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Sample records for ameliorate prepulse inhibition

  1. The glutamatergic compounds sarcosine and N-acetylcysteine ameliorate prepulse inhibition deficits in metabotropic glutamate 5 receptor knockout mice

    PubMed Central

    Stoker, Astrid; Markou, Athina

    2010-01-01

    Rationale Mice lacking metabotropic glutamate receptors 5 (mGluR5) exhibit reduced glutamatergic function and behavioral abnormalities, including deficits in prepulse inhibition (PPI) of the startle response that may be relevant to schizophrenia. Thus, these mice are an animal model that may be used for preclinical evaluation of potentially new classes of antipsychotic compounds. Recent clinical studies have suggested several compounds that modulate glutamatergic transmission through distinct mechanisms, such as potentiation of the N-methyl-d-aspartate (NMDA) receptor glycine site, activation of group II mGluR, and activation of glutamate-cysteine antiporters, as being efficacious in the treatment of schizophrenia. Objectives The aim of this work is to evaluate the effects of sarcosine (a selective inhibitor of the glycine transporter 1 [GlyT1]), LY379268 (a group II mGluR agonist), and N-acetylcysteine (a cysteine prodrug that indirectly activates cystine-glutamate antiporters to increase glutamate levels in the extrasynaptic space) on PPI deficits in mGluR5 knockout mice. Results Sarcosine and N-acetylcysteine, but not LY379268, ameliorated PPI deficits in mGluR5 knockout mice. The ability of N-acetylcysteine to restore PPI deficits was not blocked by the group II mGluR antagonist LY341495, indicating that the effects of N-acetylcysteine were not attributable to activation of group II mGluRs by glutamate. Conclusions These findings provide evidence that the interactions between mGluR5 and NMDA receptors are involved in the regulation of PPI and suggest that activation of glutamate receptors, other than group II receptors, by increased endogenous glutamate transmission, may ameliorate the behavioral abnormalities associated with mGluR5 deficiency. PMID:20217053

  2. Reflexes Inhibited by a Prepulse: Intensity of Startle Stimulus and Prepulse Across Onset Intervals.

    PubMed

    Nishiyama, Ryoji; Iso, Hiroyuki

    2016-08-01

    Prepulse inhibition refers to the inhibition of the startle reflexes by a weak stimulus (prepulse) that precedes a strong startle stimulus (pulse). Previous findings suggest that prepulse intensity affects prepulse inhibition amplitude and that prepulse inhibition amplitudes vary across onset intervals between the prepulse and pulse. However, evidence regarding the effect of startle stimulus intensity is still inconclusive, especially due to variations between prepulse inhibition scores calculated by using percentage-type and difference-type formulas. Moreover, the combined effect of startle stimulus and prepulse intensities across onset intervals remains poorly understood. The present study investigated the combined effect as well as the influence of startle response amplitudes on the formulae used for the calculation. The results suggest that startle stimulus intensity could potentially affect results of percentage-type formulae for calculating prepulse inhibition over a wide range of lead intervals. Furthermore, the results demonstrated that a combination of strong startle stimulus intensities and weak prepulse intensities could not induce prepulse inhibition at long onset intervals (1000 ms and 2000 ms).

  3. Motivated attention and prepulse inhibition of startle in rats: using conditioned reinforcers as prepulses.

    PubMed

    Baschnagel, Joseph S; Hawk, Larry W; Colder, Craig R; Richards, Jerry B

    2007-12-01

    In humans, prepulse inhibition (PPI) of startle is greater during attended prestimuli than it is during ignored prestimuli, whereas in rats, most work has focused on passive PPI, which does not require attention. In the work described in this article, researchers developed a paradigm to assess attentional modification of PPI in rats using motivationally salient prepulses. Water-deprived rats were either conditioned to attend to a conditioned stimulus (CS; 1-s, 7-dB increase in white noise) paired with water (CS(+) group), or they received uncorrelated presentations of white noise and water (CS0 group). After 10 conditioning sessions, startle probes (50 ms, 115 dB) were introduced, with the CS serving as a continuous prepulse. Three experiments examined PPI across a range of prepulse intensities (4-10 dB) and stimulus onset asynchronies (SOAs; 30-960 ms). PPI was consistently reduced in the CS(+) group, particularly with a 10-dB prepulse and a 60-ms SOA. Thus, PPI in rats differed between attended and ignored prestimuli, but the effect was reversed in the results of research with humans. A fourth study eliminated the group difference by reversing the CS-water contingency. Methodological and motivational hypotheses regarding the current findings are discussed.

  4. Habituation and prepulse inhibition of acoustic startle in rodents.

    PubMed

    Valsamis, Bridget; Schmid, Susanne

    2011-09-01

    The acoustic startle response is a protective response, elicited by a sudden and intense acoustic stimulus. Facial and skeletal muscles are activated within a few milliseconds, leading to a whole body flinch in rodents(1). Although startle responses are reflexive responses that can be reliably elicited, they are not stereotypic. They can be modulated by emotions such as fear (fear potentiated startle) and joy (joy attenuated startle), by non-associative learning processes such as habituation and sensitization, and by other sensory stimuli through sensory gating processes (prepulse inhibition), turning startle responses into an excellent tool for assessing emotions, learning, and sensory gating, for review see( 2, 3). The primary pathway mediating startle responses is very short and well described, qualifying startle also as an excellent model for studying the underlying mechanisms for behavioural plasticity on a cellular/molecular level(3). We here describe a method for assessing short-term habituation, long-term habituation and prepulse inhibition of acoustic startle responses in rodents. Habituation describes the decrease of the startle response magnitude upon repeated presentation of the same stimulus. Habituation within a testing session is called short-term habituation (STH) and is reversible upon a period of several minutes without stimulation. Habituation between testing sessions is called long-term habituation (LTH)(4). Habituation is stimulus specific(5). Prepulse inhibition is the attenuation of a startle response by a preceding non-startling sensory stimulus(6). The interval between prepulse and startle stimulus can vary from 6 to up to 2000 ms. The prepulse can be any modality, however, acoustic prepulses are the most commonly used. Habituation is a form of non-associative learning. It can also be viewed as a form of sensory filtering, since it reduces the organisms' response to a non-threatening stimulus. Prepulse inhibition (PPI) was originally

  5. Prepulse inhibition in HIV-associated neurocognitive disorders.

    PubMed

    Minassian, Arpi; Henry, Brook L; Woods, Steven Paul; Vaida, Florin; Grant, Igor; Geyer, Mark A; Perry, William

    2013-07-01

    Sensorimotor inhibition, or the ability to filter out excessive or irrelevant information, theoretically supports a variety of higher-level cognitive functions. Impaired inhibition may be associated with increased impulsive and risky behavior in everyday life. Individuals infected with HIV frequently show impairment on tests of neurocognitive function, but sensorimotor inhibition in this population has not been studied and may be a contributor to the profile of HIV-associated neurocognitive disorders (HAND). Thirty-seven HIV-infected individuals (15 with HAND) and 48 non-infected comparison subjects were assessed for prepulse inhibition (PPI), an eyeblink startle paradigm measuring sensorimotor gating. Although HIV status alone was not associated with PPI deficits, HIV-positive participants meeting criteria for HAND showed impaired PPI compared to cognitively intact HIV-positive subjects. In HIV-positive subjects, PPI was correlated with working memory but was not associated with antiretroviral therapy or illness factors. In conclusion, sensorimotor disinhibition in HIV accompanies deficits in higher-order cognitive functions, although the causal direction of this relationship requires investigation. Subsequent research on the role of sensorimotor gating on decision-making and risk behaviors in HIV may be indicated.

  6. Prepulse Inhibition in HIV-Associated Neurocognitive Disorders

    PubMed Central

    Minassian, Arpi; Henry, Brook L.; Woods, Steven Paul; Vaida, Florin; Grant, Igor; Geyer, Mark A.; Perry, William

    2013-01-01

    Sensorimotor inhibition, or the ability to filter out excessive or irrelevant information, theoretically supports a variety of higher-level cognitive functions. Impaired inhibition may be associated with increased impulsive and risky behavior in everyday life. Individuals infected with HIV frequently show impairment on tests of neurocognitive function, but sensorimotor inhibition in this population has not been studied and may be a contributor to the profile of HIV-associated Neurocognitive Disorders (HAND). 37 HIV-infected individuals (15 with HAND) and 48 non-infected comparison subjects were assessed for prepulse inhibition (PPI), an eyeblink startle paradigm measuring sensorimotor gating. Although HIV status alone was not associated with PPI deficits, HIV-positive participants meeting criteria for HAND showed impaired PPI compared to cognitively intact HIV-positive subjects. In HIV-positive subjects, PPI was correlated with working memory but was not associated with antiretroviral therapy or illness factors. In conclusion, sensorimotor disinhibition in HIV accompanies deficits in higher-order cognitive functions, though the causal direction of this relationship requires investigation. Subsequent research on the role of sensorimotor gating on decision-making and risk behaviors in HIV may be indicated. PMID:23552464

  7. Prepulse inhibition modulation by contextual conditioning of dopaminergic activity.

    PubMed

    Mena, Auxiliadora; De la Casa, Luis G

    2013-09-01

    When a neutral stimulus is repeatedly paired with a drug, an association is established between them that can induce two different responses: either an opponent response that counteracts the effect of the drug, or a response that is similar to that induced by the drug. In this paper, we focus on the analysis of the associations that can be established between the contextual cues and the administration of dopamine agonists or antagonists. Our hypothesis suggests that repeated administration of drugs that modulate dopaminergic activity in the presence of a specific context leads to the establishment of an association that subsequently results in a conditioned response to the context that is similar to that induced by the drug. To test this hypothesis, we conducted two experiments that revealed that contextual cues acquired the property to modulate pre-pulse inhibition by prior pairings of such context with the dopamine antagonist haloperidol (Experiment 1), and with the dopamine agonist d-amphetamine (Experiment 2). The implications of these results are discussed both at a theoretical level, and attending to the possibilities that could involve the use of context cues for the therapeutic administration of dopaminergic drugs.

  8. Reduced Prepulse Inhibition as a Biomarker of Schizophrenia.

    PubMed

    Mena, Auxiliadora; Ruiz-Salas, Juan C; Puentes, Andrea; Dorado, Inmaculada; Ruiz-Veguilla, Miguel; De la Casa, Luis G

    2016-01-01

    The startle response is composed by a set of reflex behaviors intended to prepare the organism to face a potentially relevant stimulus. This response can be modulated by several factors as, for example, repeated presentations of the stimulus (startle habituation), or by previous presentation of a weak stimulus (Prepulse Inhibition [PPI]). Both phenomena appear disrupted in schizophrenia that is thought to reflect an alteration in dopaminergic and glutamatergic neurotransmission. In this paper we analyze whether the reported deficits are indicating a transient effect restricted to the acute phase of the disease, or if it reflects a more general biomarker or endophenotype of the disorder. To this end, we measured startle responses in the same set of thirteen schizophrenia patients with a cross-sectional design at two periods: 5 days after hospital admission and 3 months after discharge. The results showed that both startle habituation and PPI were impaired in the schizophrenia patients at the acute stage as compared to a control group composed by 13 healthy participants, and that PPI but not startle habituation remained disrupted when registered 3 months after the discharge. These data point to the consideration of PPI, but not startle habituation, as a schizophrenia biomarker.

  9. Reduced Prepulse Inhibition as a Biomarker of Schizophrenia

    PubMed Central

    Mena, Auxiliadora; Ruiz-Salas, Juan C.; Puentes, Andrea; Dorado, Inmaculada; Ruiz-Veguilla, Miguel; De la Casa, Luis G.

    2016-01-01

    The startle response is composed by a set of reflex behaviors intended to prepare the organism to face a potentially relevant stimulus. This response can be modulated by several factors as, for example, repeated presentations of the stimulus (startle habituation), or by previous presentation of a weak stimulus (Prepulse Inhibition [PPI]). Both phenomena appear disrupted in schizophrenia that is thought to reflect an alteration in dopaminergic and glutamatergic neurotransmission. In this paper we analyze whether the reported deficits are indicating a transient effect restricted to the acute phase of the disease, or if it reflects a more general biomarker or endophenotype of the disorder. To this end, we measured startle responses in the same set of thirteen schizophrenia patients with a cross-sectional design at two periods: 5 days after hospital admission and 3 months after discharge. The results showed that both startle habituation and PPI were impaired in the schizophrenia patients at the acute stage as compared to a control group composed by 13 healthy participants, and that PPI but not startle habituation remained disrupted when registered 3 months after the discharge. These data point to the consideration of PPI, but not startle habituation, as a schizophrenia biomarker. PMID:27803654

  10. Stimulus quality affects expression of the acoustic startle response and prepulse inhibition in mice.

    PubMed

    Stoddart, C W; Noonan, J; Martin-Iverson, M T

    2008-06-01

    The relationship between stimulus intensity and startle response magnitude (SIRM) can assess the startle reflex and prepulse inhibition (PPI) with advantages over more commonly used methods. The current study used the SIRM relationships in mice to determine differences between white noise and pure tone (5 kHz) stimuli. Similarly to rats, the SIRM relationship showed a sigmoid pattern. The SIRM-derived reflex capacity (RMAX) and response efficacy (slope) of the white noise and pure tone stimuli in the absence of prepulses were equivalent. However, the pure tone startle response threshold (DMIN) was increased whereas the stimulus potency (1/ES50) was decreased when compared to white noise. Prepulses of both stimulus types inhibited RMAX and increased DMIN, but the white noise prepulses were more effective. Both stimulus intensity gating and motor capacity gating processes are shown to occur, dependent on prepulse intensity and stimulus onset asynchrony. Prepulse intensities greater than 10 dB below the startle threshold appear to produce PPI via stimulus intensity gating, whereas a motor capacity gating component appears at prepulse intensities near to the startle threshold.

  11. 5-HT6 receptor antagonist reversal of emotional learning and prepulse inhibition deficits induced by apomorphine or scopolamine.

    PubMed

    Mitchell, Ellen S; Neumaier, John F

    2008-01-01

    5-HT6 receptors have been implicated in consolidation of visuospatial and reward-based learning tasks. Since 5-HT6 receptors may be important in modulation of sensory gating which is often affected in schizophrenic patients, we tested whether Ro 4368554, a 5-HT6 selective antagonist at a dose of 10 mg/kg, could reverse the loss of prepulse inhibition from apomorphine or scopolamine. In addition, we also tested whether Ro 4368554 altered fear conditioning using fear potentiated startle, a model for emotional learning. Prepulse inhibition of startle was disrupted by apomorphine (0.5 mg/kg) when prepulse emissions were 5 dB above background but not above 15 dB, while scopolamine (0.5 mg/kg) caused disruption at both prepulse levels. Scopolamine-mediated disruption was not reversed by Ro 4368854 but apomorphine-mediated disruption was significantly ameliorated by 5-HT6 inhibition. For fear potentiated startle, scopolamine and/or Ro 4368554 were administered before two daily fear conditioning sessions; rats were tested on the following day. Rats that received scopolamine displayed no fear potentiated startle but Ro 4368554 reversed this scopolamine deficit. Additionally, we mapped Fos induction in rats treated with scopolamine and/or Ro 4368554; scopolamine increased Fos expression in the central nucleus of the amygdala and this was attenuated by Ro 4368554. In summary, we have demonstrated the efficacy of 5-HT6 antagonists in modulating sensory gating and fear conditioning, and thus may be of therapeutic use for schizophrenia-related disorders.

  12. Perceived location specificity in perceptual separation-induced but not fear conditioning-induced enhancement of prepulse inhibition in rats.

    PubMed

    Lei, Ming; Luo, Lu; Qu, Tianshu; Jia, Hongxiao; Li, Liang

    2014-08-01

    Prepulse inhibition (PPI) is the suppression of the startle reflex when the startling stimulus is shortly preceded by a non-startling stimulus (the prepulse). Previous studies have shown that both fear conditioning of a prepulse and precedence-effect-induced perceptual separation between the conditioned prepulse and a noise masker facilitate selective attention to the prepulse and consequently enhance PPI with a remarkable prepulse-feature specificity. This study investigated whether the two types of attentional enhancements of PPI in rats also exhibit a prepulse-location specificity. The results showed that when a prepulse was delivered by each of the two spatially separated loudspeakers, fear conditioning of the prepulse at a particularly perceived location (left or right to the tested rat) enhanced PPI without exhibiting any perceived-location specificity. However, when a noise masker was presented, the precedence-effect-induced perceptual separation between the conditioned prepulse and the noise masker further enhanced PPI when the prepulse was perceived as coming from the location that was conditioned but not the location without being conditioned. Moreover, both conditioning-induced and perceptual separation-induced PPI enhancements were eliminated by extinction learning, whose effect could be blocked by systemic injection of the selective antagonist of metabotropic glutamate receptor subtype 5 (mGluR5), 2-methyl-6-(phenylethynyl)-pyridine (MPEP). Thus, fear conditioning of a prepulse perceived at a particular location not only facilitates selective attention to the conditioned prepulse but also induces a learning-based spatial gating effect on the spatial unmasking of the conditioned prepulse, leading to that the perceptual separation-induced PPI enhancement becomes perceived-location specific.

  13. Prepulse inhibition (PPI) disrupting effects of Glycyrrhiza glabra extract in mice: a possible role of monoamines.

    PubMed

    Michel, Haidy E; Tadros, Mariane G; Abdel-Naim, Ashraf B; Khalifa, Amani E

    2013-06-07

    Liquorice extract was reported to have nootropic and/or antiamnestic effects. Prepulse inhibition (PPI) of startle response is a multimodal, cross-species phenomenon used as a measure of sensorimotor gating. Previous studies indicated that liquorice/its constituents augmented mouse brain monoamine levels. Increased brain monoamines' transmission was suggested to underlie PPI disruption. However, the effect of antiamnestic dose(s) of the extract on PPI has not been investigated despite the coexistence of impaired memory and PPI deficit in some neurological disorders. The effect of administration of the antiamnestic dose of the extract (150 mg/kg for 7 days) was tested on PPI of acoustic startle response in mice. It resulted in PPI disruption and therefore its effect on monoamines' levels was investigated in a number of mouse brain areas involved in PPI response mediation. Results demonstrated that the extract antiamnestic dose augmented cortical, hippocampal and striatal monoamine levels. It was therefore concluded that liquorice extract (150 mg/kg)-induced PPI deficit was mediated through augmenting monoaminergic transmission in the cortex, hippocampus and striatum. These findings can be further investigated in experimental models for autism, psychosis and Huntington's disease to decide the safety of using liquorice extract in ameliorating memory disturbance in disorders manifesting PPI deficit.

  14. Acoustic prepulse inhibition: One ear is better than two, but why and when?

    PubMed Central

    Kumari, Veena; Hamid, Aseel; Brand, Andrew; Antonova, Elena

    2015-01-01

    We examined whether monaural prepulses produce more prepulse inhibition (PPI) because they might be more attention capturing (unambiguous to locate) than binaural prepulses. Monaural and binaural PPI was tested under normal and verbal and visuospatial attention manipulation conditions in 55 healthy men, including 29 meditators. Attention manipulations abolished monaural PPI superiority, similarly in meditators and meditation-naïve individuals, and this was most strongly evident for right ear PPI under visuospatial attention manipulation. Meditators performed better than meditation-naïve individuals on attention tasks (verbal: more targets detected; visuospatial: faster reaction time). Spatial attention processes contribute to monaural PPI, particularly with the right ear. Better attentional performance, with similar attentional modulation of PPI, may indicate a stronger attentional capacity in meditators, relative to meditation-naïve individuals. PMID:25476733

  15. Acoustic prepulse inhibition: one ear is better than two, but why and when?

    PubMed

    Kumari, Veena; Hamid, Aseel; Brand, Andrew; Antonova, Elena

    2015-05-01

    We examined whether monaural prepulses produce more prepulse inhibition (PPI) because they might be more attention capturing (unambiguous to locate) than binaural prepulses. Monaural and binaural PPI was tested under normal and verbal and visuospatial attention manipulation conditions in 55 healthy men, including 29 meditators. Attention manipulations abolished monaural PPI superiority, similarly in meditators and meditation-naïve individuals, and this was most strongly evident for right ear PPI under visuospatial attention manipulation. Meditators performed better than meditation-naïve individuals on attention tasks (verbal: more targets detected; visuospatial: faster reaction time). Spatial attention processes contribute to monaural PPI, particularly with the right ear. Better attentional performance, with similar attentional modulation of PPI, may indicate a stronger attentional capacity in meditators, relative to meditation-naïve individuals.

  16. 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…

  17. Prepulse inhibition and facilitation of the postauricular reflex, a vestigial remnant of pinna startle.

    PubMed

    Hackley, Steven A; Ren, Xi; Underwood, Amy; Valle-Inclán, Fernando

    2017-04-01

    If the postauricular reflex (PAR) is to be used effectively in studies of emotion and attention, its sensitivity to basic modulatory effects such as prepulse inhibition and facilitation must be determined. Two experiments were carried out with healthy young adults to assess the effects of transient and sustained visual prestimuli on the pinna-flexion response to trains of startle probes. In the first experiment, participants passively viewed a small white square. It was displayed from 1,000 ms prior to onset of a train of noise bursts until the end of that train. Relative to no-prepulse control trials, PAR amplitude was inhibited, possibly due to the withdrawal of attentional resources from the auditory modality. In the second experiment, participants performed a visual oddball task in which irrelevant trains of startle probes followed most briefly displayed task stimuli (checkerboards). Prepulse inhibition was observed when a transient stimulus preceded the first probe at a lead time of 100 ms. Amplitude facilitation was observed at longer lead times. In addition to documenting the existence of prepulse inhibition and facilitation, the data suggest that the PAR is not elicited by visual stimuli, that temporal expectancy does not influence its amplitude or latency, and that this vestigial microreflex is resistant to habituation. Results are interpreted in light of a recent theory that the human PAR is a highly degraded pinna startle, in which the reflex arc no longer includes the startle center (nucleus reticularis pontis caudalis).

  18. 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

  19. 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

  20. Alterations in neonatal neurosteroids affect exploration during adolescence and prepulse inhibition in adulthood.

    PubMed

    Darbra, Sònia; Pallarès, Marc

    2010-05-01

    Allopregnanolone (AlloP) is a neurosteroid that plays an important role during neural development. Alterations of endogenous neonatal allopregnanolone levels alter the localisation and function of GABA neurons in the adult brain and affect behaviour in adulthood. We have carried out research into the effects of an increase (AlloP administration) or a decrease (administration of finasteride, inhibitor of the AlloP synthesis) of neonatal AlloP levels during the fifth to ninth postnatal days in male Wistar rats on the novelty exploration (Boissier test) at adolescent ages (40 and 60 days old), and on the prepulse inhibition achievement in adulthood (85 days). We also investigated the role of a GABA(A) modulator (midazolam, 1, 1.75 or 2.5mg/kg body weight) in the long-lasting behavioural changes in adulthood (85 days). Results indicate that neonatal finasteride decreases both novelty-exploration (head-dipping and locomotion) and anxiety-relevant scores (the distance travelled in and the number of entries into the central zone) at adolescent age, along with a reduction in body weight and general locomotion. Also, neonatal AlloP administration decreases prepulse inhibition in adulthood. Prepulse inhibition disruption was only partially reproduced decreasing the neonatal AlloP levels by means of finasteride administration. Although there was no interaction between neonatal neurosteroid manipulation and adult benzodiazepine treatments, the effects of midazolam were dose-dependent: the lowest dose of midazolam increased whereas the highest disrupted the expected progressive reduction of the startle response (and the consequent improvement of the PPI percentage) after the gradual increase in prepulse intensity. Reduced prepulse inhibition of startle provides evidence of deficient sensorimotor gating in several disorders, including schizophrenia. Alterations of AlloP levels during maturation could partly explain the inter-individual differences shown by adult subjects in

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

    PubMed

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

    2008-06-01

    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.

  2. 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

  3. Lesions of the paraventricular thalamic nucleus attenuates prepulse inhibition of the acoustic startle reflex.

    PubMed

    Öz, Pınar; Kaya Yertutanol, F Duygu; Gözler, Tayfun; Özçetin, Ayşe; Uzbay, I Tayfun

    2017-03-06

    The paraventricular thalamic nucleus (PVT) is a midline nucleus with strong connections to cortical and subcortical brain regions such as the prefrontal cortex, amygdala, nucleus accumbens and hippocampus and receives strong projections from brain stem nuclei. Prepulse inhibition (PPI) is mediated and modulated by complex cortical and subcortical networks that are yet to be fully identified in detail. Here, we suggest that the PVT may be an important brain region for the modulation of PPI. In our study, the paraventricular thalamic nuclei of rats were electrolytically lesioned. Two weeks after the surgery, the PPI responses of the animals were monitored and recorded using measurements of acoustic startle reflex. Our results show that disruption of the PVT dramatically attenuated PPI at prepulse intensities of 74, 78 and 86dB compared to that in the sham lesion group. Thus, we suggest that the PVT may be an important part of the PPI network in the rat brain.

  4. 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

  5. Modality-specific attention under imminent but not remote threat of shock: evidence from differential prepulse inhibition of startle.

    PubMed

    Cornwell, Brian R; Echiverri, Aileen M; Covington, Matthew F; Grillon, Christian

    2008-06-01

    Theories of animal defensive behavior postulate that imminent, predictable threat elicits highly focused attention toward the threat source, whereas remote, unpredictable threat elicits distributed attention to the overall environment. We used threat of shock combined with measurement of prepulse inhibition of the startle reflex to test these claims in humans. Twenty-seven participants experienced periods of threat and safety. Threat and safe periods were short or long, with the short threat periods conveying relatively predictable, imminent shocks and the long threat periods conveying unpredictable shocks. Startle reflexes were elicited with equal numbers of acoustic probes presented alone, preceded by a tactile prepulse, or preceded by an auditory prepulse. We observed enhanced tactile relative to auditory prepulse inhibition during short threat periods only. This finding supports the notion that imminent threat, but not remote threat, elicits attention focused toward the relevant modality, potentially reflecting preparatory activity to minimize the impact of the noxious stimulus.

  6. 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.

  7. Differential Neural Responses Underlying the Inhibition of the Startle Response by Pre-Pulses or Gaps in Mice

    PubMed Central

    Moreno-Paublete, Rocio; Canlon, Barbara; Cederroth, Christopher R.

    2017-01-01

    Gap pre-pulse inhibition of the acoustic startle (GPIAS) is a behavioral paradigm used for inferring the presence of tinnitus in animal models as well as humans. In contrast to pre-pulse inhibition (PPI), the neural circuitry controlling GPIAS is poorly understood. To increase our knowledge on GPIAS, a comparative study with PPI was performed in mice combining these behavioral tests and c-Fos activity mapping in brain areas involved in the inhibition of the acoustic startle reflex (ASR). Both pre-pulses and gaps efficiently inhibited the ASR and abolished the induction of c-Fos in the pontine reticular nucleus. Differential c-Fos activation was found between PPI and GPIAS in the forebrain whereby PPI activated the lateral globus pallidus and GPIAS activated the primary auditory cortex. Thus, different neural maps are regulating the inhibition of the startle response by pre-pulses or gaps. To further investigate this differential response to PPI and GPIAS, we pharmacologically disrupted PPI and GPIAS with D-amphetamine or Dizocilpine (MK-801) to target dopamine efflux and to block NMDA receptors, respectively. Both D-amp and MK-801 efficiently decreased PPI and GPIAS. We administered Baclofen, an agonist GABAB receptor, but failed to detect any robust rescue of the effects of D-amp and MK-801 suggesting that PPI and GPIAS are GABAB-independent. These novel findings demonstrate that the inhibition of the ASR by pre-pulses or gaps is orchestrated by different neural pathways. PMID:28239338

  8. Differential Neural Responses Underlying the Inhibition of the Startle Response by Pre-Pulses or Gaps in Mice.

    PubMed

    Moreno-Paublete, Rocio; Canlon, Barbara; Cederroth, Christopher R

    2017-01-01

    Gap pre-pulse inhibition of the acoustic startle (GPIAS) is a behavioral paradigm used for inferring the presence of tinnitus in animal models as well as humans. In contrast to pre-pulse inhibition (PPI), the neural circuitry controlling GPIAS is poorly understood. To increase our knowledge on GPIAS, a comparative study with PPI was performed in mice combining these behavioral tests and c-Fos activity mapping in brain areas involved in the inhibition of the acoustic startle reflex (ASR). Both pre-pulses and gaps efficiently inhibited the ASR and abolished the induction of c-Fos in the pontine reticular nucleus. Differential c-Fos activation was found between PPI and GPIAS in the forebrain whereby PPI activated the lateral globus pallidus and GPIAS activated the primary auditory cortex. Thus, different neural maps are regulating the inhibition of the startle response by pre-pulses or gaps. To further investigate this differential response to PPI and GPIAS, we pharmacologically disrupted PPI and GPIAS with D-amphetamine or Dizocilpine (MK-801) to target dopamine efflux and to block NMDA receptors, respectively. Both D-amp and MK-801 efficiently decreased PPI and GPIAS. We administered Baclofen, an agonist GABAB receptor, but failed to detect any robust rescue of the effects of D-amp and MK-801 suggesting that PPI and GPIAS are GABAB-independent. These novel findings demonstrate that the inhibition of the ASR by pre-pulses or gaps is orchestrated by different neural pathways.

  9. Stuttering and sensory gating: a study of acoustic startle prepulse inhibition.

    PubMed

    Alm, Per A

    2006-06-01

    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 controls regarding the degree of PPI. No significant differences were found between the stuttering adults and the control group; the groups showed similar means and distribution. Likewise, no relation between the degree of PPI and the effect of altered auditory feedback on stuttering was found. In summary, the results of the study indicate that there is no relation between stuttering and PPI.

  10. Metabotropic glutamate subtype 5 receptors modulate fear-conditioning induced enhancement of prepulse inhibition in rats.

    PubMed

    Zou, Dan; Huang, Juan; Wu, Xihong; Li, Liang

    2007-02-01

    Non-startling acoustic events 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. The present study investigated whether PPI can be modulated by fear conditioning, whose acquisition can be blocked by the specific antagonist of metabotropic glutamate receptors subtype 5 (mGluR5), 2-methyl-6-(phenylethynyl)-pyridine (MPEP). The results show that a gap embedded in otherwise continuous noise sounds, which were delivered by two spatially separated loudspeakers, could inhibit the startle reflex induced by an intense sound that was presented 50 ms after the gap. The inhibitory effect depended on the duration of the gap, and was enhanced by fear conditioning that was introduced by temporally pairing the gap with footshock. Intraperitoneal injection of MPEP (0.5 or 5mg/kg) 30 min before fear conditioning blocked the enhancing effect of fear conditioning on PPI, but did not affect either the baseline startle magnitude or PPI if no fear conditioning was introduced. These results indicate that PPI is enhanced when the prepulse signifies an aversive event after fear conditioning. Also, mGlu5Rs play a role in preserving the fear-conditioning-induced enhancement of PPI.

  11. Dorsal striatum D1-expressing neurons are involved with sensorimotor gating on prepulse inhibition test.

    PubMed

    Rodrigues, Samanta; Salum, Cristiane; Ferreira, Tatiana L

    2017-04-01

    Prepulse inhibition (PPI) is a behavioral test in which the startle reflex response to a high-intensity stimulus (pulse) is inhibited by the prior presentation of a weak stimulus (prepulse). The classic neural circuitry that mediates startle response is localized in the brainstem; however, recent studies point to the contribution of structures involved in higher cognitive functions in regulating the sensorimotor gating, particularly forebrain regions innervated by dopaminergic nuclei. The aim of the present study was to verify the role of dorsal striatum (DS) and dopaminergic transmitting mediated by D1 and D2 receptors on PPI test in rats. DS inactivation induced by muscimol injection did not affect PPI (%PPI and startle response), although it impaired the locomotor activity and caused catalepsy. Infusion of D1-like antagonist SCH23390 impaired %PPI but did not disturb the startle response and locomotor activity evaluated immediately after PPI test. D2 antagonist microinjection (sulpiride) did not affect %PPI and startle response, but impaired motor activity. These results point to an important role of DS, probably mediated by direct basal ganglia pathway, on modulation of sensorimotor gating, in accordance with clinical studies showing PPI deficits in schizophrenia, Tourette syndrome, and compulsive disorders - pathologies related to basal ganglia dysfunctions.

  12. 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.

  13. 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

  14. Sex-Related Differences in Prepulse Inhibition of Startle in Irritable Bowel Syndrome (IBS)

    PubMed Central

    Kilpatrick, L. A.; Ornitz, E.; Ibrahimovic, H.; Treanor, M.; Craske, M.; Nazarian, M.; Labus, J.; Mayer, E. A.; Naliboff, B. D.

    2010-01-01

    Alterations in central networks involved in regulation of arousal, attention, and cognition may be critical for IBS symptom maintenance and exacerbation. Differential sensitivities in these networks may underlie sex differences noted in IBS. The current study examined prepulse inhibition (PPI), a measure of sensorimotor gating, in male and female IBS patients. Relationships between PPI and symptom severity were examined, as well as potential menstrual status effects. Compared to healthy controls, male IBS patients had significantly reduced PPI; whereas female IBS patients (particularly naturally cycling women) had significantly enhanced PPI suggesting hypervigilance. Considering previously demonstrated sex-related differences in perceptual and brain imaging findings in IBS patients, the current findings suggest different neurobiological mechanisms underlie symptom presentation in male and female IBS patients. Compromised filtering of information in male IBS patients may be due to compromised top down (prefrontal, midcingulate) control mechanisms while increased attention to threat due to increased limbic and paralimbic circuits may be characteristic of female IBS patients. PMID:20193731

  15. Antipsychotic potential of CCK-based treatments: an assessment using the prepulse inhibition model of psychosis.

    PubMed

    Feifel, D; Reza, T; Robeck, S

    1999-02-01

    Systemic injections of cholecystokinin (CCK), a "gut-brain" peptide, have been shown to modulate brain dopamine function and produce neuroleptic-like effects on such dopamine-regulated behaviors as locomotor activity. However, clinical trials of CCK agonists in schizophrenia patients showed mixed results. To re-examine the antipsychotic potential of CCK-based treatments, we examined systemic injections of CCK analogs in an animal model with strong face and construct validity for sensorimotor-gating deficits seen in schizophrenia patients and with strong predictive validity for antipsychotic drug activity. Prepulse inhibition (PPI) occurs when a weak acoustic lead stimulus ("prepulse") inhibits the startle response to a sudden loud sound ("pulse"). PPI is significantly reduced in schizophrenia patients and rats treated with dopamine agonists. Antipsychotics reverse decreased PPI in rats to a degree highly correlated with their clinical efficacy. Subcutaneous (s.c.) injections of caerulein (10 micrograms/kg) a mixed CCKA/B agonist, partially reversed amphetamine-induced reduction of PPI; whereas, s.c. haloperidol (0.5 mg/kg) totally reversed amphetamine-induced disruption of PPI. Caerulein's effect on PPI was blocked by pretreatment with a CCKA antagonist (devazepide) but not a CCKB antagonist (L-365,260). CCK-4, a preferential CCKB agonist, had no significant effect on PPI. These results suggest that caerulein produces a weak neuroleptic-like effect on PPI that is mediated by stimulation of CCKA receptors. Possible circuities in this effect are discussed. In a separate experiment, s.c. caerulein produced to a more potent neuroleptic-like profile on amphetamine-induced hyperlocomotion, suggesting that selection of preclinical paradigms may be important in evaluating the antipsychotic potential of CCK-based treatments.

  16. Effects of brain-derived and glial cell line-derived neurotrophic factors on startle response and disrupted prepulse inhibition in mice of DBA/2J inbred strain.

    PubMed

    Naumenko, Vladimir S; Bazovkina, Daria V; Morozova, Maryana V; Popova, Nina K

    2013-08-29

    Prepulse inhibition (PPI), the reduction in acoustic startle reflex when it is preceded by weak prepulse stimuli, is a measure of critical to normal brain functioning sensorimotor gating. PPI deficit was shown in a variety of psychiatric disorders including schizophrenia, and in DBA/2J mouse strain. In the current study, we examined the effects of brain-derived (BDNF) and glial cell line-derived (GDNF) neurotrophic factors on acoustic startle response and PPI in DBA/2J mice. It was found that BDNF (300 ng, i.c.v.) significantly increased amplitude of startle response and restored disrupted PPI in 7 days after acute administration. GDNF (800 ng, i.c.v.) did not produce significant alteration neither in amplitude of startle response nor in PPI in DBA/2J mice. The reversal effect of BDNF on PPI deficit was unusually long-lasting: significant increase in PPI was found 1.5 months after single acute BDNF administration. Long-term ameliorative effect BDNF on disrupted PPI suggested the implication of epigenetic mechanism in BDNF action on neurogenesis. BDNF rather than GDNF could be a perspective drug for the treatment of sensorimotor gating impairments.

  17. 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.

  18. 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.

  19. The effects of Eph-ephrin mutations on pre-pulse inhibition in mice

    PubMed Central

    Liuzzo, Andrea M.; Gray, Lincoln; Wallace, Matthew M.; Gabriele, Mark L.

    2014-01-01

    Eph-ephrin signaling is known to be important in directing topographic projections in the afferent auditory pathway, including connections to various subdivisions of the inferior colliculus (IC). The acoustic startle-response (ASR) is a reliable reflexive behavioral response in mammals elicited by an unexpected intense acoustic startle-eliciting stimulus (ES). It is mediated by a sub-cortical pathway that includes the IC. The ASR amplitude can be measured with an accelerometer under the subject and can be decreased in amplitude by presenting a less intense, non-startling stimulus 5–300 ms before the ES. This reflexive decrement in ASR is called pre-pulse inhibition (PPI) and indicates that the relatively soft pre-pulse was heard. PPI is a general trait among mammals. Mice have been used recently to study this response and to reveal how genetic mutations affect neural circuits and hence the ASR and PPI. In this experiment, we measured the effect of Eph-ephrin mutations using control mice (C57BL/6J), mice with compromised EphA4 signaling (EphA4lacZ/+, EphA4lacZ/lacZ), and knockout ephrin-B3 mice (ephrin-B3 +/−, −/−). Control and EphA4lacZ/+ strains showed robust PPI (up to 75% decrement in ASR) to an offset of a 70 dB SPL background noise at 50 ms before the ES. Ephrin-B3 knockout mice and EphA4 homozygous mutants were only marginally significant in PPI (< 25% decrement and <33% decrement, respectively) to the same conditions. This decrement in PPI highlights the importance of ephrin-B3 and EphA4 interactions in ordering auditory behavioral circuits. Thus, different mutations in certain members of the signaling family produce a full range of changes in PPI, from minimal to nearly maximal. This technique can be easily adapted to study other aspects of hearing in a wider range of mutations. Along with ongoing neuroanatomical studies, this allows careful quantification of how the auditory anatomical, physiological and now behavioral phenotype is affected by

  20. Reduced prepulse inhibition in adolescents at risk for psychosis: a 2-year follow-up study

    PubMed Central

    Ziermans, Tim; Schothorst, Patricia; Magnée, Maurice; van Engeland, Herman; Kemner, Chantal

    2011-01-01

    Background Reduced prepulse inhibition (PPI) of the auditory startle reflex is a hallmark feature of attention-processing deficits in patients with schizophrenia and other psychotic disorders. Recent evidence suggests that these deficits may also be present before the onset of psychosis in individuals at ultra-high risk (UHR) and become progressively worse as psychosis develops. We conducted a longitudinal follow-up study to observe the development of PPI over time in UHR adolescents and healthy controls. Methods Two-year follow-up data of PPI measures were compared between UHR adolescents and a matched control group of typically developing individuals. Results We included 42 UHR adolescents and 32 matched controls in our study. Compared with controls, UHR individuals showed reduced PPI at both assessments. Clinical improvement in UHR individuals was associated with an increase in PPI parameters. Limitations A developmental increase in startle magnitude partially confined the interpretation of the association between clinical status and PPI. Furthermore, post hoc analyses for UHR individuals who became psychotic between assessments had limited power owing to a low transition rate (14%). Conclusion Deficits in PPI are present before the onset of psychosis and represent a stable vulnerability marker over time in UHR individuals. The magnitude of this marker may partially depend on the severity of clinical symptoms. PMID:21266126

  1. 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.

  2. Characterizing cannabis-induced psychosis: a study with prepulse inhibition of the startle reflex.

    PubMed

    Morales-Muñoz, Isabel; Jurado-Barba, Rosa; Ponce, Guillermo; Martínez-Gras, Isabel; Jiménez-Arriero, Miguel Ángel; Moratti, Stephan; Rubio, Gabriel

    2014-12-15

    Cannabis-induced psychotic disorder (CIPD) refers to psychotic symptoms that arise in the context of cannabis intoxication. Prepulse inhibition (PPI) deficits have been extensively identified in schizophrenia and in cannabis abusers. We aimed to characterize PPI in CIPD patients. We used a sample of 48 CIPD patients, 54 schizophrenia patients and cannabis abuse (SCHZ), 44 cannabis dependents (CD), and 44 controls. CIPD, SCHZ and CD were abstinent of cannabis consumption for 9 months. Participants were assessed with PPI at 30, 60, and 120 ms. At 30 ms, CIPD showed lower PPI levels than controls, and SCHZ obtained worse functioning than controls and CD. At 60 ms, only SCHZ exhibited worse PPI percentages (of object) than controls. Finally, at 120 ms, CIPD showed higher PPI levels than SCHZ, and SCHZ obtained lower percentages than controls. We found that CIPD and SCHZ patients showed deficits at the most pre-attentional levels, whereas CIPD patients performed better than SCHZ at higher attentional levels. These results suggest that CIPD constitutes a different group of patients than that of SCHZ. Deficits in PPI functioning at 30 ms could be a useful psychophysiological measure to detect CIPD patients, who are frequently confused with cannabis abusers whose symptoms may mimic that of schizophrenia.

  3. Between Site Reliability of Startle Prepulse Inhibition Across Two Early Psychosis Consortia

    PubMed Central

    Addington, Jean; Cannon, Tyrone D.; Cornblatt, Barbara A.; de la Fuente-Sandoval, Camilo; Mathalon, Dan H.; Perkins, Diana O.; Seidman, Larry J.; Tsuang, Ming; Walker, Elaine F.; Woods, Scott W.; Bachman, Peter; Belger, Ayse; Carrión, Ricardo E.; Donkers, Franc C.L.; Duncan, Erica; Johannesen, Jason; León-Ortiz, Pablo; Light, Gregory; Mondragón, Alejandra; Niznikiewicz, Margaret; Nunag, Jason; Roach, Brian J.; Solís-Vivanco, Rodolfo

    2014-01-01

    Prepulse inhibition (PPI) and reactivity of the acoustic startle response are widely used biobehavioral markers in psychopathology research. Previous studies have demonstrated that PPI and startle reactivity exhibit substantial within-site stability; between-site stability, however, has not been established. In two separate consortia investigating biomarkers of early psychosis, traveling subjects studies were performed as part of quality assurance procedures in order to assess the fidelity of data across sites. In the North American Prodromal Longitudinal Studies (NAPLS) Consortium, 8 normal subjects traveled to each of the 8 NAPLS sites and were tested twice at each site on the startle PPI paradigm. In preparation for a binational study, 10 healthy subjects were assessed twice in both San Diego and Mexico City. Intraclass correlations between and within sites were significant for PPI and startle response parameters, confirming the reliability of startle measures across sites in both consortia. There were between site differences in startle magnitude in the NAPLS study that did not appear to be related to methods or equipment. In planning multi-site studies, it is essential to institute quality assurance procedures early and establish between site reliability to assure comparable data across sites. PMID:23799460

  4. 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.

  5. Prepulse inhibition of the startle reflex: a window on the brain in schizophrenia.

    PubMed

    Braff, David L

    2010-01-01

    Prepulse inhibition (PPI) of the startle response is an important measure of information processing deficits and inhibitory failure in schizophrenia patients. PPI is especially useful because it occurs in the same lawful manner in all mammals, from humans to rodents, making it an ideal candidate for cross-species translational research. PPI deficits occur across the "schizophrenia spectrum" from schizophrenia patients to their clinically unaffected relatives. Parallel animal model and human brain imaging studies have demonstrated that PPI is modulated by cortico-striato-pallido-thalamic (and pontine) circuitry. This circuitry is also implicated in schizophrenia neuropathology and neurophysiology. The finding of PPI deficits in schizophrenia patients has been replicated by many groups, and these deficits correlate with measures of thought disorder and appear to be "normalized" by second generation antipsychotic (SGA) medications. Consistent pharmacological effects on PPI have been demonstrated; among these, dopamine agonists induce PPI deficits and (in animal models) these are reversed by first and SGA medications. PPI is also significantly heritable in humans and animals and can be used as a powerful endophenotype in studies of families of schizophrenia patients. Genomic regions, including the NRGL-ERBB4 complex with its glutamatergic influences, are strongly implicated in PPI deficits in schizophrenia. PPI continues to hold promise as an exciting translational cross-species measure that can be used to understand the pathophysiology and treatment of the schizophrenias via pharmacological, anatomic, and genetic studies.

  6. Social isolation stress significantly enhanced the disruption of prepulse inhibition in mice repeatedly treated with methamphetamine.

    PubMed

    Dai, Hongmei; Okuda, Hirotomo; Iwabuchi, Kentaro; Sakurai, Eiko; Chen, Zhong; Kato, Motohisa; Iinuma, Kazuie; Yanai, Kazuhiko

    2004-10-01

    Repeated administration of methamphetamine (METH) causes reverse tolerance or behavioral sensitization in mice. However, the effects of social isolation stress on the METH-caused reverse tolerance have not been studied until now. The aim of this study was to investigate the effects of social isolation stress on METH-caused reverse tolerance by examining the prepulse inhibition of startle response (PPI). PPI was tested in socially isolated and grouped mice after repeated METH injections. Locomotor activity and PPI were also examined just after a four-week isolation rearing period as a control experiment. After completing behavioral experiments, the mice were sacrificed, and the contents of monoamines, including histamine in the brain, were measured. Social isolation stress significantly lowered the locomotion and disrupted PPI. Repeated injections of METH enhanced the effects of social isolation on PPI. The content of dopamine and histamine significantly increased in the cortex, and the turnover rate of dopamine decreased significantly. These findings demonstrate that social isolation stress significantly enhances METH-induced behavioral sensitization and that the altered histaminergic neuron system might play an important role in METH-induced behavioral sensitization in addition to dopaminergic and serotoninergic neurotransmission. Our data suggest that social isolation is involved in the development of METH-induced psychosis, schizophrenia, and other related psychiatric disorders.

  7. Effect of stress and attention on startle response and prepulse inhibition.

    PubMed

    De la Casa, Luis Gonzalo; Mena, Auxiliadora; Ruiz-Salas, Juan Carlos

    2016-10-15

    The startle reflex magnitude can be modulated when a weak stimulus is presented before the onset of the startle stimulus, a phenomenon termed prepulse inhibition (PPI). Previous research has demonstrated that emotional processes can modulate PPI and startle intensity, but the available evidence is inconclusive. In order to obtain additional evidence in this domain, we conducted two experiments intended to analyze the effect of induced stress and attentional load on PPI and startle magnitude. Specifically, in Experiment 1 we used a between subject strategy to evaluate the effect on startle response and PPI magnitude of performing a difficult task intended to induce stress in the participants, as compared to a group exposed to a control task. In Experiment 2 we evaluated the effect of diverting attention from the acoustic stimulus on startle and PPI intensity. The results seem to indicate that induced stress can reduce PPI, and that startle reflex intensity is reduced when attention is directed away from the auditory stimulus that induces the reflex.

  8. Simultaneous evaluation of prepulse inhibition with EMG and EEG using advanced artifact removal techniques.

    PubMed

    Fraga, Francisco J; Noya, Claudemiro V; Zimiani, Maria I; Avila, Milton A; Shuhama, Rosana; Del-Ben, Cristina M; Menezes, Paulo R; Martin, Rodrigo S; Salum, Cristiane

    2016-08-01

    Prepulse inhibition (PPI) consists of a reduction of the acoustic startle reflex (SR) magnitude (measured with EMG) when a startling stimulus is preceded by a non-startling one. This behavior has been extensively investigated in studies related to schizophrenia, since sensory-motor deficit plays a central role in its pathophysiology. However, the same auditory stimuli that trigger the SR also provoke intense auditory evoked responses (AEP), which can be measured with EEG. Comparing these two types of responses, acquired simultaneously, is a great opportunity to investigate the dependence and interdependence of their neural pathways. Nonetheless, so far very few studies have dared to perform such simultaneous recordings, because SR produces strong eye blinks and muscle contraction artifacts that contaminate EEG electrodes placed on the scalp. In this study we investigated the possibility of simultaneously obtaining both the acoustic SR (using EMG) and the AEP (using EEG) measures, through the use of advanced artifact removal techniques, to better characterize PPI in healthy humans.

  9. Prepulse inhibition in HIV-1 gp120 transgenic mice after withdrawal from chronic methamphetamine.

    PubMed

    Henry, Brook L; Geyer, Mark A; Buell, Mahalah R; Perry, William; Young, Jared W; Minassian, Arpi

    2014-02-01

    HIV infection is frequently comorbid with methamphetamine (METH) dependence. Both factors are associated with impairment in inhibitory function that continues even after abstinence from the drug. Deficits in prepulse inhibition (PPI), a measure of sensorimotor gating, are induced by acute stimulant administration, but the combined effect of HIV and chronic METH exposure on PPI is not well characterized. We quantified baseline acoustic startle and PPI in mice expressing the HIV-1 gp120 envelope protein (gp120tg) and in wild-type (WT) littermates; thereafter, we administered a chronic regimen of METH or vehicle and tested startle and PPI after 7 days of drug withdrawal. We hypothesized that METH-treated gp120tg mice would exhibit PPI deficits compared with vehicle-treated WT or gp120tg animals. Before METH administration, drug-naive female gp120tg mice exhibited decreased PPI compared with female WT mice, whereas male gp120tg mice exhibited increased startle compared with other groups. After drug withdrawal, no consistent genotype effect was observed, but METH-treated mice exhibited increased PPI compared with vehicle, in contrast to previous reports of acute METH-induced PPI deficits. In summary, PPI impairment in HIV could depend on factors such as sex, whereas changes in PPI following METH withdrawal may depend on the quantity and duration of drug exposure.

  10. Prepulse inhibition in HIV-1 gp120 transgenic mice after withdrawal from chronic methamphetamine

    PubMed Central

    Henry, Brook L.; Geyer, Mark A.; Buell, Mahalah R.; Perry, William; Young, Jared W.; Minassian, Arpi

    2014-01-01

    HIV infection is frequently comorbid with methamphetamine (METH) dependence. Both factors are associated with impairment in inhibitory function that continues even after abstinence from the drug. Deficits in prepulse inhibition (PPI), a measure of sensorimotor gating, are induced by acute stimulant administration, but the combined effect of HIV and chronic METH exposure on PPI is not well characterized. We quantified baseline acoustic startle and PPI in mice expressing the HIV-1 gp120 envelope protein (gp120tg) and in wild-type (WT) littermates; thereafter, we administered a chronic regimen of METH or vehicle and tested startle and PPI after 7 days of drug withdrawal. We hypothesized that METH-treated gp120tg mice would exhibit PPI deficits compared with vehicle-treated WT or gp120tg animals. Before METH administration, drug-naive female gp120tg mice exhibited decreased PPI compared with female WT mice, whereas male gp120tg mice exhibited increased startle compared with other groups. After drug withdrawal, no consistent genotype effect was observed, but METH-treated mice exhibited increased PPI compared with vehicle, in contrast to previous reports of acute METH-induced PPI deficits. In summary, PPI impairment in HIV could depend on factors such as sex, whereas changes in PPI following METH withdrawal may depend on the quantity and duration of drug exposure. PMID:24281153

  11. Sex-related differences in prepulse inhibition of startle in irritable bowel syndrome (IBS).

    PubMed

    Kilpatrick, L A; Ornitz, E; Ibrahimovic, H; Treanor, M; Craske, M; Nazarian, M; Labus, J S; Mayer, E A; Naliboff, B D

    2010-05-01

    Alterations in central networks involved in the regulation of arousal, attention, and cognition may be critical for irritable bowel syndrome (IBS) symptom maintenance and exacerbation. Differential sensitivities in these networks may underlie sex differences noted in IBS. The current study examined prepulse inhibition (PPI), a measure of sensorimotor gating, in male and female IBS patients. Relationships between PPI and symptom severity were examined, as well as potential menstrual status effects. Compared to healthy controls, male IBS patients had significantly reduced PPI; whereas female IBS patients (particularly naturally cycling women) had significantly enhanced PPI suggesting hypervigilance. Considering previously demonstrated sex-related differences in perceptual and brain imaging findings in IBS patients, the current findings suggest that different neurobiological mechanisms underlie symptom presentation in male and female IBS patients. Compromised filtering of information in male IBS patients may be due to compromised top down (prefrontal, midcingulate) control mechanisms while increased attention to threat due to increased limbic and paralimbic circuits may be characteristic of female IBS patients.

  12. 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

  13. Modafinil disrupts prepulse inhibition in mice: strain differences and involvement of dopaminergic and serotonergic activation.

    PubMed

    Kwek, Perrin; van den Buuse, Maarten

    2013-01-15

    Modafinil is a wakefulness-promoting agent with possible beneficial effects for the management of addiction and in psychiatric conditions, but also with abuse potential of its own. The mechanism of action of modafinil remains unclear. We studied pharmacological mechanisms in the effect of modafinil on prepulse inhibition (PPI), a model of sensorimotor gating. Mice were tested in automated startle boxes after administration of modafinil and antagonist drugs. Oral administration of 100mg/kg of modafinil, but not lower doses, caused a significant reduction of PPI in C57Bl/6 mice, but not Balb/c mice. This effect of modafinil could be blocked by co-treatment with the dopamine D(2) receptor antagonist, haloperidol, and the serotonin (5-HT) 2A receptor antagonist, ketanserin, but not the 5-HT(1A) receptor antagonist, WAY100,635. At 30mg/kg, which did not influence PPI, modafinil inhibited PPI disruption caused by the dopamine transporter inhibitor, GBR12909. There was no interaction between modafinil and the serotonin transporter inhibitor, fluoxetine. There were no consistent effects of modafinil on startle amplitude. These results show that oral modafinil treatment may cause disruption of PPI in mice. This effect was strain-dependent, involving dopamine D(2) and 5-HT(2A) receptor activation, and was likely mediated by an interaction with the dopamine transporter. These results extend our insight into the behavioral effects of modafinil and could be of importance for the clinical use of this agent as they may indicate an increased risk of side-effects in conditions where PPI is already reduced, such as in schizophrenia and bipolar disorder.

  14. Interaction Between the Effects of Corticotropin-Releasing Factor and Prepulse Parameters on Prepulse Inhibition in Two Inbred Rat Strains and the F1 Generation of a Cross Between Them

    PubMed Central

    Conti, Lisa H.; Sutherland, Jane E.; Muhlhauser, Carey M.

    2009-01-01

    Levels of prepulse inhibition (PPI) depend on the interval between the startling and prepulse stimuli. Brown Norway rats show less PPI of the acoustic startle response than Wistar-Kyoto (WKY) rats when the interval between the prepulse and startling stimulus is 100 msec. Central administration of corticotropin-releasing factor (CRF) decreases PPI at this inter-stimulus interval. Here, the effect of CRF on PPI over a range of inter-stimulus intervals was examined in WKY and BN rats, and in the F1 generation of a cross between them. Rats received an intracerebroventricular infusion of either saline or CRF 30 min prior to testing PPI. Test trials included startle stimulus alone trials, and trials on which a prepulse stimulus of either 6, 12, or 15 dB above background preceded the startling stimulus by either 20, 75, 100, 500 or 2000 msec. CRF decreased PPI in WKY rats at all inter-stimulus intervals and all prepulse intensities, while the effect of CRF on PPI in BN rats only occurred at intermediate intervals. BN and WKY rats showed different levels of PPI only at the intermediate intervals. Baseline PPI in the F1 rats resembled the WKY phenotype. The CRF-induced change in PPI in the F1 generation has some qualities of the effects in each of the progenitor strains. These results suggest that both the effect of rats strain and of CRF on PPI depend on the inter-stimulus interval, and that there is an interaction between prepulse stimulus intensity and the inter-stimulus interval. PMID:19373982

  15. M4 muscarinic receptor knockout mice display abnormal social behavior and decreased prepulse inhibition

    PubMed Central

    2012-01-01

    Background In the central nervous system (CNS), the muscarinic system plays key roles in learning and memory, as well as in the regulation of many sensory, motor, and autonomic processes, and is thought to be involved in the pathophysiology of several major diseases of the CNS, such as Alzheimer's disease, depression, and schizophrenia. Previous studies reveal that M4 muscarinic receptor knockout (M4R KO) mice displayed an increase in basal locomotor activity, an increase in sensitivity to the prepulse inhibition (PPI)-disrupting effect of psychotomimetics, and normal basal PPI. However, other behaviorally significant roles of M4R remain unclear. Results In this study, to further investigate precise functional roles of M4R in the CNS, M4R KO mice were subjected to a battery of behavioral tests. M4R KO mice showed no significant impairments in nociception, neuromuscular strength, or motor coordination/learning. In open field, light/dark transition, and social interaction tests, consistent with previous studies, M4R KO mice displayed enhanced locomotor activity compared to their wild-type littermates. In the open field test, M4R KO mice exhibited novelty-induced locomotor hyperactivity. In the social interaction test, contacts between pairs of M4R KO mice lasted shorter than those of wild-type mice. In the sensorimotor gating test, M4R KO mice showed a decrease in PPI, whereas in the startle response test, in contrast to a previous study, M4R KO mice demonstrated normal startle response. M4R KO mice also displayed normal performance in the Morris water maze test. Conclusions These findings indicate that M4R is involved in regulation of locomotor activity, social behavior, and sensorimotor gating in mice. Together with decreased PPI, abnormal social behavior, which was newly identified in the present study, may represent a behavioral abnormality related to psychiatric disorders including schizophrenia. PMID:22463818

  16. Sleep deprivation disrupts prepulse inhibition of the startle reflex: reversal by antipsychotic drugs.

    PubMed

    Frau, Roberto; Orrù, Marco; Puligheddu, Monica; Gessa, Gian Luigi; Mereu, Giampaolo; Marrosu, Francesco; Bortolato, Marco

    2008-11-01

    Sleep deprivation (SD) is known to induce perceptual impairments, ranging from perceptual distortion to hallucinatory states. Although this phenomenon has been extensively described in the literature, its neurobiological underpinnings remain elusive. In rodents, SD induces a series of behavioural patterns that might be reflective of psychosis and mania, such as hyperlocomotion and sensitization to psychotogenic drugs. Notably, such changes are accompanied by transitory alterations of dopaminergic signalling. Based on the hypothesis that both psychotic and manic disorders reflect gating impairments, the present study was aimed at the assessment of the impact of SD on the behavioural model of prepulse inhibition (PPI) of the startle reflex, a reliable paradigm for the study of informational filtering. Rats subjected to SD (24 h, 48 h, 72 h) exhibited a time-dependent increase in startle reflex and a dramatic deficit in PPI. Both alterations were reversed 24 h after termination of the SD period. Interestingly, PPI disruption was efficiently prevented by haloperidol (0.1 mg/kg i.p.) clozapine (5 mg/kg i.p.) and risperidone (1 mg/kg i.p.). Conversely, neither the anxiolytic diazepam (5 mg/kg i.p.) nor the antidepressant citalopram (5 mg/kg i.p) affected the PPI disruption mediated by SD, although diazepam reversed the enhancement in startle reflex magnitude induced by this manipulation. Our data suggest that SD induces gating deficits that might be relevant to the hallucinatory phenomena observed in humans, and provide a novel reliable animal model where such relationship can be studied.

