and/or impaired emotional behavioral phenotype. These mice also exhibited impaired context-dependent memory and long-term memory retention. Furthermore, crmp1−/− mice exhibited decreased prepulse inhibition, and this phenotype was rescued by administration of chlorpromazine, a typical antipsychotic drug. In addition, in vivo microdialysis revealed that the methamphetamine-induced release of dopamine in prefrontal cortex was exaggerated in crmp1−/− mice, suggesting that enhanced mesocortical dopaminergic transmission contributes to their hyperactivity phenotype. These observations suggest that impairment of CRMP1 function may be involved in the pathogenesis of schizophrenia. We propose that crmp1−/− mouse may model endophenotypes present in this neuropsychiatric disorder. PMID:24409129

  15. MODERATE LEVEL PRENATAL ALCOHOL EXPOSURE ENHANCES ACOUSTIC STARTLE MAGNITUDE AND DISRUPTS PREPULSE INHIBITION IN ADULT RHESUS MONKEYS

    PubMed Central

    Schneider, Mary L.; Larson, Julie A.; Rypstat, Craig W.; Resch, Leslie M.; Roberts, Andrew; Moore, Colleen F.

    2013-01-01

    Background Prenatal alcohol exposure can contribute to a wide range of neurodevelopmental impairments in children and adults including behavioral and neuropsychiatric disorders. In rhesus monkeys we examined whether moderate level prenatal alcohol exposure would alter acoustic startle responses and prepulse inhibition of the acoustic startle (PPI). PPI is a highly quantifiable measure of inhibitory neural processes or sensorimotor gating associated with neuropsychiatric disorders. Methods Acoustic startle and PPI of the acoustic startle was tested in 37 adult rhesus monkeys (Macaca mulatta) from four experimental conditions: (a) moderate level prenatal alcohol-exposed, (b) prenatally-stressed, (c) moderate level prenatal alcohol-exposed + prenatally-stressed, and (d) sucrose controls. Results Prenatal alcohol-exposed monkeys showed a higher magnitude of acoustic startle response and disrupted PPI compared with monkeys not exposed to alcohol prenatally. Monkeys in all conditions showed higher HPA-axis responses after undergoing the startle procedure, but HPA responses were unrelated to startle response magnitude, latency, or PPI. Conclusion Finding altered PPI in monkeys prenatally exposed to a moderate dose of alcohol suggests that reduced sensorimotor gating is one effect of prenatal alcohol exposure. Because reduced sensorimotor gating is observed in many neuropsychiatric disorders, sensorimotor gating deficits could be an aspect of the co-morbidity between FASD and mental health conditions. PMID:23763712

  16. The influence of bilateral subthalamic nucleus deep brain stimulation on impulsivity and prepulse inhibition in Parkinson’s disease patients

    PubMed Central

    Gee, Lucy; Smith, Heather; Cruz, Priscilla De La; Campbell, Joannalee; Fama, Chris; Haller, Jessica; Ramirez-Zamora, Adolfo; Durphy, Jennifer; Hanspal, Era; Molho, Eric; Barba, Anne; Shin, Damian; Pilitsis, Julie G.

    2015-01-01

    Background At least 14% of Parkinson disease (PD) patients develop impulse control disorders (ICDs). The pathophysiology behind these behaviors and the impact of deep brain stimulation in a real-life setting remains unclear. Objectives We prospectively examined the impact of bilateral subthalamic nucleus deep brain stimulation (STN-DBS) on ICDs in PD patients, as well as the relationship between impaired sensorimotor gaiting and impulsivity. Methods Patients undergoing bilateral STN-DBS were assessed for ICDs preoperatively and 1-year postoperatively using a validated questionnaire (QUIP-RS). A subset of patients completed the Balloon Analog Risk Task (BART) and auditory pre-pulse inhibition (PPI) testing. Results Analysis revealed 12 patients had an improvement in score assessing ICDs (“good responders” – GR; p = 0.006) while 4 had a worse or stable score (“poor responders” – PR; p > 0.05). GR further exemplified a significant decrease in hypersexual behavior (p = 0.005) and binge eating (p = 0.01). Impaired PPI responses also significantly correlated with impulsivity in BART (r = −0.72, p = 0.044). Discussion Following bilateral STN-DBS 75% of our cohort had a reduction in ICDs, thus suggesting deep brain stimulation effectively manages ICDs in PD. The role of impaired PPI in predisposition to ICDs in PD warrants further investigation. PMID:26066569

  17. Meclizine Enhancement of Sensorimotor Gating in Healthy Male Subjects with High Startle Responses and Low Prepulse Inhibition

    PubMed Central

    Larrauri, José A; Kelley, Lisalynn D; Jenkins, Mason R; Westman, Eric C; Schmajuk, Nestor A; Rosenthal, M Zachary; Levin, Edward D

    2014-01-01

    Histamine H1 receptor systems have been shown in animal studies to have important roles in the reversal of sensorimotor gating deficits, as measured by prepulse inhibition (PPI). H1-antagonist treatment attenuates the PPI impairments caused by either blockade of NMDA glutamate receptors or facilitation of dopamine transmission. The current experiment brought the investigation of H1 effects on sensorimotor gating to human studies. The effects of the histamine H1 antagonist meclizine on the startle response and PPI were investigated in healthy male subjects with high baseline startle responses and low PPI levels. Meclizine was administered to participants (n=24) using a within-subjects design with each participant receiving 0, 12.5, and 25 mg of meclizine in a counterbalanced order. Startle response, PPI, heart rate response, galvanic skin response, and changes in self-report ratings of alertness levels and affective states (arousal and valence) were assessed. When compared with the control (placebo) condition, the two doses of meclizine analyzed (12.5 and 25 mg) produced significant increases in PPI without affecting the magnitude of the startle response or other physiological variables. Meclizine also caused a significant increase in overall self-reported arousal levels, which was not correlated with the observed increase in PPI. These results are in agreement with previous reports in the animal literature and suggest that H1 antagonists may have beneficial effects in the treatment of subjects with compromised sensorimotor gating and enhanced motor responses to sensory stimuli. PMID:24045586

  18. Meclizine enhancement of sensorimotor gating in healthy male subjects with high startle responses and low prepulse inhibition.

    PubMed

    Larrauri, José A; Kelley, Lisalynn D; Jenkins, Mason R; Westman, Eric C; Schmajuk, Nestor A; Rosenthal, M Zachary; Levin, Edward D

    2014-02-01

    Histamine H1 receptor systems have been shown in animal studies to have important roles in the reversal of sensorimotor gating deficits, as measured by prepulse inhibition (PPI). H1-antagonist treatment attenuates the PPI impairments caused by either blockade of NMDA glutamate receptors or facilitation of dopamine transmission. The current experiment brought the investigation of H1 effects on sensorimotor gating to human studies. The effects of the histamine H1 antagonist meclizine on the startle response and PPI were investigated in healthy male subjects with high baseline startle responses and low PPI levels. Meclizine was administered to participants (n=24) using a within-subjects design with each participant receiving 0, 12.5, and 25 mg of meclizine in a counterbalanced order. Startle response, PPI, heart rate response, galvanic skin response, and changes in self-report ratings of alertness levels and affective states (arousal and valence) were assessed. When compared with the control (placebo) condition, the two doses of meclizine analyzed (12.5 and 25 mg) produced significant increases in PPI without affecting the magnitude of the startle response or other physiological variables. Meclizine also caused a significant increase in overall self-reported arousal levels, which was not correlated with the observed increase in PPI. These results are in agreement with previous reports in the animal literature and suggest that H1 antagonists may have beneficial effects in the treatment of subjects with compromised sensorimotor gating and enhanced motor responses to sensory stimuli. PMID:24045586

  19. Hippocampal ether-à-go-go1 potassium channels blockade: effects in the startle reflex and prepulse inhibition.

    PubMed

    Issy, A C; Fonseca, J R; Pardo, L A; Stühmer, W; Del Bel, E A

    2014-01-24

    Recently, our group described the ether-à-go-go1(Eag1) voltage-gated potassium (K(+)) channel (Kv10.1) expression in the dopaminergic cells indicating that these channels are part of the diversified group of ion channels related to dopaminergic neurons function. The increase of dopamine neurotransmission induces a reduction in the prepulse inhibition (PPI) of the acoustic startle reflex in rodents, which is a reliable index of sensorimotor gating deficits. The PPI response has been reported to be abnormally reduced in schizophrenia patients. The role of Eag1 K(+) channels in the PPI reaction had not been revealed until now, albeit the singular distribution of Eag1 in the dentate gyrus of the hippocampus and the hippocampal regulation of the startle reflex and PPI. The aim of this work was to investigate if Eag1 blockade on hippocampus modifies the PPI-disruptive effects of apomorphine in Wistar rats. Bilateral injection of anti-Eag1 single-chain antibody into the dentate gyrus of hippocampus did not modify apomorphine-disruptive effects in the PPI response. However, Eag1 antibody completely restored the startle amplitude decrease revealed after dentate gyrus surgery. These potentially biological important phenomenon merits further investigation regarding the role of Eag1 K(+) channels, mainly, on startle reflex modulation, since the physiological role of these channels remain obscure. PMID:24284010

  20. Association between prepulse inhibition of the startle response and latent inhibition of two-way avoidance acquisition: A study with heterogeneous NIH-HS rats.

    PubMed

    Sánchez-González, Ana; Esnal, Aitor; Río-Álamos, Cristóbal; Oliveras, Ignasi; Cañete, Toni; Blázquez, Gloria; Tobeña, Adolf; Fernández-Teruel, Alberto

    2016-03-01

    This study presents the first evaluation of the associations between responses in two paradigms related to schizophrenia in the genetically heterogeneous NIH-HS rat stock. NIH-HS rats are a stock of genetically heterogeneous animals that have been derived from eight different inbred strains. A rotational breeding schedule has been followed for more than eighty generations, leading to a high level of genetic recombination that makes the NIH-HS rats a unique tool for studying the genetic basis of (biological, behavioral, disease-related) complex traits. Previous work has dealt with the characterization of coping styles, cognitive and anxiety/fear-related profiles of NIH-HS rats. In the present study we have completed their characterization in two behavioral models, prepulse inhibition (PPI) and latent inhibition (LI) of the two-way active avoidance response, that appear to be related to schizophrenia or to schizophrenia-relevant symptoms. We have found that these rats display PPI for each of the four prepulse intensities tested, allowing their stratification in high, medium and low PPI subgroups. When testing these three subgroups for LI of two-way active avoidance acquisition it has been observed that the LowPPI and MediumPPI subgroups present impaired LI, which, along with the fact that the HighPPI group presents significant LI, allows us to hypothesize that responses in these two paradigms are somehow related and that selection of NIH-HS rats for Low vs HighPPI could make a promising animal model for the study of clusters of schizophrenia-relevant symptoms and their underlying neurobiological mechanisms. PMID:26700617

  1. POSSIBLE ROLE OF THE BRAINSTEM IN THE MEDIATION OF PREPULSE INHIBITION IN THE RAT (JOURNAL VERSION)

    EPA Science Inventory

    Bilateral stimulation of electrodes aimed at the cuneiform nucleus produced significant inhibition of the startle response produced by presentation of an 8 KHz, 110 dB tone. Stimulation of electrodes aimed at the deep mesencephalic nucleus also reduced the magnitude of the startl...

  2. Knockout Zbtb33 gene results in an increased locomotion, exploration and pre-pulse inhibition in mice.

    PubMed

    Kulikov, Alexander V; Korostina, Valeria S; Kulikova, Elizabeth A; Fursenko, Dariya V; Akulov, Andrey E; Moshkin, Mikhail P; Prokhortchouk, Egor B

    2016-01-15

    The Zbtb33 gene encodes the Kaiso protein-a bimodal transcriptional repressor. Here, the effects of Zbtb33 gene disruption on the brain and behaviour of the Kaiso-deficient (KO) and C57BL/6 (WT) male mice were investigated. Behaviour was studied using the open field, novel object, elevated plus maze and acoustic startle reflex tests. Brain morphology was investigated with magnetic resonance imaging. Biogenic amine levels and gene expression in the brain were measured with high-performance liquid chromatography and quantitative real-time RT-PCR, respectively. Zbtb33 gene mRNA was not detected in the brain of KO mice. KO mice exhibited increased locomotion, exploration in the open field, novel object and elevated plus-maze test. At the same time, Zbtb33 gene disruption did not alter anxiety-related behaviour in the elevated plus-maze test. KO mice showed elevated amplitudes and pre-pulse inhibitions of the acoustic startle reflex. These behavioural alterations were accompanied by significant reductions in the volumes of the lateral ventricles without significant alterations in the volumes of the hippocampus, striatum, thalamus and corpus callosum. Norepinephrine concentration was reduced in the hypothalami and hippocampi in KO mice, while the levels of serotonin, dopamine, their metabolites as well as mRNA of the gene coding brain-derived neurotrophic factor were not altered in the brain of KO mice compared to WT mice. This study is the first to reveal the involvement of the Zbtb33 gene in the regulation of behaviour and the central nervous system. PMID:26454239

  3. Mice with Deficient BK Channel Function Show Impaired Prepulse Inhibition and Spatial Learning, but Normal Working and Spatial Reference Memory

    PubMed Central

    Azzopardi, Erin; Ruettiger, Lukas; Ruth, Peter; Schmid, Susanne

    2013-01-01

    Genetic variations in the large-conductance, voltage- and calcium activated potassium channels (BK channels) have been recently implicated in mental retardation, autism and schizophrenia which all come along with severe cognitive impairments. In the present study we investigate the effects of functional BK channel deletion on cognition using a genetic mouse model with a knock-out of the gene for the pore forming α-subunit of the channel. We tested the F1 generation of a hybrid SV129/C57BL6 mouse line in which the slo1 gene was deleted in both parent strains. We first evaluated hearing and motor function to establish the suitability of this model for cognitive testing. Auditory brain stem responses to click stimuli showed no threshold differences between knockout mice and their wild-type littermates. Despite of muscular tremor, reduced grip force, and impaired gait, knockout mice exhibited normal locomotion. These findings allowed for testing of sensorimotor gating using the acoustic startle reflex, as well as of working memory, spatial learning and memory in the Y-maze and the Morris water maze, respectively. Prepulse inhibition on the first day of testing was normal, but the knockout mice did not improve over the days of testing as their wild-type littermates did. Spontaneous alternation in the y-maze was normal as well, suggesting that the BK channel knock-out does not impair working memory. In the Morris water maze knock-out mice showed significantly slower acquisition of the task, but normal memory once the task was learned. Thus, we propose a crucial role of the BK channels in learning, but not in memory storage or recollection. PMID:24303038

  4. Using prepulse inhibition to detect functional D3 receptor antagonism: effects of WC10 and WC44.

    PubMed

    Weber, Martin; Chang, Wei-Li; Durbin, John P; Park, Paula E; Luedtke, Robert R; Mach, Robert H; Swerdlow, Neal R

    2009-08-01

    Prepulse inhibition of startle (PPI) is an operational measure of sensorimotor gating that is impaired in schizophrenia. Treatment with mixed dopamine D2/D3 antagonists diminishes schizophrenia symptoms, and opposes dopamine agonist-induced PPI deficits in rats. There are reasons to believe that functional D3 receptor antagonists might offer more favorable therapeutic profiles compared to current antipsychotics. However, D3-related drug discovery is hampered by the absence of assays sensitive to D3-mediated (antipsychotic) properties in vivo. Here, we characterized two putative D3-active compounds - WC10 and WC44 - in a PPI-based screening assay, comparing the sensitivity of test compounds to oppose PPI deficits induced by the mixed D1/D2-like agonist apomorphine vs. the preferential D3 agonist pramipexole in rats. WC10, WC44 (0, 1, 3, 10 mg/kg, each), and the preferential D2 antagonist L741,626 (0, 1 mg/kg) were studied, in combination with apomorphine (0, 0.5 mg/kg), or pramipexole (0, 1 mg/kg). L741,626 prevented apomorphine-, but not pramipexole-induced PPI deficits. WC10, but not WC44, prevented apomorphine-induced PPI deficits; both compounds opposed pramipexole-induced PPI deficits, suggesting functional D3 and D1/D2 antagonist profiles for WC10, and functional D3 receptor antagonism for WC44. This assay may be valuable for detecting predominantly D3 vs. D2 receptor-linked mechanisms of action in vivo. PMID:19426754

  5. CDP-choline attenuates scopolamine induced disruption of prepulse inhibition in rats: involvement of central nicotinic mechanism.

    PubMed

    Uslu, Gulsah; Savci, Vahide; Buyukuysal, Levent R; Goktalay, Gokhan

    2014-05-21

    It has been shown that cholinergic system plays an important role in schizophrenia-associated cognitive deficits, therefore cholinergic drugs are novel targets for the treatment of cognitive deficits seen in schizophrenia. We aimed to test the effects of CDP-choline on sensorimotor gating functioning, which is an important function for the integration of sensory and cognitive information processing and the execution of appropriate motor responses. In this study, prepulse inhibition (PPI) of the acoustic startle reflex was used to test the sensorimotor gating functioning, and the effects of CDP-choline on scopolamine induced PPI disruption were evaluated in rats. Furthermore, the contribution of the cholinergic mechanism in these effects was determined. CDP-choline (75, 250, 500mg/kg) by itself had no effect on the PPI in naïve animals. Scopolamine (0.4mg/kg; s.c.) significantly decreased the PPI levels and intraperitoneal administration of CDP-choline (250mg/kg) attenuated the effects of scopolamine. A non-specific nicotinic receptor antagonist, mecamylamine and an alpha 7 nicotinic receptor (α7-nAChR) antagonist, methyllycaconitine were used to investigate the mechanism underlying the effects of CDP-choline. Mecamylamine (3mg/kg; s.c.), and methyllycaconitine (10μg; i.c.v.) completely blocked the reversal effects of CDP-choline on scopolamine induced disruption of PPI. These results demonstrate that exogenous administration of CDP-choline attenuates scopolamine induced PPI disruption and show that the activation of central α7-nAChR may play a critical role in this effect. PMID:24708927

  6. Effects of the psychotomimetic benzomorphan N-allylnormetazocine (SKF 10,047) on prepulse inhibition of startle in mice.

    PubMed

    Halberstadt, Adam L; Hyun, James; Ruderman, Michael A; Powell, Susan B

    2016-09-01

    N-allylnormetazocine (NANM; SKF 10,047) is a benzomorphan opioid that produces psychotomimetic effects. (+)-NANM is the prototypical agonist for the sigma-1 (σ1) receptor, and there is a widespread belief that the hallucinogenic effects of NANM and other benzomorphan derivatives are mediated by interactions with σ1 sites. However, NANM is also an agonist at the κ opioid receptor (KOR) and binds to the PCP site located within the channel pore of the NMDA receptor, interactions that could potentially contribute to the effects of NANM. NMDA receptor antagonists such as phencyclidine (PCP) and ketamine are known to disrupt prepulse inhibition (PPI) of acoustic startle, a measure of sensorimotor gating, in rodents. We recently found that racemic NANM disrupts PPI in rats, but it is not clear whether the effect is mediated by blockade of the NMDA receptor, or alternatively whether interactions with KOR and σ1 receptors are involved. The present studies examined whether NANM and its stereoisomers alter PPI in C57BL/6J mice, and tested whether the effects on PPI are mediated by KOR or σ1 receptors. Racemic NANM produced a dose-dependent disruption of PPI (3-30mg/kg SC). (+)-NANM also disrupted PPI, whereas (-)-NANM was ineffective. Pretreatment with the selective KOR antagonist nor-binaltorphimine (10mg/kg SC) or the selective σ1 antagonist NE-100 (1mg/kg IP) failed to attenuate the reduction in PPI produced by racemic NANM. We also found that the selective KOR agonist (-)-U-50,488H (10-40mg/kg SC) had no effect on PPI. These findings confirm that NANM reduces sensorimotor gating in rodents, and indicate that the effect is mediated by interactions with the PCP receptor and not by activation of KOR or σ1 receptors. This observation is consistent with evidence indicating that the σ1 receptor is not linked to hallucinogenic or psychotomimetic effects. PMID:27236030

  7. Dissociation between the effects of pre-weaning and/or post-weaning social isolation on prepulse inhibition and latent inhibition in adult Sprague--Dawley rats.

    PubMed

    Weiss, I C; Domeney, A M; Moreau, J L; Russig, H; Feldon, J

    2001-06-01

    Human attentional impairments can be modelled in the rat using the prepulse inhibition (PPI) or the latent inhibition (LI) paradigm. The present study investigated the consequences of a combination of pre-weaning maternal separation (MS) and post-weaning social isolation (SI) on both PPI and LI in male and female Sprague--Dawley rats tested as adults. We report here a double dissociation between the effects of MS (repeated 4 h daily separations) and SI on PPI and LI: MS did not modify PPI, but enhanced LI. In contrast, SI disrupted PPI, the deficits being restricted to male rats, but left LI intact. There were no additive effects of MS and SI on PPI or LI. While MS improved avoidance learning, SI impaired it. Although both PPI and LI assess processes of selective attention, our results support the contention, already stated in the literature, that they involve differing neuro-psychological mechanisms. Furthermore, the fact that only males exhibited PPI deficits following SI has implications for the well-known differential vulnerability of human males to certain psychiatric disorders (e.g. schizophrenia). Finally, the combination of MS and SI could represent a relevant animal model for some aspects of schizophrenia, since both PPI and LI were altered. PMID:11275298

  8. Prepulse inhibition and latent inhibition deficits in Roman high-avoidance vs. Roman low-avoidance rats: Modeling schizophrenia-related features.

    PubMed

    Esnal, Aitor; Sánchez-González, Ana; Río-Álamos, Cristóbal; Oliveras, Ignasi; Cañete, Toni; Blázquez, Gloria; Tobeña, Adolf; Fernández-Teruel, Alberto

    2016-09-01

    The aim of the present study was to obtain further evidence supporting the validity of a new genetically-based rat model for the study of schizophrenia-relevant symptoms. The Roman high- (RHA-I) and low-avoidance (RLA-I) inbred rats have been psychogenetically selected for their rapid versus extremely poor acquisition of the two-way avoidance task in the shuttle box and present two well-differentiated profiles regarding several traits related to anxiety, impulsivity and sensitivity to (dopaminergic) psychostimulants. In this study we have tested animals from both strains in two behavioral paradigms that are related to schizophrenia, i.e. prepulse inhibition (PPI) and latent inhibition (LI) of fear-potentiated startle (FPS). The results show that while RLA-I rats display good PPI and LI to the context, RHA-Is show an impairment of PPI and no sign of an LI effect, which goes in the direction of the results obtained in schizophrenic patients. Therefore, although further behavioral and psychopharmacological work needs to be done, the present findings and previous studies carried out in our laboratory and others allow us to propose the RHA-I rat strain as a putative genetic rat model of differential schizophrenia-related features. PMID:27184235

  9. Cytotoxic lesion of the medial prefrontal cortex abolishes the partial reinforcement extinction effect, attenuates prepulse inhibition of the acoustic startle reflex and induces transient hyperlocomotion, while sparing spontaneous object recognition memory in the rat.

    PubMed

    Yee, B K

    2000-01-01

    The partial reinforcement extinction effect refers to the increase in resistance to extinction of an operant response acquired under partial reinforcement relative to that acquired under continuous reinforcement. Prepulse inhibition of the acoustic startle response refers to the reduction in startle reactivity towards an intense acoustic pulse stimulus when it is shortly preceded by a weak prepulse stimulus. These two behavioural phenomena appear to be related to different forms of attentional processes. While the prepulse inhibition effect reflects an inherent early attentional gating mechanism, the partial reinforcement extinction effect is believed to involve the development of acquired inattention, i.e. the latter requires the animals to learn about what to and what not to attend. Impairments in prepulse inhibition and the partial reinforcement extinction effect have been independently linked to the neuropsychology of attentional dysfunctions seen in schizophrenia. The proposed neural substrates underlying these behaviourial phenomena also appear to overlap considerably: both focus on the nucleus accumbens and emphasize the functional importance of its limbic afferents, including that originating from the medial prefrontal cortex, on accumbal output/activity. The present study demonstrated that cytotoxic medial prefrontal cortex lesions which typically damaged the prelimbic, the infralimbic and the dorsal anterior cingulate areas could lead to the abolition of the partial reinforcement extinction effect and the attenuation of prepulse inhibition. The lesions also resulted in a transient elevation of spontaneous locomotor activity. In contrast, the same lesions spared performance in a spontaneous object recognition memory test, in which the lesioned animals displayed normal preference for a novel object when the novel object was presented in conjunction with a familiar object seen 10 min earlier within an open field arena. The present results lend support to the

  10. Inhibition of Neutrophil Exocytosis Ameliorates Acute Lung Injury in Rats

    PubMed Central

    Uriarte, Silvia M.; Rane, Madhavi J.; Merchant, Michael L.; Jin, Shunying; Lentsch, Alex B.; Ward, Richard A.; McLeish, Kenneth R.

    2013-01-01

    Exocytosis of neutrophil granules contributes to acute lung injury (ALI) induced by infection or inflammation, suggesting that inhibition of neutrophil exocytosis in vivo could be a viable therapeutic strategy. This study was conducted to determine the effect of a cell-permeable fusion protein that inhibits neutrophil exocytosis (TAT-SNAP-23) on ALI using an immune complex deposition model in rats. The effect of inhibition of neutrophil exocytosis by intravenous administration of TAT-SNAP-23 on ALI was assessed by albumin leakage, neutrophil infiltration, lung histology, and proteomic analysis of bronchoalveolar lavage fluid (BALf). Administration of TAT-SNAP-23, but not TAT-Control, significantly reduced albumin leakage, total protein levels in the BALf, and intra-alveolar edema and hemorrhage. Evidence that TAT-SNAP-23 inhibits neutrophil exocytosis included a reduction in plasma membrane CD18 expression by BALf neutrophils and a decrease in neutrophil granule proteins in BALf. Similar degree of neutrophil accumulation in the lungs and/or BALf suggests that TAT-SNAP-23 did not alter vascular endothelial cell function. Proteomic analysis of BALf revealed that components of the complement and coagulation pathways were significantly reduced in BALf from TAT-SNAP-23-treated animals. Our results indicate that administration of a TAT-fusion protein that inhibits neutrophil exocytosis reduces in vivo ALI. Targeting neutrophil exocytosis is a potential therapeutic strategy to ameliorate ALI. PMID:23364427

  11. Genetic inhibition of JNK3 ameliorates spinal muscular atrophy.

    PubMed

    Genabai, Naresh K; Ahmad, Saif; Zhang, Zhanying; Jiang, Xiaoting; Gabaldon, Cynthia A; Gangwani, Laxman

    2015-12-15

    Mutation of the Survival Motor Neuron 1 (SMN1) gene causes spinal muscular atrophy (SMA), an autosomal recessive neurodegenerative disorder that occurs in early childhood. Degeneration of spinal motor neurons caused by SMN deficiency results in progressive muscle atrophy and death in SMA. The molecular mechanism underlying neurodegeneration in SMA is unknown. No treatment is available to prevent neurodegeneration and reduce the burden of illness in SMA. We report that the c-Jun NH2-terminal kinase (JNK) signaling pathway mediates neurodegeneration in SMA. The neuron-specific isoform JNK3 is required for neuron degeneration caused by SMN deficiency. JNK3 deficiency reduces degeneration of cultured neurons caused by low levels of SMN. Genetic inhibition of JNK pathway in vivo by Jnk3 knockout results in amelioration of SMA phenotype. JNK3 deficiency prevents the loss of spinal cord motor neurons, reduces muscle degeneration, improves muscle fiber thickness and muscle growth, improves motor function and overall growth and increases lifespan of mice with SMA that shows a systemic rescue of phenotype by a SMN-independent mechanism. JNK3 represents a potential (non-SMN) therapeutic target for the treatment of SMA. PMID:26423457

  12. Further Advances in Optimizing (2-Phenylcyclopropyl)methylamines as Novel Serotonin 2C Agonists: Effects on Hyperlocomotion, Prepulse Inhibition, and Cognition Models.

    PubMed

    Cheng, Jianjun; Giguere, Patrick M; Schmerberg, Claire M; Pogorelov, Vladimir M; Rodriguiz, Ramona M; Huang, Xi-Ping; Zhu, Hu; McCorvy, John D; Wetsel, William C; Roth, Bryan L; Kozikowski, Alan P

    2016-01-28

    A series of novel compounds with two halogen substituents have been designed and synthesized to further optimize the 2-phenylcyclopropylmethylamine scaffold in the quest for drug-like 5-HT2C agonists. Compound (+)-22a was identified as a potent 5-HT2C receptor agonist, with good selectivity against the 5-HT2B and the 5-HT2A receptors. ADMET assays showed that compound (+)-22a possessed desirable properties in terms of its microsomal stability, and CYP and hERG inhibition, along with an excellent brain penetration profile. Evaluation of (+)-22a in animal models of schizophrenia-related behaviors revealed that it had a desirable activity profile, as it reduced d-amphetamine-stimulated hyperlocomotion in the open field test, it restored d-amphetamine-disrupted prepulse inhibition, it induced cognitive improvements in the novel object recognition memory test in NR1-KD animals, and it produced very little catalepsy relative to haloperidol. These data support the further development of (+)-22a as a drug candidate for the treatment of schizophrenia. PMID:26704965

  13. Murine Double Minute-2 Inhibition Ameliorates Established Crescentic Glomerulonephritis.

    PubMed

    Mulay, Shrikant R; Romoli, Simone; Desai, Jyaysi; Honarpisheh, Mohammad Mohsen; Kumar, Santhosh V; Anders, Hans-Joachim; Thomasova, Dana

    2016-06-01

    Rapidly progressive glomerulonephritis is characterized by glomerular necroinflammation and crescent formation. Its treatment includes unspecific and toxic agents; therefore, the identification of novel therapeutic targets is required. The E3-ubiquitin ligase murine double minute (MDM)-2 is a nonredundant element of NF-κB signaling and the negative regulator of tumor suppressor gene TP53-mediated cell cycle arrest and cell death. We hypothesized that the MDM2 would drive crescentic glomerulonephritis by NF-κB-dependent glomerular inflammation and by p53-dependent parietal epithelial cell hyperproliferation. Indeed, the pre-emptive MDM2 blockade by nutlin-3a ameliorated all aspects of crescentic glomerulonephritis. MDM2 inhibition had identical protective effects in Trp53-deficient mice, with the exception of crescent formation, which was not influenced by nutlin-3a treatment. In vitro experiments confirmed the contribution of MDM2 for induction of NF-κB-dependent cytokines in murine glomerular endothelial cells and for p53-dependent parietal epithelial cell proliferation. To evaluate MDM2 blockade as a potential therapeutic intervention in rapidly progressive glomerulonephritis, we treated mice with established glomerulonephritis with nutlin-3a. Delayed onset of nutlin-3a treatment was equally protective as the pre-emptive treatment in abrogating crescentic glomerulonephritis. Together, the pathogenic effects of MDM2 are twofold, that is, p53-independent NF-κB activation increasing intraglomerular inflammation and p53-dependent parietal epithelial cell hyperplasia and crescent formation. We therefore propose MDM2 blockade as a potential novel therapeutic strategy in rapidly progressive glomerulonephritis. PMID:27102769

  14. Evidence for impaired sound intensity processing during prepulse inhibition of the startle response in a rodent developmental disruption model of schizophrenia.

    PubMed

    Ewing, Samuel G; Grace, Anthony A

    2013-11-01

    A number of studies have implicated disruptions in prepulse inhibition (PPI) of the startle response in both schizophrenia patients and animal models of this disorder. These disruptions are believed to reflect deficits in sensorimotor gating and are ascribed to aberrant filtering of sensory inputs leading to sensory overload and enhanced "noise" in neural structures. Here we examined auditory evoked potentials in a rodent model of schizophrenia (MAM-GD17) during an auditory PPI paradigm to better understand this phenomenon. MAM rats exhibited reductions in specific components of auditory evoked potentials in the orbitofrontal cortex and an abolition of the graded response to stimuli of differing intensities indicating deficient intensity processing in the orbitofrontal cortex. These data indicate that aberrant sensory information processing, rather than being attributable to enhanced noise in neural structures, may be better attributed to diminished evoked amplitudes resulting in a reduction in the "signal-to-noise" ratio. Therefore, the ability for sensory input to modulate the ongoing background activity may be severely disrupted in schizophrenia yielding an internal state which is insufficiently responsive to external input. PMID:23932574

  15. Developmental Trajectories of Auditory Cortex Synaptic Structures and Gap-Prepulse Inhibition of Acoustic Startle Between Early Adolescence and Young Adulthood in Mice.

    PubMed

    Moyer, Caitlin E; Erickson, Susan L; Fish, Kenneth N; Thiels, Edda; Penzes, Peter; Sweet, Robert A

    2016-05-01

    Cortical excitatory and inhibitory synapses are disrupted in schizophrenia, the symptoms of which often emerge during adolescence, when cortical excitatory synapses undergo pruning. In auditory cortex, a brain region implicated in schizophrenia, little is known about the development of excitatory and inhibitory synapses between early adolescence and young adulthood, and how these changes impact auditory cortex function. We used immunohistochemistry and quantitative fluorescence microscopy to quantify dendritic spines and GAD65-expressing inhibitory boutons in auditory cortex of early adolescent, late adolescent, and young adult mice. Numbers of spines decreased between early adolescence and young adulthood, during which time responses increased in an auditory cortex-dependent sensory task, silent gap-prepulse inhibition of the acoustic startle reflex (gap-PPI). Within-bouton GAD65 protein and GAD65-expressing bouton numbers decreased between late adolescence and young adulthood, a delay in onset relative to spine and gap-PPI changes. In mice lacking the spine protein kalirin, there were no significant changes in spine number, within-bouton GAD65 protein, or gap-PPI between adolescence and young adulthood. These results illustrate developmental changes in auditory cortex spines, inhibitory boutons, and auditory cortex function between adolescence and young adulthood, and provide insights into how disrupted adolescent neurodevelopment could contribute to auditory cortex synapse pathology and auditory impairments. PMID:25759333

  16. Evidence for impaired sound intensity processing during prepulse inhibition of the startle response in a rodent developmental disruption model of schizophrenia

    PubMed Central

    Ewing, Samuel G.; Grace, Anthony A.

    2013-01-01

    A number of studies have implicated disruptions in prepulse inhibition (PPI) of the startle response in both schizophrenia patients and animal models of this disorder. These disruptions are believed to reflect deficits in sensorimotor gating and are ascribed to aberrant filtering of sensory inputs leading to sensory overload and enhanced “noise” in neural structures. Here we examined auditory evoked potentials in a rodent model of schizophrenia (MAM-GD17) during an auditory PPI paradigm to better understand this phenomenon. MAM rats exhibited reductions in specific components of auditory evoked potentials in the orbtiofrontal cortex and an abolition of the graded response to stimuli of differing intensities indicating deficient intensity processing in the orbitofrontal cortex. These data indicate that aberrant sensory information processing, rather than being attributable to enhanced noise in neural structures, may be better attributed to diminished evoked amplitudes resulting in a reduction in the “signal-to-noise” ratio. Therefore, the ability for sensory input to modulate the ongoing background activity may be severely disrupted in schizophrenia yielding an internal state which is insufficiently responsive to external input. PMID:23932574

  17. Effects of prenatal infection on prepulse inhibition in the rat depend on the nature of the infectious agent and the stage of pregnancy.

    PubMed

    Fortier, Marie-Eve; Luheshi, Giamal N; Boksa, Patricia

    2007-08-01

    Maternal infection during pregnancy is a risk factor for some psychiatric illnesses of neurodevelopmental origin such as schizophrenia and autism. In experimental animals, behavioral and neuropathological outcomes relevant to schizophrenia have been observed in offspring of infected dams. However, the type of infectious agent used and gestational age at time of administration have varied. The objective of the present study was to compare the effects of prenatal challenge with different immune agents given at different time windows during gestation on behavioral outcomes in offspring. For this, pregnant rats were administered bacterial endotoxin (lipopolysaccharide, LPS), the viral mimic polyinosinic: polycytidylic acid (poly I:C), or turpentine, an inducer of local inflammation, at doses known to produce fever, at three different stages in pregnancy: embryonic day (E)10-11, E15-16 and E18-19. Prepulse inhibition of acoustic startle (PPI) was later measured in male adult offspring. PPI was significantly decreased in offspring after prenatal LPS treatment at E15-16 and E18-19. Intramuscular injection of pregnant dams with turpentine at E15-16 also decreased PPI in adult offspring. Maternal poly I:C administration had no significant effect on PPI in offspring. In contrast to prenatal LPS exposure, acute LPS administration to naive adult males had no effect on PPI. Thus, prenatal exposure both to a systemic immunogen and to local inflammation at brief periods during later pregnancy produced lasting deficits in PPI in rat offspring. These findings support the idea that maternal infection during critical windows of pregnancy could contribute to sensorimotor gating deficits in schizophrenia. PMID:17553574

  18. Integration of genome-wide association and extant brain expression QTL identifies candidate genes influencing prepulse inhibition in inbred F1 mice

    PubMed Central

    Sittig, L. J.; Carbonetto, P.; Engel, K. A.; Krauss, K. S.; Palmer, A. A.

    2016-01-01

    Genetic association mapping in structured populations of model organisms can offer a fruitful complement to human genetic studies by generating new biological hypotheses about complex traits. Here we investigated prepulse inhibition (PPI), a measure of sensorimotor gating that is disrupted in a number of psychiatric disorders. To identify genes that influence PPI, we constructed a panel of half-sibs by crossing 30 females from common inbred mouse strains with inbred C57BL/6J males to create male and female F1 offspring. We used publicly available single nucleotide polymorphism (SNP) genotype data from these inbred strains to perform a genome-wide association scan using a dense panel of over 150 000 SNPs in a combined sample of 604 mice representing 30 distinct F1 genotypes. We identified two independent PPI-associated loci on Chromosomes 2 and 7, each of which explained 12 – 14% of the variance in PPI. Searches of available databases did not identify any plausible causative coding polymorphisms within these loci. However, previously collected expression quantitative trait locus (eQTL) data from hippocampus and striatum indicated that the SNPs on Chromosomes 2 and 7 that showed the strongest association with PPI were also strongly associated with expression of several transcripts, some of which have been implicated in human psychiatric disorders. This integrative approach successfully identified a focused set of genes which can be prioritized for follow-up studies. More broadly, our results show that F1 crosses among common inbred strains can be used in combination with other informatics and expression datasets to identify candidate genes for complex behavioral traits. PMID:26482417

  19. Prepulse inhibition of the startle reflex and its attentional modulation in the human S-ketamine and N,N-dimethyltryptamine (DMT) models of psychosis.

    PubMed

    Heekeren, K; Neukirch, A; Daumann, J; Stoll, M; Obradovic, M; Kovar, K-A; Geyer, M A; Gouzoulis-Mayfrank, E

    2007-05-01

    Patients with schizophrenia exhibit diminished prepulse inhibition (PPI) of the acoustic startle reflex and deficits in the attentional modulation of PPI. Pharmacological challenges with hallucinogens are used as models for psychosis in both humans and animals. Remarkably, in contrast to the findings in schizophrenic patients and in animal hallucinogen models of psychosis, previous studies with healthy volunteers demonstrated increased levels of PPI after administration of low to moderate doses of either the antiglutamatergic hallucinogen ketamine or the serotonergic hallucinogen psilocybin. The aim of the present study was to investigate the influence of moderate and high doses of the serotonergic hallucinogen N,N-dimethyltryptamine (DMT) and the N-methyl-D-aspartate antagonist S-ketamine on PPI and its attentional modulation in humans. Fifteen healthy volunteers were included in a double-blind cross-over study with two doses of DMT and S-ketamine. Effects on PPI and its attentional modulation were investigated. Nine subjects completed both experimental days with the two doses of both drugs. S-ketamine increased PPI in both dosages, whereas DMT had no significant effects on PPI. S-ketamine decreased and DMT tended to decrease startle magnitude. There were no significant effects of either drug on the attentional modulation of PPI. In human experimental hallucinogen psychoses, and even with high, clearly psychotogenic doses of DMT or S-ketamine, healthy subjects failed to exhibit the predicted attenuation of PPI. In contrast, PPI was augmented and the startle magnitude was decreased after S-ketamine. These data point to important differences between human hallucinogen models and both animal hallucinogen models of psychosis and naturally occurring schizophrenia. PMID:17591658

  20. Inhibition of integrin α2β1 ameliorates glomerular injury.

    PubMed

    Borza, Corina M; Su, Yan; Chen, Xiwu; Yu, Ling; Mont, Stacey; Chetyrkin, Sergei; Voziyan, Paul; Hudson, Billy G; Billings, Paul C; Jo, Hyunil; Bennett, Joel S; Degrado, William F; Eckes, Beate; Zent, Roy; Pozzi, Ambra

    2012-06-01

    Mesangial cells and podocytes express integrins α1β1 and α2β1, which are the two major collagen receptors that regulate multiple cellular functions, including extracellular matrix homeostasis. Integrin α1β1 protects from glomerular injury by negatively regulating collagen production, but the role of integrin α2β1 in renal injury is unclear. Here, we subjected wild-type and integrin α2-null mice to injury with adriamycin or partial renal ablation. In both of these models, integrin α2-null mice developed significantly less proteinuria and glomerulosclerosis. In addition, selective pharmacological inhibition of integrin α2β1 significantly reduced adriamycin-induced proteinuria, glomerular injury, and collagen deposition in wild-type mice. This inhibitor significantly reduced collagen synthesis in wild-type, but not integrin α2-null, mesangial cells in vitro, demonstrating that its effects are integrin α2β1-dependent. Taken together, these results indicate that integrin α2β1 contributes to glomerular injury by positively regulating collagen synthesis and suggest that its inhibition may be a promising strategy to reduce glomerular injury and proteinuria. PMID:22440900

  1. Inhibition of Integrin α2β1 Ameliorates Glomerular Injury

    PubMed Central

    Borza, Corina M.; Su, Yan; Chen, Xiwu; Yu, Ling; Mont, Stacey; Chetyrkin, Sergei; Voziyan, Paul; Hudson, Billy G.; Billings, Paul C.; Jo, Hyunil; Bennett, Joel S.; DeGrado, William F.; Eckes, Beate; Zent, Roy

    2012-01-01

    Mesangial cells and podocytes express integrins α1β1 and α2β1, which are the two major collagen receptors that regulate multiple cellular functions, including extracellular matrix homeostasis. Integrin α1β1 protects from glomerular injury by negatively regulating collagen production, but the role of integrin α2β1 in renal injury is unclear. Here, we subjected wild-type and integrin α2-null mice to injury with adriamycin or partial renal ablation. In both of these models, integrin α2-null mice developed significantly less proteinuria and glomerulosclerosis. In addition, selective pharmacological inhibition of integrin α2β1 significantly reduced adriamycin-induced proteinuria, glomerular injury, and collagen deposition in wild-type mice. This inhibitor significantly reduced collagen synthesis in wild-type, but not integrin α2-null, mesangial cells in vitro, demonstrating that its effects are integrin α2β1-dependent. Taken together, these results indicate that integrin α2β1 contributes to glomerular injury by positively regulating collagen synthesis and suggest that its inhibition may be a promising strategy to reduce glomerular injury and proteinuria. PMID:22440900

  2. Prepulse minimization in KALI-5000.

    PubMed

    Kumar, D Durga Praveen; Mitra, S; Senthil, K; Sharma, Vishnu K; Singh, S K; Roy, A; Sharma, Archana; Nagesh, K V; Chakravarthy, D P

    2009-07-01

    A pulse power system (1 MV, 50 kA, and 100 ns) based on Marx generator and Blumlein pulse forming line has been built for generating high power microwaves. The Blumlein configuration poses a prepulse problem and hence the diode gap had to be increased to match the diode impedance to the Blumlein impedance during the main pulse. A simple method to eliminate prepulse voltage using a vacuum sparkgap and a resistor is given. Another fundamental approach of increasing the inductance of Marx generator to minimize the prepulse voltage is also presented. Experimental results for both of these configurations are given. PMID:19655979

  3. Prepulse minimization in KALI-5000

    NASA Astrophysics Data System (ADS)

    Kumar, D. Durga Praveen; Mitra, S.; Senthil, K.; Sharma, Vishnu K.; Singh, S. K.; Roy, A.; Sharma, Archana; Nagesh, K. V.; Chakravarthy, D. P.

    2009-07-01

    A pulse power system (1 MV, 50 kA, and 100 ns) based on Marx generator and Blumlein pulse forming line has been built for generating high power microwaves. The Blumlein configuration poses a prepulse problem and hence the diode gap had to be increased to match the diode impedance to the Blumlein impedance during the main pulse. A simple method to eliminate prepulse voltage using a vacuum sparkgap and a resistor is given. Another fundamental approach of increasing the inductance of Marx generator to minimize the prepulse voltage is also presented. Experimental results for both of these configurations are given.

  4. Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration

    PubMed Central

    Zwilling, Daniel; Huang, Shao-Yi; Sathyasaikumar, Korrapati V.; Notarangelo, Francesca M.; Guidetti, Paolo; Wu, Hui-Qiu; Lee, Jason; Truong, Jennifer; Andrews-Zwilling, Yaisa; Hsieh, Eric W.; Louie, Jamie Y.; Wu, Tiffany; Scearce-Levie, Kimberly; Patrick, Christina; Adame, Anthony; Giorgini, Flaviano; Moussaoui, Saliha; Laue, Grit; Rassoulpour, Arash; Flik, Gunnar; Huang, Yadong; Muchowski, Joseph M.; Masliah, Eliezer; Schwarcz, Robert; Muchowski, Paul J.

    2011-01-01

    SUMMARY Metabolites in the kynurenine pathway of tryptophan degradation are thought to play an important role in neurodegenerative disorders such as Alzheimer’s disease and Huntington’s disease. Metabolites that cause glutamate receptor-mediated excitotoxicity and free radical formation are elevated in the blood and vulnerable brain regions in these diseases, while levels of the neuroprotective metabolite kynurenic acid are often decreased. Here we describe the synthesis and characterization of JM6, a novel small-molecule pro-drug inhibitor of kynurenine 3-monooxygenase (KMO). JM6 raises kynurenic acid and reduces extracellular glutamate in the brain after chronic oral administration by inhibiting KMO in blood. In a transgenic mouse model of Alzheimer’s disease, JM6 prevented spatial memory deficits, anxiety-related behavior, and synaptic loss. JM6 also extended life span, prevented synaptic loss, and decreased microglial activation in a mouse model of Huntington’s disease. These findings support a critical link between blood cells and neurodegeneration that is mediated by KMO and the kynurenine pathway. PMID:21640374

  5. Inhibition of prolyl hydroxylase 3 ameliorates cardiac dysfunction in diabetic cardiomyopathy.

    PubMed

    Xia, Yanfei; Gong, Luwei; Liu, Hui; Luo, Beibei; Li, Bo; Li, Rui; Li, Beibei; Lv, Mei; Pan, Jinyu; An, Fengshuang

    2015-03-01

    Prolyl hydroxylase 3 (PHD3) is a member of the prolyl hydroxylases (PHDs) family and is induced by hypoxia. It plays a critical role in regulating the abundance of hypoxia-inducible factor (HIF). Its expression is increased in diabetic rat hearts; however, its role remains unclear. We investigated the potential role and mechanism of action of PHD3 in the setting of diabetes-induced myocardial dysfunction in rats. In vivo, type 2 diabetic rat model was induced via a high-fat diet and intraperitoneal injection of streptozotocin. PHD3 expression was knocked down using lentivirus-mediated short-hairpin RNA (shRNA). In vitro, primary neonatal cardiomyocytes and H9c2 cardiomyoblasts were cultured in 33.3 mM glucose (high glucose, HG) and 5.5 mM glucose (normal glucose, NG), the latter of which was used as a control. PHD3-siRNA was used to inhibit the expression of PHD3 and to investigate the role of PHD3 in HG-induced apoptosis in H9c2 cardiomyoblasts. Rats with diabetic cardiomyopathy (DCM) exhibited severe left ventricular dysfunction as well as myocardial apoptosis and fibrosis. PHD3 expression was increased in the myocardial tissues of diabetic rats, and inhibition of PHD3 ameliorated the disease. Additionally, the inhibition of PHD3 significantly decreased HG-induced apoptosis and MAPK activation in H9c2 cardiomyoblasts. Our results suggest that PHD3 inhibition ameliorates myocardial dysfunction in the setting of diabetic cardiomyopathy. PMID:25595486

  6. Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites

    PubMed Central

    Breda, Carlo; Sathyasaikumar, Korrapati V.; Sograte Idrissi, Shama; Notarangelo, Francesca M.; Estranero, Jasper G.; Moore, Gareth G. L.; Green, Edward W.; Kyriacou, Charalambos P.; Schwarcz, Robert; Giorgini, Flaviano

    2016-01-01

    Metabolites of the kynurenine pathway (KP) of tryptophan (TRP) degradation have been closely linked to the pathogenesis of several neurodegenerative disorders. Recent work has highlighted the therapeutic potential of inhibiting two critical regulatory enzymes in this pathway—kynurenine-3-monooxygenase (KMO) and tryptophan-2,3-dioxygenase (TDO). Much evidence indicates that the efficacy of KMO inhibition arises from normalizing an imbalance between neurotoxic [3-hydroxykynurenine (3-HK); quinolinic acid (QUIN)] and neuroprotective [kynurenic acid (KYNA)] KP metabolites. However, it is not clear if TDO inhibition is protective via a similar mechanism or if this is instead due to increased levels of TRP—the substrate of TDO. Here, we find that increased levels of KYNA relative to 3-HK are likely central to the protection conferred by TDO inhibition in a fruit fly model of Huntington’s disease and that TRP treatment strongly reduces neurodegeneration by shifting KP flux toward KYNA synthesis. In fly models of Alzheimer’s and Parkinson’s disease, we provide genetic evidence that inhibition of TDO or KMO improves locomotor performance and ameliorates shortened life span, as well as reducing neurodegeneration in Alzheimer's model flies. Critically, we find that treatment with a chemical TDO inhibitor is robustly protective in these models. Consequently, our work strongly supports targeting of the KP as a potential treatment strategy for several major neurodegenerative disorders and suggests that alterations in the levels of neuroactive KP metabolites could underlie several therapeutic benefits. PMID:27114543

  7. Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites.

    PubMed

    Breda, Carlo; Sathyasaikumar, Korrapati V; Sograte Idrissi, Shama; Notarangelo, Francesca M; Estranero, Jasper G; Moore, Gareth G L; Green, Edward W; Kyriacou, Charalambos P; Schwarcz, Robert; Giorgini, Flaviano

    2016-05-10

    Metabolites of the kynurenine pathway (KP) of tryptophan (TRP) degradation have been closely linked to the pathogenesis of several neurodegenerative disorders. Recent work has highlighted the therapeutic potential of inhibiting two critical regulatory enzymes in this pathway-kynurenine-3-monooxygenase (KMO) and tryptophan-2,3-dioxygenase (TDO). Much evidence indicates that the efficacy of KMO inhibition arises from normalizing an imbalance between neurotoxic [3-hydroxykynurenine (3-HK); quinolinic acid (QUIN)] and neuroprotective [kynurenic acid (KYNA)] KP metabolites. However, it is not clear if TDO inhibition is protective via a similar mechanism or if this is instead due to increased levels of TRP-the substrate of TDO. Here, we find that increased levels of KYNA relative to 3-HK are likely central to the protection conferred by TDO inhibition in a fruit fly model of Huntington's disease and that TRP treatment strongly reduces neurodegeneration by shifting KP flux toward KYNA synthesis. In fly models of Alzheimer's and Parkinson's disease, we provide genetic evidence that inhibition of TDO or KMO improves locomotor performance and ameliorates shortened life span, as well as reducing neurodegeneration in Alzheimer's model flies. Critically, we find that treatment with a chemical TDO inhibitor is robustly protective in these models. Consequently, our work strongly supports targeting of the KP as a potential treatment strategy for several major neurodegenerative disorders and suggests that alterations in the levels of neuroactive KP metabolites could underlie several therapeutic benefits. PMID:27114543

  8. Inhibition of Protease-activated Receptor 1 Ameliorates Intestinal Radiation Mucositis in a Preclinical Rat Model

    SciTech Connect

    Wang, Junru; Kulkarni, Ashwini; Chintala, Madhu; Fink, Louis M.; Hauer-Jensen, Martin

    2013-01-01

    Purpose: To determine, using a specific small-molecule inhibitor of protease-activated receptor 1 (PAR1) signaling, whether the beneficial effect of thrombin inhibition on radiation enteropathy development is due to inhibition of blood clotting or to cellular (PAR1-mediated) thrombin effects. Methods and Materials: Rats underwent fractionated X-irradiation (5 Gy Multiplication-Sign 9) of a 4-cm small-bowel segment. Early radiation toxicity was evaluated in rats receiving PAR1 inhibitor (SCH602539, 0, 10, or 15 mg/kg/d) from 1 day before to 2 weeks after the end of irradiation. The effect of PAR1 inhibition on development of chronic intestinal radiation fibrosis was evaluated in animals receiving SCH602539 (0, 15, or 30 mg/kg/d) until 2 weeks after irradiation, or continuously until termination of the experiment 26 weeks after irradiation. Results: Blockade of PAR1 ameliorated early intestinal toxicity, with reduced overall intestinal radiation injury (P=.002), number of myeloperoxidase-positive (P=.03) and proliferating cell nuclear antigen-positive (P=.04) cells, and collagen III accumulation (P=.005). In contrast, there was no difference in delayed radiation enteropathy in either the 2- or 26-week administration groups. Conclusion: Pharmacological blockade of PAR1 seems to reduce early radiation mucositis but does not affect the level of delayed intestinal radiation fibrosis. Early radiation enteropathy is related to activation of cellular thrombin receptors, whereas platelet activation or fibrin formation may play a greater role in the development of delayed toxicity. Because of the favorable side-effect profile, PAR1 blockade should be further explored as a method to ameliorate acute intestinal radiation toxicity in patients undergoing radiotherapy for cancer and to protect first responders and rescue personnel in radiologic/nuclear emergencies.

  9. Inhibition of MEK1 Signaling Pathway in the Liver Ameliorates Insulin Resistance

    PubMed Central

    Ueyama, Atsunori; Ban, Nobuhiro; Fukazawa, Masanori; Hirayama, Tohru; Takeda, Minako; Yata, Tatsuo; Muramatsu, Hiroyasu; Hoshino, Masaki; Yamamoto, Marii; Matsuo, Masao; Kawashima, Yuka; Iwase, Tatsuhiko; Kitazawa, Takehisa; Kushima, Youichi; Yamada, Yuichiro; Kawabe, Yoshiki

    2016-01-01

    Although mitogen-activated protein kinase kinase (MEK) is a key signaling molecule and a negative regulator of insulin action, it is still uncertain whether MEK can be a therapeutic target for amelioration of insulin resistance (IR) in type 2 diabetes (T2D) in vivo. To clarify whether MEK inhibition improves T2D, we examined the effect of continuous MEK inhibition with two structurally different MEK inhibitors, RO5126766 and RO4987655, in mouse models of T2D. RO5126766 and RO4987655 were administered via dietary admixture. Both compounds decreased blood glucose and improved glucose tolerance in doses sufficient to sustain inhibition of extracellular signal-regulated kinase (ERK)1/2 phosphorylation downstream of MEK in insulin-responsive tissues in db/db mice. A hyperinsulinemic-euglycemic clamp test showed increased glucose infusion rate (GIR) in db/db mice treated with these compounds, and about 60% of the increase was attributed to the inhibition of endogenous glucose production, suggesting that the liver is responsible for the improvement of IR. By means of adenovirus-mediated Mek1 shRNA expression, we confirmed that blood glucose levels are reduced by suppression of MEK1 expression in the liver of db/db mice. Taken together, these results suggested that the MEK signaling pathway could be a novel therapeutic target for novel antidiabetic agents. PMID:26839898

  10. Inhibition of MEK1 Signaling Pathway in the Liver Ameliorates Insulin Resistance.

    PubMed

    Ueyama, Atsunori; Ban, Nobuhiro; Fukazawa, Masanori; Hirayama, Tohru; Takeda, Minako; Yata, Tatsuo; Muramatsu, Hiroyasu; Hoshino, Masaki; Yamamoto, Marii; Matsuo, Masao; Kawashima, Yuka; Iwase, Tatsuhiko; Kitazawa, Takehisa; Kushima, Youichi; Yamada, Yuichiro; Kawabe, Yoshiki

    2016-01-01

    Although mitogen-activated protein kinase kinase (MEK) is a key signaling molecule and a negative regulator of insulin action, it is still uncertain whether MEK can be a therapeutic target for amelioration of insulin resistance (IR) in type 2 diabetes (T2D) in vivo. To clarify whether MEK inhibition improves T2D, we examined the effect of continuous MEK inhibition with two structurally different MEK inhibitors, RO5126766 and RO4987655, in mouse models of T2D. RO5126766 and RO4987655 were administered via dietary admixture. Both compounds decreased blood glucose and improved glucose tolerance in doses sufficient to sustain inhibition of extracellular signal-regulated kinase (ERK)1/2 phosphorylation downstream of MEK in insulin-responsive tissues in db/db mice. A hyperinsulinemic-euglycemic clamp test showed increased glucose infusion rate (GIR) in db/db mice treated with these compounds, and about 60% of the increase was attributed to the inhibition of endogenous glucose production, suggesting that the liver is responsible for the improvement of IR. By means of adenovirus-mediated Mek1 shRNA expression, we confirmed that blood glucose levels are reduced by suppression of MEK1 expression in the liver of db/db mice. Taken together, these results suggested that the MEK signaling pathway could be a novel therapeutic target for novel antidiabetic agents. PMID:26839898

  11. NF-kappaB inhibition ameliorates angiotensin II-induced inflammatory damage in rats.

    PubMed

    Muller, D N; Dechend, R; Mervaala, E M; Park, J K; Schmidt, F; Fiebeler, A; Theuer, J; Breu, V; Ganten, D; Haller, H; Luft, F C

    2000-01-01

    We recently reported that the activation of nuclear factor-kappaB (NF-kappaB) promotes inflammation in rats harboring both human renin and angiotensinogen genes (double-transgenic rats [dTGR]). We tested the hypothesis that the antioxidant pyrrolidine dithiocarbamate (PDTC) inhibits NF-kappaB and ameliorates renal and cardiac end-organ damage. dTGR feature hypertension, severe renal and cardiac damage, and a 40% mortality rate at 7 weeks. Electrophoretic mobility shift assay showed increased NF-kappaB DNA binding activity in hearts and kidneys of dTGR. Chronic PDTC (200 mg/kg SC) treatment decreased blood pressure (162+/-8 versus 190+/-7 mm Hg; P=0.02) in dTGR compared with dTGR controls. The cardiac hypertrophy index was also significantly reduced (4.90+/-0.1 versus 5.77+/-0.1 mg/g; P<0. 001). PDTC reduced 24-hour albuminuria by >95% (2.5+/-0.8 versus 57. 1+/-8.7 mg/d; P<0.001) and prevented death. Vascular injury was ameliorated in small renal and cardiac vessels. Electrophoretic mobility shift assay showed that PDTC inhibited NF-kappaB binding activity in heart and kidney, whereas AP-1 activity in the kidney was not decreased. dTGR exhibited increased left ventricular c-fos and c-jun mRNA expression. PDTC treatment reduced c-fos but not c-jun mRNA. Immunohistochemistry showed increased p65 NF-kappaB subunit expression in the endothelium and smooth muscle cells of damaged small vessels, as well as infiltrating cells in glomeruli, tubules, and collecting ducts of dTGR. PDTC markedly reduced the immunoreactivity of p65. PDTC also prevented the NF-kappaB-dependent transactivation of the intercellular adhesion molecule ICAM-1 and inducible nitric oxide synthase. Monocyte infiltration was markedly increased in dTGR kidneys and hearts. Chronic treatment reduced monocyte/macrophage infiltration by 72% and 64%, respectively. Thus, these results demonstrate that PDTC inhibits NF-kappaB activity, ameliorates inflammation, and protects against angiotensin II-induced end

  12. Intermedin ameliorates IgA nephropathy by inhibition of oxidative stress and inflammation.

    PubMed

    Wang, Yanhong; Tian, Jihua; Guo, Haixiu; Mi, Yang; Zhang, Ruijing; Li, Rongshan

    2016-05-01

    IgA nephropathy (IgAN) is the most frequent form of glomerulonephritis worldwide. The role of oxidative stress and inflammation in the pathogenesis of IgAN has been reported. Intermedin (IMD) is a newly discovered peptide that is closely related to adrenomedullin. We have recently reported that IMD can significantly reduce renal ischemia/reperfusion injury by diminishing oxidative stress and suppressing inflammation. The present study was designed to explore whether IMD ameliorates IgAN via oxidative stress- and inflammation-dependent mechanisms. Our results showed that IMD administration resulted in the prevention of albuminuria and ameliorated renal pathomorphological changes. These findings were associated with (1) decreased renal TGF-β1 and collagen IV expression, (2) an increased SOD level and reduced MDA level, (3) the inhibition of the renal activation of NF-κB p65 and (4) the downregulation of the expression of inflammatory factors (TNF-α, MCP-1 and MMP-9) in the kidney. These results indicate that IMD in the kidney protects against IgAN by reducing oxidative stress and suppressing inflammation. PMID:25916508

  13. Divergent effects of isolation rearing on prepulse inhibition, activity, anxiety and hippocampal-dependent memory in Roman high- and low-avoidance rats: A putative model of schizophrenia-relevant features.

    PubMed

    Oliveras, Ignasi; Sánchez-González, Ana; Piludu, Maria Antonietta; Gerboles, Cristina; Río-Álamos, Cristóbal; Tobeña, Adolf; Fernández-Teruel, Alberto

    2016-11-01

    Social isolation of rats induces a constellation of behavioral alterations known as "isolation syndrome" that are consistent with some of the positive and cognitive symptoms observed in schizophrenic patients. In the present study we have assessed whether isolation rearing of inbred Roman high-avoidance (RHA-I) and Roman low-avoidance (RLA-I) strains can lead to the appearance of some of the key features of the "isolation syndrome", such as prepulse inhibition (PPI) deficits, increased anxious behavior, hyperactivity and memory/learning impairments. Compared to RLA-I rats, the results show that isolation rearing (IR) in RHA-I rats has a more profound impact, as they exhibit isolation-induced PPI deficits, increased anxiety, hyperactivity and long-term reference memory deficits, while isolated RLA-I rats only exhibit deficits in a spatial working memory task. These results give further support to the validity of RHA-I rats as a genetically-based model of schizophrenia relevant-symptoms. PMID:27478139

  14. Genipin ameliorates age-related insulin resistance through inhibiting hepatic oxidative stress and mitochondrial dysfunction.

    PubMed

    Guan, Lili; Feng, Haiyan; Gong, Dezheng; Zhao, Xu; Cai, Li; Wu, Qiong; Yuan, Bo; Yang, Mei; Zhao, Jie; Zou, Yuan

    2013-12-01

    Insulin resistance (IR) increases with age and plays a key role in the pathogenesis of type 2 diabetes mellitus. Oxidative stress and mitochondrial dysfunction are supposed to be major factors leading to age-related IR. Genipin, an extract from Gardenia jasminoides Ellis fruit, has been reported to stimulate insulin secretion in pancreatic islet cells by regulating mitochondrial function. In this study, we first investigated the effects of genipin on insulin sensitivity and the potential mitochondrial mechanisms in the liver of aging rats. The rats were randomly assigned to receive intraperitoneal injections of either 25mg/kg genipin or vehicle once daily for 12days. The aging rats showed hyperinsulinemia and hyperlipidemia, and insulin resistance as examined by the decreased glucose decay constant rate during insulin tolerance test (kITT). The hepatic tissues showed steatosis and reduced glycogen content. Hepatic malondialdehyde level and mitochondrial reactive oxygen species (ROS) were higher, and levels of mitochondrial membrane potential (MMP) and ATP were lower as compared with the normal control rats. Administration of genipin ameliorated systemic and hepatic insulin resistance, alleviated hyperinsulinemia, hyperglyceridemia and hepatic steatosis, relieved hepatic oxidative stress and mitochondrial dysfunction in aging rats. Furthermore, genipin not only improved insulin sensitivity by promoting insulin-stimulated glucose consumption and glycogen synthesis, inhibited cellular ROS overproduction and alleviated the reduction of levels of MMP and ATP, but also reversed oxidative stress-associated JNK hyperactivation and reduced Akt phosphorylation in palmitate-treated L02 hepatocytes. In conclusion, genipin ameliorates age-related insulin resistance through inhibiting hepatic oxidative stress and mitochondrial dysfunction. PMID:24041487

  15. Prenatal immune challenge in rats: altered responses to dopaminergic and glutamatergic agents, prepulse inhibition of acoustic startle, and reduced route-based learning as a function of maternal body weight gain after prenatal exposure to poly IC.

    PubMed

    Vorhees, Charles V; Graham, Devon L; Braun, Amanda A; Schaefer, Tori L; Skelton, Matthew R; Richtand, Neil M; Williams, Michael T

    2012-08-01

    Prenatal maternal immune activation has been used to test the neurodevelopmental hypothesis of schizophrenia. Most of the data are in mouse models; far less is available for rats. We previously showed that maternal weight change in response to the immune activator polyinosinic-polycytidylic acid (Poly IC) in rats differentially affects offspring. Therefore, we treated gravid Harlan Sprague-Dawley rats i.p. on embryonic day 14 with 8 mg/kg of Poly IC or Saline. The Poly IC group was divided into those that lost or gained the least weight, Poly IC (L), versus those that gained the most weight, Poly IC (H), following treatment. The study design controlled for litter size, litter sampling, sex distribution, and test experience. We found no effects of Poly IC on elevated zero maze, open-field activity, object burying, light-dark test, straight channel swimming, Morris water maze spatial acquisition, reversal, or shift navigation or spatial working or reference memory, or conditioned contextual or cued fear or latent inhibition. The Poly IC (H) group showed a significant decrease in the rate of route-based learning when visible cues were unavailable in the Cincinnati water maze and reduced prepulse inhibition of acoustic startle in females, but not males. The Poly IC (L) group exhibited altered responses to acute pharmacological challenges: exaggerated hyperactivity in response to (+)-amphetamine and an attenuated hyperactivity in response to MK-801. This model did not exhibit the cognitive, or latent inhibition deficits reported in Poly IC-treated rats but showed changes in response to drugs acting on neurotransmitter systems implicated in the pathophysiology of schizophrenia (dopaminergic hyperfunction and glutamatergic hypofunction). PMID:22473973

  16. Prenatal immune challenge in rats: Altered responses to dopaminergic and glutamatergic agents, prepulse inhibition of acoustic startle, and reduced route-based learning as a function of maternal body weight gain after prenatal exposure to Poly IC

    PubMed Central

    Vorhees, Charles V.; Graham, Devon L.; Braun, Amanda A.; Schaefer, Tori L.; Skelton, Matthew R.; Richtand, Neil M.; Williams, Michael T.

    2012-01-01

    Prenatal maternal immune activation has been used to test the neurodevelopmental hypothesis of schizophrenia. Most of the data are in mouse models; far less is available for rats. We previously showed that maternal weight change in response to the immune activator polyinosinic-polycytidylic (Poly IC) in rats differentially affects offspring. Therefore, we treated gravid Harlan Sprague-Dawley rats i.p. on embryonic day 14 with 8 mg/kg of Poly IC or Saline. The Poly IC group was divided into those that lost or gained the least weight, Poly IC (L), versus those that gained the most weight, Poly IC (H), following treatment. The study design controlled for litter size, litter sampling, sex distribution, and test experience. We found no effects of Poly IC on elevated zero-maze, open-field activity, object burying, light-dark test, straight channel swimming, Morris water maze spatial acquisition, reversal, or shift navigation or spatial working or reference memory, or conditioned contextual or cued fear or latent inhibition. The Poly IC (H) group showed a significant decrease in the rate of route-based learning when visible cues unavailable in the Cincinnati water maze and reduced prepulse inhibition of acoustic startle in females, but not males. The Poly IC (L) group exhibited altered responses to acute pharmacological challenges: exaggerated hyperactivity in response to (+)-amphetamine and an attenuated hyperactivity in response to MK-801. This model did not exhibit the cognitive, acoustic startle, or latent inhibition deficits reported in Poly IC-treated rats, but showed changes in response to drugs acting on neurotransmitter systems implicated in the pathophysiology of schizophrenia (dopaminergic hyperfunction and glutamatergic hypofunction). PMID:22473973

  17. Vitamin D inhibits development of liver fibrosis in an animal model but cannot ameliorate established cirrhosis.

    PubMed

    Abramovitch, Shirley; Sharvit, Efrat; Weisman, Yosef; Bentov, Amir; Brazowski, Eli; Cohen, Gili; Volovelsky, Oded; Reif, Shimon

    2015-01-15

    1,25(OH)2D3, the active form of vitamin D, has an antiproliferative and antifibrotic effect on hepatic stellate cells. Our aim was to investigate the potential of 1,25(OH)2D3 to inhibit the development of liver fibrosis and to ameliorate established fibrosis in vivo. The antifibrotic effect of 1,25(OH)2D3 was investigated in a thioacetamide (TAA) model (as a preventive treatment and as a remedial treatment) and in a bile duct ligation model. In the preventive model, rats received simultaneously intraperitoneum injection of TAA and/or 1,25(OH)2D3 for 10 wk. In the remedial model, rats were treated with TAA for 10 wk and then received 1,25(OH)2D3 or saline for 8 wk. Fibrotic score was determined by Masson staining. Collagen I, α-smooth muscle actin (α-SMA), tissue inhibitor of metalloproteinase-1 (TIMP1), platelet-derived growth factor (PDGF), and transforming growth factor-β (TGF-β) expression were measured by Western blot analysis and real-time PCR. Hypercalemia was detected by chemistry measurements. Preventive treatment of 1,25(OH)2D3 significantly suppressed liver fibrosis both macroscopically and microscopically and significantly lowered the fibrotic score of the TAA + 1,25(OH)2D3 group compared with the TAA group. 1,25(OH)2D3 significantly inhibited expression of PDGF and TGF-β by ∼50% and suppressed the expression of collagen Iα1, TIMP1, and α-SMA by approximately three-, two-, and threefold, respectively. In contrast, 1,25(OH)2D3 was inefficient in amelioration of established liver fibrosis. Administration of 1,25(OH)2D3 to bile duct ligation rats led to a high mortality rate probably caused by hypercalcemia. We conclude that 1,25(OH)2D3 may be considered as a potential preventive treatment in an in vivo model but failed to ameliorate established cirrhosis. PMID:25214398

  18. The cannabinoid TRPA1 agonist cannabichromene inhibits nitric oxide production in macrophages and ameliorates murine colitis

    PubMed Central

    Romano, B; Borrelli, F; Fasolino, I; Capasso, R; Piscitelli, F; Cascio, MG; Pertwee, RG; Coppola, D; Vassallo, L; Orlando, P; Di Marzo, V; Izzo, AA

    2013-01-01

    Background and Purpose The non-psychotropic cannabinoid cannabichromene is known to activate the transient receptor potential ankyrin-type1 (TRPA1) and to inhibit endocannabinoid inactivation, both of which are involved in inflammatory processes. We examined here the effects of this phytocannabinoid on peritoneal macrophages and its efficacy in an experimental model of colitis. Experimental Approach Murine peritoneal macrophages were activated in vitro by LPS. Nitrite levels were measured using a fluorescent assay; inducible nitric oxide (iNOS), cyclooxygenase-2 (COX-2) and cannabinoid (CB1 and CB2) receptors were analysed by RT-PCR (and/or Western blot analysis); colitis was induced by dinitrobenzene sulphonic acid (DNBS). Endocannabinoid (anandamide and 2-arachidonoylglycerol), palmitoylethanolamide and oleoylethanolamide levels were measured by liquid chromatography-mass spectrometry. Colonic inflammation was assessed by evaluating the myeloperoxidase activity as well as by histology and immunohistochemistry. Key Results LPS caused a significant production of nitrites, associated to up-regulation of anandamide, iNOS, COX-2, CB1 receptors and down-regulation of CB2 receptors mRNA expression. Cannabichromene significantly reduced LPS-stimulated nitrite levels, and its effect was mimicked by cannabinoid receptor and TRPA1 agonists (carvacrol and cinnamaldehyde) and enhanced by CB1 receptor antagonists. LPS-induced anandamide, iNOS, COX-2 and cannabinoid receptor changes were not significantly modified by cannabichromene, which, however, increased oleoylethanolamide levels. In vivo, cannabichromene ameliorated DNBS-induced colonic inflammation, as revealed by histology, immunohistochemistry and myeloperoxidase activity. Conclusion and Implications Cannabichromene exerts anti-inflammatory actions in activated macrophages – with tonic CB1 cannabinoid signalling being negatively coupled to this effect – and ameliorates experimental murine colitis. PMID:23373571

  19. Luteolin Ameliorates Hypertensive Vascular Remodeling through Inhibiting the Proliferation and Migration of Vascular Smooth Muscle Cells

    PubMed Central

    Su, Jie; Xu, Han-Ting; Yu, Jing-Jing; Gao, Jian-Li; Lei, Jing; Yin, Qiao-Shan; Li, Bo; Pang, Min-Xia; Su, Min-Xia; Mi, Wen-Jia; Chen, Su-Hong; Lv, Gui-Yuan

    2015-01-01

    Objectives. Preliminary researches showed that luteolin was used to treat hypertension. However, it is still unclear whether luteolin has effect on the hypertensive complication such as vascular remodeling. The present study was designed to investigate the effect of luteolin on the hypertensive vascular remodeling and its molecular mechanism. Method and Results. We evaluated the effect of luteolin on aorta thickening of hypertension in spontaneous hypertensive rats (SHRs) and found that luteolin could significantly decrease the blood pressure and media thickness of aorta in vivo. Luteolin could inhibit angiotensin II- (Ang II-) induced proliferation and migration of vascular smooth muscle cells (VSMCs). Dichlorofluorescein diacetate (DCFH-DA) staining result showed that luteolin reduced Ang II-stimulated ROS production in VSMCs. Furthermore, western blot and gelatin zymography results showed that luteolin treatment leaded to a decrease in ERK1/2, p-ERK1/2, p-p38, MMP2, and proliferating cell nuclear antigen (PCNA) protein level. Conclusion. These data support that luteolin can ameliorate hypertensive vascular remodeling by inhibiting the proliferation and migration of Ang II-induced VSMCs. Its mechanism is mediated by the regulation of MAPK signaling pathway and the production of ROS. PMID:26495010

  20. Inhibition of the kinase WNK1/HSN2 ameliorates neuropathic pain by restoring GABA inhibition.

    PubMed

    Kahle, Kristopher T; Schmouth, Jean-François; Lavastre, Valérie; Latremoliere, Alban; Zhang, Jinwei; Andrews, Nick; Omura, Takao; Laganière, Janet; Rochefort, Daniel; Hince, Pascale; Castonguay, Geneviève; Gaudet, Rébecca; Mapplebeck, Josiane C S; Sotocinal, Susana G; Duan, JingJing; Ward, Catherine; Khanna, Arjun R; Mogil, Jeffrey S; Dion, Patrick A; Woolf, Clifford J; Inquimbert, Perrine; Rouleau, Guy A

    2016-03-29

    HSN2is a nervous system predominant exon of the gene encoding the kinase WNK1 and is mutated in an autosomal recessive, inherited form of congenital pain insensitivity. The HSN2-containing splice variant is referred to as WNK1/HSN2. We created a knockout mouse specifically lacking theHsn2exon ofWnk1 Although these mice had normal spinal neuron and peripheral sensory neuron morphology and distribution, the mice were less susceptible to hypersensitivity to cold and mechanical stimuli after peripheral nerve injury. In contrast, thermal and mechanical nociceptive responses were similar to control mice in an inflammation-induced pain model. In the nerve injury model of neuropathic pain, WNK1/HSN2 contributed to a maladaptive decrease in the activity of the K(+)-Cl(-)cotransporter KCC2 by increasing its inhibitory phosphorylation at Thr(906)and Thr(1007), resulting in an associated loss of GABA (γ-aminobutyric acid)-mediated inhibition of spinal pain-transmitting nerves. Electrophysiological analysis showed that WNK1/HSN2 shifted the concentration of Cl(-)such that GABA signaling resulted in a less hyperpolarized state (increased neuronal activity) rather than a more hyperpolarized state (decreased neuronal activity) in mouse spinal nerves. Pharmacologically antagonizing WNK activity reduced cold allodynia and mechanical hyperalgesia, decreased KCC2 Thr(906)and Thr(1007)phosphorylation, and restored GABA-mediated inhibition (hyperpolarization) of injured spinal cord lamina II neurons. These data provide mechanistic insight into, and a compelling therapeutic target for treating, neuropathic pain after nerve injury. PMID:27025876

  1. Suppression of calcium‑sensing receptor ameliorates cardiac hypertrophy through inhibition of autophagy.

    PubMed

    Liu, Lei; Wang, Chao; Lin, Yan; Xi, Yuhui; Li, Hong; Shi, Sa; Li, Hongzhu; Zhang, Weihua; Zhao, Yajun; Tian, Ye; Xu, Changqing; Wang, Lina

    2016-07-01

    The calcium-sensing receptor (CaSR) releases intracellular calcium ([Ca2+]i) by accumulating inositol phosphate. Changes in [Ca2+]i initiate myocardial hypertrophy. Furthermore, autophagy associated with [Ca2+]i. Autophagy has previously been demonstrated to participate in the hypertrophic process. The current study investigated whether suppression of CaSR affects the hypertrophic response via modulating autophagy. Isoproterenol (ISO) was used to induce cardiac hypertrophy in Wistar rats. Hypertrophic status was determined by echocardiographic assessment, hematoxylin and eosin, and Masson's staining. The protein expression levels of CaSR and autophagy level were observed. Changes of hypertrophy and autophagy indicators were observed following intravenous injection of a CaSR inhibitor. An ISO‑induced cardiomyocyte hypertrophy model was established and used determine the involvement of GdCl3. [Ca2+]i was determined using Fluo‑4/AM dye followed by confocal microscopy. The expression levels of various active proteins were analyzed by western blotting. The size of the heart, expression levels of CaSR and autophagy level were markedly increased in hypertrophic myocardium. In addition, the present study demonstrated that the indicators of hypertrophy and autophagy were effectively suppressed by CaSR inhibitor. Furthermore, similar effects were demonstrated in neonatal rat hypertrophic cardiomyocytes treated with ISO. It was also observed that CaSR regulates the Ca2+/calmodulin‑dependent protein kinase kinase β (CaMKKβ)‑AMP‑activated protein kinase (AMPK)‑mammalian target of rapamycin (mTOR) signaling pathway induced by ISO in cardiomyocytes. Furthermore, the AMPK inhibition significantly reduced the autophagy level following CaSR stimulation (P<0.05). The results of the present demonstrated that inhibition of CaSR may ameliorate cardiac hypertrophy induced by ISO and the effect may be associated with the inhibition of autophagy and suppression of the Ca

  2. Suppression of calcium-sensing receptor ameliorates cardiac hypertrophy through inhibition of autophagy

    PubMed Central

    LIU, LEI; WANG, CHAO; LIN, YAN; XI, YUHUI; LI, HONG; SHI, SA; LI, HONGZHU; ZHANG, WEIHUA; ZHAO, YAJUN; TIAN, YE; XU, CHANGQING; WANG, LINA

    2016-01-01

    The calcium-sensing receptor (CaSR) releases intracellular calcium ([Ca2+]i) by accumulating inositol phosphate. Changes in [Ca2+]i initiate myocardial hypertrophy. Furthermore, autophagy associated with [Ca2+]i. Autophagy has previously been demonstrated to participate in the hypertrophic process. The current study investigated whether suppression of CaSR affects the hypertrophic response via modulating autophagy. Isoproterenol (ISO) was used to induce cardiac hypertrophy in Wistar rats. Hypertrophic status was determined by echocardiographic assessment, hematoxylin and eosin, and Masson's staining. The protein expression levels of CaSR and autophagy level were observed. Changes of hypertrophy and autophagy indicators were observed following intravenous injection of a CaSR inhibitor. An ISO-induced cardiomyocyte hypertrophy model was established and used determine the involvement of GdCl3. [Ca2+]i was determined using Fluo-4/AM dye followed by confocal microscopy. The expression levels of various active proteins were analyzed by western blotting. The size of the heart, expression levels of CaSR and autophagy level were markedly increased in hypertrophic myocardium. In addition, the present study demonstrated that the indicators of hypertrophy and autophagy were effectively suppressed by CaSR inhibitor. Furthermore, similar effects were demonstrated in neonatal rat hypertrophic cardiomyocytes treated with ISO. It was also observed that CaSR regulates the Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ)-AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) signaling pathway induced by ISO in cardiomyocytes. Furthermore, the AMPK inhibition significantly reduced the autophagy level following CaSR stimulation (P<0.05). The results of the present demonstrated that inhibition of CaSR may ameliorate cardiac hypertrophy induced by ISO and the effect may be associated with the inhibition of autophagy and suppression of the Ca

  3. Prepulse inhibition predicts spatial working memory performance in the inbred Roman high- and low-avoidance rats and in genetically heterogeneous NIH-HS rats: relevance for studying pre-attentive and cognitive anomalies in schizophrenia.