  17. Combination of prenatal immune challenge and restraint stress affects prepulse inhibition and dopaminergic/GABAergic markers.

    PubMed

    Deslauriers, Jessica; Larouche, Annie; Sarret, Philippe; Grignon, Sylvain

    2013-08-01

    Gestational immune challenge with the viral-like antigen poly I:C is a well-established neurodevelopmental model of schizophrenia. However, exposure to inflammation during early life may sensitize the developing brain to secondary insults and enhance the central nervous system vulnerability. To gain a better understanding of the pathophysiology of schizophrenia, we thus developed a two-hit animal model based on prenatal poly I:C immune challenge followed by restraint stress in juvenile mice. C57BL/6 gestational mice were intraperitoneally injected with poly I:C or saline at gestational day 12. Pups were then submitted or not, to restraint stress for 2h, for three consecutive days, from postnatal days 33 to 35. Prepulse inhibition (PPI) of acoustic startle response is commonly used to assess sensorimotor gating, a neural process severely disrupted in patients with schizophrenia. Our results revealed that the combination of prenatal immune challenge with poly I:C followed by a restraint stress period was able to induce a PPI disruption in 36-day-old pups, as opposed to each insult applied separately. PPI deficits were accompanied by dopaminergic and GABAergic abnormalities in the prefrontal cortex and striatum. Indeed, measurements of cortical and striatal dopamine D2 receptor (D2R) mRNA and protein levels revealed that the combination of gestational exposure to poly I:C and postnatal restraint stress induced an increase in D2R protein and mRNA levels. Likewise, the combination of both insults reduced the mRNA and protein expression levels of the 67 kDa form of glutamic acid decarboxylase (GAD67), in those two brain regions. To our knowledge, this two-hit animal model is the first in vivo model reporting PPI deficits at pubertal age. This two-hit animal model may also help in studying innovative therapies dedicated to the treatment of schizophrenia, especially in its early phase.

  18. Cannabidiol, among Other Cannabinoid Drugs, Modulates Prepulse Inhibition of Startle in the SHR Animal Model: Implications for Schizophrenia Pharmacotherapy

    PubMed Central

    Peres, Fernanda F.; Levin, Raquel; Almeida, Valéria; Zuardi, Antonio W.; Hallak, Jaime E.; Crippa, José A.; Abilio, Vanessa C.

    2016-01-01

    Schizophrenia is a severe psychiatric disorder that involves positive, negative and cognitive symptoms. Prepulse inhibition of startle reflex (PPI) is a paradigm that assesses the sensorimotor gating functioning and is impaired in schizophrenia patients as well as in animal models of this disorder. Recent data point to the participation of the endocannabinoid system in the pathophysiology and pharmacotherapy of schizophrenia. Here, we focus on the effects of cannabinoid drugs on the PPI deficit of animal models of schizophrenia, with greater focus on the SHR (Spontaneously Hypertensive Rats) strain, and on the future prospects resulting from these findings. PMID:27667973

  19. Does genetic BDNF deficiency in rats interact with neurotransmitter control of prepulse inhibition? Implications for schizophrenia.

    PubMed

    van den Buuse, Maarten; Biel, Davina; Radscheit, Kathrin

    2017-04-03

    Several studies have suggested a role of BDNF in the development of schizophrenia. For example, post-mortem studies have shown significantly reduced levels of BDNF protein expression in the brain of schizophrenia patients. We investigated the relationship between reduced levels of BDNF in the brain and the regulation of prepulse inhibition (PPI), a behavioral endophenotype of schizophrenia. We used BDNF heterozygous mutant rats which display a 50% decrease of mature BDNF protein levels. Previously, we observed normal baseline PPI and responses to the dopamine D1/D2 receptor agonist, apomorphine, in these rats. Here, we focused on the effects of the NMDA receptor antagonist, MK-801, its interaction with mGluR2/3 and mGluR5 receptors, and the PPI response to serotonergic drugs. MK-801 administration caused a dose-dependent reduction of PPI and increase of startle amplitudes. Baseline PPI and the effect of 0.02-0.1mg/kg of MK-801 were not significantly altered in male or female BDNF heterozygous rats, although the MK-801-induced increase in startle levels was reduced. Co-treatment with the mGluR2/3 agonist, LY379,268, or the mGluR5 antagonist, MPEP, did not alter the effect of MK-801 on PPI in controls or BDNF mutant rats. Treatment with the serotonin-1A receptor agonist, 8-OH-DPAT, the serotonin-2A receptor agonist, DOI, or the serotonin releaser, fenfluramine, induced differential effects on PPI and startle but these effects were not different between the genotypes. These results show that a significant decrease of BDNF protein expression does not lead to reduced PPI at baseline or changes in the regulation of PPI via NMDA receptors or serotonergic mechanisms. These findings in a genetic rat model of BDNF deficiency do not support a role for similar reductions of BDNF levels in schizophrenia in the disruption of PPI, widely reported as an endophenotype of the illness. The potential implications of these results for our understanding of changes in PPI and BDNF

  20. 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.

  1. 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

  2. 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

  3. 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

  4. Involvement of pallidotegmental neurons in methamphetamine- and MK-801-induced impairment of prepulse inhibition of the acoustic startle reflex in mice: reversal by GABAB receptor agonist baclofen.

    PubMed

    Arai, Sawako; Takuma, Kazuhiro; Mizoguchi, Hiroyuki; Ibi, Daisuke; Nagai, Taku; Takahashi, Kenji; Kamei, Hiroyuki; Nabeshima, Toshitaka; Yamada, Kiyofumi

    2008-12-01

    We have previously demonstrated that pallidotegmental GABAergic neurons play a crucial role in prepulse inhibition (PPI) of the startle reflex in mice through the activation of GABA(B) receptors in pedunculopontine tegmental neurons. In this study, we investigated whether PPI disruption induced by methamphetamine (METH) or MK-801 is associated with the dysfunction of pallidotegmental neurons. Furthermore, we examined the effects of baclofen, a GABA(B) receptor agonist, on METH- and MK-801-induced PPI impairment. Acute treatment with METH (3 mg/kg, subcutaneouly (s.c.)) and MK-801 (>0.3 mg/kg, s.c.) significantly disrupted PPI, accompanied by the suppression of c-Fos expression in lateral globus pallidus induced by PPI. Furthermore, acute treatment with METH and MK-801 stimulated c-Fos expression in the caudal pontine reticular nucleus (PnC) in mice subjected to the PPT test, although PPI alone had no effect on c-Fos expression. Repeated treatment with 1 mg/kg METH for 7 days, which did not affect PPI acutely, showed similar effects on PPI and c-Fos expression to acute treatment with METH (3 mg/kg). Baclofen dose-dependently ameliorated PPI impairment induced by acute treatment with METH (3 mg/kg) and MK-801 (1 mg/kg), and decreased METH- and MK-801-stimulated c-Fos expression in PnC to the basal level. These results suggest that dysfunction of pallidotegmental neurons is involved in PPI disruption caused by METH and MK-801 in mice. GABA(B) receptor may constitute a putative target in treating neuropsychiatric disorders with sensorimotor gating deficits, such as schizophrenia and METH psychosis.

  5. Altered object-in-place recognition memory, prepulse inhibition, and locomotor activity in the offspring of rats exposed to a viral mimetic during pregnancy.

    PubMed

    Howland, J G; Cazakoff, B N; Zhang, Y

    2012-01-10

    Infection during pregnancy (i.e., prenatal infection) increases the risk of psychiatric illnesses such as schizophrenia and autism in the adult offspring. The present experiments examined the effects of prenatal immune challenge on behavior in three paradigms relevant to these disorders: prepulse inhibition (PPI) of the acoustic startle response, locomotor responses to an unfamiliar environment and the N-methyl-d-aspartate antagonist MK-801, and three forms of recognition memory. Pregnant Long-Evans rats were exposed to the viral mimetic polyinosinic-polycytidylic acid (PolyI:C; 4 mg/kg, i.v.) on gestational day 15. Offspring were tested for PPI and locomotor activity before puberty (postnatal days (PNDs)35 and 36) and during young adulthood (PNDs 56 and 57). Four prepulse-pulse intervals (30, 50, 80, and 140 ms) were employed in the PPI test. Recognition memory testing was performed using three different spontaneous novelty recognition tests (object, object location, and object-in-place recognition) after PND 60. Regardless of sex, offspring of PolyI:C-treated dams showed disrupted PPI at 50-, 80-, and 140-ms prepulse-pulse intervals. In the prepubescent rats, we observed prepulse facilitation for the 30-ms prepulse-pulse interval trials that was selectively retained in the adult PolyI:C-treated offspring. Locomotor responses to MK-801 were significantly reduced before puberty, whereas responses to an unfamiliar environment were increased in young adulthood. Both male and female PolyI:C-treated offspring showed intact object and object location recognition memory, whereas male PolyI:C-treated offspring displayed significantly impaired object-in-place recognition memory. Females were unable to perform the object-in-place test. The present results demonstrate that prenatal immune challenge during mid/late gestation disrupts PPI and locomotor behavior. In addition, the selective impairment of object-in-place recognition memory suggests tasks that depend on prefrontal

  6. Restraint stress-induced reduction in prepulse inhibition in Brown Norway rats: Role of the CRF2 receptor

    PubMed Central

    Sutherland, Jane E.; Conti, Lisa H.

    2011-01-01

    Stress plays a role in many psychiatric disorders that are characterized by deficits in prepulse inhibition (PPI), a form of sensorimotor gating. Corticotropin-releasing factor (CRF) is one of the most important neurotransmitters involved in behavioral components of the stress response. Central infusion of CRF reduces PPI in both rats and mice. In mice, it has been shown that CRF1 receptor activation mediates the effect of exogenous CRF on PPI. However, the roles of the two CRF receptors in a stress-induced reduction in PPI are not known. We sought to determine whether CRF1 and/or CRF2 receptor blockade attenuates a stress-induced reduction of PPI in rats. In separate experiments, we assessed PPI in Brown Norway rats after exposure to five days of 2-hour restraint, and after pretreatment with the CRF1 receptor antagonist, CP-154,526 (20.0 mg/kg), or the CRF2 receptor antagonist, antisauvagine-30 (10.0 µg). Repeated, but not acute, restraint decreased PPI and attenuated the increase in PPI caused by repeated PPI testing. Blockade of the CRF1 receptor did not attenuate the effect of repeated restraint on PPI or grooming behavior. While CRF2 receptor blockade did attenuate the effect of repeated restraint on PPI, repeated ICV infusion of the selective CRF2 receptor agonist urocortin III, did not affect PPI. These findings demonstrate the effect of stress on sensorimotor gating and suggest that the CRF2 receptor mediates this effect in rats. PMID:21185316

  7. Effects of Repeated Ropinirole Treatment on Phencyclidine-Induced Hyperlocomotion, Prepulse Inhibition Deficits, and Social Avoidance in Rats.

    PubMed

    Maple, Amanda M; Call, Tanessa; Kimmel, Phylicia C; Hammer, Ronald P

    2017-04-01

    Phencyclidine (PCP), a noncompetitive N-methyl d-aspartate (NMDA) receptor antagonist, provides the most complete pharmacologic model of schizophrenia in humans and animals. Acute PCP causes hyperlocomotion, disrupts prepulse inhibition (PPI), and increases social avoidance in rats. We have previously shown that repeated treatment with the dopamine (DA) D2-like receptor agonists, quinpirole or ropinirole, prevents agonist-induced PPI disruption. In the present study, we examined whether repeated ropinirole treatment similarly attenuates the effects of PCP in a more complete model of schizophrenia symptoms and examined the effect of repeated D2-like agonist treatment on locomotion, PPI, and social interaction after acute PCP challenge. The acute effect of PCP (3.0 or 6.0 mg/kg) on locomotor activity was examined to establish a minimum effective dose. Thereafter, the effect of PCP challenge (3.0 mg/kg) on locomotor activity, PPI, and social interaction was assessed in adult male rats before or 7-10 days after termination of repeated daily treatment with ropinirole (0.1 mg/kg) or saline vehicle (0.1 ml/kg) for 28 days. Repeated ropinirole treatment attenuates PCP-induced hyperlocomotion, PPI deficits, and social avoidance. These findings suggest that repeated ropinirole treatment might affect a final common pathway that is vulnerable to both PCP- and dopamine agonist-induced behavioral disruption, thereby providing an alternative approach to block the effects of PCP.

  8. Enhancement of acoustic prepulse inhibition by contextual fear conditioning in mice is maintained even after contextual fear extinction.

    PubMed

    Ishii, Daisuke; Matsuzawa, Daisuke; Fujita, Yuko; Sutoh, Chihiro; Ohtsuka, Hiroyuki; Matsuda, Shingo; Kanahara, Nobuhisa; Hashimoto, Kenji; Iyo, Masaomi; Shimizu, Eiji

    2010-02-01

    Prepulse inhibition (PPI) of the acoustic startle response is one of the few and major paradigms for investigating sensorimotor gating systems in humans and rodents in a similar fashion. PPI deficits are observed not only in patients with schizophrenia, but also in patients with anxiety disorders. Previous studies have shown that PPI in rats can be enhanced by auditory fear conditioning. In this study, we evaluated the effects of contextual fear conditioning (FC) for six times a day and fear extinction (FE) for seven days on PPI in mice. C57BL/6J mice (male, 8-12 weeks) were divided into three groups; no-FC (control), FC and FC + FE. We measured PPI at the following three time points, (1) baseline before FC, (2) after FC, and (3) after FE. The results showed that PPI was increased after FC. Moreover, the enhanced PPI following FC was observed even after FE with decreased freezing behaviors. These results suggested contextual fear conditioning could enhance acoustic PPI, and that contextual fear extinction could decrease freezing behaviors, but not acoustic PPI.

  9. The medial septum mediates impairment of prepulse inhibition of acoustic startle induced by a hippocampal seizure or phencyclidine.

    PubMed

    Ma, Jingyi; Shen, Bixia; Rajakumar, N; Leung, L Stan

    2004-11-05

    The involvement of the septohippocampal system on the impaired sensorimotor gating induced by phencyclidine (PCP) or by an electrically induced hippocampal seizure was examined in behaving rats. An impaired sensorimotor gating, measured by prepulse inhibition (PPI) of the acoustic startle response, was observed following a hippocampal afterdischarge (AD) or systemic injection of PCP and was accompanied with an increase in hippocampal gamma waves (30-70 Hz). The medial septum infusion with muscimol (0.25 microg), a GABA(A) receptor agonist, 15 min prior to PCP or a hippocampal AD, prevented the impairment of sensorimotor gating and the increase in gamma waves. By itself, muscimol (0.25 microg) injection into the medial septum did not affect PPI, although it significantly suppressed spontaneous gamma waves. In order to identify subpopulations of neurons mediating the sensorimotor gating deficit and the hippocampal gamma wave increase, 0.14-0.21 microg of p75 antibody conjugated to saporin (192 IgG-saporin) was injected into the medial septum to selectively lesion the septohippocampal cholinergic neurons. Neither the PPI deficit nor the gamma wave increase induced by PCP or a hippocampal AD was affected by 192 IgG-saporin lesion of the medial septum. It is concluded that increase in neural activity in the medial septum participates in the impairment of sensorimotor gating and the increase in hippocampal gamma waves induced by PCP or a hippocampal AD. It is suggested that the GABAergic but not the cholinergic septohippocampal neurons mediate the sensorimotor gating deficit.

  10. Sex differences in the effects of N,N-diethyllysergamide (LSD) on behavioural activity and prepulse inhibition.

    PubMed

    Pálenícek, Tomás; Hlinák, Zdenek; Bubeníková-Valesová, Vera; Novák, Tomás; Horácek, Jirí

    2010-05-30

    The aim of this study was to describe sex differences in the behavioural effects of N,N-diethyllysergamide (LSD) (locomotor activity and other behavioural repertoire in the open field) and its effects on sensorimotor gating in rats (prepulse inhibition (PPI) of the acoustic startle reaction). Three groups of animals were analysed: males, oestral and pro-oestral phase females (EP females), and metoestral and dioestral phase females (MD females). LSD (5, 50 and 200 microg/kg subcutaneously) attenuated locomotor activity and normal behavioural repertoire, and induced flat body posture, wet dog shakes and disrupted PPI. The most prominent behavioural findings of LSD were for LSD 200 microg/kg which suppressed almost all behavioural activity. LSD had mainly inhibitory locomotor effects in males and MD females, yet in EP female rats LSD increased locomotion during the second half of testing period. The main sex differences were observed in locomotor and exploratory behaviour. Both EP and MD females were less sensitive to hypolocomotor effects of LSD and had less pronounced thigmotaxis than males. Further EP females had increased rearing after LSD 5microg/kg. On the contrary although LSD disrupted PPI in males and MD female rats, EP females were protected from this disruptive effect. Thus, EP females seem to have a lower sensitivity to LSD behavioural actions.

  11. Role of the substantia nigra pars reticulata in sensorimotor gating, measured by prepulse inhibition of startle in rats.

    PubMed

    Koch, M; Fendt, M; Kretschmer, B D

    2000-12-20

    The substantia nigra pars reticulata (SNR) is one of the major output nuclei of the basal ganglia. It connects the dorsal and ventral striatum with the thalamus, superior colliculus and pontomedullary brainstem. The SNR is therefore in a strategic position to regulate sensorimotor behavior. We here assessed the effects of SNR lesions on prepulse inhibition (PPI) of the acoustic startle response (ASR), stereotypy and locomotion in drug-free rats, as well as after systemic administration of the dopamine agonist DL-amphetamine (2 mg/kg), and the NMDA receptor antagonists dizocilpine (0.16 mg/kg) and CGP 40116 (2 mg/kg). SNR lesions reduced PPI, enhanced spontaneous sniffing and potentiated the locomotor stimulation by dizocilpine and CGP 40116. PPI was impaired by dizocilpine and CGP 40116 in controls. The ASR was enhanced in controls by dizocilpine and amphetamine. SNR lesions prevented the enhancement of the ASR by amphetamine. A second experiment tested the hypothesis that the SNR mediates PPI via a GABAergic inhibition of the startle pathway. Infusion of the GABA(B) antagonist phaclofen but not the GABA(A) antagonist picrotoxin into the caudal pontine reticular nucleus reduced PPI. Hence, lesion of the SNR reduces sensorimotor gating possibly by elimination of a nigroreticular GABAergic projection interacting with GABA(B) receptors. Moreover, destruction of the SNR enhances the motor stimulatory effects of amphetamine and of the NMDA antagonists dizocilpine and CGP 40116. We conclude that the SNR exerts a tonic GABAergic inhibition on sensorimotor behavior that is regulated by the dorsal and the ventral striatum.

  12. Fear-potentiated startle to threat, and prepulse inhibition among young adult non-smokers, abstinent smokers, and non-abstinent smokers

    PubMed Central

    Grillon, Christian; Avenevoli, Shelli; Daurignac, Elsa; Merikangas, Kathleen R

    2007-01-01

    Background Evidence suggests that the transition from experimental to regular smoking is facilitated by the influence of tobacco on affective and attentional mechanisms. The objective of this study was to examine affective and attentional responses in young adult smokers using fear-potentiated startle and prepulse inhibition. Methods Participants were 56 college non smokers, non-abstinent smokers, and overnight-abstinent smokers. The fear-potentiated startle test examined phasic responses to imminent threat cues and more sustained responses to unpredictable aversive events. Prepulse inhibition investigated responses to attended and ignored prepulse stimuli. Results Abstinent and non-abstinent smokers showed increased sustained potentiation of startle to contextual cues, compared to controls. Abstinent smokers showed increased fear-potentiated startle to threat cues, compared to non-smokers. PPI did not discriminate between abstinent or non-abstinent smokers and controls. Conclusion These findings suggest that negative affectivity or anxiety is associated with smoking, particularly during withdrawal. Potentiated startle may provide a valuable tool in understanding the biologic mechanisms underlying nicotine withdrawal and inform cessation and prevention efforts. PMID:17543892

  13. 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.

  14. Structural and functional abnormalities of the hippocampal formation in rats with environmentally induced reductions in prepulse inhibition of acoustic startle.

    PubMed

    Greene, J R; Kerkhoff, J E; Guiver, L; Totterdell, S

    2001-01-01

    The effects of social isolation on prepulse inhibition of acoustic startle (PPI), electrophysiology and morphology of subicular pyramidal neurons and the densities of interneuronal sub-types in the hippocampal formation were examined. Wistar rats (male weanlings) were housed socially (socials, n=8) or individually (isolates, n=7). When tested eight weeks later, PPI was lower in isolates. Rats then received terminal anaesthesia before slices of hippocampal formation were made in which the electrophysiological properties of a total of 108 subicular neurons were characterized. There were no differences in neuronal sub-types recorded in socials compared with isolates. Intrinsically burst-firing and regular spiking pyramidal neurons were examined in detail. There were no differences in resting membrane potential or input resistance in isolates compared with socials but action potential height was reduced and action potential threshold raised in isolates. A limited morphological examination of Neurobiotin-filled intrinsically burst-firing neurons did not reveal differences in cell-body area or in number of primary dendrites. Sections from the contralateral hemispheres of the same rats were stained with antibodies to calretinin, parvalbumin and the neuronal isoform of nitric oxide synthase (nNOS). In isolates, the density of calretinin positive neurons was increased in the dentate gyrus but unchanged in areas CA3, CA1 and subiculum. Parvalbumin and nNOS positive neuronal densities were unchanged. Hence in rats with environmentally induced reductions in PPI there are structural and functional abnormalities in the hippocampal formation. If the reduction in PPI stems from these abnormalities, and reduced PPI in rats is relevant to schizophrenia, then drugs that correct the reported electrophysiological changes might have antipsychotic effects.

  15. 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

  16. 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.

  17. Repeated forced swimming impairs prepulse inhibition and alters brain-derived neurotrophic factor and astroglial parameters in rats.

    PubMed

    Borsoi, Milene; Antonio, Camila Boque; Müller, Liz Girardi; Viana, Alice Fialho; Hertzfeldt, Vivian; Lunardi, Paula Santana; Zanotto, Caroline; Nardin, Patrícia; Ravazzolo, Ana Paula; Rates, Stela Maris Kuze; Gonçalves, Carlos-Alberto

    2015-01-01

    Glutamate perturbations and altered neurotrophin levels have been strongly associated with the neurobiology of neuropsychiatric disorders. Environmental stress is a risk factor for mood disorders, disrupting glutamatergic activity in astrocytes in addition to cognitive behaviours. Despite the negative impact of stress-induced neuropsychiatric disorders on public health, the molecular mechanisms underlying the response of the brain to stress has yet to be fully elucidated. Exposure to repeated swimming has proven useful for evaluating the loss of cognitive function after pharmacological and behavioural interventions, but its effect on glutamate function has yet to be fully explored. In the present study, rats previously exposed to repeated forced swimming were evaluated using the novel object recognition test, object location test and prepulse inhibition (PPI) test. In addition, quantification of brain-derived neurotrophic factor (BDNF) mRNA expression and protein levels, glutamate uptake, glutathione, S100B, GluN1 subunit of N-methyl-D-aspartate receptor and calmodulin were evaluated in the frontal cortex and hippocampus after various swimming time points. We found that swimming stress selectively impaired PPI but did not affect memory recognition. Swimming stress altered the frontal cortical and hippocampal BDNF expression and the activity of hippocampal astrocytes by reducing hippocampal glutamate uptake and enhancing glutathione content in a time-dependent manner. In conclusion, these data support the assumption that astrocytes may regulate the activity of brain structures related to cognition in a manner that alters complex behaviours. Moreover, they provide new insight regarding the dynamics immediately after an aversive experience, such as after behavioural despair induction, and suggest that forced swimming can be employed to study altered glutamatergic activity and PPI disruption in rodents.

  18. 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.

  19. Periadolescent ethanol vapor exposure produces reductions in hippocampal volume that are correlated with deficits in prepulse inhibition of the startle

    PubMed Central

    Ehlers, Cindy L.; Oguz, Ipek; Budin, Francois; Wills, Derek N.; Crews, Fulton T.

    2013-01-01

    BACKGROUND Epidemiological studies suggest that excessive alcohol consumption is prevalent among adolescents and may have lasting neurobehavioral consequences. The use of animal models allows for the separation of the effects of adolescent ethanol exposure from genetic background and other environmental insults. In the present study the effects of moderate ethanol vapor exposure, during adolescence, on structural diffusion tensor imaging (DTI) and behavioral measures were evaluated in adulthood. METHODS A total of 53 Wistar rats were received at postnatal day (PD) 21, and were randomly assigned to ethanol vapor (14 hrs on/10 hrs off/day) or air exposure for 35 days from PD 23-PD 58 (average blood ethanol concentration (BEC): 169 mg%). Animals were received in two groups that were subsequently sacrificed at two time points following withdrawal from ethanol vapor: (1) at 72 days of age, 2 weeks following withdrawal or (2) at day 128, 10 weeks following withdrawal. In the second group, behavior in the light/dark box and prepulse inhibition of the startle (PPI) were also evaluated. Fifteen animals in each group were scanned, post mortem, for structural DTI. RESULTS There were no significant differences in body weight between ethanol and control animals. Volumetric data, demonstrated that total brain, hippocampal, corpus callosum but not ventricular volume was significantly larger in the 128 day sacrificed animals as compared to the 72 day animals. The hippocampus was smaller and the ventricles larger at 128 days as compared to 72 days, in the ethanol exposed animals, leading to a significant group × time effect. Ethanol exposed animals sacrificed at 128 days also had diminished PPI and more rears in the light box that were significantly correlated with hippocampal size. CONCLUSIONS These studies demonstrate that DTI volumetric measures of hippocampus are significantly impacted by age and periadolescent ethanol exposure and withdrawal in Wistar rats. PMID:23578102

  20. Inhibition of auditory evoked potentials and prepulse inhibition of startle in DBA/2J and DBA/2Hsd inbred mouse substrains.

    PubMed

    Connolly, Patrick M; Maxwell, Christina R; Kanes, Stephen J; Abel, Ted; Liang, Yuling; Tokarczyk, Jan; Bilker, Warren B; Turetsky, Bruce I; Gur, Raquel E; Siegel, Steven J

    2003-11-28

    Previous data have shown differences among inbred mouse strains in sensory gating of auditory evoked potentials, prepulse inhibition (PPI) of startle, and startle amplitude. These measures of sensory and sensorimotor gating have both been proposed as models for genetic determinants of sensory processing abnormalities in patients with schizophrenia and their first-degree relatives. Data from our laboratory suggest that auditory evoked potentials of DBA/2J mice differ from those previously described for DBA/2Hsd. Therefore, we compared evoked potentials and PPI in these two closely related substrains based on the hypothesis that any observed endophenotypic differences are more likely to distinguish relevant from incidental genetic heterogeneity than similar approaches using inbred strains that vary across the entire genome. We found that DBA/2Hsd substrain exhibited reduced inhibition of evoked potentials and reduced startle relative to the DBA/2J substrain without alterations in auditory sensitivity, amplitude of evoked potentials or PPI of startle. These results suggest that gating of auditory evoked potentials and PPI of startle measure different aspects of neuronal function. The differences between the substrains might reflect genetic drift. Alternatively, differences could arise from different rearing environments or other non-genetic factors. Future studies will attempt to determine the cause of these differences in sensory and sensorimotor processing between these two closely related inbred mouse strains.

  1. 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.

  2. Neonatal intrahippocampal injection of lipopolysaccharide induces deficits in social behavior and prepulse inhibition and microglial activation in rats: Implication for a new schizophrenia animal model.

    PubMed

    Zhu, Furong; Zhang, Lulu; Ding, Yu-qiang; Zhao, Jingping; Zheng, Yingjun

    2014-05-01

    Several lines of evidence have suggested that the dysregulation of immune system is involved in the pathogenesis of schizophrenia. Microglia are the resident macrophage of the brain and the major player in innate immunity in the brain. We hypothesized that microglia activation may be closely associated with the neuropathology of schizophrenia. Neonatal intrahippocampal injection of lipopolysaccharide (LPS), an activator of microglia, was performed in rats at postnatal day 7 (PD7), and they were separately treated with saline or minocycline for consecutive 3days. Behavioral changes (locomotor activity, social interaction and prepulse inhibition) were examined in adulthood, and the number of microglia was assessed using immunohistochemistry at PD9, PD21 and PD67. The adult rats in LPS-injected group showed obvious behavioral alterations (deficits in social behavior and prepulse inhibition) and a persistently dramatic increase of number of activated microglial cells in the hippocampus, cerebral cortex and thalamus compared to those in saline-injected group. Interestingly, pretreatment with minocycline could significantly rescue the behavioral deficits and prevent microglia activation. Our results suggest that neonatal intrahippocampal LPS injection may serve as a potential schizophrenia animal model, and inhibition of microglia activation may be a potential treatment strategy for schizophrenia.

  3. Investigation of the effects of head irradiation with gamma rays and protons on startle and pre-pulse inhibition behavior in mice.

    PubMed

    Haerich, Paul; Eggers, Cara; Pecaut, Michael J

    2012-05-01

    With the increased international emphasis on manned space exploration, there is a growing need to understand the impact of the spaceflight environment on health and behavior. One particularly important aspect of this environment is low-dose radiation. In the present studies, we first characterized the γ- and proton-irradiation dose effect on acoustic startle and pre-pulse inhibition behaviors in mice exposed to 0-5 Gy brain-localized irradiation, and assessed these effects 2 days later. Subsequently, we used 2 Gy to assess the time course of γ- and proton-radiation effects on startle reactivity 0-8 days after exposure. Exposures targeted the brain to minimize the impact of peripheral inflammation-induced sickness behavior. The effects of radiation on startle were subtle and acute. Radiation reduced the startle response at 2 and 5 Gy. Following a 2-Gy exposure, the response reached a minimum at the 2-day point. Proton and γ-ray exposures did not differ in their impact on startle. We found there were no effects of radiation on pre-pulse inhibition of the startle response.

  4. Atypical antipsychotic clozapine reversed deficit on prepulse inhibition of the acoustic startle reflex produced by microinjection of DOI into the inferior colliculus in rats.

    PubMed

    de Oliveira, Rodolpho Pereira; Nagaishi, Karen Yuriko; Barbosa Silva, Regina Cláudia

    2017-05-15

    Dysfunctions of the serotonergic system have been suggested to be important in the neurobiology of schizophrenia. Patients with schizophrenia exhibit deficits in an operational measure of sensorimotor gating: prepulse inhibition (PPI) of startle. PPI is the normal reduction in the startle response caused by a low intensity non-startling stimulus (prepulse) which is presented shortly before the startle stimulus (pulse). The hallucinogen 2,5-dimethoxy-4-iodoamphetamine (DOI), a 5-hydroxytryptamine(HT)2 receptor agonist disrupted PPI in rats. The inferior colliculus (IC) is a critical nucleus of the auditory pathway mediating acoustic PPI. The activation of the IC by the acoustic prepulse reduces startle magnitude. The present study investigated the role of serotonergic transmission in the IC on the expression of acoustic PPI. For that we investigated whether 5-HT2A receptor activation or blockade would affect this response. Unilateral microinjection of DOI (10μg/0.3μl) into the IC disrupted PPI, while microinjection of the 5-HT2A receptor antagonist ritanserin (4μg/0.3μl), into this structure did not alter PPI. We also examined the ability of the atypical antipsychotic clozapine (5.0mg/kg; I.P.) to reverse the disruption of PPI produced by unilateral microinjections of DOI into the IC of rats. Pretreatment with clozapine blocked DOI-induced disruption of PPI. Altogether, these results suggest that serotonin-mediated mechanisms of the IC are involved in the expression of PPI in rodents and that this response is sensitive to atypical antipsychotic clozapine.

  5. 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

  6. The influence of DHEA pretreatment on prepulse inhibition and the HPA-axis stress response in rat offspring exposed prenatally to polyriboinosinic-polyribocytidylic-acid (PIC).

    PubMed

    Maayan, Rachel; Ram, Edward; Biton, Doron; Cohen, Hagit; Baharav, Ehud; Strous, Rael D; Weizman, Abraham

    2012-07-11

    Prenatal exposure to maternal infection may be associated with the development of neurodevelopmental disorders as well as increased susceptibility to the development of schizophrenia. Prenatal administration of polyriboinosinic-polyribocytidilic-acid, mimicking RNA virus exposure, has been shown to induce schizophrenia-like behavioral, neurochemical and neuorophysiological abnormalities in rodent offspring. In the present study PIC prenatal administration at gestation day 15 was associated with alterations in the acoustic-startle-response/prepulse-inhibition [ASR/PPI] and the HPA-axis stress response in rat offspring on day 90. We show that pretreatment with dehydroepiandrosterone (DHEA) reverses PIC-related ASR/PPI disruption in female rats and normalizes HPA-axis stress response in a united group of male and female rats. Further research in both animal and human studies is recommended in order to confirm these preliminary findings and their application to the understanding and management of schizophrenia and related conditions.

  7. 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.

  8. Atomoxetine reverses locomotor hyperactivity, impaired novel object recognition, and prepulse inhibition impairment in mice lacking pituitary adenylate cyclase-activating polypeptide.

    PubMed

    Shibasaki, Y; Hayata-Takano, A; Hazama, K; Nakazawa, T; Shintani, N; Kasai, A; Nagayasu, K; Hashimoto, R; Tanida, M; Katayama, T; Matsuzaki, S; Yamada, K; Taniike, M; Onaka, Y; Ago, Y; Waschek, J A; Köves, K; Reglődi, D; Tamas, A; Matsuda, T; Baba, A; Hashimoto, H

    2015-06-25

    Attention-deficit/hyperactivity disorder (ADHD) is a complex neurobehavioral disorder that is characterized by attention difficulties, impulsivity, and hyperactivity. A non-stimulant drug, atomoxetine (ATX), which is a selective noradrenaline reuptake inhibitor, is widely used for ADHD because it exhibits fewer adverse effects compared to conventional psychostimulants. However, little is known about the therapeutic mechanisms of ATX. ATX treatment significantly alleviated hyperactivity of pituitary adenylate cyclase-activating polypeptide (PACAP)-deficient (PACAP(-/-)) mice with C57BL/6J and 129S6/SvEvTac hybrid background. ATX also improved impaired novel object recognition memory and prepulse inhibition in PACAP(-/-) mice with CD1 background. The ATX-induced increases in extracellular noradrenaline and dopamine levels were significantly higher in the prefrontal cortex of PACAP(-/-) mice compared to wild-type mice with C57BL/6J and 129S6/SvEvTac hybrid background. These results suggest that ATX treatment-induced increases in central monoamine metabolism may be involved in the rescue of ADHD-related abnormalities in PACAP(-/-) mice. Our current study suggests that PACAP(-/-) mice are an ideal rodent model with predictive validity for the study of ADHD etiology and drug development. Additionally, the potential effects of differences in genetic background of PACAP(-/-) mice on behaviors are discussed.

  9. Genetic inhibition of JNK3 ameliorates spinal muscular atrophy

    PubMed Central

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

    2015-01-01

    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

  10. The effect of restraint stress on prepulse inhibition and on corticotropin-releasing factor (CRF) and CRF receptor gene expression in Wistar-Kyoto and Brown Norway rats

    PubMed Central

    Sutherland, Jane E.; Burian, Linda C.; Covault, Jonathan; Conti, Lisa H.

    2010-01-01

    Stress plays a role in many psychiatric disorders that are characterized by deficits in prepulse inhibition (PPI), a form of sensorimotor gating. Corticotropin-releasing factor (CRF) is one of the most important neurotransmitters involved in behavioral components of the stress response, and central infusion of CRF decreases PPI in rodents. We recently demonstrated that restraint stress decreases PPI and attenuates the increase in PPI caused by repeated testing. To broaden our investigation into how restraint affects PPI, we subjected Wistar-Kyoto (WKY) and Brown Norway (BN) rats to 10 consecutive days of 2-hour restraint, or to brief handling, prior to assessing PPI. We next examined the effects of 1 or 10 days of 2-hour restraint on plasma corticosterone levels in order to determine whether the endocrine response to stress parallels the behavioral effect of stress. Finally, we examined the effects of 1 or 10 days of 2-hour restraint on CRF and CRF receptor gene expression in the amygdala, hippocampus, frontal cortex, and hypothalamus in order to determine whether a temporal pattern of gene expression parallels the change in the behavioral response to stress. The major findings of the present study are that 1) restraint stress attenuates the increase in PPI caused by repeated testing in both WKY and BN rats, and BN rats are more sensitive to the effects of restraint on PPI than WKY rats, 2) restraint-induced increases in corticosterone levels mirror the effect of restraint on PPI in WKY rats but not in BN rats, 3) laterality effects on gene expression were observed for the amygdala, whereby restraint increases CRF gene expression in the left, but not right, amygdala, and 4) some restraint-induced changes in CRF and CRF receptor gene expression precede changes in PPI while other changes coincide with altered PPI in a rat strain- and brain region-dependent manner. PMID:20709096

  11. The effects of the preferential 5-HT2A agonist psilocybin on prepulse inhibition of startle in healthy human volunteers depend on interstimulus interval.

    PubMed

    Vollenweider, Franz X; Csomor, Philipp A; Knappe, Bernhard; Geyer, Mark A; Quednow, Boris B

    2007-09-01

    Schizophrenia patients exhibit impairments in prepulse inhibition (PPI) of the startle response. Hallucinogenic 5-HT(2A) receptor agonists are used for animal models of schizophrenia because they mimic some symptoms of schizophrenia in humans and induce PPI deficits in animals. Nevertheless, one report indicates that the 5-HT(2A) receptor agonist psilocybin increases PPI in healthy humans. Hence, we investigated these inconsistent results by assessing the dose-dependent effects of psilocybin on PPI in healthy humans. Sixteen subjects each received placebo or 115, 215, and 315 microg/kg of psilocybin at 4-week intervals in a randomized and counterbalanced order. PPI at 30-, 60-, 120-, 240-, and 2000-ms interstimulus intervals (ISIs) was measured 90 and 165 min after drug intake, coinciding with the peak and post-peak effects of psilocybin. The effects of psilocybin on psychopathological core dimensions and sustained attention were assessed by the Altered States of Consciousness Rating Scale (5D-ASC) and the Frankfurt Attention Inventory (FAIR). Psilocybin dose-dependently reduced PPI at short (30 ms), had no effect at medium (60 ms), and increased PPI at long (120-2000 ms) ISIs, without affecting startle reactivity or habituation. Psilocybin dose-dependently impaired sustained attention and increased all 5D-ASC scores with exception of Auditory Alterations. Moreover, psilocybin-induced impairments in sustained attention performance were positively correlated with reduced PPI at the 30 ms ISI and not with the concomitant increases in PPI observed at long ISIs. These results confirm the psilocybin-induced increase in PPI at long ISIs and reveal that psilocybin also produces a decrease in PPI at short ISIs that is correlated with impaired attention and consistent with deficient PPI in schizophrenia.

  12. Nicotine withdrawal disrupts both foreground and background contextual fear conditioning but not pre-pulse inhibition of the acoustic startle response in C57BL/6 mice.

    PubMed

    André, Jessica M; Gulick, Danielle; Portugal, George S; Gould, Thomas J

    2008-07-19

    Nicotine withdrawal is associated with multiple symptoms such as anxiety, increased appetite, and disrupted cognition in humans. Although animal models have provided insights into the somatic and affective symptoms of nicotine withdrawal, less research has focused on the effects of nicotine withdrawal on cognition. Therefore, in this study, C57BL/6J mice were used to test the effects of withdrawal from chronic nicotine on foreground and background contextual fear conditioning, which present the context as a primary or secondary stimulus, respectively. Mice withdrawn from 12 days of chronic nicotine (6.3mg/kg/day) or saline were trained and tested in either foreground or background contextual fear conditioning; nicotine withdrawal-associated deficits in contextual fear conditioning were observed in both conditions. Mice were also tested for the effects of withdrawal on pre-pulse inhibition of the acoustic startle reflex (PPI), a measure of sensory gating, and on the acoustic startle reflex. Mice withdrawn from 12 days of chronic nicotine (6.3 or 12.6 mg/kg/day) or saline underwent one 30-min PPI and startle session; no effect of withdrawal from chronic nicotine on PPI or startle was observed for either dose at 24h after nicotine removal. Therefore, mice were tested at different time points following withdrawal from 12.6 mg/kg/day chronic nicotine (8, 24, and 48 h after nicotine removal). No effect of withdrawal from chronic nicotine was observed at any time point for PPI. Overall, these results demonstrate that nicotine withdrawal disrupts two methods of contextual learning but not sensory gating in C57BL/6J mice.

  13. 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

  14. Morphological correlates of sex differences in acoustic startle response and prepulse inhibition through projections from locus coeruleus to cochlear root neurons.

    PubMed

    Hormigo, Sebastian; Gómez-Nieto, Ricardo; Sancho, Consuelo; Herrero-Turrión, Javier; Carro, Juan; López, Dolores E; Horta-Júnior, José de Anchieta de Castro E

    2017-04-05

    The noradrenergic locus coeruleus (LC) plays an important role in the promotion and maintenance of arousal and alertness. Our group recently described coerulean projections to cochlear root neurons (CRNs), the first relay of the primary acoustic startle reflex (ASR) circuit. However, the role of the LC in the ASR and its modulation, prepulse inhibition (PPI), is not clear. In this study, we damaged LC neurons and fibers using a highly selective neurotoxin, DSP-4, and then assessed ASR and PPI in male and female rats. Our results showed that ASR amplitude was higher in males at 14 days after DSP-4 injection when compared to pre-administration values and those in the male control group. Such modifications in ASR amplitude did not occur in DSP-4-injected females, which exhibited ASR amplitude within the range of control values. PPI differences between males and females seen in controls were not observed in DSP-4-injected rats for any interstimulus interval tested. DSP-4 injection did not affect ASR and PPI latencies in either the male or the female groups, showing values that were consistent with the sex-related variability observed in control rats. Furthermore, we studied the noradrenergic receptor system in the cochlear nerve root using gene expression analysis. When compared to controls, DSP-4-injected males showed higher levels of expression in all adrenoceptor subtypes; however, DSP-4-injected females showed varied effects depending on the receptor type, with either up-, downregulations, or maintenance of expression levels. Lastly, we determined noradrenaline levels in CRNs and other LC-targeted areas using HPLC assays, and these results correlated with behavioral and adrenoceptor expression changes post DSP-4 injection. Our study supports the participation of LC in ASR and PPI, and contributes toward a better understanding of sex-related differences observed in somatosensory gating paradigms.

  15. 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.

  16. Interactions Between Corticotropin-Releasing Factor and the Serotonin 1A Receptor System on Acoustic Startle Amplitude and Prepulse Inhibition of the Startle Response in Two Rat Strains

    PubMed Central

    Conti, Lisa H.

    2011-01-01

    Both the neuropeptide, corticotropin-releasing factor (CRF) and the serotonin 1A (5-HT1A) receptor systems have been implicated in anxiety disorders and there is evidence that the two systems interact with each other to affect behavior. Both systems have individually been shown to affect prepulse inhibition (PPI) of the acoustic startle response. PPI is a form of sensorimotor gating that is reduced in patients with anxiety disorders including post-traumatic stress and panic disorder. Here, we examined whether the two systems interact or counteract each other to affect acoustic startle amplitude, PPI and habituation of the startle response. In experiment 1, Brown Norway (BN) and Wistar-Kyoto (WKY) rats were administered ether an intraperitoneal (IP) injection of saline or the 5-HT1A receptor agonist, 8-OH-DPAT 10 min prior to receiving an intracerebroventricular (ICV) infusion of either saline or CRF (0.3 µg). In a second experiment, rats were administered either an IP injection of saline or the 5-HT1A receptor antagonist, WAY 100,635 10 min prior to receiving an ICV infusion of saline or CRF. Thirty min after the ICV infusion, the startle response and PPI were assessed. As we have previously shown, the dose of CRF used in these experiments reduced PPI in BN rats and had no effect on PPI in WKY rats. Administration of 8-OH-DPAT alone had no effect on PPI in either rat strain when the data from the two strains were examined separately. Administration of 8-OHDPAT added to the effect of CRF in BN rats, and the combination of 8-OH-DPAT and CRF significantly reduced PPI in WKY rats. CRF alone had no effect on baseline startle amplitude in either rat strain, but CRF enhanced the 8-OH-DPAT-induced increase in startle in both strains. Administration of WAY 100,635 did not affect the CRF-induced change in PPI and there were no interactions between CRF and WAY 100,635 on baseline startle. The results suggest that activation of the 5-HT1A receptor can potentiate the effect of

  17. 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.

  18. 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.

  19. Galectin-3 inhibition ameliorates hypoxia-induced pulmonary artery hypertension

    PubMed Central

    Hao, Mingwen; Li, Miaomiao; Li, Wenjun

    2016-01-01

    Galectin-3 (Gal-3) is a β-galactoside-binding lectin, which is important in inflammation, fibrosis and heart failure. The present study aimed to investigate the role and mechanism of Gal-3 in hypoxia-induced pulmonary arterial hypertension (PAH). Male C57BL/6J and Gal-3−/− mice were exposed to hypoxia, then the right ventricular systolic pressure (RVSP) and Fulton's index were measured, and Gal-3 mRNA and protein expression in the pulmonary arteries was analyzed by reverse transcription-quantitative polymerase chain reaction and western blotting. Compared with the control, hypoxia increased the mRNA and protein expression levels of Gal-3 in wild type murine pulmonary arteries. Gal-3 deletion reduced the hypoxia-induced upregulation of RVSP and Fulton's index. Furthermore, human pulmonary arterial endothelial cells (HPAECs) and human pulmonary arterial smooth muscle cells (HPASMCs) were stimulated by hypoxia in vitro, and Gal-3 expression was inhibited by small interfering RNA. The inflammatory response of HPAECs, and the proliferation and cell cycle distribution of HPASMCs was also analyzed. Gal-3 inhibition alleviated the hypoxia-induced inflammatory response in HPAECs, including tumor necrosis factor-α and interleukin-1 secretion, expression of intercellular adhesion molecule-1 and adhesion of THP-1 monocytes. Gal-3 inhibition also reduced hypoxia-induced proliferation of HPASMCs, partially by reducing cyclin D1 expression and increasing p27 expression. Furthermore, Gal-3 inhibition suppressed HPASMC switching from a ‘contractile’ to a ‘synthetic’ phenotype. In conclusion, Gal-3 serves a fundamental role in hypoxia-induced PAH, and inhibition of Gal-3 may represent a novel therapeutic target for the treatment of hypoxia-induced PAH. PMID:27959409

  20. Spautin-1 Ameliorates Acute Pancreatitis via Inhibiting Impaired Autophagy and Alleviating Calcium Overload

    PubMed Central

    Xiao, Juan; Feng, Xueping; Huang, Xiao-Ying; Huang, Zhongshi; Huang, Yanqiang; Li, Chaogan; Li, Genliang; Nong, Song; Wu, Ruoshi; Huang, Yongzhi; Long, Xi-Dai

    2016-01-01

    Acute pancreatitis is characterized by zymogen preactivation. Severe inflammation caused by zymogen activation can eventually lead to multiple organ dysfunctions which contribute to the high mortality rate of severe acute pancreatitis. However, there is no specific treatment available for acute pancreatitis therapy. Here, we show that spautin-1, which effectively inhibits autophagy flux, ameliorated the pathogenesis of acute pancreatitis induced by cerulein or L-arginine. CaMKII phosphorylation due to cytosolic calcium overload was revealed in this paper. It was also demonstrated that autophagic protein aggregates degradation blockade accompanied by impaired autophagy correlated positively with intra-acinar cell digestive aymogen activation stimulated by cerulein or L-arginine. The role of spautin-1 in ameliorating acute pancreatitis was shown here to be associated with impaired autophagy inhibition and Ca2+ overload alleviation. We provide a promising therapy for acute pancreatitis through targeting both impaired autophagy and increased cytosolic calcium. PMID:27579473

  1. Involvement of serotoninergic 5-HT1A/2A, alpha-adrenergic and dopaminergic D1 receptors in St. John's wort-induced prepulse inhibition deficit: a possible role of hyperforin.

    PubMed

    Tadros, Mariane G; Mohamed, Mohamed R; Youssef, Amal M; Sabry, Gilane M; Sabry, Nagwa A; Khalifa, Amani E

    2009-05-16

    Prepulse inhibition (PPI) of acoustic startle response is a valuable paradigm for sensorimotor gating processes. Previous research showed that acute administration of St. John's wort extract (500 mg/kg, p.o.) to rats caused significant disruption of PPI while elevating monoamines levels in some brain areas. The cause-effect relationship between extract-induced PPI disruption and augmented monoaminergic transmission was studied using different serotoninergic, adrenergic and dopaminergic antagonists. The effects of hypericin and hyperforin, as the main active constituents of the extract, on PPI response were also tested. PPI disruption was prevented after blocking the serotoninergic 5-HT1A and 5-HT2A, alpha-adrenergic and dopaminergic D1 receptors. Results also demonstrated a significant PPI deficit after acute treatment of rats with hyperforin, and not hypericin. In some conditions manifesting disrupted PPI response, apoptosis coexists. Electrophoresis of DNA isolated from brains of hyperforin-treated animals revealed absence of any abnormal DNA fragmentation patterns. It is concluded that serotoninergic 5-HT1A and 5-HT2A, alpha-adrenergic and dopaminergic D1 receptors are involved in the disruptive effect of St. John's wort extract on PPI response in rats. We can also conclude that hyperforin, and not hypericin, is one of the active ingredients responsible for St. John's wort-induced PPI disruption with no relation to apoptotic processes.

  2. Inhibition of autophagy ameliorates atherogenic inflammation by augmenting apigenin-induced macrophage apoptosis.

    PubMed

    Wang, Qun; Zeng, Ping; Liu, Yuanliang; Wen, Ge; Fu, Xiuqiong; Sun, Xuegang

    2015-07-01

    Increasing evidences showed that the survival of macrophages promotes atherogenesis. Macrophage apoptosis in the early phase of atherosclerotic process negatively regulates the progression of atherosclerotic lesions. We demonstrated that a natural anti-oxidant apigenin could ameliorate atherogenesis in ApoE(-/-) mice. It reduced the number of foam cells and decreased the serum levels of tumor necrosis factor α, interleukin 1β (IL-1β) and IL-6. Our results showed that oxidized low-density lipoprotein (oxLDL) led to the secretion of pro-inflammatory cytokines. Apigenin-induced apoptosis and downregulated the secretion of TNF-α, IL-6 and IL-1β. It is further supported by the use of zVAD, a pan-caspase inhibitor, demonstrating that apigenin lowered cytokine profile through induction of macrophage apoptosis. Moreover, apigenin-induced Atg5/Atg7-dependent autophagy in macrophages pretreated with oxLDL. Results illustrated that autophagy inhibition increased apigenin-induced apoptosis through activation of Bax. The present findings suggest that oxLDL maintained the survival of macrophages and activated the secretion of pro-inflammatory cytokines to initiate atherosclerosis. Apigenin-induced apoptosis of lipid-laden macrophages and resolved inflammation to ameliorate atherosclerosis. In conclusion, combination of apigenin with autophagy inhibition may be a promising strategy to induce foam cell apoptosis and subdue atherogenic cytokines.

  3. 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).

  4. 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.

  5. 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

  6. Mutational inhibition of c-Myb or p300 ameliorates treatment-induced thrombocytopenia

    PubMed Central

    Hilton, Douglas J.; Kile, Benjamin T.

    2009-01-01

    The transcription factor c-Myb and coregulator p300 have a key role in maintaining production of controlled numbers of megakaryocytes and platelets. In mice, mutations in c-Myb or p300 cause thrombocytosis in otherwise wild-type animals and can ameliorate the thrombocytopenia in mice lacking the thrombopoietin receptor, c-Mpl, a model for human congenital amegakaryocytic thrombocytopenia. To examine whether inhibition of c-Myb/p300 is effective in other models of thrombocytopenia, the effect of the c-MybPlt4 mutation on thrombocytopenia associated with reduced platelet life span in Bcl-XPlt20/Plt20 mice was assessed, as were responses in c-MybPlt4 and/or p300Plt6 mutant mice to thrombocytopenia associated with antiplatelet antibodies, chemotherapy, or bone marrow transplantation. Homozygosity of the c-MybPlt4 allele ameliorated thrombocytopenia associated with reduced platelet life span, and c-MybPlt4/+ mice exhibited more rapid than normal recovery from thrombocytopenia caused by antiplatelet serum or bone marrow transplantation. Recovery to pretreatment platelet levels was unaltered in 5-fluorouracil–treated c-MybPlt4/+ mice relative to wild-type controls, but enhanced platelet production during subsequent thrombocytosis was evident. More modest enhancement of platelet recovery after 5-fluorouracil or bone marrow transplantation was also evident in p300Plt6/+ animals. The data suggest potential utility of c-Myb/p300 as a target for therapeutic intervention in thrombocytopenia of diverse origins. PMID:19252138

  7. Inhibition of G0/G1 Switch 2 Ameliorates Renal Inflammation in Chronic Kidney Disease.

    PubMed

    Matsunaga, Naoya; Ikeda, Eriko; Kakimoto, Keisuke; Watanabe, Miyako; Shindo, Naoya; Tsuruta, Akito; Ikeyama, Hisako; Hamamura, Kengo; Higashi, Kazuhiro; Yamashita, Tomohiro; Kondo, Hideaki; Yoshida, Yuya; Matsuda, Masaki; Ogino, Takashi; Tokushige, Kazutaka; Itcho, Kazufumi; Furuichi, Yoko; Nakao, Takaharu; Yasuda, Kaori; Doi, Atsushi; Amamoto, Toshiaki; Aramaki, Hironori; Tsuda, Makoto; Inoue, Kazuhide; Ojida, Akio; Koyanagi, Satoru; Ohdo, Shigehiro

    2016-11-01

    Chronic kidney disease (CKD) is a global health problem, and novel therapies to treat CKD are urgently needed. Here, we show that inhibition of G0/G1 switch 2 (G0s2) ameliorates renal inflammation in a mouse model of CKD. Renal expression of chemokine (C-C motif) ligand 2 (Ccl2) was increased in response to p65 activation in the kidneys of wild-type 5/6 nephrectomy (5/6Nx) mice. Moreover, 5/6Nx Clk/Clk mice, which carry homozygous mutations in the gene encoding circadian locomotor output cycles kaput (CLOCK), did not exhibit aggravation of apoptosis or induction of F4/80-positive cells. The renal expression of G0s2 in wild-type 5/6Nx mice was important for the transactivation of Ccl2 by p65. These pathologies were ameliorated by G0s2 knockdown. Furthermore, a novel small-molecule inhibitor of G0s2 expression was identified by high-throughput chemical screening, and the inhibitor suppressed renal inflammation in 5/6Nx mice. These findings indicated that G0s2 inhibitors may have applications in the treatment of CKD.

  8. 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.

  9. Selective Chemical Inhibition of PGC-1α Gluconeogenic Activity Ameliorates Type 2 Diabetes.

    PubMed

    Sharabi, Kfir; Lin, Hua; Tavares, Clint D J; Dominy, John E; Camporez, Joao Paulo; Perry, Rachel J; Schilling, Roger; Rines, Amy K; Lee, Jaemin; Hickey, Marc; Bennion, Melissa; Palmer, Michelle; Nag, Partha P; Bittker, Joshua A; Perez, José; Jedrychowski, Mark P; Ozcan, Umut; Gygi, Steve P; Kamenecka, Theodore M; Shulman, Gerald I; Schreiber, Stuart L; Griffin, Patrick R; Puigserver, Pere

    2017-03-23

    Type 2 diabetes (T2D) is a worldwide epidemic with a medical need for additional targeted therapies. Suppression of hepatic glucose production (HGP) effectively ameliorates diabetes and can be exploited for its treatment. We hypothesized that targeting PGC-1α acetylation in the liver, a chemical modification known to inhibit hepatic gluconeogenesis, could be potentially used for treatment of T2D. Thus, we designed a high-throughput chemical screen platform to quantify PGC-1α acetylation in cells and identified small molecules that increase PGC-1α acetylation, suppress gluconeogenic gene expression, and reduce glucose production in hepatocytes. On the basis of potency and bioavailability, we selected a small molecule, SR-18292, that reduces blood glucose, strongly increases hepatic insulin sensitivity, and improves glucose homeostasis in dietary and genetic mouse models of T2D. These studies have important implications for understanding the regulatory mechanisms of glucose metabolism and treatment of T2D.

  10. 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.

  11. Astragaloside IV ameliorates allergic inflammation by inhibiting key initiating factors in the initial stage of sensitization

    PubMed Central

    Bao, Kai-fan; Yu, Xi; Wei, Xiao; Gui, Li-li; Liu, Hai-liang; Wang, Xiao-yu; Tao, Yu; Jiang, Guo-rong; Hong, Min

    2016-01-01

    To illuminate the anti-allergy mechanism of astragaloside IV (AS-IV), we assessed its effects in a murine model of allergic contact dermatitis (ACD). AS-IV administered in the sensitization phase, rather than in the elicitation phase, dramatically alleviated the symptoms of allergic inflammation. We hypothesized that AS-IV exerts its anti-allergy effects by regulating the production of key pro-allergic cytokines based on the fact that interleukin (IL)-33 and thymic stromal lymphopoietin (TSLP) levels increase significantly in the initial stage of the sensitization phase. AS-IV administered in the initial stage of ACD inhibited TSLP and IL-33 expression and reduced the proportion of type-2 innate lymphoid cells (ILC2s). An in vitro study showed that the production of pro-allergic cytokines was significantly inhibited in AS-IV presenting HaCaT cells. We also verified that AS-IV administered only in the initial stage markedly alleviated inflammation, including ear swelling, Th2 cytokine expression, and histological changes. Taken together, these results suggest that AS-IV effectively ameliorates the progression of allergic inflammation by inhibiting key initiating factors, including TSLP and IL-33, and can be used to prevent and/or treat patients with ACD. Our data also suggest that these key pro-allergic cytokines are potential therapeutic targets for allergic diseases. PMID:27917896

  12. Potential approaches to ameliorate hepatic fat accumulation seen with MTP inhibition.

    PubMed

    Lin, Minjie; Zhao, Shuiping; Shen, Li; Xu, Danyan

    2014-04-01

    Microsomal triglyceride transfer protein (MTP) is one of the promising targets for the therapy of dyslipidemia and MTP inhibition can lead to robust plasma low-density lipoprotein cholesterol (LDL-C) reduction. Lomitapide, a small-molecule MTP inhibitor, was recently approved by the US FDA as an additional treatment for homozygous familial hypercholesterolemia (hoFH). However, liver-related side effects, including hepatic fat accumulation and transaminase elevations, are the main safety concerns associated with MTP inhibitors. Here, we review recent knowledge on the mechanisms underlying liver toxicity of MTP inhibitors. The contribution of altered levels of intracellular triglycerides, cholesteryl esters, and free cholesterols toward cellular dysfunction is specifically addressed. On this basis, therapies targeted to attenuate cellular lipid accumulation, to reduce risk factors for non-alcoholic fatty liver disease (NAFLD) (i.e., insulin resistance and oxidative stress) and to specifically inhibit intestinal MTP may be useful for ameliorating liver damage induced by MTP inhibitors. In particular, weight loss through lifestyle interventions is expected to be the most effective and safest way to minimize the undesirable side effects. Specific dietary supplementation might also have protective effects against hepatosteatosis. Despite that, to date, few clinical data support these therapeutic options in MTP inhibition-related liver damage, such proposed approaches may be further explored in the future for their use in preventing unwanted effects of MTP inhibitors.

  13. 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

  14. 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.

  15. Mangiferin ameliorates colitis by inhibiting IRAK1 phosphorylation in NF-κB and MAPK pathways.

    PubMed

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

    2014-10-05

    Mangiferin, a main constituent of the root of Anemarrhena asphodeloides and the leaves of Mangifera indica, inhibits NF-κB activation in macrophages. Therefore, we investigated effect of mangiferin on 2,3,4-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice and its anti-inflammatory mechanism in lipolysaccharide (LPS)- or peptidoglycan-stimulated mouse peritoneal macrophages. Mangiferin inhibited phosphorylation of nuclear factor-kappaB (NF-κB), interleukin-1 receptor-associated kinase 1 (IRAK1), and mitogen-activated protein kinases (MAPK) in peptidoglycan- or LPS-stimulated peritoneal macrophages. Mangiferin in the presence of SN50 inhibited LPS-stimulated NF-κB activation more potently than mangiferin alone. Mangiferin inhibited interaction of fluorescent p-IRAK1 antibody to LPS-stimulated peritoneal macrophages, but increased binding of fluorescent IRAK1 antibody. Mangiferin did not influence interaction of fluorescent LPS to toll-like receptor-4 on the macrophages. Molecular peak of mangiferin bound to IRAK1 was detected in the macrophages by mass analysis. Mangiferin (10 μM) inhibited LPS-stimulated expression of TNF-α, IL-1β and IL-6 by 81.0%, 89.5% and 88.3%, respectively, whereas it increased IL-10 expression by 131.8% compared to LPS-nontreated group. Mangiferin furthermore inhibited colon shortening, macroscopic score, and colonic myeloperoxidase activity in TNBS-induced colitic mice. Mangiferin inhibited TNBS-induced IRAK1 phosphorylation and NF-κB activation. Mangiferin suppressed TNBS-induced up-regulation of cyclooxygenase-2 and inducible NO synthase. Furthermore, mangiferin (20mg/kg) significantly inhibited TNF-α by 78%, IL-1β by 82%, and IL-6 expressions by 88% (P<0.05), but induced IL-10 expression to 79% of the normal control group (P<0.05). Based on these findings, mangiferin may ameliorate inflammatory diseases such as colitis by regulating NF-κB and MAPK signaling pathways through the inhibition of IRAK1 phosphorylation.

  16. 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

  17. Paeoniflorin Ameliorates Experimental Autoimmune Encephalomyelitis via Inhibition of Dendritic Cell Function and Th17 Cell Differentiation

    PubMed Central

    Zhang, Han; Qi, Yuanyuan; Yuan, Yuanyang; Cai, Li; Xu, Haiyan; Zhang, Lili; Su, Bing; Nie, Hong

    2017-01-01

    Paeoniflorin (PF) is a monoterpene glycoside and exhibits multiple effects, including anti-inflammation and immunoregulation. To date, the effect of PF on multiple sclerosis (MS) has not been investigated. In this study, we investigated the effect of PF in experimental autoimmune encephalomyelitis (EAE), an animal model for MS. After administered with PF, the onset and clinical symptoms of EAE mice were significantly ameliorated, and the number of Th17 cells infiltrated in central nervous system (CNS) and spleen was also dramatically decreased. Instead of inhibiting the differentiation of Th17 cells directly, PF influenced Th17 cells via suppressing the expression of costimulatory molecules and the production of interlukin-6 (IL-6) of dendritic cells (DCs) in vivo and in vitro, which may be attributable to the inhibition of IKK/NF-κB and JNK signaling pathway. When naïve CD4+ T cells were co-cultured with PF-treated dendritic cells under Th17-polarizing condition, the percentage of Th17 cells and the phosphorylation of STAT3 were decreased, as well as the mRNA levels of IL-17, RORα, and RORγt. Our study provided insights into the role of PF as a unique therapeutic agent for the treatment of multiple sclerosis and illustrated the underlying mechanism of PF from a new perspective. PMID:28165507

  18. CDK4/6 inhibition induces epithelial cell cycle arrest and ameliorates acute kidney injury

    PubMed Central

    DiRocco, Derek P.; Bisi, John; Roberts, Patrick; Strum, Jay; Wong, Kwok-Kin; Sharpless, Norman

    2013-01-01

    Acute kidney injury (AKI) is common and urgently requires new preventative therapies. Expression of a cyclin-dependent kinase (CDK) inhibitor transgene protects against AKI, suggesting that manipulating the tubular epithelial cell cycle may be a viable therapeutic strategy. Broad spectrum small molecule CDK inhibitors are protective in some kidney injury models, but these have toxicities and epithelial proliferation is eventually required for renal repair. Here, we tested a well-tolerated, novel and specific small molecule inhibitor of CDK4 and CDK6, PD 0332991, to investigate the effects of transient cell cycle inhibition on epithelial survival in vitro and kidney injury in vivo. We report that CDK4/6 inhibition induced G0/G1 cycle arrest in cultured human renal proximal tubule cells (hRPTC) at baseline and after injury. Induction of transient G0/G1 cycle arrest through CDK4/6 inhibition protected hRPTC from DNA damage and caspase 3/7 activation following exposure to the nephrotoxins cisplatin, etoposide, and antimycin A. In vivo, mice treated with PD 0332991 before ischemia-reperfusion injury (IRI) exhibited dramatically reduced epithelial progression through S phase 24 h after IRI. Despite reduced epithelial proliferation, PD 0332991 ameliorated kidney injury as reflected by improved serum creatinine and blood urea nitrogen levels 24 h after injury. Inflammatory markers and macrophage infiltration were significantly decreased in injured kidneys 3 days following IRI. These results indicate that induction of proximal tubule cell cycle arrest with specific CDK4/6 inhibitors, or “pharmacological quiescence,” represents a novel strategy to prevent AKI. PMID:24338822

  19. 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

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

    PubMed Central

    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

    2016-01-01

    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

  1. Exosomes derived from MSCs ameliorate retinal laser injury partially by inhibition of MCP-1

    PubMed Central

    Yu, Bo; Shao, Hui; Su, Chang; Jiang, Yuanfeng; Chen, Xiteng; Bai, Lingling; Zhang, Yan; Li, Qiutang; Zhang, Xiaomin; Li, Xiaorong

    2016-01-01

    Although accumulated evidence supports the notion that mesenchymal stem cells (MSCs) act in a paracrine manner, the mechanisms are still not fully understood. Recently, MSC-derived exosomes (MSC-Exos), a type of microvesicle released from MSCs, were thought to carry functional proteins and RNAs to recipient cells and play therapeutic roles. In the present study, we intravitreally injected MSCs derived from either mouse adipose tissue or human umbilical cord, and their exosomes to observe and compare their functions in a mouse model of laser-induced retinal injury. We found that both MSCs and their exosomes reduced damage, inhibited apoptosis, and suppressed inflammatory responses to obtain better visual function to nearly the same extent in vivo. Obvious down-regulation of monocyte chemotactic protein (MCP)-1 in the retina was found after MSC-Exos injection. In vitro, MSC-Exos also down-regulated MCP-1 mRNA expression in primarily cultured retinal cells after thermal injury. It was further demonstrated that intravitreal injection of an MCP-1-neutralizing antibody promoted the recovery of retinal laser injury, whereas the therapeutic effect of exosomes was abolished when MSC-Exos and MCP-1 were administrated simultaneously. Collectively, these results suggest that MSC-Exos ameliorate laser-induced retinal injury partially through down-regulation of MCP-1. PMID:27686625

  2. Inhibition of cereblon by fenofibrate ameliorates alcoholic liver disease by enhancing AMPK.

    PubMed

    Kim, Yong Deuk; Lee, Kwang Min; Hwang, Seung-Lark; Chang, Hyeun Wook; Kim, Keuk-Jun; Harris, Robert A; Choi, Hueng-Sik; Choi, Won-Sik; Lee, Sung-Eun; Park, Chul-Seung

    2015-12-01

    Alcohol consumption exacerbates alcoholic liver disease by attenuating the activity of AMP-activated protein kinase (AMPK). AMPK is activated by fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, and inhibited by direct interaction with cereblon (CRBN), a component of an E3 ubiquitin ligase complex. Based on these preliminary findings, we investigated that CRBN would be up-regulated in the liver by alcohol consumption and that CRBN deficiency would ameliorate hepatic steatosis and pro-inflammatory responses in alcohol-fed mice by increasing AMPK activity. Wild-type, CRBN and PPARα null mice were fed an alcohol-containing liquid diet and administered with fenofibrate. Gene expression profiles and metabolic changes were measured in the liver and blood of these mice. Expression of CRBN, cytochrome P450 2E1 (CYP2E1), lipogenic genes, pro-inflammatory cytokines, serum alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were increased in the Lieber-DeCarli alcohol-challenged mice. Fenofibrate attenuated the induction of CRBN and reduced hepatic steatosis and pro-inflammatory markers in these mice. Ablation of the gene encoding CRBN produced the same effect as fenofibrate. The increase in CRBN gene expression by alcohol and the reduction of CRBN expression by fenofibrate were negated in PPARα null mice. Fenofibrate increased the recruitment of PPARα on CRBN gene promoter in WT mice but not in PPARα null mice. Silencing of AMPK prevented the beneficial effects of fenofibrate. These results demonstrate that activation of PPARα by fenofibrate alleviates alcohol-induced hepatic steatosis and inflammation by reducing the inhibition of AMPK by CRBN. CRBN is a potential therapeutic target for the alcoholic liver disease.

  3. 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.

  4. Experimental colitis is ameliorated by inhibition of nitric oxide synthase activity.

    PubMed Central

    Rachmilewitz, D; Karmeli, F; Okon, E; Bursztyn, M

    1995-01-01

    Enhanced nitric oxide (NO) generation by stimulated NO synthase (NOS) activity may, through its oxidative metabolism contribute to tissue injury in experimental colitis. In this study the possible amelioration of experimental colitis by NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NOS activity, was evaluated. Colitis was induced in rats by intracolonic administration of 30 mg trinitrobenzene sulphonic acid (TNB) dissolved in 0.25 ml 50% ethanol or by flushing the colon of capsaicin pretreated rats with 2 ml of 5% acetic acid. In several experiments, L-NAME 0.1 mg/ml was added to the drinking water at the time of colitis induction with TNB or seven days before acetic acid treatment. Rats were killed at various time intervals after induction of colitis. A 10 cm distal colonic segment was isolated, weighed, lesion area measured, and explants organ cultured for 24 hours for determination of NO generation by the Greiss reaction. The rest of the mucosa was scraped for determination of myeloperoxidase and NOS activities and leukotriene generation. In TNB treated rats mean arterial pressure was also determined up to 72 hours after damage induction, with or without cotreatment with nitroprusside. L-NAME significantly decreased the extent of tissue injury in TNB treated rats. Seven days after TNB treatment lesion area was reduced by 55%, colonic weight by 37%, and myeloperoxidase and NOS activity by 59% and 42%, respectively. Acetic acid induced colitis in capsaicin pretreated rats was also significantly decreased by L-NAME. Twenty four hours after acetic acid treatment lesion area was reduced by 61%, colonic weight by 21% and NOS activity by 39%. Mean (SEM) arterial blood pressure in TNB+L-NAME treated rats was 37.6 (8.1) mm Hg higher than in TNB treated rats, an effect that was only partially abolished by nitroprusside. These results show that inhibition of NO synthesis by an L-arginine analogue significantly ameliorates the extent of tissue injury in two

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

    PubMed Central

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

    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

  6. NF-κB transcriptional inhibition ameliorates cisplatin-induced acute kidney injury (AKI).

    PubMed

    Ozkok, Abdullah; Ravichandran, Kameswaran; Wang, Qian; Ljubanovic, Danica; Edelstein, Charles L

    2016-01-05

    The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) cell signaling pathway is important in inflammation and cell survival. Inflammation and cell death in the kidney are features of cisplatin-induced AKI. While it is known that cisplatin induces NF-κB signaling in the kidney, the NF-κB responsive genes and the effect of direct NF-κB transcriptional inhibition in cisplatin-induced AKI is not known. Mice injected with cisplatin, 25mg/kg, developed AKI, acute tubular necrosis (ATN) and apoptosis on day 3. Mice were treated with JSH-23 (20 or 40 mg/kg) which directly affects NF-κB transcriptional activity. Kidney function, tubular injury (ATN, serum neutrophil gelatinase-associated lipocalin [NGAL], but not apoptosis) and myeloperoxidase (MPO) activity were significantly improved by JSH-23 (40 mg/kg). Sixty one NF-κB responsive genes were increased by cisplatin of which 21 genes were decreased by JSH-23. Genes that were decreased by JSH-23 that are known to play a role in cisplatin-induced AKI were IL-10, IFN-γ, chemokine [C-C motif] ligand 2 (CCL2) and caspase-1. Another gene, caspase recruitment domain family, member 11 (CARD11), not previously known to play a role in AKI, was increased more than 20-fold and completely inhibited by JSH-23. CXCL1 and TNF-α, known mediators of cisplatin-induced AKI, were decreased by JSH-23. RIPK1 and 3, receptor-interacting serine/threonine-protein kinases, that play an important role in necroptosis, were decreased by JSH-23. In mouse proximal tubule cells in culture, JSH-23 resulted in an increase in apoptosis suggesting that the mechanism of protection against AKI by JSH-23 is not due to a direct effect on proximal tubules. In conclusion, NF-κB transcriptional inhibition in cisplatin-induced AKI ameliorates kidney function and ATN without a significant effect on apoptosis and is associated with a decrease pro-inflammatory mediators and CARD11.

  7. Thalidomide ameliorates cisplatin-induced nephrotoxicity by inhibiting renal inflammation in an experimental model.

    PubMed

    Amirshahrokhi, Keyvan; Khalili, Ali-Reza

    2015-04-01

    Cisplatin is a platinum-based chemotherapy drug. However, its chemotherapeutic use is restricted by serious side effects, especially nephrotoxicity. Inflammatory mechanisms have a significant role in the pathogenesis of cisplatin-induced nephrotoxicity. Thalidomide is an immunomodulatory and anti-inflammatory agent and is used for the treatment of various inflammatory diseases. The purpose of this study was to investigate the potential nephroprotective effect of thalidomide in a mouse model of cisplatin-induced nephrotoxicity. Nephrotoxicity was induced in mice by a single injection of cisplatin (15 mg/kg, i.p.) and treated with thalidomide (50 and 100 mg/kg/day, orally) for 4 days, beginning 24 h prior to the cisplatin injection. Renal toxicity induced by cisplatin was demonstrated by increasing plasma levels of creatinine and blood urea nitrogen (BUN). Cisplatin increased the renal production of the proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and transforming growth factor (TGF)-β1. In addition, kidney levels of malondialdehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) were increased by cisplatin. Biochemical results showed that thalidomide reduced cisplatin-induced increase in plasma creatinine and BUN. Thalidomide treatment also significantly reduced tissue levels of the proinflammatory cytokines, MDA, MPO, and NO and increased anti-inflammatory cytokine IL-10. Furthermore, histological examination indicated that thalidomide ameliorated renal damage caused by cisplatin. These data suggest that thalidomide attenuates cisplatin-induced nephrotoxicity possibly by inhibition of inflammatory reactions. Taken together, our findings indicate that thalidomide might be a valuable candidate for the prevention of nephrotoxicity in patients receiving cisplatin.

  8. Arginase inhibition ameliorates adipose tissue inflammation in mice with diet-induced obesity.

    PubMed

    Hu, Huan; Moon, Jiyoung; Chung, Ji Hyung; Kim, Oh Yoen; Yu, Rina; Shin, Min-Jeong

    2015-08-28

    This study examined whether oral administration of an arginase inhibitor regulates adipose tissue macrophage infiltration and inflammation in mice with high fat diet (HFD)-induced obesity. Male C57BL/6 mice (n = 30) were randomly assigned to control (CTL, n = 10), HFD only (n = 10), and HFD with arginase inhibitor N(ω)-hydroxy-nor-l-arginine (HFD with nor-NOHA, n = 10) groups. Plasma and mRNA levels of cytokines in epididymal adipose tissues (EAT), macrophage infiltration into EAT, and macrophage phenotype polarization were measured in the animals after 12 weeks. Additionally, the effects of nor-NOHA on adipose tissue macrophage infiltration and mRNA expression of cytokines were measured in co-cultured 3T3-L1 adipocytes and RAW 264.7 macrophages. Macrophage infiltration into the adipocytes was significantly suppressed by nor-NOHA treatment in adipocyte/macrophage co-culture system and mice with HFD-induced obesity. Pro-inflammatory cytokines, including monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6), were significantly downregulated, and the anti-inflammatory cytokine IL-10 was significantly upregulated in nor-NOHA-treated co-cultured cells. In the mice with HFD-induced obesity, plasma and mRNA levels of MCP-1 significantly reduced after supplementation with nor-NOHA. In addition, oral supplement of nor-NOHA modified M1/M2 phenotype ratio in the EAT. Oral supplementation of an arginase inhibitor, nor-NOHA, altered M1/M2 macrophage phenotype and macrophage infiltration into HFD-induced obese adipose tissue, thereby improved adipose tissue inflammatory response. These results may indicate that arginase inhibition ameliorates obesity-induced adipose tissue inflammation.

  9. Exendin-4 ameliorates oxidized-LDL-induced inhibition of macrophage migration in vitro via the NF-κB pathway

    PubMed Central

    Ma, Ge-fei; Chen, Song; Yin, Lei; Gao, Xiang-dong; Yao, Wen-bing

    2014-01-01

    Aim: To investigate the effects of the glucagon-like peptide-1 (GLP-1) receptor agonist exendin-4 on oxidized low-density lipoprotein (ox-LDL)-induced inhibition of macrophage migration and the mechanisms underlying the effects of exendin-4. Methods: Primary peritoneal macrophages were extracted from the peritoneal cavity of mice treated with 3% thioglycollate (2 mL, ip). Migration of the macrophages was examined using a cell migration assay. Macrophage migration-related factors including leptin-like ox-LDL receptor (LOX-1), cyclooxygenase 2 (COX-2), tumor necrosis factor (TNF)-α, interleukin-1 (IL-1)β, matrix metalloproteinase-2 (MMP-2), intercellular adhesion molecule (ICAM)-1 and macrophage migration inhibitory factor (MIF) were measured using semi-quantitative RT-PCR. Expression of MIF and ICAM-1 proteins was examined with ELISA. Gelatin zymography was used to evaluate the activity of MMP-9. Activation of the NF-κB pathway was determined by confocal laser scanning microscopy. Results: Treatment of the macrophages with ox-LDL (50 μg/mL) markedly suppressed the macrophage migration. Furthermore, ox-LDL treatment substantially increased the expression of the macrophage migration-related factors, the activity of MMP-9 and the translocation of the NF-κB p65 subunit. These effects of ox-LDL were significantly ameliorated by pretreatment with the specific NF-κB inhibitor ammonium pyrrolidine dithiocarbamate (100 μmol/L). These effects of ox-LDL were also significantly ameliorated by pretreatment with exendin-4 (25 and 50 nmol/L). Conclusion: Exendin-4 ameliorates the inhibition of ox-LDL on macrophage migration in vitro, via suppressing ox-LDL-induced expression of ICAM-1 and MIF, which is probably mediated by the NF-κB pathway. PMID:24335838

  10. 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.

  11. Puerarin ameliorates experimental alcoholic liver injury by inhibition of endotoxin gut leakage, Kupffer cell activation, and endotoxin receptors expression.

    PubMed

    Peng, Jing-Hua; Cui, Tuan; Huang, Fu; Chen, Liang; Zhao, Yu; Xu, Lin; Xu, Li-Li; Feng, Qin; Hu, Yi-Yang

    2013-03-01

    Puerarin, an isoflavone component extracted from Kudzu (Pueraria lobata), has been demonstrated to alleviate alcohol-related disorders. Our study examined whether puerarin ameliorates chronic alcoholic liver injury through inhibition of endotoxin gut leakage, the subsequent Kupffer cell activation, and endotoxin receptors expression. Rats were provided with the Liber-DeCarli liquid diet for 8 weeks. Puerarin (90 mg/kg or 180 mg/kg daily) was orally administered from the beginning of the third week until the end of the experiment. Chronic alcohol intake caused increased serum alanine aminotransferase, aspartate aminotransferase, hepatic gamma-glutamyl transpeptidase, and triglyceride levels as well as fatty liver and neutrophil infiltration in hepatic lobules as determined by biochemical and histologic assays. A significant increase of liver tumor necrosis factor α was detected by enzyme-linked immunosorbent assay. These pathologic effects correlated with increased endotoxin level in portal vein and upregulated protein expression of hepatic CD68, lipopolysaccharide-binding protein, CD14, Toll-like receptor 2, and Toll-like receptor 4. Meanwhile, the intestinal microvilli were observed to be sparse, shortened, and irregularity in distribution under the transmission electron microscope in conjunction with the downregulated intestinal zonula occludens-1 protein expression. These hepatic pathologic changes were significantly inhibited in puerarin-treated animals as were the endotoxin levels and hepatic CD68 and endotoxin receptors. Moreover, the pathologic changes in intestinal microvillus and the decreased intestinal zonula occludens-1 were also ameliorated with puerarin treatment. These results thus demonstrate that puerarin inhibition of endotoxin gut leakage, Kupffer cell activation, and endotoxin receptors expression is involved in the alleviation of chronic alcoholic liver injury in rats.

  12. 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.

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

    PubMed Central

    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

  14. Linagliptin-mediated DPP-4 inhibition ameliorates kidney fibrosis in streptozotocin-induced diabetic mice by inhibiting endothelial-to-mesenchymal transition in a therapeutic regimen.

    PubMed

    Kanasaki, Keizo; Shi, Sen; Kanasaki, Megumi; He, Jianhua; Nagai, Takako; Nakamura, Yuka; Ishigaki, Yasuhito; Kitada, Munehiro; Srivastava, Swayam Prakash; Koya, Daisuke

    2014-06-01

    Kidney fibrosis is the final common pathway of all progressive chronic kidney diseases, of which diabetic nephropathy is the leading cause. Endothelial-to-mesenchymal transition (EndMT) has emerged as one of the most important origins of matrix-producing fibroblasts. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been introduced into the market as antidiabetes drugs. Here, we found that the DPP-4 inhibitor linagliptin ameliorated kidney fibrosis in diabetic mice without altering the blood glucose levels associated with the inhibition of EndMT and the restoration of microRNA 29s. Streptozotocin-induced diabetic CD-1 mice exhibited kidney fibrosis and strong immunoreactivity for DPP-4 by 24 weeks after the onset of diabetes. At 20 weeks after the onset of diabetes, mice were treated with linagliptin for 4 weeks. Linagliptin-treated diabetic mice exhibited a suppression of DPP-4 activity/protein expression and an amelioration of kidney fibrosis associated with the inhibition of EndMT. The therapeutic effects of linagliptin on diabetic kidneys were associated with the suppression of profibrotic programs, as assessed by mRNA microarray analysis. We found that the induction of DPP-4 observed in diabetic kidneys may be associated with suppressed levels of microRNA 29s in diabetic mice; linagliptin restored microRNA 29s and suppressed DPP-4 protein levels. Using cultured endothelial cells, we found that linagliptin inhibited TGF-β2-induced EndMT, and such anti-EndMT effects of linagliptin were mediated through microRNA 29 induction. These results indicate the possible novel pleiotropic action of linagliptin to restore normal kidney function in diabetic patients with renal impairment.

  15. BET N-terminal bromodomain inhibition selectively blocks Th17 cell differentiation and ameliorates colitis in mice.

    PubMed

    Cheung, Kalung; Lu, Geming; Sharma, Rajal; Vincek, Adam; Zhang, Ruihua; Plotnikov, Alexander N; Zhang, Fan; Zhang, Qiang; Ju, Ying; Hu, Yuan; Zhao, Li; Han, Xinye; Meslamani, Jamel; Xu, Feihong; Jaganathan, Anbalagan; Shen, Tong; Zhu, Hongfa; Rusinova, Elena; Zeng, Lei; Zhou, Jiachi; Yang, Jianjun; Peng, Liang; Ohlmeyer, Michael; Walsh, Martin J; Zhang, David Y; Xiong, Huabao; Zhou, Ming-Ming

    2017-03-14

    T-helper 17 (Th17) cells have important functions in adaptor immunity and have also been implicated in inflammatory disorders. The bromodomain and extraterminal domain (BET) family proteins regulate gene transcription during lineage-specific differentiation of naïve CD4(+) T cells to produce mature T-helper cells. Inhibition of acetyl-lysine binding of the BET proteins by pan-BET bromodomain (BrD) inhibitors, such as JQ1, broadly affects differentiation of Th17, Th1, and Th2 cells that have distinct immune functions, thus limiting their therapeutic potential. Whether these BET proteins represent viable new epigenetic drug targets for inflammatory disorders has remained an unanswered question. In this study, we report that selective inhibition of the first bromodomain of BET proteins with our newly designed small molecule MS402 inhibits primarily Th17 cell differentiation with a little or almost no effect on Th1 or Th2 and Treg cells. MS402 preferentially renders Brd4 binding to Th17 signature gene loci over those of housekeeping genes and reduces Brd4 recruitment of p-TEFb to phosphorylate and activate RNA polymerase II for transcription elongation. We further show that MS402 prevents and ameliorates T-cell transfer-induced colitis in mice by blocking Th17 cell overdevelopment. Thus, selective pharmacological modulation of individual bromodomains likely represents a strategy for treatment of inflammatory bowel diseases.

  16. Inhibition of PI3Kδ reduces kidney infiltration by macrophages and ameliorates systemic lupus in the mouse.

    PubMed

    Suárez-Fueyo, Abel; Rojas, José M; Cariaga, Ariel E; García, Esther; Steiner, Bart H; Barber, Domingo F; Puri, Kamal D; Carrera, Ana C

    2014-07-15

    Systemic lupus erythematosus (SLE) is a human chronic inflammatory disease generated and maintained throughout life by autoreactive T and B cells. Class I phosphoinositide 3-kinases (PI3K) are heterodimers composed of a regulatory and a catalytic subunit that catalyze phosphoinositide-3,4,5-P3 formation and regulate cell survival, migration, and division. Activity of the PI3Kδ isoform is enhanced in human SLE patient PBLs. In this study, we analyzed the effect of inhibiting PI3Kδ in MRL/lpr mice, a model of human SLE. We found that PI3Kδ inhibition ameliorated lupus progression. Treatment of these mice with a PI3Kδ inhibitor reduced the excessive numbers of CD4(+) effector/memory cells and B cells. In addition, this treatment reduced serum TNF-α levels and the number of macrophages infiltrating the kidney. Expression of inactive PI3Kδ, but not deletion of the other hematopoietic isoform PI3Kγ, reduced the ability of macrophages to cross the basement membrane, a process required to infiltrate the kidney, explaining MRL/lpr mice improvement by pharmacologic inhibition of PI3Kδ. The observations that p110δ inhibitor prolonged mouse life span, reduced disease symptoms, and showed no obvious secondary effects indicates that PI3Kδ is a promising target for SLE.

  17. Inhibition of RXR and PPARγ ameliorates diet-induced obesity and type 2 diabetes

    PubMed Central

    Yamauchi, Toshimasa; Waki, Hironori; Kamon, Junji; Murakami, Koji; Motojima, Kiyoto; Komeda, Kajuro; Miki, Hiroshi; Kubota, Naoto; Terauchi, Yasuo; Tsuchida, Atsuko; Tsuboyama-Kasaoka, Nobuyo; Yamauchi, Naoko; Ide, Tomohiro; Hori, Wataru; Kato, Shigeaki; Fukayama, Masashi; Akanuma, Yasuo; Ezaki, Osamu; Itai, Akiko; Nagai, Ryozo; Kimura, Satoshi; Tobe, Kazuyuki; Kagechika, Hiroyuki; Shudo, Koichi; Kadowaki, Takashi

    2001-01-01

    PPARγ is a ligand-activated transcription factor and functions as a heterodimer with a retinoid X receptor (RXR). Supraphysiological activation of PPARγ by thiazolidinediones can reduce insulin resistance and hyperglycemia in type 2 diabetes, but these drugs can also cause weight gain. Quite unexpectedly, a moderate reduction of PPARγ activity observed in heterozygous PPARγ-deficient mice or the Pro12Ala polymorphism in human PPARγ, has been shown to prevent insulin resistance and obesity induced by a high-fat diet. In this study, we investigated whether functional antagonism toward PPARγ/RXR could be used to treat obesity and type 2 diabetes. We show herein that an RXR antagonist and a PPARγ antagonist decrease triglyceride (TG) content in white adipose tissue, skeletal muscle, and liver. These inhibitors potentiated leptin’s effects and increased fatty acid combustion and energy dissipation, thereby ameliorating HF diet-induced obesity and insulin resistance. Paradoxically, treatment of heterozygous PPARγ-deficient mice with an RXR antagonist or a PPARγ antagonist depletes white adipose tissue and markedly decreases leptin levels and energy dissipation, which increases TG content in skeletal muscle and the liver, thereby leading to the re-emergence of insulin resistance. Our data suggested that appropriate functional antagonism of PPARγ/RXR may be a logical approach to protection against obesity and related diseases such as type 2 diabetes. PMID:11581301

  18. Inhibition of RXR and PPARgamma ameliorates diet-induced obesity and type 2 diabetes.

    PubMed

    Yamauchi, T; Waki, H; Kamon, J; Murakami, K; Motojima, K; Komeda, K; Miki, H; Kubota, N; Terauchi, Y; Tsuchida, A; Tsuboyama-Kasaoka, N; Yamauchi, N; Ide, T; Hori, W; Kato, S; Fukayama, M; Akanuma, Y; Ezaki, O; Itai, A; Nagai, R; Kimura, S; Tobe, K; Kagechika, H; Shudo, K; Kadowaki, T

    2001-10-01

    PPARgamma is a ligand-activated transcription factor and functions as a heterodimer with a retinoid X receptor (RXR). Supraphysiological activation of PPARgamma by thiazolidinediones can reduce insulin resistance and hyperglycemia in type 2 diabetes, but these drugs can also cause weight gain. Quite unexpectedly, a moderate reduction of PPARgamma activity observed in heterozygous PPARgamma-deficient mice or the Pro12Ala polymorphism in human PPARgamma, has been shown to prevent insulin resistance and obesity induced by a high-fat diet. In this study, we investigated whether functional antagonism toward PPARgamma/RXR could be used to treat obesity and type 2 diabetes. We show herein that an RXR antagonist and a PPARgamma antagonist decrease triglyceride (TG) content in white adipose tissue, skeletal muscle, and liver. These inhibitors potentiated leptin's effects and increased fatty acid combustion and energy dissipation, thereby ameliorating HF diet-induced obesity and insulin resistance. Paradoxically, treatment of heterozygous PPARgamma-deficient mice with an RXR antagonist or a PPARgamma antagonist depletes white adipose tissue and markedly decreases leptin levels and energy dissipation, which increases TG content in skeletal muscle and the liver, thereby leading to the re-emergence of insulin resistance. Our data suggested that appropriate functional antagonism of PPARgamma/RXR may be a logical approach to protection against obesity and related diseases such as type 2 diabetes.

  19. 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.

  20. 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.

  1. Soyasaponin Ab ameliorates colitis by inhibiting the binding of lipopolysaccharide (LPS) to Toll-like receptor (TLR)4 on macrophages.

    PubMed

    Lee, In-Ah; Park, Young-Jun; Joh, Eun-Ha; Kim, Dong-Hyun

    2011-12-28

    Many clinical studies have shown that daily intake of soybean [ Glycine max (L.) Merr., Fabacease] or its foods may reduce the risk of osteoporosis, heart attack, hyperlipidemia, coronary heart disease, cardiovascular and chronic renal diseases, and cancers, including prostate, colon, and breast cancers. Of the soy constituents, soyasaponins exhibit anti-aging, antioxidant, apoptotic, and anti-inflammatory effects. However, the anti-inflammatory effect of soyasaponin Ab has not been thoroughly studied. Therefore, we investigated its anti-inflammatory effects in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitic mice and lipopolysaccharide (LPS)-stimulated peritoneal macrophages. Soyasaponin Ab inhibited colon shortening, myeloperoxidase activity, the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), and activation of the transcription factor nuclear factor-κB (NF-κB). Soyasaponin Ab (1, 2, 5, and 10 μM) inhibited the production of NO (IC(50) = 1.6 ± 0.1 μM) and prostaglandin E(2) (IC(50) = 2.0 ± 0.1 ng/mL), the expression of tumor necrosis factor (TNF)-α (IC(50) = 1.3 ± 0.1 ng/mL), interleukin (IL)-1β (IC(50) = 1.5 ± 0.1 pg/mL), and toll-like receptor (TLR)4, and the phosphorylation of interleukin-1 receptor-associated kinase (IRAK)-1 in LPS-stimulated peritoneal macrophages. Soyasaponin Ab weakly inhibited the phosphorylation of ERK, JNK, and p38. Soyasaponin Ab significantly reduced the binding of Alexa-Fluor-594-conjugated LPS to peritoneal macrophages. Soyasaponin Ab did not affect TLR4 expression or LPS-induced NF-κB activation in TLR4 siRNA-treated peritoneal macrophages (knockdown efficiency of TLR4 > 94%). On the basis of these findings, soyasaponin Ab may ameliorate colitis by inhibiting the binding of LPS to TLR4 on macrophages.

  2. Neuronal damage and functional deficits are ameliorated by inhibition of aquaporin and HIF1α after traumatic brain injury (TBI).

    PubMed

    Shenaq, Mohammed; Kassem, Hassan; Peng, Changya; Schafer, Steven; Ding, Jamie Y; Fredrickson, Vance; Guthikonda, Murali; Kreipke, Christian W; Rafols, José A; Ding, Yuchuan

    2012-12-15

    The present study, using a rodent model of closed-head diffuse traumatic brain injury (TBI), investigated the role of dysregulated aquaporins (AQP) 4 and 9, as well as hypoxia inducible factor -1α(HIF-1α) on brain edema formation, neuronal injury, and functional deficits. TBI was induced in adult (400-425 g), male Sprague-Dawley rats using a modified Marmarou's head impact-acceleration device (450 g weight dropped from 2m height). Animals in each treatment group were administered intravenous anti-AQP4 or -AQP9 antibodies or 2-Methoxyestradiol (2ME2, an inhibitor of HIF-1α) 30 min after injury. At 24h post-TBI, animals (n=6 each group) were sacrificed to examine the extent of brain edema by water content, as well as protein expression of AQP and HIF-1α by Western immune-blotting. At 48-hours post-TBI, neuronal injury (n=8 each group) was assessed by FluoroJade (FJ) histochemistry. Spatial learning and memory deficits were evaluated by radial arm maze (n=8 each group) up to 21 days post-TBI. Compared to non-injured controls, significant (p<0.05) increases in the expression of AQP4 and -9 were detected in the brains of injured animals. In addition, significant (p<0.05) brain edema after TBI was associated with increases (p <0.05) both in neuronal injury (FJ labeling) and neurobehavioral deficits. Selective inhibition of either AQP4 or -9, or HIF-1α significantly (p<0.05) decreased the expression of the proteins. In addition, inhibition of the AQPs and HIF-1α significantly (p<0.05) ameliorated brain edema, as well as the number of injured neurons in cortical layers II/III and V/VI, striatum and hippocampal regions CA1/CA3. Finally, compared to the non-treated TBI animals, AQP or HIF-1α inhibition significantly (p<0.01) improved neurobehavioral outcomes after TBI. Taken together, the present data supports a causal relation between HIF-AQP mediated cerebral edema, secondary neuronal injury, and tertiary behavioral deficits post-TBI. The data further suggests that

  3. Curcumin ameliorated diabetic neuropathy partially by inhibition of NADPH oxidase mediating oxidative stress in the spinal cord.

    PubMed

    Zhao, Wei-Cheng; Zhang, Bin; Liao, Mei-Juan; Zhang, Wen-Xuan; He, Wan-You; Wang, Han-Bing; Yang, Cheng-Xiang

    2014-02-07

    Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases are the main enzymes that produce oxidative stress, which plays an important role in painful diabetic neuropathy. Curcumin has been reported to exert an antinociceptive effect in a rat model of diabetic neuropathy by suppressing oxidative stress in the spinal cord. However, it remains unknown whether the mechanism by which curcumin ameliorates diabetic neuropathy can be attributed to spinal NADPH oxidases. This study was designed to determine the effect of curcumin on diabetic neuropathy and to investigate its precise mechanism in relation to NADPH oxidase-mediating oxidative stress in the spinal cord. Diabetic neuropathy was induced in Sprague-Dawley rats by intraperitoneal injection with 1% streptozotocin (STZ; 60 mg/kg). After the onset of diabetic neuropathy, a subset of the diabetic rats received daily intragastric administrations of curcumin (200mg/kg) or intraperitoneal injections of apocynin (2.5mg/kg) for 14 consecutive days, whereas other diabetic rats received equivalent volumes of normal saline (NS). STZ resulted in diabetic neuropathy with hyperglycemia and a lower paw withdrawal threshold (PWT), accompanied by elevations in the expression of the NADPH oxidase subunits p47(phox) and gp91(phox) and in the levels of hydrogen peroxide (H2O2) and malondialdehyde (MDA) and a reduction in superoxide dismutase (SOD) activity (P<0.05) in the spinal cord. Both curcumin and apocynin ameliorated diabetic neuropathy. In conclusion, curcumin attenuated neuropathic pain in diabetic rats, at least partly by inhibiting NADPH oxidase-mediating oxidative stress in the spinal cord.

  4. A Mushroom Extract Piwep from Phellinus igniarius Ameliorates Experimental Autoimmune Encephalomyelitis by Inhibiting Immune Cell Infiltration in the Spinal Cord

    PubMed Central

    Li, Lan; Wu, Guang; Choi, Bo Young; Jang, Bong Geom; Kim, Jin Hee; Sung, Gi Ho; Cho, Jae Youl; Park, Hyoung Jin

    2014-01-01

    The present study aimed to evaluate the therapeutic potential of a mushroom extract from Phellinus igniarius in an animal model of multiple sclerosis. The medicinal mushroom, Phellinus igniarius, contains biologically active compounds that modulate the human immune system. Experimental autoimmune encephalomyelitis (EAE) was induced by immunization with myelin oligodendrocyte glycoprotein (MOG 35–55) in C57BL/6 female mice. A water-ethanol extract of Phellinus igniarius (Piwep) was delivered intraperitoneally every other day for the entire experimental course. Three weeks after the initial immunization, demyelination and immune cell infiltration in the spinal cord were examined. Piwep injection profoundly decreased the daily incidence rate and clinical score of EAE. The Piwep-mediated inhibition of the clinical course of EAE was accompanied by suppression of demyelination and infiltration of encephalitogenic immune cells including CD4+ T cells, CD8+ T cells, macrophages, and B cells in the spinal cord. Piwep reduced expression of vascular cell adhesion molecule-1 (VCAM-1) in the spinal cord and integrin-α4 in the lymph node of EAE mice. Piwep also inhibited proliferation of lymphocytes and secretion of interferon-γ in the lymph node of EAE mice. The results suggest that a mushroom extract, Piwep, may have a high therapeutic potential for ameliorating multiple sclerosis progression. PMID:24592383

  5. 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

  6. 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

  7. 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.

  8. Resveratrol ameliorates oxidative stress and inhibits aquaporin 4 expression following rat cerebral ischemia-reperfusion injury.

    PubMed

    Li, Weina; Tan, Changhong; Liu, Yi; Liu, Xi; Wang, Xin; Gui, Yuejiang; Qin, Lu; Deng, Fen; Yu, Zhen; Hu, Changlin; Chen, Lifen

    2015-11-01

    Cerebral ischemia-reperfusion (I/R) is associated with increased levels of reactive oxygen species (ROS) and brain edema, which lead to the deterioration of patient prognosis. Resveratrol serves a neuroprotective role in I/R injury, and this role may be associated with its anti‑oxidative effects. However, resveratrol's mechanism of action in cerebral I/R injury remains to be fully understood. In order to investigate the effect of resveratrol in cerebral I/R‑induced injury, male Sprague‑Dawley rats were randomly assigned to four groups: The sham‑operation group, the I/R group and the edaravone and resveratrol groups (I/R + E and I/R + R groups). Infarct volume was evaluated by 2,3,5‑tripenyltetrazolium chloride staining, brain edema was evaluated by the water content in the reperfused brain and malondialdehyde (MDA) was measured by the thiobarbituric acid method. Superoxide dismutase (SOD) levels were measured using the Total Superoxide Dismutase Assay kit. Inducible nitric oxide synthase (iNOS) levels in the hippocampus and cortex were measured by ELISA, and aquaporin 4 (AQP4) expression was measured by immunohistochemical staining and western blot analysis. The results demonstrated that resveratrol reduced the infarct volume and the incidence of brain edema and reduced neurological deficits. These outcomes were accompanied by reduced levels of MDA, iNOS and AQP4, and increased SOD levels in cerebral I/R injury. In conclusion, resveratrol protected against cerebral I/R injury by ameliorating oxidative stress and reducing AQP4 expression.

  9. Antrodia cinnamomea Extract Inhibits Th17 Cell Differentiation and Ameliorates Imiquimod-Induced Psoriasiform Skin Inflammation.

    PubMed

    Li, Ming-Han; Wu, Hsin-Chieh; Yao, Hsin-Jan; Lin, Chi-Chen; Wen, Shu-Fang; Pan, I-Horng

    2015-01-01

    Antrodia cinnamomea (A. cinnamomea) is a Chinese medicinal herb that possesses a broad range of bioactivities, including anti-inflammation. Given that the proinflammatory cytokine IL-17 plays a critical role in the pathogenesis of autoimmune diseases, we investigated whether A. cinnamomea could inhibit the development of Th17 cells, the main producer of IL-17, and exhibit therapeutic effects on an animal model of psoriasis. We found that A. cinnamomea extract (AC) inhibited the differentiation of Th17 cells as well as the production of IL-17A, IL-21, and IL-22 from these cells. This effect was associated with the inhibition of STAT3 phosphorylation and RORγt expression. Notably, the oral administration of AC reduced psoriasis-like inflammation in imiquimod-mediated dermal damage, repressed the expression of IL-17A, IL-22, and TNF-α in skin lesions, and decreased the infiltration of CD4⁺ T cells, CD8⁺ T cells, and neutrophils into the dermis. Finally, serum levels of IL-17A were decreased in AC-treated mice with psoriasis-like skin inflammation. Taken together, these findings indicate that AC inhibits Th17 cell differentiation, suggesting a role for A. cinnamomea in the treatment of psoriasis and other Th17 cell-mediated inflammatory diseases.

  10. 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.

  11. Minocycline ameliorates LPS-induced inflammation in human monocytes by novel mechanisms including LOX-1, Nur77 and LITAF inhibition

    PubMed Central

    Pang, Tao; Wang, Juan; Benicky, Julius; Saavedra, Juan M.

    2012-01-01

    Background Minocycline exhibits anti-inflammatory properties independent of its antibiotic activity, ameliorating inflammatory responses in monocytes and macrophages. However, the mechanisms of minocycline anti-inflammatory effects are only partially understood. Methods Human circulating monocytes were cultured in the presence of lipopolysaccharide (LPS), 50 ng/ml, and minocycline (10–40 µM). Gene expression was determined by RT-PCR, cytokine and prostaglandin E2 (PGE2) release by ELISA, protein expression, phosphorylation and nuclear translocation by Western blotting. Results Minocycline significantly reduced the inflammatory response in LPS-challenged monocytes, decreasing LPS-induced transcription of pro-inflammatory tumor-necrosis factor alpha (TNF-α), interleukin-1 beta, interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2), and the LPS-stimulated TNF-α, IL-6 and PGE2 release. Minocycline inhibited LPS-induced activation of the lectin-like oxidized low density lipoprotein receptor-1 (LOX-1), NF-κB, LPS-induced TNF-α factor (LITAF) and the Nur77 nuclear receptor. Mechanisms involved in the anti-inflammatory effects of minocycline include a reduction of LPS-stimulated p38 mitogen-activated protein kinase (p38 MAPK) activation and stimulation of the phosphoinositide 3-kinase (PI3K)/Akt pathway. Conclusions We provide novel evidence demonstrating that the anti-inflammatory effects of minocycline in human monocytes include, in addition to decreased NF-κB activation, abrogation of the LPS-stimulated LOX-1, LITAF, Nur77 pathways, p38 MAPK inhibition and PI3K/Akt activation. Our results reveal that minocycline inhibits points of convergence of distinct and interacting signaling pathways mediating multiple inflammatory signals which may influence monocyte activation, traffic and recruitment into the brain. General significance Our results in primary human monocytes contribute to explain the profound anti-inflammatory and protective effects of minocycline in

  12. Ethyl pyruvate ameliorates experimental colitis in mice by inhibiting the HMGB1-Th17 and Th1/Tc1 responses.

    PubMed

    Guo, Xianghua; Guo, Runhua; Luo, Xia; Zhou, Lian

    2015-12-01

    Ethyl pyruvate (EP), a simple lipophilic pyruvate ester, has demonstrated protective effects against murine colitis through inhibition the release of inflammatory factor high-mobility group protein box 1 (HMGB1). HMGB1 has been implicated in several autoimmune diseases by inducing Thl and Thl7 cells activation. This study was designed to investigate whether EP amelioration of murine colitis is related to the blocking of the HMGB1-Th17/Thl pathway. We induced murine colitis by intrarectal administration of 2, 4, 6-trinitrobenzene sulfonic acid (TNBS). Ethyl pyruvate was injected intraperitoneally once a day for 7days. One week after intrarectal challenge with TNBS, HMGB1, IL-17 and IFN-γ protein levels were remarkably increased following severe colon inflammation. Meanwhile, excessive infiltration of Th17 cells in colonic tissues, and an upregulated proportion of Th17 and Th1/Tc1 cells in the spleen and mesenteric lymph nodes (MLN) were found in the TNBS-treated group compared to the control group. Treatment with the HMGB1 inhibitor EP not only remarkably improved colon pathological damage, but also significantly reduced the number of Th17 cells in the local tissues of the colitis-induced mice. Furthermore, the percentage of Th1/Tc1 and Th17 cells in the spleen and MLN, as well as levels of serum IFN-γ and IL-17A, were all markedly decreased in the EP-treated group. Moreover, in vitro, our results showed that EP in a dose dependent manner inhibited HMGB1 release induced by LPS from CT26 cells (murine colon adenocarcinoma cell line). These results suggest that HMGB1 contributes to the development of murine colitis by promoting the Th17 and Th1/Tc1 responses, and that EP can significantly inhibit HMGB1-Th17 and Thl/Tc1 pathway activation, which may provide better protection to mice with TNBS-induced colitis.

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

    PubMed

    Tsuchida, K

    2008-07-01

    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-beta 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.

  14. 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

  15. 7,8-Dihydroxyflavone Ameliorates Cognitive Impairment by Inhibiting Expression of Tau Pathology in ApoE-Knockout Mice

    PubMed Central

    Tan, Yang; Nie, Shuke; Zhu, Wende; Liu, Fang; Guo, Hailong; Chu, Jiewen; Cao, Xue B.; Jiang, Xingjun; Zhang, Yunjian; Li, Yuzhen

    2016-01-01

    7,8-Dihydroxyflavone (7,8-DHF), a tyrosine kinase B agonist that mimics the neuroprotective properties of brain-derived neurotrophic factor, which can not efficiently deliver into the brain, has been reported to be useful in ameliorating cognitive impairment in many diseases. Researches have indicated that apolipoprotein E-knockout (ApoE-KO) mouse was associated with cognitive alteration via various mechanisms. Our present study investigated the possible mechanisms of cognitive impairment of ApoE-KO mouse fed with western type diet and the protective effects of 7,8-DHF in improving spatial learning and memory in ApoE-KO mouse. Five-weeks-old ApoE-KO mice and C57BL/6 mice were chronically treated with 7,8-DHF (with a dosage of 5 mg/kg) or vehicles orally for 25 weeks, and then subjected to Morris water maze at the age of 30 weeks to evaluate the cognitive performances. Afterward, histology analysis and western blotting were performed. Spatial learning and memory deficits were observed in ApoE-KO mice, which were consistent with higher expression of active-asparaginyl endopeptidase (active-AEP) as well as AEP-derived truncated tau N368 compared with normal group. In addition to that, long-term treatment of 7,8-DHF dramatically ameliorated cognitive decline in ApoE-KO mice, accompanied by the activation in phosphorylated protein kinase B (Akt)/glycogen synthase kinase-3β (GSK-3β) pathway and down-regulated expression of tau S396 and PHF-tau (phosphorylated tau at ser396 and ser404 epitope). These findings suggested that cognitive impairment of ApoE-KO mouse might associate with tau pathology and 7,8-DHF could activate AKT and then phosphorylate its downstream molecule to inhibit expression of abnormal tau, meanwhile, 7,8-DHF could reduce the expression of active-AEP and then inhibit production of truncated tau N368. PMID:27965573

  16. Inhibition of H3K9 methyltransferase G9a ameliorates methylglyoxal-induced peritoneal fibrosis

    PubMed Central

    Maeda, Kazuya; Doi, Shigehiro; Nakashima, Ayumu; Nagai, Takuo; Irifuku, Taisuke; Ueno, Toshinori; Masaki, Takao

    2017-01-01

    Activity of H3K9 histone methyltransferase G9a is reportedly induced by transforming growth factor-β1 (TGF-β1) and plays an important role in the progression of cancer and fibrosis. In this study, we investigated whether inhibition of G9a-mediated H3K9 methylation attenuates peritoneal fibrosis in mice and human peritoneal mesothelial cells (HPMCs). Nonadherent cells of peritoneal dialysis (PD) patients were isolated from PD effluent to examine expression of G9a. Peritoneal fibrosis was induced by peritoneal injection of methylglyoxal (MGO) in male C57/B6 mice for 3 weeks. BIX01294, a G9a inhibitor, was administered by subcutaneous injection. Effects of BIX01294 on MGO-induced pathological and functional changes in mice were evaluated by immunohistochemistry and a peritoneal equilibration test. HPMCs were isolated from human omentum, and the inhibitory effect of BIX01294 on TGF-β1-induced fibrotic changes was investigated in the HPMCs by western blotting. G9a was upregulated in nonadherent cells of human PD effluent, the peritoneum of MGO-injected mice, and TGF-β1-stimulated HPMCs. BIX01294 significantly reduced the submesothelial zone thickness and cell density in MGO-injected mice. Immunohistochemical staining revealed that BIX01294 treatment decreased not only mono-methylation of H3K9 (H3K9me1), but also the number of mesenchymal cells, accumulation of collagen, and infiltration of monocytes. In addition to the pathological changes, BIX01294 reduced the level of TGF-β1 in peritoneal fluid and improved peritoneal functions. Furthermore, BIX01294 inhibited TGF-β1-induced fibrotic changes along with suppression of H3K9me1 in HPMCs. Therefore, inhibition of H3K9 methyltransferase G9a suppresses peritoneal fibrosis through a reduction of H3K9me1. PMID:28278257

  17. Inhibition of H3K9 methyltransferase G9a ameliorates methylglyoxal-induced peritoneal fibrosis.

    PubMed

    Maeda, Kazuya; Doi, Shigehiro; Nakashima, Ayumu; Nagai, Takuo; Irifuku, Taisuke; Ueno, Toshinori; Masaki, Takao

    2017-01-01

    Activity of H3K9 histone methyltransferase G9a is reportedly induced by transforming growth factor-β1 (TGF-β1) and plays an important role in the progression of cancer and fibrosis. In this study, we investigated whether inhibition of G9a-mediated H3K9 methylation attenuates peritoneal fibrosis in mice and human peritoneal mesothelial cells (HPMCs). Nonadherent cells of peritoneal dialysis (PD) patients were isolated from PD effluent to examine expression of G9a. Peritoneal fibrosis was induced by peritoneal injection of methylglyoxal (MGO) in male C57/B6 mice for 3 weeks. BIX01294, a G9a inhibitor, was administered by subcutaneous injection. Effects of BIX01294 on MGO-induced pathological and functional changes in mice were evaluated by immunohistochemistry and a peritoneal equilibration test. HPMCs were isolated from human omentum, and the inhibitory effect of BIX01294 on TGF-β1-induced fibrotic changes was investigated in the HPMCs by western blotting. G9a was upregulated in nonadherent cells of human PD effluent, the peritoneum of MGO-injected mice, and TGF-β1-stimulated HPMCs. BIX01294 significantly reduced the submesothelial zone thickness and cell density in MGO-injected mice. Immunohistochemical staining revealed that BIX01294 treatment decreased not only mono-methylation of H3K9 (H3K9me1), but also the number of mesenchymal cells, accumulation of collagen, and infiltration of monocytes. In addition to the pathological changes, BIX01294 reduced the level of TGF-β1 in peritoneal fluid and improved peritoneal functions. Furthermore, BIX01294 inhibited TGF-β1-induced fibrotic changes along with suppression of H3K9me1 in HPMCs. Therefore, inhibition of H3K9 methyltransferase G9a suppresses peritoneal fibrosis through a reduction of H3K9me1.

  18. Cinnamaldehyde Ameliorates Cadmium-Inhibited Root Elongation in Tobacco Seedlings via Decreasing Endogenous Hydrogen Sulfide Production.

    PubMed

    Ye, Xie-Feng; Xue, Yanfeng; Ling, Tianxiao; Wang, Yong; Yu, Xiao-Na; Cheng, Changxin; Feng, Guosheng; Hu, Liangbin; Shi, Zhiqi; Chen, Jian

    2016-12-24

    Cinnamaldehyde (CA) is natural plant-derived compound that has been highly appreciated for its medicinal properties. However, little information is known about the regulation of plant intrinsic physiology by CA. To address these gaps, physiological, histochemical, and biochemical approaches were applied to investigate CA-facilitated cadmium (Cd) tolerance in the roots of tobacco (Nicotiana tabacum) seedlings. Treatment with CdCl₂ at 20 μM for 72 h resulted in the significant decrease in root elongation by 40.39% as compared to control. CA alleviated Cd-inhibited root elongation in dose- and time-dependent manners. The addition of CA at 20 μM induced significant increase in root elongation by 42.58% as compared to Cd treatment alone. CA abolished Cd-induced ROS (reactive oxygen species) accumulation, lipid peroxidation, loss of membrane integrity, cell death, and free Cd(2+) accumulation in roots. CA blocked the Cd-induced increase in the endogenous H₂S level through the down-regulation of d-cysteine desulfhydrase (DCD) expression. H₂S scavenger hypotaurine (HT) or potent H₂S-biosynthetic inhibitor dl-propargylglicine (PAG) were able mimic the action of CA on the blockade of Cd-induced H₂S accumulation, cell death, and growth inhibition. Enhancement of the endogenous H₂S level with NaHS (H₂S donor) abrogated all the beneficial capabilities of CA, HT, and PAG. Collectively, these results suggest that CA has great potential to confer plant tolerance against Cd stress, which is closely associated with its capability to inhibit Cd-induced H₂S production. This study not only provides evidences for the regulation of plant physiology by CA but also sheds new light on the cross-talk between CA and H₂S in physiological modulations.

  19. Pycnogenol Ameliorates Asthmatic Airway Inflammation and Inhibits the Function of Goblet Cells.

    PubMed

    Liu, Zhaoe; Han, Bo; Chen, Xing; Wu, Qiaoling; Wang, Lijun; Li, Gang

    2016-11-01

    Pycnogenol(®) (PYC) is utilized in the treatment of various diseases ranging from chronic inflammation to circulatory diseases, but its efficacy and functional mechanism in pediatric asthma continue to remain obscure. Therefore, the purpose of this study was to investigate the effectiveness and molecular mechanism of PYC on regulation of asthmatic airway inflammation. We found that PYC with tail intravenous injection of 50 mg/kg or intragastric administration of 100 mg/kg all reduced ovalbumin (OVA)-induced airway injury. Pharmacokinetics of PYC was evaluated by high-performance liquid chromatography assay, indicating that PYC was quickly absorbed into the blood after intragastric administration, and PYC metabolism was later improved gradually with increase of time after PYC administration. PYC has a higher bioavailability of 71.96%, and it was more easily absorbed by the body. PYC inhibited the number of total inflammatory cells and levels of interleukin (IL)-4, IL-5, IL-9, and IL-13 in bronchoalveolar lavage fluid of OVA-induced mice. PYC inhibited IL-13 secretion from the Th2 cells, thereby causing a reduction in expression of the signaling molecules in JAK/STAT6 pathway in airway epithelial cells. STAT6 silence suppressed IL-13-increased acetylcholine level. STAT6 overexpression promoted expression of goblet cell metaplasia-associated molecules (FOXA3, SPDEF, and Muc5ac). PYC suppressed OVA-induced expression of FOXA3, SPDEF, and Muc5ac in lung. Our findings indicate that PYC has a higher bioavailability and it prevents emergence of OVA-induced airway injury and airway inflammation in mice by inhibiting IL-13/JAK/STAT6 pathway and blocking release of acetylcholine to reduce goblet cell metaplasia.

  20. Ascorbic acid ameliorates seizures and brain damage in rats through inhibiting autophagy.

    PubMed

    Dong, Yan; Wang, Shengjun; Zhang, Tongxia; Zhao, Xiuhe; Liu, Xuewu; Cao, Lili; Chi, Zhaofu

    2013-10-16

    Oxidative stress is a mechanism of cell death induced by seizures. Antioxidant compounds have neuroprotective effects due to their ability to inhibit free radical production. Autophagy is a process in which cytoplasmic components such as organelles and proteins are delivered to the lysosomal compartment for degradation, and plays an essential role in the maintenance of cellular homeostasis. The activity of autophagy is enhanced during oxidative stress. The objectives of this work were first to study the inhibitory action of antioxidant ascorbic acid on behavioral changes and brain damage induced by high doses of pilocarpine, then to study the effect of ascorbic acid on oxidative stress (MDA and SOD were used to estimate oxidative stress) and activated autophagy (beclin 1 was used to estimate autophagy) induced by seizures, aiming to further clarify the mechanism of action of this antioxidant compound. In order to determinate neuroprotective effects, we studied the effects of ascorbic acid (500 mg/kg, i.p.) on the behavior and brain lesions observed after seizures induced by pilocarpine (340 mg/kg, i.p., P340 model) in rats. Ascorbic acid injections prior to pilocarpine suppressed behavioral seizure episodes by increasing the latency to the first myoclonic, clonic and tonic seizure and decreasing the percentage of incidence of clonic and tonic seizures as well as the mortality rate. These findings suggested that oxidative stress can be produced and autophagy is increased during brain damage induced by seizures. In the P340 model, ascorbic acid significantly decreased cerebral damage, reduced oxidative stress and inhibited autophagy by reducing de novo synthesis of beclin 1. Antioxidant compound can exert neuroprotective effects associated with inhibition of free radical production and autophagy. These results highlighted the promising therapeutic potential of ascorbic acid in treatment for seizures.

  1. 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

  2. HIF-1α inhibition ameliorates neonatal brain injury in a rat pup hypoxic-ischemic model

    PubMed Central

    Chen, Wanqiu; Jadhav, Vikram; Tang, Jiping; Zhang, John H.