    PubMed

    Oliveras, Ignasi; Río-Álamos, Cristóbal; Cañete, Toni; Blázquez, Gloria; Martínez-Membrives, Esther; Giorgi, Osvaldo; Corda, Maria G; Tobeña, Adolf; Fernández-Teruel, Alberto

    2015-01-01

    Animal models of schizophrenia-relevant symptoms are increasingly important for progress in our understanding of the neurobiological basis of the disorder and for discovering novel and more specific treatments. Prepulse inhibition (PPI) and working memory, which are impaired in schizophrenic patients, are among the symptoms/processes modeled in those animal analogs. We have evaluated whether a genetically-selected rat model, the Roman high-avoidance inbred strain (RHA-I), displays PPI deficits as compared with its Roman low-avoidance (RLA-I) counterpart and the genetically heterogeneous NIH-HS rat stock. We have investigated whether PPI deficits predict spatial working memory impairments (in the Morris water maze; MWM) in these three rat types (Experiment 1), as well as in a separate sample of NIH-HS rats stratified according to their extreme (High, Medium, Low) PPI scores (Experiment 2). The results from Experiment 1 show that RHA-I rats display PPI and spatial working memory deficits compared to both RLA-I and NIH-HS rats. Likewise, in Experiment 2, "Low-PPI" NIH-HS rats present significantly impaired working memory with respect to "Medium-PPI" and "High-PPI" NIH-HS subgroups. Further support to these results comes from correlational, factorial, and multiple regression analyses, which reveal that PPI is positively associated with spatial working memory performance. Conversely, cued learning in the MWM was not associated with PPI. Thus, using genetically-selected and genetically heterogeneous rats, the present study shows, for the first time, that PPI is a positive predictor of performance in a spatial working memory task. These results may have translational value for schizophrenia symptom research in humans, as they suggest that either by psychogenetic selection or by focusing on extreme PPI scores from a genetically heterogeneous rat stock, it is possible to detect a useful (perhaps "at risk") phenotype to study cognitive anomalies linked to schizophrenia. PMID

  4. Prepulse inhibition predicts spatial working memory performance in the inbred Roman high- and low-avoidance rats and in genetically heterogeneous NIH-HS rats: relevance for studying pre-attentive and cognitive anomalies in schizophrenia

    PubMed Central

    Oliveras, Ignasi; Río-Álamos, Cristóbal; Cañete, Toni; Blázquez, Gloria; Martínez-Membrives, Esther; Giorgi, Osvaldo; Corda, Maria G.; Tobeña, Adolf; Fernández-Teruel, Alberto

    2015-01-01

    Animal models of schizophrenia-relevant symptoms are increasingly important for progress in our understanding of the neurobiological basis of the disorder and for discovering novel and more specific treatments. Prepulse inhibition (PPI) and working memory, which are impaired in schizophrenic patients, are among the symptoms/processes modeled in those animal analogs. We have evaluated whether a genetically-selected rat model, the Roman high-avoidance inbred strain (RHA-I), displays PPI deficits as compared with its Roman low-avoidance (RLA-I) counterpart and the genetically heterogeneous NIH-HS rat stock. We have investigated whether PPI deficits predict spatial working memory impairments (in the Morris water maze; MWM) in these three rat types (Experiment 1), as well as in a separate sample of NIH-HS rats stratified according to their extreme (High, Medium, Low) PPI scores (Experiment 2). The results from Experiment 1 show that RHA-I rats display PPI and spatial working memory deficits compared to both RLA-I and NIH-HS rats. Likewise, in Experiment 2, “Low-PPI” NIH-HS rats present significantly impaired working memory with respect to “Medium-PPI” and “High-PPI” NIH-HS subgroups. Further support to these results comes from correlational, factorial, and multiple regression analyses, which reveal that PPI is positively associated with spatial working memory performance. Conversely, cued learning in the MWM was not associated with PPI. Thus, using genetically-selected and genetically heterogeneous rats, the present study shows, for the first time, that PPI is a positive predictor of performance in a spatial working memory task. These results may have translational value for schizophrenia symptom research in humans, as they suggest that either by psychogenetic selection or by focusing on extreme PPI scores from a genetically heterogeneous rat stock, it is possible to detect a useful (perhaps “at risk”) phenotype to study cognitive anomalies linked to

  5. Tenuigenin ameliorates acute lung injury by inhibiting NF-κB and MAPK signalling pathways.

    PubMed

    Lv, Hongming; Zhu, Chao; Liao, Yuanjun; Gao, Yawen; Lu, Gejin; Zhong, Weiting; Zheng, Yuwei; Chen, Wei; Ci, Xinxin

    2015-09-15

    We aimed to explore the protective effect of tenuigenin (TNG) on lipopolysaccharide (LPS)-stimulated inflammatory responses in acute lung injury (ALI). Thus, we assessed the effects of TNG on the LPS-induced production of tumour necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β in the culture supernatants of RAW 264.7 cells. Male BALB/c mice were pretreated with commercial TNG (2, 4 and 8 mg/kg) and dexamethasone (Dex, 5mg/kg) for 1h prior to LPS (0.5 mg/kg) challenge. After 12h, airway inflammation was assessed. Our results showed that TNG dramatically decreased the production of TNF-α, IL-1β, and IL-6 in vitro and in vivo as well as the expression of COX-2 protein in vivo. Treatment with TNG not only significantly ameliorated LPS-stimulated histopathological changes but also reduced the myeloperoxidase (MPO) activity and the wet-to-dry weight ratio of the lungs. Furthermore, TNG blocked IκBα phosphorylation and degradation and inhibited p38/ERK phosphorylation in LPS-induced ALI. These findings suggest that TNG may have a protective effect on LPS-induced ALI and may be useful for the prevention and treatment of ALI in the clinical setting. PMID:25930113

  6. Corosolic acid ameliorates acute inflammation through inhibition of IRAK-1 phosphorylation in macrophages.

    PubMed

    Kim, Seung-Jae; Cha, Ji-Young; Kang, Hye Suk; Lee, Jae-Ho; Lee, Ji Yoon; Park, Jae-Hyung; Bae, Jae-Hoon; Song, Dae-Kyu; Im, Seung-Soon

    2016-05-01

    Corosolic acid (CA), a triterpenoid compound isolated from Lagerstroemia speciosa L. (Banaba) leaves, exerts anti-inflammatory effects by regulating phosphorylation of interleukin receptor-associated kinase (IRAK)-2 via the NF-κB cascade. However, the protective effect of CA against endotoxic shock has not been reported. LPS (200 ng/mL, 30 min) induced phosphorylation of IRAK-1 and treatment with CA (10 μM) significantly attenuated this effect. In addition, CA also reduced protein levels of NLRP3 and ASC which are the main components of the inflammasome in BMDMs. LPS-induced inflammasome assembly through activation of IRAK-1 was down-regulated by CA challenge. Treatment with Bay11-7082, an inhibitor of IκB-α, had no effect on CA-mediated inhibition of IRAK-1 activation, indicating that CA-mediated attenuation of IRAK-1 phosphorylation was independent of NF-κB signaling. These results demonstrate that CA ameliorates acute inflammation in mouse BMDMs and CA may be useful as a pharmacological agent to prevent acute inflammation. [BMB Reports 2016; 49(5): 276-281]. PMID:26615974

  7. Cinnamomum loureirii Extract Inhibits Acetylcholinesterase Activity and Ameliorates Trimethyltin-Induced Cognitive Dysfunction in Mice.

    PubMed

    Kim, Cho Rong; Choi, Soo Jung; Kwon, Yoon Kyung; Kim, Jae Kyeom; Kim, Youn-Jung; Park, Gwi Gun; Shin, Dong-Hoon

    2016-01-01

    The pathogenesis of Alzheimer's disease (AD) has been linked to the deficiency of neurotransmitter acetylcholine (ACh) in the brain, and the main treatment strategy for improving AD symptoms is the inhibition of acetylcholinesterase (AChE) activity. In the present study, we aimed to identify potent AChE inhibitors from Cinnamomum loureirii extract via bioassay-guided fractionation. We demonstrated that the most potent AChE inhibitor present in the C. loureirii extract was 2,4-bis(1,1-dimethylethyl)phenol. To confirm the antiamnesic effects of the ethanol extract of C. loureirii, mice were intraperitoneally injected with the neurotoxin trimethyltin (2.5 mg/kg) to induce cognitive dysfunction, and performance in the Y-maze and passive avoidance tests was assessed. Treatment with C. loureirii extract significantly improved performance in both behavioral tests, suggesting that this extract may be neuroprotective and therefore beneficial in preventing or ameliorating the degenerative processes of AD, potentially by restoring cholinergic function. PMID:27374288

  8. EPA-enriched phospholipids ameliorate cancer-associated cachexia mainly via inhibiting lipolysis.

    PubMed

    Du, Lei; Yang, Yu-Hong; Wang, Yu-Ming; Xue, Chang-Hu; Kurihara, Hideyuki; Takahashi, Koretaro

    2015-12-01

    Excessive loss of fat mass is considered as a key feature of body weight loss in cancer-associated cachexia (CAC). It affects the efficacy and tolerability of cancer therapy and reduces the quality and length of cancer patients' lives. The aim of the present study was to evaluate the effects of EPA-enriched phospholipids (EPA-PL) derived from starfish Asterias amurensis on cachectic weight loss in mice bearing S180 ascitic tumor, and TNF-α-stimulated lipolysis in 3T3-L1 adipocytes and to elucidate the possible mechanisms involved. Our findings revealed that oral administration of EPA-PL at 100 mg per kg body weight (BW) per day for 14 days prevented body weight loss in CAC mice by preserving the white adipose tissue (WAT) mass. We found that serum levels of nonesterified fatty acid (NEFA) and pro-inflammatory cytokines such as tumor necrosis factor α (TNF-α) and interleukin (IL)-6 increased in CAC mice but decreased significantly after oral treatment of EPA-PL. In addition, EPA-PL treatment also suppressed the overexpression of several key lipolytic factors and raised the mRNA levels of some adipogenic factors in the WAT of CAC mice. Moreover, treatment of EPA-PL (200 and 400 μM) markedly inhibited TNF-α-stimulated lipolysis in adipocytes. Furthermore, the antilipolytic effects of EPA-PL were stimulated by the extracellular signal-regulated kinase 1/2 (ERK 1/2) inhibitor PD 98059 and blocked via the AMP-activated protein kinase (AMPK) inhibitor compound C and the phosphoinositide-3-kinase (PI3K) inhibitor LY 294002. Taken together, these data suggest that the dietary EPA-PL ameliorates CAC mainly via inhibiting lipolysis and at least in part for recovering the function of adipogenesis. PMID:26373883

  9. Inhibition of SET Domain-Containing Lysine Methyltransferase 7/9 Ameliorates Renal Fibrosis.

    PubMed

    Sasaki, Kensuke; Doi, Shigehiro; Nakashima, Ayumu; Irifuku, Taisuke; Yamada, Kyoko; Kokoroishi, Keiko; Ueno, Toshinori; Doi, Toshiki; Hida, Eisuke; Arihiro, Koji; Kohno, Nobuoki; Masaki, Takao

    2016-01-01

    TGF-β1 activity results in methylation of lysine 4 of histone H3 (H3K4) through SET domain-containing lysine methyltransferase 7/9 (SET7/9) induction, which is important for the transcriptional activation of fibrotic genes in vitro. However, in vivo studies utilizing an experimental model of renal fibrosis are required to develop therapeutic interventions that target SET7/9. In this study, we investigated the signaling pathway of TGF-β1-induced SET7/9 expression and whether inhibition of SET7/9 suppresses renal fibrosis in unilateral ureteral obstruction (UUO) mice and kidney cell lines. Among the SET family, SET7/9 was upregulated on days 3 and 7 in UUO mice, and the upregulation was suppressed by TGF-β1 neutralizing antibody. TGF-β1 induced SET7/9 expression via Smad3 in normal rat kidney (NRK)-52E cells. In human kidney biopsy specimens from patients diagnosed with IgA nephropathy and membranous nephropathy, SET7/9 expression was positively correlated with the degree of interstitial fibrosis (r=0.59, P=0.001 in patients with IgA nephropathy; and r=0.58, P<0.05 in patients with membranous nephropathy). In addition, small interfering RNA-mediated knockdown of SET7/9 expression significantly attenuated renal fibrosis in UUO mice. Sinefungin, an inhibitor of SET7/9, also suppressed the expression of mesenchymal markers and extracellular matrix proteins and inhibited H3K4 mono-methylation (H3K4me1) in kidneys of UUO mice. Moreover, sinefungin had an inhibitory effect on TGF-β1-induced α-smooth muscle actin expression and H3K4me1 in both NRK-52E and NRK-49F cells. In conclusion, sinefungin, a SET7/9 inhibitor, ameliorates renal fibrosis by inhibiting H3K4me1 and may be a candidate therapeutic agent. PMID:26045091

  10. Inhibiting DNA Methylation by 5-Aza-2′-deoxycytidine Ameliorates Atherosclerosis Through Suppressing Macrophage Inflammation

    PubMed Central

    Cao, Qiang; Wang, Xianfeng; Jia, Lin; Mondal, Ashis K.; Diallo, Abdoulaye; Hawkins, Gregory A.; Das, Swapan K.; Parks, John S.; Yu, Liqing; Shi, Huidong

    2014-01-01

    Inflammation marks all stages of atherogenesis. DNA hypermethylation in the whole genome or specific genes is associated with inflammation and cardiovascular diseases. Therefore, we aimed to study whether inhibiting DNA methylation by DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (5-aza-dC) ameliorates atherosclerosis in low-density lipoprotein receptor knockout (Ldlr−/−) mice. Ldlr−/− mice were fed an atherogenic diet and adminisered saline or 5-aza-dC (0.25 mg/kg) for up to 30 weeks. 5-aza-dC treatment markedly decreased atherosclerosis development in Ldlr−/− mice without changes in body weight, plasma lipid profile, macrophage cholesterol levels and plaque lipid content. Instead, this effect was associated with decreased macrophage inflammation. Macrophages with 5-aza-dC treatment had downregulated expression of genes involved in inflammation (TNF-α, IL-6, IL-1β, and inducible nitric oxidase) and chemotaxis (CD62/L-selectin, chemokine [C-C motif] ligand 2/MCP-1 [CCL2/MCP-1], CCL5, CCL9, and CCL2 receptor CCR2). This resulted in attenuated macrophage migration and adhesion to endothelial cells and reduced macrophage infiltration into atherosclerotic plaques. 5-aza-dC also suppressed macrophage endoplasmic reticulum stress, a key upstream signal that activates macrophage inflammation and apoptotic pathways. Finally, 5-aza-dC demethylated liver X receptor α (LXRα) and peroxisome proliferator-activated receptor γ1 (PPARγ1) promoters, which are both enriched with CpG sites. This led to overexpression of LXRα and PPARγ, which may be responsible for 5-aza-dC's anti-inflammatory and atheroprotective effect. Our findings provide strong evidence that DNA methylation may play a significant role in cardiovascular diseases and serve as a therapeutic target for prevention and treatment of atherosclerosis. PMID:25251587

  11. Faecalibacterium prausnitzii Inhibits Interleukin-17 to Ameliorate Colorectal Colitis in Rats

    PubMed Central

    Zhang, Mingming; Qiu, Xinyun; Zhang, Hao; Yang, Xiaotong; Hong, Na; Yang, Yonghua; Chen, Hui; Yu, Chenggong

    2014-01-01

    Background and Aims It has been shown that Faecalibacterium prausnitzii (F. prausnitzii), one of the dominant intestinal bacterial flora, may protect colonic mucosa against the development of inflammation and subsequent inflammatory bowel disease (IBD), with the underlying mechanisms being unclear. Methods The impacts of F. prausnitzii and its metabolites on IL-23/Th17/IL-17 pathway markers were determined in human monocytes and a rat model of colitis induced by 2,4,6-trinitrobenzene sulfonic acid. F. prausnitzii and its culture medium (containing complete metabolites) were used to treat the rats in vivo, as well as rat splenocytes and human monocytes in vitro. Inflammatory cytokines were measured in colon tissue, plasma and cell culture medium. Results The culture supernatant of F. prausnitzii increased plasma anti-Th17 cytokines (IL-10 and IL-12)and suppressed IL-17 levels in both plasma and colonic mucosa, with ameliorated colonic colitis lesions. This inhibition of IL-17 release has also been observed in both rat splenocytes and human venous monocytes in vitro. The culture supernatant of F. prausnitzii also suppressed Th17 cell differentiation induced by cytokines (TGF-ß and IL-6) and bone marrow-derived dendritic cells (BMDCs) in vitro. The metabolites of F. prausnitzii in the culture supernatant exert a stronger anti-inflammatory effect than the bacterium itself. F. prausnitzii protected the colon mucosa against the development of IBD by its metabolites, suggesting a promising potential for the use of F. prausnitzii and its metabolic products in the treatment of IBD. PMID:25275569

  12. Ameliorative Effect of Grape Seed Proanthocyanidin Extract on Cadmium-Induced Meiosis Inhibition During Oogenesis in Chicken Embryos.

    PubMed

    Hou, Fuyin; Xiao, Min; Li, Jian; Cook, Devin W; Zeng, Weidong; Zhang, Caiqiao; Mi, Yuling

    2016-04-01

    Cadmium (Cd) is an environmental endocrine disruptor that has toxic effects on the female reproductive system. Here the ameliorative effect of grape seed proanthocyanidin extract (GSPE) on Cd-induced meiosis inhibition during oogenesis was explored. As compared with controls, chicken embryos exposed to Cd (3 µg/egg) displayed a changed oocyte morphology, decreased number of meiotic germ cells, and decreased expression of the meiotic marker protein γH2AX. Real time RT-PCR also revealed a significant down-regulation in the mRNA expressions of various meiosis-specific markers (Stra8, Spo11, Scp3, and Dmc1) together with those of Raldh2, a retinoic acid (RA) synthetase, and of the receptors (RARα and RARβ). In addition, exposure to Cd increased the production of H2 O2 and malondialdehyde in the ovaries and caused a corresponding reduction in glutathione and superoxide dismutase. Simultaneous supplementation of GSPE (150 µg/egg) markedly alleviated the aforementioned Cd-induced embryotoxic effects by upregulating meiosis-related proteins and gene expressions and restoring the antioxidative level. Collectively, the findings provided novel insights into the underlying mechanism of Cd-induced meiosis inhibition and indicated that GSPE might potentially ameliorate related reproductive disorders. PMID:26799944

  13. Sodium valproate ameliorates diabetes-induced fibrosis and renal damage by the inhibition of histone deacetylases in diabetic rat.

    PubMed

    Khan, Sabbir; Jena, Gopabandhu; Tikoo, Kulbhushan

    2015-04-01

    Recent reports emphasize the contribution of histone deacetylases (HDACs) in the pathogenesis of diabetic renal injury and fibrosis. Valproic acid (VPA) is a first-line drug used for the treatment of epilepsy and migraine as well as established as a HDAC inhibitor. The present study was aimed to evaluate the anti-fibrotic and renoprotective effects of VPA in diabetic nephropathy (DN). Diabetes was induced by single injection of STZ (50mg/kg), whereas VPA at the doses of 150 and 300mg/kg/day was administered for 8 consecutive weeks by oral route in Sprague Dawley rats. The renal injuries and fibrosis were assessed by histology, fibrosis specific staining and fibroblast activation by a transmission electron microscope, while expression of proteins of interest was evaluated by western blotting and immunohistochemistry. VPA treatment ameliorated the histological alterations as well as fibrosis, and decreased the expression of TGF-β1, CTGF, α-SMA, fibronectin, collagen I, COX-2, ICAM-1 and HDAC4/5/7. Further, VPA treatment significantly increased histone H3 acetylation and MMP-2 expression. The present study clearly established that VPA treatment ameliorates the renal injury and fibrosis in diabetic kidney by preventing the myofibroblast activation and fibrogenesis by HDAC inhibition and associated mechanisms, thereby improving the profibrotic and anti-fibrotic protein balance. PMID:25576297

  14. Dipeptidyl peptidase-4 inhibition by Pterocarpus marsupium and Eugenia jambolana ameliorates streptozotocin induced Alzheimer's disease.

    PubMed

    Kosaraju, Jayasankar; Madhunapantula, Subbarao V; Chinni, Santhivardhan; Khatwal, Rizwan Basha; Dubala, Anil; Muthureddy Nataraj, Satish Kumar; Basavan, Duraiswamy

    2014-07-01

    Alzheimer's disease (AD), the most common form of dementia, is characterized by the loss of normal functions of brain cells and neuronal death, ultimately leading to memory loss. Recent accumulating evidences have demonstrated the therapeutic potential of anti-diabetic agents, such as dipeptidyl peptidase-4 (DPP-4) inhibitors, for the treatment of Alzheimer's disease (AD), providing opportunities to explore and test the DPP-4 inhibitors for treating this fatal disease. Prior studies determining the efficacy of Pterocarpus marsupium (PM, Fabaceae) and Eugenia jambolana (EJ, Myrtaceae) extracts for ameliorating type 2 diabetes have demonstrated the DPP-4 inhibitory properties indicating the possibility of using of these extracts even for the treating AD. Therefore, in the present study, the neuroprotective roles of PM and EJ for ameliorating the streptozotocin (STZ) induced AD have been tested in rat model. Experimentally, PM and EJ extracts, at a dose range of 200 and 400mg/kg, were administered orally to STZ induced AD Wistar rats and cognitive evaluation tests were performed using radial arm maze and hole-board apparatus. Following 30 days of treatment with the extracts, a dose- and time-dependent attenuation of AD pathology, as evidenced by decreasing amyloid beta 42, total tau, phosphorylated tau and neuro-inflammation with an increase in glucagon-like peptide-1 (GLP-1) levels was observed. Therefore, PM and EJ extracts contain cognitive enhancers as well as neuroprotective agents against STZ induced AD. PMID:24667360

  15. Reinforcement and Stimulant Medication Ameliorate Deficient Response Inhibition in Children with Attention-Deficit/Hyperactivity Disorder.

    PubMed

    Rosch, Keri S; Fosco, Whitney D; Pelham, William E; Waxmonsky, James G; Bubnik, Michelle G; Hawk, Larry W

    2016-02-01

    This study examined the degree to which reinforcement, stimulant medication, and their combination impact response inhibition in children with Attention-Deficit/Hyperactivity Disorder (ADHD). Across three studies, participants with ADHD (n = 111, 25 girls) and typically-developing (TD) controls (n = 33, 6 girls) completed a standard version of the stop signal task (SST) and/or a reinforcement-manipulation SST with performance-contingent points. In two of these studies, these tasks were performed under placebo or 0.3 and 0.6 mg/kg methylphenidate (MPH) conditions. Cross-study comparisons were conducted to test hypotheses regarding the separate and combined effects of reinforcement and methylphenidate on response inhibition among children with ADHD relative to TD controls. Baseline response inhibition was worse among children with ADHD compared to controls. MPH produced dose-related improvements in response inhibition in children with ADHD; compared to non-medicated TD controls, 0.3 mg/kg MPH normalized deficient response inhibition, and 0.6 mg/kg MPH resulted in better inhibition in children with ADHD. Reinforcement improved response inhibition to a greater extent for children with ADHD than for TD children, normalizing response inhibition. The combination of MPH and reinforcement improved response inhibition among children with ADHD compared to reinforcement alone and MPH alone, also resulting in normalization of response inhibition despite repeated task exposure. Deficient response inhibition commonly observed in children with ADHD is significantly improved with MPH and/or reinforcement, normalizing inhibition relative to TD children tested under standard conditions. PMID:25985978

  16. Apple pectin, a dietary fiber, ameliorates myocardial injury by inhibiting apoptosis in a rat model of ischemia/reperfusion

    PubMed Central

    Lim, Sun Ha; Kim, Mi Young

    2014-01-01

    BACKGROUND/OBJECTIVE Myocardial cell death due to occlusion of the coronary arteries leads to myocardial infarction, a subset of coronary heart disease (CHD). Dietary fiber is known to be associated with a reduced risk of CHD, the underlying mechanisms of which were suggested to delay the onset of occlusion by ameliorating risk factors. In this study, we tested a hypothesis that a beneficial role of dietary fiber could arise from protection of myocardial cells against ischemic injury, manifested after occlusion of the arteries. MATERIALS/METHODS Three days after rats were fed apple pectin (AP) (with 10, 40, 100, and 400 mg/kg/day), myocardial ischemic injury was induced by 30 min-ligation of the left anterior descending coronary artery, followed by 3 hr-reperfusion. The area at risk and infarct area were evaluated using Evans blue dye and 2,3,5-triphenyltetrazolium chloride (TTC) staining, respectively. DNA nicks reflecting the extent of myocardial apoptosis were assessed by TUNEL assay. Levels of cleaved caspase-3, Bcl-2, and Bax were assessed by immunohistochemistry. RESULTS Supplementation of AP (with 100 and 400 mg/kg/day) resulted in significantly attenuated infarct size (IS) (ratio of infarct area to area at risk) by 21.9 and 22.4%, respectively, in the AP-treated group, compared with that in the control group. This attenuation in IS showed correlation with improvement in biomarkers involved in the apoptotic cascades: reduction of apoptotic cells, inhibition of conversion of procaspase-3 to caspase-3, and increase of Bcl-2/Bax ratio, a determinant of cell fate. CONCLUSIONS The findings indicate that supplementation of AP results in amelioration of myocardial infarction by inhibition of apoptosis. Thus, the current study suggests that intake of dietary fiber reduces the risk of CHD, not only by blocking steps leading to occlusion, but also by protecting against ischemic injury caused by occlusion of the arteries. PMID:25110558

  17. Activation of Cannabinoid Receptor 2 Ameliorates DSS-Induced Colitis through Inhibiting NLRP3 Inflammasome in Macrophages.

    PubMed

    Ke, Ping; Shao, Bo-Zong; Xu, Zhe-Qi; Wei, Wei; Han, Bin-Ze; Chen, Xiong-Wen; Su, Ding-Feng; Liu, Chong

    2016-01-01

    Activation of cannabinoid receptor 2 (CB2R) ameliorates inflammation, but the underlying mechanism remains unclear. In the present study, we examined whether activation of CB2R could suppress the nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome. In peritoneal macrophages isolated from C57BL/6 mice, LPS/DSS challenge for 24 h increased the expression of the components of NLRP3 inflammasome NLRP3, Casp-1 p20/Casp-1 p45 ratio, proIL-1β and IL-1β and also enhanced autophagy (LC3-II/LC3-I ratio, Beclin-1 and SQSTM1). Pretreatment of peritoneal macrophages with HU 308, a selective CB2R agonist, attenuated LPS/DSS-induced NLRP3 inflammasome activation, but further enhanced autophagy. In comparison with wild-type (WT) control, peritoneal macrophages from CB2R knockout (KO) mice had more robust NLRP3 inflammasome activation and attenuated autophagy upon LPS/DSS challenge. Knockdown autophagy-related gene 5 (Atg5) with a siRNA in peritoneal macrophages attenuated the inhibitory effects of HU 308 on LPS/DSS-induced NLRP3 inflammasome activation in vitro. In vivo, HU308 treatment attenuated DSS-induced colitis mice associated with reduced colon inflammation and inhibited NLRP3 inflammasome activation in wild-type mice. In CB2R KO mice, DSS-induced inflammation and NLRP3 inflammasome activation were more pronounced than those in WT control. Finally, we demonstrated that AMPK-mTOR-P70S6K signaling pathway was involved in this CB2R-mediated process. We conclude that activation of CB2R ameliorates DSS-induced colitis through enhancing autophagy that may inhibit NLRP3 inflammasome activation in macrophages. PMID:27611972

  18. Poly ADP-Ribose Polymerase Inhibition Ameliorates Hind Limb Ischemia Reperfusion Injury in a Murine Model of Type 2 Diabetes

    PubMed Central

    Long, Chandler A.; Boloum, Valy; Albadawi, Hassan; Tsai, Shirling; Yoo, Hyung-Jin; Oklu, Rahmi; Goldman, Mitchell H.; Watkins, Michael T.

    2013-01-01

    Introduction Diabetes is known to increase poly-ADP-ribose-polymerase (PARP) activity and posttranslational poly-ADP-ribosylation of several regulatory proteins involved in inflammation and energy metabolism. These experiments test the hypothesis that PARP inhibition will modulate hind limb ischemia reperfusion (IR) in a mouse model of type-II diabetes; ameliorate the ribosylation and the activity/transnuclear localization of the key glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Methods db/db mice underwent 1.5hrs of hind limb ischemia followed by 1, 7, or 24hrs reperfusion. The treatment group received the PARP inhibitor PJ34 (PJ34) over a 24hrs period; the untreated group received Lactated ringer’s (LR) at the same time points. IR muscles were analyzed for indices of PARP activity, fiber injury, metabolic activity, inflammation, GAPDH activity /intracellular localization and poly-ADP-ribosylation of GAPDH. Results PARP activity was significantly lower in the PJ34 treated groups compared to the LR group at 7 and 24 hours reperfusion. There was significantly less muscle fiber injury in the PJ34 treated group compared to LR treated mice at 24 hrs reperfusion. PJ34 lowered levels of select proinflammatory molecules at 7hrs and 24hrs IR. There were significant increases in metabolic activity only at 24 hours IR in the PJ34 group, which temporally correlated with increase in GAPDH activity, decreased GAPDH poly ADP-ribosylation and nuclear translocation of GAPDH. Conclusions PJ34 reduced PARP activity, GAPDH ribosylation, GAPDH translocation, ameliorated muscle fiber injury, and increased metabolic activity following hind limb IR injury in a murine model of type-II diabetes. PARP inhibition might be a therapeutic strategy following IR in diabetic humans. PMID:23549425

  19. Liposomes ameliorate Crizotinib- and Nilotinib-induced inhibition of the cardiac IKr channel and QTc prolongation.

    PubMed

    Shopp, George M; Helson, Lawrence; Bouchard, Annie; Salvail, Dany; Majeed, Muhammad

    2014-09-01

    Crizotinib (Xalkori®) and nilotinib (Tasigna®) are tyrosine kinase inhibitors approved for the treatment of non-small cell lung cancer and chronic myeloid leukemia, respectively. Both have been shown to result in electrocardiogram rate-corrected Q-wave T-wave interval (QTc) prolongation in humans and animals. Liposomes have been shown to ameliorate drug-induced effects on the cardiac-delayed rectifier K(+) current (IKr, KV11.1), coded by the human ether-a-go-go-related gene (hERG). This study was undertaken to determine if liposomes would also decrease the effect of crizotinib and nilotinib on the IKr channel. Crizotinib and nilotinib were tested in an in vitro IKr assay using human embryonic kidney (HEK) 293 cells stably transfected with the hERG. Dose-responses were determined and the 50% inhibitory concentrations (IC50s) were calculated. When the HEK 293 cells were treated with crizotinib or nilotinib that were mixed with liposomes, there was a significant decrease in the IKr channel inhibitory effects of these two drugs. When isolated, rabbit hearts were exposed to crizotinib or nilotinib, there were significant increases in QTc prolongation. Mixing either of the drugs with liposomes ameliorated the effects of the drugs. Rabbits dosed intravenously (IV) with crizotinib or nilotinib showed QTc prolongation. When liposomes were injected prior to crizotinib or nilotinib, the liposomes decreased the effects on the QTc interval. The use of liposomal encapsulated QT-prolongation agents, or giving liposomes in combination with drugs, may decrease their cardiac liability. PMID:25202051

  20. Graptopetalum paraguayense Ameliorates Airway Inflammation and Allergy in Ovalbumin- (OVA-) Sensitized BALB/C Mice by Inhibiting Th2 Signal

    PubMed Central

    Lee, Bao-Hong; Wu, She-Ching

    2013-01-01

    Role of inflammation-induced oxidative stress in the pathogenesis and progression of chronic inflammatory airways diseases has received increasing attention in recent years. Nuclear factor erythroid 2-related factor 2 is the primary transcription factor that regulates the expression of antioxidant and detoxifying enzymes. Graptopetalum paraguayense E. Walther, a vegetable consumed in Taiwan, has been used in folk medicine for protection against liver injury through elevating antioxidation. Recently, we found that gallic acid is an active compound of Graptopetalum paraguayense E. Walther, which has been reported to inhibit T-helper 2 cytokines. Currently, we assumed that Graptopetalum paraguayense E. Walther may potentially protect against ovalbumin-induced allergy and airway inflammation. Results demonstrated that Graptopetalum paraguayense E. Walther ethanolic extracts (GPE) clearly inhibited airway inflammation, mucus cell hyperplasia, and eosinophilia in OVA-challenged mice. Additionally, GPE also prevented T-cell infiltration and Th2 cytokines, including interleukin- (IL-)4, IL-5, and IL-13 generations in bronchial alveolar lavage fluid. The adhesion molecules ICAM-1 and VCAM-1 were substantially reduced by GPE treatment mediated by Nrf2 activation. Moreover, GPE attenuated GATA3 expression and inhibited Th2 signals of the T cells. These findings suggested that GPE ameliorated the development of airway inflammation through immune regulation. PMID:23843865

  1. Panhistone deacetylase inhibitors inhibit proinflammatory signaling pathways to ameliorate interleukin-18-induced cardiac hypertrophy

    PubMed Central

    Majumdar, Gipsy; Rooney, Robert J.; Johnson, I. Maria

    2011-01-01

    We investigated the genome-wide consequences of pan-histone deacetylase inhibitors (HDACIs) trichostatin A (TSA) and m-carboxycinnamic acid bis-hydroxamide (CBHA) in the hearts of BALB/c mice eliciting hypertrophy in response to interleukin-18 (IL-18). Both TSA and CBHA profoundly altered cardiac chromatin structure that occurred concomitantly with normalization of IL-18-induced gene expression and amelioration of cardiac hypertrophy. The hearts of mice exposed to IL-18 +/− TSA or CBHA elicited distinct gene expression profiles. Of 184 genes that were differentially regulated by IL-18 and TSA, 33 were regulated in an opposite manner. The hearts of mice treated with IL-18 and/or CBHA elicited 147 differentially expressed genes (DEGs), a third of which were oppositely regulated by IL-18 and CBHA. Ingenuity Pathways and Kyoto Encyclopedia of Genes and Genomes analyses of DEGs showed that IL-18 impinged on TNF-α- and IFNγ-specific gene networks relegated to controlling immunity and inflammation, cardiac metabolism and energetics, and cell proliferation and apoptosis. These TNF-α- and IFNγ-specific gene networks, extensively connected with PI3K, MAPK, and NF-κB signaling pathways, were oppositely regulated by IL-18 and pan-HDACIs. Evidently, both TSA and CBHA caused a two- to fourfold induction of phosphatase and tensin homolog expression to counteract IL-18-induced proinflammatory signaling and cardiac hypertrophy. PMID:21954451

  2. Sphingosine kinase inhibition ameliorates chronic hypoperfusion-induced white matter lesions.

    PubMed

    Yang, Ying; Torta, Federico; Arai, Ken; Wenk, Markus R; Herr, Deron R; Wong, Peter T-H; Lai, Mitchell K P

    2016-03-01

    White matter lesions (WML) are thought to contribute to vascular cognitive impairment in elderly patients. Growing evidence show that failure of myelin formation arising from the disruption of oligodendrocyte progenitor cell (OPC) differentiation is a cause of chronic vascular white matter damage. The sphingosine kinase (SphK)/sphingosine-1-phosphate (S1P) signaling pathway regulates oligodendroglia differentiation and function, and is known to be altered in hypoxia. In this study, we measured SphK, S1P as well as markers of WML, hypoxia and OPC (NG2) in a mouse bilateral carotid artery stenosis (BCAS) model of chronic cerebral hypoperfusion. Our results indicated that BCAS induced hypoxia inducible factor (HIF)-1α, Sphk2, S1P, and NG2 up-regulation together with accumulation of WML. In contrast, BCAS mice treated with the SphK inhibitor, SKI-II, showed partial reversal of SphK2, S1P and NG2 elevation and amelioration of WML. In an in vitro model of hypoxia, SKI-II reversed the suppression of OPC differentiation. Our study suggests a mechanism for hypoperfusion-associated WML involving HIF-1α-SphK2-S1P-mediated disruption of OPC differentiation, and proposes the SphK signaling pathway as a potential therapeutic target for white matter disease. PMID:26921668

  3. VEGF ameliorates pulmonary hypertension through inhibition of endothelial apoptosis in experimental lung fibrosis in rats

    PubMed Central

    Farkas, Laszlo; Farkas, Daniela; Ask, Kjetil; Möller, Antje; Gauldie, Jack; Margetts, Peter; Inman, Mark; Kolb, Martin

    2009-01-01

    Idiopathic pulmonary fibrosis (IPF) can lead to the development of secondary pulmonary hypertension (PH) and ultimately death. Despite this known association, the precise mechanism of disease remains unknown. Using a rat model of IPF, we explored the role of the proangiogenic and antiapoptotic growth factor VEGF in the vascular remodeling that underlies PH. In this model, adenoviral delivery of active TGF-β1 induces pulmonary arterial remodeling, loss of the microvasculature in fibrotic areas, and increased pulmonary arterial pressure (PAP). Immunohistochemistry and mRNA analysis revealed decreased levels of VEGF and its receptor, which were inversely correlated with PAP and endothelial cell apoptosis in both the micro- and macrovasculature. Treatment of IPF rats with adenoviral delivery of VEGF resulted in reduced endothelial apoptosis, increased vascularization, and improved PAP due to reduced remodeling but worsened PF. These data show that experimental pulmonary fibrosis (PF) leads to loss of the microvasculature through increased apoptosis and to remodeling of the pulmonary arteries, with both processes resulting in PH. As administration of VEGF ameliorated the PH in this model but concomitantly aggravated the fibrogenic process, VEGF-based therapies should be used with caution. PMID:19381013

  4. Pharmacologic inhibition of L-tyrosine degradation ameliorates cerebral dopamine deficiency in murine phenylketonuria (PKU)

    PubMed Central

    Harding, Cary O.; Winn, Shelley R.; Gibson, K. Michael; Arning, Erland; Bottiglieri, Teodoro; Grompe, Markus

    2014-01-01

    Summary Monoamine neurotransmitter deficiency has been implicated in the etiology of neuropsychiatric symptoms associated with chronic hyperphenylalaninemia in phenylketonuria (PKU). Two proposed explanations for neurotransmitter deficiency in PKU include first, that chronically elevated blood L-phenylalanine (Phe) inhibits the transport of L-tyrosine (Tyr) and L-tryptophan (Trp), the substrates for dopamine and serotonin synthesis respectively, into brain. In the second hypothesis, elevated Phe competitively inhibits brain tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) activities, the rate limiting steps in dopamine and serotonin synthesis. Dietary supplementation with large neutral amino acids (LNAA) including Tyr and Trp has been recommended for individuals with chronically elevated blood Phe in an attempt to restore amino acid and monoamine homeostasis in brain. As a potential alternative treatment approach, we demonstrate that pharmacologic inhibition of Tyr degradation through oral administration of nitisinone (NTBC) yielded sustained increases in blood and brain Tyr, decreased blood and brain Phe, and consequently increased dopamine synthesis in a murine model of PKU. Our results suggest that Phe-mediated inhibition of TH activity is the likely mechanism of impaired dopamine synthesis in PKU. Pharmacologic inhibition of Tyr degradation may be a promising adjunct therapy for CNS monoamine neurotransmitter deficiency in hyperphenylalaninemic individuals with PKU. PMID:24487571

  5. Pharmacologic inhibition of L-tyrosine degradation ameliorates cerebral dopamine deficiency in murine phenylketonuria (PKU).

    PubMed

    Harding, Cary O; Winn, Shelley R; Gibson, K Michael; Arning, Erland; Bottiglieri, Teodoro; Grompe, Markus

    2014-09-01

    Monoamine neurotransmitter deficiency has been implicated in the etiology of neuropsychiatric symptoms associated with chronic hyperphenylalaninemia in phenylketonuria (PKU). Two proposed explanations for neurotransmitter deficiency in PKU include first, that chronically elevated blood L-phenylalanine (Phe) inhibits the transport of L-tyrosine (Tyr) and L-tryptophan (Trp), the substrates for dopamine and serotonin synthesis respectively, into brain. In the second hypothesis, elevated Phe competitively inhibits brain tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) activities, the rate limiting steps in dopamine and serotonin synthesis. Dietary supplementation with large neutral amino acids (LNAA) including Tyr and Trp has been recommended for individuals with chronically elevated blood Phe in an attempt to restore amino acid and monoamine homeostasis in brain. As a potential alternative treatment approach, we demonstrate that pharmacologic inhibition of Tyr degradation through oral administration of nitisinone (NTBC) yielded sustained increases in blood and brain Tyr, decreased blood and brain Phe, and consequently increased dopamine synthesis in a murine model of PKU. Our results suggest that Phe-mediated inhibition of TH activity is the likely mechanism of impaired dopamine synthesis in PKU. Pharmacologic inhibition of Tyr degradation may be a promising adjunct therapy for CNS monoamine neurotransmitter deficiency in hyperphenylalaninemic individuals with PKU. PMID:24487571

  6. A new phenylpyrazoleanilide, y-320, inhibits interleukin 17 production and ameliorates collagen-induced arthritis in mice and cynomolgus monkeys.