    2008-01-01

    Hypoxia-inducible factor-1alpha (HIF-1α) has been considered as a regulator of both prosurvival and prodeath pathways in the nervous system. The present study was designed to elucidate the role of HIF-1α in neonatal hypoxic-ischemic (HI) brain injury. Rice-Vannucci model of neonatal hypoxic-ischemic brain injury was used in seven-day-old rats, by subjecting unilateral carotid artery ligation followed by 2h of hypoxia (8% O2 at 37°C). HIF-1α activity was inhibited by 2-methoxyestradiol (2ME2) and enhanced by dimethyloxalylglycine (DMOG). Results showed that 2ME2 exhibited dose-dependent neuroprotection by decreasing infarct volume and reducing brain edema at 48 h post HI. The neuroprotection was lost when 2ME2 was administered 3 h post HI. HIF-1α upregulation by DMOG increased the permeability of the BBB and brain edema compared with HI group. 2ME2 attenuated the increase in HIF-1α and VEGF 24 h after HI. 2ME2 also had a long-term effect of protecting against the loss of brain tissue. The study showed that the early inhibition of HIF-1α acutely after injury provided neuroprotection after neonatal hypoxia-ischemia which was associated with preservation of BBB integrity, attenuation of brain edema, and neuronal death. PMID:18602008

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

    PubMed Central

    Rais, Rana; Jiang, Weiwei; Zhai, Huihong; Wozniak, Krystyna M.; Stathis, Marigo; Hollinger, Kristen R.; Thomas, Ajit G.; Rojas, Camilo; Vornov, James J.; Marohn, Michael; 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

  4. Choline ameliorates cardiovascular damage by improving vagal activity and inhibiting the inflammatory response in spontaneously hypertensive rats

    PubMed Central

    Liu, Longzhu; Lu, Yi; Bi, Xueyuan; Xu, Man; Yu, Xiaojiang; Xue, Runqing; He, Xi; Zang, Weijin

    2017-01-01

    Autonomic dysfunction and abnormal immunity lead to systemic inflammatory responses, which result in cardiovascular damage in hypertension. The aim of this report was to investigate the effects of choline on cardiovascular damage in hypertension. Eight-week-old male spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats were intraperitoneally injected with choline or vehicle (8 mg/kg/day). After 8 weeks, choline restored the cardiac function of the SHRs, as evidenced by decreased heart rate, systolic blood pressure, left ventricle systolic pressure, and ±dp/dtmax and increased ejection fraction and fractional shortening. Choline also ameliorated the cardiac hypertrophy of the SHRs, as indicated by reduced left ventricle internal dimensions and decreased cardiomyocyte cross-sectional area. Moreover, choline improved mesenteric arterial function and preserved endothelial ultrastructure in the SHRs. Notably, the protective effect of choline may be due to its anti-inflammatory effect. Choline downregulated expression of interleukin (IL)-6 and tumour necrosis factor-α and upregulated IL-10 in the mesenteric arteries of SHRs, possibly because of the inhibition of Toll-like receptor 4. Furthermore, choline restored baroreflex sensitivity and serum acetylcholine level in SHRs, thus indicating that choline improved vagal activity. This study suggests that choline elicits cardiovascular protective effects and may be useful as a potential adjunct therapeutic approach for hypertension. PMID:28225018

  5. Treadmill exercise ameliorates motor dysfunction through inhibition of Purkinje cell loss in cerebellum of valproic acid-induced autistic rats

    PubMed Central

    Cho, Han-Sam; Kim, Tae-Woon; Ji, Eun-Sang; Park, Hye-Sang; Shin, Mal-Soon; Baek, Seung-Soo

    2016-01-01

    Autism is a complex developmental disorder with impairments in social interaction, communication, repetitive behavior and motor skills. Exercise enhances cognitive function, ameliorates motor dysfunction, and provides protective profits against neurodegeneration. In the present study, we evaluated the effect of treadmill exercise on the motor coordination and Purkinje cell loss in relation with reactive astrocytes and microglial activation in the cerebellum using valproic acid (VPA)-induced autism rat model. On the 12th day of pregnancy, the pregnant rats in the VPA-exposed group received intraperitoneal injections of 600-mg/kg VPA. After birth, the rat pups were divided into four groups: the control group, the exercise group, the VPA-treated group, the VPA-treated and exercise group. The rat pups in the exercise groups were forced to run on a treadmill for 30 min once a day, 5 times a week for 4 weeks. In the present results, motor balance and coordination was disturbed by induction of autism, in contrast, treadmill exercise alleviated motor dysfunction in the autistic rats. Purkinje cell loss, reactive astrocytes, and microglial activation were occurred by induction of autism, in contrast, treadmill exercise enhanced survival rate of Purkinje neurons through inhibition of reactive astrocytes and microglia in the autistic rats. The present study showed that exercise may provide a potential therapeutic strategy for the alleviation of motor dysfunction in autistic patients. PMID:27656625

  6. 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.

  7. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance.

    PubMed

    Holland, William L; Brozinick, Joseph T; Wang, Li-Ping; Hawkins, Eric D; Sargent, Katherine M; Liu, Yanqi; Narra, Krishna; Hoehn, Kyle L; Knotts, Trina A; Siesky, Angela; Nelson, Don H; Karathanasis, Sotirios K; Fontenot, Greg K; Birnbaum, Morris J; Summers, Scott A

    2007-03-01

    Insulin resistance occurs in 20%-25% of the human population, and the condition is a chief component of type 2 diabetes mellitus and a risk factor for cardiovascular disease and certain forms of cancer. Herein, we demonstrate that the sphingolipid ceramide is a common molecular intermediate linking several different pathological metabolic stresses (i.e., glucocorticoids and saturated fats, but not unsaturated fats) to the induction of insulin resistance. Moreover, inhibition of ceramide synthesis markedly improves glucose tolerance and prevents the onset of frank diabetes in obese rodents. Collectively, these data have two important implications. First, they indicate that different fatty acids induce insulin resistance by distinct mechanisms discerned by their reliance on sphingolipid synthesis. Second, they identify enzymes required for ceramide synthesis as therapeutic targets for combating insulin resistance caused by nutrient excess or glucocorticoid therapy.

  8. Phosphodiesterase 5 inhibition ameliorates angiotensin II-dependent hypertension and renal vascular dysfunction.

    PubMed

    Thieme, Manuel; Sivritas, Sema H; Mergia, Evanthia; Potthoff, Sebastian A; Yang, Guang; Hering, Lydia; Grave, Katharina; Hoch, Henning; Rump, Lars C; Stegbauer, Johannes

    2017-03-01

    Changes in renal hemodynamics have a major impact on blood pressure (BP). Angiotensin (Ang) II has been shown to induce vascular dysfunction by interacting with phosphodiesterase (PDE)1 and PDE5. The predominant PDE isoform responsible for renal vascular dysfunction in hypertension is unknown. Here, we measured the effects of PDE5 (sildenafil) or PDE1 (vinpocetine) inhibition on renal blood flow (RBF), BP, and renal vascular function in normotensive and hypertensive mice. During acute short-term Ang II infusion, sildenafil decreased BP and increased RBF in C57BL/6 (WT) mice. In contrast, vinpocetine showed no effect on RBF and BP. Additionally, renal cGMP levels were significantly increased after acute sildenafil but not after vinpocetine infusion, indicating a predominant role of PDE5 in renal vasculature. Furthermore, chronic Ang II infusion (500 ng·kg(-1)·min(-1)) increased BP and led to impaired NO-dependent vasodilation in kidneys of WT mice. Additional treatment with sildenafil (100 mg·kg(-1)·day(-1)) attenuated Ang II-dependent hypertension and improved NO-mediated vasodilation. During chronic Ang II infusion, urinary nitrite excretion, a marker for renal NO generation, was increased in WT mice, whereas renal cGMP generation was decreased and restored after sildenafil treatment, suggesting a preserved cGMP signaling after PDE5 inhibition. To investigate the dependency of PDE5 effects on NO/cGMP signaling, we next analyzed eNOS-KO mice, a mouse model characterized by low vascular NO/cGMP levels. In eNOS-KO mice, chronic Ang II infusion increased BP but did not impair NO-mediated vasodilation. Moreover, sildenafil did not influence BP or vascular function in eNOS-KO mice. These results highlight PDE5 as a key regulator of renal hemodynamics in hypertension.

  9. Dipotassium Glycyrrhizate Inhibits HMGB1-Dependent Inflammation and Ameliorates Colitis in Mice

    PubMed Central

    Vitali, Roberta; Palone, Francesca; Cucchiara, Salvatore; Negroni, Anna; Cavone, Leonardo; Costanzo, Manuela; Aloi, Marina; Dilillo, Anna; Stronati, Laura

    2013-01-01

    Background High mobility group box-1 (HMGB1) is a DNA-binding protein that is released from injured cells during inflammation. Advances in targeting HMGB1 represent a major challenge to improve the treatment of acute/chronic inflammation. Aim This study is aimed at verifying whether the inhibition of HMGB1 through dipotassium glycyrrhizate (DPG) is a good strategy to reduce intestinal inflammation. Methods Human colon adenocarcinoma cell line, HT29, human epithelial colorectal adenocarcinoma, Caco2, and murine macrophage cell line, RAW 264.7, were cultured to investigate the effect of DPG on the secretion of HMGB1. Acute colitis was induced in C57BL/6 mice through administration of 3% dextran sodium sulphate (DSS); a combined treatment with DSS and 3 or 8 mg/kg/day DPG was used to investigate the effects of DPG on intestinal inflammation. Animals were euthanized at seventh day and colonic samples underwent molecular and histological analyses. Results DPG significantly reduces in vitro the release of HMGB1 in the extracellular matrix as well as expression levels of pro-inflammatory cytokines, TNF-alpha, IL-1beta and IL-6, by inhibiting HMGB1. Moreover, DPG significantly decreases the severity of DSS-induced colitis in mice. Murine colonic samples show decreased mRNA levels of pro-inflammatory cytokines TNF-alpha, IL-1beta and IL-6, as well as HMGB1 receptors, RAGE and TLR4. Finally, HMGB1, abundantly present in the feces of mice with DSS-induced colitis, is strongly reduced by DPG. Conclusions HMGB1 is an early pro-inflammatory cytokine and an active protagonist of mucosal gut inflammation. DPG exerts inhibitory effects against HMGB1 activity, significantly reducing intestinal inflammation. Thus, we reason that DPG could represent an innovative tool for the management of human intestinal inflammation. PMID:23840500

  10. Selective ORAI1 inhibition ameliorates autoimmune CNS inflammation by suppressing effector but not regulatory T cell function

    PubMed Central

    Kaufmann, Ulrike; Shaw, Patrick J.; Kozhaya, Lina; Subramanian, Raju; Gaida, Kevin; Unutmaz, Derya; McBride, Helen J.; Feske, Stefan

    2015-01-01

    The function of CD4+ T cells is dependent on Ca2+ influx through Ca2+ release-activated Ca2+ (CRAC) channels formed by ORAI proteins. To investigate the role of ORAI1 in pro-inflammatory Th1 and Th17 cells and autoimmune diseases, we genetically and pharmacologically modulated ORAI1 function. Immunization of mice lacking Orai1 in T cells with MOG peptide resulted in attenuated severity of experimental autoimmune encephalomyelitis (EAE). The numbers of T cells and innate immune cells in the CNS of ORAI1-deficient animals were strongly reduced along with almost completely abolished production of IL-17, IFN-γ and GM-CSF despite only partially reduced Ca2+ influx. In Th1 and Th17 cells differentiated in vitro, ORAI1 was required for cytokine production but not the expression of Th1- and Th17-specific transcription factors T-bet and RORγt. The differentiation and function of induced iTreg cells, by contrast, was independent of ORAI1. Importantly, induced genetic deletion of Orai1 in adoptively transferred, MOG-specific T cells was able to halt EAE progression after disease onset. Likewise, treatment of wild-type mice with a selective CRAC channel inhibitor after EAE onset ameliorated disease. Genetic deletion of Orai1 and pharmacological ORAI1 inhibition reduced the leukocyte numbers in the CNS and attenuated Th1/Th17 cell-mediated cytokine production. In human CD4+ T cells, CRAC channel inhibition reduced the expression of IL-17, IFN-γ and other cytokines in a dose-dependent manner. Taken together, these findings support the conclusion that Th1 and Th17 cell function is particularly dependent on CRAC channels, which could be exploited as a therapeutic approach to T cell-mediated autoimmune diseases. PMID:26673135

  11. Baicalin ameliorates renal fibrosis via inhibition of transforming growth factor β1 production and downstream signal transduction.

    PubMed

    Zheng, Long; Zhang, Chao; Li, Long; Hu, Chao; Hu, Mushuang; Sidikejiang, Niyazi; Wang, Xuanchuan; Lin, Miao; Rong, Ruiming

    2017-04-01

    Previous studies have demonstrated the potential antifibrotic effects of baicalin in vitro, via examination of 21 compounds isolated from plants. However, its biological activity and underlying mechanisms of action in vivo remain to be elucidated. The present study aimed to evaluate the effect of baicalin on renal fibrosis in vivo, and the potential signaling pathways involved. A unilateral ureteral obstruction (UUO)‑induced renal fibrosis model was established using Sprague‑Dawley rats. Baicalin was administrated intraperitoneally every 2 days for 10 days. The degree of renal damage and fibrosis was investigated by histological assessment, and detection of fibronectin and collagen I mRNA expression levels. Epithelial‑mesenchymal transition (EMT) markers, transforming growth factor-β1 (TGF-β1) levels and downstream phosphorylation of mothers against decapentaplegic 2/3 (Smad2/3) were examined in vivo and in an NRK‑52E rat renal tubular cell line in vitro. Baicalin was demonstrated to markedly ameliorate renal fibrosis and suppress EMT, as evidenced by reduced interstitial collagen accumulation, decreased fibronectin and collagen I mRNA expression levels, upregulation of N‑ and E‑cadherin expression levels, and downregulation of α‑smooth muscle actin and vimentin expression. Furthermore, baicalin decreased TGF‑β1 expression levels in serum and kidney tissue following UUO, and suppressed Smad2/3 phosphorylation in rat kidney tissue. In vitro studies identified that baicalin may inhibit the phosphorylation of Smad2/3 under the same TGF‑β1 concentration. In conclusion, baicalin may protect against renal fibrosis, potentially via inhibition of TGF‑β1 production and its downstream signal transduction.

  12. 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.

  13. Deficiency of DJ-1 Ameliorates Liver Fibrosis through Inhibition of Hepatic ROS Production and Inflammation.

    PubMed

    Yu, Yingxue; Sun, Xuehua; Gu, Jinyang; Yu, Chang; Wen, Yankai; Gao, Yueqiu; Xia, Qiang; Kong, Xiaoni

    2016-01-01

    Liver fibrosis is a global health problem and previous studies have demonstrated that reactive oxygen species (ROS) play important roles in fibrogenesis. Parkinson disease (autosomal recessive, early onset) 7 (Park7) also called DJ-1 has an essential role in modulating cellular ROS levels. DJ-1 therefore may play functions in liver fibrogenesis and modulation of DJ-1 may be a promising therapeutic approach. Here, wild-type (WT) and DJ-1 knockout (DJ-1 KO) mice were administrated with carbon tetrachloride (CCl4) to induce liver fibrosis or acute liver injury. Results showed that DJ-1 depletion significantly blunted liver fibrosis, accompanied by marked reductions in liver injury and ROS production. In the acute CCl4 model, deficiency of DJ-1 showed hepatic protective functions as evidenced by decreased hepatic damage, reduced ROS levels, diminished hepatic inflammation and hepatocyte proliferation compared to WT mice. In vitro hepatic stellate cells (HSCs) activation assays indicated that DJ-1 has no direct effect on the activation of HSCs in the context of with or without TGFβ treatment. Thus our present study demonstrates that in CCl4-induced liver fibrosis, DJ-1 deficiency attenuates mice fibrosis by inhibiting ROS production and liver injury, and further indirectly affecting the activation of HSCs. These results are in line with previous studies that ROS promote HSC activation and fibrosis development, and suggest the therapeutic value of DJ-1 in treatment of liver fibrosis.

  14. Inhibition of COX-2/PGE2 cascade ameliorates cisplatin-induced mesangial cell apoptosis

    PubMed Central

    Yu, Xiaowen; Yang, Yunwen; Yuan, Hui; Wu, Meng; Li, Shuzhen; Gong, Wei; Yu, Jing; Xia, Weiwei; Zhang, Yue; Ding, Guixia; Huang, Songming; Jia, Zhanjun; Zhang, Aihua

    2017-01-01

    Cisplatin is one of the most potent cytotoxic drug for the treatment of many types of cancer. However, the side effects on normal tissues, particularly on the kidney, greatly limited its use in clinic. Emerging evidence demonstrated that cisplatin could directly cause mesangial cell apoptosis, while the potential mechanism is still elusive. Here we examined the contribution of COX-2 in cisplatin-induced mesangial cell apoptosis. Firstly, we found cisplatin induced cell apoptosis in mesangial cells shown by increased number of apoptotic cells in parallel with the upregulation of Bax and the downregulation of Bcl-2. Interestingly, cisplatin-induced cell apoptosis was accompanied by an upregulation of COX-2 at both mRNA and protein levels in dose- and time-dependent manners. Importantly, inhibition of COX-2 via a specific COX-2 inhibitor celecoxib markedly blocked cisplatin-induced mesangial cell apoptosis as evidenced by the decreased number of apoptotic cells, blocked increments of cleaved caspase-3 and Bax, and reversed Bcl-2 downregulation. Meanwhile, cisplatin-induced PGE2 production was markedly blocked by the treatment of celecoxib. In conclusion, this study indicated that COX-2/PGE2 cascade activation mediated cisplatin-induced mesangial cell apoptosis. The findings not only offered new insights into the understanding of cisplatin nephrotoxicity but also provided the therapeutic potential by targeting COX-2/PGE2 cascade in treating cisplatin-induced kidney injury. PMID:28386348

  15. Deficiency of DJ-1 Ameliorates Liver Fibrosis through Inhibition of Hepatic ROS Production and Inflammation

    PubMed Central

    Yu, Yingxue; Sun, Xuehua; Gu, Jinyang; Yu, Chang; Wen, Yankai; Gao, Yueqiu; Xia, Qiang; Kong, Xiaoni

    2016-01-01

    Liver fibrosis is a global health problem and previous studies have demonstrated that reactive oxygen species (ROS) play important roles in fibrogenesis. Parkinson disease (autosomal recessive, early onset) 7 (Park7) also called DJ-1 has an essential role in modulating cellular ROS levels. DJ-1 therefore may play functions in liver fibrogenesis and modulation of DJ-1 may be a promising therapeutic approach. Here, wild-type (WT) and DJ-1 knockout (DJ-1 KO) mice were administrated with carbon tetrachloride (CCl4) to induce liver fibrosis or acute liver injury. Results showed that DJ-1 depletion significantly blunted liver fibrosis, accompanied by marked reductions in liver injury and ROS production. In the acute CCl4 model, deficiency of DJ-1 showed hepatic protective functions as evidenced by decreased hepatic damage, reduced ROS levels, diminished hepatic inflammation and hepatocyte proliferation compared to WT mice. In vitro hepatic stellate cells (HSCs) activation assays indicated that DJ-1 has no direct effect on the activation of HSCs in the context of with or without TGFβ treatment. Thus our present study demonstrates that in CCl4-induced liver fibrosis, DJ-1 deficiency attenuates mice fibrosis by inhibiting ROS production and liver injury, and further indirectly affecting the activation of HSCs. These results are in line with previous studies that ROS promote HSC activation and fibrosis development, and suggest the therapeutic value of DJ-1 in treatment of liver fibrosis. PMID:27766037

  16. Chrysophanol Inhibits NALP3 Inflammasome Activation and Ameliorates Cerebral Ischemia/Reperfusion in Mice

    PubMed Central

    Zhang, Nan; Liu, Xiaoxia; Wang, Hong; Xue, Jing; Yu, Jingying; Kang, Ning; Wang, Xiaolu

    2014-01-01

    The most effective way to contain cerebral ischemic injury is reperfusion; however, reperfusion itself may result in tissue injury, for which inflammatory damage is one of the main causative factors. NALP3 inflammasome is a multiprotein complex. It consists of NALP3, ASC, and caspase-1, whose function is to switch on the inflammatory process. Chrysophanol is an extract from plants of Rheum genus and it possesses many pharmacological effects including its anti-inflammation activity. In this study, the effects of chrysophanol in cerebral ischemia/reperfusion and the potential mechanisms were investigated. Male CD1 mice were subject to transient middle cerebral artery occlusion (tMCAO). The NALP3 inflammasome activation status and its dynamic expression during the natural inflammatory response induced by tMCAO were first profiled. The neuroprotective effects of chrysophanol were then assessed and the potential mechanisms mediating the observed neuroprotection were then explored. Physical parameters including neurological deficit, infarct size, brain edema, and BBB permeability were measured at 24 h after tMCAO. Confocal microscopy, Western blotting, immunohistochemistry, and qRT-PCR techniques were utilized to analyze the expression of NALP3 inflammasome and IL-1β. Our results indicated that the brain tissue damage during cerebral ischemia/reperfusion is accompanied by NALP3 inflammasome activation. Chrysophanol could inhibit the activation of NALP3 inflammasome and protect cerebral ischemic stroke. PMID:24876671

  17. Telmisartan ameliorates cisplatin-induced nephrotoxicity by inhibiting MAPK mediated inflammation and apoptosis.

    PubMed

    Malik, Salma; Suchal, Kapil; Gamad, Nanda; Dinda, Amit Kumar; Arya, Dharamvir Singh; Bhatia, Jagriti

    2015-02-05

    Nephrotoxicity is a major adverse effect of the widely used anticancer drug cisplatin. Oxidative stress, inflammation and apoptosis are implicated in the pathophysiology of cisplatin-induced acute renal injury. Moreover, cisplatin activates many signal transduction pathways involved in cell injury and death, particularly mitogen activated protein kinase (MAPK) pathway. With this background, we aimed to investigate the protective effect of telmisartan, a widely used antihypertensive drug, in cisplatin-induced nephrotoxicity model in rats. To accomplish this, male albino wistar rats (150-200 g) were divided into 6 groups: Normal, cisplatin-control, telmisartan (2.5, 5 and 10 mg/kg) and telmisartan per se treatment groups. Normal saline or telmisartan was administered orally to rats for 10 days and cisplatin was given on 7th day (8 mg/kg; i.p.) to induce nephrotoxicity. On 10th day, rats were killed and both the kidneys were harvested for biochemical, histopathological and molecular studies. Cisplatin injected rats showed depressed renal function, altered proxidant-antioxidant balance and acute tubular necrosis which was significantly normalized by telmisartan co-treatment. Furthermore, cisplatin administration activated MAPK pathway that caused tubular inflammation and apoptosis in rats. Telmisartan treatment significantly prevented MAPK mediated inflammation and apoptosis. Among the three doses studied telmisartan at 10 mg/kg dose showed maximum nephroprotective effect which could be due to maintenance of cellular redox status and inhibition of MAPK activation.

  18. Catalase ameliorates hepatic fibrosis by inhibition of hepatic stellate cells activation.

    PubMed

    Dong, Yuwei; Qu, Ying; Xu, Mingyi; Wang, Xingpeng; Lu, Lungen

    2014-01-01

    Catalase, an endogenous antioxidant enzyme, is thought to have rescue effects on hepatic fibrosis. In this study, the regulation of catalase in CCl₄-induced hepatic fibrogenesis was investigated. Our results indicated that catalase expression was decreased upon CCl₄ treatment in a time-dependent manner, while the expression of several profibrosis and proangiogenic factors, including transforming growth factor (TGF)-beta 1, vascular endothelial growth factor (VEGF), and angiopoietin 1 were significantly increased. To assess the role of catalase in hepatic fibrosis, catalase was overexpressed in HSC-T6 cells. This overexpression resulted in the inhibition of cell proliferation, migratory activity, and alpha-smooth muscle actin (alpha-SMA) expression, key features that characterize activation of hepatic stellate cells (HSC). Overexpression of catalase led to a decrease in the secretion of collagen type 1 and angiopoietin 1. These results indicate that loss of catalase activity is involved in the pathogenesis of hepatic fibrosis caused by the activation of HSCs.

  19. Spiegelmer inhibition of CCL2/MCP-1 ameliorates lupus nephritis in MRL-(Fas)lpr mice.

    PubMed

    Kulkarni, Onkar; Pawar, Rahul D; Purschke, Werner; Eulberg, Dirk; Selve, Norma; Buchner, Klaus; Ninichuk, Volha; Segerer, Stephan; Vielhauer, Volker; Klussmann, Sven; Anders, Hans-Joachim

    2007-08-01

    The monocyte chemoattractant protein CCL2 is crucial for monocyte and T cell recruitment from the vascular to the extravascular compartment at sites of inflammation. CCL2 is expressed in human lupus nephritis and was shown to mediate experimental lupus; therefore, CCL2 antagonists may be beneficial for therapy. This study describes the l-enantiomeric RNA oligonucleotide mNOX-E36, a so-called Spiegelmer that binds murine CCL2 with high affinity and neutralizes its action in vitro and in vivo. The mirror image configuration of the Spiegelmer confers nuclease resistance and thus excellent biostability. mNOX-E36 does not induce type I IFN via Toll-like receptor-7 or cytosolic RNA receptors, as recently shown for certain synthetic D-RNA. Autoimmune-prone MRL(lpr/lpr) mice that were treated with a polyethylene glycol form of mNOX-E36 from weeks 14 to 24 of age showed prolonged survival associated with a robust improvement of lupus nephritis, peribronchial inflammation, and lupus-like inflammatory skin lesions. Thus, mNOX-E36-based inhibition of CCL2 represents a novel strategy for the treatment of autoimmune tissue injury, such as lupus nephritis.

  20. Protein arginine deiminase 4 inhibition is sufficient for the amelioration of collagen-induced arthritis.

    PubMed

    Willis, V C; Banda, N K; Cordova, K N; Chandra, P E; Robinson, W H; Cooper, D C; Lugo, D; Mehta, G; Taylor, S; Tak, P P; Prinjha, R K; Lewis, H D; Holers, V M

    2017-01-27

    Citrullination of joint proteins by the protein arginine deiminase (PAD) family of enzymes is recognized increasingly as a key process in the pathogenesis of rheumatoid arthritis. This present study was undertaken to explore the efficacy of a novel PAD4-selective inhibitor, GSK199, in the murine collagen-induced arthritis model of rheumatoid arthritis. Mice were dosed daily from the time of collagen immunization with GSK199. Efficacy was assessed against a wide range of end-points, including clinical disease scores, joint histology and immunohistochemistry, serum and joint citrulline levels and quantification of synovial autoantibodies using a proteomic array containing joint peptides. Administration of GSK199 at 30 mg/kg led to significant effects on arthritis, assessed both by global clinical disease activity and by histological analyses of synovial inflammation, pannus formation and damage to cartilage and bone. In addition, significant decreases in complement C3 deposition in both synovium and cartilage were observed robustly with GSK199 at 10 mg/kg. Neither the total levels of citrulline measurable in joint and serum, nor levels of circulating collagen antibodies, were affected significantly by treatment with GSK199 at any dose level. In contrast, a subset of serum antibodies reactive against citrullinated and non-citrullinated joint peptides were reduced with GSK199 treatment. These data extend our previous demonstration of efficacy with the pan-PAD inhibitor Cl-amidine and demonstrate robustly that PAD4 inhibition alone is sufficient to block murine arthritis clinical and histopathological end-points.

  1. Pharmacological inhibition of soluble epoxide hydrolase ameliorates diet-induced metabolic syndrome in rats.

    PubMed

    Iyer, Abishek; Kauter, Kathleen; Alam, Md Ashraful; Hwang, Sung Hee; Morisseau, Christophe; Hammock, Bruce D; Brown, Lindsay

    2012-01-01

    The signs of metabolic syndrome following chronic excessive macronutrient intake include body weight gain, excess visceral adipose deposition, hyperglycaemia, glucose and insulin intolerances, hypertension, dyslipidaemia, endothelial damage, cardiovascular hypertrophy, inflammation, ventricular contractile dysfunction, fibrosis, and fatty liver disease. Recent studies show increased activity of soluble epoxide hydrolase (sEH) during obesity and metabolic dysfunction. We have tested whether sEH inhibition has therapeutic potential in a rat model of diet-induced metabolic syndrome. In these high-carbohydrate, high-fat-fed rats, chronic oral treatment with trans-4-[4-(3-adamantan-1-ylureido)-cyclohexyloxy]-benzoic acid (t-AUCB), a potent sEH inhibitor, alleviated the signs of metabolic syndrome in vivo including glucose, insulin, and lipid abnormalities, changes in pancreatic structure, increased systolic blood pressure, cardiovascular structural and functional abnormalities, and structural and functional changes in the liver. The present study describes the pharmacological responses to this selective sEH inhibitor in rats with the signs of diet-induced metabolic syndrome.

  2. Serotonergic involvement in the amelioration of behavioral abnormalities in dopamine transporter knockout mice by nicotine.

    PubMed

    Uchiumi, Osamu; Kasahara, Yoshiyuki; Fukui, Asami; Hall, F Scott; Uhl, George R; Sora, Ichiro

    2013-01-01

    Dopamine transporter knockout (DAT KO) mice exhibit elevated extracellular dopamine levels in brain regions that include the striatum and the nucleus accumbens, but not the prefrontal cortex. DAT KO mice model some aspects of psychiatric disorders, including schizophrenia. Smoking is more common in patients with schizophrenia, suggesting that nicotine might ameliorate aspects of the behavioral abnormalities and/or treatment side effects seen in these individuals. We report nicotine-induced normalization of effects on locomotion and prepulse inhibition of acoustic startle (PPI) in DAT KO mice that require intact serotonin 5-HT1A systems. First, we observed that the marked hyperactivity displayed by DAT KO mice was reduced by administration of nicotine. This nicotine effect was blocked by pretreatment with the non-specific nicotinic acetylcholine (nACh) receptor antagonist mecamylamine, or the 5-HT1A antagonist WAY100635. Secondly, we examined the effects of nicotine on PPI in DAT KO mice. Treatment with nicotine significantly ameliorated the PPI deficits observed in DAT KO mice. The ameliorating action of nicotine on PPI deficits in DAT KO mice was blocked by mecamylamine, the α₇ nACh receptor antagonist methyllycaconitine or WAY100635, while the α₄β₂ nACh receptor antagonist dihydro-β-erythroidinehydrobromide (DHβE) produced only a non-significant trend toward attenuation of nicotine effects. Finally, we observed that administration of the 5-HT1A receptor agonist 8-OH-DPAT also ameliorated the deficit in PPI observed in DAT KO mice. This amelioration was antagonized by pretreatment with WAY100635. These data support the idea that nicotine might ameliorate some of the cognitive dysfunctions found in schizophrenia in a 5-HT1A-dependent fashion. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

  3. D-ribose ameliorates cisplatin-induced nephrotoxicity by inhibiting renal inflammation in mice.

    PubMed

    Ueki, Masaaki; Ueno, Masaki; Morishita, Jun; Maekawa, Nobuhiro

    2013-01-01

    Cisplatin is one of the most potent chemotherapeutic anticancer drugs, but it can produce side effects such as nephrotoxicity. Inflammatory cytokines, chemokines and adhesion molecules have important roles in the pathogenesis of cisplatin-induced nephrotoxicity. D-Ribose is a naturally occurring five-carbon monosaccharide that is found in all living cells, and has anti-inflammatory effects in renal ischemia/reperfusion injury. The purpose of this study was to determine the protective effects of D-ribose on cisplatin-induced nephrotoxicity. Forty-eight mice were randomly divided into four groups: control, cisplatin, cisplatin + ribose, and ribose. Mice were given cisplatin (20 mg/kg body weight, intraperitoneally) with or without D-ribose (400 mg/kg body weight, intraperitoneally, immediately after cisplatin injection). At 72 h after cisplatin injection, we measured serum and renal tumor necrosis factor (TNF)-α and renal monocyte chemoattractant protein (MCP)-1 concentrations by enzyme-linked immunosorbent assay; renal expression of intercellular adhesion molecule (ICAM)-1 mRNA by real-time polymerase chain reaction; serum blood urea nitrogen and creatinine; and histological changes. Cisplatin increased serum and renal TNF-α concentrations, renal MCP-1 concentration, and renal ICAM-1 mRNA expression. Treatment with D-ribose attenuated the increase in serum and renal TNF-α concentrations, renal MCP-1 concentration, and renal ICAM-1 mRNA expression. Consequently, cisplatin-induced renal dysfunction and renal tubular necrosis were attenuated by D-ribose treatment. This is believed to be the first time that protective effects of D-ribose on cisplatin-induced nephrotoxicity via inhibition of inflammatory reactions have been investigated. Thus, D-ribose may become a new therapeutic candidate for the treatment of cisplatin-induced nephrotoxicity.

  4. Resveratrol ameliorates methotrexate-induced hepatotoxicity in rats via inhibition of lipid peroxidation.

    PubMed

    Dalaklioglu, S; Genc, G E; Aksoy, N H; Akcit, F; Gumuslu, S

    2013-06-01

    Hepatotoxicity is one of the major complications of methotrexate (MTX) therapy. This study was carried out to evaluate the possible protective effect of resveratrol (trans-3,5,4'-trihydroxystilbene, RVT) against MTX-induced hepatotoxicity. Rats were randomly divided into four groups as control, MTX treated (7 mg/kg/day, intraperitoneally (i.p.), once daily for 3 consecutive days), MTX + RVT treated (20 mg/kg/day, i.p.), and RVT treated. First dose of RVT was administrated 3 days before the MTX injection and continued for 3 days. Histopathology of liver was evaluated by light microscopy. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) were used as biochemical markers of MTX-induced hepatic injury. The levels of thiobarbituric acid reactive substances (TBARS, a marker of lipid peroxidation) and activities of hepatic antioxidant enzymes such as catalase (CAT) and glutathione-S-transferase (GST) were used to analyze the oxidative stress-mediated lipid peroxidation in liver sections. Our results showed that MTX administration significantly increased ALT, ASP, and ALP levels. TBARS, CAT, and GST levels were also markedly increased in liver after MTX administration. RVT treatment significantly prevented MTX-induced hepatotoxicity, as indicated by AST, ALT, and ALP levels and liver histopathology. Moreover, administration of RVT significantly decreased the elevated levels of TBARS and activities of CAT and GST in the liver compared to MTX-treated group. These results revealed that RVT may have a protective effect against MTX-induced hepatotoxicity by inhibiting oxidative stress-mediated lipid peroxidation. Consequently, RVT treatment might be a promising strategy against MTX-induced hepatotoxicity.

  5. Pharmacological inhibition of mannose-binding lectin ameliorates neurobehavioral dysfunction following experimental traumatic brain injury.

    PubMed

    De Blasio, Daiana; Fumagalli, Stefano; Longhi, Luca; Orsini, Franca; Palmioli, Alessandro; Stravalaci, Matteo; Vegliante, Gloria; Zanier, Elisa R; Bernardi, Anna; Gobbi, Marco; De Simoni, Maria-Grazia

    2017-03-01

    Mannose-binding lectin is present in the contusion area of traumatic brain-injured patients and in that of traumatic brain-injured mice, where mannose-binding lectin-C exceeds mannose-binding lectin-A. The reduced susceptibility to traumatic brain injury of mannose-binding lectin double knock-out mice (mannose-binding lectin(-/-)) when compared to wild type mice suggests that mannose-binding lectin may be a therapeutic target following traumatic brain injury. Here, we evaluated the effects of a multivalent glycomimetic mannose-binding lectin ligand, Polyman9, following traumatic brain injury in mice. In vitro surface plasmon resonance assay indicated that Polyman9 dose-dependently inhibits the binding to immobilized mannose residues of plasma mannose-binding lectin-C selectively over that of mannose-binding lectin-A. Male C57Bl/6 mice underwent sham/controlled cortical impact traumatic brain injury and intravenous treatment with Polyman9/saline. Ex-vivo surface plasmon resonance studies confirmed that Polyman9 effectively reduces the binding of plasma mannose-binding lectin-C to immobilized mannose residues. In vivo studies up to four weeks post injury, showed that Polyman9 induces significant improvement in sensorimotor deficits (by neuroscore and beam walk), promotes neurogenesis (73% increase in doublecortin immunoreactivity), and astrogliosis (28% increase in glial fibrillary acid protein). Polyman9 administration in brain-injured mannose-binding lectin(-/-) mice had no effect on post-traumatic brain-injured functional deficits, suggestive of the specificity of its neuroprotective effects. The neurobehavioral efficacy of Polyman9 implicates mannose-binding lectin-C as a novel therapeutic target for traumatic brain injury.

  6. 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).

  7. 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).

  8. Suplatast tosilate ameliorates airway hyperreactivity and inflammation through inhibition of the GATA‑3/IL‑5 signaling pathway in asthmatic rats.

    PubMed

    Tan, Yupin; Li, Yun; Liu, Dan; Zhong, Lili

    2013-07-01

    Airway hyperreactivity and inflammation are important factors in the aggravation of lung function. Suplatast tosilate (IPD) is a novel and unique anti‑asthma clinical compound. However, the mechanisms of IPD action in the inhibition of asthma remain to be elucidated. The present study aimed to investigate the role of the GATA binding protein 3 (GATA‑3)/interleukin (IL)‑5 signaling pathway in IPD‑induced inhibition of asthma. Sprague‑Dawley rats were sensitized by intraperitoneal injection with ovalbumin (OVA) to establish an animal model of asthma. IPD was administered continuously (C‑IPD) or at a later stage (L‑IPD). Budesonide (BUD) was used as a positive control. Airway resistance and the expression of genes at the mRNA and protein levels were measured. Morphological changes in lung tissue and the percentage of eosinophils (EOS) in peripheral blood were observed and correlation analysis was performed. The results revealed that sensitization by OVA significantly increased airway resistance and the percentage of EOS in peripheral blood and induced significant inflammatory changes in lung tissue, as demonstrated by thick epithelium, goblet cell hyperplasia and submucosal cell infiltration. In addition, sensitization by OVA was found to markedly upregulate IL‑5 mRNA and protein expression. Airway resistance was found to positively correlate with the expression of IL‑5 in the rat lung tissues. Sensitization by OVA was also observed to markedly enhance GATA‑3 protein expression and GATA‑3 levels were found to positively correlate with airway resistance and IL‑5 levels. Similar to the effect of BUD, treatment with C‑IPD or L‑IPD was found to significantly attenuate OVA‑induced increases in airway resistance and the percentage of EOS in peripheral blood. Notably, treatment with C‑IPD or L‑IPD markedly reduced the OVA-induced expression of IL‑5 and GATA‑3. In the present study, IPD intervention was demonstrated to ameliorate airway

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

    PubMed Central

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

    2016-01-01

    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

  10. Phytosphingosine derivatives ameliorate skin inflammation by inhibiting NF-κB and JAK/STAT signaling in keratinocytes and mice.

    PubMed

    Kim, Byung-Hak; Lee, Ji Min; Jung, Yong-Gyu; Kim, Sanghee; Kim, Tae-Yoon

    2014-04-01

    Phytosphingosine is abundant in plants and fungi and is found in mammalian epidermis, including the stratum corneum. Phytosphingosine and its derivatives N-acetyl phytosphingosine and tetraacetyl phytosphingosine are part of the natural defense system of the body. However, these molecules exhibit strong toxicities at high concentrations. We synthesized phytosphingosine derivatives, mYG-II-6 ((Z)-4-oxo-4-(((2S,3S,4R)-1,3,4-trihydroxyoctadecan-2-yl)amino)but-2-enoic acid) and fYG-II-6 ((E)-4-oxo-4-(((2S,3S,4R)-1,3,4-trihydroxyoctadecan-2-yl)amino)but-2-enoic acid), to increase efficacy and decrease toxicity, and the biological activities of the derivatives in the inflammatory response were examined. Both YG-II-6 compounds effectively suppressed 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammatory skin damage and inflammatory response in a mouse model. In addition, topical application of fYG-II-6 suppressed ear swelling and psoriasiform dermatitis in the ears of IL-23-injected mice. Anti-inflammatory and antipsoriatic activities of the phytosphingosine derivatives inhibited NF-κB, JAK/signal transducer and activator of transcription (JAK/STAT), and mitogen-activated protein kinase (MAPK) signaling. Finally, the YG-II-6 compounds induced programmed cell death in keratinocytes and mouse skin and were less toxic than phytosphingosine. Our study demonstrated that the phytosphingosine-derived YG-II-6 compounds have much stronger biological potencies than the lead compounds. The YG-II-6 compounds ameliorated inflammatory skin damage. Thus, YG-II-6 compounds are potential topical agents for treating chronic inflammatory skin diseases, such as psoriasis.

  11. 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

  12. Electroacupuncture ameliorates learning and memory in rats with cerebral ischemia-reperfusion injury by inhibiting oxidative stress and promoting p-CREB expression in the hippocampus.

    PubMed

    Lin, Ruhui; Lin, Yukun; Tao, Jing; Chen, Bin; Yu, Kunqiang; Chen, Jixiang; Li, Xiaojie; Chen, Li-Dian

    2015-11-01

    The present study aimed to investigate the mechanisms by which electroacupuncture (EA) ameliorates learning and memory in rats with cerebral ischemic‑reperfusion (I/R) injury. Focal cerebral ischemia was induced in adult male Sprague‑Dawley (SD) rats by transient middle cerebral artery occlusion (MCAO). Following MCAO surgery, the rats received EA at the Shenting (DU24) and Baihui (DU20) acupoints. The results of the present study demonstrated that treatment with EA significantly ameliorated neurological deficits and reduced cerebral infarct volume (P<0.05). In addition, EA improved the learning and memory ability of the rats, and markedly activated the cyclic adenosine monophosphate (cAMP) response element‑binding protein (CREB) signaling pathway, resulting in the inhibition of cerebral cell apoptosis in the ischemic penumbra. Furthermore, EA increased the activity of superoxide dismutase and glutathione peroxidase, the protein expression levels of phosphorylated‑CREB and B‑cell lymphoma 2 (Bcl‑2), and the mRNA expression levels of Bcl‑2. Conversely, EA decreased the levels of malondialdehyde and inhibited the expression levels of Bcl2‑associated X protein. The results of the present study suggest that treatment with EA may result in the amelioration of learning and memory ability in rats with cerebral I/R injury.

  13. 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

  14. ErbB inhibitors ameliorate behavioral impairments of an animal model for schizophrenia: implication of their dopamine-modulatory actions

    PubMed Central

    Mizuno, M; Sotoyama, H; Namba, H; Shibuya, M; Eda, T; Wang, R; Okubo, T; Nagata, K; Iwakura, Y; Nawa, H

    2013-01-01

    Ligands for ErbB receptors, including epidermal growth factor (EGF) and neuregulin-1, have a neurotrophic activity on midbrain dopaminergic neurons and are implicated in the pathophysiology of schizophrenia. Although ErbB kinase inhibitors ameliorate behavioral deficits of the schizophrenia model that was established by hippocampal lesioning of rat pups, the antipsychotic action of ErbB kinase inhibitors and its general applicability to other models are not fully characterized. Using a different animal model, here, we examined whether and how ErbB kinase inhibitors ameliorate the behavioral endophenotypes relevant to schizophrenia. The animal model for schizophrenia was prepared by exposing neonatal rats to the cytokine EGF. Intraventricular infusion of the ErbB1 inhibitors ZD1839 and PD153035 in these animals ameliorated the deficits in startle response and prepulse inhibition in a dose-dependent manner. The deficits of latent inhibition of fear learning were also alleviated by ZD1839 with its limited effects on body weight gain or locomotor activity. ZD1839 infusion also decreased the busting activity of nigral dopamine (DA) neurons and reduced pallidal DA metabolism, a result that mimics the anti-dopaminergic profile of risperidone and haloperidol in this brain region. ErbB inhibitors appear to have anti-dopaminergic actions to alleviate some of the behavioral deficits common to animal models for schizophrenia. PMID:23632456

  15. SIRT1 activator ameliorates the renal tubular injury induced by hyperglycemia in vivo and in vitro via inhibiting apoptosis.

    PubMed

    Wang, Xue-Ling; Wu, Li-Yan; Zhao, Long; Sun, Li-Na; Liu, Hai-Ying; Liu, Gang; Guan, Guang-Ju

    2016-10-01

    We aimed to explore the role of SIRT1 in apoptosis in human kidney proximal tubule epithelial (HK-2) cells, and to determine whether resveratrol (RSV, a SIRT1 activator) could ameliorate apoptosis in rats with streptozotocin-induced diabetes mellitus (DM) and/or in high glucose (HG, 30mM) - stimulated HK-2 cells. Rats were distributed randomly into three groups: 1) control group, 2) DM group, and 3) DM with RSV group (DM+RSV; rats treated with 30mg/kg/d of RSV for 16 weeks). The physical, biochemical, and morphological parameters were then examined. Additionally, the deacetylase activity of SIRT1, and the expression levels of SIRT1 and of representative apoptosis markers, such as p53, acetylated p53, cleaved caspase-3, caspase-9, and cleaved PARP, were measured. HK-2 cells were stimulated by HG for different lengths of time to study the effect of HG on apoptosis. HK-2 cells were treated with or without RSV (25μM) to investigate if RSV has a protective effect on HG-induced apoptosis. A gene-specific small interfering RNA against SIRT1 was used to study the role of SIRT1 in apoptosis. More apoptosis was found in the DM rats than in the control rats. Similarly, the expression levels of cleaved caspase-3, cleaved PARP, and acetylated p53 were significantly higher, and the level of SIRT1 was significantly lower, in the HK-2 cells that were cultured under HG conditions than those in the HK-2 cells that were cultured under low glucose (5.5mM) conditions. Notably, treatment with RSV lessened the HG-induced changes in the levels of apoptosis indicators, and this inhibition of HG-induced apoptosis in HK-2 cells by RSV treatment was abolished by SIRT1 silencing. Our study showed that hyperglycemia contributes to apoptosis in rat kidney and HK-2 cells. SIRT1 activation by RSV can reduce urinary albumin excretion and proximal tubule epithelial apoptosis both in vitro and in vivo. Based on our study, SIRT1/p53 axis played an important role in the hyperglycemia induced apoptosis

  16. 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.

  17. The prolyl oligopeptidase inhibitor IPR19 ameliorates cognitive deficits in mouse models of schizophrenia.

    PubMed

    Prades, Roger; Munarriz-Cuezva, Eva; Urigüen, Leyre; Gil-Pisa, Itziar; Gómez, Lídia; Mendieta, Laura; Royo, Soledad; Giralt, Ernest; Tarragó, Teresa; Meana, J Javier

    2017-02-01

    Cognitive deficits are considered a key feature of schizophrenia, and they usually precede the onset of the illness and continue after psychotic symptoms appear. Current antipsychotic drugs have little or no effect on the cognitive deficits of this disorder. Prolyl oligopeptidase (POP) is an 81-kDa monomeric serine protease that is expressed in brain and other tissues. POP inhibitors have shown neuroprotective, anti-amnesic and cognition-enhancing properties. Here we studied the potential of IPR19, a new POP inhibitor, for the treatment of the cognitive symptoms related to schizophrenia. The efficacy of the inhibitor was evaluated in mouse models based on subchronic phencyclidine and acute dizocilpine administration, and in adult offspring from mothers with immune reaction induced by polyinosinic:polycytidylic acid administration during pregnancy. Acute IPR19 administration (5mg/kg, i.p.) reversed the cognitive performance deficits of the three mouse models in the novel object recognition test, T-maze, and eight-arm radial maze. The compound also ameliorates deficits of the prepulse inhibition response. The in vitro inhibitory efficacy and selectivity, brain penetration and exposure time after injection of IPR19 were also addressed. Our results indicate that the inhibition of POP using IPR19 may offer a promising strategy to develop drugs to ameliorate the cognitive deficits of schizophrenia.

  18. 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.

  19. 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

  20. 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

    2016-07-04

    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.

  1. Intense gigawatt relativistic electron beam generation in the presence of prepulse

    NASA Astrophysics Data System (ADS)

    Mondal, J.; Kumar, D. D. P.; Roy, A.; Mitra, S.; Sharma, A.; Singh, S. K.; Rao, G. V.; Mittal, K. C.; Nagesh, K. V.; Chakravarthy, D. P.

    2007-02-01

    Large pulse power systems in the presence of prepulse can deliver gigawatt power pulses into a matched load. While employing these pulse power systems for the generation of intense relativistic electron beams (IREBs), the prepulse initiated plasma closes the anode cathode gap, if the gap distance is set by the Child-Langmuir formula. In order to reduce the prepulse effect, the anode cathode gap has been increased for the generation of IREB with output parameters of 400kV, 20kA, and 100ns pulse duration. In this paper the generation of IREB in the presence of prepulse without using any prepulse switch has been discussed.

  2. 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.

  3. 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

  4. Inhibition of central angiotensin converting enzyme ameliorates scopolamine induced memory impairment in mice: role of cholinergic neurotransmission, cerebral blood flow and brain energy metabolism.

    PubMed

    Tota, Santoshkumar; Nath, Chandishwar; Najmi, Abul Kalam; Shukla, Rakesh; Hanif, Kashif

    2012-06-15

    Evidences indicate that inhibition of central Renin angiotensin system (RAS) ameliorates memory impairment in animals and humans. Earlier we have reported involvement of central angiotensin converting enzyme (ACE) in streptozotocin induced neurodegeneration and memory impairment. The present study investigated the role of central ACE in cholinergic neurotransmission, brain energy metabolism and cerebral blood flow (CBF) in model of memory impairment induced by injection of scopolamine in mice. Perindopril (0.05 and 0.1 mg/kg, PO) was given orally for one week before administration of scopolamine (3mg/kg, IP). Then, memory function was evaluated by Morris water maze and passive avoidance tests. CBF was measured by laser Doppler flowmetry. Biochemical and molecular parameters were estimated after the completion of behavioral studies. Scopolamine caused impairment in memory which was associated with reduced CBF, acetylcholine (ACh) level and elevated acetylcholinesterase (AChE) activity and malondialdehyde (MDA) level. Perindopril ameliorated scopolamine induced amnesia in both the behavioral paradigms. Further, perindopril prevented elevation of AChE and MDA level in mice brain. There was a significant increase in CBF and ACh level in perindopril treated mice. However, scopolamine had no significant effect on ATP level and mRNA expression of angiotensin receptors and ACE in cortex and hippocampus. But, perindopril significantly decreased ACE activity in brain without affecting its mRNA expression. The study clearly showed the interaction between ACE and cholinergic neurotransmission and beneficial effect of perindopril can be attributed to improvement in central cholinergic neurotransmission and CBF.

  5. Berberine ameliorates experimental diabetes-induced renal inflammation and fibronectin by inhibiting the activation of RhoA/ROCK signaling.

    PubMed

    Xie, Xi; Chang, Xiuting; Chen, Lei; Huang, Kaipeng; Huang, Juan; Wang, Shaogui; Shen, Xiaoyan; Liu, Peiqing; Huang, Heqing

    2013-12-05

    The accumulation of glomerular extracellular matrix proteins, especially fibronectin (FN), is a critical pathological characteristic of diabetic renal fibrosis. Inflammation mediated by nuclear factor-κB (NF-κB) plays a critical role in the pathogenesis of diabetic nephropathy (DN). RhoA/ROCK signaling is responsible for FN accumulation and NF-κB activation. Berberine (BBR) treatment significantly inhibited renal inflammation and thus improved renal damage in diabetes. Here, we study whether BBR inhibits FN accumulation and NF-κB activation by inhibiting RhoA/ROCK signaling and the underlying mechanisms involved. Results showed that BBR effectively inhibited RhoA/ROCK signaling activation in diabetic rat kidneys and high glucose-induced glomerular mesangial cells (GMCs) and simultaneously down-regulated NF-κB activity, which was accompanied by reduced intercellular adhesionmolecule-1, transforming growth factor-beta 1 and FN overproduction. Furthermore, we observed that BBR abrogated high glucose-mediated reactive oxygen species generation in GMCs. BBR and N-acetylcysteine inhibited RhoA/ROCK signaling activation in high glucose-exposed GMCs. Collectively, our data suggest that the renoprotective effect of BBR on DN partly depends on RhoA/ROCK inhibition. The anti-oxidative stress effect of BBR is responsible for RhoA/ROCK inhibition in DN.

  6. 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

  7. Low-dose paclitaxel ameliorates renal fibrosis in rat UUO model by inhibition of TGF-beta/Smad activity.

    PubMed

    Zhang, Dongshan; Sun, Lin; Xian, Wang; Liu, Fuyou; Ling, Guanghui; Xiao, Li; Liu, Yanhong; Peng, Youmin; Haruna, Yoshisuke; Kanwar, Yashpal S

    2010-03-01

    Transforming growth factor-beta (TGF-beta) has a pivotal function in the progression of renal fibrosis in a wide variety of renal diseases. Smad proteins have been identified to have an important function in regulating the expression of extracellular matrix (ECM) proteins through TGF-beta signaling pathway. Aberrant TGF-beta/Smad signaling can be modulated by stabilization of microtubules with paclitaxel. In this study, we investigated if paclitaxel can attenuate tubulointerstitial fibrosis in a rat model of unilateral ureteral obstruction (UUO). Rats in groups of six were subjected to UUO and received low-dose intraperitoneal injection of paclitaxel (0.3 mg/kg) twice a week. They were killed at day 7 and 14 after UUO or Sham operation. TGF-beta signaling cascade and status of various ECM proteins were evaluated by RT-PCR, western blotting and immunohistochemical or immunofluorescence staining. The paclitaxel treatment markedly suppressed Smad2 and Smad3 phosphorylation. This was associated with attenuated expression of integrin-linked kinase, collagens I and III, fibronectin (FN) and alpha-smooth muscle actin, and a substantial decrease in renal fibrosis in animals that underwent UUO and received paclitaxel. These data indicate that the low-dose paclitaxel ameliorates renal tubulointerstitial fibrosis by modulating TGF-beta signaling, and thus, the paclitaxel may have some therapeutic value in humans.

  8. Partial Amelioration of Synaptic and Cognitive Deficits by Inhibiting Cofilin Dephosphorylation in an Animal Model of Alzheimer's Disease.

    PubMed

    Deng, Yulei; Wei, Jing; Cheng, Jia; Zhong, Ping; Xiong, Zhe; Liu, Aiyi; Lin, Lin; Chen, Shengdi; Yan, Zhen

    2016-06-28

    The loss of synaptic structure and function has been linked to the cognitive impairment of Alzheimer's disease (AD). Dysregulation of the actin cytoskeleton, which plays a key role in regulating the integrity of synapses and the transport of synaptic proteins, has been suggested to contribute to the pathology of AD. In this study, we found that glutamate receptor surface expression and synaptic function in frontal cortical neurons were significant diminished in a familial AD (FAD) model, which was correlated with the reduction of phosphorylated cofilin, a key protein regulating the dynamics of actin filaments. Injecting a cofilin dephosphorylation inhibitory peptide to FAD mice led to the partial rescue of the surface expression of AMPA and NMDA receptor subunits, as well as the partial restoration of AMPAR- and NMDAR-mediated synaptic currents. Moreover, the impaired working memory and novel object recognition memory in FAD mice were partially ameliorated by injections of the cofilin dephosphorylation inhibitory peptide. These results suggest that targeting the cofilin-actin signaling holds promise to mitigate the physiological and behavioral abnormality in AD.

  9. Boron inhibits the proliferating cell nuclear antigen index, molybdenum containing proteins and ameliorates oxidative stress in hepatocellular carcinoma.

    PubMed

    Zafar, Hina; Ali, Shakir

    2013-01-15

    Hepatocellular carcinoma (HCC) is a common malignancy and the main cause of mortality in patients with chronic liver diseases. This study reports the inhibitory effect of boron on HCC induced in rats by administering thioacetamide (TAA) (0.03%) in drinking water for 400days. Boron (4mg/kg body weight) was administered orally after induction of carcinoma. Treatment was continued for 122days, and cell proliferation, histology and biochemistry of treated and control group of rats were studied. Proliferating cell nuclear antigen (PCNA), and [(3)H]-thymidine incorporation, which increased in rats exposed to carcinogen, significantly decreased after boron treatment. PCNA index decreased from 80 in HCC rats to 32 after boron treatment. In the control group, it was 20. Boron caused a dose-dependent decrease in carcinogen-induced [(3)H]-thymidine uptake by the rat hepatocyte. It could partially reverse the activity of selected biochemical indicators of hepatic damage, oxidative stress, selenium and serum retinol, which are depleted in liver cancer, and improved overall health of animal. The study implicates the elevated levels of mammalian molybdenum Fe-S containing flavin hydroxylases, which increase the free radical production and oxidative stress, consequently causing increased hepatic cell proliferation in HCC, and reports boron to ameliorate these changes in liver cancer.

  10. Kakkalide and its metabolite irisolidone ameliorate carrageenan-induced inflammation in mice by inhibiting NF-κB pathway.

    PubMed

    Min, Sung-Won; Park, Young-Jun; Kim, Dong-Hyun

    2011-10-01

    The anti-inflammatory activities of kakkalide, a major constituent of the flower of Pueraria thunbergiana, and irisolidone, a metabolite of kakkalide produced by intestinal microflora, against carrageenan-induced inflammation in air pouches on the backs of mice and in lipopolysaccharide (LPS)-stimulated peritoneal macrophages were investigated. Kakkalide and irisolidone down-regulated the gene expression of cytokines [tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β)] and cyclooxygenase-2 (COX-2) and the production of pro-inflammatory cytokines, TNF-α and IL-1β, and inflammatory mediators, NO and prostaglandin E(2) (PGE(2)), in LPS-stimulated peritoneal macrophages. These agents also inhibited the phosphorylation of IκB-α and the nuclear translocation of nuclear factor-kappa B (NF-κB). Orally administered kakkalide and irisolidone significantly reduced carrageenan-induced inflammatory markers, leukocyte number, and protein amount in the exudates of the air pouch. These constituents also inhibited PGE(2) production and COX-2 inducible nitric oxide synthase, IL-1β, and TNF-α expression. These agents also inhibited NF-κB activation. The anti-inflammatory effects of irisolidone were more potent than those of kakkalide. Based on these findings, kakkalide and irisolidone may inhibit inflammatory reactions via NF-κB pathway, and irisolidone, a metabolite of kakkalide, may more potently inhibit these inflammatory reactions.

  11. miR-23b targets Smad 3 and ameliorates the LPS-inhibited osteogenic differentiation in preosteoblast MC3T3-E1 cells.

    PubMed

    Liu, Hongzhi; Hao, Wei; Wang, Xin; Su, Hao

    2016-04-01

    Lipopolysaccharide (LPS) has been confirmed to be the main inhibitor in osteogenic differentiation, posing a clinical challenge to bone healing, particularly for trauma followed by endotoxinemia/sepsis. However, the molecular mechanism remains ambiguous. miR-23b, which regulates multiple signaling pathways in inflammation, has been shown to be deregulated by LPS. In this study, we examined the LPS-mediated regulation on the expression of miR-23b and Smad 3 in preosteoblast MC3T3-E1 cells. Then we determined the regulation of miR-23b overexpression on the Smad 3 expression and on the LPS-mediated inhibition of bone morphogenetic protein-2 (BMP-2)-induced osteogenic differentiation. Our results demonstrated that LPS significantly downregulated the expression of miR-23b, while upregulating Smad 3 in MC3T3-E1 cells. However, the transfection with miR-23b mimics markedly downregulated the Smad 3 in both mRNA and protein levels, via the specific binding to the 3'-untranslated region (UTR) of Smad 3. Moreover, though LPS markedly downregulated the BMP-2-induced osteogenic differentiation of MC3T3-E1 cells by inhibiting the expression of alkaline phosphatase (ALP), Osteocalcin (OCN), Osteopontin (OPN) and Runt-related transcription factor 2 (RUNX2). The upregulated miR-23b reversed such downregulation of ALP, OCN, OPN and RUNX2 in the MC3T3-E1 cells which were treated both with LPS and BMP-2. In conclusion, our data indicates that miR-23b ameliorates the LPS-mediated inhibition of BMP-2-induced osteogenic differentiation in MC3T3-E1 cells, implying the protective role of miR-23b in the LPS-mediated inhibition of osteogenic differentiation and bone formation.

  12. 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.

  13. 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.

  14. Adipose-derived stem cells ameliorate renal interstitial fibrosis through inhibition of EMT and inflammatory response via TGF-β1 signaling pathway.

    PubMed

    Song, Yan; Peng, Changliang; Lv, Shasha; Cheng, Jing; Liu, Shanshan; Wen, Qing; Guan, Guangju; Liu, Gang

    2017-03-01

    Adipose-derived stem cells (ADSCs) have been successfully used to treat acute kidney injury or acute renal failure. However, the effect of ADSCs on treating renal interstitial fibrosis remains unknown. Here, we assessed the therapeutic efficacy of ADSCs on renal interstitial fibrosis induced by unilateral ureter obstruction (UUO) and explored the potential mechanisms. After 7days of UUO, rats were injected with ADSCs (5×10(6)) or vehicle via tail vein. We found that ADSCs administration significantly ameliorated renal interstitial fibrosis, the occurrence of epithelial-mesenchymal transition (EMT) and inflammatory response. Furthermore, ADSCs administration could inhibit the activation of transforming growth factor-β1 (TGF-β1) signaling pathway, which might play a crucial role in renal interstitial fibrosis of the UUO model rats. These results suggested that ADSCs treatment attenuates renal interstitial fibrosis possibly through inhibition of EMT and inflammatory response via TGF-β1 signaling pathway. Therefore, ADSCs may be an effective therapeutic strategy for the treatment of renal interstitial fibrosis.

  15. Tomatidine, a tomato sapogenol, ameliorates hyperlipidemia and atherosclerosis in apoE-deficient mice by inhibiting acyl-CoA:cholesterol acyl-transferase (ACAT).

    PubMed

    Fujiwara, Yukio; Kiyota, Naoko; Tsurushima, Keiichiro; Yoshitomi, Makiko; Horlad, Hasita; Ikeda, Tsuyoshi; Nohara, Toshihiro; Takeya, Motohiro; Nagai, Ryoji

    2012-03-14

    It was previously revealed that esculeoside A, a new glycoalkaloid, and esculeogenin A, a new aglycon of esculeoside A, contained in ripe tomato ameliorate atherosclerosis in apoE-deficent mice. This study examined whether tomatidine, the aglycone of tomatine, which is a major tomato glycoalkaloid, also shows similar inhibitory effects on cholesterol ester (CE) accumulation in human monocyte-derived macrophages (HMDM) and atherogenesis in apoE-deficient mice. Tomatidine significantly inhibited the CE accumulation induced by acetylated LDL in HMDM in a dose-dependent manner. Tomatidine also inhibited CE formation in Chinese hamster ovary cells overexpressing acyl-CoA:cholesterol acyl-transferase (ACAT)-1 or ACAT-2, suggesting that tomatidine suppresses both ACAT-1 and ACAT-2 activities. Furthermore, the oral administration of tomatidine to apoE-deficient mice significantly reduced levels of serum cholesterol, LDL-cholesterol, and areas of atherosclerotic lesions. The study provides the first evidence that tomatidine significantly suppresses the activity of ACAT and leads to reduction of atherogenesis.

  16. Piracetam ameliorated oxygen and glucose deprivation-induced injury in rat cortical neurons via inhibition of oxidative stress, excitatory amino acids release and P53/Bax.

    PubMed

    He, Zhi; Hu, Min; Zha, Yun-hong; Li, Zi-cheng; Zhao, Bo; Yu, Ling-ling; Yu, Min; Qian, Ying

    2014-05-01

    Our previous work has demonstrated that piracetam inhibited the decrease in amino acid content induced by chronic hypoperfusion, ameliorated the dysfunction of learning and memory in a hypoperfusion rat model, down-regulated P53, and BAX protein, facilitated the synaptic plasticity, and may be helpful in the treatment of vascular dementia. To explore the precise mechanism, the present study further evaluated effects of piracetam on Oxygen and glucose deprivation (OGD)-induced neuronal damage in rat primary cortical cells. The addition of piracetam to the cultured cells 12 h before OGD for 4 h significantly reduced neuronal damage as determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and lactate dehydrogenase release experiments. Piracetam also lowered the levels of malondialdehyde, nitrogen monoxidum, and xanthine oxidase which was increased in the OGD cells, and enhanced the activities of superoxide dismutase and glutathione peroxidase, which were decreased in the OGD cells. We also demonstrated that piracetam could decrease glutamate and aspartate release when cortical cells were subjected to OGD. Furthermore, Western blot study demonstrated that piracetam attenuated the increased expression of P53 and BAX protein in OGD cells. These observations demonstrated that piracetam reduced OGD-induced neuronal damage by inhibiting the oxidative stress and decreasing excitatory amino acids release and lowering P53/Bax protein expression in OGD cells.

  17. Dehydroepiandrosterone ameliorates H2O2-induced Leydig cells oxidation damage and apoptosis through inhibition of ROS production and activation of PI3K/Akt pathways.

    PubMed

    Ding, Xiao; Wang, Dian; Li, Longlong; Ma, Haitian

    2016-01-01

    Dehydroepiandrosterone (DHEA) is widely used as a nutritional supplement, and administration of DHEA produces a number of beneficial effects in the elderly. Many researchers have suggested that DHEA exerts it function after conversion into more biologically active hormones in peripheral target cells. The actions of DHEA in Leydig cells, a major target cell of DHEA biotransformation in males, are not clear. The present study found that DHEA increased cell viability and decreased reactive oxygen species (ROS) and malondialdehyde contents in H2O2-induced Leydig cells. DHEA significantly increased the activities of superoxide dismutase, catalase and peroxidase, and decreased the DNA damage in H2O2-induced Leydig cells. Apoptosis was significant decreased in H2O2-induced Leydig cells after DHEA treatment. DHEA inhibited the loss of mitochondrial membrane potential (ΔΨm) and the upregulation of the caspase-3 protein level induced by H2O2 in Leydig cells. DHEA also reversed the decrease in PI3K and p-Akt protein levels induced by H2O2. These data showed that DHEA could ameliorate H2O2-induced oxidative damage by increasing anti-oxidative enzyme activities, which resulted in reduced ROS content, and decreased apoptosis, mainly by preventing the loss of ΔΨm and inhibiting caspase-3 protein levels via activation of PI3K/Akt signaling pathways. These results increase our understanding of the molecular mechanism of the anti-ageing effect of DHEA.

  18. 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

  19. Asiaticoside ameliorates β-amyloid-induced learning and memory deficits in rats by inhibiting mitochondrial apoptosis and reducing inflammatory factors

    PubMed Central

    Zhang, Zhuo; Li, Xiaobin; Li, Duo; Luo, Mao; Li, Yongjie; Song, Li; Jiang, Xian

    2017-01-01

    The present study aimed to investigate the effects of asiaticoside (AS) on the pathology and associated mechanisms of β-amyloid (Aβ)-induced Alzheimer's disease (AD) in rats. An AD rat model was established by lateral intracerebroventricular injection of Aβ 1–42 oligomers. Learning and memory function were evaluated by Morris water maze (MWM) test. In addition, hematoxylin and eosin (H&E) staining, transmission electron microscopy (TEM), immunohistochemistry, ELISA and western blot analysis were performed to evaluate the disease pathogenesis. The results indicated that AS exerted protective effects in rats treated with Aβ oligomers, in a dose-dependent manner, as evidenced by the improved learning and memory function in the MWM test. In addition, H&E staining of hippocampal tissue showed that the histological structure was damaged in the model group, which was restored by AS treatment. Aβ deposition was dramatically increased in the model group, and the pathological changes were reversed by AS treatment. TEM revealed that the subcellular structure was injured by Aβ oligomers, however, the structure was ameliorated by AS treatment. Furthermore, AS was found to reduce the elevated levels of pro-inflammatory cytokines, interleukin-6 and tumor necrosis factor-α, in the brains of Aβ-treated rats. In addition, AS treatment resulted in a significant decrease in the expression of caspases-3, whereas the expression of B-cell lymphoma-2 was significantly increased, in these Aβ-treated rats. According to the findings of the observed study, AS has a marked protective effect on Aβ-induced AD pathology, and the underlying mechanism may be associated with the alleviation of the mitochondrial injuries, the anti-inflammatory activities, and the influence on the expression levels of apoptosis-associated proteins. PMID:28352309

  20. Hsp90 inhibition ameliorates CD4+ T cell‐mediated acute Graft versus Host disease in mice

    PubMed Central

    Kerkau, Thomas; Werner, Sandra; Wolf, Nelli; Winter, Nadine; Hünig, Thomas; Einsele, Hermann; Topp, Max S.; Beyersdorf, Niklas

    2016-01-01

    Abstract Introduction For many patients with leukemia only allogeneic bone marrow transplantion provides a chance of cure. Co‐transplanted mature donor T cells mediate the desired Graft versus Tumor (GvT) effect required to destroy residual leukemic cells. The donor T cells very often, however, also attack healthy tissue of the patient inducing acute Graft versus Host Disease (aGvHD)—a potentially life‐threatening complication. Methods Therefore, we used the well established C57BL/6 into BALB/c mouse aGvHD model to evaluate whether pharmacological inhibition of heat shock protein 90 (Hsp90) would protect the mice from aGvHD. Results Treatment of the BALB/c recipient mice from day 0 to +2 after allogeneic CD4+ T cell transplantation with the Hsp90 inhibitor 17‐(dimethylaminoethylamino)‐17‐demethoxygeldanamycin (DMAG) partially protected the mice from aGvHD. DMAG treatment was, however, insufficient to prolong overall survival of leukemia‐bearing mice after transplantation of allogeneic CD4+ and CD8+ T cells. Ex vivo analyses and in vitro experiments revealed that DMAG primarily inhibits conventional CD4+ T cells with a relative resistance of CD4+ regulatory and CD8+ T cells toward Hsp90 inhibition. Conclusions Our data, thus, suggest that Hsp90 inhibition might constitute a novel approach to reduce aGvHD in patients without abrogating the desired GvT effect. PMID:27980780

  1. Riluzole But Not Melatonin Ameliorates Acute Motor Neuron Degeneration and Moderately Inhibits SOD1-Mediated Excitotoxicity Induced Disrupted Mitochondrial Ca2+ Signaling in Amyotrophic Lateral Sclerosis

    PubMed Central

    Jaiswal, Manoj Kumar

    2017-01-01

    Selective motoneurons (MNs) degeneration in the brain stem, hypoglossal motoneurons (HMNs), and the spinal cord resulting in patients paralysis and eventual death are prominent features of amyotrophic lateral sclerosis (ALS). Previous studies have suggested that mitochondrial respiratory impairment, low Ca2+ buffering and homeostasis and excitotoxicity are the pathological phenotypes found in mice, and cell culture models of familial ALS (fALS) linked with Cu/Zn-superoxide dismutase 1 (SOD1) mutation. In our study, we aimed to understand the impact of riluzole and melatonin on excitotoxicity, neuronal protection and Ca2+ signaling in individual HMNs ex vivo in symptomatic adult ALS mouse brain stem slice preparations and in WT and SOD1-G93A transfected SH-SY5Y neuroblastoma cell line using fluorescence microscopy, calcium imaging with high speed charged coupled device camera, together with immunohistochemistry, cell survival assay and histology. In our experiments, riluzole but not melatonin ameliorates MNs degeneration and moderately inhibit excitotoxicity and cell death in SH-SY5YWT or SH-SY5YG93A cell lines induced by complex IV blocker sodium azide. In brain stem slice preparations, riluzole significantly inhibit HMNs cell death induced by inhibiting the mitochondrial electron transport chain by Na-azide. In the HMNs of brainstem slice prepared from adult (14–15 weeks) WT, and corresponding symptomatic SOD1G93A mice, we measured the effect of riluzole and melatonin on [Ca2+]i using fura-2 AM ratiometric calcium imaging in individual MNs. Riluzole caused a significant decrease in [Ca2+]i transients and reversibly inhibited [Ca2+]i transients in Fura-2 AM loaded HMNs exposed to Na-azide in adult symptomatic SOD1G93A mice. On the contrary, melatonin failed to show similar effects in the HMNs of WT and SOD1G93A mice. Intrinsic nicotinamide adenine dinucleotide (NADH) fluorescence, an indicator of mitochondrial metabolism and health in MNs, showed enhanced

  2. The Small Tellurium Compound AS101 Ameliorates Rat Crescentic Glomerulonephritis: Association with Inhibition of Macrophage Caspase-1 Activity via Very Late Antigen-4 Inactivation

    PubMed Central

    Hachmo, Yafit; Kalechman, Yona; Skornick, Itai; Gafter, Uzi; Caspi, Rachel R.; Sredni, Benjamin

    2017-01-01

    Crescentic glomerulonephritis (CGN) is the most aggressive form of GN and, if untreated, patients can progress to end-stage renal failure within weeks of presentation. The α4β1 integrin very late antigen-4 (VLA-4) is an adhesion molecule of fundamental importance to the recruitment of leukocytes in inflammation. We addressed the role of VLA-4 in mediating progressive renal injury in a rat model of CGN using a small tellurium compound. AS101 [ammonium trichloro(dioxoethylene-o,o′)tellurate]. This compound has been previously shown to uniquely inhibit VLA-4 activity by redox inactivation of adjacent thiols in the exofacial domain of VLA-4. The study shows that administration of AS101 either before or after glomerular basement membrane anti-serum injection ameliorates crescent formation or preserves renal function. This was associated with profound inhibition of critical inflammatory mediators, accompanied by decreased glomerular infiltration of macrophages. Mechanistic studies demonstrated vla-4 inactivation on glomerular macrophages both in vitro and in vivo as well as inhibition of caspase-1 activity. Importantly, this cysteine protease activity modification was dependent on VLA-4 inactivation and was associated with the anti-inflammatory activity of AS101. We propose that inactivation of macrophage VLA-4 by AS101 in vivo results in a decrease of inflammatory cytokines and chemokines produced in the glomeruli of diseased rats, resulting in decreased further macrophage recruitment and decreased extracellular matrix expansion. Thus, AS101, which is currently in clinical trials for other indications, might be beneficial for treatment of CGN. PMID:28326083

  3. Low-protein diet supplemented with ketoacids ameliorates proteinuria in 3/4 nephrectomised rats by directly inhibiting the intrarenal renin-angiotensin system.

    PubMed

    Zhang, Jia-Ying; Yin, Ying; Ni, Li; Long, Quan; You, Li; Zhang, Qian; Lin, Shan-Yan; Chen, Jing

    2016-11-01

    Low-protein diet plus ketoacids (LPD+KA) has been reported to decrease proteinuria in patients with chronic kidney diseases (CKD). However, the mechanisms have not been clarified. As over-activation of intrarenal renin-angiotensin system (RAS) has been shown to play a key role in the progression of CKD, the current study was performed to investigate the direct effects of LPD+KA on intrarenal RAS, independently of renal haemodynamics. In this study, 3/4 subtotal renal ablated rats were fed 18 % normal-protein diet (Nx-NPD), 6 % low-protein diet (Nx-LPD) or 5 % low-protein diet plus 1 % ketoacids (Nx-LPD+KA) for 12 weeks. Sham-operated rats fed NPD served as controls. The level of proteinuria and expression of renin, angiotensin II (AngII) and its type 1 receptors (AT1R) in the renal cortex were markedly higher in Nx-NPD group than in the sham group. LPD+KA significantly decreased the proteinuria and inhibited intrarenal RAS activation. To exclude renal haemodynamic impact on intrarenal RAS, the serum samples derived from the different groups were added to the culture medium of mesangial cells. It showed that the serum from Nx-NPD directly induced higher expression of AngII, AT1R, fibronectin and transforming growth factor-β1 in the mesangial cells than in the control group. Nx-LPD+KA serum significantly inhibited these abnormalities. Then, proteomics and biochemical detection suggested that the mechanisms underlying these beneficial effects of LPD+KA might be amelioration of the nutritional metabolic disorders and oxidative stress. In conclusion, LPD+KA could directly inhibit the intrarenal RAS activation, independently of renal haemodynamics, thus attenuating the proteinuria in CKD rats.

  4. 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

  5. Emodin, a natural product, selectively inhibits 11β-hydroxysteroid dehydrogenase type 1 and ameliorates metabolic disorder in diet-induced obese mice

    PubMed Central

    Feng, Ying; Huang, Su-ling; Dou, Wei; Zhang, Song; Chen, Jun-hua; Shen, Yu; Shen, Jian-hua; Leng, Ying

    2010-01-01

    BACKGROUND AND PURPOSE 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an attractive therapeutic target of type 2 diabetes and metabolic syndrome. Emodin, a natural product and active ingredient of various Chinese herbs, has been demonstrated to possess multiple biological activities. Here, we investigated the effects of emodin on 11β-HSD1 and its ability to ameliorate metabolic disorders in diet-induced obese (DIO) mice. EXPERIMENTAL APPROACH Scintillation proximity assay was performed to evaluate inhibition of emodin against recombinant human and mouse 11β-HSDs. The ability of emodin to inhibit prednisone- or dexamethasone-induced insulin resistance was investigated in C57BL/6J mice and its effect on metabolic abnormalities was observed in DIO mice. KEY RESULTS Emodin is a potent and selective 11β-HSD1 inhibitor with the IC50 of 186 and 86 nM for human and mouse 11β-HSD1, respectively. Single oral administration of emodin inhibited 11β-HSD1 activity of liver and fat significantly in mice. Emodin reversed prednisone-induced insulin resistance in mice, whereas it did not affect dexamethasone-induced insulin resistance, which confirmed its inhibitory effect on 11β-HSD1 in vivo. In DIO mice, oral administration of emodin improved insulin sensitivity and lipid metabolism, and lowered blood glucose and hepatic PEPCK, and glucose-6-phosphatase mRNA. CONCLUSIONS AND IMPLICATIONS This study demonstrated a new role for emodin as a potent and selective inhibitor of 11β-HSD1 and its beneficial effects on metabolic disorders in DIO mice. This highlights the potential value of analogues of emodin as a new class of compounds for the treatment of metabolic syndrome or type 2 diabetes. PMID:20718744

  6. 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

  7. Inhibition of activin A ameliorates skeletal muscle injury and rescues contractile properties by inducing efficient remodeling in female mice.

    PubMed

    Yaden, Benjamin C; Wang, Yan X; Wilson, Jonathan M; Culver, Alexander E; Milner, Andrea; Datta-Mannan, Amita; Shetler, Pamela; Croy, Johnny E; Dai, Guoli; Krishnan, Venkatesh

    2014-04-01

    Activin A, a member of the transforming growth factor-β superfamily, provides pleiotropic regulation of fibrosis and inflammation. We aimed at determining whether selective inhibition of activin A would provide a regenerative benefit. The introduction of activin A into normal muscle increased the expression of inflammatory and muscle atrophy genes Tnf, Tnfrsf12a, Trim63, and Fbxo32 by 3.5-, 10-, 2-, and 4-fold, respectively. The data indicate a sensitive response of muscle to activin A. Two hours after cardiotoxin-induced muscle damage, local activin A protein expression increased by threefold to ninefold. Neutralization of activin A with a specific monoclonal antibody in this muscle injury model decreased the muscle protein levels of lymphotoxin α and Il17a by 32% and 42%, respectively. Muscle histopathological features showed that activin A antibody-treated mice displayed an increase in muscle degradation, with the concomitant 9.2-fold elevation in F4/80-positive cells 3 days after injury. At the same time, the number of Pax7/Myod1-positive cells also increased, indicative of potentiated muscle precursor activation. Ultimately, activin A inhibition resulted in rapid recovery of muscle contractile properties indicated by a restoration of maximum and specific force. In summary, selective inhibition of activin A with a monoclonal antibody in muscle injury leads to the early onset of tissue degradation and subsequent enhanced myogenesis, thereby accelerating muscle repair and functional recovery.

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

    PubMed Central

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

    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

  9. 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.

  10. Local disruption of the celiac ganglion inhibits substance P release and ameliorates caerulein-induced pancreatitis in rats.

    PubMed

    Noble, Marc D; Romac, Joelle; Wang, Yu; Hsu, Jay; Humphrey, John E; Liddle, Rodger A

    2006-07-01

    Primary sensory neurons of the C and Adelta subtypes express the vanilloid capsaicin receptor TRPV1 and contain proinflammatory peptides such as substance P (SP) that mediate neurogenic inflammation. Pancreatic injury stimulates these neurons causing the release of SP in the pancreas resulting in pancreatic edema and neutrophil infiltration that contributes to pancreatitis. Axons of primary sensory neurons innervating the pancreas course through the celiac ganglion. We hypothesized that disruption of the celiac ganglion by surgical excision or inhibition of C and Adelta fibers through blockade of TRPV1 would reduce the severity of experimental pancreatitis by inhibiting neurogenic inflammation. Resiniferatoxin (RTX) is a specific TRPV1 agonist that, in high doses, selectively destroys C and Adelta fibers. Sprague-Dawley rats underwent surgical ganglionectomy or application of 10 microg RTX (vs. vehicle alone) to the celiac ganglion. One week later, pancreatitis was induced by six hourly intraperitoneal injections of caerulein (50 microg/kg). The severity of pancreatitis was assessed by serum amylase, pancreatic edema, and pancreatic myeloperoxidase (MPO) activity. SP receptor (neurokinin-1 receptor, NK-1R) internalization in acinar cells, used as an index of endogenous SP release, was assessed by immunocytochemical quantification of NK-1R endocytosis. Caerulein administration caused significant increases in pancreatic edema, serum amylase, MPO activity, and NK-1R internalization. RTX treatment and ganglionectomy significantly reduced pancreatic edema by 46% (P < 0.001) and NK-1R internalization by 80% and 51% (P < 0.001 and P < 0.05, respectively). RTX administration also significantly reduced MPO activity by 47% (P < 0.05). Neither treatment affected serum amylase, consistent with a direct effect of caerulein. These results demonstrate that disruption of or local application of RTX to the celiac ganglion inhibits SP release in the pancreas and reduces the severity

  11. 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.

  12. Zingerone ameliorates lipopolysaccharide-induced acute kidney injury by inhibiting Toll-like receptor 4 signaling pathway.

    PubMed

    Song, Jie; Fan, Hao-jun; Li, Hui; Ding, Hui; Lv, Qi; Hou, Shi-ke

    2016-02-05

    Acute kidney injury (AKI) is a serious complication of sepsis. Zingerone, a phenolic alkanone isolated from ginger, has been reported to have anti-inflammatory effect. The aim of this study was to investigate the therapeutic effects of zingerone on lipopolysaccharide (LPS)-induced AKI in mice. Zingerone was administrated 1h after LPS challenge. The production of blood urea nitrogen (BUN) and creatinine were measured in this study. The expressions of inflammatory cytokines in serum and kidney tissues were detected by ELISA. The expressions of Toll-like receptor 4 (TLR4), MyD88, TRIF, Nuclear factor Kappa B (NF-κB) and IκB were measured by Western blotting. The results showed that zingerone suppressed LPS-induced BUN, creatinine, and inflammatory cytokines TNF-α, IL-6 and IL-1β levels in a dose-dependent manner. Zingerone also attenuated LPS-induced kidney histopathologic changes. Furthermore, zingerone was found to inhibit LPS-induced TLR4, MyD88, TRIF expression and NF-κB activation. In conclusion, the current study demonstrated that zingerone inhibited LPS-induced AKI by suppressing TLR4/NF-κB signaling pathway.

  13. Apigenin ameliorates chronic mild stress-induced depressive behavior by inhibiting interleukin-1β production and NLRP3 inflammasome activation in the rat brain.

    PubMed

    Li, Ruipeng; Wang, Xiangxiang; Qin, Tingting; Qu, Rong; Ma, Shiping

    2016-01-01

    Increasing evidence suggests that inflammation and oxidative stress may contribute to the development of major depressive disorder (MDD). Apigenin, a type of bioflavonoid widely found in citrus fruits, has a number of biological actions including anti-inflammatory and antioxidant effects. Although apigenin has potential antidepressant activity, the mechanisms of this effect remain unclear. The present study aims to investigate the effects of apigenin on behavioral changes and inflammatory responses induced by chronic unpredictable mild stress (CUMS) in rats. GW9662, a selective peroxisome proliferator-activated receptor gamma (PPARγ) inhibitor, was administered 30 min before apigenin. We found that treatment with apigenin (20mg/kg, intragastrically) for three weeks remarkably ameliorated CUMS-induced behavioral abnormalities, such as decreased locomotor activity and reduced sucrose consumption. In response to oxidative stress, the NLRP3 inflammasome was activated and IL-1β secretion increased in the prefrontal cortex (PFC) of CUMS rats. However, apigenin treatment upregulated PPARγ expression and downregulated the expression of NLRP3, which subsequently downregulated the production of IL-1β. In addition, GW9662 diminished the inhibitory effects of apigenin on the NLRP3 inflammasome. In conclusion, our results demonstrate that apigenin exhibits antidepressant-like effects in CUMS rats, possibly by inhibiting IL-1β production and NLRP3 inflammasome expression via the up-regulation of PPARγ expression.

  14. Momordica charantia polysaccharides ameliorate oxidative stress, hyperlipidemia, inflammation, and apoptosis during myocardial infarction by inhibiting the NF-κB signaling pathway.

    PubMed

    Raish, Mohammad

    2017-04-01

    The polysaccharide extract of Momordica charantia has various biological activities; however, its effect on endothelial dysfunction in myocardial infarction remains unclear. To elucidate this, myocardial infarction was induced in rats using isoproterenol (ISP). Pretreatment with M. charantia polysaccharides (MCP; 150 or 300mg/kg) for 25days significantly inhibited increases in heart weight, the heart-weight-to-body-weight ratio, and infarction size, and ameliorated the increased serum levels of aspartate transaminase, creatine kinase, lactate dehydrogenase, total cholesterol, triglycerides, very-low-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. In addition, MCP enhanced the activity of superoxide dismutase, catalase, and non-protein sulfhydryls, and decreased the level of lipid peroxidation. Moreover, MCP pretreatment downregulated the expression of proinflammatory cytokines (tumor necrosis factor alpha, interleukin (IL)-6, and IL-10), inflammatory markers (nitric oxide, myeloperoxidase, and inducible nitric oxide synthase), and apoptotic markers (caspase-3 and BAX), and upregulated Bcl-2 expression. Pretreatment with MCP reduced myonecrosis, edema, and inflammatory cell infiltration, and restored cardiomyocytes architecture. This myocardial protective effect could be related to the enhancement of the antioxidant defense system through the nuclear factor kappa B (NF-kB) pathways, and to anti-apoptosis through regulation of Bax, caspase-3, and Bcl-2.

  15. 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

  16. Coenzyme Q10 Ameliorates Ultraviolet B Irradiation Induced Cell Death Through Inhibition of Mitochondrial Intrinsic Cell Death Pathway

    PubMed Central

    Jing, Li; Kumari, Santosh; Mendelev, Natalia; Li, P. Andy

    2011-01-01

    Ultraviolet B (UVB) induces cell death by increasing free radical production, activating apoptotic cell death pathways and depolarizing mitochondrial membrane potential. Coenzyme Q10 (CoQ10), an essential cofactor in the mitochondrial electron transport chain, serves as a potent antioxidant in the mitochondria. The aim of the present study is to establish whether CoQ10 is capable of protecting neuronal cells against UVB-induced damage. Murine hippocampal HT22 cells were treated with 0.01, 0.1 or 1 μM of CoQ10 3 or 24 h prior to the cells being exposed to UVB irradiation. The CoQ10 concentrations were maintained during irradiation and 24 h post-UVB. Cell viability was assessed by counting viable cells and MTT conversion assay. Superoxide production and mitochondrial membrane potential were measured using fluorescent probes. Levels of cleaved caspase-9, caspase-3, and apoptosis-inducing factor (AIF) were detected using immunocytochemistry and Western blotting. The results showed that UVB irradiation decreased cell viability and such damaging effect was associated with increased superoxide production, mitochondrial depolarization, and activation of caspase-9 and caspase-3. Treatment with CoQ10 at three different concentrations started 24 h before UVB exposure significantly increased the cell viability. The protective effect of CoQ10 was associated with reduction in superoxide production, normalization of mitochondrial membrane potential and inhibition of caspase-9 and caspase-3 activation. It is concluded that the neuroprotective effect of CoQ10 results from inhibiting oxidative stress and blocking caspase-3 dependent cell death pathway. PMID:22174665

  17. Inhibition of GSK-3 Ameliorates Aβ Pathology in an Adult-Onset Drosophila Model of Alzheimer's Disease

    PubMed Central

    Killick, Richard; Augustin, Hrvoje; Gandy, Carina; Allen, Marcus J.; Hardy, John; Lovestone, Simon; Partridge, Linda

    2010-01-01

    Aβ peptide accumulation is thought to be the primary event in the pathogenesis of Alzheimer's disease (AD), with downstream neurotoxic effects including the hyperphosphorylation of tau protein. Glycogen synthase kinase-3 (GSK-3) is increasingly implicated as playing a pivotal role in this amyloid cascade. We have developed an adult-onset Drosophila model of AD, using an inducible gene expression system to express Arctic mutant Aβ42 specifically in adult neurons, to avoid developmental effects. Aβ42 accumulated with age in these flies and they displayed increased mortality together with progressive neuronal dysfunction, but in the apparent absence of neuronal loss. This fly model can thus be used to examine the role of events during adulthood and early AD aetiology. Expression of Aβ42 in adult neurons increased GSK-3 activity, and inhibition of GSK-3 (either genetically or pharmacologically by lithium treatment) rescued Aβ42 toxicity. Aβ42 pathogenesis was also reduced by removal of endogenous fly tau; but, within the limits of detection of available methods, tau phosphorylation did not appear to be altered in flies expressing Aβ42. The GSK-3–mediated effects on Aβ42 toxicity appear to be at least in part mediated by tau-independent mechanisms, because the protective effect of lithium alone was greater than that of the removal of tau alone. Finally, Aβ42 levels were reduced upon GSK-3 inhibition, pointing to a direct role of GSK-3 in the regulation of Aβ42 peptide level, in the absence of APP processing. Our study points to the need both to identify the mechanisms by which GSK-3 modulates Aβ42 levels in the fly and to determine if similar mechanisms are present in mammals, and it supports the potential therapeutic use of GSK-3 inhibitors in AD. PMID:20824130

  18. Tyrosol ameliorates lipopolysaccharide-induced ocular inflammation in rats via inhibition of nuclear factor (NF)-κB activation

    PubMed Central

    SATO, Kazuaki; MIHARA, Yuko; KANAI, Kazutaka; YAMASHITA, Yohei; KIMURA, Yuya; ITOH, Naoyuki

    2016-01-01

    We evaluated the anti-inflammatory effect of tyrosol (Tyr) on endotoxin-induced uveitis (EIU) in rats. EIU was induced in male Lewis rats by subcutaneous injection of lipopolysaccharide (LPS). Tyr (10, 50 or 100 mg/kg) was intravenously injected 2 hr before, simultaneously and 2 hr after LPS injection. The aqueous humor (AqH) was collected 24 hr after LPS injection; the infiltrating cell number, protein concentration, and tumor necrosis factor (TNF)-α, prostaglandin (PG)-E2 and nitric oxide (NO) levels were determined. Histopathologic examination and immunohistochemical studies for nuclear factor (NF)-κB, inhibitor of κB (IκB)-α, cyclooxygenase (COX)-2 and inducible NO synthase (iNOS) in the iris–ciliary body (ICB) were performed at 3 or 24 hr after LPS injection. To further clarify the anti-inflammatory effects, RAW264.7 macrophages were stimulated with LPS in the presence or absence of Tyr. Tyr reduced, in a dose-dependent manner, the infiltrating cell number, protein concentration, and TNF-α, PGE2 and NO levels in AqH and improved histopathologic scores of EIU. Tyr also inhibited LPS-induced COX-2 and iNOS expression, IκB-α degradation and nuclear translocation of activated NF-κB in ICB. Tyr significantly suppressed inflammatory mediator production in the culture medium and COX-2 and iNOS expression and activated NF-κB translocation in LPS-stimulated RAW264.7 cells. These results suggest that Tyr suppresses ocular inflammation of EIU by inhibiting NF-κB activation and subsequent proinflammatory mediator production. PMID:27238160

  19. Notch3 Ameliorates Cardiac Fibrosis After Myocardial Infarction by Inhibiting the TGF-β1/Smad3 Pathway.

    PubMed

    Zhang, Mingming; Pan, Xietian; Zou, Qian; Xia, Yuesheng; Chen, Jiangwei; Hao, Qimeng; Wang, Haichang; Sun, Dongdong

    2016-10-01

    Notch3 and TGF-β1 signaling play a key role in the pathogenesis and progression of chronic cardiovascular disease. However, whether Notch3 protects against myocardial infarction (MI) and the underlying mechanisms remains unknown. C57BL/6 mice were randomized to be treated with Notch3 siRNA (siNotch3) or lentivirus carrying Notch3 cDNA (Notch3) before coronary artery ligation. Four weeks after constructing MI model, cardiac function and fibrosis were compared between groups. The cardiac fibroblast cells (CFs) were isolated from newborn C57BL/6 mice (1-3 days old) and transfected with lentivirus carrying Notch3 cDNA. TGF-β1 (5 ng/ml), a well-known pro-fibrotic factor, was administered 72 h after Notch3 cDNA administration in CFs. The related proteins of fibrosis such as a-smooth muscle actin (a-SMA), Type I collagen, metalloprotease (MMP)-9 and the tissue inhibitor of metalloproteinases (TIMP)-2 were examined by western blot analysis. Notch3 cDNA treatment attenuated cardiac damage and inhibited fibrosis in mice with MI. Meanwhile, Notch3 siRNA administration aggravated cardiac function damage and markedly enhanced cardiac fibrosis in mice with MI. Overexpression of Notch3 inhibited TGF-β1-induced fibroblast-myofibroblast transition of mouse cardiac fibroblast cells, as evidenced by down-regulating a-SMA and Type I collagen expression. Notch3 cDNA treatment also increased MMP-9 expression and decreased TIMP-2 expression in the TGF-β1-stimulated cells. This study indicates that Notch3 is an important protective factor for cardiac fibrosis in a MI model, and the protective effect of Notch3 is attributable to its action on TGF-β1/Smad3 signaling.

  20. 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

  1. 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

  2. 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.

  3. G-CSF ameliorates neuronal apoptosis through GSK-3β inhibition in neonatal hypoxia–ischemia in rats

    PubMed Central

    Li, Li; Klebe, Damon; Doycheva, Desislava; McBride, Devin W.; Krafft, Paul R.; Flores, Jerry; Zhou, Changman; Zhang, John H.; Tang, Jiping

    2014-01-01

    Granulocyte-colony stimulating factor (G-CSF), a growth factor, has known neuroprotective effects in a variety of experimental brain injury models. Herein we show that G-CSF administration attenuates neuronal apoptosis after neonatal hypoxia-ischemia (HI) via glycogen synthase kinase-3β (GSK-3β) inhibition. Ten day old Sprague-Dawley rat pups (n=157) were subjected to unilateral carotid artery ligation followed by 2.5hrs of hypoxia or sham surgery. HI animals received control siRNA, GSK-3β siRNA (4μL/pup), G-CSF (50μg/kg), G-CSF combined with 0.1 or 0.4nM G-CSF receptor (G-CSFR) siRNA, phosphatidylinositol 3-kinase (PI3K) inhibitor Wortmannin (86ng/pup), or DMSO (vehicle for Wortmannin). Pups were euthanized 48hrs post-HI to quantify brain infarct volume. G-CSFR, activated Akt (p-Akt), activated GSK-3β (p-GSK-3β), Cleaved Caspase-3 (CC3), Bcl-2, and Bax were quantified using Western blot analysis and the localizations of each was visualized via immunofluorescence staining. Neuronal cell death was determined using terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling (TUNEL). Our results showed p-GSK-3β increased after HI until its peak at 48hrs post-ictus, and both GSK-3β siRNA and G-CSF administration reduced p-GSK-3β expression, as well as infarct volume. p-GSK-3β and CC3 were generally co-localized in neurons. Furthermore, G-CSF increased p-Akt expression and the Bcl-2/Bax ratio and also decreased p-GSK-3β and CC3 expression levels in the ipsilateral hemisphere, which were all reversed by G-CSFR siRNA, Wortmannin, and GSK-3β siRNA. In conclusion, G-CSF attenuated caspase activation and reduced brain injury by inhibiting GSK-3β activity after experimental HI in rat pups. This neuroprotective effect was abolished by both G-CSFR siRNA and Wortmannin. PMID:25448005

  4. Arjunolic acid ameliorates reactive oxygen species via inhibition of p47phox-serine phosphorylation and mitochondrial dysfunction

    PubMed Central

    Miriyala, Sumitra; Chandra, Mini; Maxey, Benjamin; Day, Alicia; St. Clair, Daret K.; Panchatcharam, Manikandan

    2015-01-01

    Impaired cardiovascular function during acute myocardial infarction (MI) is partly associated with recruitment of activated polymorphonuclear neutrophils. The protective role of arjunolic acid (AA; 2:3:23-Trihydroxy olean-12-en-28-oic acid) is studied in the modulation of neutrophil functions in vitro by measuring the reactive oxygen species (ROS) generation. Neutrophils were isolated from normal and acute MI mice to find out the efficacy of AA in reducing oxidative stress. Stimulation of neutrophils with phorbol-12-myristate-13-acetate (PMA) resulted in an oxidative burst of superoxide anion (O2•−) and enhanced release of lysosomal enzymes. The treatment of neutrophils with PMA induced phosphorylation of Ser345 on p47phox, a cytosolic component of NADPH oxidase. Furthermore, we observed activated ERK induced phosphorylation of Ser345 in MI neutrophils. Treatment with AA significantly inhibited the phosphorylation of P47phox and ERK in the stimulated controls and MI neutrophils. Oxidative phosphorylation activities in MI cells were lower than in control, while the glycolysis rates were elevated in MI cells compared to the control. In addition, we observed AA decreased intracellular oxidative stress and reduced the levels of O2•− in neutrophils. This study therefore identifies targets for AA in activated neutrophils mediated by the MAPK pathway on p47phox involved in ROS generation. PMID:26319153

  5. Restoring GM1 ganglioside expression ameliorates axonal outgrowth inhibition and cognitive impairments induced by blast traumatic brain injury

    PubMed Central

    Rubovitch, Vardit; Zilberstein, Yael; Chapman, Joab; Schreiber, Shaul; Pick, Chaim G.

    2017-01-01

    Blast induced traumatic brain injury (B-TBI) may cause various degrees of cognitive and behavioral disturbances but the exact brain pathophysiology involved is poorly understood. It was previously suggested that ganglioside alteration on the axon surface as well as axonal regenerating inhibitors (ARIs) such as myelin associated glycoprotein (MAG) were involved in axonal outgrowth inhibition (AOI), leading to brain damage. GM1 ganglioside content in the brain was significantly reduced while GD1 ganglioside was not affected. The axonal regeneration was also reduced as seen by the phosphorylated NF-H expression. Moreover, B-TBI induced a significant elevation in MAG expression in the brains of the injured mice. The blast injured mice exhibited a significant decline in spatial memory as seen by the Y-maze test. In addition, the injured mice showed pronounced damage to the visual memory (as evaluated by the Novel object recognition test). A single low dose of GM1 (2 mg/kg; IP), shortly after the injury, prevented both the cognitive and the cellular changes in the brains of the injured mice. These results enlighten part of the complicated mechanism that underlies the damage induced by B-TBI and may also suggest a potential new treatment strategy for brain injuries. PMID:28112258

  6. Silencing megalin and cubilin genes inhibits myeloma light chain endocytosis and ameliorates toxicity in human renal proximal tubule epithelial cells.

    PubMed

    Li, Min; Balamuthusamy, Saravanan; Simon, Eric E; Batuman, Vecihi

    2008-07-01

    Using target-specific short interfering (si) RNAs, we silenced the tandem endocytic receptors megalin and cubilin genes in cultured human renal proximal tubule epithelial cells. Transfection by siRNA resulted in up to 90% suppression of both megalin and cubilin protein and mRNA expression. In HK-2 cells exposed to kappa-light chain for up to 24 h, light chain endocytosis was reduced in either megalin- or cubilin-silenced cells markedly but incompletely. Simultaneous silencing of both the cubilin and megalin genes, however, resulted in near-complete inhibition of light chain endocytosis, as determined by measuring kappa-light chain protein concentration in cell cytoplasm and by flow cytometry using FITC-labeled kappa-light chain. In these cells, light chain-induced cytokine responses (interleukin-6 and monocyte chemoattractant protein-1) and epithelial-to-mesenchymal transition as well as the associated cellular and morphological alterations were also markedly suppressed. The results demonstrate that light chain endocytosis is predominantly mediated by the megalin-cubilin tandem endocytic receptor and identify endocytosis as a key step in light chain cytotoxicity. Blocking light chain endocytosis prevents its nephrotoxic effects on human kidney proximal tubule cells.

  7. 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

  8. Amelioration of sepsis by inhibiting sialidase-mediated disruption of the CD24-SiglecG interaction.

    PubMed

    Chen, Guo-Yun; Chen, Xi; King, Samantha; Cavassani, Karen A; Cheng, Jiansong; Zheng, Xincheng; Cao, Hongzhi; Yu, Hai; Qu, Jingyao; Fang, Dexing; Wu, Wei; Bai, Xue-Feng; Liu, Jin-Qing; Woodiga, Shireen A; Chen, Chong; Sun, Lei; Hogaboam, Cory M; Kunkel, Steven L; Zheng, Pan; Liu, Yang

    2011-05-01

    Suppression of inflammation is critical for effective therapy of many infectious diseases. However, the high rates of mortality caused by sepsis attest to the need to better understand the basis of the inflammatory sequelae of sepsis and to develop new options for its treatment. In mice, inflammatory responses to host danger-associated molecular patterns (DAMPs), but not to microbial pathogen-associated molecular patterns (PAMPs), are repressed by the interaction [corrected] of CD24 and SiglecG (SIGLEC10 in human). Here we use an intestinal perforation model of sepsis to show that microbial sialidases target the sialic acid-based recognition of CD24 by SiglecG/10 to exacerbate inflammation. Sialidase inhibitors protect mice against sepsis by a mechanism involving both CD24 and Siglecg, whereas mutation of either gene exacerbates sepsis. Analysis of sialidase-deficient bacterial mutants confirms the key contribution of disrupting sialic acid-based pattern recognition to microbial virulence and supports the clinical potential of sialidase inhibition for dampening inflammation caused by infection.

  9. PPAR-γ/IL-10 axis inhibits MyD88 expression and ameliorates murine polymicrobial sepsis.

    PubMed

    Ferreira, Ana Elisa; Sisti, Flavia; Sônego, Fabiane; Wang, Suojuan; Filgueiras, Luciano Ribeiro; Brandt, Stephanie; Serezani, Ana Paula Moreira; Du, Hong; Cunha, Fernando Q; Alves-Filho, Jose Carlos; Serezani, Carlos Henrique

    2014-03-01

    Polymicrobial sepsis induces organ failure and is accompanied by overwhelming inflammatory response and impairment of microbial killing. Peroxisome proliferator-activated receptor (PPAR)-γ is a nuclear receptor with pleiotropic effects on lipid metabolism, inflammation, and cell proliferation. The insulin-sensitizing drugs thiazolidinediones (TZDs) are specific PPAR-γ agonists. TZDs exert anti-inflammatory actions in different disease models, including polymicrobial sepsis. The TZD pioglitazone, which has been approved by the U.S. Food and Drug Administration, improves sepsis outcome; however, the molecular programs that mediate its effect have not been determined. In a murine model of sepsis, we now show that pioglitazone treatment improves microbial clearance and enhances neutrophil recruitment to the site of infection. We also observed reduced proinflammatory cytokine production and high IL-10 levels in pioglitazone-treated mice. These effects were associated with a decrease in STAT-1-dependent expression of MyD88 in vivo and in vitro. IL-10R blockage abolished PPAR-γ-mediated inhibition of MyD88 expression. These data demonstrate that the primary mechanism by which pioglitazone protects against polymicrobial sepsis is through the impairment of MyD88 responses. This appears to represent a novel regulatory program. In this regard, pioglitazone provides advantages as a therapeutic tool, because it improves different aspects of host defense during sepsis, ultimately enhancing survival.

  10. 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.

  11. Ginsenoside Rg5 Ameliorates Cisplatin-Induced Nephrotoxicity in Mice through Inhibition of Inflammation, Oxidative Stress, and Apoptosis

    PubMed Central

    Li, Wei; Yan, Meng-Han; Liu, Ying; Liu, Zhi; Wang, Zi; Chen, Chen; Zhang, Jing; Sun, Yin-Shi

    2016-01-01

    Although cisplatin is an effective anti-cancer agent that is widely used for treating various types of malignant solid tumors, the nephrotoxicity induced by cisplatin severely limits its clinical application. The present study was designed to explore the potential protective effect of ginsenoside Rg5, a rare ginsenoside generated during steaming ginseng, on cisplatin-induced nephrotoxicity in a mouse experimental model. The possible mechanisms underlying this nephroprotective effect were also investigated for the first time. Rg5 was given at doses of 10 and 20 mg/kg for 10 consecutive days. On Day 7, a single nephrotoxic dose of cisplatin (25 mg/kg) was injected to mice. Cisplatin administration resulted in renal dysfunction as evidenced by increase in serum creatinine (CRE) and blood urea nitrogen (BUN) levels. In addition, cisplatin increased the level of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), the makers of lipid peroxidation, and depleted glutathione (GSH) content and superoxide dismutase (SOD) activity in renal tissues. These effects were associated with the significantly increased levels of cytochrome P450 E1 (CYP2E1), 4-hydroxynonenal (4-HNE), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, nuclear factor-kappa B (NF-κB) p65, and cyclooxygenase-2 (COX-2) in renal tissues. However, pretreatment with ginsenoside Rg5 significantly attenuated the renal dysfunction, oxidative stress and inflammation response induced by cisplatin. Furthermore, ginsenoside Rg5 supplementation inhibited activation of apoptotic pathways through increasing Bcl-2 and decreasing Bax expression levels. Histopathological examination further confirmed the nephroprotective effect of Rg5. Collectively, these results clearly suggest that Rg5-mediated alleviation of cisplatin-induced nephrotoxicity may be related to its anti-oxidant, anti-apoptotic and anti-inflammatory effects. PMID:27649238

  12. Inhibiting MicroRNA-503 and MicroRNA-181d with Losartan Ameliorates Diabetic Nephropathy in KKAy Mice

    PubMed Central

    Zhu, XinWang; Zhang, CongXiao; Fan, QiuLing; Liu, XiaoDan; Yang, Gang; Jiang, Yi; Wang, LiNing

    2016-01-01

    Background Diabetic nephropathy (DN) is the most lethal diabetic microvascular complication; it is a major cause of renal failure, and an increasingly globally prominent healthcare problem. Material/Methods To identify susceptible microRNAs for the pathogenesis of DN and the targets of losartan treatment, microRNA arrays were employed to survey the glomerular microRNA expression profiles of KKAy mice treated with or without losartan. KKAy mice were assigned to either a losartan-treated group or a non-treatment group, with C57BL/6 mice used as a normal control. Twelve weeks after treatment, glomeruli from the mice were isolated. MicroRNA expression profiles were analyzed using microRNA arrays. Real-time PCR was used to confirm the results. Results Losartan treatment improved albuminuria and the pathological lesions of KKAy mice. The expression of 10 microRNAs was higher, and the expression of 12 microRNAs was lower in the glomeruli of the KKAy untreated mice than that of the CL57BL/6 mice. The expression of 4 microRNAs was down-regulated in the glomeruli of the KKAy losartan-treated mice compared to that of the untreated mice. The expression of miRNA-503 and miRNA-181d was apparently higher in the glomeruli of the KKAy untreated mice, and was inhibited by losartan treatment. Conclusions The over-expression of miR-503 and miR-181d in glomeruli of KKAy mice may be responsible for the pathogenesis of DN and are potential therapeutic targets for DN. PMID:27770539

  13. Acanthopanax versus 3-Methyladenine Ameliorates Sodium Taurocholate-Induced Severe Acute Pancreatitis by Inhibiting the Autophagic Pathway in Rats

    PubMed Central

    Zhou, Guoxiong; Liu, Chun; Wei, Ronglong; Zhu, Shunxing; Xu, Yuefen; Wu, Mengjie; Miao, Qing

    2016-01-01

    Objectives. To observe the therapeutic effects of Acanthopanax and 3-methyladenine against severe acute pancreatitis (SAP). Methods. Sodium taurocholate-induced SAP rats were equally randomized into a SAP group, an Acanthopanax group, and a 3-methyladenine group. Serum amylase levels were determined by ELISA; protein and mRNA expression levels of nucleus nuclear factor kappa B (NF-κB) p65, light chain 3II (LC3-II), and Beclin-1 and mRNA expression levels of Class III phosphatidylinositol 3-kinase (PI3K-III) in pancreas tissue were detected by Western blot and quantitative real-time PCR, respectively; mortality and pathological change of the pancreas were observed at 3, 12, and 24 h after operation. Results. There was no significant difference in mortality between SAP group and both treatment groups (P > 0.05). Serum amylase levels, protein, and mRNA expression levels of nucleus NF-κB p65, LC3-II, and Beclin-1 protein, mRNA expression levels of PI3K-III, and pathological score of the pancreas in both treatment groups were significantly lower than those in SAP group at 12 and 24 h after operation (P < 0.05 or 0.01). The number of autophagosomes and autophagolysosomes of pancreatic acinar cells in both treatment groups was smaller than that in SAP group at 12 and 24 h. Conclusions. Acanthopanax and 3-methyladenine had similar therapeutic effects against SAP in rats. The mechanism may be through inhibiting abnormal autophagy activation of pancreatic acinar cells. PMID:28115794

  14. Ginsenoside Rg5 Ameliorates Cisplatin-Induced Nephrotoxicity in Mice through Inhibition of Inflammation, Oxidative Stress, and Apoptosis.

    PubMed

    Li, Wei; Yan, Meng-Han; Liu, Ying; Liu, Zhi; Wang, Zi; Chen, Chen; Zhang, Jing; Sun, Yin-Shi

    2016-09-13

    Although cisplatin is an effective anti-cancer agent that is widely used for treating various types of malignant solid tumors, the nephrotoxicity induced by cisplatin severely limits its clinical application. The present study was designed to explore the potential protective effect of ginsenoside Rg5, a rare ginsenoside generated during steaming ginseng, on cisplatin-induced nephrotoxicity in a mouse experimental model. The possible mechanisms underlying this nephroprotective effect were also investigated for the first time. Rg5 was given at doses of 10 and 20 mg/kg for 10 consecutive days. On Day 7, a single nephrotoxic dose of cisplatin (25 mg/kg) was injected to mice. Cisplatin administration resulted in renal dysfunction as evidenced by increase in serum creatinine (CRE) and blood urea nitrogen (BUN) levels. In addition, cisplatin increased the level of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), the makers of lipid peroxidation, and depleted glutathione (GSH) content and superoxide dismutase (SOD) activity in renal tissues. These effects were associated with the significantly increased levels of cytochrome P450 E1 (CYP2E1), 4-hydroxynonenal (4-HNE), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, nuclear factor-kappa B (NF-κB) p65, and cyclooxygenase-2 (COX-2) in renal tissues. However, pretreatment with ginsenoside Rg5 significantly attenuated the renal dysfunction, oxidative stress and inflammation response induced by cisplatin. Furthermore, ginsenoside Rg5 supplementation inhibited activation of apoptotic pathways through increasing Bcl-2 and decreasing Bax expression levels. Histopathological examination further confirmed the nephroprotective effect of Rg5. Collectively, these results clearly suggest that Rg5-mediated alleviation of cisplatin-induced nephrotoxicity may be related to its anti-oxidant, anti-apoptotic and anti-inflammatory effects.

  15. Emodin ameliorates lipopolysaccharide-induced mastitis in mice by inhibiting activation of NF-κB and MAPKs signal pathways.

    PubMed

    Li, Depeng; Zhang, Naisheng; Cao, Yongguo; Zhang, Wen; Su, Gaoli; Sun, Yong; Liu, Zhicheng; Li, Fengyang; Liang, Dejie; Liu, Bo; Guo, Mengyao; Fu, Yunhe; Zhang, Xichen; Yang, Zhengtao

    2013-04-05

    Emodin is an anthraquinone derivative from the Chinese herb Radix et Rhizoma Rhei. It has been reported that emodin possesses a number of biological properties, such as anti-inflammatory, anti-virus, anti-bacteria, anti-tumor, and immunosuppressive properties. However, the effect of emodin on mastitis is not yet known. The aim of this study was to investigate whether emodin has protective effect against lipopolysaccharide (LPS)-induced mastitis in a mouse model. The mouse model of mastitis was induced by injection of LPS through the duct of mammary gland. Emodin was administered intraperitoneally with the dose of 1, 2, and 4 mg/kg respectively 1h before and 12h after induction of LPS. Emodin significantly reduced infiltration of neutrophilic granulocyte, activation of myeloperoxidase (MPO), concentration of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6), mRNA expression levels of TNF-α, IL-1β and IL-6, which were increased in LPS-induced mouse mastitis. In addition, emodin influenced nuclear factor kappa-B signal transduction pathway by inhibiting activation of nuclear transcription factor-kappaB (NF-κB) p65 and degradation inhibitor of NF-κB α (IκBα), and emodin also influenced mitogen activated protein kinases signal transduction pathway by depression activation of p38, extracellular signal-regulated kinase (ERK), and c-jun NH2-terminal kinase (JNK). In conclusion, these results indicated that emodin could exert beneficial effects on experimental mastitis induced by LPS and may represent a novel treatment strategy for mastitis.

  16. 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

  17. Astragaloside IV ameliorates acute pancreatitis in rats by inhibiting the activation of nuclear factor-κB

    PubMed Central

    QIU, LEI; YIN, GUOJIAN; CHENG, LI; FAN, YUTING; XIAO, WENQIN; YU, GE; XING, MIAO; JIA, RONGRONG; SUN, RUIQING; MA, XIUYING; HU, GUOYONG; WANG, XINGPENG; TANG, MAOCHUN; ZHAO, YAN

    2015-01-01

    This study aimed to investigate the effects of astragaloside IV (AS-IV; 3-O-β-D-xylopyranosyl-6-O-β-D-glucopyranosylcycloastragenol), which has been reported to have comprehensive pharmacological functions, on sodium taurocholate (NaTc)/L-arginine (L-Arg)-induced acute pancreatitis (AP) in rats in vivo and in rat pancreatic acinar cells in vitro. NaTc-induced experimental AP was induced in rats by injecting 4% NaTc (0.1 ml/100 g) in the retrograde direction of the biliopancreatic duct. L-Arg-induced experimental AP was induced in rats by 2 intraperitoneal injections of 20% L-arg (3 g/kg), with an interval of 1 h between the injections. The rats were pre-treated AS-IV (50 mg/kg) or the vehicle (DMSO) 2 h prior to the induction of AP. Enzyme-linked immunosorbent assay, H&E staining, myeloperoxidase (MPO) activity, reverse transcription-quantitative PCR, western blot analysis and immunohistochemistry were used to evaluate the effects of AS-IV on AP. The results revealed that treatment with AS-IV significantly reduced serum amylase and lipase levels, pancreatic pathological alterations, the secretion of pro-inflammatory cytokines, MPO activity, and the protein expression of nuclear factor-κB (NF-κB) in vivo. Moreover, pre-treatment with AS-IV significantly increased the expression levels of manganese superoxide dismutase and cuprum/zinc superoxide dismutase. In the in vitro experiment, treatment of the cells with AS-IV aslo reduced rat pancreatic acinar cell necrosis and nuclear NF-κB activity, and enhanced the protein expression of superoxide dismutase. In conclusion, this study indicates that the protective effects of AS-IV on experimental AP in rats may be closely related to the inhibition of NF-κB. In addition, our results indicate that AS-IV may exert potential antioxidant effects on AP. Therefore, AS-IV may be an effective therapeutic agent for AP. PMID:25604657

  18. 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

  19. Polydatin ameliorates Staphylococcus aureus-induced mastitis in mice via inhibiting TLR2-mediated activation of the p38 MAPK/NF-κB pathway

    PubMed Central

    Jiang, Kang-feng; Zhao, Gan; Deng, Gan-zhen; Wu, Hai-chong; Yin, Nan-nan; Chen, Xiu-ying; Qiu, Chang-wei; Peng, Xiu-li

    2017-01-01

    Recent studies show that Polydatin (PD) extracted from the roots of Polygonum cuspidatum Sieb, a widely used traditional Chinese remedies, possesses anti-inflammatory activity in several experimental models. In this study, we investigated the anti-inflammatory effects of PD on Staphylococcus aureus-induced mastitis in mice and elucidated the potential mechanisms. In mice with S aureus-induced mastitis, administration of PD (15, 30, 45 mg/kg, ip) or dexamethasone (Dex, 5 mg/kg, ip) significantly suppressed the infiltration of inflammatory cells, ameliorated the mammary structural damage, and inhibited the activity of myeloperoxidase, a biomarker of neutrophils accumulation. Furthermore, PD treatment dose-dependently decreased the levels of TNF-α, IL-1β, IL-6 and IL-8 in the mammary gland tissues. PD treatment also dose-dependently decreased the expression of TLR2, MyD88, IRAK1, IRAK4 and TRAF6 as well as the phosphorylation of TAK1, MKK3/6, p38 MAPK, IκB-α and NF-κB in the mammary gland tissues. In mouse mammary epithelial cells (mMECs) infected by S aureus in vitro, pretreatment with PD dose-dependently suppressed the upregulated pro-inflammatory cytokines and signaling proteins, and the nuclear translocation of NF-κB p65 and AP-1. A TLR2-neutralizing antibody mimicked PD in its suppression on S aureus-induced upregulation of MyD88, p-p38 and p-p65 levels in mMECs. PD (50, 100 μg/mL) affected neither the growth of S aureus in vitro, nor the viability of mMECs. In conclusion, PD does not exhibit antibacterial activity against S aureus, its therapeutic effects in mouse S aureus-induced mastitis depend on its ability to down-regulate pro-inflammatory cytokine levels via inhibiting TLR2-mediated activation of the p38 MAPK/NF-κB signaling pathway. PMID:27890916

  20. 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.

  1. 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

  2. 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.