    PubMed

    Ushio, Hiroyuki; Ishibuchi, Seigo; Oshita, Koichi; Seki, Noriyasu; Kataoka, Hirotoshi; Sugahara, Kunio; Adachi, Kunitomo; Chiba, Kenji

    2013-01-01

    Interleukin (IL)-15 and IL-17 are thought to play an important role in the pathogenesis of rheumatoid arthritis (RA) because both pro-inflammatory cytokines are found in synovial fluid of RA patients. In this study, we examined the pharmacological profiles of Y-320, a new phenylpyrazoleanilide immunomodulator. Y-320 inhibited IL-17 production by CD4 T cells stimulated with IL-15 with IC50 values of 20 to 60 nM. Oral administration of Y-320 (0.3 to 3 mg/kg) significantly inhibited the development and progression of arthritis and joint destruction with reduction of IL-17 mRNA expression in arthritic joints of type II collagen-induced arthritis (CIA) in DBA/1J mice. Y-320 in combination with anti-murine tumor necrosis factor-α monoclonal antibody showed a synergistic effect on mouse CIA. Moreover, therapeutic treatment with Y-320 (0.3 and 1 mg/kg orally) ameliorated CIA in cynomolgus monkeys. Our results suggest that Y-320, an orally active inhibitor for IL-17 production, provides a useful therapy for RA. PMID:24366113

  7. YiQiFuMai Powder Injection Ameliorates Cerebral Ischemia by Inhibiting Endoplasmic Reticulum Stress-Mediated Neuronal Apoptosis

    PubMed Central

    Hu, Yang

    2016-01-01

    YiQiFuMai (YQFM) powder injection as a modern preparation derived from Sheng Mai San, a traditional Chinese medicine, has been widely used in the treatment of cardiovascular and cerebrovascular diseases. However, its neuroprotective effect and underlying mechanism in cerebral ischemia remain to be explored. The present study was designed to investigate the neuroprotective effect of YQFM on endoplasmic reticulum (ER) stress-mediated neuronal apoptosis in the permanent middle cerebral artery occlusion- (MCAO-) injured mice and the oxygen-glucose deprivation- (OGD-) induced pheochromocytoma (PC12) cells. The results showed that single administration of YQFM (1.342 g/kg, i.p.) could reduce the brain infarction and improve the neurological deficits and the cerebral blood flow (CBF) after MCAO for 24 h in mice. Moreover, incubation with YQFM (100, 200, and 400 μg/mL) could increase the cell viability, decrease the caspase-3 activity, and inhibit the cell apoptosis in OGD-induced PC12 cells for 12 h. In addition, YQFM treatment could significantly modulate cleaved caspase-3 and Bcl-2 expressions and inhibit the expressions of ER stress-related marker proteins and signaling pathways in vivo and in vitro. In conclusion, our findings provide the first evidence that YQFM ameliorates cerebral ischemic injury linked with modulating ER stress-related signaling pathways, which provided some new insights for its prevention and treatment of cerebral ischemia diseases. PMID:27087890

  8. Tribulus terrestris ameliorates metronidazole-induced spermatogenic inhibition and testicular oxidative stress in the laboratory mouse

    PubMed Central

    Kumari, Mrinalini; Singh, Poonam

    2015-01-01

    Objective: The present study was undertaken to evaluate the protective effects of the fruit extract of Tribulus terrestris (TT) on the metronidazole (MTZ)-induced alterations in spermatogenesis, sperm count, testicular functions, and oxidative stress. Materials and Methods: Thirty adult Swiss strain mice were divided into six groups. Animals of Groups I and II served as untreated and vehicle-treated controls, while that of Groups III and IV were administered with MTZ (500 mg/kg BW/day) and TT (200 mg/kg BW/day) alone for 28 days, respectively. Low (100 mg/kg BW/day) and high (200 mg/kg BW/day) doses of TT along with MTZ (500 mg/kg BW/day) were administered for 28 days in the mice of Groups V and VI, respectively. Twenty four hours after the last treatment, all the animals were euthanized to study the histological changes in the testis and sperm count in the epididymis. Testicular functional markers, lipid peroxidation (LPO) and the activities of antioxidant enzymes, e.g., superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase, were also assessed in the mice of all the groups. Results: Metronidazole caused marked alterations in the testicular weight, spermatogenesis, activities of antioxidant enzymes, lactate dehydrogenase, alkaline phosphatase, and the level of LPO. The epididymal sperm count also declined significantly in MTZ-treated group. These changes were partially restored following co-administration of 500 mg/kg BW/day of MTZ and 100 mg/kg BW/day of TT. However, in the mice co-administered with 500 mg/kg BW/day of MTZ and 200 mg/kg BW/day of TT, the changes reverted back completely, similar to that of the controls. Conclusion: The fruit extract of TT ameliorates the MTZ-induced alterations in the testis. PMID:26069369

  9. Inhibition of Lipolysis Ameliorates Diabetic Phenotype in a Mouse Model of Obstructive Sleep Apnea.

    PubMed

    Weiszenstein, Martin; Shimoda, Larissa A; Koc, Michal; Seda, Ondrej; Polak, Jan

    2016-08-01

    Obstructive sleep apnea (OSA) is associated with insulin resistance, glucose intolerance, and type 2 diabetes. Causal mechanisms mediating this association are not well defined; however, augmented lipolysis in adipose might be involved. Here, we investigated the effect of acipimox treatment (lipolysis inhibitor) on glucose tolerance and insulin sensitivity in mice exposed to intermittent hypoxia (IH). C57BL6/J mice were exposed for 14 days to IH or control conditions. IH was created by decreasing the fraction of inspired oxygen from 20.9 to 6.5%, 60 times/h. Control exposure was air (fraction of inspired oxygen, 20.9%) delivered at an identical flow rate. Acipimox was provided in drinking water (0.5 g/ml) during exposures. After exposures, intraperitoneal insulin (0.5 IU/kg) and glucose (1 g/kg) tolerance tests were performed, and primary adipocytes were isolated for lipolysis experiments. IH elevated fasting glucose by 51% and worsened glucose tolerance and insulin sensitivity by 33 and 102%, respectively. In parallel, IH increased spontaneous lipolysis by 264%, and reduced epididymal fat mass by 15% and adipocyte size by 8%. Acipimox treatment prevented IH-induced lipolysis and increased epididymal fat mass and adipocyte size by 19 and 10%, respectively. Acipimox fully prevented IH-induced impairments in fasting glycemia, glucose tolerance, and insulin sensitivity. For all reported results, P less than 0.05 was considered significant. Augmented lipolysis contributes to insulin resistance and glucose intolerance observed in mice exposed to IH. Acipimox treatment ameliorated the metabolic consequences of IH and might represent a novel treatment option for patients with obstructive sleep apnea. PMID:26978122

  10. The inhibition of EZH2 ameliorates osteoarthritis development through the Wnt/β-catenin pathway.

    PubMed

    Chen, Linwei; Wu, Yaosen; Wu, Yan; Wang, Ye; Sun, Liaojun; Li, Fangcai

    2016-01-01

    The purpose of our study was to elucidate the role of the histone methyltransferase enhancer of zeste homologue 2 (EZH2) in the pathophysiology of osteoarthritis (OA) and to develop a strategy to modulate EZH2 activity for OA treatment. The expression of EZH2 in normal and OA human cartilage was compared by western blotting. The effect of EZH2 overexpression and inhibition on chondrocyte hypertrophy related gene expression was examined by real-time PCR, and histone methylation on the promoter of the Wnt inhibitor SFRP1 was analyzed using a chromatin immunoprecipitation (ChIP) PCR. Histological assessment of OA mice joint was carried out to assess the in vivo effects of EZH2 inhibitor EPZ005687. We found EZH2 level was significantly increased in the chondrocytes of OA patients compared to normal humans. Overexpression of EZH2 promoted Indian Hedgehog, MMP-13, ADAMTS-5 and COLX expression, while inhibition of EZH2 reversed this trend. Furthermore, the induction of EZH2 led to β-catenin signaling activation by increasing H3K27me3 on the promoter of SFRP1, while the inhibition of EZH2 silenced β-catenin signaling. Finally, intraarticular injection of EPZ005687 delayed OA development in mice. These results implicated EZH2 activity in OA development. Pharmacological inhibition of EZH2 may be an effective therapeutic approach for osteoarthritis. PMID:27539752

  11. The inhibition of EZH2 ameliorates osteoarthritis development through the Wnt/β-catenin pathway

    PubMed Central

    Chen, Linwei; Wu, Yaosen; Wu, Yan; Wang, Ye; Sun, Liaojun; Li, Fangcai

    2016-01-01

    The purpose of our study was to elucidate the role of the histone methyltransferase enhancer of zeste homologue 2 (EZH2) in the pathophysiology of osteoarthritis (OA) and to develop a strategy to modulate EZH2 activity for OA treatment. The expression of EZH2 in normal and OA human cartilage was compared by western blotting. The effect of EZH2 overexpression and inhibition on chondrocyte hypertrophy related gene expression was examined by real-time PCR, and histone methylation on the promoter of the Wnt inhibitor SFRP1 was analyzed using a chromatin immunoprecipitation (ChIP) PCR. Histological assessment of OA mice joint was carried out to assess the in vivo effects of EZH2 inhibitor EPZ005687. We found EZH2 level was significantly increased in the chondrocytes of OA patients compared to normal humans. Overexpression of EZH2 promoted Indian Hedgehog, MMP-13, ADAMTS-5 and COLX expression, while inhibition of EZH2 reversed this trend. Furthermore, the induction of EZH2 led to β-catenin signaling activation by increasing H3K27me3 on the promoter of SFRP1, while the inhibition of EZH2 silenced β-catenin signaling. Finally, intraarticular injection of EPZ005687 delayed OA development in mice. These results implicated EZH2 activity in OA development. Pharmacological inhibition of EZH2 may be an effective therapeutic approach for osteoarthritis. PMID:27539752

  12. Inhibition of Phosphodiesterase 2 Augments cGMP and cAMP Signaling to Ameliorate Pulmonary Hypertension

    PubMed Central

    Bubb, Kristen J; Trinder, Sarah L; Baliga, Reshma S; Patel, Jigisha; Clapp, Lucie H; MacAllister, Raymond J; Hobbs, Adrian J

    2014-01-01

    Background Pulmonary hypertension (PH) is a life-threatening disorder characterized by increased pulmonary artery pressure, remodeling of the pulmonary vasculature, and right ventricular failure. Loss of endothelium-derived nitric oxide (NO) and prostacyclin (PGI2) contributes to PH pathogenesis and current therapies are targeted to restore these pathways. Phosphodiesterases (PDEs) are a family of enzymes that break down cGMP and cAMP which underpin the bioactivity of NO and PGI2. The PDE5 inhibitor (PDE5i) sildenafil is licensed for PH, but a role for PDE2 in lung physiology and disease has yet to be established. Herein, we investigated whether PDE2 inhibition modulates pulmonary cyclic nucleotide signaling and ameliorates experimental PH. Methods and Results The selective PDE2 inhibitor BAY 60-7550 augmented atrial natriuretic peptide (ANP) and treprostinil -evoked pulmonary vascular relaxation in isolated arteries from chronically hypoxic rats. BAY 60-7550 prevented the onset of both hypoxia- and bleomycin-induced PH, and produced a significantly greater reduction in disease severity when given in combination with a neutral endopeptidase inhibitor (enhances endogenous natriuretic peptides), the PGI2 analogue treprostinil, inorganic nitrate (NO donor), or a PDE5i. Proliferation of pulmonary artery smooth muscle cells from PAH patients was reduced by BAY 60-7550, an effect further enhanced in the presence of ANP, NO and treprostinil. Conclusions PDE2 inhibition elicits pulmonary dilation, prevents pulmonary vascular remodeling, and reduces the RVH characteristic of PH. This favorable pharmacodynamic profile is dependent on natriuretic peptide bioactivity, and is additive with PGI2 analogues, PDE5i, and NO. PDE2 inhibition represents a viable, orally-active therapy for PH. PMID:24899690

  13. Ghrelin ameliorates intestinal barrier dysfunction in experimental colitis by inhibiting the activation of nuclear factor-kappa B

    SciTech Connect

    Cheng, Jian; Zhang, Lin; Dai, Weiqi; Mao, Yuqing; Li, Sainan; Wang, Jingjie; Li, Huanqing; Guo, Chuanyong; Fan, Xiaoming

    2015-02-27

    Aim: This study aimed to investigate the effect and underlying mechanism of ghrelin on intestinal barrier dysfunction in dextran sulfate sodium (DSS)-induced colitis. Methods and results: Acute colitis was induced in C57BL/6J mice by administering 2.5% DSS. Saline or 25, 125, 250 μg/kg ghrelin was administrated intraperitoneally (IP) to mice 1 day before colitis induction and on days 4, 5, and 6 after DSS administration. IP injection of a ghrelin receptor antagonist, [D-lys{sup 3}]-GHRP-6, was performed immediately prior to ghrelin injection. Ghrelin (125 or 250 μg/kg) could reduce the disease activity index, histological score, and myeloperoxidase activities in experimental colitis, and also prevented shortening of the colon. Ghrelin could prevent the reduction of transepithelial electrical resistance and tight junction expression, and bolstered tight junction structural integrity and regulated cytokine secretion. Ultimately, ghrelin inhibited nuclear factor kappa B (NF-κB), inhibitory κB-α, myosin light chain kinase, and phosphorylated myosin light chain 2 activation. Conclusions: Ghrelin prevented the breakdown of intestinal barrier function in DSS-induced colitis. The protective effects of ghrelin on intestinal barrier function were mediated by its receptor GHSR-1a. The inhibition of NF-κB activation might be part of the mechanism underlying the effects of ghrelin that protect against barrier dysfunction. - Highlights: • Ghrelin ameliorates intestinal barrier dysfunction in experimental colitis. • The effect of ghrelin is mediated by GHSR-1a. • Inhibition of NF-κB activation.

  14. Myostatin inhibition by a follistatin-derived peptide ameliorates the pathophysiology of muscular dystrophy model mice

    PubMed Central

    Tsuchida, K

    2008-01-01

    Summary Gene-targeted therapies, such as adeno-associated viral vector (AAV)-mediated gene therapy and cell-mediated therapy using myogenic stem cells, are hopeful molecular strategies for muscular dystrophy. In addition, drug therapies based on the pathophysiology of muscular dystrophy patients are desirable. Multidisciplinary approaches to drug design would offer promising therapeutic strategies. Myostatin, a member of the transforming growth factor-β superfamily, is predominantly produced by skeletal muscle and negatively regulates the growth and differentiation of cells of the skeletal muscle lineage. Myostatin inhibition would increase the skeletal muscle mass and prevent muscle degeneration, regardless of the type of muscular dystrophy. Myostatin inhibitors include myostatin antibodies, myostatin propeptide, follistatin and follistatin-related protein. Although follistatin possesses potent myostatin-inhibiting activity, it works as an efficient inhibitor of activins. Unlike myostatin, activins regulate the growth and differentiation of nearly all cell types, including cells of the gonads, pituitary gland and skeletal muscle. We have developed a myostatin-specific inhibitor derived from follistatin, designated FS I-I. Transgenic mice expressing this myostatin-inhibiting peptide under the control of a skeletal muscle-specific promoter showed increased skeletal muscle mass and strength. mdx mice were crossed with FS I-I transgenic mice and any improvement of the pathological signs was investigated. The resulting mdx/FS I-I mice exhibited increased skeletal muscle mass and reduced cell infiltration in muscles. Muscle strength was also recovered in mdx/FS I-I mice. Our data indicate that myostatin inhibition by this follistatin-derived peptide has therapeutic potential for muscular dystrophy. PMID:19108572

  15. Pharmacological inhibition of fibroblast growth factor (FGF) receptor signaling ameliorates FGF23-mediated hypophosphatemic rickets.

    PubMed

    Wöhrle, Simon; Henninger, Christine; Bonny, Olivier; Thuery, Anne; Beluch, Noemie; Hynes, Nancy E; Guagnano, Vito; Sellers, William R; Hofmann, Francesco; Kneissel, Michaela; Graus Porta, Diana

    2013-04-01

    Fibroblast growth factor 23 (FGF23) is a circulating factor secreted by osteocytes that is essential for phosphate homeostasis. In kidney proximal tubular cells FGF23 inhibits phosphate reabsorption and leads to decreased synthesis and enhanced catabolism of 1,25-dihydroxyvitamin D3 (1,25[OH]2 D3 ). Excess levels of FGF23 cause renal phosphate wasting and suppression of circulating 1,25(OH)2 D3 levels and are associated with several hereditary hypophosphatemic disorders with skeletal abnormalities, including X-linked hypophosphatemic rickets (XLH) and autosomal recessive hypophosphatemic rickets (ARHR). Currently, therapeutic approaches to these diseases are limited to treatment with activated vitamin D analogues and phosphate supplementation, often merely resulting in partial correction of the skeletal aberrations. In this study, we evaluate the use of FGFR inhibitors for the treatment of FGF23-mediated hypophosphatemic disorders using NVP-BGJ398, a novel selective, pan-specific FGFR inhibitor currently in Phase I clinical trials for cancer therapy. In two different hypophosphatemic mouse models, Hyp and Dmp1-null mice, resembling the human diseases XLH and ARHR, we find that pharmacological inhibition of FGFRs efficiently abrogates aberrant FGF23 signaling and normalizes the hypophosphatemic and hypocalcemic conditions of these mice. Correspondingly, long-term FGFR inhibition in Hyp mice leads to enhanced bone growth, increased mineralization, and reorganization of the disturbed growth plate structure. We therefore propose NVP-BGJ398 treatment as a novel approach for the therapy of FGF23-mediated hypophosphatemic diseases. PMID:23129509

  16. Estrogen ameliorates microglial activation by inhibiting the Kir2.1 inward-rectifier K(+) channel.

    PubMed

    Wu, Shih-Ying; Chen, Yun-Wen; Tsai, Sheng-Feng; Wu, Sheng-Nan; Shih, Yao-Hsiang; Jiang-Shieh, Ya-Fen; Yang, Ting-Ting; Kuo, Yu-Min

    2016-01-01

    Microglial activation is implicated in the pathogenesis of Parkinson's disease (PD). Although the etiology of PD remains unclear, age and male gender are known PD risk factors. By comparing microglia and dopaminergic (DA) neurons in the substantia nigra (SN) of male and female mice of different ages, we found that the degrees of microglial activation and DA neuron loss increased with age in both genders, but were more pronounced in males, as were peripheral lipopolysaccharide (LPS)-induced microglial activation and DA neuron loss. A bilateral ovariectomy (OVX) eliminated the female-associated protection against age- and LPS-induced microglial activation, which suggests that ovary hormones are involved in gender-specific responses. Treating female mice with 17β-estradiol supplements reduced the age-associated microglial activation in OVX mice. Moreover, pretreating mouse BV2 microglial cells with 17β-estradiol inhibited LPS-induced elevation of Toll-like receptor 4, phosphorylated p38, and TNF-α levels. We then examined the effect of 17β-estradiol on inward-rectifier K(+) channel Kir2.1, a known regulator of microglial activation. We found that 17β-estradiol inhibited the Kir2.1 activity of BV2 cells by reducing the probability that the channel would be open. We conclude that age- and inflammation-associated microglial activation is attenuated by ovarian estrogen, because it inhibits Kir2.1. PMID:26960267

  17. Estrogen ameliorates microglial activation by inhibiting the Kir2.1 inward-rectifier K+ channel

    PubMed Central

    Wu, Shih-Ying; Chen, Yun-Wen; Tsai, Sheng-Feng; Wu, Sheng-Nan; Shih, Yao-Hsiang; Jiang-Shieh, Ya-Fen; Yang, Ting-Ting; Kuo, Yu-Min

    2016-01-01

    Microglial activation is implicated in the pathogenesis of Parkinson’s disease (PD). Although the etiology of PD remains unclear, age and male gender are known PD risk factors. By comparing microglia and dopaminergic (DA) neurons in the substantia nigra (SN) of male and female mice of different ages, we found that the degrees of microglial activation and DA neuron loss increased with age in both genders, but were more pronounced in males, as were peripheral lipopolysaccharide (LPS)-induced microglial activation and DA neuron loss. A bilateral ovariectomy (OVX) eliminated the female-associated protection against age- and LPS-induced microglial activation, which suggests that ovary hormones are involved in gender-specific responses. Treating female mice with 17β-estradiol supplements reduced the age-associated microglial activation in OVX mice. Moreover, pretreating mouse BV2 microglial cells with 17β-estradiol inhibited LPS-induced elevation of Toll-like receptor 4, phosphorylated p38, and TNF-α levels. We then examined the effect of 17β-estradiol on inward-rectifier K+ channel Kir2.1, a known regulator of microglial activation. We found that 17β-estradiol inhibited the Kir2.1 activity of BV2 cells by reducing the probability that the channel would be open. We conclude that age- and inflammation-associated microglial activation is attenuated by ovarian estrogen, because it inhibits Kir2.1. PMID:26960267

  18. Pathological hypertrophy amelioration by PRAS40-mediated inhibition of mTORC1

    PubMed Central

    Völkers, Mirko; Toko, Haruhiro; Doroudgar, Shirin; Din, Shabana; Quijada, Pearl; Joyo, Anya Y.; Ornelas, Luis; Joyo, Eri; Thuerauf, Donna J.; Konstandin, Mathias H.; Gude, Natalie; Glembotski, Christopher C.; Sussman, Mark A.

    2013-01-01

    Mechanistic target of rapamycin complex 1 (mTORC1), necessary for cellular growth, is regulated by intracellular signaling mediating inhibition of mTORC1 activation. Among mTORC1 regulatory binding partners, the role of Proline Rich AKT Substrate of 40 kDa (PRAS40) in controlling mTORC1 activity and cellular growth in response to pathological and physiological stress in the heart has never been addressed. This report shows PRAS40 is regulated by AKT in cardiomyocytes and that AKT-driven phosphorylation relieves the inhibitory function of PRAS40. PRAS40 overexpression in vitro blocks mTORC1 in cardiomyocytes and decreases pathological growth. Cardiomyocyte-specific overexpression in vivo blunts pathological remodeling after pressure overload and preserves cardiac function. Inhibition of mTORC1 by PRAS40 preferentially promotes protective mTORC2 signaling in chronic diseased myocardium. In contrast, strong PRAS40 phosphorylation by AKT allows for physiological hypertrophy both in vitro and in vivo, whereas cardiomyocyte-specific overexpression of a PRAS40 mutant lacking capacity for AKT-phosphorylation inhibits physiological growth in vivo, demonstrating that AKT-mediated PRAS40 phosphorylation is necessary for induction of physiological hypertrophy. Therefore, PRAS40 phosphorylation acts as a molecular switch allowing mTORC1 activation during physiological growth, opening up unique possibilities for therapeutic regulation of the mTORC1 complex to mitigate pathologic myocardial hypertrophy by PRAS40. PMID:23842089

  19. Berberine ameliorates TNBS induced colitis by inhibiting inflammatory responses and Th1/Th17 differentiation.

    PubMed

    Li, Chengzhen; Xi, Yebin; Li, Shan; Zhao, Qing; Cheng, Wenjing; Wang, Zhengting; Zhong, Jie; Niu, Xiaoyin; Chen, Guangjie

    2015-10-01

    Th1 and Th17 cells, and their associated cytokines, have been associated with the pathogenesis of Crohn's disease. Berberine (BBR), a compound long used in traditional Chinese medicines, has been reported to have therapeutic effects in treating experimental colitis. In this study, we show that BBR had a protective effect on mice with TNBS-induced colitis. BBR inhibited levels of IFN-γ, IL-17, IL-6, IL-1β and TNF-α both in the local colon and sera, and transiently increased levels of IL-22. BBR also markedly increased sIgA expression in the colon. BBR had pronounced effects on macrophage populations. Treatment with BBR adjusted the M2/M1 ratio. In addition, BBR exerted effects on adaptive immunity by suppressing numbers of Th1 and Th17 cells, as well as expression levels of their associated cytokines and transcriptional factors. BBR downregulated STAT3 and STAT1 phosphorylation, and inhibited phosphorylation of NF-kB. In vitro experiments showed that BBR inhibited the differentiation of Th17 and, to a lesser degree, Th1 cells, without affecting regulatory T cells. Therefore, we conclude that BBR plays a regulatory role in modulating the balance of immune responses in TNBS-induced colitis. Our study will help us understand the regulatory mechanisms exerted by BBR in the treatment of IBD. PMID:26224047

  20. Mammalian target of rapamycin signaling inhibition ameliorates vascular calcification via Klotho upregulation.

    PubMed

    Zhao, Yang; Zhao, Ming-Ming; Cai, Yan; Zheng, Ming-Fei; Sun, Wei-Liang; Zhang, Song-Yang; Kong, Wei; Gu, Jun; Wang, Xian; Xu, Ming-Jiang

    2015-10-01

    Vascular calcification (VC) is a major risk factor for cardiovascular mortality in chronic renal failure (CRF) patients, but the pathogenesis remains partially unknown and effective therapeutic targets should be urgently explored. Here we pursued the therapeutic role of rapamycin in CRF-related VC. Mammalian target of rapamycin (mTOR) signal was activated in the aortic wall of CRF rats. As expected, oral rapamycin administration significantly reduced VC by inhibiting mTOR in rats with CRF. Further in vitro results showed that activation of mTOR by both pharmacological agent and genetic method promoted, while inhibition of mTOR reduced, inorganic phosphate-induced vascular smooth muscle cell (VSMC) calcification and chondrogenic/osteogenic gene expression, which were independent of autophagy and apoptosis. Interestingly, the expression of Klotho, an antiaging gene that suppresses VC, was reduced in calcified vasculature, whereas rapamycin reversed membrane and secreted Klotho decline through mTOR inhibition. When mTOR signaling was enhanced by either mTOR overexpression or deletion of tuberous sclerosis 1, Klotho mRNA was further decreased in phosphate-treated VSMCs, suggesting a vital association between mTOR signaling and Klotho expression. More importantly, rapamycin failed to reduce VC in the absence of Klotho by using either siRNA knockdown of Klotho or Klotho knockout mice. Thus, Klotho has a critical role in mediating the observed decrease in calcification by rapamycin in vitro and in vivo. PMID:26061549

  1. The inhibition of calpains ameliorates vascular restenosis through MMP2/TGF-β1 pathway

    PubMed Central

    Tang, Lianghu; Pei, Haifeng; Yang, Yi; Wang, Xiong; Wang, Ting; Gao, Erhe; Li, De; Yang, Yongjian; Yang, Dachun

    2016-01-01

    Restenosis limits the efficacy of vascular percutaneous intervention, in which vascular smooth muscle cell (VSMC) proliferation and activation of inflammation are two primary causal factors. Calpains influence VSMC proliferation and collagen synthesis. However, the roles of calpastatin and calpains in vascular restenosis remain unclear. Here, restenosis was induced by ligating the left carotid artery, and VSMCs were pretreated with platelet-derived growth factor (PDGF)-BB. Adenovirus vector carrying MMP2 sequence and specific small interfering RNA against calpain-1/2 were introduced. Finally, restenosis enhanced the expression of calpain-1/2, but reduced calpastatin content. In calpastatin transgenic mice, lumen narrowing was attenuated gradually and peaked on days 14–21. Cell proliferation and migration as well as collagen synthesis were inhibited in transgenic mice, and expression of calpain-1/2 and MMP2/transforming growth factor-β1 (TGF-β1). Consistently, in VSMCs pretreated with PDGF-BB, calpastatin induction and calpains inhibition suppressed the proliferation and migration of VSMCs and collagen synthesis, and reduced expression of calpain-1/2 and MMP2/TGF-β1. Moreover, simvastatin improved restenosis indicators by suppressing the HIF-1α/calpains/MMP2/TGF-β1 pathway. However, MMP2 supplementation eliminated the vascular protection of calpastatin induction and simvastatin. Collectively, calpains inhibition plays crucial roles in vascular restenosis by preventing neointimal hyperplasia at the early stage via suppression of the MMP2/TGF-β1 pathway. PMID:27453531

  2. SERCA2a upregulation ameliorates cellular alternans induced by metabolic inhibition.

    PubMed

    Stary, Victoria; Puppala, Dheeraj; Scherrer-Crosbie, Marielle; Dillmann, Wolfgang H; Armoundas, Antonis A

    2016-04-15

    Cardiac alternans has been associated with the incidence of ventricular tachyarrhythmias and sudden cardiac death. The aim of this study was to investigate the effect of impaired mitochondrial function in the genesis of cellular alternans and to examine whether modulating the sarcoplasmic reticulum (SR) Ca(2+)ameliorates the level of alternans. Cardiomyocytes isolated from control and doxycyline-induced sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a (SERCA2a)-upregulated mice were loaded with two different Ca(2+)indicators to selectively measure mitochondrial and cytosolic Ca(2+)using a custom-made fluorescence photometry system. The degree of alternans was defined as the alternans ratio (AR) [1 - (small Ca(2+)intensity)/(large Ca(2+)intensity)]. Blocking of complex I and II, cytochrome-coxidase, F0F1synthase, α-ketoglutarate dehydrogenase of the electron transport chain, increased alternans in both control and SERCA2a mice (P< 0.01). Changes in AR in SERCA2a-upregulated mice were significantly less pronounced than those observed in control in seven of nine tested conditions (P< 0.04).N-acetyl-l-cysteine (NAC), rescued alternans in myocytes that were previously exposed to an oxidizing agent (P< 0.001). CGP, an antagonist of the mitochondrial Na(+)-Ca(2+)exchanger, had the most severe effect on AR. Exposure to cyclosporin A, a blocker of the mitochondrial permeability transition pore reduced CGP-induced alternans (P< 0.0001). The major findings of this study are that impairment of mitochondrial Ca(2+)cycling and energy production leads to a higher amplitude of alternans in both control and SERCA2a-upregulated mice, but changes in SERCA2a-upregulated mice are less severe, indicating that SERCA2a mice are more capable of sustaining electrical stability during stress. This suggests a relationship between sarcoplasmic Ca(2+)content and mitochondrial dysfunction during alternans, which may potentially help to understand changes in Ca(2+)signaling in myocytes from

  3. Janus kinase inhibition lessens inflammation and ameliorates disease in murine models of hemophagocytic lymphohistiocytosis.

    PubMed

    Das, Rupali; Guan, Peng; Sprague, Leslee; Verbist, Katherine; Tedrick, Paige; An, Qi Angel; Cheng, Cheng; Kurachi, Makoto; Levine, Ross; Wherry, E John; Canna, Scott W; Behrens, Edward M; Nichols, Kim E

    2016-03-31

    Hemophagocytic lymphohistiocytosis (HLH) comprises an emerging spectrum of inherited and noninherited disorders of the immune system characterized by the excessive production of cytokines, including interferon-γ and interleukins 2, 6, and 10 (IL-2, IL-6, and IL-10). The Janus kinases (JAKs) transduce signals initiated following engagement of specific receptors that bind a broad array of cytokines, including those overproduced in HLH. Based on the central role for cytokines in the pathogenesis of HLH, we sought to examine whether the inhibition of JAK function might lessen inflammation in murine models of the disease. Toward this end, we examined the effects of JAK inhibition using a model of primary (inherited) HLH in which perforin-deficient (Prf1(-∕-)) mice are infected with lymphocytic choriomeningitis virus (LCMV) and secondary (noninherited) HLH in which C57BL/6 mice receive repeated injections of CpG DNA. In both models, treatment with the JAK1/2 inhibitor ruxolitinib significantly lessened the clinical and laboratory manifestations of HLH, including weight loss, organomegaly, anemia, thrombocytopenia, hypercytokinemia, and tissue inflammation. Importantly, ruxolitinib treatment also significantly improved the survival of LCMV-infectedPrf1(-∕-)mice. Mechanistic studies revealed that in vivo exposure to ruxolitinib inhibited signal transducer and activation of transcription 1-dependent gene expression, limited CD8(+)T-cell expansion, and greatly reduced proinflammatory cytokine production, without effecting degranulation and cytotoxic function. Collectively, these findings highlight the JAKs as novel, druggable targets for mitigating the cytokine-driven hyperinflammation that occurs in HLH. These observations also support the incorporation of JAK inhibitors such as ruxolitinib into future clinical trials for patients with these life-threatening disorders. PMID:26825707

  4. Synthetic retinoid AM80 inhibits Th17 cells and ameliorates experimental autoimmune encephalomyelitis.

    PubMed

    Klemann, Christian; Raveney, Benjamin J E; Klemann, Anna K; Ozawa, Tomoko; von Hörsten, Stephan; Shudo, Koichi; Oki, Shinji; Yamamura, Takashi

    2009-06-01

    Recent evidence suggests that interleukin-17-producing CD4(+) T cells (Th17 cells) are the dominant pathogenic cellular component in autoimmune inflammatory diseases, including multiple sclerosis. It has recently been demonstrated that all-trans retinoic acid can suppress Th17 differentiation and promote the generation of Foxp3(+) regulatory T cells via retinoic acid receptor signals. Here, we investigated the effects of AM80, a synthetic retinoid with enhanced biological properties to all-trans retinoic acid, on Th17 differentiation and function and evaluated its therapeutic potential in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. AM80 treatment was more effective than all-trans retinoic acid in inhibiting Th17 differentiation in vitro. Oral administration of AM80 was protective for the early development of EAE and the down-modulation of Th17 differentiation and effector functions in vivo. Moreover, AM80 inhibited interleukin-17 production by splenic memory T cells, in vitro-differentiated Th17 cells, and central nervous system-infiltrating effector T cells. Accordingly, AM80 was effective when administered therapeutically after the onset of EAE. Continuous AM80 treatment, however, was ineffective at inhibiting late EAE symptoms despite the maintained suppression of RORgammat and interleukin-17 expression levels by central nervous system-infiltrating T cells. We reveal that continuous AM80 treatment also led to the suppression of interleukin-10 production by a distinct T cell subset that expressed both Foxp3 and RORgammat. These findings suggest that retinoid signaling regulates both inflammatory Th17 cells and Th17-like regulatory cells. PMID:19389933

  5. Synthetic Retinoid AM80 Inhibits Th17 Cells and Ameliorates Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Klemann, Christian; Raveney, Benjamin J.E.; Klemann, Anna K.; Ozawa, Tomoko; von Hörsten, Stephan; Shudo, Koichi; Oki, Shinji; Yamamura, Takashi

    2009-01-01

    Recent evidence suggests that interleukin-17-producing CD4+ T cells (Th17 cells) are the dominant pathogenic cellular component in autoimmune inflammatory diseases, including multiple sclerosis. It has recently been demonstrated that all-trans retinoic acid can suppress Th17 differentiation and promote the generation of Foxp3+ regulatory T cells via retinoic acid receptor signals. Here, we investigated the effects of AM80, a synthetic retinoid with enhanced biological properties to all-trans retinoic acid, on Th17 differentiation and function and evaluated its therapeutic potential in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. AM80 treatment was more effective than all-trans retinoic acid in inhibiting Th17 differentiation in vitro. Oral administration of AM80 was protective for the early development of EAE and the down-modulation of Th17 differentiation and effector functions in vivo. Moreover, AM80 inhibited interleukin-17 production by splenic memory T cells, in vitro-differentiated Th17 cells, and central nervous system-infiltrating effector T cells. Accordingly, AM80 was effective when administered therapeutically after the onset of EAE. Continuous AM80 treatment, however, was ineffective at inhibiting late EAE symptoms despite the maintained suppression of RORγt and interleukin-17 expression levels by central nervous system-infiltrating T cells. We reveal that continuous AM80 treatment also led to the suppression of interleukin-10 production by a distinct T cell subset that expressed both Foxp3 and RORγt. These findings suggest that retinoid signaling regulates both inflammatory Th17 cells and Th17-like regulatory cells. PMID:19389933

  6. Inhibition of 11β-hydroxysteroid dehydrogenase type 1 ameliorates obesity-related insulin resistance.

    PubMed

    Shao, Shiying; Zhang, Xiaojie; Zhang, Muxun

    2016-09-01

    Excess 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) may be implicated in the development of obesity related metabolic disorders. The present study measured the expression level of 11β-HSD1 in visceral adipose tissues from 23 patients undergoing abdominal operation. Correlation of 11β-HSD1 expression with BMI, waist-to-hip ratio (WHR), HOMA-IR, and serum lipids was evaluated by spearman correlation analysis. High-fat diet-induced obese (DIO) rats were orally dosed with BVT.2733 for 4 weeks. Weight, plasma insulin, and lipids were detected at the end of the treatment. The effects of 11β-HSD1 inhibition on the key insulin-signaling cascade and adipocytokines were measured by western blot and ELISA respectively. 11β-HSD1 was increased in patients with central obesity, the expression level of which was closely related with WHR (r = 0.5851), BMI (r = 0.4952), and HOMA-IR (r = 0.4637). Obesity related insulin resistance in high-fat DIO rats, as reflected by a marked decrease in IRS-1, IRS-2, GLUT4, and PI3K, could be attenuated by 11β-HSD1 inhibition. Furthermore, the down-regulation of 11β-HSD1 could correct the disordered profiles of adipocytokines including adiponectin, IL-6, and TNF-α. These findings indicated that 11β-HSD1 inhibition can give a potential benefit in reducing obesity and lowering insulin resistance by modulating the insulin-signaling pathway and adipocytokine production. PMID:27268236

  7. Mangosteen pericarp extract inhibits the formation of pentosidine and ameliorates skin elasticity.

    PubMed

    Ohno, Rei-Ichi; Moroishi, Narumi; Sugawa, Hikari; Maejima, Kazuhiro; Saigusa, Musashi; Yamanaka, Mikihiro; Nagai, Mime; Yoshimura, Morio; Amakura, Yoshiaki; Nagai, Ryoji

    2015-07-01

    The inhibition of advanced glycation end-products (AGEs) by daily meals is believed to become an effective prevention for lifestyle-related diseases. In the present study, the inhibitory effect of hot water extracts of mangosteen (Garcinia mangostana L.) pericarp (WEM) on the formation of pentosidine, one of AGEs, in vitro and in vivo and the remedial effect on skin conditions were measured. WEM significantly inhibited pentosidine formation during gelatin incubation with ribose. Several compounds purified from WEM, such as garcimangosone D and rhodanthenone B, were identified as inhibitors of pentosidine formation. Oral administration of WEM at 100 mg/day to volunteer subjects for 3 months reduced the serum pentosidine contents. Because obtaining skin biopsies from healthy volunteers is ethically difficult, AGE accumulation in the skin was estimated by a fluorescence detector. The oral administration of WEM significantly reduced the skin autofluorescence intensity, demonstrating that WEM also reduced AGE accumulation in the skin. Furthermore, the elasticity and moisture content of the skin was also improved by WEM. These results demonstrate that intakes of WEM reduces the glycation stress and results in the improvement of skin conditions. PMID:26236097

  8. FOLH1/GCPII is elevated in IBD patients, and its inhibition ameliorates murine IBD abnormalities

    PubMed Central

    Wozniak, Krystyna M.; Stathis, Marigo; Hollinger, Kristen R.; Thomas, Ajit G.; Rojas, Camilo; Vornov, James J.; Marohn, Michael; Li, Xuhang; Slusher, Barbara S.

    2016-01-01

    Recent gene-profiling analyses showed significant upregulation of the folate hydrolase (FOLH1) gene in the affected intestinal mucosa of patients with inflammatory bowel disease (IBD). The FOLH1 gene encodes a type II transmembrane glycoprotein termed glutamate carboxypeptidase II (GCPII). To establish that the previously reported increased gene expression was functional, we quantified the glutamate carboxypeptidase enzymatic activity in 31 surgical specimens and report a robust 2.8- to 41-fold increase in enzymatic activity in the affected intestinal mucosa of IBD patients compared with an uninvolved area in the same patients or intestinal mucosa from healthy controls. Using a human-to-mouse approach, we next showed a similar enzymatic increase in two well-validated IBD murine models and evaluated the therapeutic effect of the potent FOLH1/ GCPII inhibitor 2-phosphonomethyl pentanedioic acid (2-PMPA) (IC50 = 300 pM). In the dextran sodium sulfate (DSS) colitis model, 2-PMPA inhibited the GCPII activity in the colonic mucosa by over 90% and substantially reduced the disease activity. The significance of the target was confirmed in FOLH1−/− mice who exhibited resistance to DSS treatment. In the murine IL-10−/− model of spontaneous colitis, daily 2-PMPA treatment also significantly reduced both macroscopic and microscopic disease severity. These results provide the first evidence of FOLH1/GCPII enzymatic inhibition as a therapeutic option for IBD. PMID:27536732

  9. CLK2 inhibition ameliorates autistic features associated with SHANK3 deficiency.

    PubMed

    Bidinosti, Michael; Botta, Paolo; Krüttner, Sebastian; Proenca, Catia C; Stoehr, Natacha; Bernhard, Mario; Fruh, Isabelle; Mueller, Matthias; Bonenfant, Debora; Voshol, Hans; Carbone, Walter; Neal, Sarah J; McTighe, Stephanie M; Roma, Guglielmo; Dolmetsch, Ricardo E; Porter, Jeffrey A; Caroni, Pico; Bouwmeester, Tewis; Lüthi, Andreas; Galimberti, Ivan

    2016-03-11

    SH3 and multiple ankyrin repeat domains 3 (SHANK3) haploinsufficiency is causative for the neurological features of Phelan-McDermid syndrome (PMDS), including a high risk of autism spectrum disorder (ASD). We used unbiased, quantitative proteomics to identify changes in the phosphoproteome of Shank3-deficient neurons. Down-regulation of protein kinase B (PKB/Akt)-mammalian target of rapamycin complex 1 (mTORC1) signaling resulted from enhanced phosphorylation and activation of serine/threonine protein phosphatase 2A (PP2A) regulatory subunit, B56β, due to increased steady-state levels of its kinase, Cdc2-like kinase 2 (CLK2). Pharmacological and genetic activation of Akt or inhibition of CLK2 relieved synaptic deficits in Shank3-deficient and PMDS patient-derived neurons. CLK2 inhibition also restored normal sociability in a Shank3-deficient mouse model. Our study thereby provides a novel mechanistic and potentially therapeutic understanding of deregulated signaling downstream of Shank3 deficiency. PMID:26847545

  10. Inhibition of autophagy ameliorates pulmonary microvascular dilation and PMVECs excessive proliferation in rat experimental hepatopulmonary syndrome

    PubMed Central

    Xu, Duo; Chen, Bing; Gu, Jianteng; Chen, Lin; Belguise, Karine; Wang, Xiaobo; Yi, Bin; Lu, Kaizhi

    2016-01-01

    Hepatopulmonary syndrome (HPS) is a defective liver-induced pulmonary vascular disorder with massive pulmonary microvascular dilation and excessive proliferation of pulmonary microvascular endothelial cells (PMVECs). Growing evidence suggests that autophagy is involved in pulmonary diseases, protectively or detrimentally. Thus, it is interesting and important to explore whether autophagy might be involved in and critical in HPS. In the present study, we report that autophagy was activated in common bile duct ligation (CBDL) rats and cultured pulmonary PMVECs induced by CBDL rat serum, two accepted in vivo and in vitro experimental models of HPS. Furthermore, pharmacological inhibition of autophagy with 3-methyladenine (3-MA) significantly alleviated pathological alterations and typical symptom of HPS in CBDL rats in vivo, and consistently 3-MA significantly attenuated the CBDL rat serum-induced excessive proliferation of PMVECs in vitro. All these changes mediated by 3-MA might explain the observed prominent improvement of pulmonary appearance, edema, microvascular dilatation and arterial oxygenation in vivo. Collectively, these results suggest that autophagy activation may play a critical role in the pathogenesis of HPS, and autophagy inhibition may have a therapeutic potential for this disease. PMID:27480323

  11. Inhibition of Ceramide De Novo Synthesis Ameliorates Diet Induced Skeletal Muscles Insulin Resistance

    PubMed Central

    Kurek, Krzysztof; Mikłosz, Agnieszka; Łukaszuk, Bartłomiej; Chabowski, Adrian; Górski, Jan; Żendzian-Piotrowska, Małgorzata

    2015-01-01

    Nowadays wrong nutritional habits and lack of physical activity give a rich soil for the development of insulin resistance and obesity. Many researches indicate lipids, especially the one from the sphingolipids class, as the group of molecules heavily implicated in the progress of insulin resistance in skeletal muscle. Recently, scientists have focused their scrutiny on myriocin, a potent chemical compound that inhibits ceramide (i.e., central hub of sphingolipids signaling pathway) de novo synthesis. In the present research we evaluated the effects of myriocin application on type 2 diabetes mellitus in three different types of skeletal muscles: (1) slow-oxidative (red gastrocnemius), (2) oxidative-glycolytic (soleus), and (3) glycolytic (white gastrocnemius). For these reasons the animals were randomly divided into four groups: “control” (C), “myriocin” (M), “high fat diet” (HFD), “high fat diet” (HFD), and “high fat diet + myriocin” (HFD + M). Our in vivo study demonstrated that ceramide synthesis inhibition reduces intramuscular ceramide, its precursor sphinganine, and its derivatives sphingosine and sphingosine-1-phosphate concentrations. Moreover, FFA and TG contents were also decreased after myriocin treatment. Thus, myriocin presents potential therapeutic perspectives with respect to the treatment of insulin resistance and its serious consequences in obese patients. PMID:26380311

  12. Inhibition of SHP2 ameliorates the pathogenesis of systemic lupus erythematosus

    PubMed Central

    Wang, Jianxun; Zeng, Li-Fan; Bronson, Roderick; Finnell, Michele; Terhorst, Cox; Kyttaris, Vasileios C.; Zhang, Zhong-Yin; Kontaridis, Maria I.

    2016-01-01

    Systemic lupus erythematosus (SLE) is a devastating multisystemic autoimmune disorder. However, the molecular mechanisms underlying its pathogenesis remain elusive. Some patients with Noonan syndrome, a congenital disorder predominantly caused by gain-of-function mutations in the protein tyrosine phosphatase SH2 domain–containing PTP (SHP2), have been shown to develop SLE, suggesting a functional correlation between phosphatase activity and systemic autoimmunity. To test this directly, we measured SHP2 activity in spleen lysates isolated from lupus-prone MRL/lpr mice and found it was markedly increased compared with that in control mice. Similar increases in SHP2 activity were seen in peripheral blood mononuclear cells isolated from lupus patients relative to healthy patients. To determine whether SHP2 alters autoimmunity and related immunopathology, we treated MRL/lpr mice with an SHP2 inhibitor and found increased life span, suppressed crescentic glomerulonephritis, reduced spleen size, and diminished skin lesions. SHP2 inhibition also reduced numbers of double-negative T cells, normalized ERK/MAPK signaling, and decreased production of IFN-γ and IL-17A/F, 2 cytokines involved in SLE-associated organ damage. Moreover, in cultured human lupus T cells, SHP2 inhibition reduced proliferation and decreased production of IFN-γ and IL-17A/F, further implicating SHP2 in lupus-associated immunopathology. Taken together, these data identify SHP2 as a critical regulator of SLE pathogenesis and suggest targeting of its activity as a potent treatment for lupus patients. PMID:27183387

  13. Fumigaclavine C ameliorates dextran sulfate sodium-induced murine experimental colitis via NLRP3 inflammasome inhibition.

    PubMed

    Guo, Wenjie; Hu, Shasha; Elgehama, Ahmed; Shao, Fenli; Ren, Ren; Liu, Wen; Zhang, Wenjing; Wang, Xinlei; Tan, Renxiang; Xu, Qiang; Sun, Yang; Jiao, Ruihua

    2015-10-01

    In the present study, the effect of Fumigaclavine C, a fungal metabolite, on murine experimental colitis induced by dextran sulfate sodium (DSS) and its possible mechanism were examined in vivo and vitro. Oral administration of Fumigaclavine C dose-dependently attenuated the loss of body weight and shortening of colon length induced by DSS. The disease activity index, histopathologic scores of musco was also significantly reduced by Fumigaclavine C treatment. Protein and mRNA levels of DSS-induced pro-inflammatory cytokines in colon, including TNF-α, IL-1β and IL-17A, were markedly suppressed by Fumigaclavine C. At the same time, decreased activation of caspase-1 in peritoneal macrophages was detected in Fumigaclavine C -treated mice which suggested that the NLRP3 inflammasome activation was suppressed. Furthermore, in the LPS plus ATP cell model, we found that Fumigaclavine C dose-dependent inhibited IL-1β release and caspase-1 activation. Taken together, our results demonstrate the ability of Fumigaclavine C to inhibit NLRP3 inflammasome activation and give some evidence for its potential use in the treatment of inflammatory bowel diseases. PMID:26320672

  14. Mangosteen pericarp extract inhibits the formation of pentosidine and ameliorates skin elasticity

    PubMed Central

    Ohno, Rei-ichi; Moroishi, Narumi; Sugawa, Hikari; Maejima, Kazuhiro; Saigusa, Musashi; Yamanaka, Mikihiro; Nagai, Mime; Yoshimura, Morio; Amakura, Yoshiaki; Nagai, Ryoji

    2015-01-01

    The inhibition of advanced glycation end-products (AGEs) by daily meals is believed to become an effective prevention for lifestyle-related diseases. In the present study, the inhibitory effect of hot water extracts of mangosteen (Garcinia mangostana L.) pericarp (WEM) on the formation of pentosidine, one of AGEs, in vitro and in vivo and the remedial effect on skin conditions were measured. WEM significantly inhibited pentosidine formation during gelatin incubation with ribose. Several compounds purified from WEM, such as garcimangosone D and rhodanthenone B, were identified as inhibitors of pentosidine formation. Oral administration of WEM at 100 mg/day to volunteer subjects for 3 months reduced the serum pentosidine contents. Because obtaining skin biopsies from healthy volunteers is ethically difficult, AGE accumulation in the skin was estimated by a fluorescence detector. The oral administration of WEM significantly reduced the skin autofluorescence intensity, demonstrating that WEM also reduced AGE accumulation in the skin. Furthermore, the elasticity and moisture content of the skin was also improved by WEM. These results demonstrate that intakes of WEM reduces the glycation stress and results in the improvement of skin conditions. PMID:26236097

  15. Inhibiting LDL glycation ameliorates increased cholesteryl ester synthesis in macrophages and hypercholesterolemia and aortic lipid peroxidation in streptozotocin diabetic rats

    PubMed Central

    Cohen, Margo P.; Shea, Elizabeth A.; Wu, Van-Yu

    2009-01-01

    Increased nonenzymatic glycation of apoB-containing lipoproteins impairs uptake and metabolism by the high affinity low density lipoprotein (LDL) receptor, and is one of the post-secretory modifications contributory to accelerated atherosclerosis in diabetes. The present study evaluated in vitro and in vivo effects of 2,2-chlorophenylaminophenylacetate (CAP22) to probe the influence of glycated lipoprotein on cholesterol homeostasis. This compound prevented the increased formation of glycated products in LDL incubated with 200 mM glucose and the increased cholesteryl ester synthesis in THP-1 macrophages induced by apoB-containing lipoproteins preincubated with high glucose concentration. The elevated circulating concentrations of glycated lipoprotein and cholesterol and higher vascular levels of lipid peroxidation products observed in streptozotocin diabetic rats compared to nondiabetic controls were significantly reduced in diabetic animals treated for six months with test compound. These results are the first to demonstrate that inhibiting nonenzymatic glycation of apoB-containing lipoproteins ameliorates abnormalities contributory to hypercholesterolemia and atherogenic risk in diabetes. PMID:19922964

  16. Salvianolic Acid B Ameliorates Cerebral Ischemia/Reperfusion Injury Through Inhibiting TLR4/MyD88 Signaling Pathway.

    PubMed

    Wang, Yujue; Chen, Guang; Yu, Xiangdong; Li, Yunchao; Zhang, Li; He, Zongze; Zhang, Nannan; Yang, Xiuping; Zhao, Yansheng; Li, Na; Qiu, Hong

    2016-08-01

    Ischemic stroke can activate multiple transcription factors and cause inflammatory reactions, which involve pattern recognition receptors with immunostimulatory effects. Toll-like receptor 4 (TLR4) is one of the receptors related to innate immunity and several inflammatory reactions. The promising anti- inflammatory activity of salvianolic acid B (SAB) had been previously reported, but its effect on ischemic stroke remains unknown. An oxygen-glucose deprivation and reoxygenation (OGD/R) model in vitro and a middle cerebral artery occlusion (MCAO) model in vivo were used in this paper, and the results showned that SAB remarkably increased the viabilities of PC12 cells and primary cortical neurons after OGD/R injury and notably prevented cerebral ischemia/reperfusion (I/R) injury. SAB also significantly ameliorated NeuN release from primary cortical neurons. Further research indicated that the neuroprotection of SAB was completed through inhibiting the TLR4/MyD88/TRAF6 signaling pathway. The blocking of TLR4 by SAB also restrained NF-kB transcriptional activity and pro-inflammatory cytokine responses (IL-1β, IL-6, and TNF-α). These findings supply a new insight that will aid in clarifying the effect of SAB against cerebral I/R injury and provide the development of SAB as a potential candidate for treating ischemic stroke. PMID:27255374

  17. Inhibition of α2A-Adrenoceptors Ameliorates Dextran Sulfate Sodium-Induced Acute Intestinal Inflammation in Mice.

    PubMed

    Zádori, Zoltán S; Tóth, Viktória E; Fehér, Ágnes; Al-Khrasani, Mahmoud; Puskár, Zita; Kozsurek, Márk; Timár, Júlia; Tábi, Tamás; Helyes, Zsuzsanna; Hein, Lutz; Holzer, Peter; Gyires, Klára

    2016-09-01

    It has been hypothesized that α2-adrenoceptors (α2-ARs) may be involved in the pathomechanism of colitis; however, the results are conflicting because both aggravation and amelioration of colonic inflammation have been described in response to α2-AR agonists. Therefore, we aimed to analyze the role of α2-ARs in acute murine colitis. The experiments were carried out in wild-type, α2A-, α2B-, and α2C-AR knockout (KO) C57BL/6 mice. Colitis was induced by dextran sulfate sodium (DSS, 2%); alpha2-AR ligands were injected i.p. The severity of colitis was determined both macroscopically and histologically. Colonic myeloperoxidase (MPO) and cytokine levels were measured by enzyme-linked immunosorbent assay and proteome profiler array, respectively. The nonselective α2-AR agonist clonidine induced a modest aggravation of DSS-induced colitis. It accelerated the disease development and markedly enhanced the weight loss of animals, but did not influence the colon shortening, tissue MPO levels, or histologic score. Clonidine induced similar changes in α2B- and α2C-AR KO mice, whereas it failed to affect the disease activity index scores and caused only minor weight loss in α2A-AR KO animals. In contrast, selective inhibition of α2A-ARs by BRL 44408 significantly delayed the development of colitis; reduced the colonic levels of MPO and chemokine (C-C motif) ligand 3, chemokine (C-X-C motif) ligand 2 (CXCL2), CXCL13, and granulocyte-colony stimulating factor; and elevated that of tissue inhibitor of metalloproteinases-1. In this work, we report that activation of α2-ARs aggravates murine colitis, an effect mediated by the α2A-AR subtype, and selective inhibition of these receptors reduces the severity of gut inflammation. PMID:27418171

  18. PAR-1 antagonist SCH79797 ameliorates apoptosis following surgical brain injury through inhibition of ASK1-JNK in rats

    PubMed Central

    Manaenko, Anatol; Sun, Xuejun; Kim, Cherine; Yan, Junhao; Ma, Qingyi

    2012-01-01

    Neurosurgical procedures inevitably produce intraoperative hemorrhage. The subsequent entry of blood into the brain parenchyma results in the release of large amounts of thrombin, a known contributor to perihematomal edema formation and apoptosis after brain injury. The present study seeks to test 1) the effect of surgically induced brain injury (SBI) on thrombin activity, expression of thrombin’s receptor PAR-1, and PAR-1 mediated apoptosis; 2) the effect of thrombin inhibition by argatroban and PAR-1 inhibition by SCH79797 on the development of secondary brain injury in the SBI model on rats. A total of 88 Sprague-Dawley male rats were randomly divided into sham, vehicle-, argatroban-, or SCH79797-treated groups. SBI involved partial resection of the right frontal lobe under inhalation isoflurane anesthesia. Sham-operated animals received only craniotomy. Thrombin activity, brain water content, and neurological deficits were measured at 24 hours following SBI. Involvement of the Ask1/JNK pathway in PAR-1-induced post-SBI apoptosis was characterized by using Ask1 or JNK inhibitors. We observed that SBI increased thrombin activity, yet failed to demonstrate any effect on PAR-1 expression. Argatroban and SCH79797 reduced SBI-induced brain edema and neurological deficits in a dose-dependent manner. SBI-induced apoptosis seemed mediated by the PAR-1/Ask1/JNK pathways. Administration of SCH79797 ameliorated the apoptosis following SBI. Our finding indicate that PAR-1 antagonist protects against secondary brain injury after SBI by decreasing both brain edema and apoptosis by inactivating PAR-1/Ask1/JNK pathway. The anti-apoptotic effect of PAR-1 antagonists may provide a promising path for therapy following SBI. PMID:23000356

  19. Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66Shc

    PubMed Central

    Bock, Fabian; Shahzad, Khurrum; Wang, Hongjie; Stoyanov, Stoyan; Wolter, Juliane; Dong, Wei; Pelicci, Pier Giuseppe; Kashif, Muhammed; Ranjan, Satish; Schmidt, Simone; Ritzel, Robert; Schwenger, Vedat; Reymann, Klaus G.; Esmon, Charles T.; Madhusudhan, Thati; Nawroth, Peter P.; Isermann, Berend

    2013-01-01

    The coagulation protease activated protein C (aPC) confers cytoprotective effects in various in vitro and in vivo disease models, including diabetic nephropathy. The nephroprotective effect may be related to antioxidant effects of aPC. However, the mechanism through which aPC may convey these antioxidant effects and the functional relevance of these properties remain unknown. Here, we show that endogenous and exogenous aPC prevents glomerular accumulation of oxidative stress markers and of the redox-regulating protein p66Shc in experimental diabetic nephropathy. These effects were predominately observed in podocytes. In vitro, aPC inhibited glucose-induced expression of p66Shc mRNA and protein in podocytes (via PAR-1 and PAR-3) and various endothelial cell lines, but not in glomerular endothelial cells. Treatment with aPC reversed glucose-induced hypomethylation and hyperacetylation of the p66Shc promoter in podocytes. The hyperacetylating agent sodium butyrate abolished the suppressive effect of aPC on p66Shc expression both in vitro and in vivo. Moreover, sodium butyrate abolished the beneficial effects of aPC in experimental diabetic nephropathy. Inhibition of p66Shc expression and mitochondrial translocation by aPC normalized mitochondrial ROS production and the mitochondrial membrane potential in glucose-treated podocytes. Genetic ablation of p66Shc compensated for the loss of protein C activation in vivo, normalizing markers of diabetic nephropathy and oxidative stress. These studies identify a unique mechanism underlying the cytoprotective effect of aPC. Activated PC epigenetically controls expression of the redox-regulating protein p66Shc, thus linking the extracellular protease aPC to mitochondrial function in diabetic nephropathy. PMID:23267072

  20. Inhibition of HIF-1{alpha} activity by BP-1 ameliorates adjuvant induced arthritis in rats

    SciTech Connect

    Shankar, J.; Thippegowda, P.B.; Kanum, S.A.

    2009-09-18

    Rheumatoid arthritis (RA) is a chronic inflammatory, angiogenic disease. Inflamed synovitis is a hallmark of RA which is hypoxic in nature. Vascular endothelial growth factor (VEGF), one of the key regulators of angiogenesis, is overexpressed in the pathogenesis of RA. VEGF expression is regulated by hypoxia-inducible factor-1{alpha} (HIF-1{alpha}), a master regulator of homeostasis which plays a pivotal role in hypoxia-induced angiogenesis. In this study we show that synthetic benzophenone analogue, 2-benzoyl-phenoxy acetamide (BP-1) can act as a novel anti-arthritic agent in an experimental adjuvant induced arthritis (AIA) rat model by targeting VEGF and HIF-1{alpha}. BP-1 administered hypoxic endothelial cells and arthritic animals clearly showed down regulation of VEGF expression. Further, BP-1 inhibits nuclear translocation of HIF-1{alpha}, which in turn suppresses transcription of the VEGF gene. These results suggest a further possible clinical application of the BP-1 derivative as an anti-arthritic agent in association with conventional chemotherapeutic agents.

  1. Irreversible tubulointerstitial damage associated with chronic aminonucleoside nephrosis. Amelioration by angiotensin I converting enzyme inhibition.

    PubMed Central

    Diamond, J. R.; Anderson, S.

    1990-01-01

    severity of tubulointerstitial morphologic abnormalities, as suggested by the beneficial effect of converting enzyme inhibition on both of these untoward processes. Images Figure 1 Figure 5 Figure 6 PMID:2260622

  2. Inhibiting monoacylglycerol acyltransferase 1 ameliorates hepatic metabolic abnormalities but not inflammation and injury in mice.

    PubMed

    Soufi, Nisreen; Hall, Angela M; Chen, Zhouji; Yoshino, Jun; Collier, Sara L; Mathews, James C; Brunt, Elizabeth M; Albert, Carolyn J; Graham, Mark J; Ford, David A; Finck, Brian N

    2014-10-24

    Abnormalities in hepatic lipid metabolism and insulin action are believed to play a critical role in the etiology of nonalcoholic steatohepatitis. Monoacylglycerol acyltransferase (MGAT) enzymes convert monoacylglycerol to diacylglycerol, which is the penultimate step in one pathway for triacylglycerol synthesis. Hepatic expression of Mogat1, which encodes an MGAT enzyme, is increased in the livers of mice with hepatic steatosis, and knocking down Mogat1 improves glucose metabolism and hepatic insulin signaling, but whether increased MGAT activity plays a role in the etiology of nonalcoholic steatohepatitis is unclear. To examine this issue, mice were placed on a diet containing high levels of trans fatty acids, fructose, and cholesterol (HTF-C diet) or a low fat control diet for 4 weeks. Mice were injected with antisense oligonucleotides (ASOs) to knockdown Mogat1 or a scrambled ASO control for 12 weeks while remaining on diet. The HTF-C diet caused glucose intolerance, hepatic steatosis, and induced hepatic gene expression markers of inflammation, macrophage infiltration, and stellate cell activation. Mogat1 ASO treatment, which suppressed Mogat1 expression in liver and adipose tissue, attenuated weight gain, improved glucose tolerance, improved hepatic insulin signaling, and decreased hepatic triacylglycerol content compared with control ASO-treated mice on HTF-C chow. However, Mogat1 ASO treatment did not reduce hepatic diacylglycerol, cholesterol, or free fatty acid content; improve histologic measures of liver injury; or reduce expression of markers of stellate cell activation, liver inflammation, and injury. In conclusion, inhibition of hepatic Mogat1 in HTF-C diet-fed mice improves hepatic metabolic abnormalities without attenuating liver inflammation and injury. PMID:25213859

  3. Inhibiting Monoacylglycerol Acyltransferase 1 Ameliorates Hepatic Metabolic Abnormalities but Not Inflammation and Injury in Mice*

    PubMed Central

    Soufi, Nisreen; Hall, Angela M.; Chen, Zhouji; Yoshino, Jun; Collier, Sara L.; Mathews, James C.; Brunt, Elizabeth M.; Albert, Carolyn J.; Graham, Mark J.; Ford, David A.; Finck, Brian N.

    2014-01-01

    Abnormalities in hepatic lipid metabolism and insulin action are believed to play a critical role in the etiology of nonalcoholic steatohepatitis. Monoacylglycerol acyltransferase (MGAT) enzymes convert monoacylglycerol to diacylglycerol, which is the penultimate step in one pathway for triacylglycerol synthesis. Hepatic expression of Mogat1, which encodes an MGAT enzyme, is increased in the livers of mice with hepatic steatosis, and knocking down Mogat1 improves glucose metabolism and hepatic insulin signaling, but whether increased MGAT activity plays a role in the etiology of nonalcoholic steatohepatitis is unclear. To examine this issue, mice were placed on a diet containing high levels of trans fatty acids, fructose, and cholesterol (HTF-C diet) or a low fat control diet for 4 weeks. Mice were injected with antisense oligonucleotides (ASOs) to knockdown Mogat1 or a scrambled ASO control for 12 weeks while remaining on diet. The HTF-C diet caused glucose intolerance, hepatic steatosis, and induced hepatic gene expression markers of inflammation, macrophage infiltration, and stellate cell activation. Mogat1 ASO treatment, which suppressed Mogat1 expression in liver and adipose tissue, attenuated weight gain, improved glucose tolerance, improved hepatic insulin signaling, and decreased hepatic triacylglycerol content compared with control ASO-treated mice on HTF-C chow. However, Mogat1 ASO treatment did not reduce hepatic diacylglycerol, cholesterol, or free fatty acid content; improve histologic measures of liver injury; or reduce expression of markers of stellate cell activation, liver inflammation, and injury. In conclusion, inhibition of hepatic Mogat1 in HTF-C diet-fed mice improves hepatic metabolic abnormalities without attenuating liver inflammation and injury. PMID:25213859

  4. Heme oxygenase/carbon monoxide pathway inhibition plays a role in ameliorating fibrosis following splenectomy.

    PubMed

    Wang, Qiu-Ming; Duan, Zhi-Jun; Du, Jian-Ling; Guo, Shi-Bin; Sun, Xiao-Yu; Liu, Zhen

    2013-05-01

    Splenectomy is a recognized therapy for liver cirrhosis with splenomegaly, since it decreases free iron concentration that accompanies the destruction of red blood cells. Heme oxygenase (HO)-1 and its by-products, iron and carbon monoxide (CO), play crucial roles in hepatic fibrosis. The aim of the present study was to determine whether splenectomy in cirrhotic rats induced by bile duct ligation (BDL), through the HO/CO pathway, could slow down the development of liver fibrosis. Male Sprague-Dawley rats were divided randomly into the sham, BDL, splenectomy, Fe, zinc protoporphyrin (Znpp) and cobalt protoporphyrin (Copp) treatment groups, for inhibiting and inducing HO-1 expression. The level of HO-1 was detected by western blot analysis and reverse transcription-polymerase chain reaction. Serum carboxyhemoglobin (COHb), iron and portal vein pressure (PVP) were also quantified. Liver iron was measured by atomic absorption spectrometry with acetylene-air flame atomization. HO-1 and α-smooth muscle actin (α-SMA) were localized by immunohistochemistry. Liver and spleen iron were visualized by Perls' Prussian blue staining. Hepatic fibrosis was assessed using hematoxylin and eosin (H&E) staining. Enzyme-linked immunosorbent assay (ELISA) was used to detect serum transforming growth factor-β1 (TGF-β1). The results showed that liver, spleen and serum levels of HO-1, COHb and iron were greatly enhanced in the BDL group compared with the sham group; they were reduced following splenectomy and Znpp treatment, but were elevated in the Copp and Fe groups. Hydroxyproline, TGF-β1, α-SMA, PVP and malonaldehyde levels were lower in the splenectomy and Znpp groups compared to BDL, while higher levels were observed in the Copp and Fe-treated groups. Our study shows that splenectomy reduces iron and CO levels in part by reducing HO-1 expression, and it decreases portal pressure and slightly decreases hepatic fibroproliferation. PMID:23525258

  5. Resveratrol ameliorates renal injury in spontaneously hypertensive rats by inhibiting renal micro-inflammation.

    PubMed

    Xue, Hai-Yan; Yuan, Li; Cao, Ying-Jie; Fan, Ya-Ping; Chen, Xiao-Lan; Huang, Xin-Zhong

    2016-07-01

    Micro-inflammation plays an important role in the pathogenesis of spontaneously hypertensive rat (SHR). In the present study, we investigated the therapeutic potential of resveratrol (RSV), a polyphenol with anti-fibrosis activity in hypertensive renal damage model. In SHR renal damage model, RSV treatment blunted the increase in urine albumin excretion, urinary β2-microglobulin (β2-MG), attenuated the decrease in creatinine clearance rate (CCR). The glomerular sclerosis index (1.54±0.33 compared with 0.36±0.07) and tubulointerstitial fibrosis (1.57±0.31 compared with 0.19±0.04) were significantly higher in SHRs compared with Wistar Kyoto rats (WKYs), which were significantly lower by RSV treatment. The increases in mesangium accumulation and the expression of renal collagen type I (Col I), fibronectin (Fn), plasminogen activator inhibitor-1 (PAI-1) and transforming growth factor-β1 (TGF-β1) in SHR were also reduced by RSV treatment. Nuclear factor κB (NF-κB) expression was increased in the cytoplasm and nuclei of the SHR kidneys, which was significantly decreased by RSV treatment. Furthermore, the protein level of IκB-α significantly decreased in the kidneys of the SHR when compared with the WKYs. RSV treatment partially restored the decreased IκB-α level. In SHR kidney, increased expression of interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein 1 (MCP-1) were observed. These changes were attenuated by RSV treatment. No changes in blood pressure were detected between SHR group and SHR + RSV group. Taken together, the present study demonstrated that RSV treatment may significantly attenuate renal damage in the SHR model of chronic kidney disease (CKD). The renal protective effect is associated with inhibition of IL-6, ICAM-1 and MCP-1 expression via the regulation of the nuclear translocation of NF-κB, which suggesting that micro-inflammation may be a potential therapeutic target of hypertensive

  6. Inhibiting Matrix Metalloproteinase 3 Ameliorates Neuronal Loss in the Ganglion Cell Layer of Rats in Retinal Ischemia/Reperfusion.

    PubMed

    Hu, Tu; You, Qiuting; Chen, Dan; Tong, Jianbin; Shang, Lei; Luo, Jia; Qiu, Yi; Yu, Huimin; Zeng, Leping; Huang, Jufang

    2016-05-01

    It has been demonstrated that matrix metalloproteinase 3 (MMP3) is integrally involved in the neuronal degeneration of the central nervous system by promoting glial activation, neuronal apoptosis and damage to the brain-blood barrier. However, whether MMP3 also contributes to the neuronal degeneration induced by retinal ischemia/reperfusion is still uncertain. In the present study, we detected the cellular localization of MMP3 in adult rat retinae and explored the relationship of its expression with neuronal loss in the ganglion cell layer (GCL) in retinal ischemia/reperfusion. We found that MMP3 was widely expressed in many cells throughout the layers of the rat retinae, including Vertebrate neuron-specific nuclear protein (NeuN)-, parvalbumin-, calbindin-, protein kinase C-α-, glial fibrillary acidic protein-, glutamine synthetase- and CD11b-positive cells. Furthermore, all rats were treated with high intraocular pressure (HIOP) for 1 h (h) and sacrificed at 6 h, 1 day (d), 3 d, and 7 d after HIOP. Compared to the normal control, the expression of both proenzyme MMP3 and active MMP3 were significantly up-regulated after HIOP treatment without alteration of the laminar distribution pattern. Moreover, inhibiting MMP3 ameliorated the loss of NeuN-positive cells in the GCL following HIOP. In summary, our data demonstrates that MMP3 is expressed in multiple types of neurons and glial cells in normal rat retinae. Simultaneously, the up-regulation of its expression and activity are closely involved in neuronal loss in the GCL in retinal ischemia/reperfusion. PMID:26830289

  7. Probucol inhibits LPS-induced microglia activation and ameliorates brain ischemic injury in normal and hyperlipidemic mice

    PubMed Central

    Jung, Yeon Suk; Park, Jung Hwa; Kim, Hyunha; Kim, So Young; Hwang, Ji Young; Hong, Ki Whan; Bae, Sun Sik; Choi, Byung Tae; Lee, Sae-Won; Shin, Hwa Kyoung

    2016-01-01

    Aim: Increasing evidence suggests that probucol, a lipid-lowering agent with anti-oxidant activities, may be useful for the treatment of ischemic stroke with hyperlipidemia via reduction in cholesterol and neuroinflammation. In this study we examined whether probucol could protect against brain ischemic injury via anti-neuroinflammatory action in normal and hyperlipidemic mice. Methods: Primary mouse microglia and murine BV2 microglia were exposed to lipopolysaccharide (LPS) for 3 h, and the release NO, PGE2, IL-1β and IL-6, as well as the changes in NF-κB, MAPK and AP-1 signaling pathways were assessed. ApoE KO mice were fed a high-fat diet containing 0.004%, 0.02%, 0.1% (wt/wt) probucol for 10 weeks, whereas normal C57BL/6J mice received probucol (3, 10, 30 mg·kg-1·d-1, po) for 4 d. Then all the mice were subjected to focal cerebral ischemia through middle cerebral artery occlusion (MCAO). The neurological deficits were scored 24 h after the surgery, and then brains were removed for measuring the cerebral infarct size and the production of pro-inflammatory mediators. Results: In LPS-treated BV2 cells and primary microglial cells, pretreatment with probucol (1, 5, 10 μmol/L) dose-dependently inhibited the release of NO, PGE2, IL-1β and IL-6, which occurred at the transcription levels. Furthermore, the inhibitory actions of probucol were associated with the downregulation of the NF-κB, MAPK and AP-1 signaling pathways. In the normal mice with MCAO, pre-administration of probucol dose-dependently decreased the infarct volume and improved neurological function. These effects were accompanied by the decreased production of pro-inflammatory mediators (iNOS, COX-2, IL-1, IL-6). In ApoE KO mice fed a high-fat diet, pre-administration of 0.1% probucol significantly reduced the infarct volume, improved the neurological deficits following MCAO, and decreased the total- and LDL-cholesterol levels. Conclusion: Probucol inhibits LPS-induced microglia activation and

  8. Vitamin D Can Ameliorate Chlorhexidine Gluconate-Induced Peritoneal Fibrosis and Functional Deterioration through the Inhibition of Epithelial-to-Mesenchymal Transition of Mesothelial Cells

    PubMed Central

    Lee, Yi-Che; Hung, Shih-Yuan; Liou, Hung-Hsiang; Lin, Tsun-Mei; Tsai, Chu-Hung; Lin, Sheng-Hsiang; Tsai, Yau-Sheng; Chang, Min-Yu; Wang, Hsi-Hao; Ho, Li-Chun; Chen, Yi-Ting; Wu, Ching-Fang; Chen, Ho-Ching; Chen, Hsin-Pao; Liu, Kuang-Wen; Chen, Chih-I.; She, Kuan Min; Wang, Hao-Kuang; Lin, Chi-Wei; Chiou, Yuan-Yow

    2015-01-01

    Background. Peritoneal dialysis (PD) can induce fibrosis and functional alterations in PD patients' peritoneal membranes, due to long-term unphysiological dialysate exposure, partially occurring via triggering of epithelial-to-mesenchymal transition (EMT) in peritoneal mesothelial cells (MCs). Vitamin D can ameliorate these negative effects; however, the mechanism remains unexplored. Therefore, we investigated its possible links to MCs EMT inhibition. Methods. Peritoneal fibrosis was established in Sprague-Dawley rats by chlorhexidine gluconate (CG) intraperitoneal injection for 21 days, with and without 1α,25(OH)2D3 treatment. Morphological and functional evaluation and western blot analysis of EMT marker were performed upon peritoneum tissue. In vitro study was also performed in a primary human peritoneal MC culture system; MCs were incubated with transforming growth factor-β1 (TGF-β1) in the absence or presence of 1α,25(OH)2D3. EMT marker expression, migration activities, and cytoskeleton redistribution of MCs were determined. Results. 1α,25(OH)2D3 ameliorated CG-induced morphological and functional deterioration in animal model, along with CG-induced upregulation of α-SMA and downregulation of E-cadherin expression. Meanwhile, 1α,25(OH)2D3 also ameliorated TGF-β1-induced decrease in E-cadherin expression, increase in Snai1 and α-SMA expression, intracellular F-actin redistribution, and migration activity in vitro. Conclusion. 1α,25(OH)2D3 can ameliorate CG-induced peritoneal fibrosis and attenuate functional deterioration through inhibiting MC EMT. PMID:26495304

  9. Pulse compression and prepulse suppression apparatus

    DOEpatents

    Dane, Clifford B.; Hackel, Lloyd A.; George, Edward V.; Miller, John L.; Krupke, William F.

    1993-01-01

    A pulse compression and prepulse suppression apparatus (10) for time compressing the output of a laser (14). A pump pulse (46) is separated from a seed pulse (48) by a first polarized beam splitter (20) according to the orientation of a half wave plate (18). The seed pulse (48) is directed into an SBS oscillator (44) by two plane mirrors (22, 26) and a corner mirror (24), the corner mirror (24) being movable to adjust timing. The pump pulse (46) is directed into an SBS amplifier 34 wherein SBS occurs. The seed pulse (48), having been propagated from the SBS oscillator (44), is then directed through the SBS amplifier (34) wherein it sweeps the energy of the pump pulse (46) out of the SBS amplifier (34) and is simultaneously compressed, and the time compressed pump pulse (46) is emitted as a pulse output (52). A second polarized beam splitter (38) directs any undepleted pump pulse 58 away from the SBS oscillator (44).

  10. Pulse compression and prepulse suppression apparatus

    DOEpatents

    Dane, C.B.; Hackel, L.A.; George, E.V.; Miller, J.L.; Krupke, W.F.

    1993-11-09

    A pulse compression and prepulse suppression apparatus (10) for time compressing the output of a laser (14). A pump pulse (46) is separated from a seed pulse (48) by a first polarized beam splitter (20) according to the orientation of a half wave plate (18). The seed pulse (48) is directed into an SBS oscillator (44) by two plane mirrors (22, 26) and a corner mirror (24), the corner mirror (24) being movable to adjust timing. The pump pulse (46) is directed into an SBS amplifier 34 wherein SBS occurs. The seed pulse (48), having been propagated from the SBS oscillator (44), is then directed through the SBS amplifier (34) wherein it sweeps the energy of the pump pulse (46) out of the SBS amplifier (34) and is simultaneously compressed, and the time compressed pump pulse (46) is emitted as a pulse output (52). A second polarized beam splitter (38) directs any undepleted pump pulse 58 away from the SBS oscillator (44).

  11. Astilbin inhibits Th17 cell differentiation and ameliorates imiquimod-induced psoriasis-like skin lesions in BALB/c mice via Jak3/Stat3 signaling pathway.

    PubMed

    Di, Ting-Ting; Ruan, Zhi-Tong; Zhao, Jing-Xia; Wang, Yan; Liu, Xin; Wang, Ying; Li, Ping

    2016-03-01

    The flavonoid astilbin is the major active component extracted from the rhizome of Smilax glabra, which has been widely used in China to treat inflammatory and autoimmune diseases, Psoriasis is a common chronic inflammatory disease in which T helper 17 (Th17) cells play an important role, provoking inflammation. We employed an imiquimod (IMQ)-induced psoriasis-like mouse model to investigate the effect of astilbin in inflammation. Mice were administered 25 to 50mg/kg astilbin. Inflammation of psoriasis-like lesions was assessed by histology, circulating levels of T cells were assessed by flow cytometry and cytokines by bead-based immunoassay. Jak/Stat3 in isolated T cells was assessed by Western blotting and RORγt expression was assessed by RT-PCR. Administration of astilbin ameliorated IMQ-induced keratinocyte proliferation, infiltration of CD3+ cells to psoriatic lesions and ameliorated elevations in circulating CD4+ and CD8+ T cells and inflammatory cytokines (IL-17A, TNF-α, IL-6, IFN-γ and IL-2). In vitro, astilbin inhibited Th17 cell differentiation and IL-17 secretion of isolated T cells, and inhibited Jak/Stat3 signaling in Th17 cells, while up-regulating Stat3 inhibitor SCOSE3 expression in psoriatic lesions. Thus, astilbin likely alleviates psoriasis-like skin lesions by inhibiting Th17 related inflammation. Astilbin represents as an interesting candidate drug for immunoregulation of psoriasis. PMID:26784569

  12. Rescue of GABAB and GIRK function in the lateral habenula by protein phosphatase 2A inhibition ameliorates depression-like phenotypes in mice.

    PubMed

    Lecca, Salvatore; Pelosi, Assunta; Tchenio, Anna; Moutkine, Imane; Lujan, Rafael; Hervé, Denis; Mameli, Manuel

    2016-03-01

    The lateral habenula (LHb) encodes aversive signals, and its aberrant activity contributes to depression-like symptoms. However, a limited understanding of the cellular mechanisms underlying LHb hyperactivity has precluded the development of pharmacological strategies to ameliorate depression-like phenotypes. Here we report that an aversive experience in mice, such as foot-shock exposure (FsE), induces LHb neuronal hyperactivity and depression-like symptoms. This occurs along with increased protein phosphatase 2A (PP2A) activity, a known regulator of GABAB receptor (GABABR) and G protein-gated inwardly rectifying potassium (GIRK) channel surface expression. Accordingly, FsE triggers GABAB1 and GIRK2 internalization, leading to rapid and persistent weakening of GABAB-activated GIRK-mediated (GABAB-GIRK) currents. Pharmacological inhibition of PP2A restores both GABAB-GIRK function and neuronal excitability. As a consequence, PP2A inhibition ameliorates depression-like symptoms after FsE and in a learned-helplessness model of depression. Thus, GABAB-GIRK plasticity in the LHb represents a cellular substrate for aversive experience. Furthermore, its reversal by PP2A inhibition may provide a novel therapeutic approach to alleviate symptoms of depression in disorders that are characterized by LHb hyperactivity. PMID:26808347

  13. Space radiation-induced inhibition of neurogenesis in the hippocampal dentate gyrus and memory impairment in mice: ameliorative potential of the melatonin metabolite, AFMK.

    PubMed

    Manda, Kailash; Ueno, Megumi; Anzai, Kazunori

    2008-11-01

    Evaluation of potential health effects from high energy charged particle radiation exposure during long duration space travel is important for the future of manned missions. Cognitive health of an organism is considered to be maintained by the capacity of hippocampal precursors to proliferate and differentiate. Environmental stressors including irradiation have been shown to inhibit neurogenesis and are associated with the onset of cognitive impairments. The present study reports on the protective effects of N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (AFMK), a melatonin metabolite, against high energy charged particle radiation-induced oxidative damage to the brain. We observed that radiation exposure (2.0 Gy of 500 MeV/nucleon (56)Fe beams, a ground-based model of space radiation) impaired the spatial memory of mice at later intervals without affecting the motor activities. AFMK pretreatment significantly ameliorated these neurobehavioral ailments. Radiation-induced changes in the population of immature and proliferating neurons in the dentate gyrus were localized using anti-doublecortin (Dcx) and anti-Ki-67 expression. AFMK pretreatment significantly inhibited the loss of Dcx and Ki-67 positive cells. Moreover, AFMK pretreatment ameliorated the radiation-induced augmentation of protein carbonyls and 4-hydroxyalkenal + malondialdehyde (MDA + HAE) in the brain and maintained the total antioxidant capacity of plasma and nonprotein sulfhydryl contents in brain. PMID:18631288

  14. Oridonin ameliorates lupus-like symptoms of MRL(lpr/lpr) mice by inhibition of B-cell activating factor (BAFF).

    PubMed

    Zhou, Lin; Sun, Lijuan; Wu, Hongkun; Zhang, Lingzhen; Chen, Mingcang; Liu, Jianwen; Zhong, Renqian

    2013-09-01

    Oridonin, a pharmacologically safe agent extracted from Isodon Serra, has been shown to possess potent anti-inflammatory properties. However, it is not clear whether Oridonin affects B-cell activating factor (BAFF) expression, thereby exerting beneficial effects in the treatment of BAFF-associated autoimmune diseases such as systemic lupus erythematosus (SLE). Thus, the current study aimed to find the function of Oridonin in regulation of BAFF and amelioration of SLE. In vitro, we explored the effect of Oridonin on BAFF expression and production in mouse macrophages. Moreover, using a spontaneous murine SLE model, we investigated the role of Oridonin delivery in the treatment of lupus-like disease in MRL(lpr/lpr) mice, by measuring the changes in lupus symptoms, renal damage, BAFF expression, and B cell subsets. Our results showed that Oridonin significantly inhibited BAFF expression in mouse macrophages by suppressing the transcriptional activation of its promoter. And in vivo administration of Oridonin efficiently ameliorated the serological and clinical manifestations of SLE in MRL(lpr/lpr) mice, as shown by increased survival benefit, reduced proteinuria levels, diminished production of specific auto-antibodies, and attenuated renal damage, in association with down-regulation of BAFF and a lower rate of B-cell maturation and differentiation. Thus, it suggests that Oridonin will serve as a novel natural therapeutic strategy for SLE by inhibition of BAFF. PMID:23712004

  15. Upregulation of miR-21 by Ghrelin Ameliorates Ischemia/Reperfusion-Induced Acute Kidney Injury by Inhibiting Inflammation and Cell Apoptosis.

    PubMed

    Zhang, Wanzhe; Shu, Liliang

    2016-08-01

    Renal ischemia-reperfusion (I/R) injury can be caused by cardiac surgery, renal vascular obstruction, and kidney transplantation, mainly leading to acute kidney injury (AKI), which is complicated by lack of effective preventative and therapeutic strategies. Ghrelin has recently been reported to possess anti-inflammatory properties in several types of cells; however, little attention has been given to the role of ghrelin in I/R-induced AKI. The aim of this study is to explore the role of ghrelin in I/R-induced AKI. In this study, an I/R-induced rat AKI model and a hypoxia-induced NRK-52E cell I/R model were successfully constructed. Ghrelin expression was increased significantly in these rat and cell models. After enhancing ghrelin level by injecting exogenous ghrelin into rats or transfecting a ghrelin-pcDNA3.1 vector into renal tubular epithelial cells, we observed that I/R-induced AKI can be ameliorated by ghrelin, as shown by alterations in histology, as well as changes in serum creatinine (SCr) level, cell apoptosis, and the levels of inflammatory factors. Based on the importance of microRNA-21 (miR-21) in renal disease and the modulation effect of ghrelin on miR-21 in gastric epithelial cells, we tested whether miR-21 participates in the protective effect of ghrelin on I/R-induced AKI. Ghrelin could upregulate the PI3K/AKT signaling pathway by increasing the miR-21 level, which led to the protective effect of ghrelin on I/R-induced AKI by inhibiting the inflammatory response and renal tubular epithelial cell apoptosis. Our research identifies that ghrelin can ameliorate I/R-induced AKI by upregulating miR-21, which advances the understanding of mechanisms by which ghrelin ameliorates I/R-induced AKI. PMID:27152763

  16. Inhibiting effects of rhynchophylline on zebrafish methamphetamine dependence are associated with amelioration of neurotransmitters content and down-regulation of TH and NR2B expression.

    PubMed

    Jiang, Mingjin; Chen, Yifei; Li, Chan; Peng, Qiuxian; Fang, Miao; Liu, Wei; Kang, Qunzhao; Lin, Yingbo; Yung, Ken Kin Lam; Mo, Zhixian

    2016-07-01

    Others and we have reported that rhynchophylline reverses amphetamine-induced conditioned place preference (CPP) effect which may be partly mediated by amelioration of central neurotransmitters and N-methyl-d-aspartate receptor 2B (NR2B) levels in the rat brains. The current study investigated the inhibiting effects of rhynchophylline on methamphetamine-induced (METH-induced) CPP in adult zebrafish and METH-induced locomotor activity in tyrosine hydroxylase-green fluorescent protein (TH-GFP) transgenic zebrafish larvae and attempted to confirm the hypothesis that these effects were mediated via regulation of neurotransmitters and dopaminergic and glutamatergic systems. After baseline preference test (on days 1-3), zebrafish were injected intraperitoneally METH (on days 4, 6 and 8) or the same volume of fish physiological saline (on days 5 and 7) and were immediately conditioned. Rhynchophylline was administered at 12h after injection of METH. On day 9, zebrafish were tested for METH-induced CPP. Results revealed that rhynchophylline (100mg/kg) significantly inhibited the acquisition of METH-induced CPP, reduced the content of dopamine and glutamate and down-regulated the expression of TH and NR2B in the CPP zebrafish brains. Furthermore, the influence of rhynchophylline on METH-induced locomotor activity was also observed in TH-GFP transgenic zebrafish larvae. Results showed that rhynchophylline (50mg/L) treatment led to a significant reduction on the locomotor activity and TH expression in TH-GFP transgenic zebrafish larvae. Taken together, these data indicate that the inhibition of the formation of METH dependence by rhynchophylline in zebrafish is associated with amelioration of the neurotransmitters dopamine and glutamate content and down-regulation of TH and NR2B expression. PMID:27009763

  17. Arctigenin ameliorates inflammation in vitro and in vivo by inhibiting the PI3K/AKT pathway and polarizing M1 macrophages to M2-like macrophages.