  3. Limitation on Prepulse Level for Cone-Guided Fast-Ignition Inertial Confinement Fusion

    SciTech Connect

    MacPhee, A. G.; Divol, L.; Kemp, A. J.; Chen, C. D.; Chen, H.; Hey, D. S.; Henesian, M.; Key, M. H.; Le Pape, S.; Mackinnon, A. J.; Patel, P. K.; Phillips, T. W.; Tabak, M.; Town, R.; Wilks, S. C.; Akli, K. U.; Stephens, R. B.; Beg, F. N.; Wei, M. S.; Fedosejevs, R. J.

    2010-02-05

    The viability of fast-ignition (FI) inertial confinement fusion hinges on the efficient transfer of laser energy to the compressed fuel via multi-MeV electrons. Preformed plasma due to the laser prepulse strongly influences ultraintense laser plasma interactions and hot electron generation in the hollow cone of an FI target. We induced a prepulse and consequent preplasma in copper cone targets and measured the energy deposition zone of the main pulse by imaging the emitted K{sub {alpha}} radiation. Simulation of the radiation hydrodynamics of the preplasma and particle in cell modeling of the main pulse interaction agree well with the measured deposition zones and provide an insight into the energy deposition mechanism and electron distribution. It was demonstrated that a under these conditions a 100 mJ prepulse eliminates the forward going component of {approx}2-4 MeV electrons.

  4. Numerical simulation of multipolar configuration and prepulse technique to obtain spatially reverse recruitment order.

    PubMed

    Dali, Melissa; Rossel, Olivier; Guiraud, David

    2016-08-01

    In the context of functional electrical stimulation of peripheral nerves, the control of a specific motor or sensory functions may need selective stimulation to target the desired effect without others. In implanted stimulation, spatial selectivity is obtained using multipolar CUFF electrodes with specific spread of the current over each contact. Furthermore, electrical stimulation recruits large fibers before small ones, whereas the targeted function could be elicited by a specific fiber type i.e. fiber diameter. In our work, numerical simulations were used to investigate the combination of multipolar configuration and prepulses, in order to obtain spatially reverse recruitment order. Multipolar stimulation provides efficient spatial selectivity, whereas sub-threshold prepulses were used to reverse recruitment order with a reasonable increase of the injected charges. We compared several selective configurations combined with prepulses to show that some are able to guarantee both the spatial selectivity while one fiber's diameter can be preferentially activated.

  5. Hot electron temperature and coupling efficiency scaling with prepulse for cone-guided fast ignition.

    PubMed

    Ma, T; Sawada, H; Patel, P K; Chen, C D; Divol, L; Higginson, D P; Kemp, A J; Key, M H; Larson, D J; Le Pape, S; Link, A; MacPhee, A G; McLean, H S; Ping, Y; Stephens, R B; Wilks, S C; Beg, F N

    2012-03-16

    The effect of increasing prepulse energy levels on the energy spectrum and coupling into forward-going electrons is evaluated in a cone-guided fast-ignition relevant geometry using cone-wire targets irradiated with a high intensity (10(20) W/cm(2)) laser pulse. Hot electron temperature and flux are inferred from Kα images and yields using hybrid particle-in-cell simulations. A two-temperature distribution of hot electrons was required to fit the full profile, with the ratio of energy in a higher energy (MeV) component increasing with a larger prepulse. As prepulse energies were increased from 8 mJ to 1 J, overall coupling from laser to all hot electrons entering the wire was found to fall from 8.4% to 2.5% while coupling into only the 1-3 MeV electrons dropped from 0.57% to 0.03%.

  6. Artemisia princeps Pamp. Essential oil and its constituents eucalyptol and α-terpineol ameliorate bacterial vaginosis and vulvovaginal candidiasis in mice by inhibiting bacterial growth and NF-κB activation.

    PubMed

    Trinh, Hien-Trung; Lee, In-Ah; Hyun, Yang-Jin; Kim, Dong-Hyun

    2011-12-01

    To investigate the inhibitory effects of Artemisia princeps Pamp. (family Asteraceae) essential oil (APEO) and its main constituents against bacterial vaginosis and vulvovaginal candidiasis, their antimicrobial activities against Gardnerella vaginalis and Candida albicans in vitro and their anti-inflammatory effects against G. vaginalis-induced vaginosis and vulvovaginal candidiasis were examined in mice. APEO and its constituents eucalyptol and α-terpineol were found to inhibit microbe growths. α-Terpineol most potently inhibited the growths of G. vaginalis and C. albicans with MIC values of 0.06 and 0.125 % (v/v), respectively. The antimicrobial activity of α-terpineol was found to be comparable to that of clotrimazole. Intravaginal treatment with APEO, eucalyptol, or α-terpineol significantly decreased viable G. vaginalis and C. albicans numbers in the vaginal cavity and myeloperoxidase activity in mouse vaginal tissues compared with controls. These agents also inhibited the expressions of proinflammatory cytokines (IL-1 β, IL-6, TNF- α), COX-2, iNOS, and the activation of NF- κB and increased expression of the anti-inflammatory cytokine IL-10. In addition, they inhibited the expressions of proinflammatory cytokines and the activation of NF- κB in lipopolysaccharide-stimulated peritoneal macrophages, and α-terpineol most potently inhibited the expressions of proinflammatory cytokines and NF- κB activation. Based on these findings, APEO and its constituents, particularly α-terpineol, ameliorate bacterial vaginosis and vulvovaginal candidiasis by inhibiting the growths of vaginal pathogens and the activation of NF- κB.

  7. SVα-MSH, a novel α-melanocyte stimulating hormone analog, ameliorates autoimmune encephalomyelitis through inhibiting autoreactive CD4(+) T cells activation.

    PubMed

    Fang, Jie; Han, Deping; Hong, Jinsheng; Zhang, Hengshan; Ying, Ying; Tian, Yeping; Zhang, Lurong; Lin, Jianhua

    2014-04-15

    Alpha-melanocyte stimulating hormone (α-MSH) plays a crucial role in the regulation of immune and inflammatory reactions. Here we report that SVα-MSH, a novel α-MSH analog, could ameliorate the clinical severity of experimental autoimmune encephalomyelitis (EAE) in a preventive and therapeutic manner. SVα-MSH treatment induced the production of regulatory T (Treg) cells and reduced the Th17 cells in the CNS of EAE mice. SVα-MSH-treated PLP peptide 139-151-specific T cells showed a down-regulation of T cell activation markers CD69 and CD134. SVα-MSH did not induce apoptosis but blocked the G1/S phase transition, reduced the expression of cyclin E, Cdk2 and the activity of NFAT and AP-1 transcription factors. Thus, SVα-MSH acts as a novel immunotherapeutic approach in the treatment of autoimmune attack on the CNS.

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

    PubMed

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

    2012-09-01

    Brain-derived neurotrophic factor (BDNF) signalling through its receptor, TrkB is known to regulate GABAergic function and glutamic acid decarboxylase (GAD) 67 expression in neurons. Alterations in BDNF signalling 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 behavioural and neurochemical abnormalities similar to schizophrenia. In this 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.d, through drinking water) for 30 d 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 behavioural 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 signalling plays an important role in GAD67 regulation by cysteamine.

  9. Sirtuin-2 inhibition affects hippocampal functions and sodium butyrate ameliorates the reduction in novel object memory, cell proliferation, and neuroblast differentiation

    PubMed Central

    Jung, Hyo Young; Yoo, Dae Young; Kim, Jong Whi; Kim, Dae Won; Choi, Jung Hoon; Chung, Jin Young; Won, Moo-Ho; Yoon, Yeo Sung

    2016-01-01

    We investigated the effects of the sirtuin-2 (SIRT2) inhibitor AK-7 on novel object memory, cell proliferation, and neuroblast differentiation in the dentate gyrus. In addition, we also observed the relationships with sodium butyrate, a histone deacetylase inhibitor, on the hippocampal functions. To investigate the effects of AK-7 on hippocampal functions, 10-week-old C57BL/6 mice were daily injected intraperitoneally with 20 mg/kg AK-7 alone or in combination with subcutaneous administration of 300 mg/kg sodium butyrate, a histone deacetylase inhibitor, for 21 days. A novel object recognition test was conducted on days 20 (training) and 21 (testing) of treatment. Thereafter, the animals were sacrificed for immunohistochemistry for Ki67 (cell proliferation) and doublecortin (DCX, neuroblast differentiation). AK-7 administration significantly reduced the time spent exploring new objects, while treatment in combination with sodium butyrate significantly alleviated this reduction. Additionally, AK-7 administration significantly reduced the number of Ki67-positive cells and DCX-immunoreactive neuroblasts in the dentate gyrus, while the treatment in combination with sodium butyrate ameliorated these changes. This result suggests that the reduction of SIRT2 may be closely related to age-related phenotypes including novel object memory, as well as cell proliferation and neuroblast differentiation in the dentate gyrus. In addition, sodium butyrate reverses SIRT2-related age phenotypes. PMID:28053616

  10. 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.

  11. A novel human truncated IL12rβ1-Fc fusion protein ameliorates experimental autoimmune encephalomyelitis via specific binding of p40 to inhibit Th1 and Th17 cell differentiation

    PubMed Central

    Wang, Xin; Luo, Cheng; Yu, Dongmei; Wang, Yuheng; Chen, Yucong; Lei, Wen; Gao, Xiangdong; Yao, Wenbing

    2015-01-01

    Interleukin (IL)-12 and IL-23 respectively driving polarization of T helper (Th) 1 and Th17 cells has been strongly implicated in the pathogenesis of both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). In this study, we first constructed, expressed and purified a novel human truncated IL12rβ1-Fc fusion protein (tIL12rβ1/Fc) binding multiple forms of the p40 subunit of human IL-12 and IL-23. tIL12rβ1/Fc was found to effectively ameliorate MOG35–55-induced EAE through reducing the production of Th1- and Th17-polarized pro-inflammatory cytokines and suppressing inflammation and demyelination in the focused parts. Moreover, tIL12rβ1/Fc suppressed Th1 (IFN-γ+ alone) and IFN-γ+ IL-17+ as well as the population of classic Th17 (IL-17+ alone) cells in vivo. Furthermore, tIL12rβ1/Fc ameliorated EAE at the peak of disease via the inhibition of STAT pathway, thereby causing a prominent reduction of RORγt (Th17) and T-bet (Th1) expression. Notably, tIL12rβ1/Fc could increase the relative number of CD4+ Foxp3+ regulatory T cells. These findings indicates that tIL12rβ1/Fc is a novel fusion protein for specific binding multiple forms of p40 subunit to exert potent anti-inflammatory effects and provides a valuable approach for the treatment of MS and other autoimmune diseases. PMID:26384304

  12. 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

  13. Dexmedetomidine ameliorates intracerebral hemorrhage-induced memory impairment by inhibiting apoptosis and enhancing brain-derived neurotrophic factor expression in the rat hippocampus.

    PubMed

    Hwang, Lakkyong; Choi, In-Young; Kim, Sung-Eun; Ko, Il-Gyu; Shin, Mal-Soon; Kim, Chang-Ju; Kim, Sang-Hoon; Jin, Jun-Jang; Chung, Jun-Young; Yi, Jae-Woo

    2013-05-01

    Intracerebral hemorrhage (ICH) is a severe type of stroke causing neurological dysfunction with a high mortality rate. Dexmedetomidine is an agonist for α2‑adrenoreceptors with sedative, anxiolytic, analgesic and anesthetic effects. In the present study, we investigated the effects of dexmedetomidine on short‑term and spatial learning memory, as well as its effects on apoptosis following the induction of ICH in rats. A rat model of IHC was created by an injection of collagenase into the hippocampus using a stereotaxic instrument. Dexmedetomidine was administered intraperitoneally daily for 14 consecutive days, commencing 1 day after the induction of ICH. The step‑down avoidance test for short‑term memory and the radial 8‑arm maze test for spatial learning memory were conducted. Terminal deoxynucleotidyl transferase‑mediated dUTP nick end-labeling (TUNEL) assay, immunohistochemistry for caspase‑3, and western blot analysis for Bcl‑2, Bax, Bid and caspase-3 expression were performed for the detection of apoptosis in the hippocampus. Western blot analysis for the brain‑derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) was also performed for the detection of cell survival in the hippocampus. The induction of ICH deteriorated short‑term and spatial learning memory, increased apoptosis and suppressed BDNF and TrkB expression in the hippocampus. Treatment with dexmedetomidine ameliorated the ICH‑induced impairment of short‑term and spatial learning memory by suppressing apoptosis and enhancing BDNF and TrkB expression. In the normal rats, dexmedetomidine exerted no significant effects on memory function and apoptosis. The present results suggest the possibility that dexmedetomidine may be used as a therapeutic agent for the conservation of memory function in stroke patients.

  14. Lactobacillus sakei OK67 ameliorates high-fat diet-induced blood glucose intolerance and obesity in mice by inhibiting gut microbiota lipopolysaccharide production and inducing colon tight junction protein expression.

    PubMed

    Lim, Su-Min; Jeong, Jin-Ju; Woo, Kyung Hee; Han, Myung Joo; Kim, Dong-Hyun

    2016-04-01

    A high-fat diet (HFD) induces obesity and the associated increases in blood glucose and inflammation through changes in gut microbiota, endotoxemia, and increased gut permeability. To counteract this, researchers have suggested that the use of probiotics that suppress production of proinflammatory lipopolysaccharide (LPS). Here, we tested whether Lactobacillus sakei OK67, which inhibits gut microbiota LPS production selected from among the lactic acid bacteria isolated from kimchi, exerted antihypoglycemic or anti-inflammatory effects in HFD-fed mice. Mice were randomly divided into 2 groups and fed an HFD or a low-fat diet for 4 weeks. These groups were further subdivided; 1 subgroup was treated with L sakei OK67 and fed the experimental diet for 4.5 weeks, whereas the other subgroup was fed the experimental diet alone. L sakei OK67 treatment lowered HFD-elevated LPS levels in blood and colonic fluid and significantly decreased HFD-elevated fasting blood glucose levels and the area under the curve in an oral glucose tolerance test. L sakei OK67 treatment inhibited HFD-induced body and epididymal fat weight gains, suppressed HFD-induced tumor necrosis factor-α and interleukin-1β expression and nuclear factor-κB activation in the colon, and significantly increased HFD-suppressed interleukin-10 and tight junction protein expression in the colon. Oral administration of L sakei OK67 significantly downregulated HFD-induced expression of peroxisome proliferator-activated receptor γ, fatty acid synthase, and tumor necrosis factor-α in adipose tissue. In addition, L sakei OK67 treatment strongly inhibited nuclear factor-κB activation in LPS-stimulated peritoneal macrophages. We report that L sakei OK67 ameliorates HFD-induced hyperglycemia and obesity by reducing inflammation and increasing the expression of colon tight junction proteins in mice.

  15. Celastrol ameliorates HIV-1 Tat-induced inflammatory responses via NF-kappaB and AP-1 inhibition and heme oxygenase-1 induction in astrocytes

    SciTech Connect

    Youn, Gi Soo; Kwon, Dong-Joo; Ju, Sung Mi; Rhim, Hyangshuk; Bae, Yong Soo; Choi, Soo Young; Park, Jinseu

    2014-10-01

    HIV-1 Tat causes extensive neuroinflammation that may progress to AIDS-related encephalitis and dementia. Celastrol possesses various biological activities such as anti-oxidant, anti-tumor, and anti-inflammatory activities. In this study, we investigated the modulatory effects of celastrol on HIV-1 Tat-induced inflammatory responses and the molecular mechanisms underlying its action in astrocytes. Pre-treatment of CRT-MG human astroglioma cells with celastrol significantly inhibited HIV-1 Tat-induced expression of ICAM-1/VCAM-1 and subsequent monocyte adhesiveness in CRT-MG cells. In addition, celastrol suppressed HIV-1 Tat-induced expression of pro-inflammatory chemokines, such as CXCL10, IL-8, and MCP-1. Celastrol decreased HIV-1 Tat-induced activation of JNK MAPK, AP-1, and NF-κB. Furthermore, celastrol induced mRNA and protein expression of HO-1 as well as Nrf2 activation. Blockage of HO-1 expression using siRNA reversed the inhibitory effect of celastrol on HIV-1 Tat-induced inflammatory responses. These results suggest that celastrol has regulatory effects on HIV-1 Tat-induced inflammatory responses by blocking the JNK MAPK-AP-1/NF-κB signaling pathways and inducing HO-1 expression in astrocytes. - Highlights: • Celastrol suppressed HIV-1 Tat-induced expression of pro-inflammatory genes. • Celastrol inhibited HIV-1 Tat -induced activation of JNK MAPK. • Celastrol inhibited HIV-1 Tat-induced activation of both NF-κB and AP-1. • Celastrol inhibited HIV-1 Tat-induced inflammatory responses via HO-1 induction.

  16. A low toxicity synthetic cinnamaldehyde derivative ameliorates renal inflammation in mice by inhibiting NLRP3 inflammasome and its related signaling pathways.

    PubMed

    Ka, Shuk-Man; Kuoping Chao, Louis; Lin, Jung-Chen; Chen, Shui-Tein; Li, Wen-Tai; Lin, Chien-Nan; Cheng, Jen-Che; Jheng, Huei-Ling; Chen, Ann; Hua, Kuo-Feng

    2016-02-01

    Uncontrolled inflammation is a leading cause of various chronic diseases. Cinnamaldehyde (CA) is a major bioactive compound isolated from the essential oil of the leaves of Cinnamomum osmophloeum kaneh that exhibits anti-inflammatory activity; however, the use of CA is limited by its cytotoxicity. Here, we synthesized three CA derivatives and identified 4-hydroxycinnamaldehyde-galactosamine (HCAG) as a low toxicity anti-inflammatory compound in vitro (HCAG IC50 ≫ 1600 µM; CA IC50=40 µM) and in vivo. HCAG reduced pro-inflammatory mediator expression in LPS-activated macrophages by inhibiting MAPK and PKC-α/δ phosphorylation, decreasing ROS generation and reducing NF-κB activation. HCAG also reduced NLRP3 inflammasome-derived IL-1β secretion by inhibiting the ATP-mediated phosphorylation of AKT and PKC-α/δ. In a mouse model of LPS-induced renal inflammation, we observed reduced albuminuria and a mild degree of glomerular proliferation, glomerular sclerosis and periglomerular inflammation in the HCAG-treated mice compared with the vehicle-treated mice. The underlying mechanisms for these renoprotective effects involved: (1) inhibited NLRP3 inflammasome activation; (2) decreased superoxide anion levels and apoptosis; and (3) suppressed activation of NF-κB and related downstream inflammatory mediators.

  17. Hohlraum glint and laser pre-pulse detector for NIF experiments using velocity interferometer system for any reflector.

    PubMed

    Moody, J D; Clancy, T J; Frieders, G; Celliers, P M; Ralph, J; Turnbull, D P

    2014-11-01

    Laser pre-pulse and early-time laser reflection from the hohlraum wall onto the capsule (termed "glint") can cause capsule imprint and unwanted early-time shocks on indirect drive implosion experiments. In a minor modification to the existing velocity interferometer system for any reflector diagnostic on NIF a fast-response vacuum photodiode was added to detect this light. The measurements show evidence of laser pre-pulse and possible light reflection off the hohlraum wall and onto the capsule.

  18. Artesunate ameliorates severe acute pancreatitis (SAP) in rats by inhibiting expression of pro-inflammatory cytokines and Toll-like receptor 4.

    PubMed

    Cen, Yanyan; Liu, Chao; Li, Xiaoli; Yan, Zifei; Kuang, Mei; Su, Yujie; Pan, Xichun; Qin, Rongxin; Liu, Xin; Zheng, Jiang; Zhou, Hong

    2016-09-01

    Severe acute pancreatitis (SAP) is a severe clinical condition with significant morbidity and mortality. Multiple organs dysfunction (MOD) is the leading cause of SAP-related death. The over-release of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α is the underlying mechanism of MOD; however, there is no effective agent against the inflammation. Herein, artesunate (AS) was found to increase the survival of SAP rats significantly when injected with 3.5% sodium taurocholate into the biliopancreatic duct in a retrograde direction, improving their pancreatic pathology and decreasing serum amylase and pancreatic lipase activities along with substantially reduced pancreatic IL-1β and IL-6 release. In vitro, AS-pretreatment strongly inhibited IL-1β and IL-6 release and their mRNA expressions in the pancreatic acinar cells treated with lipopolysaccharide (LPS) but exerted little effect on TNF-α release. Additionally, AS reduced the mRNA expressions of Toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) p65 as well as their protein expressions in the pancreatic acinar cells. In conclusion, our results demonstrated that AS could significantly protect SAP rats, and this protection was related to the reduction of digestive enzyme activities and pro-inflammatory cytokine expressions via inhibition of TLR4/NF-κB signaling pathway. Therefore, AS may be considered as a potential therapeutic agent against SAP.

  19. Up-regulation of miR-26a promotes neurite outgrowth and ameliorates apoptosis by inhibiting PTEN in bupivacaine injured mouse dorsal root ganglia.

    PubMed

    Cui, Changlei; Xu, Gong; Qiu, Jinpeng; Fan, Xiushuang

    2015-08-01

    Local anesthetic of bupivacaine may inhibit neurite outgrowth and induce apoptosis in mouse dorsal root ganglia (DRG) neurons. In this work, we intended to investigate the functional role of microRNA 26a (miR-26a) in regulating bupivacaine-induced nerve injury in DRG neurons. DRG neurons were extracted from C57BL/6 mice and cultured in vitro. Bupivacaine was applied in vitro and it induced apoptosis, inhibited neurite growth, and significantly down-regulated miR-26a gene in DRG neurons. MiR-26a mimic was then used to up-regulate miR-26a expression in DRG neurons. We found that miR-26a up-regulation promoted neurite outgrowth and reduced apoptosis in bupivacaine-injured DRG neurons. Luciferase assay and Western blot confirmed that Phosphatase and tensin homolog (PTEN) was down-stream target of miR-26a in DRG neurons. Ectopic PTEN up-regulation was then able to reverse the protective effect of miR-26a overexpression on bupivacaine-induced nerve injury in DRG neurons. Overall, this work demonstrated that miR-26a had a functional role in regulating bupivacaine-induced nerve injury in DRG neurons. Up-regulating miR-26a to suppress PTEN signaling pathway may be an effective method to protect local anesthetic-induced nerve injury in spinal cord.

  20. Diallyl Trisulfide Inhibits Growth of NCI-H460 in Vitro and in Vivo, and Ameliorates Cisplatin-Induced Oxidative Injury in the Treatment of Lung Carcinoma in Xenograft Mice

    PubMed Central

    Jiang, Xiaoyan; Zhu, Xiaosong; Liu, Na; Xu, Hongya; Zhao, Zhongxi; Li, Siying; Li, Shanzhong; Cai, Jianhua; Cao, Jimin

    2017-01-01

    Diallyl trisulfide (DATS), an organosulfuric component of garlic oil, exhibits potential anticancer and chemopreventive effects. Cisplatin (DDP), a common chemotherapeutic agent, has provided great therapeutic contributions to treating solid tumors, but with serious side effects. Here, we verified the anti-tumor properties of DATS on lung cancer in vitro and in vivo, and evaluated synergistic effects of DATS combined with DDP on the NCI-H460 xenograft model. Significantly decreased cell viabilities, cell cycle G1 arrest, and apoptosis induction were observed in DATS treated NCI-H460 cells (p<0.05). And injection of DATS (30 or 40 mg/kg) to female Balb/c mice significantly inhibited the growth of human NCI-H460 cell tumor xenograft (p<0.001). Moreover, DATS in combination with DDP exhibited enhanced anti-tumor activity via induction of apoptosis. Apoptosis pathways were confirmed by modulation of p53, Bcl-2 family members; induction of active caspase-3/8/9 and activation of JNK- and p38-MAPK pathways. Interestedly, DATS+DDP administration exerted fewer side effects, such as suppressing the weight loss and ameliorating DDP-induced oxidative injury, especially in renal parenchyma. In addition, increased E-cadherin and decreased MMP-9 expression levels were observed in DATS-treated tumor tissues. These studies provide supports that DATS might be a potential candidate for combination with DDP in cancer treatment. PMID:28255269

  1. Diallyl Trisulfide Inhibits Growth of NCI-H460 in Vitro and in Vivo, and Ameliorates Cisplatin-Induced Oxidative Injury in the Treatment of Lung Carcinoma in Xenograft Mice.

    PubMed

    Jiang, Xiaoyan; Zhu, Xiaosong; Liu, Na; Xu, Hongya; Zhao, Zhongxi; Li, Siying; Li, Shanzhong; Cai, Jianhua; Cao, Jimin

    2017-01-01

    Diallyl trisulfide (DATS), an organosulfuric component of garlic oil, exhibits potential anticancer and chemopreventive effects. Cisplatin (DDP), a common chemotherapeutic agent, has provided great therapeutic contributions to treating solid tumors, but with serious side effects. Here, we verified the anti-tumor properties of DATS on lung cancer in vitro and in vivo, and evaluated synergistic effects of DATS combined with DDP on the NCI-H460 xenograft model. Significantly decreased cell viabilities, cell cycle G1 arrest, and apoptosis induction were observed in DATS treated NCI-H460 cells (p<0.05). And injection of DATS (30 or 40 mg/kg) to female Balb/c mice significantly inhibited the growth of human NCI-H460 cell tumor xenograft (p<0.001). Moreover, DATS in combination with DDP exhibited enhanced anti-tumor activity via induction of apoptosis. Apoptosis pathways were confirmed by modulation of p53, Bcl-2 family members; induction of active caspase-3/8/9 and activation of JNK- and p38-MAPK pathways. Interestedly, DATS+DDP administration exerted fewer side effects, such as suppressing the weight loss and ameliorating DDP-induced oxidative injury, especially in renal parenchyma. In addition, increased E-cadherin and decreased MMP-9 expression levels were observed in DATS-treated tumor tissues. These studies provide supports that DATS might be a potential candidate for combination with DDP in cancer treatment.

  2. Gallic acid ameliorates renal functions by inhibiting the activation of p38 MAPK in experimentally induced type 2 diabetic rats and cultured rat proximal tubular epithelial cells.

    PubMed

    Ahad, Amjid; Ahsan, Haseeb; Mujeeb, Mohd; Siddiqui, Waseem Ahmad

    2015-10-05

    Diabetic nephropathy (DN) is one of the leading causes of morbidity and mortality in diabetic patients that accounts for about 40% of deaths in type 2 diabetes. p38 mitogen activated protein kinase (p38 MAPK), a serine-threonine kinase, plays an important role in tissue inflammation and is known to be activated under conditions of oxidative stress and hyperglycemia. The role of p38 MAPK has been demonstrated in DN, and its inhibition has been suggested as an alternative approach in the treatment of DN. In the present study, we investigated the nephroprotective effects of an anti-inflammatory phenolic compound, gallic acid (GA, 3,4,5-trihydroxybenzoic acid), in high fat diet/streptozotocin (HFD/STZ) induce type 2 diabetic wistar albino rats. GA (25 mg/kgbw and 50 mg/kgbw, p.o.) treatment for 16 weeks post induction of diabetes led to a significant reduction in the levels of blood glucose, HbA1c, serum creatinine, blood urea nitrogen and proteinuria as well as a significant reduction in the levels of creatinine clearance. GA significantly inhibited the renal p38 MAPK and nuclear factor kappa B (N-κB) activation as well as significantly reduced the levels of renal transforming growth factor beta (TGF-β) and fibronectin. Treatment with GA resulted in a significant reduction in the serum levels of proinflammatory cytokines viz. interleukin 1 beta (IL-1β), IL-6 and tumor necrosis factor alpha (TNF-α). Moreover, GA significantly lowered renal pathology and attenuated renal oxidative stress. In cultured rat NRK 52E proximal tubular epithelial cells, GA treatment inhibited high glucose induced activation of p38 MAPK and NF-κB as well as suppressed proinflammatory cytokine synthesis. The results of the present study provide in vivo and in vitro evidences that the p38 MAPK pathway plays an important role in the pathogenesis of DN, and GA attenuates the p38 MAPK-mediated renal dysfunction in HFD/STZ induced type 2 diabetic rats.

  3. Demonstration of Pulse Switching with > 1011 Prepulse Contrast by Cascaded Optical Parametric Amplification

    NASA Astrophysics Data System (ADS)

    Haefner, Constantin; Jovanovic, Igor; Wattelier, Benoit; Barty, C. P. J.

    The use of chirped-pulse amplification (CPA) in high-energy systems allows the generation of high-peak power and ultrahigh intensity, and has led to intensities greater than 1020 W · cm-2 [1]-[3]. These systems are of especially high interest for exploring high-energy dense plasma physics and for fast ignition in inertial confinement fusion [4]. In these systems the control of the prepulses is crucial as their intensity might perturb the target before the main pulse arrives. Plasma generation thresholds of solid targets are generally of the order of 1010 W · cm-2 and hence require a contrast ratio exceeding 1010 for a 1020 W · cm-2 system. Optical parametric chirped-pulse amplification (OPCPA), a CPA technique which relies on the three-wave mixing process in a nonlinear crystal, has received much attention due to its superior characteristics for broadband amplification in high-power laser system front-ends. In fact, OPCPA operated near degeneracy and thus providing high gain while maintaining broad spectral bandwidth is increasingly replacing Ti:sapphire front-ends in Nd:glass short-pulse lasers [5]-[8]. With respect to the prepulse contrast ratio, an OPCPA system offers enormous advantages. High-gain regenerative amplifiers usually produce a train of prepulses caused by the cavity leakage due to the limited extinction ratio of the intracavity polarizer, and they thus require additional postamplification temporal pulse cleaning techniques (e.g. [9],[10]). OPCPA amplifies only a single pulse out of the oscillator pulse train resulting in a prepulse contrast enhancement equal to the total saturated gain, provided that the pump pulse duration is sufficiently short so that there is no temporal overlap of the pump pulse with preceding or subsequent pulses.

  4. Total Flavonoids from Rosa laevigata Michx Fruit Ameliorates Hepatic Ischemia/Reperfusion Injury through Inhibition of Oxidative Stress and Inflammation in Rats.

    PubMed

    Tao, Xufeng; Sun, Xiance; Xu, Lina; Yin, Lianhong; Han, Xu; Qi, Yan; Xu, Youwei; Zhao, Yanyan; Wang, Changyuan; Peng, Jinyong

    2016-07-08

    The effects of total flavonoids (TFs) from Rosa laevigata Michx fruit against liver damage and cerebral ischemia/reperfusion (I/R) injury have been reported, but its action on hepatic I/R injury remains unknown. In this work, the effects and possible mechanisms of TFs against hepatic I/R injury were examined using a 70% partial hepatic warm ischemia rat model. The results demonstrated TFs decreased serum aspartate transaminase (AST), alanine aminotransferase (ALT), myeloperoxidase (MPO), and lactate dehydrogenase (LDH) activities, improved liver histopathology and ultrastructure through hematoxylin-eosin (HE) staining and electron microscope observation. In addition, TFs significantly decreased malondialdehyde (MDA) and increased the levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), which indicated that TFs alleviated oxidative stress caused by I/R injury. RT-PCR results proved that TFs downregulated the gene levels of inflammatory factors including interleukin-1 beta (IL-1β), interleukin-1 (IL-6), and tumor necrosis factor alpha (TNF-α). Further research indicated that TF-induced hepatoprotection was completed through inhibiting TLR4/MyD88 and activating Sirt1/Nrf2 signaling pathways. Blockade of the TLR4 pathway by TFs inhibited NF-κB and AP-1 transcriptional activities and inflammatory reaction. Activation of Sirt1/Nrf2 pathway by TFs increased the protein levels of HO-1 and GST to improve oxidative stress. Collectively, these findingsconfirmed the potent effects of TFs against hepatic I/R injury, which should be developed as a candidate for the prevention of this disease.

  5. Oral administration of heat-killed Lactobacillus brevis SBC8803 ameliorates the development of dermatitis and inhibits immunoglobulin E production in atopic dermatitis model NC/Nga mice.

    PubMed

    Segawa, Shuichi; Hayashi, Atsushi; Nakakita, Yasukazu; Kaneda, Hirotaka; Watari, Junji; Yasui, Hisako

    2008-05-01

    We have previously shown that the oral administration of heat-killed Lactobacillus brevis (L. brevis) SBC8803 strain inhibits IgE production in ovalbumin (OVA)-sensitized BALB/c mice through improvement of the type-1 helper T (Th1)/Th2 balance toward Th1 dominance. Atopic dermatitis is one of the most common skin diseases and is frequently associated with elevated immunoglobulin E (IgE) antibodies against many kinds of allergens. In this study, we investigated the inhibitory effect of oral administration of L. brevis SBC8803 on the development of dermatitis and IgE elevation using the NC/Nga atopic dermatitis model mice. Male 8-week-old NC/Nga mice were sensitized by the topical application of picryl chloride to foot pads and shaved abdomen. These mice were boosted with picryl chloride by topical application onto the ears once a week for 9 weeks. The mice (n=10 per group) were fed a diet containing 0%, 0.05% or 0.5% of heat-killed L. brevis SBC8803 from 2 weeks before the first sensitization to the end of the study. Total IgE concentration in serum, clinical score, and ear thickness were periodically examined throughout the study. Finally, cytokine (interleukin (IL)-4, IL-5, IL-6, IL-10, IL-12, IFN-gamma and transforming growth factor (TGF)-beta) productions from splenocytes and Peyer's patch (PP) cells of mice were measured. Oral administration of L. brevis SBC8803 significantly inhibited IgE production and ear swelling, and suppressed the development of dermatitis in a dose-dependent manner. Immunosuppressive cytokines such as IL-10 and TGF-beta production from PP cells significantly increased in the 0.5% group compared to the control group although Th1-type and Th2-type cytokines production was not affected.

  6. Total Flavonoids from Rosa laevigata Michx Fruit Ameliorates Hepatic Ischemia/Reperfusion Injury through Inhibition of Oxidative Stress and Inflammation in Rats

    PubMed Central

    Tao, Xufeng; Sun, Xiance; Xu, Lina; Yin, Lianhong; Han, Xu; Qi, Yan; Xu, Youwei; Zhao, Yanyan; Wang, Changyuan; Peng, Jinyong

    2016-01-01

    The effects of total flavonoids (TFs) from Rosa laevigata Michx fruit against liver damage and cerebral ischemia/reperfusion (I/R) injury have been reported, but its action on hepatic I/R injury remains unknown. In this work, the effects and possible mechanisms of TFs against hepatic I/R injury were examined using a 70% partial hepatic warm ischemia rat model. The results demonstrated TFs decreased serum aspartate transaminase (AST), alanine aminotransferase (ALT), myeloperoxidase (MPO), and lactate dehydrogenase (LDH) activities, improved liver histopathology and ultrastructure through hematoxylin-eosin (HE) staining and electron microscope observation. In addition, TFs significantly decreased malondialdehyde (MDA) and increased the levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), which indicated that TFs alleviated oxidative stress caused by I/R injury. RT-PCR results proved that TFs downregulated the gene levels of inflammatory factors including interleukin-1 beta (IL-1β), interleukin-1 (IL-6), and tumor necrosis factor alpha (TNF-α). Further research indicated that TF-induced hepatoprotection was completed through inhibiting TLR4/MyD88 and activating Sirt1/Nrf2 signaling pathways. Blockade of the TLR4 pathway by TFs inhibited NF-κB and AP-1 transcriptional activities and inflammatory reaction. Activation of Sirt1/Nrf2 pathway by TFs increased the protein levels of HO-1 and GST to improve oxidative stress. Collectively, these findingsconfirmed the potent effects of TFs against hepatic I/R injury, which should be developed as a candidate for the prevention of this disease. PMID:27399769

  7. Ethanol extract of mango (Mangifera indica L.) peel inhibits α-amylase and α-glucosidase activities, and ameliorates diabetes related biochemical parameters in streptozotocin (STZ)-induced diabetic rats.

    PubMed

    Gondi, Mahendranath; Prasada Rao, U J S

    2015-12-01

    Peel is a major by-product during processing of mango fruit into pulp. Recent report indicates that the whole peel powder ameliorated diabetes. In the present study, ethanolic extract of mango peel was analysed for its bioactive compounds, evaluated for α-amylase and α-glucosidase inhibitory properties, oral glucose tolerance test, antioxidant properties, plasma insulin level and biochemical parameters related to diabetes. In addition to gallic and protocatechuic acids, the extract also had chlorogenic and ferulic acids, which were not reported earlier in mango peel extracts. The peel extract inhibited α-amylase and α-glucosidase activities, with IC50 values of 4.0 and 3.5 μg/ml. Ethanolic extract of peel showed better glucose utilization in oral glucose tolerance test. Treatment of streptozotocin-induced diabetic rats with the extract decreased fasting blood glucose, fructosamine and glycated hemoglobin levels, and increased plasma insulin level. Peel extract treatment decreased malondialdehyde level, but increased the activities of antioxidant enzymes significantly in liver and kidney compared to diabetic rats. These beneficial effects were comparable to metformin, but better than gallic acid treated diabetic rats. The beneficial effects of peel extract may be through different mechanism like increased plasma insulin levels, decreased oxidative stress and inhibition of carbohydrate hydrolyzing enzyme activities by its bioactive compounds. Thus, results suggest that the peel extract can be a potential source of nutraceutical or can be used in functional foods and this is the first report on antidiabetic properties of mango peel extract.

  8. Limitation on Pre-pulse Level for Cone-Guided Fast-Ignition ICF

    SciTech Connect

    MacPhee, A G; Akli, K U; Beg, F N; Chen, C D; Chen, H; Divol, L; Hey, D S; Freeman, R R; Henesian, M; Kemp, A J; Key, M H; Pape, S L; Link, A; Ma, T; Mackinnon, A J; Ovchinnikov, V M; Patel, P K; Phillips, T W; Stephens, R B; Tabak, M; Town, R; Van Woerkom, L D; Wei, M S; Wilks, S C

    2009-09-01

    The viability of fast-ignition (FI) inertial confinement fusion hinges on the efficient transfer of laser energy to the compressed fuel via multi-MeV electrons. Pre-formed plasma due to laser pre-pulse strongly influences ultra-intense laser plasma interactions and hot electron generation in the hollow cone of an FI target. We induced a prepulse and consequent preplasma in copper cone targets and measured the energy deposition zone of the main pulse by imaging the emitted K{sub {alpha}} radiation. An integrated simulation of radiation hydrodynamics for the pre-plasma and particle in cell for the main pulse interactions agree well with the measured deposition zones and provide an insight into the enrgy deposition mechanism and electron distribution. It was demonstrated that a under these conditions a 100mJ pre-pulse completely eliminates the forward going component of {approx}2-4MeV electrons. Consequences for cone-guided fast-ignition are discussed.

  9. Use of microsecond current prepulse for dramatic improvements of wire array Z-pinch implosion

    SciTech Connect

    Calamy, H.; Lassalle, F.; Loyen, A.; Zucchini, F.; Chittenden, J. P.; Hamann, F.; Maury, P.; Georges, A.; Bedoch, J. P.; Morell, A.

    2008-01-15

    The Sphinx machine [F. Lassalle et al., 'Status on the SPHINX machine based on the 1microsecond LTD technology'] based on microsecond linear transformer driver (LTD) technology is used to implode an aluminium wire array with an outer diameter up to 140 mm and maximum current from 3.5 to 5 MA. 700 to 800 ns implosion Z-pinch experiments are performed on this driver essentially with aluminium. Best results obtained before the improvement described in this paper were 1-3 TW radial total power, 100-300 kJ total yield, and 20-30 kJ energy above 1 keV. An auxiliary generator was added to the Sphinx machine in order to allow a multi microsecond current to be injected through the wire array load before the start of the main current. Amplitude and duration of this current prepulse are adjustable, with maxima {approx}10 kA and 50 {mu}s. This prepulse dramatically changes the ablation phase leading to an improvement of the axial homogeneity of both the implosion and the final radiating column. Total power was multiplied by a factor of 6, total yield by a factor of 2.5 with a reproducible behavior. This paper presents experimental results, magnetohydrodynamic simulations, and analysis of the effect of such a long current prepulse.

  10. Investigation of pre-pulse pumping laser for preserving temporal waveform of stimulated Raman scattering

    NASA Astrophysics Data System (ADS)

    Chen, Junchi; Su, Hongpeng; Peng, Yujie; Guo, Xiaoyang; Wang, Zhanshan; Leng, Yuxin

    2017-01-01

    A modified polarized beam combination technique is proposed for preserving the temporal waveforms of stimulated Raman scattering. 1064 nm pre-pulse pumping lasers prior to the main pumping laser with a delay time are generated and injected into a Ba(NO3)2 Raman medium to excite the crystal firstly. The influences of pre-pulse lasers with various energy levels on the temporal shapes of Raman lasers are investigated, and it is demonstrated that the temporal waveforms of the Raman laser are distorted once the energies of the pre-pulse are below and above the required energy for preserving the temporal shapes of Stokes radiation. It is also discovered that the temporal shape of the 1197 nm Raman laser cannot be perfectly preserved if the energy of the 1064 nm main laser is too low or the relative delay time is too large. Moreover, the optical conversion efficiency and Stokes laser energy obtained under pumping lasers with single and double intensity peaks are compared.

  11. Hot electron production in laser solid interactions with a controlled pre-pulse

    SciTech Connect

    Culfa, O.; Tallents, G. J.; Wagenaars, E.; Ridgers, C. P.; Dance, R. J.; Rossall, A. K.; Woolsey, N. C.; Gray, R. J.; McKenna, P.; Brown, C. D. R.; James, S. F.; Hoarty, D. J.; Booth, N.; Robinson, A. P. L.; Lancaster, K. L.; Pikuz, S. A.; Faenov, A. Ya.; Kampfer, T.; Schulze, K. S.; Uschmann, I.

    2014-04-15

    Hot electron generation plays an important role in the fast ignition approach to inertial confinement fusion (ICF) and other applications with ultra-intense lasers. Hot electrons of temperature up to 10–20 MeV have been produced by high contrast picosecond duration laser pulses focussed to intensities of ∼10{sup 20} W cm{sup −2} with a deliberate pre-pulse on solid targets using the Vulcan Petawatt Laser facility. We present measurements of the number and temperature of hot electrons obtained using an electron spectrometer. The results are correlated to the density scale length of the plasma produced by a controlled pre-pulse measured using an optical probe diagnostic. 1D simulations predict electron temperature variations with plasma density scale length in agreement with the experiment at shorter plasma scale lengths (<7.5μm), but with the experimental temperatures (13–17 MeV) dropping below the simulation values (20–25 MeV) at longer scale lengths. The experimental results show that longer interaction plasmas produced by pre-pulses enable significantly greater number of hot electrons to be produced.

  12. Apigenin protects blood-brain barrier and ameliorates early brain injury by inhibiting TLR4-mediated inflammatory pathway in subarachnoid hemorrhage rats.

    PubMed

    Zhang, Tingting; Su, Jingyuan; Guo, Bingyu; Wang, Kaiwen; Li, Xiaoming; Liang, Guobiao

    2015-09-01

    Early brain injury (EBI) following subarachnoid hemorrhage (SAH) is associated with high morbidity and mortality. Inflammation has been considered as the major contributor to brain damage after SAH. SAH induces a systemic increase in pro-inflammatory cytokines and chemokines. Disruption of blood-brain barrier (BBB) facilitates the influx of inflammatory cells. It has been reported that the activation of toll-like receptor 4 (TLR4)/NF-κB signaling pathway plays a vital role in the central nervous system diseases. Apigenin, a common plant flavonoid, possesses anti-inflammation effect. In this study, we focused on the effects of apigenin on EBI following SAH and its anti-inflammation mechanism. Our results showed that apigenin (20mg/kg) administration significantly attenuated EBI (including brain edema, BBB disruption, neurological deficient, severity of SAH, and cell apoptosis) after SAH in rats by suppressing the expression of TLR4, NF-κB and their downstream pro-inflammatory cytokines in the cortex and by up-regulating the expression of tight junction proteins of BBB. Double immunofluorescence staining demonstrated that TLR4 was activated following SAH in neurons, microglia cells, and endothelial cells but not in astrocytes. Apigenin could suppress the activation of TLR4 induced by SAH and inhibit apoptosis of cells in the cortex. These results suggested that apigenin could attenuate EBI after SAH in rats by suppressing TLR4-mediated inflammation and protecting against BBB disruption.

  13. The ligand-bound thyroid hormone receptor in macrophages ameliorates kidney injury via inhibition of nuclear factor-κB activities

    PubMed Central

    Furuya, Fumihiko; Ishii, Toshihisa; Tamura, Shogo; Takahashi, Kazuya; Kobayashi, Hidetoshi; Ichijo, Masashi; Takizawa, Soichi; Kaneshige, Masahiro; Suzuki-Inoue, Katsue; Kitamura, Kenichiro

    2017-01-01

    In chronic kidney disease (CKD) patients, inflammation plays a pivotal role in the progression of renal fibrosis. Hypothyroidism is associated with an increased occurrence of atherosclerosis and inflammation, suggesting protective roles of thyroid hormones and their receptors against inflammatory processes. The contribution of thyroid hormone receptors to macrophage differentiation has not been well documented. Here, we focused on the endogenous thyroid hormone receptor α (TRα) in macrophages and examined the role of ligand-bound TRα in macrophage polarization-mediated anti-inflammatory effects. TRα-deficient irradiated chimeric mice showed exacerbated tubulointerstitial injury in a unilateral ureteral obstruction model. Compared with wild-type macrophages, macrophages isolated from the obstructed kidneys of mice lacking TRα displayed increased expression of proinflammatory cytokines that was accompanied by enhanced nuclear translocation of p65. Comparison of TRα-deficient bone marrow-derived macrophages with wild-type macrophages confirmed the propensity of the former cells to produce excessive IL-1β levels. Co-culture of these macrophages with renal epithelial cells induced more severe damage to the epithelial cells via the IL-1 receptor. Our findings indicate that ligand-bound TRα on macrophages plays a protective role in kidney inflammation through the inhibition of NF-κB pathways, possibly by affecting the pro- and anti-inflammatory balance that controls the development of CKD. PMID:28272516

  14. NDRG2 ameliorates hepatic fibrosis by inhibiting the TGF-β1/Smad pathway and altering the MMP2/TIMP2 ratio in rats.

    PubMed

    Yang, Jiandong; Zheng, Jin; Wu, Lin; Shi, Ming; Zhang, Hongtao; Wang, Xing; Xia, Ning; Wang, Desheng; Liu, Xinping; Yao, Libo; Li, Yan; Dou, Kefeng

    2011-01-01

    Liver fibrosis is a worldwide clinical issue. It has been well established that activated hepatic stellate cells (HSCs) are responsible for excessive extracellular matrix (ECM) deposition in chronically damaged livers. The identification of key elements that control HSCs activation will help to further our understanding of liver fibrosis and improve the outcome of clinical treatment. This study demonstrates that N-Myc downstream-regulated gene 2 (NDRG2) is a potential regulator of liver fibrosis as NDRG2 mRNA and protein levels were reduced during HSCs activation. In addition, enhanced NDRG2 expression reduced Smad3 transcription and phosphorylation, which inhibited HSCs activation by blocking the TGF-β1 signal. Moreover, NDRG2 contributed to an increase in the ratio of matrix metalloproteinase 2 (MMP2) to tissue inhibitor of matrix metalloproteinase 2 (TIMP2), which may facilitate the degradation of the ECM. In dimethylnitrosamine (DMN)-induced fibrotic rat livers, adenovirus-mediated NDRG2 overexpression resulted in decreased ECM deposition and improved liver function compared with controls. In conclusion, the present findings indicate that the modulation of NDRG2 is a promising strategy for the treatment of liver fibrosis.

  15. CRISPR/dCas9-mediated Transcriptional Inhibition Ameliorates the Epigenetic Dysregulation at D4Z4 and Represses DUX4-fl in FSH Muscular Dystrophy.

    PubMed

    Himeda, Charis L; Jones, Takako I; Jones, Peter L

    2016-03-01

    Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent myopathies, affecting males and females of all ages. Both forms of the disease are linked by epigenetic derepression of the D4Z4 macrosatellite repeat array at chromosome 4q35, leading to aberrant expression of D4Z4-encoded RNAs in skeletal muscle. Production of full-length DUX4 (DUX4-fl) mRNA from the derepressed D4Z4 array results in misexpression of DUX4-FL protein and its transcriptional targets, and apoptosis, ultimately leading to accumulated muscle pathology. Returning the chromatin at the FSHD locus to its nonpathogenic, epigenetically repressed state would simultaneously affect all D4Z4 RNAs, inhibiting downstream pathogenic pathways, and is thus an attractive therapeutic strategy. Advances in CRISPR/Cas9-based genome editing make it possible to target epigenetic modifiers to an endogenous disease locus, although reports to date have focused on more typical genomic regions. Here, we demonstrate that a CRISPR/dCas9 transcriptional inhibitor can be specifically targeted to the highly repetitive FSHD macrosatellite array and alter the chromatin to repress expression of DUX4-fl in primary FSHD myocytes. These results implicate the promoter and exon 1 of DUX4 as potential therapeutic targets and demonstrate the utility of CRISPR technology for correction of the epigenetic dysregulation in FSHD.

  16. Inhibition of Glycogen Synthase Kinase-3β (GSK-3β) as potent therapeutic strategy to ameliorates L-dopa-induced dyskinesia in 6-OHDA parkinsonian rats

    PubMed Central

    Xie, Cheng-long; Lin, Jing-Ya; Wang, Mei-Hua; Zhang, Yu; Zhang, Su-fang; Wang, Xi-Jin; Liu, Zhen-Guo

    2016-01-01

    Levodopa (L-dopa) is the dominating therapy drug for exogenous dopaminergic substitution and can alleviate most of the manifestations of Parkinson’s disease (PD), but long-term therapy is associated with the emergence of L-dopa-induced dyskinesia (LID). Evidence points towards an involvement of Glycogen Synthase Kinase-3β (GSK-3β) in development of LID. In the present study, we found that animals rendered dyskinetic by L-dopa treatment, administration of TDZD8 (2mg/kg) obviously prevented the severity of AIM score, as well as improvement in motor function (P < 0.05). Moreover, the TDZD8-induced reduction in dyskinetic behavior correlated with a reduction in molecular correlates of LID. TDZD8 reduced the phosphorylation levels of tau, DARPP32, ERK and PKA protein, which represent molecular markers of LID, as well as reduced L-dopa-induced FosB mRNA and PPEB mRNA levels in the lesioned striatum. In addition, we found that TDZD8 antidyskinetic properties were overcome by D1 receptor, as pretreatment with SKF38393 (5 mg/kg, 10 mg/kg, reapectively), a D1 receptor agonist, blocked TDZD8 antidyskinetic actions. This study supported the hypothesis that GSK-3β played an important role in the development and expression of LID. Inhibition of GSK-3β with TDZD8 reduced the development of ALO AIM score and associated molecular changes in 6-OHDA-lesioned rats. PMID:26997328

  17. CRISPR/dCas9-mediated Transcriptional Inhibition Ameliorates the Epigenetic Dysregulation at D4Z4 and Represses DUX4-fl in FSH Muscular Dystrophy

    PubMed Central

    Himeda, Charis L; Jones, Takako I; Jones, Peter L

    2016-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent myopathies, affecting males and females of all ages. Both forms of the disease are linked by epigenetic derepression of the D4Z4 macrosatellite repeat array at chromosome 4q35, leading to aberrant expression of D4Z4-encoded RNAs in skeletal muscle. Production of full-length DUX4 (DUX4-fl) mRNA from the derepressed D4Z4 array results in misexpression of DUX4-FL protein and its transcriptional targets, and apoptosis, ultimately leading to accumulated muscle pathology. Returning the chromatin at the FSHD locus to its nonpathogenic, epigenetically repressed state would simultaneously affect all D4Z4 RNAs, inhibiting downstream pathogenic pathways, and is thus an attractive therapeutic strategy. Advances in CRISPR/Cas9-based genome editing make it possible to target epigenetic modifiers to an endogenous disease locus, although reports to date have focused on more typical genomic regions. Here, we demonstrate that a CRISPR/dCas9 transcriptional inhibitor can be specifically targeted to the highly repetitive FSHD macrosatellite array and alter the chromatin to repress expression of DUX4-fl in primary FSHD myocytes. These results implicate the promoter and exon 1 of DUX4 as potential therapeutic targets and demonstrate the utility of CRISPR technology for correction of the epigenetic dysregulation in FSHD. PMID:26527377

  18. The ligand-bound thyroid hormone receptor in macrophages ameliorates kidney injury via inhibition of nuclear factor-κB activities.

    PubMed

    Furuya, Fumihiko; Ishii, Toshihisa; Tamura, Shogo; Takahashi, Kazuya; Kobayashi, Hidetoshi; Ichijo, Masashi; Takizawa, Soichi; Kaneshige, Masahiro; Suzuki-Inoue, Katsue; Kitamura, Kenichiro

    2017-03-08

    In chronic kidney disease (CKD) patients, inflammation plays a pivotal role in the progression of renal fibrosis. Hypothyroidism is associated with an increased occurrence of atherosclerosis and inflammation, suggesting protective roles of thyroid hormones and their receptors against inflammatory processes. The contribution of thyroid hormone receptors to macrophage differentiation has not been well documented. Here, we focused on the endogenous thyroid hormone receptor α (TRα) in macrophages and examined the role of ligand-bound TRα in macrophage polarization-mediated anti-inflammatory effects. TRα-deficient irradiated chimeric mice showed exacerbated tubulointerstitial injury in a unilateral ureteral obstruction model. Compared with wild-type macrophages, macrophages isolated from the obstructed kidneys of mice lacking TRα displayed increased expression of proinflammatory cytokines that was accompanied by enhanced nuclear translocation of p65. Comparison of TRα-deficient bone marrow-derived macrophages with wild-type macrophages confirmed the propensity of the former cells to produce excessive IL-1β levels. Co-culture of these macrophages with renal epithelial cells induced more severe damage to the epithelial cells via the IL-1 receptor. Our findings indicate that ligand-bound TRα on macrophages plays a protective role in kidney inflammation through the inhibition of NF-κB pathways, possibly by affecting the pro- and anti-inflammatory balance that controls the development of CKD.

  19. Bofutsushosan ameliorates obesity in mice through modulating PGC-1α expression in brown adipose tissues and inhibiting inflammation in white adipose tissues.

    PubMed

    Chen, Ying-Ying; Yan, Yan; Zhao, Zheng; Shi, Mei-Jing; Zhang, Yu-Bin

    2016-06-01

    The inducible co-activator PGC-1α plays a crucial role in adaptive thermogenesis and increases energy expenditure in brown adipose tissue (BAT). Meanwhile, chronic inflammation caused by infiltrated-macrophage in the white adipose tissue (WAT) is a target for the treatment of obesity. Bofutsushosan (BF), a traditional Chinese medicine composed of 17 crude drugs, has been widely used to treat obesity in China, Japan, and other Asia countries. However, the mechanism underlying anti-obesity remains to be elucidated. In the present study, we demonstrated that BF oral administration reduced the body weight of obese mice induced by high-fat diet (HFD) and alleviated the level of biochemical markers (P < 0.05), including blood glucose (Glu), total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL-C) and insulin. Our further results also indicated that oral BF administration increased the expression of PGC-1α and UCP1 in BAT. Moreover, BF also reduced the expression of inflammatory cytokines in WAT, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). These findings suggested that the mechanism of BF against obesity was at least partially through increasing gene expression of PGC-1α and UCP1 for energy consumption in BAT and inhibiting inflammation in WAT.

  20. Celastrol ameliorates HIV-1 Tat-induced inflammatory responses via NF-kappaB and AP-1 inhibition and heme oxygenase-1 induction in astrocytes.

    PubMed

    Youn, Gi Soo; Kwon, Dong-Joo; Ju, Sung Mi; Rhim, Hyangshuk; Bae, Yong Soo; Choi, Soo Young; Park, Jinseu

    2014-10-01

    HIV-1 Tat causes extensive neuroinflammation that may progress to AIDS-related encephalitis and dementia. Celastrol possesses various biological activities such as anti-oxidant, anti-tumor, and anti-inflammatory activities. In this study, we investigated the modulatory effects of celastrol on HIV-1 Tat-induced inflammatory responses and the molecular mechanisms underlying its action in astrocytes. Pre-treatment of CRT-MG human astroglioma cells with celastrol significantly inhibited HIV-1 Tat-induced expression of ICAM-1/VCAM-1 and subsequent monocyte adhesiveness in CRT-MG cells. In addition, celastrol suppressed HIV-1 Tat-induced expression of pro-inflammatory chemokines, such as CXCL10, IL-8, and MCP-1. Celastrol decreased HIV-1 Tat-induced activation of JNK MAPK, AP-1, and NF-κB. Furthermore, celastrol induced mRNA and protein expression of HO-1 as well as Nrf2 activation. Blockage of HO-1 expression using siRNA reversed the inhibitory effect of celastrol on HIV-1 Tat-induced inflammatory responses. These results suggest that celastrol has regulatory effects on HIV-1 Tat-induced inflammatory responses by blocking the JNK MAPK-AP-1/NF-κB signaling pathways and inducing HO-1 expression in astrocytes.

  1. Inhibition of Receptor-Interacting Protein Kinase 1 with Necrostatin–1s ameliorates disease progression in elastase-induced mouse abdominal aortic aneurysm model

    PubMed Central

    Wang, Qiwei; Zhou, Ting; Liu, Zhenjie; Ren, Jun; Phan, Noel; Gupta, Kartik; Stewart, Danielle M.; Morgan, Stephanie; Assa, Carmel; Kent, K. Craig; Liu, Bo

    2017-01-01

    Abdominal aortic aneurysm (AAA) is a common aortic disease with a progressive nature. There is no approved pharmacological treatment to effectively slow aneurysm growth or prevent rupture. Necroptosis is a form of programmed necrosis that is regulated by receptor-interacting protein kinases (RIPs). We have recently demonstrated that the lack of RIP3 in mice prevented aneurysm formation. The goal of the current study is to test whether perturbing necroptosis affects progression of existing aneurysm using the RIP1 inhibitors Necrostatin-1 (Nec-1) and an optimized form of Nec-1, 7-Cl-O-Nec-1 (Nec-1s). Seven days after aneurysm induction by elastase perfusion, mice were randomly administered DMSO, Nec-1 (3.2 mg/kg/day) and Nec-1s (1.6 mg/kg/day) via intraperitoneal injection. Upon sacrifice on day 14 postaneurysm induction, the aortic expansion in the Nec-1s group (64.12 ± 4.80%) was significantly smaller than that of the DMSO group (172.80 ± 13.68%) (P < 0.05). The mean aortic diameter of Nec-1 treated mice appeared to be smaller (121.60 ± 10.40%) than the DMSO group, though the difference was not statistically significant (P = 0.1). Histologically, the aortic structure of Nec-1s-treated mice appeared normal, with continuous and organized elastin laminae and abundant αActin-expressing SMCs. Moreover, Nect-1s treatment diminished macrophage infiltration and MMP9 accumulation and increased aortic levels of tropoelastin and lysyl oxidase. Together, our data suggest that pharmacological inhibition of necroptosis with Nec-1s stabilizes pre-existing aneurysms by diminishing inflammation and promoting connective tissue repair. PMID:28186202

  2. Inhibition of Receptor-Interacting Protein Kinase 1 with Necrostatin-1s ameliorates disease progression in elastase-induced mouse abdominal aortic aneurysm model.