    PubMed

    Hyam, Supriya R; Lee, In-Ah; Gu, Wan; Kim, Kyung-Ah; Jeong, Jin-Ju; Jang, Se-Eun; Han, Myung Joo; Kim, Dong-Hyun

    2013-05-15

    Seeds of Arctium lappa, containing arctigenin and its glycoside arctiin as main constituents, have been used as a diuretic, anti-inflammatory and detoxifying agent in Chinese traditional medicine. In our preliminary study, arctigenin inhibited IKKβ and NF-κB activation in peptidoglycan (PGN)- or lipopolysaccharide (LPS)-induced peritoneal macrophages. To understand the anti-inflammatory effect of arctigenin, we investigated its anti-inflammatory effect in LPS-stimulated peritoneal macrophages and on LPS-induced systemic inflammation as well as 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice. Arctigenin inhibited LPS-increased IL-1β, IL-6 and TNF-α expression in LPS-stimulated peritoneal macrophages, but increased LPS-reduced IL-10 and CD204 expression. Arctigenin inhibited LPS-induced PI3K, AKT and IKKβ phosphorylation, but did not suppress LPS-induced IRAK-1 phosphorylation. However, arctigenin did not inhibit NF-κB activation in LPS-stimulated PI3K siRNA-treated peritoneal macrophages. Arctigenin suppressed the binding of p-PI3K antibody and the nucleus translocation of NF-κB p65 in LPS-stimulated peritoneal macrophages. Arctigenin suppressed blood IL-1β and TNF-α level in mice systemically inflamed by intraperitoneal injection of LPS. Arctigenin also inhibited colon shortening, macroscopic scores and myeloperoxidase activity in TNBS-induced colitic mice. Arctigenin inhibited TNBS-induced IL-1β, TNF-α and IL-6 expression, as well as PI3K, AKT and IKKβ phosphorylation and NF-κB activation in mice, but increased IL-10 and CD204 expression. However, it did not affect IRAK-1 phosphorylation. Based on these findings, arctigenin may ameliorate inflammatory diseases, such as colitis, by inhibiting PI3K and polarizing M1 macrophages to M2-like macrophages. PMID:23375938

  18. Inhibition of p38 mitogen-activated protein kinase ameliorates radiation-induced ototoxicity in zebrafish and cochlea-derived cell lines.

    PubMed

    Shin, Yoo Seob; Hwang, Hye Sook; Kang, Sung Un; Chang, Jae Won; Oh, Young-Taek; Kim, Chul-Ho

    2014-01-01

    Radiation is a widely used treatment for head and neck cancers, and one of its most severe side effects is ototoxicity. Radiation-induced ototoxicity has been demonstrated to be linked to the increased production of ROS and MAPK. We intended to investigate the effect of p38 inhibition on radiation-induced ototoxicity in cochlea-derived HEI-OC1 cells and in a zebrafish model. The otoprotective effect of p38 inhibition against radiation was tested in vitro in the organ of Corti-derived cell line, HEI-OC1, and in vivo in a zebrafish model. Radiation-induced apoptosis, mitochondrial dysfunction, and an increase of intracellular NO generation were demonstrated in HEI-OC1 cells. The p38-specific inhibitor, SB203580, ameliorated radiation-induced apoptosis and mitochondrial injury in HEI-OC1 cells. p38 inhibition reduced radiation-induced activation of JNK, p38, cytochrome c, and cleavage of caspase-3 and PARP in HEI-OC1 cells. Scanning electron micrography showed that SB203580 prevented radiation-induced destruction of kinocilium and stereocilia in zebrafish neuromasts. The results of this study suggest that p38 plays an important role in mediating radiation-induced ototoxicity and inhibition of p38 could be a plausible option for preventing radiation ototoxicity. PMID:24374476

  19. Extracellular superoxide dismutase ameliorates house dust mite-induced atopic dermatitis-like skin inflammation and inhibits mast cell activation in mice.

    PubMed

    Lee, Yun Sang; Choi, Jung-Hye; Lee, Ji-Hyun; Lee, Han-Woong; Lee, Weontae; Kim, Woo Taek; Kim, Tae-Yoon

    2016-08-01

    Extracellular superoxide dismutase (EC-SOD) is an enzyme that catalyses the dismutation of superoxide anions. It has multiple functions, such as reactive oxygen species scavenging, anti-angiogenic, anti-inflammatory, antichemotatic and antitumor activities. Recently, we demonstrated that EC-SOD inhibits ovalbumin-induced allergic airway inflammation in mice. However, the anti-allergic effect of EC-SOD on skin tissue and the role of EC-SOD in mast cells, which are important for allergic responses, have not been well studied. In this study, we investigated whether EC-SOD can alleviate atopic dermatitis in mice and inhibit mast cell activation. Treatment with human recombinant EC-SOD ameliorated house dust mite-induced atopic dermatitis in mice. Furthermore, the levels of pro-allergic cytokine gene expression and histamine release increased in EC-SOD KO mast cells and decreased in EC-SOD overexpressing mast cells, suggesting that EC-SOD inhibits mast cell activation. Consistently, a passive cutaneous anaphylaxis experiment showed more blood leakage from EC-SOD KO mouse ear skin, implying that the lack of EC-SOD increases allergic responses. These results suggest that EC-SOD inhibits mast cell activation and atopic dermatitis and that the loss of EC-SOD causes more severe allergic responses, implying that EC-SOD might be a good drug candidate for treatment of allergic disorders, such as atopic dermatitis. PMID:27061078

  20. Mangiferin treatment inhibits hepatic expression of acyl-coenzyme A:diacylglycerol acyltransferase-2 in fructose-fed spontaneously hypertensive rats: a link to amelioration of fatty liver

    SciTech Connect

    Xing, Xiaomang; Li, Danyang; Chen, Dilong; Zhou, Liang; Chonan, Ritsu; Yamahara, Johji; Wang, Jianwei; Li, Yuhao

    2014-10-15

    Mangiferin, a xanthone glucoside, and its associated traditional herbs have been demonstrated to improve abnormalities of lipid metabolism. However, its underlying mechanisms remain largely unclear. This study investigated the anti-steatotic effect of mangiferin in fructose-fed spontaneously hypertensive rat (SHR)s that have a mutation in sterol regulatory element binding protein (SREBP)-1. The results showed that co-administration of mangiferin (15 mg/kg, once daily, by oral gavage) over 7 weeks dramatically diminished fructose-induced increases in hepatic triglyceride content and Oil Red O-stained area in SHRs. However, blood pressure, fructose and chow intakes, white adipose tissue weight and metabolic parameters (plasma concentrations of glucose, insulin, triglyceride, total cholesterol and non-esterified fatty acids) were unaffected by mangiferin treatment. Mechanistically, mangiferin treatment suppressed acyl-coenzyme A:diacylglycerol acyltransferase (DGAT)-2 expression at the mRNA and protein levels in the liver. In contrast, mangiferin treatment was without effect on hepatic mRNA and/or protein expression of SREBP-1/1c, carbohydrate response element binding protein, liver pyruvate kinase, fatty acid synthase, acetyl-CoA carboxylase-1, stearoyl-CoA desaturase-1, DGAT-1, monoacyglycerol acyltransferase-2, microsomal triglyceride transfer protein, peroxisome proliferator-activated receptor-alpha, carnitine palmitoyltransferase-1 and acyl-CoA oxidase. Collectively, our results suggest that mangiferin treatment ameliorates fatty liver in fructose-fed SHRs by inhibiting hepatic DGAT-2 that catalyzes the final step in triglyceride biosynthesis. The anti-steatotic effect of mangiferin may occur independently of the hepatic signals associated with de novo fatty acid synthesis and oxidation. - Highlights: • We investigated the anti-steatotic effect of mangiferin (MA) in fructose-fed SHR. • MA (15 mg/kg/day for 7 weeks) ameliorated fructose-induced fatty liver in

  1. Curcumin Ameliorates Furazolidone-Induced DNA Damage and Apoptosis in Human Hepatocyte L02 Cells by Inhibiting ROS Production and Mitochondrial Pathway.

    PubMed

    Dai, Chongshan; Li, Daowen; Gong, Lijing; Xiao, Xilong; Tang, Shusheng

    2016-01-01

    Furazolidone (FZD), a synthetic nitrofuran derivative, has been widely used as an antibacterial and antiprotozoal agent. Recently, the potential toxicity of FZD has raised concerns, but its mechanism is still unclear. This study aimed to investigate the protective effect of curcumin on FZD-induced cytotoxicity and the underlying mechanism in human hepatocyte L02 cells. The results showed that curcumin pre-treatment significantly ameliorated FZD-induced oxidative stress, characterized by decreased reactive oxygen species (ROS) and malondialdehyde formation, and increased superoxide dismutase, catalase activities and glutathione contents. In addition, curcumin pre-treatment significantly ameliorated the loss of mitochondrial membrane potential, the activations of caspase-9 and -3, and apoptosis caused by FZD. Alkaline comet assay showed that curcumin markedly reduced FZD-induced DNA damage in a dose-dependent manner. Curcumin pre-treatment consistently and markedly down-regulated the mRNA expression levels of p53, Bax, caspase-9 and -3 and up-regulated the mRNA expression level of Bcl-2. Taken together, these results reveal that curcumin protects against FZD-induced DNA damage and apoptosis by inhibiting oxidative stress and mitochondrial pathway. Our study indicated that curcumin may be a promising combiner with FZD to reduce FZD-related toxicity in clinical applications. PMID:27556439

  2. Tellurium compound AS101 ameliorates experimental autoimmune encephalomyelitis by VLA-4 inhibition and suppression of monocyte and T cell infiltration into the CNS.

    PubMed

    Lee, Jun-Ho; Halperin-Sheinfeld, Meital; Baatar, Dolgar; Mughal, Mohamed R; Tae, Hyun-Jin; Kim, Jie-Wan; Carter, Arnell; Lustig, Ana; Snir, Omri; Lavie, Gad; Okun, Eitan; Mattson, Mark P; Sredni, Benjamin; Taub, Dennis D

    2014-06-01

    Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system (CNS) involving demyelinating and neurodegenerative processes. Several of the major pathological CNS alterations and behavioral deficits of MS are recapitulated in the experimental autoimmune encephalitis (EAE) mouse model in which the disease process is induced by administration of myelin peptides. Development of EAE requires infiltration of inflammatory cytokine-generating monocytes and macrophages, and auto-reactive T cells, into the CNS. Very late antigen-4 (VLA-4, α4β1) is an integrin molecule that plays a role in inflammatory responses by facilitating the migration of leukocytes across the blood-brain barrier during inflammatory disease, and antibodies against VLA-4 exhibit therapeutic efficacy in mouse and monkey MS models. Here, we report that the tellurium compound AS101 (ammonium trichloro (dioxoethylene-o,o') tellurate) ameliorates EAE by inhibiting monocyte and T cell infiltration into the CNS. CD49d is an alpha subunit of the VLA-4 (α4β1) integrin. During the peak stage of EAE, AS101 treatment effectively ameliorated the disease process by reducing the number of CD49d(+) inflammatory monocyte/macrophage cells in the spinal cord. AS101 treatment markedly reduced the pro-inflammatory cytokine levels, while increasing anti-inflammatory cytokine levels. In contrast, AS101 treatment did not affect the peripheral populations of CD11b(+) monocytes and macrophages. AS101 treatment reduced the infiltration of CD4(+) and CD49(+)/VLA4 T cells. In addition, treatment of T cells from MS patients with AS101 resulted in apoptosis, while such treatment did not affect T cells from healthy donors. These results suggest that AS101 reduces accumulation of leukocytes in the CNS by inhibiting the activity of the VLA-4 integrin and provide a rationale for the potential use of Tellurium IV compounds for the treatment of MS. PMID:24272426

  3. Inhibition in the Human Auditory Cortex

    PubMed Central

    Inui, Koji; Nakagawa, Kei; Nishihara, Makoto; Motomura, Eishi; Kakigi, Ryusuke

    2016-01-01

    Despite their indispensable roles in sensory processing, little is known about inhibitory interneurons in humans. Inhibitory postsynaptic potentials cannot be recorded non-invasively, at least in a pure form, in humans. We herein sought to clarify whether prepulse inhibition (PPI) in the auditory cortex reflected inhibition via interneurons using magnetoencephalography. An abrupt increase in sound pressure by 10 dB in a continuous sound was used to evoke the test response, and PPI was observed by inserting a weak (5 dB increase for 1 ms) prepulse. The time course of the inhibition evaluated by prepulses presented at 10–800 ms before the test stimulus showed at least two temporally distinct inhibitions peaking at approximately 20–60 and 600 ms that presumably reflected IPSPs by fast spiking, parvalbumin-positive cells and somatostatin-positive, Martinotti cells, respectively. In another experiment, we confirmed that the degree of the inhibition depended on the strength of the prepulse, but not on the amplitude of the prepulse-evoked cortical response, indicating that the prepulse-evoked excitatory response and prepulse-evoked inhibition reflected activation in two different pathways. Although many diseases such as schizophrenia may involve deficits in the inhibitory system, we do not have appropriate methods to evaluate them; therefore, the easy and non-invasive method described herein may be clinically useful. PMID:27219470

  4. Extreme prepulse contrast utilizing cascaded-optical parametric amplification

    SciTech Connect

    Jovanovic, I; Haefner, C; Wattellier, B; Barty, C J

    2006-06-15

    It has been shown recently that an optical parametric chirped-pulse amplifier can be easily reconfigured into a cascaded-optical parametric amplifier (COPA), enabling complete prepulse removal and optical switching with a window defined by the pump pulse duration. We have demonstrated instrument-limited measurement of the COPA prepulse contrast >1.4 x 10{sup 11} using 30-mJ pulses. The COPA technique is applicable to all energy ranges and pulse durations. A convenient millijoule-scale implementation of this technique is presented using a single, large-aspect-ratio quasi-phase-matched nonlinear crystal.

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

    SciTech Connect

    MadanKumar, Perumal; NaveenKumar, Perumal; Manikandan, Samidurai; Devaraj, Halagowder; NiranjaliDevaraj, Sivasithamparam

    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. Soluble epoxide hydrolase inhibition ameliorates proteinuria-induced epithelial-mesenchymal transition by regulating the PI3K-Akt-GSK-3β signaling pathway.

    PubMed

    Liang, Yaoxian; Jing, Ziyang; Deng, Hui; Li, Zhengqian; Zhuang, Zhen; Wang, Song; Wang, Yue

    Soluble epoxide hydrolase (sEH) plays an essential role in chronic kidney disease by hydrolyzing renoprotective epoxyeicosatrienoic acids to the corresponding inactive dihydroxyeicosatrienoic acids. However, there have been few mechanistic studies elucidating the role of sEH in epithelial-mesenchymal transition (EMT). The present study investigated, in vitro and in vivo, the role of sEH in proteinuria-induced renal tubular EMT and the underlying signaling pathway. We report that urinary protein (UP) induced EMT in cultured NRK-52E cells, as evidenced by decreased E-cadherin expression, increased alpha-smooth muscle actin (α-SMA) expression, and the morphological conversion to a myofibroblast-like phenotype. UP incubation also resulted in upregulated sEH, activated phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB/Akt) signaling and increased phosphorylated glycogen synthase kinase-3β (GSK-3β). The PI3K inhibitor LY-294002 inhibited phosphorylation of Akt and GSK-3β as well as blocking EMT. Importantly, pharmacological inhibition of sEH with 12-(3-adamantan-1-yl- ureido)-dodecanoic acid (AUDA) markedly suppressed PI3K-Akt activation and GSK-3β phosphorylation. EMT associated E-cadherin suppression, α-SMA elevation and phenotypic transition were also attenuated by AUDA. Furthermore, in rats with chronic proteinuric renal disease, AUDA treatment inhibited PI3K-Akt activation and GSK-3β phosphorylation, while attenuating levels of EMT markers. Overall, our findings suggest that sEH inhibition ameliorates proteinuria-induced renal tubular EMT by regulating the PI3K-Akt-GSK-3β signaling pathway. Targeting sEH might be a potential strategy for the treatment of EMT and renal fibrosis. PMID:25986738

  7. ω-3 PUFAs ameliorate liver fibrosis and inhibit hepatic stellate cells proliferation and activation by promoting YAP/TAZ degradation

    PubMed Central

    Zhang, Kun; Chang, Yanan; Shi, Zhemin; Han, Xiaohui; Han, Yawei; Yao, Qingbin; Hu, Zhimei; Cui, Hongmei; Zheng, Lina; Han, Tao; Hong, Wei

    2016-01-01

    Elevated levels of the transcriptional regulators Yes-associated protein (YAP) and transcriptional coactivators with PDZ-binding motif (TAZ), key effectors of the Hippo pathway, have been shown to play essential roles in controlling liver cell fate and the activation of hepatic stellate cells (HSCs). The dietary intake of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) has been positively associated with a number of health benefits including prevention and reduction of cardiovascular diseases, inflammation and cancers. However, little is known about the impact of ω-3 PUFAs on liver fibrosis. In this study, we used CCl4-induced liver fibrosis mouse model and found that YAP/TAZ is over-expressed in the fibrotic liver and activated HSCs. Fish oil administration to the model mouse attenuates CCl4-induced liver fibrosis. Further study revealed that ω-3 PUFAs down-regulate the expression of pro-fibrogenic genes in activated HSCs and fibrotic liver, and the down-regulation is mediated via YAP, thus identifying YAP as a target of ω-3 PUFAs. Moreover, ω-3 PUFAs promote YAP/TAZ degradation in a proteasome-dependent manner. Our data have identified a mechanism of ω-3 PUFAs in ameliorating liver fibrosis. PMID:27435808

  8. Lateral ventricle injection of orexin-A ameliorates central precocious puberty in rat via inhibiting the expression of MEG3

    PubMed Central

    Tao, Yue-Hong; Sharif, Nazir; Zeng, Bi-He; Cai, Yan-Yan; Guo, Yu-Xiu

    2015-01-01

    Background: Central precocious puberty (CPP) is characterized as increasing gonadotropin-releasing hormone (GnRH) release. Orexin-A has also been shown to affect GnRH release. However, there are few reports about the effect of orexin A on the treatment of CPP. Methods: After establishing the precocious puberty model, the rats were divided into four groups: normal control, precocious puberty rats, precocious puberty rats treated with normal saline and precocious puberty rats treated with orexin-A. The vaginal opening time, second estrus cycle, ovarian index and uterus index of rats in each group were detected. qRT-PCR was performed to examine the expression of MEG3 and kisspeptin in rats. HT22 cells were transfected with pcDNA-MEG3 to detect the expression of Kisspeptin. Results: In this study, we found that orexin-A not only delayed the day of vaginal opening and regular estrus cycle days but also decreased the ovarian index and uterus index in rats with CPP. In addition, orexin-A reversed the up-regulation of MEG3 and kisspeptin in rats with CPP. In HT22 cells, the mRNA and protein level of kisspeptin were enhanced by pcDNA-MEG3. Conclusion: Our results suggest that orexin-A ameliorates central precocious puberty in rat and MEG3 might be involved in this effect, suggesting that MEG3 might be a novel target in treating central precocious puberty. PMID:26722445

  9. ω-3 PUFAs ameliorate liver fibrosis and inhibit hepatic stellate cells proliferation and activation by promoting YAP/TAZ degradation.

    PubMed

    Zhang, Kun; Chang, Yanan; Shi, Zhemin; Han, Xiaohui; Han, Yawei; Yao, Qingbin; Hu, Zhimei; Cui, Hongmei; Zheng, Lina; Han, Tao; Hong, Wei

    2016-01-01

    Elevated levels of the transcriptional regulators Yes-associated protein (YAP) and transcriptional coactivators with PDZ-binding motif (TAZ), key effectors of the Hippo pathway, have been shown to play essential roles in controlling liver cell fate and the activation of hepatic stellate cells (HSCs). The dietary intake of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) has been positively associated with a number of health benefits including prevention and reduction of cardiovascular diseases, inflammation and cancers. However, little is known about the impact of ω-3 PUFAs on liver fibrosis. In this study, we used CCl4-induced liver fibrosis mouse model and found that YAP/TAZ is over-expressed in the fibrotic liver and activated HSCs. Fish oil administration to the model mouse attenuates CCl4-induced liver fibrosis. Further study revealed that ω-3 PUFAs down-regulate the expression of pro-fibrogenic genes in activated HSCs and fibrotic liver, and the down-regulation is mediated via YAP, thus identifying YAP as a target of ω-3 PUFAs. Moreover, ω-3 PUFAs promote YAP/TAZ degradation in a proteasome-dependent manner. Our data have identified a mechanism of ω-3 PUFAs in ameliorating liver fibrosis. PMID:27435808

  10. A natural flavonoid glucoside icariin inhibits Th1 and Th17 cell differentiation and ameliorates experimental autoimmune encephalomyelitis.

    PubMed

    Shen, Ruile; Deng, Wenjing; Li, Chun; Zeng, Guangwei

    2015-02-01

    Multiple sclerosis (MS) is an autoimmune disease that is characterized by recurrent episodes of T cell-mediated immune attack on central nervous system (CNS) myelin, leading to axon damage and progressive disability. Icariin, a natural flavonoid glucoside isolated from plants in the Epimedium family, has been proved to have various pharmacological activities. However, the effect of icariin on experimental autoimmune encephalomyelitis (EAE) has never been investigated. In our current study, we found that icariin treatment leads to alleviated inflammatory infiltration and reduced blood-brain barrier leakage (BBB) of the paracellular tracer (FITC-dextran) in EAE. Mice that received icariin-treated T cells also displayed lower EAE scores and better clinical recovery from EAE. Icariin administration suppresses the frequencies of Th1 and Th17 cells in the splenocytes and lymph node cells. Icariin-treated mice also show lower frequency of Th17 cells in CNS mononuclear cells. The effect of icariin on Th1 and Th17 cell differentiation may be mediated via modulation of dendritic cells (DCs). Furthermore, icariin suppresses the proliferation of T cells and the differentiation of Th1 and Th17 cells in vitro. In conclusion, icariin ameliorates EAE and this was associated with suppressed Th1 and Th17 cell differentiation. PMID:25528476

  11. Concerted actions of ameliorated colitis, aberrant crypt foci inhibition and 15-hydroxyprostaglandin dehydrogenase induction by sonic hedgehog inhibitor led to prevention of colitis-associated cancer.

    PubMed

    Kangwan, Napapan; Kim, Yoon-Jae; Han, Young-Min; Jeong, Migyeong; Park, Jong-Min; Hahm, Ki-Baik

    2016-03-15

    The sonic hedgehog (Shh) signaling has been known to contribute to carcinogenesis in organ, where hedgehog exerted organogenesis and in cancers, which are developed based on mutagenic inflammation. Therefore, colitis-associated cancer (CAC) can be a good model to prove whether Shh inhibitors can be applied to prevent, as the efforts to discover potent anti-inflammatory agent are active to prevent CAC. Here, under the hypothesis that Shh inhibitors can prevent CAC, mouse model was generated to develop CAC by azoxymethane (AOM)-initiated, dextran sodium sulfate-promoted carcinogenesis. Shh inhibitors, cerulenin and itraconazole were treated by oral gavage and the mice were sacrificed at early phase of 3 weeks and late phase of 16 weeks. Compared to control group, the number of aberrant crypt foci at 3 weeks and tumor incidence at 16 weeks were all significantly decreased with Shh inhibitor. Significant attenuations of macrophage infiltration accompanied with significant decreases of IL-6, COX-2, STAT3 and NF-κB as well as significant ameliorations of β-catenin nuclear translocation, cyclin D1 and CDK4 were imposed with Shh inhibitors. Especially, CAC was accompanied with significant cancellation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), but their levels were significantly preserved with Shh inhibitors. Among inflammatory mediators, significantly decreased levels of IL-6 and TNF-α, regulated with repressed NF-κb and STAT3, were prominent with Shh inhibitor, whereas significant inductions of apoptosis were noted with Shh inhibitors. In conclusion, Shh inhibitors significantly prevented CAC covering either ameliorating oncogenic inflammation or suppressing tumor proliferation, especially supported with significant inhibition of IL-6 and STAT3 signaling, 15-PGDH preservation and apoptosis induction. PMID:26476372

  12. Geranylgeranylacetone Ameliorates Inflammatory Response to Lipopolysaccharide (LPS) in Murine Macrophages: Inhibition of LPS Binding to The Cell Surface

    PubMed Central

    Mochida, Shinsuke; Matsura, Tatsuya; Yamashita, Atsushi; Horie, Shunsuke; Ohata, Shuzo; Kusumoto, Chiaki; Nishida, Tadashi; Minami, Yukari; Inagaki, Yoshimi; Ishibe, Yuichi; Nakada, Junya; Ohta, Yoshiji; Yamada, Kazuo

    2007-01-01

    We investigated whether pretreatment with geranylgeranylacetone (GGA), a potent heat shock protein (HSP) inducer, could inhibit proinflammatory cytokine liberation and nitric oxide (NO) production in lipopolysaccharide (LPS)-treated murine macrophages. The levels of NO and tumor necrosis factor-α (TNF-α) released from murine macrophage RAW 264 cells were increased dose- and time-dependently following treatment with LPS (1 µg/ml). GGA (80 µM) treatment 2 h before LPS addition significantly suppressed TNF-α and NO productions at 12 h and 24 h after LPS, respectively, indicating that GGA inhibits activation of macrophages. However, replacement by fresh culture medium before LPS treatment abolished the inhibitory effect of GGA on NO production in LPS-treated cells. Furthermore, GGA inhibited both HSP70 and inducible NO synthase expressions induced by LPS treatment despite an HSP inducer. When it was examined whether GGA interacts with LPS and/or affects expression of Toll-like receptor 4 (TLR4) and CD14 on the cell surface, GGA inhibited the binding of LPS to the cell surface, while GGA did not affect TLR4 and CD14 expressions. These results indicate that GGA suppresses the binding of LPS to the cell surface of macrophages, resulting in inhibiting signal transduction downstream of TLR4. PMID:18193105

  13. Apple Flavonoid Phloretin Inhibits Escherichia coli O157:H7 Biofilm Formation and Ameliorates Colon Inflammation in Rats ▿ †

    PubMed Central

    Lee, Jin-Hyung; Regmi, Sushil Chandra; Kim, Jung-Ae; Cho, Moo Hwan; Yun, Hyungdon; Lee, Chang-Soo; Lee, Jintae

    2011-01-01

    Pathogenic biofilms have been associated with persistent infections due to their high resistance to antimicrobial agents, while commensal biofilms often fortify the host's immune system. Hence, controlling biofilm formation of both pathogenic bacteria and commensal bacteria is important in bacterium-related diseases. We investigated the effect of plant flavonoids on biofilm formation of enterohemorrhagic Escherichia coli O157:H7. The antioxidant phloretin, which is abundant in apples, markedly reduced E. coli O157:H7 biofilm formation without affecting the growth of planktonic cells, while phloretin did not harm commensal E. coli K-12 biofilms. Also, phloretin reduced E. coli O157:H7 attachment to human colon epithelial cells. Global transcriptome analyses revealed that phloretin repressed toxin genes (hlyE and stx2), autoinducer-2 importer genes (lsrACDBF), curli genes (csgA and csgB), and dozens of prophage genes in E. coli O157:H7 biofilm cells. Electron microscopy confirmed that phloretin reduced fimbria production in E. coli O157:H7. Also, phloretin suppressed the tumor necrosis factor alpha-induced inflammatory response in vitro using human colonic epithelial cells. Moreover, in the rat model of colitis induced by trinitrobenzene sulfonic acid (TNBS), phloretin significantly ameliorated colon inflammation and body weight loss. Taken together, our results suggest that the antioxidant phloretin also acts as an inhibitor of E. coli O157:H7 biofilm formation as well as an anti-inflammatory agent in inflammatory bowel diseases without harming beneficial commensal E. coli biofilms. PMID:21930760

  14. Sodium meta-arsenite ameliorates hyperglycemia in obese diabetic db/db mice by inhibition of hepatic gluconeogenesis.

    PubMed

    Lee, Young-Sun; Lee, Eun-Kyu; Oh, Hyun-Hee; Choi, Cheol Soo; Kim, Sujong; Jun, Hee-Sook

    2014-01-01

    Sodium meta-arsenite (SA) is implicated in the regulation of hepatic gluconeogenesis-related genes in vitro; however, the effects in vivo have not been studied. We investigated whether SA has antidiabetic effects in a type 2 diabetic mouse model. Diabetic db/db mice were orally intubated with SA (10 mg kg(-1) body weight/day) for 8 weeks. We examined hemoglobin A1c (HbA1c), blood glucose levels, food intake, and body weight. We performed glucose, insulin, and pyruvate tolerance tests and analyzed glucose production and the expression of gluconeogenesis-related genes in hepatocytes. We analyzed energy metabolism using a comprehensive animal metabolic monitoring system. SA-treated diabetic db/db mice had reduced concentrations of HbA1c and blood glucose levels. Exogenous glucose was quickly cleared in glucose tolerance tests. The mRNA expressions of genes for gluconeogenesis-related enzymes, glucose 6-phosphatase (G6Pase), and phosphoenolpyruvate carboxykinase (PEPCK) were significantly reduced in the liver of SA-treated diabetic db/db mice. In primary hepatocytes, SA treatment decreased glucose production and the expression of G6Pase, PEPCK, and hepatocyte nuclear factor 4 alpha (HNF-4α) mRNA. Small heterodimer partner (SHP) mRNA expression was increased in hepatocytes dependent upon the SA concentration. The expression of Sirt1 mRNA and protein was reduced, and acetylated forkhead box protein O1 (FoxO1) was induced by SA treatment in hepatocytes. In addition, SA-treated diabetic db/db mice showed reduced energy expenditure. Oral intubation of SA ameliorates hyperglycemia in db/db mice by reducing hepatic gluconeogenesis through the decrease of Sirt1 expression and increase in acetylated FoxO1. PMID:25610880

  15. MAD ointment ameliorates Imiquimod-induced psoriasiform dermatitis by inhibiting the IL-23/IL-17 axis in mice.

    PubMed

    OuYang, Qiong; Pan, YaQian; Luo, HanQiong; Xuan, ChunXiao; Liu, JinE; Liu, Jun

    2016-10-01

    Psoriasis is a chronic auto-immune inflammation disease with skin lesions and abnormal keratinocyte proliferation. The IL-23/IL-17 axis plays an important role in the pathogenesis of psoriasis. Madecassoside (MAD) was the most important constituents isolated from Centella asiatica, which has long been used in dermatology, and it is supposed that MAD may have effects on psoriasis. In the present study, the BALB/c mice ear and back skin received IMQ for 6 consecutive days to induce psoriasis-like dermatitis. MAD ointment was applied 6h later after IMQ treatment, and the IL-23/IL-17 pathway was investigated. The HE staining, BrdU and Psoriasis Area and Severity Index (PASI) were used to score the severity of keratinocyte proliferation and inflammation of the skin. Real-time PCR and Western Blot were used to detect the IL-23/IL-17 related cytokines. Flow Cytometry were applied to observe the numbers of Th17 cells. Daily application of IMQ for 6days on mouse ear skin and back skin induced psoriasis-like dermatitis. Real-time PCR showed that mRNA level of IL-23, IL-22, IL-17A were significantly decreased by MAD ointment treatment in ear skin. HE staining and BrdU incorporation implied that MAD ointment reduced keratinocyte proliferation. Flow Cytometry results showed MAD ointment decreased the numbers of Th17 cells. Thus, MAD ointment ameliorates Imiquimod-induced skin inflammation and abnormal keratinocyte through regulate the IL-23/IL-17 axis. PMID:27540765

  16. Paeoniflorin ameliorates acute myocardial infarction of rats by inhibiting inflammation and inducible nitric oxide synthase signaling pathways.

    PubMed

    Chen, Chang; Du, Ping; Wang, Junjie

    2015-09-01

    Paeoniflorin (PF) is the main active component of the commonly used Traditional Chinese Medicine peony, Paeonia Suffruticosa. PF has diverse biological functions and exhibits anti‑oxidative, anti‑inflammatory and anti‑apoptotic activity. Inducible nitric oxide synthase (iNOS) is a catalyzing enzyme that is involved in the synthesis of nitric oxide (NO). NO has an important regulatory role in the cardiovascular, immune and nervous systems. PF has previously been demonstrated to inhibit the gene expression of iNOS. The present study aimed to identify a potentially novel cytoprotective function of PF, and to elucidate its effects against myocardial ischemic damage in a rat model of acute myocardial infarction (AMI). PF was able to significantly decrease the myocardial infarct size as well as the activities of creatine kinase (CK), the MB isoenzyme of CK, lactate dehydrogenase and cardiac troponin T. In addition, in the PF‑treated groups, the expression levels of tumor necrosis factor‑α, interleukin (IL)‑1β, IL‑6 and nuclear factor‑κB were markedly inhibited. Furthermore, treatment with PF inhibited the activities and protein expression levels of iNOS. Decreased caspase‑3 and caspase‑9 activities were also observed in the AMI rat model treated with various doses of PF. The results of the present study indicated that the cardioprotective effects of PF may be associated with the inhibition of inflammation and iNOS signaling pathways. PMID:26035555

  17. Penta-O-galloyl-β-D-glucose ameliorates inflammation by inhibiting MyD88/NF-κB and MyD88/MAPK signalling pathways

    PubMed Central

    Jang, Se-Eun; Hyam, Supriya R; Jeong, Jin-Ju; Han, Myung Joo; Kim, Dong-Hyun

    2013-01-01

    Background and Purpose The gallnut of Rhus chinensis MILL and its main constituent penta-O-galloyl-β-D-glucose (PGG) inhibited NF-κB activation in LPS-stimulated peritoneal and colonic macrophages. Here we have investigated PGG mechanisms underlying anti-inflammatory effects of PGG in vitro and in vivo. Experimental Approach Male C57BL/6 mice (18–22 g, 6 weeks old) were used to prepare peritoneal and colonic macrophages and for the induction of colitis by intrarectal administration of 2,3,4-trinitrobenzene sulphonic acid (TNBS). A range of inflammatory markers and transcription factors were evaluated by elisa, immunoblotting, flow cytometry and confocal microscopy. Key Results Expression of Toll-like receptor (TLR)-4 or Lipopolysaccharide (LPS) binding to TLR-4 in LPS-stimulated peritoneal macrophages was not affected by PGG. However PGG inhibited binding of an anti-MyD88 antibody to peritoneal macrophages, but did not reduce binding of anti–IL-1 receptor-associated kinase (IRAK1) and IRAK4 antibodies to the macrophages with or without transfection with MyD88 siRNA. PGG potently reduced the activation of IRAK1, NF-κB, and MAPKs in LPS- or pepetidoglycan-stimulated peritoneal and colonic macrophages. PGG suppressed IL-1β, TNF-α and IL-6 in LPS-stimulated peritoneal macrophages, while increasing expression of the anti-inflammatorycytokine IL-10. Oral administration of PGG inhibited colon shortening and myeloperoxidase activity in mice with TNBS-induced colitis, along with reducing NF-κB activation and IL-1β, TNF-α, and IL-6 levels, whereas it increased IL-10. Conclusions and Implications PGG reduced activation of NF-κB and MAPK signalling pathways by directly interacting with the MyD88 adaptor protein. PGG may ameliorate inflammatory diseases such as colitis. PMID:23941302

  18. 6-Shogaol has anti-amyloidogenic activity and ameliorates Alzheimer's disease via CysLT1R-mediated inhibition of cathepsin B.

    PubMed

    Na, Ji-Young; Song, Kibbeum; Lee, Ju-Woon; Kim, Sokho; Kwon, Jungkee

    2016-08-12

    Although 6-shogaol, a constituent of ginger, has been reported to have anti-inflammatory and anti-oxidant effects on neuronal cells, the effects of 6-shogaol on Alzheimer's disease (AD) have not yet been investigated. Here we aimed to determine whether 6-shogaol exerts neuroprotective effects against AD. Specifically, we investigated the effects of 6-shogaol on the cysteinyl leukotriene 1 receptor (CysLT1R), a major factor in AD pathogenesis. Moreover, we clarified the relationship between CysLT1R and cathepsin B, a cysteine protease. We used in vitro and in vivo models to determine whether 6-shogaol inhibits CysLT1R/cathepsin B in an amyloid-beta (Aβ; 1-42)-induced model of neurotoxicity. We first confirmed that CysLT1R and cathepsin B are upregulated by Aβ (1-42) and that CysLT1R activation induces cathepsin B. In contrast, we found that 6-shogaol-mediated inhibition of CysLT1R downregulates cathepsin B in both in vitro and in vivo models. Furthermore, we found that 6-shogaol-mediated inhibition of CysLT1R/cathepsin B reduces Aβ deposition in the brain and ameliorates behavioral deficits in APPSw/PS1-dE9 Tg mice. Our results indicate that 6-shogaol is a CysLT1R/cathepsin B inhibitor and is a novel potential therapeutic agent for the treatment of various neurodegenerative diseases, including AD. PMID:27286707

  19. Sodium Tanshinone IIA Sulfonate Ameliorates Bladder Fibrosis in a Rat Model of Partial Bladder Outlet Obstruction by Inhibiting the TGF-β/Smad Pathway Activation.

    PubMed

    Jiang, Xiaoxiao; Chen, Yaping; Zhu, Haitao; Wang, Bo; Qu, Ping; Chen, Renfu; Sun, Xiaoqing

    2015-01-01

    Transforming growth factor (TGF)-β1 is known to play a pivotal role in a diverse range of biological systems including modulation of fibrosis in several organs. The precise role of TGF-β/Smad signaling in the progression of bladder fibrosis secondary to partial bladder outlet obstruction (PBOO) is yet to be conclusively. Using a rat PBOO model, we investigated TGF-β1 expression and exaimined whether sodium tanshinone IIA sulfonate (STS) could inhibit TGF-β/Smad signaling pathway activation and ameliorate bladder fibrosis. Forty-eight female Sprague-Dawley rats were randomly divided into three groups: sham operation group (n = 16), PBOO operation without STS treatment group (n = 16) and PBOO operation with STS treatment group (n = 16). Thirty-two rats underwent the operative procedure to create PBOO and subsequently received intraperitoneal injections of STS (10 mg/kg/d; n = 16) or vehicle (n = 16) two days after the surgery. Sham surgery was conducted on 16 rats, which received intraperitoneal vehicle injection two days later. In each of the three groups, an equal number of rats were sacrificed at weeks 4 and 8 after the PBOO or sham operation. The TGF-β/Smad signaling pathway was analyzed using western blotting, immunohistochemical staining and reverse transcriptase polymerase chain reaction (RT-PCR). One-way analysis of variance was conducted to draw statistical inferences. At 4 and 8 weeks, the expression of TGF-β1 and phosphorylated Smad2 and Smad3 in STS-treated PBOO rats was significantly lower than in the PBOO rats not treated with STS. Alpha smooth muscle actin (α-SMA), collagen I and collagen III expression at 4 and 8 weeks post PBOO was lower in STS-treated PBOO rats when compared to that in PBOO rats not treated with STS. Our findings indicate that STS ameliorates bladder fibrosis by inhibiting TGF-β/Smad signaling pathway activation, and may prove to be a potential therapeutic measure for preventing bladder fibrosis secondary to PBOO operation

  20. Sodium Tanshinone IIA Sulfonate Ameliorates Bladder Fibrosis in a Rat Model of Partial Bladder Outlet Obstruction by Inhibiting the TGF-β/Smad Pathway Activation

    PubMed Central

    Wang, Bo; Qu, Ping; Chen, Renfu; Sun, Xiaoqing

    2015-01-01

    Transforming growth factor (TGF)-β1 is known to play a pivotal role in a diverse range of biological systems including modulation of fibrosis in several organs. The precise role of TGF-β/Smad signaling in the progression of bladder fibrosis secondary to partial bladder outlet obstruction (PBOO) is yet to be conclusively. Using a rat PBOO model, we investigated TGF-β1 expression and exaimined whether sodium tanshinone IIA sulfonate (STS) could inhibit TGF-β/Smad signaling pathway activation and ameliorate bladder fibrosis. Forty-eight female Sprague-Dawley rats were randomly divided into three groups: sham operation group (n = 16), PBOO operation without STS treatment group (n = 16) and PBOO operation with STS treatment group (n = 16). Thirty-two rats underwent the operative procedure to create PBOO and subsequently received intraperitoneal injections of STS (10 mg/kg/d; n = 16) or vehicle (n = 16) two days after the surgery. Sham surgery was conducted on 16 rats, which received intraperitoneal vehicle injection two days later. In each of the three groups, an equal number of rats were sacrificed at weeks 4 and 8 after the PBOO or sham operation. The TGF-β/Smad signaling pathway was analyzed using western blotting, immunohistochemical staining and reverse transcriptase polymerase chain reaction (RT-PCR). One-way analysis of variance was conducted to draw statistical inferences. At 4 and 8 weeks, the expression of TGF-β1 and phosphorylated Smad2 and Smad3 in STS-treated PBOO rats was significantly lower than in the PBOO rats not treated with STS. Alpha smooth muscle actin (α-SMA), collagen I and collagen III expression at 4 and 8 weeks post PBOO was lower in STS-treated PBOO rats when compared to that in PBOO rats not treated with STS. Our findings indicate that STS ameliorates bladder fibrosis by inhibiting TGF-β/Smad signaling pathway activation, and may prove to be a potential therapeutic measure for preventing bladder fibrosis secondary to PBOO operation

  1. Targeted Inhibition of Heat Shock Protein 90 Suppresses Tumor Necrosis Factor–α and Ameliorates Murine Intestinal Inflammation

    PubMed Central

    Collins, Colm B.; Strassheim, Derek; Aherne, Carol M.; Yeckes, Alyson R.; Jedlicka, Paul; de Zoeten, Edwin F.