    PubMed

    Wang, Qiwei; Zhou, Ting; Liu, Zhenjie; Ren, Jun; Phan, Noel; Gupta, Kartik; Stewart, Danielle M; Morgan, Stephanie; Assa, Carmel; Kent, K Craig; Liu, Bo

    2017-02-10

    Abdominal aortic aneurysm (AAA) is a common aortic disease with a progressive nature. There is no approved pharmacological treatment to effectively slow aneurysm growth or prevent rupture. Necroptosis is a form of programmed necrosis that is regulated by receptor-interacting protein kinases (RIPs). We have recently demonstrated that the lack of RIP3 in mice prevented aneurysm formation. The goal of the current study is to test whether perturbing necroptosis affects progression of existing aneurysm using the RIP1 inhibitors Necrostatin-1 (Nec-1) and an optimized form of Nec-1, 7-Cl-O-Nec-1 (Nec-1s). Seven days after aneurysm induction by elastase perfusion, mice were randomly administered DMSO, Nec-1 (3.2 mg/kg/day) and Nec-1s (1.6 mg/kg/day) via intraperitoneal injection. Upon sacrifice on day 14 postaneurysm induction, the aortic expansion in the Nec-1s group (64.12 ± 4.80%) was significantly smaller than that of the DMSO group (172.80 ± 13.68%) (P < 0.05). The mean aortic diameter of Nec-1 treated mice appeared to be smaller (121.60 ± 10.40%) than the DMSO group, though the difference was not statistically significant (P = 0.1). Histologically, the aortic structure of Nec-1s-treated mice appeared normal, with continuous and organized elastin laminae and abundant αActin-expressing SMCs. Moreover, Nect-1s treatment diminished macrophage infiltration and MMP9 accumulation and increased aortic levels of tropoelastin and lysyl oxidase. Together, our data suggest that pharmacological inhibition of necroptosis with Nec-1s stabilizes pre-existing aneurysms by diminishing inflammation and promoting connective tissue repair.

  3. Silencing of galectin-1 inhibits retinal neovascularization and ameliorates retinal hypoxia in a murine model of oxygen-induced ischemic retinopathy.

    PubMed

    Yang, Ning; Zhang, Wenxi; He, Tao; Xing, Yiqiao

    2017-02-28

    Aberrant neovascularization is a consequence of inappropriate angiogenic signaling and contributes to several diseases. Although many regulators of pathogenic angiogenesis have been identified, the understanding of this process remains incomplete. Galectin-1 (Gal-1), as a homodimeric protein with a single carbohydrate-recognition domain, is implicated in several pathologic processes, including angiogenesis; however, its involvement in retinal neovascularization (RNV) remains unknown. Here, we investigated the anti-angiogenic effect of silencing Gal-1 through intravitreal injection in a mouse model of oxygen-induced retinopathy (OIR). Our results revealed that Gal-1 was overexpressed and closely related to retinal neo-vessels in OIR retinas. After silencing Gal-1 via intravitreal injection of adenoviral-Gal-1-RNA interference (Ad-Gal-1-RNAi), RNV and retinal hypoxia were significantly attenuated, indicating the anti-angiogenic effect of Gal-1 inhibition. Western blot analysis and real-time polymerase chain reaction indicated that the expression of both neuropilin-1 (Nrp-1) and B cell lymphoma-2 (Bcl-2) decreased after intravitreal injection of Ad-Gal-1-RNAi, implying the possible involvement of Nrp-1 and Bcl-2 in Gal-1-related angiogenic processes. Additionally, whole-mount fluorescence and hematoxylin and eosin staining showed that intravitreal injection of Ad-Gal-1-RNAi did not significantly disrupt the retinal vasculature and neuronal structure of room air mice. Moreover, Ad-Gal-1-RNAi transfer promoted retinal vascular sprouting and increased retinal vascular perfusion, likely through decreased phosphorylation of myosin phosphatase target protein-1. Collectively, our results demonstrated that Gal-1 functions as an important regulator in RNV and offers a promising strategy for the treatment of RNV diseases, such as proliferative diabetic retinopathy and retinopathy of prematurity.

  4. Retinoic Acid Ameliorates Pancreatic Fibrosis and Inhibits the Activation of Pancreatic Stellate Cells in Mice with Experimental Chronic Pancreatitis via Suppressing the Wnt/β-Catenin Signaling Pathway

    PubMed Central

    Yin, Guojian; Fan, Yuting; Wu, Deqing; Qiu, Lei; Yu, Ge; Xing, Miao; Hu, Guoyong; Wang, Xingpeng; Wan, Rong

    2015-01-01

    Pancreatic fibrosis, a prominent feature of chronic pancreatitis (CP), induces persistent and permanent damage in the pancreas. Pancreatic stellate cells (PSCs) provide a major source of extracellular matrix (ECM) deposition during pancreatic injury, and persistent activation of PSCs plays a vital role in the progression of pancreatic fibrosis. Retinoic acid (RA), a retinoid, has a broad range of biological functions, including regulation of cell differentiation and proliferation, attenuating progressive fibrosis of multiple organs. In the present study, we investigated the effects of RA on fibrosis in experimental CP and cultured PSCs. CP was induced in mice by repetitive cerulein injection in vivo, and mouse PSCs were isolated and activated in vitro. Suppression of pancreatic fibrosis upon administration of RA was confirmed based on reduction of histological damage, α-smooth muscle actin (α-SMA) expression and mRNA levels of β-catenin, platelet-derived growth factor (PDGF)-Rβ transforming growth factor (TGF)-βRII and collagen 1α1 in vivo. Wnt 2 and β-catenin protein levels were markedly down-regulated, while Axin 2 expression level was up-regulated in the presence of RA, both in vivo and in vitro. Nuclear translation of β-catenin was significantly decreased following RA treatment, compared with cerulein-induced CP in mice and activated PSCs. Furthermore, RA induced significant PSC apoptosis, inhibited proliferation, suppressed TCF/LEF-dependent transcriptional activity and ECM production of PSC via down-regulation of TGFβRII, PDGFRβ and collagen 1α1 in vitro. These results indicate a critical role of the Wnt/β-catenin signaling pathway in RA-induced effects on CP and PSC regulation and support the potential of RA as a suppressor of pancreatic fibrosis in mice. PMID:26556479

  5. A Grape Seed Procyanidin Extract Ameliorates Fructose-Induced Hypertriglyceridemia in Rats via Enhanced Fecal Bile Acid and Cholesterol Excretion and Inhibition of Hepatic Lipogenesis.

    PubMed

    Downing, Laura E; Heidker, Rebecca M; Caiozzi, Gianella C; Wong, Brian S; Rodriguez, Kelvin; Del Rey, Fernando; Ricketts, Marie-Louise

    2015-01-01

    The objective of this study was to determine whether a grape seed procyanidin extract (GSPE) exerts a triglyceride-lowering effect in a hyperlipidemic state using the fructose-fed rat model and to elucidate the underlying molecular mechanisms. Rats were fed either a starch control diet or a diet containing 65% fructose for 8 weeks to induce hypertriglyceridemia. During the 9th week of the study, rats were maintained on their respective diet and administered vehicle or GSPE via oral gavage for 7 days. Fructose increased serum triglyceride levels by 171% after 9 weeks, compared to control, while GSPE administration attenuated this effect, resulting in a 41% decrease. GSPE inhibited hepatic lipogenesis via down-regulation of sterol regulatory element binding protein 1c and stearoyl-CoA desaturase 1 in the fructose-fed animals. GSPE increased fecal bile acid and total lipid excretion, decreased serum bile acid levels and increased the expression of genes involved in cholesterol synthesis. However, bile acid biosynthetic gene expression was not increased in the presence of GSPE and fructose. Serum cholesterol levels remained constant, while hepatic cholesterol levels decreased. GSPE did not modulate expression of genes responsible for esterification or biliary export of the newly synthesized cholesterol, but did increase fecal cholesterol excretion, suggesting that in the presence of GSPE and fructose, the liver may secrete more free cholesterol into the plasma which may then be shunted to the proximal small intestine for direct basolateral to apical secretion and subsequent fecal excretion. Our results demonstrate that GSPE effectively lowers serum triglyceride levels in fructose-fed rats after one week administration. This study provides novel insight into the mechanistic actions of GSPE in treating hypertriglyceridemia and demonstrates that it targets hepatic de novo lipogenesis, bile acid homeostasis and non-biliary cholesterol excretion as important mechanisms for

  6. Senegenin Ameliorate Acute Lung Injury Through Reduction of Oxidative Stress and Inhibition of Inflammation in Cecal Ligation and Puncture-Induced Sepsis Rats.

    PubMed

    Liu, Chun-Hong; Zhang, Wei-Dong; Wang, Jian-Jie; Feng, Shan-Dan

    2016-04-01

    The purpose of this study was to assess the protective effect of senegenin on acute lung injury (ALI) in rats induced by sepsis. Rat ALI model was reproduced by cecal ligation and puncture (CLP). All rats were randomly divided into five groups: group 1 (control), group 2 (CLP), group 3 (CLP + senegenin 15 mg/kg), group 4 (CLP + senegenin 30 mg/kg), and group 5 (CLP + senegenin 60 mg/kg). CLP + senegenin groups received senegenin by gavage daily for consecutive 5 days, respectively, while the mice in control and CLP groups were given an equivalent volume of saline. We detected the lung wet/dry weight ratios and the histopathology of the lung. The levels of lung tissue myeloperoxidase (MPO), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) were determined. Meanwhile, the nuclear factor-kappa B (NF-κB) activation, tumor necrosis factor-alpha (TNF-α), and interleukin-1β (IL-1β) levels were studied. The results demonstrated that senegenin treatment significantly attenuated CLP-induced lung injury, including reduction of lung wet/dry weight ratio, protein leak, infiltration of leukocytes, and MPO activity. In addition, senegenin markedly decreased MDA content and increased SOD activity and GSH level. Serum levels of TNF-α and IL-1β were also decreased by senegenin administration. Furthermore, senegenin administration inhibited the nuclear translocation of NF-κB in the lungs. These findings indicate that senegenin exerts protective effects on CLP-induced septic rats. Senegenin may be a potential therapeutic agent against sepsis.

  7. Rutin ameliorates renal fibrosis and proteinuria in 5/6-nephrectomized rats by anti-oxidation and inhibiting activation of TGFβ1-smad signaling

    PubMed Central

    Han, Yu; Lu, Jin-Shan; Xu, Yong; Zhang, Lei; Hong, Bao-Fa

    2015-01-01

    Objectives: Rutin, a polyphenolic flavonoid, was reported to have beneficial effect on drug induced nephropathy. The present study aimed to introduce 5/6 nephrectomized rat model to further evaluate its renal protective effect. Methods: Adult Wistar rats were induced to develop chronic renal failure through 5/6 nephrectomy (5/6 Nx). After that, animals were treated orally with saline, rutin at 15 and 45 mg/kg, and losartan (10 mg/kg) daily for 20 weeks; sham-operated animals were also involved as control. After treatment for 8 and 20 weeks, blood and urine samples were collected for biochemical examination; all the kidney remnants were collected for histological examination. The protein levels of TGF-β1, smad2 and phosphorylated-smad2 (p-smad2) in kidney were measured. Immunohistochemistry was used to analyze the expression of TGF-β1, fibronectin and collagen IV in kidney tissues. Results: Results suggested that rutin could reduce the proteinurea, blood urine nitrogen and blood creatinine in 5/6 Nx animals significantly, as well as oxidation stress in the kidney. By histological examination, rutin administration alleviated glomerular sclerosis scores and tubulointerstitial injuries in a dose-dependent manner (P<0.01). Immunohistochemistry also suggested rutin could reduce the expression of TGF-β1, fibronectin and collagen IV in kidney tissues. By western blot, we found the rutin could reduce the TGF-β1, p-smad2 expression in the kidney tissues of rats. Conclusions: This study suggests that the rutin can improve renal function in 5/6 Nx rats effectively. Its effect may be due to its anti-oxidation and inhibiting TGFβ1-Smad signaling. PMID:26191162

  8. Expression of the alpha(2)delta subunit interferes with prepulse facilitation in cardiac L-type calcium channels.

    PubMed Central

    Platano, D; Qin, N; Noceti, F; Birnbaumer, L; Stefani, E; Olcese, R

    2000-01-01

    We investigated the role of the accessory alpha(2)delta subunit on the voltage-dependent facilitation of cardiac L-type Ca(2+) channels (alpha(1C)). alpha(1C) Channels were coexpressed in Xenopus oocytes with beta(3) and alpha(2)delta calcium channel subunits. In alpha(1C) + beta(3), the amplitude of the ionic current (measured during pulses to 10 mV) was in average approximately 1.9-fold larger after the application of a 200-ms prepulse to +80 mV. This phenomenon, commonly referred to as voltage-dependent facilitation, was not observed when alpha(2)delta was coexpressed with alpha(1C) + beta(3). In alpha(1C) + beta(3), the prepulse produced a left shift ( approximately 40 mV) of the activation curve. Instead, the activation curve for alpha(1C) + beta(3) + alpha(2)delta was minimally affected by the prepulse and had a voltage dependence very similar to the G-V curve of the alpha(1C) + beta(3) channel facilitated by the prepulse. Coexpression of alpha(2)delta with alpha(1C) + beta(3) seems to mimic the prepulse effect by shifting the activation curve toward more negative potentials, leaving little room for facilitation. The facilitation of alpha(1C) + beta(3) was associated with an increase of the charge movement. In the presence of alpha(2)delta, the charge remained unaffected after the prepulse. Coexpression of alpha(2)delta seems to set all the channels in a conformational state from where the open state can be easily reached, even without prepulse. PMID:10827975

  9. Cucumis melo ssp. Agrestis var. Agrestis Ameliorates High Fat Diet Induced Dyslipidemia in Syrian Golden Hamsters and Inhibits Adipogenesis in 3T3-L1 Adipocytes

    PubMed Central

    Shankar, Kripa; Singh, Sumit K.; Kumar, Durgesh; Varshney, Salil; Gupta, Abhishek; Rajan, Sujith; Srivastava, Ankita; Beg, Muheeb; Srivastava, Anurag Kumar; Kanojiya, Sanjeev; Mishra, Dipak K.; Gaikwad, Anil N.

    2015-01-01

    Background: Cucumis melo ssp. agrestis var. agrestis (CMA) is a wild variety of C. melo. This study aimed to explore anti-dyslipidemic and anti-adipogenic potential of CMA. Materials and Methods: For initial anti-dyslipidemic and antihyperglycemic potential of CMA fruit extract (CMFE), male Syrian golden hamsters were fed a chow or high-fat diet with or without CMFE (100 mg/kg). Further, we did fractionation of this CMFE into two fractions namely; CMA water fraction (CMWF) and CMA hexane fraction (CMHF). Phytochemical screening was done with liquid chromatography-mass spectrometry LC- (MS)/MS and direct analysis in real time-MS to detect active compounds in the fractions. Further, high-fat diet fed dyslipidemic hamsters were treated with CMWF and CMHF at 50 mg/kg for 7 days. Results: Oral administration of CMFE and both fractions (CMWF and CMHF) reduced the total cholesterol, triglycerides, low‐density lipoprotein cholesterol, and very low‐density lipoprotein-cholesterol levels in high fat diet-fed dyslipidemic hamsters. CMHF also modulated expression of genes involved in lipogenesis, lipid metabolism, and reverse cholesterol transport. Standard biochemical diagnostic tests suggested that neither of fractions causes any toxicity to hamster liver or kidneys. CMFE and CMHF also decreased oil-red-O accumulation in 3T3-L1 adipocytes. Conclusion: Based on these results, it is concluded that CMA possesses anti-dyslipidemic and anti-hyperglycemic activity along with the anti-adipogenic activity. SUMMARY The oral administration of Cucumis melo agrestis fruit extract (CMFE) and its fractions (CMWF and CMHF) improved serum lipid profile in HFD fed dyslipidemic hamsters.CMFE, CMWF and CMHF significantly attenuated body weight gain and eWAT hypertrophy.The CMHF decreased lipogenesis in both liver and adipose tissue.CMFE and CMHF also inhibited adipogenesis in 3T3-L1 adipocytes. Abbreviation used: CMA: Cucumis melo ssp. agrestis var. agrestis, CMFE: CMA fruit extract, CMWF

  10. Assessing the Comprehensive Soldier Fitness Program: Measuring Startle Response and Prepulse Inhibition

    DTIC Science & Technology

    2011-04-01

    prescribed anxiolytic (anxiety-reducing) drugs, which can artificially increase PPI and decrease startle response (Braff et al., 2001). Nicotine can...increase PPI, but dopamine agonists can have the opposite effect by reducing PPI. Fortunately, caffeine appears to have no significant effect on PPI

  11. Lasing in Ne-Like Argon Capillary Discharge at Low Current and the Effect of Current Prepulse

    SciTech Connect

    Kwek, K. H.; Tan, C. A.

    2009-01-21

    The output characteristics of saturated capillary discharge 46.9 nm Ne-like argon soft x-ray laser obtained with relatively low main discharge current of less than 20 kA, with the lowest being 9 kA. The 3 mm diameter and 200 mm long alumina capillary with Argon filling pressure range between 0.1-0.4 mbar was pumped by a discharge current with a quarter-cycle of about 40 ns. A current pulse with a typical RC shape (decay time {approx}30 {mu}s) was used as a prepulse. Measurements indicate that the laser output is affected by the timing of the application of the prepulse. This effect is most significant when the time delay between the application of the prepulse and the onset of the main current is around 2 to 4 {mu}s, and beyond these times, the effect is less significant.

  12. Influence of the main pulse and prepulse intensity on high-order harmonic generation in silver plasma ablation

    SciTech Connect

    Elouga Bom, L. B.; Kieffer, J.-C.; Ozaki, T.; Ganeev, R. A.; Suzuki, M.; Kuroda, H.

    2007-03-15

    We present experimental studies of high-order harmonic generation in silver plasma ablation performed with the Ti:sapphire laser beams of the Advanced Laser Light Source (800 nm wavelength, 360 mJ total energy). We have independently varied the intensity of the prepulse (which creates the plasma ablation) and the intensity of the main pulse (which generates the harmonics), and studied their influence on the harmonic spectrum. We show here that the presence of doubly ionized atoms in the ablation, created either by a strong prepulse intensity or with the irradiation of the main pulse, is ineffective for the generation of harmonics.

  13. D-saccharic acid-1,4-lactone ameliorates alloxan-induced diabetes mellitus and oxidative stress in rats through inhibiting pancreatic beta-cells from apoptosis via mitochondrial dependent pathway

    SciTech Connect

    Bhattacharya, Semantee; Manna, Prasenjit; Sil, Parames C.

    2011-12-15

    Oxidative stress plays a vital role in diabetic complications. To suppress the oxidative stress mediated damage in diabetic pathophysiology, a special focus has been given on naturally occurring antioxidants present in normal diet. D-saccharic acid 1,4-lactone (DSL), a derivative of D-glucaric acid, is present in many dietary plants and is known for its detoxifying and antioxidant properties. The aim of the present study was to evaluate the beneficial role of DSL against alloxan (ALX) induced diabetes in the pancreas tissue of Swiss albino rats. A dose-dependent study for DSL (20-120 mg/kg body weight) was carried out to find the effective dose of the compound in ALX-induced diabetic rats. ALX exposure elevated the blood glucose, glycosylated Hb, decreased the plasma insulin and disturbed the intra-cellular antioxidant machineries whereas oral administration of DSL at a dose of 80 mg/kg body weight restored these alterations close to normal. Investigating the mechanism of the protective activity of DSL we observed that it prevented the pancreatic {beta}-cell apoptosis via mitochondria-dependent pathway. Results showed decreased mitochondrial membrane potential, enhanced cytochrome c release in the cytosol and reciprocal regulation of Bcl-2 family proteins in the diabetic rats. These events were also found to be associated with increased level of Apaf-1, caspase 9, and caspase 3 that ultimately led to pancreatic {beta}-cell apoptosis. DSL treatment, however, counteracted these changes. In conclusion, DSL possesses the capability of ameliorating the oxidative stress in ALX-induced diabetes and thus could be a promising approach in lessening diabetic complications. Highlights: Black-Right-Pointing-Pointer Oxidative stress is suggested as a key event in the pathogenesis of diabetes. Black-Right-Pointing-Pointer D-saccharic acid 1,4-lactone (DSL) reduces the alloxan-induced diabetes mellitus. Black-Right-Pointing-Pointer DSL normalizes cellular antioxidant machineries

  14. Combined effects of pre-pulsing and target geometry on efficient EUV production from laser produced plasma experiments and modeling

    NASA Astrophysics Data System (ADS)

    Hassanein, A.; Sizyuk, T.; Sizyuk, V.; Harilal, S. S.

    2011-04-01

    Laser produced plasmas (LPP) is currently a promising source of an efficient extreme ultraviolet (EUV) photon source production for advanced lithography. Optimum laser pulse parameters with adjusted wavelength, energy, and duration for simple planar or spherical tin target can provide 2-3% conversion efficiency (CE) in laboratory experiments. These values are also in good agreement with modeling results. Additional effects such as targets with complex geometry and tin-doped targets using pre-pulsing of laser beams can significantly increase CE. Recent studies showed that such improvements in LPP system are due to reduction in laser energy losses by decreasing photons transmission (higher harmonic of Nd:YAG laser) or photons reflection (for CO2 laser). Optimization of target heating using pre-pulses or ablating low-density and nanoporous tin oxide can further improve LLP sources by creating more efficient plasma plumes and as a result increasing CE, the most important parameter for EUV sources. The second important challenge in developing LPP devices is to decrease fast ions and target debris to protect the optical collection system and increase its lifetime. We investigated the combined effects of pre-pulsing with various parameters and different target geometries on EUV conversion efficiency and on energetic ions production. The much higher reflectivity of CO2 laser from a tin target leads to two possible ways for system improvement using pre-pulses with shorter laser wavelengths or using more complex targets geometries with special grooves as developed previously by the authors.

  15. Variants near CCK receptors are associated with electrophysiological responses to prepulse startle stimuli in a Mexican American cohort

    PubMed Central

    Norden-Krichmar, Trina M.; Gizer, Ian R.; Phillips, Evelyn; Wilhelmsen, Kirk C.; Schork, Nicholas J.; Ehlers, Cindy L.

    2016-01-01

    Neurophysiological measurements of the response to prepulse and startle stimuli have been suggested to represent an important endophenotype for both substance dependence and other select psychiatric disorders. We have previously shown, in young adult Mexican Americans (MA), that presentation of a short delay acoustic prepulse, prior to the startle stimuli can elicit a late negative component at about 400 msec (N4S), in the event-related potential (ERP), recorded from frontal cortical areas. In the present study we investigated whether genetic factors associated with this endophenotype could be identified. The study included 420 (age 18 – 30 years) MA men (n=170) and women (n=250). DNA was genotyped using an Affymetrix Axiom Exome1A chip. An association analysis revealed that the CCKAR and CCKBR (cholecystokinin A and B receptor) genes each had a nearby variant that showed suggestive significance with the amplitude of the N4S component to prepulse stimuli. The neurotransmitter cholecystokinin (CCK), along with its receptors, CCKAR and CCKBR, have been previously associated with psychiatric disorders, suggesting that variants near these genes may play a role in the prepulse/startle response in this cohort. PMID:26608796

  16. A computational and functional study elicits the ameliorating effect of the Chinese herbal formula Huo Luo Xiao Ling Dan on experimental ischemia-induced myocardial injury in rats via inhibition of apoptosis

    PubMed Central

    Han, Xiang-Dong; Zhou, Zhi-Wei; Yang, Wei; Ye, Hang-Cheng; Xu, Ying-Zi; Huang, Yun-Feng; Zhang, Tong; Zhou, Shu-Feng

    2015-01-01

    rise/descent of left ventricular pressure levels. Administration of HLXLD significantly ameliorated coronary artery ligation-induced tissue damage in the left ventricle, with restored arrangement of myocardial fibers and recovered myoplasm in rats. Furthermore, HLXLD markedly increased the expression level of Bcl-2 but decreased the level of cleaved caspase 3. Taken together, administration of HLXLD attenuated acute myocardial ischemia-induced damage in cardiomyocytes and inhibited apoptotic death of cardiomyocytes, thereby exerting a cardioprotective effect in rats with IHD. These findings suggest that HLXLD may represent a promising herbal formula for the treatment of cardiovascular disease by counteracting apoptotic cell death via multiple active compounds. More studies are warranted to fully elucidate the mechanisms of action, identify the therapeutic targets, and validate the efficacy and safety of HLXLD in the treatment of IHD. PMID:25733819

  17. INTERACTION OF LASER RADIATION WITH MATTER. LASER PLASMA: Study of symmetrising action of laser prepulse on inhomogeneity of thin foil heating

    NASA Astrophysics Data System (ADS)

    Ilyasov, A. O.; Lebo, I. G.; Mikhailov, Yu A.; Rozanov, Vladislav B.; Sklizkov, G. V.; Starodub, Aleksandr N.; Tishkin, V. F.

    2005-07-01

    The results of theoretical and experimental studies of plasma heating by laser radiation having an inhomogeneous spatial structure are presented as well as the results of investigation of the symmetrising action of a laser prepulse on the inhomogeneity of heating of thin foils modelling thin-walled laser thermonuclear synthesis targets. The high efficiency of the method of ablation pressure symmetrisation by a laser prepulse is demonstrated.

  18. Effect of a short weak prepulse on laser-triggered front-surface heavy-ion acceleration

    SciTech Connect

    Bochkarev, S. G.; Bychenkov, V. Yu.; Golovin, G. V.; Uryupina, D. S.; Shulyapov, S. A.; Savel'ev, A. B.; Andriyash, A. V.

    2012-10-15

    A suppression of light-ion acceleration (from surface water contaminants) was observed when a moderate-intensity subpicosecond laser pulse was focused on a thick metal target. Simultaneously, an effective generation of high-energy multicharge ions of the target material (Fe) was experimentally observed. A numerical simulation based on the Boltzmann-Vlasov-Poisson model revealed that this is due to the very specific regime of cleaning contaminants from the target surface by the short weak prepulse preceding the main pulse by more than 10 ns and having an intensity below the surface breakdown threshold. Because this prepulse causes the contaminant layer to boil explosively, a low-density gap forms above the target surface. These conditions are consequently favorable for boosting the energy of heavy ions.

  19. 1,2,3,4,6 Penta-O-galloyl-β-d-glucose, a bioactivity guided isolated compound from Mangifera indica inhibits 11β-HSD-1 and ameliorates high fat diet-induced diabetes in C57BL/6 mice.

    PubMed

    Mohan, C G; Viswanatha, G L; Savinay, G; Rajendra, C E; Halemani, Praveen D

    2013-03-15

    Methanolic leaf extract of Mangifera indica (MEMI) was subjected to bioactivity guided fractionation in order to identify the active antidiabetic constituent. 32 fractions were evaluated for possible 11β-HSD-1 inhibition activity under in vitro conditions. The EA-7/8-9/10-4 fraction was evolved as a most potent fraction among all the fractions and it was identified as well known gallotannin compound 1,2,3,4,6 penta-O-galloyl-β-d-glucose (PGG) by spectral analysis. Based on these results the PGG was further evaluated in ex vivo 11β-HSD-1 inhibition assay and high fat diet (HFD)-induced diabetes in male C57BL/6 mice. Single dose (10, 25, 50 and 100mg/kg) of PGG and carbenoxolone (CBX) have dose dependently inhibited the 11β-HSD-1 activity in liver and adipose tissue. Furthermore, HFD appraisal to male C57BL/6 mice caused severe hyperglycemia, hypertriglyceridemia, elevated levels of plasma corticosterone and insulin, increased liver and white adipose mass with increase in body weight was observed compare to normal control. Also, oral glucose tolerance was significantly impaired compare to normal control. Interestingly, post-treatment with PGG for 21 days had alleviated the HFD-induced biochemical alterations and improved oral glucose tolerance compare to HFD-control. In conclusion, the PGG isolated from MEMI inhibits 11β-HSD-1 activity and ameliorates HFD-induced diabetes in male C57BL/6 mice.

  20. Curcumin Ameliorates the Reduction Effect of PGE2 on Fibrillar β-Amyloid Peptide (1-42)-Induced Microglial Phagocytosis through the Inhibition of EP2-PKA Signaling in N9 Microglial Cells.

    PubMed

    He, Gen-Lin; Luo, Zhen; Yang, Ju; Shen, Ting-Ting; Chen, Yi; Yang, Xue-Sen

    2016-01-01

    Inflammatory activation of microglia and β amyloid (Aβ) deposition are considered to work both independently and synergistically to contribute to the increased risk of Alzheimer's disease (AD). Recent studies indicate that long-term use of phenolic compounds provides protection against AD, primarily due to their anti-inflammatory actions. We previously suggested that phenolic compound curcumin ameliorated phagocytosis possibly through its anti-inflammatory effects rather than direct regulation of phagocytic function in electromagnetic field-exposed N9 microglial cells (N9 cells). Here, we explored the prostaglandin-E2 (PGE2)-related signaling pathway that involved in curcumin-mediated phagocytosis in fibrillar β-amyloid peptide (1-42) (fAβ42)-stimulated N9 cells. Treatment with fAβ42 increased phagocytosis of fluorescent-labeled latex beads in N9 cells. This increase was attenuated in a dose-dependent manner by endogenous and exogenous PGE2, as well as a selective EP2 or protein kinase A (PKA) agonist, but not by an EP4 agonist. We also found that an antagonist of EP2, but not EP4, abolished the reduction effect of PGE2 on fAβ42-induced microglial phagocytosis. Additionally, the increased expression of endogenous PGE2, EP2, and cyclic adenosine monophosphate (AMP), and activation of vasodilator-stimulated phosphoprotein, cyclic AMP responsive element-binding protein, and PKA were depressed by curcumin administration. This reduction led to the amelioration of the phagocytic abilities of PGE2-stimulated N9 cells. Taken together, these data suggested that curcumin restored the attenuating effect of PGE2 on fAβ42-induced microglial phagocytosis via a signaling mechanism involving EP2 and PKA. Moreover, due to its immune modulatory effects, curcumin may be a promising pharmacological candidate for neurodegenerative diseases.

  1. Curcumin Ameliorates the Reduction Effect of PGE2 on Fibrillar β-Amyloid Peptide (1-42)-Induced Microglial Phagocytosis through the Inhibition of EP2-PKA Signaling in N9 Microglial Cells

    PubMed Central

    Yang, Ju; Shen, Ting-ting; Chen, Yi; Yang, Xue-Sen

    2016-01-01

    Inflammatory activation of microglia and β amyloid (Aβ) deposition are considered to work both independently and synergistically to contribute to the increased risk of Alzheimer’s disease (AD). Recent studies indicate that long-term use of phenolic compounds provides protection against AD, primarily due to their anti-inflammatory actions. We previously suggested that phenolic compound curcumin ameliorated phagocytosis possibly through its anti-inflammatory effects rather than direct regulation of phagocytic function in electromagnetic field-exposed N9 microglial cells (N9 cells). Here, we explored the prostaglandin-E2 (PGE2)-related signaling pathway that involved in curcumin-mediated phagocytosis in fibrillar β-amyloid peptide (1–42) (fAβ42)-stimulated N9 cells. Treatment with fAβ42 increased phagocytosis of fluorescent-labeled latex beads in N9 cells. This increase was attenuated in a dose-dependent manner by endogenous and exogenous PGE2, as well as a selective EP2 or protein kinase A (PKA) agonist, but not by an EP4 agonist. We also found that an antagonist of EP2, but not EP4, abolished the reduction effect of PGE2 on fAβ42-induced microglial phagocytosis. Additionally, the increased expression of endogenous PGE2, EP2, and cyclic adenosine monophosphate (AMP), and activation of vasodilator-stimulated phosphoprotein, cyclic AMP responsive element-binding protein, and PKA were depressed by curcumin administration. This reduction led to the amelioration of the phagocytic abilities of PGE2-stimulated N9 cells. Taken together, these data suggested that curcumin restored the attenuating effect of PGE2 on fAβ42-induced microglial phagocytosis via a signaling mechanism involving EP2 and PKA. Moreover, due to its immune modulatory effects, curcumin may be a promising pharmacological candidate for neurodegenerative diseases. PMID:26824354

  2. K{sub α} and bremsstrahlung x-ray radiation backlighter sources from short pulse laser driven silver targets as a function of laser pre-pulse energy

    SciTech Connect

    Jarrott, L. C.; Mariscal, D.; McGuffey, C.; Beg, F. N.; Kemp, A. J.; Divol, L.; Chen, C.; Hey, D.; Maddox, B.; Hawreliak, J.; Park, H.-S.; Remington, B.; MacPhee, A.; Westover, B.; Suggit, M.; Wei, M. S.

    2014-03-15

    Measurements of silver K-shell and bremsstrahlung emission from thin-foil laser targets as a function of laser prepulse energy are presented. The silver targets were chosen as a potential 22 keV backlighter source for the National Ignition Facility Experiments. The targets were irradiated by the Titan laser with an intensity of 8 × 10{sup 17} W/cm{sup 2} with 40 ps pulse length. A secondary nanosecond timescale laser pulse with controlled, variable energy was used to emulate the laser prepulse. Results show a decrease in both K{sub α} and bremsstrahlung yield with increasing artificial prepulse. Radiation hydrodynamic modeling of the prepulse interaction determined that the preplasma and intact target fraction were different in the three prepulse energies investigated. Interaction of the short pulse laser with the resulting preplasma and target was then modeled using a particle-in-cell code PSC which explained the experimental results. The relevance of this work to future Advanced Radiographic Capability laser x-ray backlighter sources is discussed.

  3. 4,4'-Diisothiocyanostilbene-2,2'-disulfonic Acid (DIDS) Ameliorates Ischemia-Hypoxia-Induced White Matter Damage in Neonatal Rats through Inhibition of the Voltage-Gated Chloride Channel ClC-2

    PubMed Central

    Zhao, Baixiong; Quan, Hongyu; Ma, Teng; Tian, Yanping; Cai, Qiyan; Li, Hongli

    2015-01-01

    Chronic cerebral hypoperfusion is believed to cause white matter lesions (WMLs), leading to cognitive impairment. Previous studies have shown that inflammation and apoptosis of oligodendrocytes (OLs) are involved in the pathogenesis of WMLs, but effective treatments have not been studied. In this study, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), a chloride (Cl−) channel blocker, was injected into chronic cerebral ischemia-hypoxia rat models at different time points. Our results showed that DIDS significantly reduced the elevated mRNA levels and protein expression of chloride channel 2 (ClC-2) in neonatal rats induced by ischemia-hypoxia. Meanwhile, DIDS application significantly decreased the concentrations of reactive oxygen species (ROS); and the mRNA levels of inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha TNF-α in neonatal rats with hypoxic-ischemic damage. Myelin staining was weaker in neonatal rats with hypoxic-ischemic damage compared to normal controls in corpus callosum and other white matter, which was ameliorated by DIDS. Furthermore, the elevated number of caspase-3 and neural/glial antigen 2 (NG-2) double-labeled positive cells was attenuated by DIDS after ischemia anoxic injury. Administration of DIDS soon after injury alleviated damage to OLs much more effectively in white matter. In conclusion, our study suggests that early application of DIDS after ischemia-hypoxia injury may partially protect developing OLs. PMID:25961953

  4. Catalpol ameliorates diabetic atherosclerosis in diabetic rabbits

    PubMed Central

    Liu, Jiang-Yue; Zheng, Chen-Zhao; Hao, Xin-Ping; Zhang, Dai-Juan; Mao, An-Wei; Yuan, Ping

    2016-01-01

    Catalpol, isolated from the roots of Rehmanniaglutinosa, Chinese foxglove, is an iridoid glycoside with antioxidant, anti-inflammatory and anti-hyperglycemic agent. The present study was to investigate the effects of catalpol on diabetic atherosclerosis in alloxan-induced diabetic rabbits. Diabetes was induced in rabbits by a hyperlipidemic diet and intravenous injection of alloxan (100 mg/kg). Rabbits were treated for 12 weeks. The fasting blood glucose, insulin, homeostasis model of insulin resistance, total cholesterol and triglyceride were measured. The thoracic aorta was excised for histology. The plasma and vascular changes including some markers of oxidative stress, inflammatory cytokines and fibrosis factors were examined. Plasma levels of fasting blood glucose, insulin and homeostasis model of insulin resistance were significantly decreased in catalpol group. Catalpol treatment ameliorated diabetic atherosclerosis in diabetic rabbits as demonstrated by significantly inhibited neointimal hyperplasia and macrophages recruitment. Catalpol treatment also enhanced the activities of superoxide dismutase, glutathione peroxidase, and increased the plasma levels of total antioxidant status, meanwhile reduced the levels of malondialdehyde, protein carbonyl groups and advanced glycation end product. Furthermore, catalpol also reduced circulating levels of tumor necrosis factor-α, monocyte chemotactic protein-1 and vascular cell adhesion molecule-1. Catalpol also decreased transforming growth factor-β1 and collagen IV mRNA and protein expressions in the vessels. Catalpol exerts an ameliorative effect on atherosclerotic lesion in alloxan-induced diabetic rabbits. The possible mechanisms may be related to inhibition of oxidative stress inflammatory response and anti-fibrosis and reduced aggregation of extracellular matrix. PMID:27830011

  5. Inhibition of SH2-domain-containing inositol 5-phosphatase (SHIP2) ameliorates palmitate induced-apoptosis through regulating Akt/FOXO1 pathway and ROS production in HepG2 cells

    SciTech Connect

    Gorgani-Firuzjaee, Sattar; Adeli, Khosrow; Meshkani, Reza

    2015-08-21

    The serine–threonine kinase Akt regulates proliferation and survival by phosphorylating a network of protein substrates; however, the role of a negative regulator of the Akt pathway, the SH2-domain-containing inositol 5-phosphatase (SHIP2) in apoptosis of the hepatocytes, remains unknown. In the present study, we studied the molecular mechanisms linking SHIP2 expression to apoptosis using overexpression or suppression of SHIP2 gene in HepG2 cells exposed to palmitate (0.5 mM). Overexpression of the dominant negative mutant SHIP2 (SHIP2-DN) significantly reduced palmitate-induced apoptosis in HepG2 cells, as these cells had increased cell viability, decreased apoptotic cell death and reduced the activity of caspase-3, cytochrome c and poly (ADP-ribose) polymerase. Overexpression of the wild-type SHIP2 gene led to a massive apoptosis in HepG2 cells. The protection from palmitate-induced apoptosis by SHIP2 inhibition was accompanied by a decrease in the generation of reactive oxygen species (ROS). In addition, SHIP2 inhibition was accompanied by an increased Akt and FOXO-1 phosphorylation, whereas overexpression of the wild-type SHIP2 gene had the opposite effects. Taken together, these findings suggest that SHIP2 expression level is an important determinant of hepatic lipoapotosis and its inhibition can potentially be a target in treatment of hepatic lipoapoptosis in diabetic patients. - Highlights: • Lipoapoptosis is the major contributor to the development of NAFLD. • The PI3-K/Akt pathway regulates apoptosis in different cells. • The role of negative regulator of this pathway, SHIP2 in lipoapoptosis is unknown. • SHIP2 inhibition significantly reduces palmitate-induced apoptosis in HepG2 cells. • SHIP2 inhibition prevents palmitate induced-apoptosis by regulating Akt/FOXO1 pathway.

  6. Gap-Prepulse Inhibition of the Acoustic Startle Reflex (GPIAS) for Tinnitus Assessment: Current Status and Future Directions

    PubMed Central

    Galazyuk, Alexander; Hébert, Sylvie

    2015-01-01

    The progress in the field of tinnitus largely depends on the development of a reliable tinnitus animal model. Recently, a new method based on the acoustic startle reflex modification was introduced for tinnitus screening in laboratory animals. This method was enthusiastically adopted and now widely used by many scientists in the field due to its seeming simplicity and a number of advantages over the other methods of tinnitus assessment. Furthermore, this method opened an opportunity for tinnitus assessment in humans as well. Unfortunately, multiple modifications of data collection and interpretation implemented in different labs make comparisons across studies very difficult. In addition, recent animal and human studies have challenged the original “filling-in” interpretation of the paradigm. Here, we review the current literature to emphasize on the commonalities and differences in data collection and interpretation across laboratories that are using this method for tinnitus assessment. We also propose future research directions that could be taken in order to establish whether or not this method is warranted as an indicator of the presence of tinnitus. PMID:25972836

  7. Interactions of Stress and Nicotine on Amplitude, Pre-Pulse Inhibition and Habituation of the Acoustic Startle Reflex

    DTIC Science & Technology

    1992-09-24

    stress. " Hans Selye (1973 ) Cigarette smoking is the most preventable environmental factor contributing to illness and death in the United States...following noise stress on an auditory vigilance task. A possible explanation has been offered by Eysenck (1973) for some of the inconsistent...effects of nicotine on stress reduction . Eysenck (1973) argued that discordant effects can be accounted for when the effects of the organism ’ s initial

  8. Prepulse-induced shock waves in the gas jet target of a laser plasma EUV radiation source

    NASA Astrophysics Data System (ADS)

    Garbaruk, A. V.; Gritskevich, M. S.; Kalmykov, S. G.; Mozharov, A. M.; Sasin, M. E.

    2017-01-01

    In experiments with a laser-plasma EUV-radiation source, the main IR Nd:YAG laser pulse was preceded by that of a UV KrF excimer laser. Dramatic modulations of EUV plasma emissivity have been observed at long interpulse times, from hundreds of nanoseconds up to microseconds. To discover the nature of these prepulse-produced long-living perturbations of the target, a fluid dynamics numerical simulation of the Xe gas jet has been carried out. The prepulse has been found to generate a quasi-spherical shock wave with a thin dense front layer and a vast rarefied inside area. In the course of time, the front expands and simultaneously drifts downstream along with the gas. Depending on the interpulse time, the IR laser beam either intersects the dense layer or propagates within the rarefied gas cavity whereby the above-mentioned variations in the plasma emission can be explained. The possibilities of making use of the discovered phenomena to enhance the observed EUV plasma brightness are discussed.

  9. Chinese medicine CGA formula ameliorates DMN-induced liver fibrosis in rats via inhibiting MMP2/9, TIMP1/2 and the TGF-β/Smad signaling pathways

    PubMed Central

    Li, Xue-mei; Peng, Jing-hua; Sun, Zhao-lin; Tian, Hua-jie; Duan, Xiao-hua; Liu, Lin; Ma, Xin; Feng, Qin; Liu, Ping; Hu, Yi-yang

    2016-01-01

    Aim: Chinese medicine CGA formula consists of polysaccharide from Cordyceps sinensis mycelia (CS-PS), gypenosides and amygdalin, which is derived from Fuzheng Huayu (FZHY) capsule for treating liver fibrosis. In this study we attempted to confirm the therapeutic effects of CGA formula in dimethylnitrosamine (DMN)-induced liver fibrosis in rats, and to identify the mechanisms of anti-fibrotic actions. Methods: Rats were injected with DMN (10 mg·kg−1·d−1, ip) for 3 consecutive days per week over a 4-week period. The rats then were orally administered with CGA formula (CS-PS 60 mg·kg−1·d−1, gypenosides 50 mg·kg−1·d−1 and amygdalin 80 mg·kg−1·d−1) daily in the next 2 weeks. CS-PS, gypenosides or amygdalin alone were administered as individual component controls, whereas colchicine and FZHY were used as positive controls. Serum biomarkers were measured. Hepatic injury, collagen deposition and stellate cell activation were examined. The MMP activities, expression of TIMP protein and proteins involved in the TGF-β1/Smad signaling pathways in liver tissues were assayed. Results: In DMN-treated rats, administration of CGA formula significantly decreased serum ALT, AST and total bilirubin and hepatic hydroxyproline levels, increased serum albumin level, and attenuated liver fibrosis as shown by histological examination. Furthermore, these effects were comparable to those caused by administration of FZHY, and superior to those caused by administration of colchicine or the individual components of CGA formula. Moreover, administration of CGA formula significantly decreased the protein levels of α-SMA, TGF-β1, TGF-β1 receptor (TβR-I), p-TβR-I, p-TβR-II, p-Smad2, p-Smad3, TIMP1 and TIMP2, as well as MMP2 and MMP9 activities in liver tissues of DMN-treated rats. Conclusion: Chinese medicine CGA formula ameliorates DMN-induced liver fibrosis in rats, and this effect was likely associated with the down-regulation of MMP2/9 activities, TIMP1/2 protein

  10. Orally Administrated Lactobacillus pentosus var. plantarum C29 Ameliorates Age-Dependent Colitis by Inhibiting the Nuclear Factor-Kappa B Signaling Pathway via the Regulation of Lipopolysaccharide Production by Gut Microbiota

    PubMed Central

    Jeong, Jin-Ju; Kim, Kyung-Ah; Jang, Se-Eun; Woo, Jae-Yeon; Han, Myung Joo; Kim, Dong-Hyun

    2015-01-01

    To evaluate the anti-inflammaging effect of lactic acid bacteria (LAB) on age-dependent inflammation, we first screened and selected a tumor necrosis factor (TNF)-α and reactive oxygen species (ROS)-inhibitory LAB, Lactobacillus pentosus var. plantarum C29, among the LABs isolated from fermented vegetables using LPS-stimulated mouse peritoneal macrophages. Oral administration of C29 (2 × 109 CFU/rat) for 8 weeks in aged Fischer 344 rats (age, 16 months) inhibited the expression of the inflammatory markers myeloperoxidase, inducible nitric oxide (NO) synthase, cyclooxygenase-2, pro-inflammatory cytokines tumor necrosis factor (TNF)-α and IL-6 and the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), activator protein 1 (AP1), and mitogen-activated protein kinases (MAPKs). Treatment with C29 induced the expression of tight junction proteins ZO-1, occludin, and claudin-1, and reduced intestinal microbial LPS and plasmatic LPS levels and ROS, as well as the Firmicutes to Bacteroidetes ratio, which is significantly higher in aged rats than in young rats. C29 treatment also reduced plasmatic reactive oxygen species, malondialdehyde, C-reactive protein, and TNF-α, and suppressed expression of senescence markers p16 and p53 in the colon of the aged rats, but increased SIRT 1 expression. Based on these findings, we concluded that C29 treatment may suppress aging-dependent colitis by inhibiting NF-κB, AP1, and MAPK activation via the inhibition of gut microbiota LPS production and the induction of tight junction protein expression. PMID:25689583

  11. Trans-Cinnamaldehyde, An Essential Oil in Cinnamon Powder, Ameliorates Cerebral Ischemia-Induced Brain Injury via Inhibition of Neuroinflammation Through Attenuation of iNOS, COX-2 Expression and NFκ-B Signaling Pathway.

    PubMed

    Chen, Yuh-Fung; Wang, Yu-Wen; Huang, Wei-Shih; Lee, Ming-Ming; Wood, W Gibson; Leung, Yuk-Man; Tsai, Huei-Yann

    2016-09-01

    Trans-cinnamaldehyde (TCA), an essential oil in cinnamon powder, may have beneficial effects as a treatment for stroke which is the second leading cause of death worldwide. Post-ischemic inflammation induces neuronal cell damage after stroke, and activation of microglia, in particular, has been thought as the main contributor of proinflammatory and neurotoxic factors. The purpose of this study was to investigate the neuroprotective effects of TCA in an animal model of ischemia/reperfusion (I/R)-induced brain injury and the neuroprotective mechanism was verified in LPS-induced inflammation of BV-2 microglial cells. Our results showed that TCA (10-30 mg/kg, p.o.) significantly reduced the infarction area, neurological deficit score and decreased iNOS and COX-2 protein expression level in I/R-induced injury brain tissue. It inhibited 0.5 µg/ml LPS-induced NO production in BV-2 microglial cells without affecting cell viability, reduced protein expression of iNOS and COX-2, and attenuated inhibition of p53 protein. TCA also suppressed the effects of LPS-induced nuclear translocation of NF-κB p65 and p50 and increased cytosolic IκBα. It also reduced LPS-induced mRNA expression of iNOS, COX-2, and TNFα. We concluded that TCA has a potential neuroprotective effect to against the ischemic stroke, which may be via the inhibition of neuroinflammation through attenuating iNOS, COX-2 expression and NF-κB signaling pathway.

  12. Orally administrated Lactobacillus pentosus var. plantarum C29 ameliorates age-dependent colitis by inhibiting the nuclear factor-kappa B signaling pathway via the regulation of lipopolysaccharide production by gut microbiota.

    PubMed

    Jeong, Jin-Ju; Kim, Kyung-Ah; Jang, Se-Eun; Woo, Jae-Yeon; Han, Myung Joo; Kim, Dong-Hyun

    2015-01-01

    To evaluate the anti-inflammaging effect of lactic acid bacteria (LAB) on age-dependent inflammation, we first screened and selected a tumor necrosis factor (TNF)-α and reactive oxygen species (ROS)-inhibitory LAB, Lactobacillus pentosus var. plantarum C29, among the LABs isolated from fermented vegetables using LPS-stimulated mouse peritoneal macrophages. Oral administration of C29 (2 × 109 CFU/rat) for 8 weeks in aged Fischer 344 rats (age, 16 months) inhibited the expression of the inflammatory markers myeloperoxidase, inducible nitric oxide (NO) synthase, cyclooxygenase-2, pro-inflammatory cytokines tumor necrosis factor (TNF)-α and IL-6 and the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), activator protein 1 (AP1), and mitogen-activated protein kinases (MAPKs). Treatment with C29 induced the expression of tight junction proteins ZO-1, occludin, and claudin-1, and reduced intestinal microbial LPS and plasmatic LPS levels and ROS, as well as the Firmicutes to Bacteroidetes ratio, which is significantly higher in aged rats than in young rats. C29 treatment also reduced plasmatic reactive oxygen species, malondialdehyde, C-reactive protein, and TNF-α, and suppressed expression of senescence markers p16 and p53 in the colon of the aged rats, but increased SIRT 1 expression. Based on these findings, we concluded that C29 treatment may suppress aging-dependent colitis by inhibiting NF-κB, AP1, and MAPK activation via the inhibition of gut microbiota LPS production and the induction of tight junction protein expression.

  13. Pipoxolan Ameliorates Cerebral Ischemia via Inhibition of Neuronal Apoptosis and Intimal Hyperplasia through Attenuation of VSMC Migration and Modulation of Matrix Metalloproteinase-2/9 and Ras/MEK/ERK Signaling Pathways

    PubMed Central

    Chen, Yuh-Fung; Tsai, Huei-Yann; Wu, Kuo-Jen; Siao, Lian-Ru; Wood, W. Gibson

    2013-01-01

    Pipoxolan (PIPO) has anti-spasmodic effects, and it is used clinically to relieve smooth muscle spasms. Cerebrovascular disease is one of the leading causes of disability and death worldwide. The main aim of this study was to investigate the effects of PIPO on cerebral ischemia and vascular smooth muscle cell (VSMC) migration in vivo and in vitro. Cerebral infarction area, ratio of intima to media area (I/M ratio) and PCNA antibody staining of the carotid artery in vivo were measured. Cell viability of A7r5 cells, PDGF-BB-stimulated cell migration, and potential mechanisms of PIPO were evaluated by wound healing, transwell and Western blotting. PIPO (10 and 30 mg/kg p.o.) reduced: the cerebral infarction area; neurological deficit; TUNEL-positive cells; cleaved caspase 3-positive cells; intimal hyperplasia; and inhibited proliferating cell nuclear antigen (PCNA)-positive cells in rodents. PIPO (5, 10 and 15 µM) significantly inhibited PDGF-BB-stimulated VSMC migration and reduced Ras, MEK, and p-ERK levels. Moreover, PIPO decreased levels of matrix metalloproteinases -2 and -9 in PDGF-BB-stimulated A7r5 cells. In summary, PIPO is protective in models of ischemia/reperfusion-induced cerebral infarction, carotid artery ligation-induced intimal hyperplasia and VSMC migration both in vivo and in vitro. PIPO could be potentially efficacious in preventing cerebrovascular and vascular diseases. PMID:24086601

  14. Pipoxolan ameliorates cerebral ischemia via inhibition of neuronal apoptosis and intimal hyperplasia through attenuation of VSMC migration and modulation of matrix metalloproteinase-2/9 and Ras/MEK/ERK signaling pathways.

    PubMed

    Chen, Yuh-Fung; Tsai, Huei-Yann; Wu, Kuo-Jen; Siao, Lian-Ru; Wood, W Gibson

    2013-01-01

    Pipoxolan (PIPO) has anti-spasmodic effects, and it is used clinically to relieve smooth muscle spasms. Cerebrovascular disease is one of the leading causes of disability and death worldwide. The main aim of this study was to investigate the effects of PIPO on cerebral ischemia and vascular smooth muscle cell (VSMC) migration in vivo and in vitro. Cerebral infarction area, ratio of intima to media area (I/M ratio) and PCNA antibody staining of the carotid artery in vivo were measured. Cell viability of A7r5 cells, PDGF-BB-stimulated cell migration, and potential mechanisms of PIPO were evaluated by wound healing, transwell and Western blotting. PIPO (10 and 30 mg/kg p.o.) reduced: the cerebral infarction area; neurological deficit; TUNEL-positive cells; cleaved caspase 3-positive cells; intimal hyperplasia; and inhibited proliferating cell nuclear antigen (PCNA)-positive cells in rodents. PIPO (5, 10 and 15 µM) significantly inhibited PDGF-BB-stimulated VSMC migration and reduced Ras, MEK, and p-ERK levels. Moreover, PIPO decreased levels of matrix metalloproteinases -2 and -9 in PDGF-BB-stimulated A7r5 cells. In summary, PIPO is protective in models of ischemia/reperfusion-induced cerebral infarction, carotid artery ligation-induced intimal hyperplasia and VSMC migration both in vivo and in vitro. PIPO could be potentially efficacious in preventing cerebrovascular and vascular diseases.

  15. Ameliorative effects of mulberry (Morus alba L.) leaves on hyperlipidemia in rats fed a high-fat diet: induction of fatty acid oxidation, inhibition of lipogenesis, and suppression of oxidative stress.

    PubMed

    Kobayashi, Yukihiro; Miyazawa, Maki; Kamei, Asuka; Abe, Keiko; Kojima, Takashi

    2010-01-01

    To determine the effects of mulberry (Morus alba L.) leaves on hyperlipidemia, we performed gene expression profiling of the liver. Rats were fed a high-fat diet and administered mulberry leaves for 7 weeks. Plasma triglyceride and non-esterified fatty acid levels were significantly lower in the rats treated with mulberry leaves as compared with the untreated rats. DNA microarray analysis revealed that mulberry leaves upregulated expression of the genes involved in α-, β- and ω-oxidation of fatty acids, mainly related to the peroxisome proliferator-activated receptor signaling pathway, and downregulated the genes involved in lipogenesis. Furthermore, treatment with mulberry leaves upregulated expression of the genes involved in the response to oxidative stress. These results indicate that consumption of fatty acids and inhibition of lipogenesis are responsible for the reduction in plasma lipids caused by mulberry administration. In addition, mulberry treatment maintains the body's oxidative state at a low level despite enhancing fatty acid oxidation.

  16. Curcumin Ameliorates Reserpine-Induced Gastrointestinal Mucosal Lesions Through Inhibiting IκB-α/NF-κB Pathway and Regulating Expression of Vasoactive Intestinal Peptide and Gastrin in Rats.

    PubMed

    Long, Lingli; Wang, Jingnan; Chen, Ningning; Zheng, Shuhui; Shi, Lanying; Xu, Yuxia; Luo, Canqiao; Deng, Yubin

    2016-06-01

    The objective of our study was to investigate whether curcumin protects against reserpine-induced gastrointestinal mucosal lesions (GMLs) in rats and to explore the mechanism of curcumin's action. Sprague-Dawley rats were randomly divided into four groups: control group, reserpine-treated group, reserpine treatment group with curcumin at high dose (200 mg/kg), and reserpine treatment group with curcumin at low dose (100 mg/kg). Rats in reserpine-treated group were induced by intraperitoneally administered reserpine (0.5 mg/kg) for 28 days. TUNEL staining and hematoxylin and eosin staining were used to evaluate the apoptotic cells and morphologic changes. In addition, to explore the mechanism of curcumin in protecting GMLs, we used serum of experimental rats to assess the level of vasoactive intestinal peptide (VIP), gastrin, interleukin-6, interleukin-10, tumor necrosis factor-α and interferon-γ by ELISA and radioimmunoassay. The protein levels of NF-κB, p-IκB-α, IκB-α, Bcl-2, Bax, and cleaved-caspase-3 were examined by western blot analysis. Data were analyzed with SPSS 19.0 software package. Curcumin treatment prevented tissue damage and cell death in the reserpine-treated rats and effectively decreased inflammatory response and balanced the expression of VIP and gastrin in the reserpine-treated rats. NF-κB, p-IκB-α, Bax, and cleaved-caspase-3 were increased in the reserpine group, but the curcumin high-dose group inhibited them. Curcumin can target the IκB-α/NF-κB pathway to inhibit inflammatory response and regulate the level of VIP and gastrin in reserpine-induced GML rats.

  17. Effects of nanosecond-scale prepulse on generation of high-energy protons in target normal sheath acceleration

    SciTech Connect

    Wang, W. P.; Shen, B. F.; Zhang, H.; Xu, Y.; Li, Y. Y.; Lu, X. M.; Wang, C.; Liu, Y. Q.; Shi, Y.; Leng, Y. X.; Liang, X. Y.; Li, R. X.; Xu, Z. Z.; Lu, J. X.; Wang, N. Y.

    2013-06-03

    A pulse cleaner based on noncollinear optical-parametric amplification and second-harmonic generation processes is used to improve the contrast of a laser of peak intensity {approx}2 Multiplication-Sign 10{sup 19} W/cm{sup 2} to {approx}10{sup 11} at 100 ps before the peak of the main pulse. A 7 MeV proton beam is observed when a 2.5 {mu}m-thick Al foil is irradiated by this high-contrast laser. The maximum proton energy decreases to 2.9 MeV when a low-contrast ({approx}10{sup 8}) laser is used. Two-dimensional particle-in-cell simulations combined with MULTI simulations show that the maximum proton energy sensitively relies on the detecting direction. The ns-time-scale prepulse can bend a thin target before the main pulse arrives, which reduces maximum proton energy in the target normal sheath acceleration.

  18. Laser prepulse induced plasma channel formation in air and relativistic self focusing of an intense short pulse

    SciTech Connect

    Kumar, Ashok; Dahiya, Deepak; Sharma, A. K.

    2011-02-15

    An analytical formalism is developed and particle-in-cell simulations are carried out to study plasma channel formation in air by a two pulse technique and subsequent relativistic self focusing of the third intense laser through it. The first prepulse causes tunnel ionization of air. The second pulse heats the plasma electrons and establishes a prolonged channel. The third pulse focuses under the combined effect of density nonuniformity of the channel and relativistic mass nonlinearity. A channel with 20% density variation over the spot size of the third pulse is seen to strongly influence relativistic self focusing at normalized laser amplitude {approx}0.4-1. In deeper plasma channels, self focusing is less sensitive to laser amplitude variation. These results are reproduced in particle-in-cell simulations. The present treatment is valid for millimeter range plasma channels.