    2015-01-01

    Inflammatory bowel diseases are chronic intestinal inflammatory diseases thought to reflect a dysregulated immune response. Although antibody-based inhibition of tumor necrosis factor-α (TNF-α) has provided relief to many inflammatory bowel diseases patients, these therapies are either ineffective in a patient subset or lose their efficacy over time, leaving an unmet need for alternatives. Given the critical role of the heat shock response in regulating inflammation, this study proposed to define the impact of selective inhibition of heat shock protein 90 (HSP90) on intestinal inflammation. Using multiple preclinical mouse models of inflammatory bowel diseases, we demonstrate a potent anti-inflammatory effect of selective inhibition of the HSP90 C-terminal ATPase using the compound novobiocin. Novobiocin-attenuated dextran sulfate sodium-induced colitis and CD45RBhigh adoptive-transfer colitis through the suppression of inflammatory cytokine secretion, including TNF-α. In vitro assays demonstrate that CD4+ T cells treated with novobiocin produced significantly less TNF-α measured by intracellular cytokine staining and by enzyme-linked immunosorbent assay. This corresponded to significantly decreased nuclear p65 translocation by Western blot and a decrease in nuclear factor-κB luciferase activity in Jurkat T cells. Finally, to verify the anti-TNF action of novobiocin, 20-week-old TNFΔARE mice were treated for 2 weeks with subcutaneous administration of novobiocin. This model has high levels of circulating TNF-α and exhibits spontaneous transmural segmental ileitis. Novobiocin treatment significantly reduced inflammatory cell infiltrate in the ileal lamina propria. HSP90 inhibition with novobiocin offers a novel method of inflammatory cytokine suppression without potential for the development of tolerance that limits current antibody-based methods. PMID:24552830

  2. Dioscin ameliorates cerebral ischemia/reperfusion injury through the downregulation of TLR4 signaling via HMGB-1 inhibition.

    PubMed

    Tao, Xufeng; Sun, Xiance; Yin, Lianhong; Han, Xu; Xu, Lina; Qi, Yan; Xu, Youwei; Li, Hua; Lin, Yuan; Liu, Kexin; Peng, Jinyong

    2015-07-01

    We previously reported the promising effect of dioscin against hepatic ischemia/reperfusion (I/R) injury, but its effect on cerebral I/R injury remains unknown. In this work, an in vitro oxygen-glucose deprivation and reoxygenation (OGD/R) model and an in vivo middle cerebral artery occlusion (MCAO) model were used. The results indicated that dioscin clearly protected PC12 cells and primary cortical neurons against OGD/R insult and significantly prevented cerebral I/R injury. Further research demonstrated that dioscin-induced neuroprotection was accompanied by a significant inhibition in the expression and the nuclear to cytosolic translocation of HMGB-1, reflected by decreased TLR4 expression. Blockade of the TLR4/MyD88/TRAF6 signaling pathway by dioscin inhibited NF-κB and AP-1 transcriptional activities, MAPK and STAT3 phosphorylation, and pro-inflammatory cytokine responses, and upregulated the levels of anti-inflammatory factors. In addition, small interfering RNA (siRNA) and overexpressed genes of HMGB-1 and TLR4 were applied in in vitro experiments, respectively, and the results further confirmed that dioscin showed an efficient neuroprotection because of its inhibiting effects on HMGB-1/TLR4 signaling and subsequent suppressing inflammation. These findings provide new insights that will aid in elucidating the effect of dioscin against cerebral I/R injury and support the development of dioscin as a potential treatment for ischemic stroke. PMID:25772012

  3. Necrostatin-1 ameliorates intracerebral hemorrhage-induced brain injury in mice through inhibiting RIP1/RIP3 pathway.

    PubMed

    Su, Xingfen; Wang, Handong; Kang, Dezhi; Zhu, Jianhong; Sun, Qing; Li, Tao; Ding, Ke

    2015-04-01

    Necroptosis is a recently discovered programmed necrosis, regulated by receptor interacting protein kinase 1 (RIP1) and RIP3 after death signal stimulation and could be specifically inhibited by necrostatin-1. The aim of this study was to investigate the role of RIP1 and RIP3 signal pathways in a mouse model of collagenase-induced intracerebral hemorrhage (ICH) and assess the effect of necrostatin-1 on brain injury after ICH. We found that RIP1 and RIP3 proteins were abundantly expressed and increased in mice brain after ICH. Necrostatin-1 pretreatment improved neurological function and attenuated brain edema in mice after ICH. Moreover, necrostatin-1 reduced RIP1-RIP3 interaction and propidium iodide (PI) positive cell death, and further inhibited microglia activation and pro-inflammatory mediator genes [tumor necrosis factor-a (TNF-α) and interleukin-1β (IL-1β)] expression after ICH. These findings indicate that RIP1/RIP3-mediated necroptosis is an important mechanism of cell death after ICH. Through inhibiting necroptosis, necrostatin-1 plays a protective role in reducing necrotic cell death after ICH. Necrostatin-1 is a promising therapeutic agent that protects cells from necroptosis and improves functional outcome. PMID:25576092

  4. Kallistatin ameliorates influenza virus pathogenesis by inhibition of kallikrein-related peptidase 1-mediated cleavage of viral hemagglutinin.

    PubMed

    Leu, Chia-Hsing; Yang, Mei-Lin; Chung, Nai-Hui; Huang, Yen-Jang; Su, Yu-Chu; Chen, Yi-Cheng; Lin, Chia-Cheng; Shieh, Gia-Shing; Chang, Meng-Ya; Wang, Shainn-Wei; Chang, Yao; Chao, Julie; Chao, Lee; Wu, Chao-Liang; Shiau, Ai-Li

    2015-09-01

    Proteolytic cleavage of the hemagglutinin (HA) of influenza virus by host trypsin-like proteases is required for viral infectivity. Some serine proteases are capable of cleaving influenza virus HA, whereas some serine protease inhibitors (serpins) inhibit the HA cleavage in various cell types. Kallikrein-related peptidase 1 (KLK1, also known as tissue kallikrein) is a widely distributed serine protease. Kallistatin, a serpin synthesized mainly in the liver and rapidly secreted into the circulation, forms complexes with KLK1 and inhibits its activity. Here, we investigated the roles of KLK1 and kallistatin in influenza virus infection. We show that the levels of KLK1 increased, whereas those of kallistatin decreased, in the lungs of mice during influenza virus infection. KLK1 cleaved H1, H2, and H3 HA molecules and consequently enhanced viral production. In contrast, kallistatin inhibited KLK1-mediated HA cleavage and reduced viral production. Cells transduced with the kallistatin gene secreted kallistatin extracellularly, which rendered them more resistant to influenza virus infection. Furthermore, lentivirus-mediated kallistatin gene delivery protected mice against lethal influenza virus challenge by reducing the viral load, inflammation, and injury in the lung. Taking the data together, we determined that KLK1 and kallistatin contribute to the pathogenesis of influenza virus by affecting the cleavage of the HA peptide and inflammatory responses. This study provides a proof of principle for the potential therapeutic application of kallistatin or other KLK1 inhibitors for influenza. Since proteolytic activation also enhances the infectivity of some other viruses, kallistatin and other kallikrein inhibitors may be explored as antiviral agents against these viruses. PMID:26149981

  5. Andrographolide Ameliorates Abdominal Aortic Aneurysm Progression by Inhibiting Inflammatory Cell Infiltration through Downregulation of Cytokine and Integrin Expression.

    PubMed

    Ren, Jun; Liu, Zhenjie; Wang, Qiwei; Giles, Jasmine; Greenberg, Jason; Sheibani, Nader; Kent, K Craig; Liu, Bo

    2016-01-01

    Abdominal aortic aneurysm (AAA), characterized by exuberant inflammation and tissue deterioration, is a common aortic disease associated with a high mortality rate. There is currently no established pharmacological therapy to treat this progressive disease. Andrographolide (Andro), a major bioactive component of the herbaceous plant Andrographis paniculata, has been found to exhibit potent anti-inflammatory properties by inhibiting nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activity in several disease models. In this study, we investigated the ability of Andro to suppress inflammation associated with aneurysms, and whether it may be used to block the progression of AAA. Whereas diseased aortae continued to expand in the solvent-treated group, daily administration of Andro to mice with small aneurysms significantly attenuated aneurysm growth, as measured by the diminished expansion of aortic diameter (165.68 ± 15.85% vs. 90.62 ± 22.91%, P < 0.05). Immunohistochemistry analyses revealed that Andro decreased infiltration of monocytes/macrophages and T cells. Mechanistically, Andro inhibited arterial NF-κB activation and reduced the production of proinflammatory cytokines [CCL2, CXCL10, tumor necrosis factor α, and interferon-γ] in the treated aortae. Furthermore, Andro suppressed α4 integrin expression and attenuated the ability of monocytes/macrophages to adhere to activated endothelial cells. These results indicate that Andro suppresses progression of AAA, likely through inhibition of inflammatory cell infiltration via downregulation of NF-κB-mediated cytokine production and α4 integrin expression. Thus, Andro may offer a pharmacological therapy to slow disease progression in patients with small aneurysms. PMID:26483397

  6. Interstitial renal fibrosis due to multiple cisplatin treatments is ameliorated by semicarbazide-sensitive amine oxidase inhibition.

    PubMed

    Katagiri, Daisuke; Hamasaki, Yoshifumi; Doi, Kent; Negishi, Kousuke; Sugaya, Takeshi; Nangaku, Masaomi; Noiri, Eisei

    2016-02-01

    Elucidation of acute kidney diseases and disorders (AKD), including acute kidney injury (AKI), is important to prevent their progression to chronic kidney disease. Current animal AKI models are often too severe for use in evaluating human AKI. Therefore, new animal models of mild kidney injury are needed. Here a new clinically relevant animal model using multiple low doses of cisplatin (CP) was used to evaluate AKD. When 10 mg/kg CP was administered intraperitoneally once weekly for three times to L-type fatty acid-binding protein (L-FABP) transgenic mice, moderate renal interstitial fibrosis and tubule dilatation occurred, accompanied by brush-border loss. Urinary L-FABP, a promising biomarker of AKI, changed more drastically than blood urea nitrogen or creatinine. Preventing fibrosis in organs was also studied. Oral administration of a recently reported selective semicarbazide-sensitive amine oxidase inhibitor, PXS-4728A, for 1 week attenuated kidney injury and interstitial fibrosis compared with vehicle. Inhibition of renal lipid accumulation in semicarbazide-sensitive amine oxidase inhibitor-treated mice, together with reduced oxidative stress and L-FABP suppression in proximal tubules, suggested an antifibrotic effect of semicarbazide-sensitive amine oxidase inhibition in this CP-AKD model, a representative onco-nephrology. Thus, semicarbazide-sensitive amine oxidase inhibitors may be promising candidates for the prevention of chronic kidney disease in patients using CP to treat malignancy. PMID:26535996

  7. Involvement of inhibition of RhoA/Rho kinase signaling in simvastatin-induced amelioration of neuropathic pain.

    PubMed

    Ohsawa, Masahiro; Ishikura, Kei-Ichiro; Mutoh, Junpei; Hisa, Hiroaki

    2016-10-01

    Small molecular G-protein plays a key role in several diseases. This study was designed to reveal the role of RhoA signaling in the pathophysiology of neuropathic pain in mice. Partial sciatic nerve injury caused thermal hyperalgesia, mechanical allodynia, and increased plasma membrane translocation of RhoA in the lumber spinal cord. GFAP-immunoreactivity (ir), Iba-1-ir, and Rho kinase 2 (ROCK2-ir) was also increased in the ipsilateral spinal dorsal horn of nerve-ligated mice. Moreover, partial nerve ligation increased the expression of phosphorylated myristoylated alanine-rich protein kinase C substrate (MARCKS)-ir in the ipsilateral spinal dorsal horn. Daily intrathecal administration of simvastatin, beginning 3days before nerve injury, completely blocked all these changes in nerve-ligated mice. Pharmacological inhibition of ROCK also attenuated the increased expression of GFAP-ir and phosphorylated MARCKS-ir. Together, it is suggested that astrogliosis initiated by the activation of RhoA/ROCK signaling results in MARCKS phosphorylation in nerve terminals, which leads to hyperalgesia in neuropathic pain. Furthermore, simvastatin exerts antihyperalgesic and antiallodynic effects through the inhibition of spinal RhoA activation. PMID:27457035

  8. Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1–dependent manner

    PubMed Central

    Pajvani, Utpal B.; Shawber, Carrie J.; Samuel, Varman T.; Birkenfeld, Andreas L.; Shulman, Gerald I.; Kitajewski, Jan; Accili, Domenico

    2012-01-01

    Summary Transcription factor FoxO1 promotes hepatic glucose production. Genetic inhibition of FoxO1 function prevents diabetes in experimental animal models, providing impetus to identify pharmacological approaches to modulate its function. Altered Notch signaling is seen in tumorigenesis, and Notch antagonists are in clinical testing for cancer application. Here, we report that FoxO1 and Notch coordinately regulate hepatic glucose metabolism. Combined haploinsufficiency of FoxO1 and Notch1 markedly improves insulin sensitivity in diet-induced insulin resistance, as does liver-specific knockout of the Notch transcriptional effector, Rbp-Jk. Conversely, Notch1 gain-of-function promotes insulin resistance in a FoxO1-dependent manner and induces Glucose-6-phosphatase expression. Pharmacological blockade of Notch signaling with γ-secretase inhibitors improves insulin sensitivity following in vivo administration in lean and in obese, insulin-resistant mice. The data identify a heretofore unknown metabolic function of Notch, and suggest that Notch inhibition is beneficial to diabetes treatment, in part by helping to offset excessive FoxO1–driven hepatic glucose production. PMID:21804540

  9. Inhibition of matrix metalloproteinase-9 activity by doxycycline ameliorates RANK ligand-induced osteoclast differentiation in vitro and in vivo

    SciTech Connect

    Franco, Gilson C.N.; Nakanishi, Tadashi; Ohta, Kouji; Rosalen, Pedro L.; Groppo, Francisco C.; Bartlett, John D.; Stashenko, Philip; Taubman, Martin A.; Kawai, Toshihisa

    2011-06-10

    Tetracycline antibiotics, including doxycycli/e (DOX), have been used to treat bone resorptive diseases, partially because of their activity to suppress osteoclastogenesis induced by receptor activator of nuclear factor kappa B ligand (RANKL). However, their precise inhibitory mechanism remains unclear. Therefore, the present study examined the effect of Dox on osteoclastogenesis signaling induced by RANKL, both in vitro and in vivo. Although Dox inhibited RANKL-induced osteoclastogenesis and down-modulated the mRNA expression of functional osteoclast markers, including tartrate-resistant acid phosphatase (TRAP) and cathepsin K, Dox neither affected RANKL-induced MAPKs phosphorylation nor NFATc1 gene expression in RAW264.7 murine monocytic cells. Gelatin zymography and Western blot analyses showed that Dox down-regulated the enzyme activity of RANKL-induced MMP-9, but without affecting its protein expression. Furthermore, MMP-9 enzyme inhibitor also attenuated both RANKL-induced osteoclastogenesis and up-regulation of TRAP and cathepsin K mRNA expression, indicating that MMP-9 enzyme action is engaged in the promotion of RANKL-induced osteoclastogenesis. Finally, Dox treatment abrogated RANKL-induced osteoclastogenesis and TRAP activity in mouse calvaria along with the suppression of MMP9 enzyme activity, again without affecting the expression of MMP9 protein. These findings suggested that Dox inhibits RANKL-induced osteoclastogenesis by its inhibitory effect on MMP-9 enzyme activity independent of the MAPK-NFATc1 signaling cascade.

  10. SOD3 Ameliorates H2O2-Induced Oxidative Damage in SH-SY5Y Cells by Inhibiting the Mitochondrial Pathway.

    PubMed

    Yang, Rong; Wei, Li; Fu, Qing-Qing; Wang, Hua; You, Hua; Yu, Hua-Rong

    2016-07-01

    This study was designed to investigate the protective effects of extracellular superoxide dismutase (SOD3) against hydrogen peroxide (H2O2) induced damage in human neuroblastoma SH-SY5Y cells and to elucidate the mechanisms responsible for this beneficial effect. SOD3-overexpressing SH-SY5Y cells were generated by adenoviral vector-mediated infection, and H2O2 was then added into the cell culture system to establish an in vitro model of oxidative stress. Cell viability, the generation of intracellular reactive oxygen species (ROS), the expression and activity of antioxidant enzymes, the levels of lipid peroxidation malondialdehyde (MDA), the expression of mitochondrial apoptosis-related genes, and calcium imaging were examined. Following H2O2 exposure, the over-expression of SOD3 promoted the survival of SH-SY5Y cells; decreased the production of ROS, MDA levels, cytochrome C, caspase-3, caspase-9, and Bax gene expression, and calcium levels; and increased the expression and activity of antioxidant enzyme genes and the expression level of Bcl-2. Together, our data demonstrate that SOD3 ameliorates H2O2-induced oxidative damage in neuroblastoma SH-SY5Y cells by inhibiting the mitochondrial pathway and provide new insights into the functional actions of SOD3 on oxidative stress-induced cell damage. PMID:27084770

  11. Amelioration of Mitochondrial Dysfunction-Induced Insulin Resistance in Differentiated 3T3-L1 Adipocytes via Inhibition of NF-κB Pathways

    PubMed Central

    Hafizi Abu Bakar, Mohamad; Sarmidi, Mohamad Roji; Kai, Cheng Kian; Huri, Hasniza Zaman; Yaakob, Harisun

    2014-01-01

    A growing body of evidence suggests that activation of nuclear factor kappa B (NF-κB) signaling pathways is among the inflammatory mechanism involved in the development of insulin resistance and chronic low-grade inflammation in adipose tissues derived from obese animal and human subjects. Nevertheless, little is known about the roles of NF-κB pathways in regulating mitochondrial function of the adipose tissues. In the present study, we sought to investigate the direct effects of celastrol (potent NF-κB inhibitor) upon mitochondrial dysfunction-induced insulin resistance in 3T3-L1 adipocytes. Celastrol ameliorates mitochondrial dysfunction by altering mitochondrial fusion and fission in adipocytes. The levels of oxidative DNA damage, protein carbonylation and lipid peroxidation were down-regulated. Further, the morphology and quantification of intracellular lipid droplets revealed the decrease of intracellular lipid accumulation with reduced lipolysis. Moreover, massive production of the pro-inflammatory mediators tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were markedly depleted. Insulin-stimulated glucose uptake activity was restored with the enhancement of insulin signaling pathways. This study signified that the treatments modulated towards knockdown of NF-κB transcription factor may counteract these metabolic insults exacerbated in our model of synergy between mitochondrial dysfunction and inflammation. These results demonstrate for the first time that NF-κB inhibition modulates mitochondrial dysfunction induced insulin resistance in 3T3-L1 adipocytes. PMID:25474091

  12. Phosphodiesterase 5 inhibition ameliorates angiontensin II-induced podocyte dysmotility via the protein kinase G-mediated downregulation of TRPC6 activity.

    PubMed

    Hall, Gentzon; Rowell, Janelle; Farinelli, Federica; Gbadegesin, Rasheed A; Lavin, Peter; Wu, Guanghong; Homstad, Alison; Malone, Andrew; Lindsey, Thomas; Jiang, Ruiji; Spurney, Robert; Tomaselli, Gordon F; Kass, David A; Winn, Michelle P

    2014-06-15

    The emerging role of the transient receptor potential cation channel isotype 6 (TRPC6) as a central contributor to various pathological processes affecting podocytes has generated interest in the development of therapeutics to modulate its function. Recent insights into the regulation of TRPC6 have revealed PKG as a potent negative modulator of TRPC6 conductance and associated signaling via its phosphorylation at two highly conserved amino acid residues: Thr(69)/Thr(70) (Thr(69) in mice and Thr(70) in humans) and Ser(321)/Ser(322) (Ser(321) in mice and Ser(322) in humans). Here, we tested the role of PKG in modulating TRPC6-dependent responses in primary and conditionally immortalized mouse podocytes. TRPC6 was phosphorylated at Thr(69) in nonstimulated podocytes, but this declined upon ANG II stimulation or overexpression of constitutively active calcineurin phosphatase. ANG II induced podocyte motility in an in vitro wound assay, and this was reduced 30-60% in cells overexpressing a phosphomimetic mutant TRPC6 (TRPC6T70E/S322E) or activated PKG (P < 0.05). Pretreatment of podocytes with the PKG agonists S-nitroso-N-acetyl-dl-penicillamine (nitric oxide donor), 8-bromo-cGMP, Bay 41-2772 (soluble guanylate cyclase activator), or phosphodiesterase 5 (PDE5) inhibitor 4-{[3',4'-(methylenedioxy)benzyl]amino}[7]-6-methoxyquinazoline attenuated ANG II-induced Thr(69) dephosphorylation and also inhibited TRPC6-dependent podocyte motility by 30-60%. These data reveal that PKG activation strategies, including PDE5 inhibition, ameliorate ANG II-induced podocyte dysmotility by targeting TRPC6 in podocytes, highlighting the potential therapeutic utility of these approaches to treat hyperactive TRPC6-dependent glomerular disease. PMID:24740790

  13. Canine Fibroblast Growth Factor 21 Ameliorates Hyperglycemia Associated with Inhibiting Hepatic Gluconeogenesis and Improving Pancreatic Beta-Cell Survival in Diabetic Mice and Dogs

    PubMed Central

    Xu, Pengfei; Zhang, Yingjie; Jiang, Xinghao; Li, Junyan; Song, Liying; Khoso, Mir Hasson; Liu, Yunye; Wu, Qiang; Ren, Guiping; Li, Deshan

    2016-01-01

    Diabetes mellitus is a common endocrinopathy in dog. Fibroblast growth factor 21 (FGF-21) is a secreted protein, which is involved in glucose homeostasis. We speculate that the recombinant canine FGF-21 (cFGF-21) has the potential to become a powerful therapeutics to treat canine diabetes. The cFGF-21 gene was cloned and expressed in E. coli Rosetta (DE3). After purification, a cFGF-21 protein with the purity exceeding 95% was obtained. Mouse 3T3-L1 adipocytes and type 1 diabetic mice/dogs induced by STZ were used to examine the biological activity of cFGF-21 in vitro and in vivo, respectively. Results showed that cFGF-21 stimulated glucose uptake in adipocytes significantly in a dose-dependent manner, and reduced plasma glucose significantly in diabetic mice/dogs. After treatment with cFGF-21, the serum insulin level, glycosylated hemoglobin (HbA1c) level and the expressions of the hepatic gluconeogenesis genes (glucose-6-phosphatase, G6Pase and phosphoenolpyruvate carboxykinase, PCK) of the diabetic mice/dogs were attenuated significantly. In the mouse experiment, we also found that the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and the expression of suppressor of cytokine signaling 3 (SOCS3) were up-regulated significantly in the livers after treatment. Histopathological and immunohistochemical results showed that treatment with cFGF-21 promoted recovery of pancreatic islets from STZ-induced apoptosis. Besides, we also found that treatment with cFGF-21 protected liver against STZ or hyperglycemia induced damage and the mechanism of this action associated with inhibiting oxidative stress. In conclusion, cFGF-21 represents a promising candidate for canine diabetes therapeutics. The mechanism of cFGF-21 ameliorates hyperglycemia associated with inhibiting hepatic gluconeogenesis by regulation of STAT3 signal pathway and improving pancreatic beta-cell survival. PMID:27203422

  14. Canine Fibroblast Growth Factor 21 Ameliorates Hyperglycemia Associated with Inhibiting Hepatic Gluconeogenesis and Improving Pancreatic Beta-Cell Survival in Diabetic Mice and Dogs.

    PubMed

    Xu, Pengfei; Zhang, Yingjie; Jiang, Xinghao; Li, Junyan; Song, Liying; Khoso, Mir Hasson; Liu, Yunye; Wu, Qiang; Ren, Guiping; Li, Deshan

    2016-01-01

    Diabetes mellitus is a common endocrinopathy in dog. Fibroblast growth factor 21 (FGF-21) is a secreted protein, which is involved in glucose homeostasis. We speculate that the recombinant canine FGF-21 (cFGF-21) has the potential to become a powerful therapeutics to treat canine diabetes. The cFGF-21 gene was cloned and expressed in E. coli Rosetta (DE3). After purification, a cFGF-21 protein with the purity exceeding 95% was obtained. Mouse 3T3-L1 adipocytes and type 1 diabetic mice/dogs induced by STZ were used to examine the biological activity of cFGF-21 in vitro and in vivo, respectively. Results showed that cFGF-21 stimulated glucose uptake in adipocytes significantly in a dose-dependent manner, and reduced plasma glucose significantly in diabetic mice/dogs. After treatment with cFGF-21, the serum insulin level, glycosylated hemoglobin (HbA1c) level and the expressions of the hepatic gluconeogenesis genes (glucose-6-phosphatase, G6Pase and phosphoenolpyruvate carboxykinase, PCK) of the diabetic mice/dogs were attenuated significantly. In the mouse experiment, we also found that the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and the expression of suppressor of cytokine signaling 3 (SOCS3) were up-regulated significantly in the livers after treatment. Histopathological and immunohistochemical results showed that treatment with cFGF-21 promoted recovery of pancreatic islets from STZ-induced apoptosis. Besides, we also found that treatment with cFGF-21 protected liver against STZ or hyperglycemia induced damage and the mechanism of this action associated with inhibiting oxidative stress. In conclusion, cFGF-21 represents a promising candidate for canine diabetes therapeutics. The mechanism of cFGF-21 ameliorates hyperglycemia associated with inhibiting hepatic gluconeogenesis by regulation of STAT3 signal pathway and improving pancreatic beta-cell survival. PMID:27203422

  15. KCa1.1 inhibition attenuates fibroblast-like synoviocyte invasiveness and ameliorates rat models of rheumatoid arthritis

    PubMed Central

    Tanner, Mark R.; Hu, Xueyou; Huq, Redwan; Tajhya, Rajeev B.; Sun, Liang; Khan, Fatima S.; Laragione, Teresina; Horrigan, Frank T.; Gulko, Pércio S.; Beeton, Christine

    2014-01-01

    Objective Fibroblast-like synoviocytes (FLS) participate in joint inflammation and damage during rheumatoid arthritis (RA) and its animal models. The purpose of this study was to define the importance of KCa1.1 (BK, Maxi-K, Slo1, KCNMA1) channel expression and function in FLS and to establish these channels as potential new targets for RA therapy. Methods We compared KCa1.1 expression levels in FLS from rats with the pristane-induced arthritis (PIA) model of RA and in FLS from healthy rats. We then used ex vivo functional assays combined with siRNA-induced knock-down, over-expression, and functional modulation of KCa1.1 in PIA-FLS. Finally, we determined the effectiveness of modulating KCa1.1 in two rat models of RA, moderate PIA and severe complete Freund’s adjuvant collagen-induced arthritis (CFA-CIA). Results We found that PIA-FLS express the KCa1.1 channel as their major potassium channel, as do FLS from patients with RA. In contrast, FLS from healthy rats expressed fewer of these channels. Inhibiting the function or expression of KCa1.1 ex vivo reduced the proliferation, production of proteases, and invasive properties of PIA-FLS whereas opening native KCa1.1 or over-expressing the channel enhanced the invasiveness of both PIA-FLS and FLS isolated from healthy rats. Treatment with a KCa1.1 channel blocker starting at onset of clinical signs stopped disease progression in both PIA and CFA-CIA, reduced joint and bone damage, and inhibited FLS invasiveness and proliferation. Conclusion Our results demonstrate a critical role for KCa1.1 channels in the regulation of FLS invasiveness and suggest they represent a potential therapeutic target for RA. PMID:25252152

  16. Protective effect of heme oxygenase-1 on Wistar rats with heart failure through the inhibition of inflammation and amelioration of intestinal microcirculation

    PubMed Central

    Zhang, Li; Gan, Zhuo-Kun; Han, Li-Na; Wang, Hao; Bai, Jie; Tan, Guo-Juan; Li, Xiao-Xia; Xu, Ya-Ping; Zhou, Yu; Gong, Mei-Liang; Lin, Mo-Si; Han, Xiao-Yang

    2015-01-01

    Background Myocardial infarction (MI) has likely contributed to the increased prevalence of heart failure (HF). As a result of reduced cardiac function, splanchnic blood flow decreases, causing ischemia in villi and damage to the intestinal barrier. The induction of heme oxygenase-1 (HO-1) could prevent, or lessen the effects of stress and inflammation. Thus, the effect and mechanism thereof of HO-1 on the intestines of rats with HF was investigated. Methods Male Wistar rats with heart failure through ligation of the left coronary artery were identified with an left ventricular ejection fraction of < 45% through echocardiography and then divided into various experimental groups based on the type of peritoneal injection they received [MI: saline; MI + Cobalt protoporphyrin (CoPP): CoPP solution; and MI + Tin mesoporphyrin IX dichloride (SnMP): SnMP solution]. The control group was comprised of rats without coronary ligation. Echocardiography was performed before ligation for a baseline and eight weeks after ligation in order to evaluate the cardiac function of the rats. The bacterial translocation (BT) incidence, mesenteric microcirculation, amount of endotoxins in the vein serum, ileum levels of HO-1, carbon oxide (CO), nitric oxide (NO), interleukin (IL)-10, tumour necrosis factor-α (TNF-α), and the ileum morphology were determined eight weeks after the operation. Results The rats receiving MI + CoPP injections exhibited a recovery in cardiac function, an amelioration of mesenteric microcirculation and change in morphology, a lower BT incidence, a reduction in serum and ileac NO and TNF-α levels, and an elevation in ileac HO-1, CO, and interleukin-10 (IL-10) levels compared to the MI group (P < 0.05). The rats that received the MI + SnMP injections exhibited results inverse to the MI (P < 0.05) group. Conclusions HO-1 exerted a protective effect on the intestines of rats with HF by inhibiting the inflammation and amelioration of microcirculation through the CO

  17. Inhibition of TYK2 and JAK1 Ameliorates Imiquimod-Induced Psoriasis-like Dermatitis by Inhibiting IL-22 and the IL-23/IL-17 axis

    PubMed Central

    Works, Melissa G.; Yin, Fangfang; Yin, Catherine C.; Yiu, Ying; Shew, Kenneth; Tran, Thanh-Thuy; Dunlap, Nahoko; Lam, Jennifer; Mitchell, Tim; Reader, John; Stein, Paul L.; D’Andrea, Annalisa

    2014-01-01

    Psoriasis is a chronic autoimmune disease affecting the skin and characterized by aberrant keratinocyte proliferation and function. Immune cells infiltrate the skin and release proinflammatory cytokines that play important roles in psoriasis. The Th17 network, including IL-23 and IL-22, has recently emerged as a critical component in the pathogenesis of psoriasis. IL-22 and IL-23 signaling is dependent on the JAK family of protein tyrosine kinases, making Janus kinase (JAK) inhibition an appealing strategy for the treatment of psoriasis. Here we report the activity of SAR-20347, a small molecule inhibitor with specificity for JAK1 and Tyrosine Kinase 2 (TYK2) over other JAK family members. In cellular assays, SAR-20347 dose-dependently (1 nM-10 μM) inhibited JAK1 and/or TYK2 dependent signaling from the IL-12/IL-23, IL-22, and IFN-α receptors. In vivo, TYK2 mutant mice or treatment of wild type mice with SAR-20347 significantly reduced IL-12 induced IFN-γ production and IL-22-dependent Serum Amyloid A (SAA) to similar extents, indicating that in these models, SAR-20347 is probably acting through inhibition of TYK2. In an imiquimod-induced psoriasis model, the administration of SAR-20347 led to a striking decrease in disease pathology, including reduced activation of keratinocytes, and proinflammatory cytokine levels compared to both TYK2 mutant mice and wild type controls. Taken together, these data indicate that targeting both JAK1 and TYK2-mediated cytokine signaling is more effective than TYK2 inhibition alone in reducing psoriasis pathogenesis. PMID:25156366

  18. Inhibition of TYK2 and JAK1 ameliorates imiquimod-induced psoriasis-like dermatitis by inhibiting IL-22 and the IL-23/IL-17 axis.

    PubMed

    Works, Melissa G; Yin, Fangfang; Yin, Catherine C; Yiu, Ying; Shew, Kenneth; Tran, Thanh-Thuy; Dunlap, Nahoko; Lam, Jennifer; Mitchell, Tim; Reader, John; Stein, Paul L; D'Andrea, Annalisa

    2014-10-01

    Psoriasis is a chronic autoimmune disease affecting the skin and characterized by aberrant keratinocyte proliferation and function. Immune cells infiltrate the skin and release proinflammatory cytokines that play important roles in psoriasis. The Th17 network, including IL-23 and IL-22, has recently emerged as a critical component in the pathogenesis of psoriasis. IL-22 and IL-23 signaling is dependent on the JAK family of protein tyrosine kinases, making JAK inhibition an appealing strategy for the treatment of psoriasis. In this study, we report the activity of SAR-20347, a small molecule inhibitor with specificity for JAK1 and tyrosine kinase 2 (TYK2) over other JAK family members. In cellular assays, SAR-20347 dose dependently (1 nM-10 μM) inhibited JAK1- and/or TYK2-dependent signaling from the IL-12/IL-23, IL-22, and IFN-α receptors. In vivo, TYK2 mutant mice or treatment of wild-type mice with SAR-20347 significantly reduced IL-12-induced IFN-γ production and IL-22-dependent serum amyloid A to similar extents, indicating that, in these models, SAR-20347 is probably acting through inhibition of TYK2. In an imiquimod-induced psoriasis model, the administration of SAR-20347 led to a striking decrease in disease pathology, including reduced activation of keratinocytes and proinflammatory cytokine levels compared with both TYK2 mutant mice and wild-type controls. Taken together, these data indicate that targeting both JAK1- and TYK2-mediated cytokine signaling is more effective than TYK2 inhibition alone in reducing psoriasis pathogenesis. PMID:25156366

  19. Inhibition of microRNA-497 ameliorates anoxia/reoxygenation injury in cardiomyocytes by suppressing cell apoptosis and enhancing autophagy

    PubMed Central

    Li, Xixian; Zeng, Zhi; Li, Qingman; Xu, Qiulin; Xie, Jiahe; Hao, Huixin; Luo, Guangjin; Liao, Wangjun; Bin, Jianping; Huang, Xiaobo; Liao, Yulin

    2015-01-01

    MiR-497 is predicted to target anti-apoptosis gene Bcl2 and autophagy gene microtubule-associated protein 1 light chain 3 B (LC3B), but the functional consequence of miR-497 in response to anoxia/reoxygenation (AR) or ischemia/reperfusion (IR) remains unknown. This study was designed to investigate the influences of miR-497 on myocardial AR or IR injury. We noted that miR-497 was enriched in cardiac tissues, while its expression was dynamically changed in murine hearts subjected to myocardial infarction and in neonatal rat cardiomyocytes (NRCs) subjected to AR. Forced expression of miR-497 (miR-497 mimic) induced apoptosis in NRCs as determined by Hoechst staining and TUNEL assay. In response to AR, silencing of miR-497 using a miR-497 sponge significantly reduced cell apoptosis and enhanced autophagic flux. Furthermore, the infarct size induced by IR in adenovirus (Ad)-miR-497 sponge infected mice was significantly smaller than in mice receiving Ad-vector or vehicle treatment, while Ad-miR-497 increased infarct size. The expression of Bcl-2 and LC3B-II in NRCs or in murine heart was significantly decreased by miR-497 mimic and enhanced by miR-497 sponge. These findings demonstrate that inhibition of miR-497 holds promise for limiting myocardial IR injury. PMID:26299920

  20. Suppressing Syndecan-1 Shedding Ameliorates Intestinal Epithelial Inflammation through Inhibiting NF-κB Pathway and TNF-α.

    PubMed

    Zhang, Yan; Wang, Zhongqiu; Liu, Jun; Zhang, Zhenyu; Chen, Ye

    2016-01-01

    Syndecan-1 (SDC1), with a long variable ectodomain carrying heparan sulfate chains, participates in many steps of inflammatory responses. But reports about the efforts of SDC1's unshedding ectodomain on intestinal epithelial inflammation and the precise underlying mechanism are limited. In our study, unshedding SDC1 from intestinal epithelial cell models was established by transfecting with unshedding SDC1 plasmid into the cell, respectively. And the role of unshedding SDC1 in intestinal inflammation was further investigated. We found that components of NF-κB pathway, including P65 and IκBα, and secretion of TNF-α were upregulated upon LPS stimulation in intestinal epithelial cells. SDC1, especially through its unshed ectodomain, significantly lessened the upregulation extent. It also functioned in inhibiting migration of neutrophils by downregulating secretion of CXCL-1. Taken together, we conclude that suppressing SDC1 shedding from intestinal epithelial cells relieves severity of intestinal inflammation by inactivating NF-κB pathway and downregulating TNF-α expression. These results indicate that the ectodomain of SDC1 might be the optional therapy for intestinal inflammation. PMID:27579035

  1. Fenugreek seed extract inhibit fat accumulation and ameliorates dyslipidemia in high fat diet-induced obese rats.

    PubMed

    Kumar, Parveen; Bhandari, Uma; Jamadagni, Shrirang

    2014-01-01

    This study investigated the inhibitory effect of aqueous extract of Trigonella foenum-graecum seeds (AqE-TFG) on fat accumulation and dyslipidemia in high fat diet- (HFD-) induced obese rats. Female Wistar rats were fed with HFD ad libitum, and the rats on HFD were treated orally with AqE-TFG or orlistat ((HFD for 28 days+AqE-TFG (0.5 and 1.0 g/kg) or orlistat (10 mg/kg) from day 8 to 28), respectively. Treatment with AqE-TFG produced significant reduction in body weight gain, body mass index (BMI), white adipose tissue (WAT) weights, blood glucose, serum insulin, lipids, leptin, lipase, and apolipoprotein-B levels and elevation in adiponectin levels. AqE-TFG improved serum aspartate amino transferase (AST), alanine amino transferase (ALT), and lactate dehydrogenase (LDH) levels. AqE-TFG treatment reduced the hepatic and cardiac thiobarbituric acid reactive substances (TBARS) and elevated the antioxidant enzyme (glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT)) levels. In addition, liver and uterine WAT lipogenic enzyme (fatty acid synthetase (FAS) and glucose-6-phosphate dehydrogenase (G6PD)) activities were restored towards normal levels. These findings demonstrated the preventive effect of AqE-TFG on fat accumulation and dyslipidemia, due to inhibition of impaired lipid digestion and absorption, in addition to improvement in glucose and lipid metabolism, enhancement of insulin sensitivity, increased antioxidant defense, and downregulation of lipogenic enzymes. PMID:24868532

  2. Inhibition of catecholamine degradation ameliorates while chemical sympathectomy aggravates the severity of acute Friend retrovirus infection in mice.

    PubMed

    Bloemker, Dominique; Mollerus, Sina; Gibbert, Kathrin; Dittmer, Ulf; del Rey, Adriana; Schedlowski, Manfred; Engler, Harald

    2016-05-01

    Several lines of evidence indicate that the sympathetic nervous system (SNS) might be involved in the pathogenesis and progression of retroviral infections. However, experimental data are scarce and findings inconsistent. Here, we investigated the role of the SNS during acute infection with Friend virus (FV), a pathogenic murine retrovirus that causes polyclonal proliferation of erythroid precursor cells and splenomegaly in adult mice. Experimental animals were infected with FV complex, and viral load, spleen weight, and splenic noradrenaline (NA) concentration was analyzed until 25 days post infection. Results show that FV infection caused a massive but transient depletion in splenic NA during the acute phase of the disease. At the peak of the virus-induced splenomegaly, splenic NA concentration was reduced by about 90% compared to naïve uninfected mice. Concurrently, expression of the catecholamine degrading enzymes monoamine oxidase A (MAO-A) and catechol-O-methyltransferase (COMT) was significantly upregulated in immune cells of the spleen. Pharmacological inhibition of MAO-A and COMT by the selective inhibitors clorgyline and 3,5-dinitrocatechol, respectively, efficiently blocked NA degradation and significantly reduced viral load and virus-induced splenomegaly. In contrast, chemical sympathectomy prior to FV inoculation aggravated the acute infection and extended the duration of the disease. Together these findings demonstrate that catecholamine availability at the site of viral replication is an important factor affecting the course of retroviral infections. PMID:26880342

  3. Suppressing Syndecan-1 Shedding Ameliorates Intestinal Epithelial Inflammation through Inhibiting NF-κB Pathway and TNF-α

    PubMed Central

    Zhang, Yan; Wang, Zhongqiu; Liu, Jun; Zhang, Zhenyu

    2016-01-01

    Syndecan-1 (SDC1), with a long variable ectodomain carrying heparan sulfate chains, participates in many steps of inflammatory responses. But reports about the efforts of SDC1's unshedding ectodomain on intestinal epithelial inflammation and the precise underlying mechanism are limited. In our study, unshedding SDC1 from intestinal epithelial cell models was established by transfecting with unshedding SDC1 plasmid into the cell, respectively. And the role of unshedding SDC1 in intestinal inflammation was further investigated. We found that components of NF-κB pathway, including P65 and IκBα, and secretion of TNF-α were upregulated upon LPS stimulation in intestinal epithelial cells. SDC1, especially through its unshed ectodomain, significantly lessened the upregulation extent. It also functioned in inhibiting migration of neutrophils by downregulating secretion of CXCL-1. Taken together, we conclude that suppressing SDC1 shedding from intestinal epithelial cells relieves severity of intestinal inflammation by inactivating NF-κB pathway and downregulating TNF-α expression. These results indicate that the ectodomain of SDC1 might be the optional therapy for intestinal inflammation. PMID:27579035

  4. Oxysophocarpine Ameliorates Carrageenan-induced Inflammatory Pain via Inhibiting Expressions of Prostaglandin E2 and Cytokines in Mice.

    PubMed

    Yang, Yang; Li, Yu-Xiang; Wang, Hong-Ling; Jin, Shao-Ju; Zhou, Ru; Qiao, Hai-Qi; Du, Juan; Wu, Jing; Zhao, Cheng-Jun; Niu, Yang; Sun, Tao; Yu, Jian-Qiang

    2015-07-01

    Oxysophocarpine is an alkaloid extracted from Sophora alopecuroides. We investigated the analgesic effect of oxysophocarpine on carrageenan-induced inflammatory pain in mice, in order to explore its possible mechanisms. Mouse ear swelling tests and carrageenan-induced paw edema tests were used to investigate the effects of oxysophocarpine on inflammatory pain in mice. Morphological changes on inflamed paw sections were measured by hematoxylin-eosin staining. The mRNA and protein expression of extracellular signal-regulated kinase, phosphorylation of extracellular signal-regulated kinase 1/2, cyclooxygenase-2, tumor necrosis factor α, interleukin-1 beta, interleukin-6 and prostaglandin E2 were investigated by real-time quantitative polymerase chain reaction, immunohistochemistry, western-blot and enzyme-linked immunosorbent assay. In our results, oxysophocarpine shows a significant anti-inflammatory effect in the mouse ear swelling test. Oxysophocarpine also significantly reduced the paw edema volume and improved mechanical allodynia threshold value on carrageenan-induced inflammatory pain, as well as relieved paw tissues inflammatory damage and reduced the numbers of neutrophils in mice. Oxysophocarpine significantly suppressed over-expression of cyclooxygenase-2, tumor necrosis factor α, interleukin-1 beta, interleukin-6 and prostaglandin E2, and inhibited the over-phosphorylation of extracellular signal-regulated kinase 1/2. Based on these findings we propose that oxysophocarpine attenuates inflammatory pain by suppressing the levels of phosphorylation of extracellular signal-regulated kinase 1/2, cyclooxygenase-2, prostaglandin E2, tumor necrosis factor α, interleukin-1 beta and interleukin-6. PMID:26132856

  5. Inhibition of microsomal prostaglandin E synthase-1 by aminothiazoles decreases prostaglandin E2 synthesis in vitro and ameliorates experimental periodontitis in vivo

    PubMed Central

    Kats, Anna; Båge, Tove; Georgsson, Pierre; Jönsson, Jörgen; Quezada, Hernán Concha; Gustafsson, Anders; Jansson, Leif; Lindberg, Claes; Näsström, Karin; Yucel-Lindberg, Tülay

    2013-01-01

    The potent inflammatory mediator prostaglandin E2 (PGE2) is implicated in the pathogenesis of several chronic inflammatory conditions, including periodontitis. The inducible enzyme microsomal prostaglandin E synthase-1 (mPGES-1), catalyzing the terminal step of PGE2 biosynthesis, is an attractive target for selective PGE2 inhibition. To identify mPGES-1 inhibitors, we investigated the effect of aminothiazoles on inflammation-induced PGE2 synthesis in vitro, using human gingival fibroblasts stimulated with the cytokine IL-1β and a cell-free mPGES-1 activity assay, as well as on inflammation-induced bone resorption in vivo, using ligature-induced experimental periodontitis in Sprague-Dawley rats. Aminothiazoles 4-([4-(2-naphthyl)-1,3-thiazol-2-yl]amino)phenol (TH-848) and 4-(3-fluoro-4-methoxyphenyl)-N-(4-phenoxyphenyl)-1,3-thiazol-2-amine (TH-644) reduced IL-1β-induced PGE2 production in fibroblasts (IC50 1.1 and 1.5 μM, respectively) as well as recombinant mPGES-1 activity, without affecting activity or expression of the upstream enzyme cyclooxygenase-2. In ligature-induced experimental periodontitis, alveolar bone loss, assessed by X-ray imaging, was reduced by 46% by local treatment with TH-848, compared to vehicle, without any systemic effects on PGE2, 6-keto PGF1α, LTB4 or cytokine levels. In summary, these results demonstrate that the aminothiazoles represent novel mPGES-1 inhibitors for inhibition of PGE2 production and reduction of bone resorption in experimental periodontitis, and may be used as potential anti-inflammatory drugs for treatment of chronic inflammatory diseases, including periodontitis.—Kats, A., Båge, T., Georgsson, P., Jönsson, J., Quezada, H. C., Gustafsson, A., Jansson, L., Lindberg, C., Näsström, K., Yucel-Lindberg, T. Inhibition of microsomal prostaglandin E synthase-1 by aminothiazoles decreases prostaglandin E2 synthesis in vitro and ameliorates experimental periodontitis in vivo. PMID:23447581

  6. Inhibition of Rac1 activity by controlled release of NSC23766 from chitosan microspheres effectively ameliorates osteoarthritis development in vivo

    PubMed Central

    Zhu, Shouan; Lu, Ping; Liu, Huanhuan; Chen, Pengfei; Wu, Yan; Wang, Yanyan; Sun, Heng; Zhang, Xiaolei; Xia, Qingqing; Heng, Boon Chin; Zhou, Yiting; Ouyang, Hong Wei

    2015-01-01

    Background Osteoarthritis (OA) is a degenerative joint disease characterised by cartilage degradation and chondrocyte hypertrophy. A recent study showed that Rac1 promoted expression of MMP13 and chondrocyte hypertrophy within the growth plate. These findings warrant further investigations on the roles of Rac1 in OA development and therapy in animal models. Objective To investigate the role and mechanistic pathway of Rac1 involvement in pathological changes of OA chondrocytes in vitro and OA development in vivo, as well as to develop a strategy of modulating Rac1 activity for OA treatment. Material and methods OA and normal cartilage from human or mice were used for immunohistochemical study and Rac1 activity assay. Chondrocytes treated with IL1β and the untreated control were subjected to the Rac1 activity assay. Chondrocytes transfected with CA-Rac1, DN-Rac1 or GFP were cultured under conditions for inducing calcification. To evaluate the effect of Rac1 in OA development, an OA model was created by anterior cruciate ligament transection in mice. CA-Rac1, DN-Rac1 and GFP lentivirus, or NSC23766, were injected intra-articularly. Joints were subjected to histological analysis. Results It was found that there is aberrant Rac1 activation in human OA cartilage. Rac1 activity could also be elevated by IL1β. Additionally, activated Rac1 promoted expression of MMP13, ADAMTS-5 and COLX by chondrocytes, partially through the β-catenin pathway. Moreover, activation of Rac1 in knee joints by CA-Rac1 lentivirus accelerated OA progression, while inhibition of Rac1 activity by DN-Rac1 lentivirus or Rac1 inhibitor NSC23766 delayed OA development. Therefore, we developed a strategy of controlled release of NSC23766 from chitosan microspheres to OA joints, which effectively protected cartilage from destruction. Conclusions These findings demonstrated that Rac1 activity is implicated in OA development. Also, controlled release of Rac1 inhibitor is a promising strategy for OA

  7. Inhibition of hypoxia inducible factor-1α ameliorates lung injury induced by trauma and hemorrhagic shock in rats

    PubMed Central

    Jiang, Hong; Huang, Yan; Xu, Hui; Hu, Rong; Li, Qi-fang

    2012-01-01

    Aim: Ischemia/reperfusion is an initial triggering event that leads to gut-induced acute lung injury (ALI). In this study, we investigated whether hypoxia inducible factor-1α (HIF-1α) played a role in the pathogenesis of lung injury induced by trauma and hemorrhagic shock (T/HS). Methods: Male Wistar rats underwent laparotomy and hemorrhagic shock for 60 min. Sham-shock animals underwent laparotomy but without hemorrhagic shock. After resuscitation for 3 hr, the rats were sacrificed. Morphologic changes of the lungs and intestines were examined. Bronchoalveolar lavage fluid (BALF) was collected. Lung water content, pulmonary myeloperoxidase (MPO) activity and the levels of malondialdehyde (MDA), nitrite/nitrate, TNF-α, IL-1β, and IL-6 in the lungs were measured. The gene expression of pulmonary HIF-1α and iNOS, and HIF-1α transcriptional activity in the lungs were also assessed. The apoptosis in the lungs was determined using TUNEL assay and cleaved caspase-3 expression. Results: Lung and intestinal injuries induced by T/HS were characterized by histological damages and a significant increase in lung water content. Compared to the sham-shock group, the BALF cell counts, the pulmonary MPO activity and the MDA, nitrite/nitrate, TNF-α, IL-1β, and IL-6 levels in the T/HS group were significantly increased. Acute lung injury was associated with a higher degree of pulmonary HIF-1α and iNOS expression as well as apoptosis in the lungs. Intratracheal delivery of HIF-1α inhibitor YC-1 (1 mg/kg) significantly attenuated lung injury, and reduced pulmonary HIF-1α and iNOS expression and HIF-1α transcriptional activity in the T/HS group. Conclusion: Local inhibition of HIF-1α by YC-1 alleviates the lung injury induced by T/HS. Our results provide novel insight into the pathogenesis of T/HS-induced ALI and a potential therapeutic application. PMID:22465950

  8. The effect of pre-pulse on the gratings coded by two interfered femtosecond pulses

    NASA Astrophysics Data System (ADS)

    Han, Yanhua; Fan, Guanghua; Qu, Shiliang

    2016-07-01

    The effect of pre-pulse on the gratings coded with two interfered femtosecond pulses is studied on silica glass. The results show that the modulation depth of the gratings is deeper than that in absence of pre-pulse, and decreases with increased arrival time of pre-pulse. For the arrival time within 120-200 fs, the free electrons produced by pre-pulse can act as seed electrons for the subsequent interfered pulses to multiply, thus deepening the depth of the gratings. With the arrival time beyond 200 fs, the self-trapped excitons can provide seed electrons for the subsequent pulse multiplying, thus deepening the gratings.

  9. Maresin 1 ameliorates iron-deficient anemia in IL-10-/- mice with spontaneous colitis by the inhibition of hepcidin expression though the IL-6/STAT3 pathway

    PubMed Central

    Wang, Honggang; Shi, Peiliang; Huang, Chuanjiang; Liu, Qinghong

    2016-01-01

    Background: Approximately 50% of patients with inflammatory bowel disease (IBD) suffer from anemia, which is prevalently caused by iron deficiency. Maresin 1 (MaR1) is a novel docosahexaenoic acid-derived pro-resolving agent that promotes the resolution of inflammation. The aim of the present study was to investigate the therapeutic effects of MaR1 on iron-deficient anemia in IL-10 knockout (IL-10-/-) mice with spontaneous chronic colitis. Methods: IL-10-/- mice of 16 weeks of age with established colitis were used for the experiments with MaR1 treatment for 2 weeks. Histologic injury, CD4+ lymphocyte values in the lamina propria, blood hemoglobin, hematocrit, serum iron concentrations, transferrin saturation, splenic iron stores, levels of inflammatory cytokines, expression of liver hepcidin mRNA, and western blotting of STAT3 were analyzed in this study. Results: MaR1 treatment (0.3 ng/mouse) effectively attenuated histological colitis typically associated with decreased CD4+ lymphocytes in the lamina propria as well as the concentrations of MPO, TNF-α, IFN-γ, IL-6 and IL-17 (P<0.05). Furthermore, reduced expression of liver hepcidin mRNA and p-STAT3 expression, as well as increased hemoglobin concentration, hematocrit, levels of serum iron, transferrin saturation and splenic iron stores were found in IL-10-/- mice after MaR1 treatment (P<0.05). Conclusions: These results indicate that MaR1 treatment ameliorates iron-deficient anemia by reducing colonic inflammation and inhibiting hepcidin expression though the IL-6/STAT3 pathway. PMID:27398158

  10. Ginsenoside Rg1 ameliorates diabetic cardiomyopathy by inhibiting endoplasmic reticulum stress-induced apoptosis in a streptozotocin-induced diabetes rat model.

    PubMed

    Yu, Haitao; Zhen, Juan; Yang, Yang; Gu, Jinning; Wu, Suisheng; Liu, Quan

    2016-04-01

    Ginsenoside Rg1 has been demonstrated to have cardiovascular protective effects. However, whether the cardioprotective effects of ginsenoside Rg1 are mediated by endoplasmic reticulum (ER) stress-induced apoptosis remain unclear. In this study, among 80 male Wistar rats, 15 rats were randomly selected as controls; the remaining 65 rats received a diet rich in fat and sugar content for 4 weeks, followed by intraperitoneal injection of streptozotocin (STZ, 40 mg/kg) to establish a diabetes model. Seven days after STZ injection, 10 rats were randomly selected as diabetic model (DM) controls, 45 eligible diabetic rats were randomized to three treatment groups and administered ginsenoside Rg1 in a dosage of 10, 15 or 20 mg/kg/day, respectively. After 12 weeks of treatment, rats were killed and serum samples obtained to determine cardiac troponin (cTn)-I. Myocardial tissues were harvested for morphological analysis to detect myocardial cell apoptosis, and to analyse protein expression of glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), and Caspase-12. Treatment with ginsenoside Rg1 (10-20 mg/kg) significantly reduced serum cTnI levels compared with DM control group (all P < 0.01). Ginsenoside Rg1 (15 and 20 mg/kg) significantly reduced the percentage of apoptotic myocardial cells and improved the parameters of cardiac function. Haematoxylin and eosin and Masson staining indicated that ginsenoside Rg1 could attenuate myocardial lesions and myocardial collagen volume fraction. Additionally, ginsenoside Rg1 significantly reduced GRP78, CHOP, and cleaved Caspase-12 protein expression in a dose-dependent manner. These findings suggest that ginsenoside Rg1 appeared to ameliorate diabetic cardiomyopathy by inhibiting ER stress-induced apoptosis in diabetic rats. PMID:26869403

  11. Penehyclidine ameliorates acute lung injury by inhibiting Toll-like receptor 2/4 expression and nuclear factor-κB activation

    PubMed Central

    WANG, NA; SU, YUE; CHE, XIANG-MING; ZHENG, HUI; SHI, ZHI-GUO

    2016-01-01

    The aim of the present study was to investigate the effect of penehyclidine (PHC) on endotoxin-induced acute lung injury (ALI), as well as to examine the mechanism underlying this effect. A total of 60 rats were randomly divided into five groups, including the control (saline), LPS and three LPS + PHC groups. ALI was induced in the rats by injection of 8 mg lipopolysaccharide (LPS)/kg body weight. The rats were then treated with or without PHC at 0.3, 1 or 3 mg/kg body weight 1 min following LPS injection. After 6 h, serum levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 were determined by ELISA. In addition, the mRNA expression levels of toll-like receptor (TLR)2 and TLR4 were examined by reverse transcription-quantitative polymerase chain reaction in the lung tissue samples, and nuclear factor (NF)-κB p65 protein expression levels were examined by western blot analysis. The results demonstrated that lung injury was ameliorated by treatment with PHC (1 and 3 mg/kg body weight) as compared with treatment with LPS alone. Injection of LPS significantly increased the mRNA expression levels of TLR2 and TLR4, as well as the protein expression levels of NF-κB p65 in the lung tissue samples. Serum levels of TNF-α and IL-6 were also upregulated by LPS injection. Treatment of the rats with PHC following LPS injection suppressed the LPS-induced increase in TLR2/4 mRNA and NF-κB p65 protein expression levels. PHC also inhibited the increase in TNF-α and IL-6 serum levels. In addition, PHC reduced LPS-induced ALI and decreased the serum levels of TNF-α and IL-6, possibly by downregulating TLR2/4 mRNA expression and inhibiting NF-κB activity, and consequently alleviating the inflammatory response. PMID:27168812

  12. Measurements of low-level prepulse on Nike KrF laser

    NASA Astrophysics Data System (ADS)

    Karasik, Max; Mostovych, A. N.; Lehmberg, R. H.; Chan, Y.; Weaver, J. L.; Obenschain, S. P.

    2005-09-01

    The krypton fluoride (KrF) laser is a leading candidate driver for inertial fusion energy. Some of the current fusion target designs call for targets with thin metallic coatings. These targets could be particularly susceptible to preheat by a low-level laser prepulse. Knowledge of the prepulse can be important in understanding and modeling the behavior of such targets. This paper presents measurements of low-level prepulse on target with the Nike KrF laser. Sources of prepulse are discussed and measurements are performed under several specific laser conditions in order to evaluate the relative contribution of these sources to the overall prepulse. Prepulse is found to be ˜2×10-7 from peak intensity for approximately 120ns prior to the main laser pulse. Prepulse energy density on target is ˜2J/cm2. The first laser amplifier in the time- and angle-multiplexed section of the laser is found to be the dominant source of prepulse.

  13. Inhibition of Reactive Oxygen Species Production Ameliorates Inflammation Induced by Influenza A Viruses via Upregulation of SOCS1 and SOCS3

    PubMed Central

    Lowther, Sue; Stambas, John

    2014-01-01

    ABSTRACT Highly pathogenic avian influenza virus infection is associated with severe mortality in both humans and poultry. The mechanisms of disease pathogenesis and immunity are poorly understood although recent evidence suggests that cytokine/chemokine dysregulation contributes to disease severity following H5N1 infection. Influenza A virus infection causes a rapid influx of inflammatory cells, resulting in increased reactive oxygen species production, cytokine expression, and acute lung injury. Proinflammatory stimuli are known to induce intracellular reactive oxygen species by activating NADPH oxidase activity. We therefore hypothesized that inhibition of this activity would restore host cytokine homeostasis following avian influenza virus infection. A panel of airway epithelial and immune cells from mammalian and avian species were infected with A/Puerto Rico/8/1934 H1N1 virus, low-pathogenicity avian influenza H5N3 virus (A/duck/Victoria/0305-2/2012), highly pathogenic avian influenza H5N1 virus (A/chicken/Vietnam/0008/2004), or low-pathogenicity avian influenza H7N9 virus (A/Anhui/1/2013). Quantitative real-time reverse transcriptase PCR showed that H5N1 and H7N9 viruses significantly stimulated cytokine (interleukin-6, beta interferon, CXCL10, and CCL5) production. Among the influenza-induced cytokines, CCL5 was identified as a potential marker for overactive immunity. Apocynin, a Nox2 inhibitor, inhibited influenza-induced cytokines and reactive oxygen species production, although viral replication was not significantly altered in vitro. Interestingly, apocynin treatment significantly increased influenza virus-induced mRNA and protein expression of SOCS1 and SOCS3, enhancing negative regulation of cytokine signaling. These findings suggest that apocynin or its derivatives (targeting host responses) could be used in combination with antiviral strategies (targeting viruses) as therapeutic agents to ameliorate disease severity in susceptible species

  14. Electroacupuncture ameliorates post-stroke learning and memory through minimizing ultrastructural brain damage and inhibiting the expression of MMP-2 and MMP-9 in cerebral ischemia-reperfusion injured rats.

    PubMed

    Lin, Ruhui; Yu, Kunqiang; Li, Xiaojie; Tao, Jing; Lin, Yukun; Zhao, Congkuai; Li, Chunyan; Chen, Li-Dian

    2016-07-01

    The aim of the present study was to investigate the potential neuroprotective effects of electroacupuncture (EA) in the treatment of cerebral ischemia/reperfusion (I/R) injury, and to elucidate the association between this neuroprotective effect and brain ultrastructure and expression of matrix metalloproteinase (MMP)‑2 and 9. Rats underwent focal cerebral I/R injury by arterial ligation and received in vivo therapeutic EA at the Baihui (DU20) and Shenting (DU24) acupoints. The therapeutic efficacy was then evaluated following the surgery. The results of the current study demonstrated that EA treatment significantly ameliorated neurological deficits and reduced cerebral infarct volume compared with I/R injured rats. Furthermore, EA improved the learning and memory ability of rats following I/R injury, inhibited blood brain barrier breakdown and reduced neuronal damage in the ischemic penumbra. Furthermore, EA attenuated ultrastructural changes in the brain tissue following ischemia and inhibited MMP‑2/MMP‑9 expression in cerebral I/R injured rats. The results suggest that EA ameliorates anatomical deterioration, and learning and memory deficits in rats with cerebral I/R injury. PMID:27177163

  15. Electroacupuncture ameliorates post-stroke learning and memory through minimizing ultrastructural brain damage and inhibiting the expression of MMP-2 and MMP-9 in cerebral ischemia-reperfusion injured rats

    PubMed Central

    LIN, RUHUI; YU, KUNQIANG; LI, XIAOJIE; TAO, JING; LIN, YUKUN; ZHAO, CONGKUAI; LI, CHUNYAN; CHEN, LI-DIAN

    2016-01-01

    The aim of the present study was to investigate the potential neuroprotective effects of electroacupuncture (EA) in the treatment of cerebral ischemia/reperfusion (I/R) injury, and to elucidate the association between this neuroprotective effect and brain ultrastructure and expression of matrix metalloproteinase (MMP)-2 and 9. Rats underwent focal cerebral I/R injury by arterial ligation and received in vivo therapeutic EA at the Baihui (DU20) and Shenting (DU24) acupoints. The therapeutic efficacy was then evaluated following the surgery. The results of the current study demonstrated that EA treatment significantly ameliorated neurological deficits and reduced cerebral infarct volume compared with I/R injured rats. Furthermore, EA improved the learning and memory ability of rats following I/R injury, inhibited blood brain barrier breakdown and reduced neuronal damage in the ischemic penumbra. Furthermore, EA attenuated ultrastructural changes in the brain tissue following ischemia and inhibited MMP-2/MMP-9 expression in cerebral I/R injured rats. The results suggest that EA ameliorates anatomical deterioration, and learning and memory deficits in rats with cerebral I/R injury. PMID:27177163

  16. Prepulse dependence in hard x-ray generation from microdroplets

    SciTech Connect

    Anand, M.; Kahaly, S.; Kumar, G. Ravindra; Sandhu, A. S.; Gibbon, P.; Krishnamurthy, M.

    2006-04-07

    We report on experiments which show that liquid microdroplets are very efficient in hard x-ray generation. We make a comparative study of hard x-ray emission from 15 {mu}m methanol microdroplets and a plain slab target of similar atomic composition at similar laser intensities. The hard X-ray yield from droplet plasmas is about 35 times more than that obtained from solid plasmas. A prepulse that is about 10ns and at least 2% in intensity of the main pulse is essential for hard x-ray generation from the droplets at about 1015 W cm-2. A hot electron temperature of 36 keV is measured from the droplets at 8 x 1014 W cm-2; three times higher intensity is needed to obtain similar hot electron temperature from solid plasmas that have similar atomic composition. We use 1D-PIC simulation to obtain qualitative correlation to the experimental observations.

  17. The effects of insulating coatings and current prepulse on tungsten planar wire array Z-pinches

    SciTech Connect

    Li, M. Li, Y.; Sheng, L.; Wang, L. P.; Zhao, C.; Yuan, Y.; Zhang, X. J.; Zhang, M.; Peng, B. D.; Zhang, J. H.; Zhang, S. G.; Qiu, M. T.; Li, X. W.

    2015-12-15

    This paper presents experimental results on the effects of insulating coatings and current prepulse on tungsten planar wire array Z-pinches on ∼100 ns main current facility. Optical framing images indicated that without a current prepulse the wire ablation process was asymmetrical and the implosion was zippered. The x-ray peak power was ∼320 GW. By using insulating coatings on the wire surface the asymmetry remained, and the processes of ablation and implosion were delayed by ∼30 ns. The x-ray burst was narrow and decreased to ∼200 GW. When current prepulses were used on both standard and insulated wire arrays, implosion symmetry was improved and the x-ray burst was improved (to ∼520 GW peak power). In addition, there was a strong emitting precursor column for insulated loads with the current prepulse.

  18. Effect of current prepulse on wire array initiation on the 1-MA ZEBRA accelerator

    SciTech Connect

    Sarkisov, G. S.; Rosenthal, S. E.; Struve, K. W.; Ivanov, V. V.; Cowan, T. E.; Astanovitskiy, A.; Haboub, A.

    2007-05-15

    Experiments on the 1-MA ZEBRA accelerator with reduced current prepulse duration, using a flashover switch, demonstrate a significant increase of initial energy deposition into the tungsten wire array before breakdown, and of total radiation energy from the Z pinch. Shorter current prepulse raises the current rate through each individual wire in the array and results in an increase of the energy deposition into wire cores before breakdown. In our experiments, the inferred tungsten wire temperature increases from {approx}800 K (with 250 ns prepulse) up to {approx}3700 K (with 60 ns prepulse). Total radiation energy increases from 12 to 16 kJ. Our experimental results relate wire-array initiation to heating of the individual array wires up to the time of breakdown.

  19. Studies of prepulses and late pulses in the 8″ electron tubes series of photomultipliers

    NASA Astrophysics Data System (ADS)

    Lubsandorzhiev, B. K.; Pokhil, P. G.; Vasiljev, R. V.; Wright, A. G.

    2000-03-01

    In this article we describe the main results of the study of prepulses and late pulses in the 8″ Electron Tubes series of photomultipliers. Photomultipliers with large hemispherical photocathodes are used widely in many large-scale underground and underwater experiments where precision timing plays a crucial role. The measurements carried out with the aim of demonstrating importance of PMT timing in the context of prepulses and late pulses.

  20. Chronic administration of the neurotrophic agent cerebrolysin ameliorates the behavioral and morphological changes induced by neonatal ventral hippocampus lesion in a rat model of schizophrenia.

    PubMed

    Vázquez-Roque, Rubén Antonio; Ramos, Brenda; Tecuatl, Carolina; Juárez, Ismael; Adame, Anthony; de la Cruz, Fidel; Zamudio, Sergio; Mena, Raúl; Rockenstein, Edward; Masliah, Eliezer; Flores, Gonzalo

    2012-01-01

    Neonatal ventral hippocampal lesion (nVHL) in rats has been widely used as a neurodevelopmental model to mimic schizophrenia-like behaviors. Recently, we reported that nVHLs result in dendritic retraction and spine loss in prefrontal cortex (PFC) pyramidal neurons and medium spiny neurons of the nucleus accumbens (NAcc). Cerebrolysin (Cbl), a neurotrophic peptide mixture, has been reported to ameliorate the synaptic and dendritic pathology in models of aging and neurodevelopmental disorder such as Rett syndrome. This study sought to determine whether Cbl was capable of reducing behavioral and neuronal alterations in nVHL rats. The behavioral analysis included locomotor activity induced by novel environment and amphetamine, social interaction, and sensoriomotor gating. The morphological evaluation included dendritic analysis by using the Golgi-Cox procedure and stereology to quantify the total cell number in PFC and NAcc. Behavioral data show a reduction in the hyperresponsiveness to novel environment- and amphetamine-induced locomotion, with an increase in the total time spent in social interactions and in prepulse inhibition in Cbl-treated nVHL rats. In addition, neuropathological analysis of the limbic regions also showed amelioration of dendritic retraction and spine loss in Cbl-treated nVHL rats. Cbl treatment also ameliorated dendritic pathology and neuronal loss in the PFC and NAcc in nVHL rats. This study demonstrates that Cbl promotes behavioral improvements and recovery of dendritic neuronal damage in postpubertal nVHL rats and suggests that Cbl may have neurotrophic effects in this neurodevelopmental model of schizophrenia. These findings support the possibility that Cbl has beneficial effects in the management of schizophrenia symptoms. PMID:21932359

  1. Effect of cathode diameter on intense relativistic electron beam generation in the presence of prepulse

    SciTech Connect

    Roy, Amitava; Menon, R.; Mitra, S.; Kumar, D. D. P.; Kumar, Senthil; Sharma, V. K.; Patel, Ankur; Sharma, Archana; Mittal, K. C.; Nagesh, K. V.; Chakravarthy, D. P.

    2008-07-01

    Intense gigawatt relativistic electron beam generation studies were carried out in the presence of prepulse. Electron beams were generated using planar and annular graphite cathodes of various diameters at a fixed 25 mm anode-cathode gap. For the planar cathode, the beam parameters obtained are 340 keV, 24 kA, and 100 ns at a 680 A/cm{sup 2} current density. With an annular cathode, 346 keV, 10 kA, and 100 ns electron beam could be generated at a 3.4 kA/cm{sup 2} current density. The peak electric field in the diode varies from 58 to 138 kV/cm. A bipolar prepulse voltage has been recorded at the diode for both the cathodes. The amplitude of the negative prepulse voltage varies with the Marx generator voltage but the time duration remains same. The positive prepulse voltage varies both in amplitude and time duration with the Marx generator voltage. Some shot to shot variation in the diode voltage and current were recorded for the annular cathode due to the nonreproducibility of the prepulse generated plasma. It was found that the effect of prepulse is more pronounced in the cathode of larger diameter.

  2. Controlling output pulse and prepulse in a resonant microwave pulse compressor

    SciTech Connect

    Shlapakovski, A.; Artemenko, S.; Chumerin, P.; Yushkov, Yu.

    2013-02-07

    A resonant microwave pulse compressor with a waveguide H-plane-tee-based energy extraction unit was studied in terms of its capability to produce output pulses that comprise a low-power long-duration (prepulse) and a high-power short-duration part. The application of such combined pulses with widely variable prepulse and high-power pulse power and energy ratios is of interest in the research area of electronic hardware vulnerability. The characteristics of output radiation pulses are controlled by the variation of the H-plane tee transition attenuation at the stage of microwave energy storage in the compressor cavity. Results of theoretical estimations of the parameters tuning range and experimental investigations of the prototype S-band compressor (1.5 MW, 12 ns output pulse; {approx}13.2 dB gain) are presented. The achievable maximum in the prepulse power is found to be about half the power of the primary microwave source. It has been shown that the energy of the prepulse becomes comparable with that of the short-duration (nanosecond) pulse, while the power of the latter decreases insignificantly. The possible range of variation of the prepulse power and energy can be as wide as 40 dB. In the experiments, the prepulse level control within the range of {approx}10 dB was demonstrated.

  3. A semisynthetic diterpenoid lactone inhibits NF-κB signalling to ameliorate inflammation and airway hyperresponsiveness in a mouse asthma model.

    PubMed

    Lim, J C-W; Goh, F-Y; Sagineedu, S-R; Yong, A C-H; Sidik, S M; Lajis, N H; Wong, W S F; Stanslas, J

    2016-07-01

    Andrographolide (AGP) and 14-deoxy-11,12-didehydroandrographolide (DDAG), two main diterpenoid constituents of Andrographis paniculata were previously shown to ameliorate asthmatic symptoms in a mouse model. However, due to inadequacies of both compounds in terms of drug-likeness, DDAG analogues were semisynthesised for assessment of their anti-asthma activity. A selected analogue, 3,19-diacetyl-14-deoxy-11,12-didehydroandrographolide (SRS27), was tested for inhibitory activity of NF-κB activation in TNF-α-induced A549 cells and was subsequently evaluated in a mouse model of ovalbumin (OVA)-induced asthma. Female BALB/c mice, 6-8weeks old were sensitized on days 0 and 14, and challenged on days 22, 23 and 24 with OVA. Compound or vehicle (3% dimethyl sulfoxide) was administered intraperitoneally 1h before and 11h after each OVA aerosol challenge. On day 25, pulmonary eosinophilia, airway hyperresponsiveness, mucus hypersecretion, inflammatory cytokines such as IL-4, -5 and -13 in BAL fluid, gene expression of inflammatory mediators such as 5-LOX, E-selectin, VCAM-1, CCL5, TNF-α, AMCase, Ym2, YKL-40, Muc5ac, CCL2 and iNOS in animal lung tissues, and serum IgE were determined. SRS27 at 30μM was found to suppress NF-κB nuclear translocation in A549 cells. In the ovalbumin-induced mouse asthma model, SRS27 at 3mg/kg displayed a substantial decrease in pulmonary eosinophilia, BAL fluid inflammatory cytokines level, serum IgE production, mucus hypersecretion and gene expression of inflammatory mediators in lung tissues. SRS27 is the first known DDAG analogue effective in ameliorating inflammation and airway hyperresponsiveness in the ovalbumin-induced mouse asthma model. PMID:27089844

  4. High doses of salicylate causes prepulse facilitation of onset-gap induced acoustic startle response.

    PubMed

    Sun, Wei; Doolittle, Lauren; Flowers, Elizabeth; Zhang, Chao; Wang, Qiuju

    2014-01-01

    Prepulse inhibition of acoustic startle reflex (PPI), a well-established method for evaluating sensorimotor gating function, has been used to detect tinnitus in animal models. Reduced gap induced PPI (gap-PPI) was considered as a sign of tinnitus. The silent gap used in the test contains both onset and offset signals. Tinnitus may affect these cues differently. In this experiment, we studied the effects of a high dose of salicylate (250 mg/kg, i.p.), an inducer of reversible tinnitus and sensorineural hearing loss, on gap-PPI induced by three different gaps: an onset-gap with 0.1 ms onset and 25 ms offset time, an offset-gap with 25 ms onset and 0.1 ms offset time, and an onset-offset-gap with 0.1 ms onset and offset time. We found that the onset-gaps induced smaller inhibitions than the offset-gaps before salicylate treatment. The offset-gap induced PPI was significantly reduced 1-3h after salicylate treatment. However, the onset-gap caused a facilitation of startle response. These results suggest that salicylate induced reduction of gap-PPI was not only caused by the decrease of offset-gap induced PPI, but also by the facilitation induced by the onset-gap. Since the onset-gap induced PPI is caused by neural offset response, our results suggest that salicylate may cause a facilitation of neural response to an offset acoustical signal. Treatment of vigabatrin (60 mg/kg/day, 14 days), which elevates the GABA level in the brain, blocked the offset-gap induced PPI and onset-gap induced facilitation caused by salicylate. These results suggest that enhancing GABAergic activities can alleviate salicylate induced tinnitus. PMID:24149068

  5. Cysteamine treatment ameliorates alterations in GAD67 expression and spatial memory in heterozygous reeler mice

    PubMed Central

    Kutiyanawalla, Ammar; Promsote, Wanwisa; Terry, Alvin; Pillai, Anilkumar

    2011-01-01

    Brain derived neurotrophic factor (BDNF) signaling through its receptor, TrkB is known to regulate GABAergic function and glutamic acid decarboxylase (GAD) 67 expression in neurons. Alterations in BDNF signaling have been implicated in the pathophysiology of schizophrenia and as a result, they are a potential therapeutic target. Interestingly, heterozygous reeler mice (HRM) have decreased GAD67 expression in the frontal cortex and hippocampus and they exhibit many behavioral and neurochemical abnormalities similar to schizophrenia. In the present study, we evaluated the potential of cysteamine, a neuroprotective compound to improve the deficits in GAD67 expression and cognitive function in HRM. We found that cysteamine administration (150 mg/kg/day, through drinking water) for 30 days significantly ameliorated the decreases in GAD67, mature BDNF and full-length TrkB protein levels found in frontal cortex and hippocampus of HRM. A significant attenuation of the increased levels of truncated BDNF in frontal cortex and hippocampus, as well as truncated TrkB in frontal cortex of HRM was also observed following cysteamine treatment. In behavioral studies, HRM were impaired in a Y-maze spatial recognition memory task, but not in a spontaneous alternation task or a sensorimotor, prepulse inhibition (PPI) procedure. Cysteamine improved Y-maze spatial recognition in HRM to the level of wide-type controls and it improved PPI in both wild-type and HRM. Finally, mice deficient in TrkB, showed a reduced response to cysteamine in GAD67 expression suggesting that TrkB signaling plays an important role in GAD67 regulation by cysteamine. PMID:21777509

  6. Inhibition of Notch Signaling Ameliorates Acute Kidney Failure and Downregulates Platelet-Derived Growth Factor Receptor β in the Mouse Model.

    PubMed

    Kramer, Jan; Schwanbeck, Ralf; Pagel, Horst; Cakiroglu, Figen; Rohwedel, Jürgen; Just, Ursula

    2016-01-01

    Ischemic acute kidney injury (AKI) is associated with high morbidity and frequent complications. Repeated episodes of AKI may lead to end-stage renal failure. The pathobiology of regeneration in AKI is not well understood and there is no effective clinical therapy that improves regeneration. The Notch signaling pathway plays an essential role in kidney development and has been implicated in tissue repair in the adult kidney. Here, we found that kidneys after experimental AKI in mice showed increased expression of Notch receptors, specifically Notch1-3, of the Notch ligands Jagged-1 (Jag1), Jag2 and Delta-like-4 (Dll4) and of the Notch target genes Hes1, Hey2, HeyL, Sox9 and platelet-derived growth factor receptor β (Pdgfrb). Treatment of ischemic mice with the x03B3;-secretase inhibitor DBZ blocked Notch signaling and specifically downregulated the expression of Notch3 and the Notch target genes Hes1, Hey2, HeyL and Pdgfrb. After DBZ treatment, the mice developed less interstitial edema and displayed altered interstitial inflammation patterns. Furthermore, serum urea and creatinine levels were significantly decreased from 6 h onwards when compared to control mice treated with DMSO only. Our data are consistent with an amelioration of the severity of kidney injury by blocking Notch activation following AKI, and suggest an involvement of Notch-regulated Pdgfrb in AKI pathogenesis. PMID:26939110

  7. 1,4-Dihydropyridines Active on the SIRT1/AMPK Pathway Ameliorate Skin Repair and Mitochondrial Function and Exhibit Inhibition of Proliferation in Cancer Cells.

    PubMed

    Valente, Sergio; Mellini, Paolo; Spallotta, Francesco; Carafa, Vincenzo; Nebbioso, Angela; Polletta, Lucia; Carnevale, Ilaria; Saladini, Serena; Trisciuoglio, Daniela; Gabellini, Chiara; Tardugno, Maria; Zwergel, Clemens; Cencioni, Chiara; Atlante, Sandra; Moniot, Sébastien; Steegborn, Clemens; Budriesi, Roberta; Tafani, Marco; Del Bufalo, Donatella; Altucci, Lucia; Gaetano, Carlo; Mai, Antonello

    2016-02-25

    Modulators of sirtuins are considered promising therapeutic targets for the treatment of cancer, cardiovascular, metabolic, inflammatory, and neurodegenerative diseases. Here we prepared new 1,4-dihydropyridines (DHPs) bearing changes at the C2/C6, C3/C5, C4, or N1 position. Tested with the SIRTainty procedure, some of them displayed increased SIRT1 activation with respect to the prototype 3a, high NO release in HaCat cells, and ameliorated skin repair in a mouse model of wound healing. In C2C12 myoblasts, two of them improved mitochondrial density and functions. All the effects were reverted by coadministration of compound C (9), an AMPK inhibitor, or of EX-527 (10), a SIRT1 inhibitor, highlighting the involvement of the SIRT1/AMPK pathway in the action of DHPs. Finally, tested in a panel of cancer cells, the water-soluble form of 3a, compound 8, displayed antiproliferative effects in the range of 8-35 μM and increased H4K16 deacetylation, suggesting a possible role for SIRT1 activators in cancer therapy. PMID:26689352

  8. Essential oil from the heartwood of Taiwan fir ameliorates LPS-induced inflammatory response by inhibiting the activation of mitogen-activated protein kinase.

    PubMed

    Liu, May-Lan; Hua, Kuo-Feng; Yang, Tzu-Jung; Chiu, Huan-Wen; Ho, Chen-Lung

    2014-10-01

    The essential oil from the heartwood of Taiwan fir (EOTC) was demonstrated to exhibit anti-inflammatory activity in lipopolysaccharide (LPS)-activated mouse macrophages. EOTC reduced nitrite oxide levels and inducible nitrite oxide synthase expression in, and tumor necrosis factor-α and interleukin-6 secretion by, LPS-activated macrophages without affecting cyclooxygenase-2 expression. EOTC reduced the levels of interleukin-lβ precursor induced by LPS and decreased the NLRP3 inflammasome-derived interleukin-lβ secretion induced by LPS and adenosine triphosphate. In addition, the phosphorylation levels of ERKI/2, JNK1/2, and p38 in LPS-activated macrophages were reduced by EOTC. Furthermore, EOTC was composed of oxygenated sesquiterpenes (68.4%), sesquiterpene hydrocarbons (28.9%) and diterpenes (0.9%). The major compounds of the oxygenated sesquiterpenes were τ-cadinol (23.9%), α-cadinol (21.1%) and cedrol (16.9%). These findings suggest that EOTC may be a candidate for the development of anti-inflammatory agents for preventing and ameliorating inflammation-related diseases. PMID:25522551

  9. Inhibition of the NF-κB pathway by R65 ribozyme gene via adeno-associatedvirus serotype 9 ameliorated oxidized LDL induced human umbilical vein endothelial cell injury

    PubMed Central

    Zhai, Hui; Chen, Qing-Jie; Gao, Xiao-Ming; Ma, Yi-Tong; Chen, Bang-Dang; Yu, Zi-Xiang; Li, Xiao-Mei; Liu, Fen; Xiang, Yang; Xie, Jia; Yang, Yi-Ning

    2015-01-01

    Objective: NF-κB signaling plays a central role in the regulation of inflammatory responses in atherosclerosis. R65 ribozyme gene suppresses activation of NF-κB pathway, therefore we studied whether R65 gene therapy can ameliorate oxidized low-density lipoprotein (ox-LDL) induced human umbilical vein endothelial cells (HUVECs) injury. Methods and results: Recombinant adeno-associated virus serotype 9 (rAVV9) vector was used to transfect the R65 ribozyme gene (rAVV9-R65) into HUVECs then following ox-LDL stimulation, expression of NF-κB p65 and p50 subunits, inflammatory mediators and cell apoptosis were examined. First, rAVV9-enhanced green fluorescent protein (eGFP)-R65 at 1×107 v.g./cell multiplicity of infection reached a long-lasting and significant increase in R65 gene expression. Second, ox-LDL treatment led to time- and dose-dependent activation of NF-κB pathway, and enhanced inflammatory response and cell death evidenced by increased expression of nuclear NF-κB p65 and p50 subunits, greater production of tumor necrosis factor α, interleukin-6 and von willebrand factor and 20.57% increasedapoptotic HUVECs. Third, over-expression ofR65 gene was 2-fold increased in HUVECs attenuated ox-LDL induced unclear accumulation and expression of p65 subunit and ameliorated inflammation and cell death (all P < 0.05). Conclusion: rAAV9-mediated R65 ribozyme gene transfection in cultured HUVECs effectively inhibits ox-LDL induced activation of NF-κB and production of inflammatory cytokines and prevents cell apoptosis. PMID:26617700

  10. Intense relativistic electron beam generation and prepulse effect in high power cylindrical diode

    SciTech Connect

    Roy, Amitava; Menon, R.; Mitra, S.; Kumar, D. D. P.; Kumar, Senthil; Sharma, Archana; Mittal, K. C.; Nagesh, K. V.; Chakravarthy, D. P.

    2008-01-01

    Intense gigawatt relativistic electron beam has been generated in a high power cylindrical diode in the presence of prepulse. A bipolar prepulse voltage, recorded at the diode, varies both in amplitude and time duration with the Marx generator voltage. It was found that only at the accelerating gap {<=}1.65 cm there is some shot to shot variation in the diode voltage and current for the same Marx generator voltage. The anode and cathode plasma expansion velocities were calculated using the perveance data. The plasma expands at 5 cm/{mu}s for 1.85 cm radial anode-cathode gap and the plasma velocity decreases for smaller gap. It was found that the effect of the prepulse is less pronounced in the cylindrical diode as compared to planar diode that allows one operation of the cylindrical diode with the gap {<=}1.85 cm.