  19. Schisandrin B Ameliorates ICV-Infused Amyloid β Induced Oxidative Stress and Neuronal Dysfunction through Inhibiting RAGE/NF-κB/MAPK and Up-Regulating HSP/Beclin Expression

    PubMed Central

    Giridharan, Vijayasree V.; Arumugam, Somasundaram; Mizuno, Makoto; Nawa, Hiroyuki; Suzuki, Kenji; Ko, Kam M.; Krishnamurthy, Prasanna; Watanabe, Kenichi

    2015-01-01

    Amyloid β (Aβ)-induced neurotoxicity is a major pathological mechanism of Alzheimer’s disease (AD). Our previous studies have demonstrated that schisandrin B (Sch B), an antioxidant lignan from Schisandra chinensis, could protect mouse brain against scopolamine- and cisplatin-induced neuronal dysfunction. In the present study, we examined the protective effect of Sch B against intracerebroventricular (ICV)-infused Aβ-induced neuronal dysfunction in rat cortex and explored the potential mechanism of its action. Our results showed that 26 days co-administration of Sch B significantly improved the behavioral performance of Aβ (1–40)-infused rats in step-through test. At the same time, Sch B attenuated Aβ-induced increases in oxidative and nitrosative stresses, inflammatory markers such as inducible nitric oxide syntheses, cyclooxygenase-2, interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α, and DNA damage. Several proteins such as receptor for advanced glycation end products (RAGE), nuclear factor-κB, mitogen-activated protein kinases, and apoptosis markers were over expressed in Aβ-infused rats but were significantly inhibited by Sch B treatment. Furthermore, Sch B negatively modulated the Aβ level with simultaneous up-regulation of HSP70 and beclin, autophagy markers in Aβ-infused rats. The aforementioned effects of Sch B suggest its protective role against Aβ-induced neurotoxicity through intervention in the negative cycle of RAGE-mediated Aβ accumulation during AD patho-physiology. PMID:26556721

  20. Schisandrin B Ameliorates ICV-Infused Amyloid β Induced Oxidative Stress and Neuronal Dysfunction through Inhibiting RAGE/NF-κB/MAPK and Up-Regulating HSP/Beclin Expression.

    PubMed

    Giridharan, Vijayasree V; Thandavarayan, Rajarajan A; Arumugam, Somasundaram; Mizuno, Makoto; Nawa, Hiroyuki; Suzuki, Kenji; Ko, Kam M; Krishnamurthy, Prasanna; Watanabe, Kenichi; Konishi, Tetsuya

    2015-01-01

    Amyloid β (Aβ)-induced neurotoxicity is a major pathological mechanism of Alzheimer's disease (AD). Our previous studies have demonstrated that schisandrin B (Sch B), an antioxidant lignan from Schisandra chinensis, could protect mouse brain against scopolamine- and cisplatin-induced neuronal dysfunction. In the present study, we examined the protective effect of Sch B against intracerebroventricular (ICV)-infused Aβ-induced neuronal dysfunction in rat cortex and explored the potential mechanism of its action. Our results showed that 26 days co-administration of Sch B significantly improved the behavioral performance of Aβ (1-40)-infused rats in step-through test. At the same time, Sch B attenuated Aβ-induced increases in oxidative and nitrosative stresses, inflammatory markers such as inducible nitric oxide syntheses, cyclooxygenase-2, interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α, and DNA damage. Several proteins such as receptor for advanced glycation end products (RAGE), nuclear factor-κB, mitogen-activated protein kinases, and apoptosis markers were over expressed in Aβ-infused rats but were significantly inhibited by Sch B treatment. Furthermore, Sch B negatively modulated the Aβ level with simultaneous up-regulation of HSP70 and beclin, autophagy markers in Aβ-infused rats. The aforementioned effects of Sch B suggest its protective role against Aβ-induced neurotoxicity through intervention in the negative cycle of RAGE-mediated Aβ accumulation during AD patho-physiology.

  1. DPP-4 inhibition with alogliptin on top of angiotensin II type 1 receptor blockade ameliorates albuminuria via up-regulation of SDF-1α in type 2 diabetic patients with incipient nephropathy.

    PubMed

    Fujita, Hiroki; Taniai, Hisanori; Murayama, Hiroko; Ohshiro, Haruyo; Hayashi, Hikaru; Sato, Seiko; Kikuchi, Nyuko; Komatsu, Taiga; Komatsu, Koga; Komatsu, Kanji; Narita, Takuma; Yamada, Yuichiro

    2014-01-01

    Dipeptidyl peptidase-4 (DPP-4) inhibitor is a new class of anti-diabetic drug which exerts its glucose-lowering action by suppressing the degradation of a gut incretin hormone glucagon-like peptide-1 (GLP-1). To elucidate whether treatment with stronger DPP-4 inhibitor on top of angiotensin II type 1 receptor blocker (ARB) provides greater renal protective effects, we performed a crossover study with two DPP-4 inhibitors, sitagliptin and alogliptin, in twelve type 2 diabetic patients with incipient nephropathy taking ARBs. This study consisted of three treatment periods: sitagliptin 50 mg/day for 4 weeks (first period), alogliptin 25 mg/day for 4 weeks (second period), and sitagliptin 50 mg/day for 4 weeks (third period). Significant changes in body mass index, blood pressure, serum lipids, serum creatinine, estimated glomerular filtration rate, and HbA1c were not observed among the three treatment periods. Reduced urinary levels of albumin and an oxidative stress marker 8-hydroxy-2'-deoxyguanosine (8-OHdG), increased urinary cAMP levels, and elevated plasma levels of stromal cell-derived factor-1α (SDF-1α) which is a physiological substrate of DPP-4 were observed after the switch from sitagliptin to a stronger DPP-4 inhibitor alogliptin. Given a large body of evidence indicating anti-oxidative action of cAMP and up-regulation of cellular cAMP production by SDF-1α, the present results suggest that more powerful DPP-4 inhibition on top of angiotensin II type 1 receptor blockade would offer additional protection against early-stage diabetic nephropathy beyond that attributed to glycemic control, via reduction of renal oxidative stress by SDF-1α-cAMP pathway activation.

  2. Status On Multi-microsecond Prepulse Technique On Sphinx Machine Going From Nested To Single Wire Array For 800 ns Implosion Time Z-pinch

    SciTech Connect

    Maury, P.; Calamy, H.; Grunenwald, J.; Lassalle, F.; Zucchini, F.; Loyen, A.; Georges, A.; Morell, A.; Bedoch, J. P.

    2009-01-21

    The Sphinx machine{sup [1]} is a 6 MA, 1 {mu}S driver based on the LTD technology, used for Z-pinch experiments. Important improvements of Sphinx radiation output were recently obtained using a multi-microsecond current prepulse{sup [2]}. Total power per unit of length is multiplied by a factor of 6 and FWHM divided by a factor of 2.5. Early breakdown of the wires during the prepulse phase dramatically changes the ablation phase leading to an improvement of axial homogeneity of both the implosion and the final radiating column. As a consequence, the cathode bubble observed on classical shots is definitively removed. The implosion is then centered and zippering effect is reduced, leading to simultaneous x-ray emission of the whole length. A great reproducibility is obtained. Nested arrays were used before to mitigate the Rayleigh-Taylor instabilities during the implosion phase. Further experiments with pre-pulse technique are described here were inner array was removed. The goal of these experiments was to see if long prepulse could give stable enough implosion with single array and at the same time increase the {eta} parameter by reducing the mass of the load. Experimental results of single wire array loads of typical dimension 5 cm in height with implosion time between 700 and 900 ns and diameter varying between 80 and 140 mm are given. Parameters of the loads were varying in term of radius and number of wires. Comparisons with nested wire array loads are done and trends are proposed. Characteristics of both the implosion and the final radiating column are shown. 2D MHD numerical simulations of single wire array become easier as there is no interaction between outer and inner array anymore. A systematic study was done using injection mass model to benchmark simulation with experiments.

  3. Inhibition of the immunoproteasome ameliorates experimental autoimmune encephalomyelitis

    PubMed Central

    Basler, Michael; Mundt, Sarah; Muchamuel, Tony; Moll, Carlo; Jiang, Jing; Groettrup, Marcus; Kirk, Christopher J

    2014-01-01

    Multiple sclerosis (MS) is a chronic demyelinating immune mediated disease of the central nervous system. The immunoproteasome is a distinct class of proteasomes found predominantly in monocytes and lymphocytes. Recently, we demonstrated a novel function of immunoproteasomes in cytokine production and T cell differentiation. In this study, we investigated the therapeutic efficacy of an inhibitor of the immunoproteasome (ONX 0914) in two different mouse models of MS. ONX 0914 attenuated disease progression after active and passive induction of experimental autoimmune encephalomyelitis (EAE), both in MOG35–55 and PLP139–151-induced EAE. Isolation of lymphocytes from the brain or spinal cord revealed a strong reduction of cytokine-producing CD4+ cells in ONX 0914 treated mice. Additionally, ONX 0914 treatment prevented disease exacerbation in a relapsing-remitting model. An analysis of draining lymph nodes after induction of EAE revealed that the differentiation to Th17 or Th1 cells was strongly impaired in ONX 0914 treated mice. These results implicate the immunoproteasome in the development of EAE and suggest that immunoproteasome inhibitors are promising drugs for the treatment of MS. PMID:24399752

  4. Dietary Amelioration of Helicobacter Infection

    PubMed Central

    Fahey, Jed W.; Stephenson, Katherine K.; Wallace, Alison J.

    2015-01-01

    We review herein the basis for using dietary components to treat and/or prevent Helicobacter pylori infection, with emphasis on: (a) work reported in the last decade, (b) dietary components for which there is mechanism-based plausibility, and (c) components for which clinical results on H. pylori amelioration are available. There is evidence that a diet-based treatment may reduce the levels and/or the virulence of H. pylori colonization without completely eradicating the organism in treated individuals. This concept was endorsed a decade ago by the participants in a small international consensus conference held in Honolulu, Hawaii, USA, and interest in such a diet-based approach has increased dramatically since then. This approach is attractive in terms of cost, treatment, tolerability and cultural acceptability. This review therefore highlights specific foods, food components, and food products, grouped as follows: bee products (e.g. honey and propolis), probiotics, dairy products, vegetables, fruits, oils, essential oils, and herbs, spices and other plants. A discussion of the small number of clinical studies that are available is supplemented by supportive in vitro and animal studies. This very large body of in vitro and pre-clinical evidence must now be followed up with rationally designed, unambiguous human trials. PMID:25799054

  5. Adriamycin cardiotoxicity amelioration by alpha-tocopherol.

    PubMed

    Krivit, W

    1979-01-01

    Adriamycin has become a potent member of the cancer chemotherapeutic program. However, the full utilization of adriamycin is limited by its cardiotoxicity. In experimental animals, alpha-tocopherol has been shown by some to ameliorate or prevent cardiac dysfunction without impairing antitumor effectiveness. During adriamycin therapy, future clinical research should consist of biochemical measurements of vitamin E in plasma, lipoperoxidation in red cells and platelets, while cars to indicate deficiency, should be considered as one method of ameliorating toxicity.

  6. Fucoidan Extracts Ameliorate Acute Colitis.

    PubMed

    Lean, Qi Ying; Eri, Rajaraman D; Fitton, J Helen; Patel, Rahul P; Gueven, Nuri

    2015-01-01

    Inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn's disease, are an important cause of morbidity and impact significantly on quality of life. Overall, current treatments do not sustain a long-term clinical remission and are associated with adverse effects, which highlight the need for new treatment options. Fucoidans are complex sulphated, fucose-rich polysaccharides, found in edible brown algae and are described as having multiple bioactivities including potent anti-inflammatory effects. Therefore, the therapeutic potential of two different fucoidan preparations, fucoidan-polyphenol complex (Maritech Synergy) and depyrogenated fucoidan (DPF) was evaluated in the dextran sulphate sodium (DSS) mouse model of acute colitis. Mice were treated once daily over 7 days with fucoidans via oral (Synergy or DPF) or intraperitoneal administration (DPF). Signs and severity of colitis were monitored daily before colons and spleens were collected for macroscopic evaluation, cytokine measurements and histology. Orally administered Synergy and DPF, but not intraperitoneal DPF treatment, significantly ameliorated symptoms of colitis based on retention of body weight, as well as reduced diarrhoea and faecal blood loss, compared to the untreated colitis group. Colon and spleen weight in mice treated with oral fucoidan was also significantly lower, indicating reduced inflammation and oedema. Histological examination of untreated colitis mice confirmed a massive loss of crypt architecture and goblet cells, infiltration of immune cells and oedema, while all aspects of this pathology were alleviated by oral fucoidan. Importantly, in this model, the macroscopic changes induced by oral fucoidan correlated significantly with substantially decreased production of at least 15 pro-inflammatory cytokines by the colon tissue. Overall, oral fucoidan preparations significantly reduce the inflammatory pathology associated with DSS-induced colitis and could therefore represent

  7. Nicotine ameliorates schizophrenia-like cognitive deficits induced by maternal LPS exposure: a study in rats

    PubMed Central

    Waterhouse, Uta; Roper, Vic E.; Brennan, Katharine A.

    2016-01-01

    ABSTRACT Maternal exposure to infectious agents is a predisposing factor for schizophrenia with associated cognitive deficits in offspring. A high incidence of smoking in these individuals in adulthood might be, at least in part, due to the cognitive-enhancing effects of nicotine. Here, we have used prenatal exposure to maternal lipopolysaccharide (LPS, bacterial endotoxin) at different time points as a model for cognitive deficits in schizophrenia to determine whether nicotine reverses any associated impairments. Pregnant rats were treated subcutaneously with LPS (0.5 mg/kg) at one of three neurodevelopmental time periods [gestation days (GD) 10-11, 15-16, 18-19]. Cognitive assessment in male offspring commenced in early adulthood [postnatal day (PND) 60] and included: prepulse inhibition (PPI), latent inhibition (LI) and delayed non-matching to sample (DNMTS). Following PND 100, daily nicotine injections (0.6 mg/kg, subcutaneously) were administered, and animals were re-tested in the same tasks (PND 110). Only maternal LPS exposure early during fetal neurodevelopment (GD 10-11) resulted in deficits in all tests compared to animals that had been prenatally exposed to saline at the same gestational time point. Repeated nicotine treatment led to global (PPI) and selective (LI) improvements in performance. Early but not later prenatal LPS exposure induced consistent deficits in cognitive tests with relevance for schizophrenia. Nicotine reversed the LPS-induced deficits in selective attention (LI) and induced a global enhancement of sensorimotor gating (PPI). PMID:27483346

  8. Gemigliptin ameliorates Western-diet-induced metabolic syndrome in mice.

    PubMed

    Choi, Seung Hee; Leem, Jaechan; Park, Sungmi; Lee, Chong-Kee; Park, Keun-Gyu; Lee, In-Kyu

    2017-02-01

    Dipeptidyl peptidase 4 (DPP-4) inhibitors are widely used antihyperglycemic agents for type 2 diabetes mellitus. Recently, increasing attention has been focused on the pleiotropic actions of DPP-4 inhibitors. The aim of the present study was to examine whether gemigliptin, a recently developed DPP-4 inhibitor, could ameliorate features of metabolic syndrome. Mice were fed a Western diet (WD) for 12 weeks and were subsequently divided into 2 groups: mice fed a WD diet alone or mice fed a WD diet supplemented with gemigliptin for an additional 4 weeks. Gemigliptin treatment attenuated WD-induced body mass gain, hypercholesterolemia, adipocyte hypertrophy, and macrophage infiltration into adipose tissue, which were accompanied by an increased expression of uncoupling protein 1 in subcutaneous fat. These events contributed to improved insulin sensitivity, as assessed by the homeostasis model assessment of insulin resistance and intraperitoneal insulin tolerance test. Furthermore, gemigliptin reduced WD-induced hepatic triglyceride accumulation via inhibition of de novo lipogenesis and activation of fatty acid oxidation, which was accompanied by AMP-dependent protein kinase activation. Gemigliptin ameliorated WD-induced hepatic inflammation and fibrosis through suppression of oxidative stress. These results suggest that DPP-4 inhibitors may represent promising therapeutic agents for metabolic syndrome beyond their current role as antihyperglycemic agents.

  9. Losartan ameliorates dystrophic epidermolysis bullosa and uncovers new disease mechanisms

    PubMed Central

    Nyström, Alexander; Thriene, Kerstin; Mittapalli, Venugopal; Kern, Johannes S; Kiritsi, Dimitra; Dengjel, Jörn; Bruckner-Tuderman, Leena

    2015-01-01

    Genetic loss of collagen VII causes recessive dystrophic epidermolysis bullosa (RDEB)—a severe skin fragility disorder associated with lifelong blistering and disabling progressive soft tissue fibrosis. Causative therapies for this complex disorder face major hurdles, and clinical implementation remains elusive. Here, we report an alternative evidence-based approach to ameliorate fibrosis and relieve symptoms in RDEB. Based on the findings that TGF-β activity is elevated in injured RDEB skin, we targeted TGF-β activity with losartan in a preclinical setting. Long-term treatment of RDEB mice efficiently reduced TGF-β signaling in chronically injured forepaws and halted fibrosis and subsequent fusion of the digits. In addition, proteomics analysis of losartan- vs. vehicle-treated RDEB skin uncovered changes in multiple proteins related to tissue inflammation. In line with this, losartan reduced inflammation and diminished TNF-α and IL-6 expression in injured forepaws. Collectively, the data argue that RDEB fibrosis is a consequence of a cascade encompassing tissue damage, TGF-β-mediated inflammation, and matrix remodeling. Inhibition of TGF-β activity limits these unwanted outcomes and thereby substantially ameliorates long-term symptoms. PMID:26194911

  10. Flurbiprofen Ameliorates Glucose Deprivation-Induced Leptin Resistance

    PubMed Central

    Hosoi, Toru; Suyama, Yuka; Kayano, Takaaki; Ozawa, Koichiro

    2016-01-01

    Leptin resistance is one of the mechanisms involved in the pathophysiology of obesity. The present study showed that glucose deprivation inhibited leptin-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3) and signal transducer and activator of transcription 5 (STAT5) in neuronal cells. Flurbiprofen reversed glucose deprivation-mediated attenuation of STAT3, but not STAT5 activation, in leptin-treated cells. Glucose deprivation increased C/EBP-homologous protein and glucose regulated protein 78 induction, indicating the activation of unfolded protein responses (UPR). Flurbiprofen did not affect the glucose deprivation-induced activation of UPR, but did attenuate the glucose deprivation-mediated induction of AMP-activated protein kinase phosphorylation. Flurbiprofen may ameliorate glucose deprivation-induced leptin resistance in neuronal cells. PMID:27746736

  11. Eupatilin ameliorates collagen induced arthritis.

    PubMed

    Kim, Juryun; Kim, Youngkyun; Yi, Hyoju; Jung, Hyerin; Rim, Yeri Alice; Park, Narae; Jung, Seung Min; Park, Sung-Hwan; Ju, Ji Hyeon

    2015-03-01

    Eupatilin is the main active component of DA-9601, an extract from Artemisia. Recently, eupatilin was reported to have anti-inflammatory properties. We investigated the anti-arthritic effect of eupatilin in a murine arthritis model and human rheumatoid synoviocytes. DA-9601 was injected into collagen-induced arthritis (CIA) mice. Arthritis score was regularly evaluated. Mouse monocytes were differentiated into osteoclasts when eupatilin was added simultaneously. Osteoclasts were stained with tartrate-resistant acid phosphatase and then manually counted. Rheumatoid synoviocytes were stimulated with TNF-α and then treated with eupatilin, and the levels of IL-6 and IL-1β mRNA expression in synoviocytes were measured by RT-PCR. Intraperitoneal injection of DA-9601 reduced arthritis scores in CIA mice. TNF-α treatment of synoviocytes increased the expression of IL-6 and IL-1β mRNAs, which was inhibited by eupatilin. Eupatilin decreased the number of osteoclasts in a concentration dependent manner. These findings, showing that eupatilin and DA-9601 inhibited the expression of inflammatory cytokines and the differentiation of osteoclasts, suggest that eupatilin and DA-9601 is a candidate anti-inflammatory agent.

  12. 27 CFR 24.178 - Amelioration.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... OF THE TREASURY ALCOHOL WINE Production of Wine § 24.178 Amelioration. (a) General. In producing natural wine from juice having a fixed acid level exceeding 5.0 grams per liter, the winemaker may adjust..., during and after fermentation. The fixed acid level of the juice is determined prior to fermentation...

  13. 27 CFR 24.178 - Amelioration.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... OF THE TREASURY LIQUORS WINE Production of Wine § 24.178 Amelioration. (a) General. In producing natural wine from juice having a fixed acid level exceeding 5.0 grams per liter, the winemaker may adjust..., during and after fermentation. The fixed acid level of the juice is determined prior to fermentation...

  14. 27 CFR 24.178 - Amelioration.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... OF THE TREASURY LIQUORS WINE Production of Wine § 24.178 Amelioration. (a) General. In producing natural wine from juice having a fixed acid level exceeding 5.0 grams per liter, the winemaker may adjust..., during and after fermentation. The fixed acid level of the juice is determined prior to fermentation...

  15. 27 CFR 24.178 - Amelioration.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... OF THE TREASURY LIQUORS WINE Production of Wine § 24.178 Amelioration. (a) General. In producing natural wine from juice having a fixed acid level exceeding 5.0 grams per liter, the winemaker may adjust..., during and after fermentation. The fixed acid level of the juice is determined prior to fermentation...

  16. 27 CFR 24.178 - Amelioration.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... OF THE TREASURY ALCOHOL WINE Production of Wine § 24.178 Amelioration. (a) General. In producing natural wine from juice having a fixed acid level exceeding 5.0 grams per liter, the winemaker may adjust..., during and after fermentation. The fixed acid level of the juice is determined prior to fermentation...

  17. Differential Occurrence of Reluctant Openings in G-Protein–Inhibited N- and P/Q-Type Calcium Channels

    PubMed Central

    Colecraft, Henry M.; Patil, Parag G.; Yue, David T.

    2000-01-01

    Voltage-dependent inhibition of N- and P/Q-type calcium channels by G proteins is crucial for presynaptic inhibition of neurotransmitter release, and may contribute importantly to short-term synaptic plasticity. Such calcium-channel modulation could thereby impact significantly the neuro-computational repertoire of neural networks. The differential modulation of N and P/Q channels could even further enrich their impact upon synaptic tuning. Here, we performed in-depth comparison of the G-protein inhibition of recombinant N and P/Q channels, expressed in HEK 293 cells with the m2 muscarinic receptor. While both channel types display classic features of G-protein modulation (kinetic slowing of activation, prepulse facilitation, and voltage dependence of inhibition), we confirmed previously reported quantitative differences, with N channels displaying stronger inhibition and greater relief of inhibition by prepulses. A more fundamental, qualitative difference in the modulation of these two channels was revealed by a modified tail-activation paradigm, as well as by a novel “slope” analysis method comparing time courses of slow activation and prepulse facilitation. The stark contrast in modulatory behavior can be understood within the context of the “willing–reluctant” model, in which binding of G-protein βγ subunits to channels induces a reluctant mode of gating, where stronger depolarization is required for opening. Our experiments suggest that only N channels could be opened in the reluctant mode, at voltages normally spanned by neuronal action potentials. By contrast, P/Q channels appear to remain closed, especially over these physiological voltages. Further, the differential occurrence of reluctant openings is not explained by differences in the rate of G-protein unbinding from the two channels. These two scenarios predict very different effects of G-protein inhibition on the waveform of Ca2+ entry during action potentials, with potentially important

  18. Amelioration of arsenic toxicity by phosphate salts in mungbean seedlings.

    PubMed

    Swarnakar, Arpita; Mukherji, Subhendu

    2005-07-01

    Sodium arsenate (Na2HAsO4.7H2O) is a potent inhibitor of mungbean seed germination and seedling growth. Germination is totally stopped at or above 50 microM Na2HAsO4.7H2O. Inhibition of seedling elongation started at a lower concentration of 5 microM As(V) and was drastically reduced at 20 microM As(V). Nutrients like salts of macroelements viz., NaH2PO4.2H2O, KH2PO4, K2SO4, MgSO4.7H2O, CaCl2.2H2O, (NH4)2SO4 NH4NO3 solutions at a concentration of 10mM and microelements viz., ZnSO4, CuSO4.5H2O, Na2MoO4.2H2O, MnCl2.4H2O, CoCl2.6H2O, FeSO4.7H2O solutions at a concentration of 1mM could help to ameliorate the toxic effects of As(V) to different degrees. Amelioration of As(V) toxicity was possible only when the mungbean seeds were pretreated with the above mentioned nutrients for 24 hr and then transferred to sodium arsenate. Simultaneous treatment of nutrients with As(V) or using nutrient solutions following As(V) treatment were of no help to reverse the toxic effects of sodium arsenate.

  19. Adrenomedullin ameliorates lipopolysaccharide-induced acute lung injury in rats.

    PubMed

    Itoh, Takefumi; Obata, Hiroaki; Murakami, Shinsuke; Hamada, Kaoru; Kangawa, Kenji; Kimura, Hiroshi; Nagaya, Noritoshi

    2007-08-01

    Adrenomedullin (AM), an endogenous peptide, has been shown to have a variety of protective effects on the cardiovascular system. However, the effect of AM on acute lung injury remains unknown. Accordingly, we investigated whether AM infusion ameliorates lipopolysaccharide (LPS)-induced acute lung injury in rats. Rats were randomized to receive continuous intravenous infusion of AM (0.1 microg x kg(-1) x min(-1)) or vehicle through a microosmotic pump. The animals were intratracheally injected with either LPS (1 mg/kg) or saline. At 6 and 18 h after intratracheal instillation, we performed histological examination and bronchoalveolar lavage and assessed the lung wet/dry weight ratio as an index of acute lung injury. Then we measured the numbers of total cells and neutrophils and the levels of tumor necrosis factor (TNF)-alpha and cytokine-induced neutrophil chemoattractant (CINC) in bronchoalveolar lavage fluid (BALF). In addition, we evaluated BALF total protein and albumin levels as indexes of lung permeability. LPS instillation caused severe acute lung injury, as indicated by the histological findings and the lung wet/dry weight ratio. However, AM infusion attenuated these LPS-induced abnormalities. AM decreased the numbers of total cells and neutrophils and the levels of TNF-alpha and CINC in BALF. AM also reduced BALF total protein and albumin levels. In addition, AM significantly suppressed apoptosis of alveolar wall cells as indicated by cleaved caspase-3 staining. In conclusion, continuous infusion of AM ameliorated LPS-induced acute lung injury in rats. This beneficial effect of AM on acute lung injury may be mediated by inhibition of inflammation, hyperpermeability, and alveolar wall cell apoptosis.

  20. Secreted calmodulin-like skin protein ameliorates scopolamine-induced memory impairment.

    PubMed

    Hayashi, Masaaki; Tajima, Hirohisa; Hashimoto, Yuichi; Matsuoka, Masaaki

    2014-06-18

    Humanin, a short bioactive peptide, inhibits cell death in a variety of cell-based death models through Humanin receptors in vitro. In vivo, Humanin ameliorates both muscarinic receptor antagonist-induced memory impairment in normal mice and memory impairment in Alzheimer's disease (AD)-relevant mouse models including aged transgenic mice expressing a familial AD-linked gene. Recently, calmodulin-like skin protein (CLSP) has been shown to be secreted from skin tissues, contain a region minimally similar to the core region of Humanin, and inhibit AD-related neuronal death through the heterotrimeric Humanin receptor on the cell surface in vitro. As CLSP is much more potent than Humanin and efficiently transported through blood circulation across the blood-brain barrier to the central nervous system, CLSP is considered as a physiological agonist that binds to the heterotrimeric Humanin receptor and triggers the Humanin-induced signals in central nervous system. However, it remains unknown whether CLSP ameliorates memory impairment in mouse dementia models as Humanin does. In this study, we show that recombinant CLSP, administered intracerebroventricularly or intraperitoneally, ameliorates scopolamine-induced dementia in mice.

  1. Immunomodulatory Activities of the Benzoxathiole Derivative BOT-4-One Ameliorate Pathogenic Skin Inflammation in Mice.

    PubMed

    Lee, Hyun Gyu; Cho, Nam-Chul; Jeong, Ae Jin; Li, Yu-Chen; Rhie, Sung-Ja; Choi, Jung Sook; Lee, Kwang-Ho; Kim, Youngsoo; Kim, Yong-Nyun; Kim, Myoung-Hwan; Pae, Ae Nim; Ye, Sang-Kyu; Kim, Byung-Hak

    2015-09-30

    T cell-mediated immune responses play an important role in body protection. However, aberrantly activated immune responses are responsible for inflammatory and autoimmune diseases. The regulation of pathological immune responses may be a potential therapeutic strategy for the treatment of these diseases. Despite multiple pharmacological properties of benzoxathiole derivatives have been defined, the molecular mechanisms underlying these properties remain to be clarified. Here, we demonstrated the benzoxathiole derivative 2-cyclohexylimino-6-methyl-6,7-dihydro-5H-benzo[1,3]oxathiol-4-one (BOT-4-one) regulated immune responses and ameliorated experimentally induced inflammatory skin diseases both in vitro and in vivo. BOT-4-one inhibited the differentiation of CD4(+) T-cell subsets by regulating the expression and production of T cell lineage-specific master transcription factors and cytokines and activating the signal transducer and activator of transcription (STAT) proteins. In addition, BOT-4-one inhibited T-cell receptor (TCR)-mediated Akt and nuclear factor-kappaB (NF-κB) signaling. Topical application of BOT-4-one ameliorated experimentally induced inflammatory skin diseases in mice models such as TNCB-induced contact and atopic dermatitis and IL-23-induced psoriasis-like skin inflammation. Our study demonstrated that BOT-4-one ameliorates inflammatory skin diseases by suppressing the pathogenic CD4(+) T cell differentiation and the overall immune responses.Journal of Investigative Dermatology accepted article preview online, 30 September 2015. doi:10.1038/jid.2015.384.

  2. Immunomodulatory Activities of the Benzoxathiole Derivative BOT-4-One Ameliorate Pathogenic Skin Inflammation in Mice.

    PubMed

    Lee, Hyun Gyu; Cho, Nam-Chul; Jeong, Ae Jin; Li, Yu-Chen; Rhie, Sung-Ja; Choi, Jung Sook; Lee, Kwang-Ho; Kim, Youngsoo; Kim, Yong-Nyun; Kim, Myoung-Hwan; Pae, Ae Nim; Ye, Sang-Kyu; Kim, Byung-Hak

    2016-01-01

    T-cell-mediated immune responses play an important role in body protection. However, aberrantly activated immune responses are responsible for inflammatory and autoimmune diseases. The regulation of pathologic immune responses may be a potential therapeutic strategy for the treatment of these diseases. Despite that multiple pharmacologic properties of benzoxathiole derivatives have been defined, the molecular mechanisms underlying these properties remain to be clarified. Here, we demonstrated the benzoxathiole derivative 2-cyclohexylimino-6-methyl-6,7-dihydro-5H-benzo[1,3]oxathiol-4-one (BOT-4-one) regulated immune responses and ameliorated experimentally induced inflammatory skin diseases both in vitro and in vivo. BOT-4-one inhibited the differentiation of CD4(+) T-cell subsets by regulating the expression and production of T-cell lineage-specific master transcription factors and cytokines and activating the signal transducer and activator of transcription proteins. In addition, BOT-4-one inhibited TCR-mediated Akt and NF-κB signaling. Topical application of BOT-4-one ameliorated experimentally induced inflammatory skin diseases in mice models such as 2,4,6-trinitrochlorobenzene-induced contact and atopic dermatitis and IL-23-induced psoriasis-like skin inflammation. Our study demonstrated that BOT-4-one ameliorates inflammatory skin diseases by suppressing the pathogenic CD4(+) T cell differentiation and overall immune responses.

  3. INSTRUMENTS AND METHODS OF INVESTIGATION: Generation of high-order harmonics of high-power lasers in plasmas produced under irradiation of solid target surfaces by a prepulse

    NASA Astrophysics Data System (ADS)

    Ganeev, Rashid A.

    2009-01-01

    Research on high-order harmonic generation in laser-produced plasmas is reviewed. We analyze the conditions for the generation of harmonics (up to the 101st order, λ = 7.9 nm) in the propagation of laser radiation through a weakly ionized plasma prepared by irradiating the surfaces of different targets with a laser prepulse. We discuss the findings of investigations into the resonance intensity enhancement of individual harmonics in a number of plasma formations, which have demonstrated a substantial increase in the conversion efficiency in the plateau region of the harmonic-order distribution (in particular, of the 13th harmonic in indium plasmas with the efficiency 10-4). We review the results of investigations of harmonic generation in nanoparticle-containing plasmas. Different techniques for increasing the intensity and order of the generated harmonics are discussed.

  4. Treadmill exercise ameliorates intracerebral hemorrhage-induced depression in rats

    PubMed Central

    Roh, Joo Hwan; Ko, Il-Gyu; Kim, Sung-Eun; Lee, Jae-Min; Ji, Eun-Sang; Kim, Ju Ho; Chang, Hyun-Kyung; Lee, Seung Kyu; Kim, Khae Hawn

    2016-01-01

    Intracerebral hemorrhage (ICH) is a severe type of stroke causing neurological dysfunction with high mortality rate. Depression is one of the most common complications of ICH. In the present study, the effects of treadmill exercise on ICH-induced depressive symptoms in relation with apoptosis were investigated using rats. ICH rat model was induced by injection of collagenase into the hippocampus using stereotaxic instrument. Open field test for activity and forced swimming test for depressive symptoms were conducted. Apoptosis in the hippocampus was detected using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, immunohistochemistry for caspase-3, and western blot for Bcl-2 and Bax. Western blot analysis for 5-hydroxy-tryptamine (5-HT, serotonin) and tryptophan hydroxylase (TPH) in the dorsal raphe was also conducted for biomarkers of depression. In the present results, immobility time was increased and climbing time was decreased by induction of ICH and treadmill exercise inhibited immobility time and increased climbing time in ICH rats. DNA fragmentation and caspase-3 expression in the hippocampal dentate gyrus were enhanced by induction of ICH and treadmill exercise suppressed ICH-induced DNA fragmentation and caspase-3 expression. Bax expression in the hippocampus was increased by induction of ICH and treadmill exercise inhibited Bax expression in the ICH rats. Expressions of 5-HT and TPH in the dorsal raphe were decreased by induction of ICH and treadmill exercise increased expressions of 5-HT and TPH in the ICH rats. In the present study, treadmill exercise ameliorated depressive symptoms through inhibiting apoptosis. PMID:27656626

  5. Probiotic BIFICO cocktail ameliorates Helicobacter pylori induced gastritis

    PubMed Central

    Yu, Hong-Jing; Liu, Wei; Chang, Zhen; Shen, Hui; He, Li-Juan; Wang, Sha-Sha; Liu, Lu; Jiang, Yuan-Ying; Xu, Guo-Tong; An, Mao-Mao; Zhang, Jun-Dong

    2015-01-01

    AIM: To determine the protective effect of triple viable probiotics on gastritis induced by Helicobacter pylori (H. pylori) and elucidate the possible mechanisms of protection. METHODS: Colonization of BIFICO strains in the mouse stomach was determined by counting colony-forming units per gram of stomach tissue. After treatment with or without BIFICO, inflammation and H. pylori colonization in the mouse stomach were analyzed by hematoxylin and eosin and Giemsa staining, respectively. Cytokine levels were determined by enzyme-linked immunosorbent assay and Milliplex. The activation of nuclear factor (NF)-κB and MAPK signaling in human gastric epithelial cells was evaluated by Western blot analysis. Quantitative reverse transcription-polymerase chain reaction was used to quantify TLR2, TLR4 and MyD88 mRNA expression in the mouse stomach. RESULTS: We demonstrated that BIFICO, which contains a mixture of Enterococcus faecalis, Bifidobacterium longum and Lactobacillus acidophilus, was tolerant to the mouse stomach environment and was able to survive both the 8-h and 3-d courses of administration. Although BIFICO treatment had no effect on the colonization of H. pylori in the mouse stomach, it ameliorated H. pylori-induced gastritis by significantly inhibiting the expression of cytokines and chemokines such as TNF-α, IL-1β, IL-10, IL-6, G-CSF and MIP-2 (P < 0.05). These results led us to hypothesize that BIFICO treatment would diminish the H. pylori-induced inflammatory response in gastric mucosal epithelial cells in vitro via the NF-κB and MAPK signaling pathways. Indeed, we observed a decrease in the expression of the NF-κB subunit p65 and in the phosphorylation of IκB-α, ERK and p38. Moreover, there was a significant decrease in the production of IL-8, TNF-α, G-CSF and GM-CSF (P < 0.05), and the increased expression of TLR2, TLR4 and MyD88 induced by H. pylori in the stomach was also significantly reduced following BIFICO treatment (P < 0.05). CONCLUSION: Our

  6. Calcium ameliorates diarrhea in immune compromised children

    PubMed Central

    Cheng, Sam X.; Bai, Harrison X.; Gonzalez-Peralta, Regino; Mistry, Pramod K.; Gorelick, Fred S.

    2015-01-01

    Treatment of infectious diarrheas remains a challenge, particularly in immunocompromised patients in whom infections usually persist and resultant diarrhea is often severe and protracted. Children with infectious diarrhea who become dehydrated are normally treated with oral or intravenous rehydration therapy. Although rehydration therapy can replace the loss of fluid, it does not ameliorate diarrhea. Thus, over the past decades, there has been continuous effort to search for ways to safely stop diarrhea. Herein, we report three cases of immunocompromised children who developed severe and/or protracted infectious diarrhea. Their diarrheas were successfully “halted” within 1-2 days following the administration of calcium. PMID:23343935

  7. Simultaneous EMG-fMRI during startle inhibition in monosymptomatic enuresis--an exploratory study.

    PubMed

    Schulz-Juergensen, Sebastian; Wunberg, David; Wolff, Stephan; Eggert, Paul; Siniatchkin, Michael

    2013-01-01

    Evidence is growing that monosymptomatic enuresis (ME) is a maturational disorder of the central nervous system with a lack of arousal and lacking inhibition of the micturition reflex. Previous studies have shown a significant reduction of prepulse inhibition (PPI) of startle in children with enuresis. However, it is still unclear whether the abnormal PPI in enuresis is based on an inhibitory deficit at brainstem or cortical level. Nine children with ME and ten healthy children were investigated using simultaneous recording of EMG from the M. orbicularis oculi and functional MRI. The experimental paradigm consisted of acoustic startle stimulation, with startle-alone stimuli and prepulse-startle combinations. Functional MRI data were processed using multiple regression and parametric modulation with startle amplitudes as a parameter. Neither patients with enuresis nor healthy children revealed measurable PPI in the MRI scanner. Startle stimuli caused equal hemodynamic changes in the acoustic cortex, medial prefrontal and orbitofrontal cortex in both groups. The amplitude of startle correlated with more prominent BOLD signal changes in the anterior cingulate cortex in healthy subjects than in patients with ME. This pronounced frontal activation in healthy controls was related to the PPI condition, indicating that the prefrontal cortex of healthy children was activated more strongly to inhibit startle than in patients with ME. In conclusion, apart from the possibility that recordings of PPI inside the MRI scanner may be compromised by methodological problems, the results of this study suggest that high cortical control mechanisms at the prefrontal level are relevant for the pathogenesis of ME.

  8. Cacao polyphenols ameliorate autoimmune myocarditis in mice.

    PubMed

    Zempo, Hirofumi; Suzuki, Jun-ichi; Watanabe, Ryo; Wakayama, Kouji; Kumagai, Hidetoshi; Ikeda, Yuichi; Akazawa, Hiroshi; Komuro, Issei; Isobe, Mitsuaki

    2016-04-01

    Myocarditis is a clinically severe disease; however, no effective treatment has been established. The aim of this study was to determine whether cacao bean (Theobroma cacao) polyphenols ameliorate autoimmune myocarditis. We used an experimental autoimmune myocarditis (EAM) model in Balb/c mice. Mice with induced EAM were treated with a cacao polyphenol extract (CPE, n=12) or vehicle (n=12). On day 21, hearts were harvested and analyzed. Elevated heart weight to body weight and fibrotic area ratios as well as high cardiac cell infiltration were observed in the vehicle-treated EAM mice. However, these increases were significantly suppressed in the CPE-treated mice. Reverse transcriptase-PCR revealed that mRNA expressions of interleukin (Il)-1β, Il-6, E-selectin, vascular cell adhesion molecule-1 and collagen type 1 were lower in the CPE group compared with the vehicle group. The mRNA expressions of nicotinamide adenine dinucleotide phosphate-oxidase (Nox)2 and Nox4 were increased in the vehicle-treated EAM hearts, although CPE treatment did not significantly suppress the transcription levels. However, compared with vehicle treatment of EAM hearts, CPE treatment significantly suppressed hydrogen peroxide concentrations. Cardiac myeloperoxidase activity, the intensity of dihydroethidium staining and the phosphorylation of nuclear factor-κB p65 were also lower in the CPE group compared with the vehicle group. Our data suggest that CPE ameliorates EAM in mice. CPE is a promising dietary supplement to suppress cardiovascular inflammation and oxidative stress.

  9. Means for limiting and ameliorating electrode shorting

    DOEpatents

    Van Konynenburg, Richard A.; Farmer, Joseph C.

    1999-01-01

    A fuse and filter arrangement for limiting and ameliorating electrode shorting in capacitive deionization water purification systems utilizing carbon aerogel, for example. This arrangement limits and ameliorates the effects of conducting particles or debonded carbon aerogel in shorting the electrodes of a system such as a capacitive deionization water purification system. This is important because of the small interelectrode spacing and the finite possibility of debonding or fragmentation of carbon aerogel in a large system. The fuse and filter arrangement electrically protect the entire system from shutting down if a single pair of electrodes is shorted and mechanically prevents a conducting particle from migrating through the electrode stack, shorting a series of electrode pairs in sequence. It also limits the amount of energy released in a shorting event. The arrangement consists of a set of circuit breakers or fuses with one fuse or breaker in the power line connected to one electrode of each electrode pair and a set of screens of filters in the water flow channels between each set of electrode pairs.

  10. Arctigenin isolated from the seeds of Arctium lappa ameliorates memory deficits in mice.

    PubMed

    Lee, In-Ah; Joh, Eun-Ha; Kim, Dong-Hyun

    2011-09-01

    The seeds of Arctium lappa L. (AL, family Asteraceae), the main constituents of which are arctiin and arctigenin, have been used as an herbal medicine or functional food to treat inflammatory diseases. These main constituents were shown to inhibit acetylcholinesterase (AChE) activity. Arctigenin more potently inhibited AChE activity than arctiin. Arctigenin at doses of 30 and 60 mg/kg (p. o.) potently reversed scopolamine-induced memory deficits by 62 % and 73 %, respectively, in a passive avoidance test. This finding is comparable with that of tacrine (10 mg/kg p. o.). Arctigenin also significantly reversed scopolamine-induced memory deficits in the Y-maze and Morris water maze tests. On the basis of these findings, arctigenin may ameliorate memory deficits by inhibiting AChE.

  11. Pathways Implicated in Tadalafil Amelioration of Duchenne Muscular Dystrophy.

    PubMed

    De Arcangelis, Valeria; Strimpakos, Georgios; Gabanella, Francesca; Corbi, Nicoletta; Luvisetto, Siro; Magrelli, Armando; Onori, Annalisa; Passananti, Claudio; Pisani, Cinzia; Rome, Sophie; Severini, Cinzia; Naro, Fabio; Mattei, Elisabetta; Di Certo, Maria Grazia; Monaco, Lucia

    2016-01-01

    Numerous therapeutic approaches for Duchenne and Becker Muscular Dystrophy (DMD and BMD), the most common X-linked muscle degenerative disease, have been proposed. So far, the only one showing a clear beneficial effect is the use of corticosteroids. Recent evidence indicates an improvement of dystrophic cardiac and skeletal muscles in the presence of sustained cGMP levels secondary to a blocking of their degradation by phosphodiesterase five (PDE5). Due to these data, we performed a study to investigate the effect of the specific PDE5 inhibitor, tadalafil, on dystrophic skeletal muscle function. Chronic pharmacological treatment with tadalafil has been carried out in mdx mice. Behavioral and physiological tests, as well as histological and biochemical analyses, confirmed the efficacy of the therapy. We then performed a microarray-based genomic analysis to assess the pattern of gene expression in muscle samples obtained from the different cohorts of animals treated with tadalafil. This scrutiny allowed us to identify several classes of modulated genes. Our results show that PDE5 inhibition can ameliorate dystrophy by acting at different levels. Tadalafil can lead to (1) increased lipid metabolism; (2) a switch towards slow oxidative fibers driven by the up-regulation of PGC-1α; (3) an increased protein synthesis efficiency; (4) a better actin network organization at Z-disk.

  12. SnoN upregulation ameliorates renal fibrosis in diabetic nephropathy

    PubMed Central

    Liu, Lirong; Shi, Mingjun; Wang, Yuanyuan; Zhang, Changzhi; Su, Bo; Xiao, Ying; Guo, Bing

    2017-01-01

    Progressive reduction of SnoN is associated with gradual elevation of TGF-β1 during diabetic nephropathy progression, suggesting SnoN to be a possible mediator of TGF-β1 signaling, with potential therapeutic benefits against TGF- β1 –induced renal fibrosis. To characterize SnoN for its role in renal fibrosis, we assessed SnoN expression patterns in response to high glucose stress, and evaluated the effects of upregulating SnoN on renal fibrosis. High glucose stress induced significantly elevated SnoN, TGF-β1, and Arkadia transcription; however, significantly reduced SnoN protein levels were observed under these conditions. Upregulating the SnoN protein was achieved by Arkadia knockdown, which resulted in inhibited high glucose-induced epithelial-mesenchymal transition (EMT) in renal tubular cells, the onset phase of renal fibrosis. Alternatively, EMT was suppressed by dominantly expressed exogenous SnoN without interfering with TGF-β1. Overall, renal SnoN upregulation ameliorates renal fibrosis by relieving high glucose-induced EMT; these findings support a translational approach targeting SnoN for the treatment of diabetic nephropathy. PMID:28350874

  13. Triptolide ameliorates colonic fibrosis in an experimental rat model

    PubMed Central

    TAO, QINGSONG; WANG, BAOCHAI; ZHENG, YU; LI, GUANWEI; REN, JIANAN

    2015-01-01

    Triptolide is known to exert anti-inflammatory and immunomodulatory activities; however, its impact on intestinal fibrosis has not been previously examined. Based on our previous studies of the suppressive activity of triptolide on human colonic subepithelial myofibroblasts and the therapeutic efficacy of triptolide in Crohn’s disease, it was hypothesized that triptolide may have beneficial effects on intestinal fibrosis. In the present study, colonic fibrosis was induced in rats by 6 weekly repeated administration with a low-dose of 2,4,6-trinitrobenzene sulfonic acid (TNBS) and was then treated with triptolide or PBS daily (control) simultaneously. Extracellular matrix (ECM) deposition in the colon was examined with image analysis of Masson Trichrome staining. Total collagen levels in colonic homogenates were measured by a Sircol assay. Collagen Iα1 transcripts and collagen I protein were measured ex vivo in the isolated colonic subepithelial myofibroblasts by reverse transcription-quantitative polymerase chain reaction and immunoblot analysis, respectively. The results indicated that triptolide decreased ECM deposition and collagen production in the colon, and inhibited collagen Iα1 transcripts and collagen I protein expression in the isolated subepithelial myofibroblasts of the rats with colonic fibrosis. In conclusion, triptolide ameliorates colonic fibrosis in the experimental rat model, suggesting triptolide may be a promising compound for inflammatory bowel disease treatment. PMID:25845760

  14. Maturation-Resistant Dendritic Cells Ameliorate Experimental Autoimmune Uveoretinitis

    PubMed Central

    Oh, Keunhee; Kim, Yon Su

    2011-01-01

    Background Endogenous uveitis is a chronic inflammatory eye disease of human, which frequently leads to blindness. Experimental autoimmune uveoretinitis (EAU) is an animal disease model of human endogenous uveitis and can be induced in susceptible animals by immunization with retinal antigens. EAU resembles the key immunological characteristics of human disease in that both are CD4+ T-cell mediated diseases. Dendritic cells (DCs) are specialized antigen-presenting cells that are uniquely capable of activating naïve T cells. Regulation of immune responses through modulation of DCs has thus been tried extensively. Recently our group reported that donor strain-derived immature DC pretreatment successfully controlled the adverse immune response during allogeneic transplantation. Methods EAU was induced by immunization with human interphotoreceptor retinoid-binding protein (IRBP) peptide1-20. Dendritic cells were differentiated from bone marrow in the presence of recombinant GM-CSF. Results In this study, we used paraformaldehyde-fixed bone marrow-derived DCs to maintain them in an immature state. Pretreatment with fixed immature DCs, but not fixed mature DCs, ameliorated the disease progression of EAU by inhibiting uveitogenic CD4+ T cell activation and differentiation. Conclusion Application of iBMDC prepared according to the protocol of this study would provide an important treatment modality for the autoimmune diseases and transplantation rejection. PMID:22346781

  15. Astragaloside IV ameliorates renal injury in db/db mice

    PubMed Central

    Sun, Huili; Wang, Wenjing; Han, Pengxun; Shao, Mumin; Song, Gaofeng; Du, Heng; Yi, Tiegang; Li, Shunmin

    2016-01-01

    Diabetic nephropathy is a lethal complication of diabetes mellitus and a major type of chronic kidney disease. Dysregulation of the Akt pathway and its downstream cascades, including mTOR, NFκB, and Erk1/2, play a critical role in the development of diabetic nephropathy. Astragaloside IV is a major component of Huangqi and exerts renal protection in a mouse model of type 1 diabetes. The current study was undertaken to investigate the protective effects of diet supplementation of AS-IV on renal injury in db/db mice, a type 2 diabetic mouse model. Results showed that administration of AS-IV reduced albuminuria, ameliorated changes in the glomerular and tubular pathology, and decreased urinary NAG, NGAL, and TGF-β1 in db/db mice. AS-IV also attenuated the diabetes-related activation of Akt/mTOR, NFκB, and Erk1/2 signaling pathways without causing any detectable hepatotoxicity. Collectively, these findings showed AS-IV to be beneficial to type 2 diabetic nephropathy, which might be associated with the inhibition of Akt/mTOR, NFκB and Erk1/2 signaling pathways. PMID:27585918

  16. Resveratrol ameliorates ionizing irradiation-induced long-term hematopoietic stem cell injury in mice.

    PubMed

    Zhang, Heng; Zhai, Zhibin; Wang, Yueying; Zhang, Junling; Wu, Hongying; Wang, Yingying; Li, Chengcheng; Li, Deguan; Lu, Lu; Wang, Xiaochun; Chang, Jianhui; Hou, Qi; Ju, Zhenyu; Zhou, Daohong; Meng, Aimin

    2013-01-01

    Our recent studies showed that total body irradiation (TBI) induces long-term bone marrow (BM) suppression in part by induction of hematopoietic stem cell (HSC) senescence through NADPH oxidase 4 (NOX4)-derived reactive oxygen species (ROS). Therefore, in this study we examined whether resveratrol (3,5,4'-trihydroxy-trans-stilbene), a potent antioxidant and a putative activator of Sirtuin 1 (Sirt1), can ameliorate TBI-induced long-term BM injury by inhibiting radiation-induced chronic oxidative stress and senescence in HSCs. Our results showed that pretreatment with resveratrol not only protected mice from TBI-induced acute BM syndrome and lethality but also ameliorated TBI-induced long-term BM injury. The latter effect is probably attributable to resveratrol-mediated reduction of chronic oxidative stress in HSCs, because resveratrol treatment significantly inhibited TBI-induced increase in ROS production in HSCs and prevented mouse BM HSCs from TBI-induced senescence, leading to a significant improvement in HSC clonogenic function and long-term engraftment after transplantation. The inhibition of TBI-induced ROS production in HSCs is probably attributable to resveratrol-mediated downregulation of NOX4 expression and upregulation of Sirt1, superoxide dismutase 2 (SOD2), and glutathione peroxidase 1 expression. Furthermore, we showed that resveratrol increased Sirt1 deacetylase activity in BM hematopoietic cells; and Ex527, a potent Sirt1 inhibitor, can attenuate resveratrol-induced SOD2 expression and the radioprotective effect of resveratrol on HSCs. These findings demonstrate that resveratrol can protect HSCs from radiation at least in part via activation of Sirt1. Therefore, resveratrol has the potential to be used as an effective therapeutic agent to ameliorate TBI-induced long-term BM injury.

  17. IV INTERNATIONAL CONFERENCE ON ATOM AND MOLECULAR PULSED LASERS (AMPL'99): Efficient long-pulse XeCl laser with a prepulse formed by an inductive energy storage device

    NASA Astrophysics Data System (ADS)

    Baksht, E. Kh; Panchenko, Aleksei N.; Tarasenko, Viktor F.

    2000-06-01

    An efficient electric-discharge XeCl laser is developed, which is pumped by a self-sustained discharge with a prepulse formed by a generator with an inductive energy storage device and a semiconductor current interrupter on a basis of semiconductor opening switch (SOS) diodes. An output energy up to 800 mJ, a pulse length up to 450 ns, and a total laser efficiency of 2.2% were attained by using spark UV preionisation.

  18. ANTIOXIDANTS AMELIORATION OF ARSENICAL-INDUCED EFFECTS IN VIVO

    EPA Science Inventory

    Antioxidant amelioration of arsenical-induced effects in vivo. ES Hunter and EH Rogers. Reproductive Toxicology Division, NHEERL, US EPA, RTP, NC.

    Antioxidants have been reported to ameliorate the effects of many developmental toxicants. We tested the hypothesis that oxi...

  19. High molecular weight polysaccharide that binds and inhibits virus

    DOEpatents

    Konowalchuk, Thomas W

    2014-01-14

    This invention provides a high molecular weight polysaccharide capable of binding to and inhibiting virus and related pharmaceutical formulations and methods on inhibiting viral infectivity and/or pathogenicity, as well as immunogenic compositions. The invention further methods of inhibiting the growth of cancer cells and of ameliorating a symptom of aging. Additionally, the invention provides methods of detecting and/or quantifying and/or isolating viruses.

  20. Ameliorated GA approach for base station planning

    NASA Astrophysics Data System (ADS)

    Wang, Andong; Sun, Hongyue; Wu, Xiaomin

    2011-10-01

    In this paper, we aim at locating base station (BS) rationally to satisfy the most customs by using the least BSs. An ameliorated GA is proposed to search for the optimum solution. In the algorithm, we mesh the area to be planned according to least overlap length derived from coverage radius, bring into isometric grid encoding method to represent BS distribution as well as its number and develop select, crossover and mutation operators to serve our unique necessity. We also construct our comprehensive object function after synthesizing coverage ratio, overlap ratio, population and geographical conditions. Finally, after importing an electronic map of the area to be planned, a recommended strategy draft would be exported correspondingly. We eventually import HongKong, China to simulate and yield a satisfactory solution.

  1. Neuronal dysfunction with aging and its amelioration.

    PubMed

    Ando, Susumu

    2012-01-01

    The author focused on the functional decline of synapses in the brain with aging to understand the underlying mechanisms and to ameliorate the deficits. The first attempt was to unravel the neuronal functions of gangliosides so that gangliosides could be used for enhancing synaptic activity. The second attempt was to elicit the neuronal plasticity in aged animals through enriched environmental stimulation and nutritional intervention. Environmental stimuli were revealed neurochemically and morphologically to develop synapses leading to enhanced cognitive function. Dietary restriction as a nutritional intervention restored the altered metabolism of neuronal membranes with aging, providing a possible explanation for the longevity effect of dietary restriction. These results obtained with aging and dementia models of animals would benefit aged people.

  2. Metformin protects against apoptosis and senescence in nucleus pulposus cells and ameliorates disc degeneration in vivo

    PubMed Central

    Chen, Deheng; Xia, Dongdong; Pan, Zongyou; Xu, Daoliang; Zhou, Yifei; Wu, Yaosen; Cai, Ningyu; Tang, Qian; Wang, Chenggui; Yan, Meijun; Zhang, Jing Jie; Zhou, Kailiang; Wang, Quan; Feng, Yongzeng; Wang, Xiangyang; Xu, Huazi; Zhang, Xiaolei; Tian, Naifeng

    2016-01-01

    Intervertebral disc degeneration (IDD) is a complicated process that involves both cellular apoptosis and senescence. Metformin has been reported to stimulate autophagy, whereas autophagy is shown to protect against apoptosis and senescence. Therefore, we hypothesize that metformin may have therapeutic effect on IDD through autophagy stimulation. The effect of metformin on IDD was investigated both in vitro and in vivo. Our study showed that metformin attenuated cellular apoptosis and senescence induced by tert-butyl hydroperoxide in nucleus pulposus cells. Autophagy, as well as its upstream regulator AMPK, was activated by metformin in nucleus pulposus cells in a dose- and time-dependent manner. Inhibition of autophagy by 3-MA partially abolished the protective effect of metformin against nucleus pulposus cells' apoptosis and senescence, indicating that autophagy was involved in the protective effect of metformin on IDD. In addition, metformin was shown to promote the expression of anabolic genes such as Col2a1 and Acan expression while inhibiting the expression of catabolic genes such as Mmp3 and Adamts5 in nucleus pulposus cells. In vivo study illustrated that metformin treatment could ameliorate IDD in a puncture-induced rat model. Thus, our study showed that metformin could protect nucleus pulposus cells against apoptosis and senescence via autophagy stimulation and ameliorate disc degeneration in vivo, revealing its potential to be a therapeutic agent for IDD. PMID:27787519

  3. 27 CFR 24.304 - Chaptalization (Brix adjustment) and amelioration record.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... ameliorating material. If fruit juice other than grape is chaptalized and this juice or wine is ameliorated... Chaptalization (Brix adjustment) and amelioration record. (a) General. A proprietor who chaptalizes juice or ameliorates juice or wine, or both, shall maintain a record of the operation and the transaction date....

  4. Resveratrol Pretreatment Ameliorates TNBS Colitis in Rats.

    PubMed

    Yildiz, Gulserap; Yildiz, Yuksel; Ulutas, Pinar A; Yaylali, Asl; Ural, Muruvvet

    2015-01-01

    Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory disease in humans constituting a major health concern today whose prevalence has been increasing over the world. Production of reactive oxygen species (ROS) and disturbed capacity of antioxidant defense in IBD subjects have been reported. Antioxidants may play a significant role in IBD treatment. This study aimed at evaluating ameliorative effects of intraperitoneal resveratrol pretreatment on trinitrobenzene sulphonic acid (TNBS)-induced colitis in rats. Thirty five Wistar-Albino female rats were divided equally into five groups. Inflammation was induced by the intrarectal administration of TNBS under anesthesia. Intraperitoneal administration of resveratrol (RSV) at a concentration of 10mg/kg/day for 5 days before the induction of colitis significantly reduced microscopy score and malondialdehyde (MDA) levels and increased glutathione peroxidase (GSH Px) activity compared to TNBS and vehicle groups. Also an insignificant increase in catalase (CAT) activity was observed in the RSV treated group compared to TNBS and vehicle groups. In this paper, the most recent patent on the identification and treatment of IBD was indicated. In conclusion, antioxidant RSV proved to have a beneficial effect on TNBS colitis in rats. In light of these advantageous results, the RSV can be considered as adjuvant agent in IBD treatments.

  5. Postauricular reflexes elicited by soft acoustic clicks and loud noise probes: Reliability, prepulse facilitation, and sensitivity to picture contents.

    PubMed

    Aaron, Rachel V; Benning, Stephen D

    2016-12-01

    The startle blink reflex is facilitated during early picture viewing, then inhibited by attention during pleasant and aversive pictures compared to neutral pictures, and finally potentiated during aversive pictures specifically. However, it is unclear whether the postauricular reflex, which is elicited by the same loud acoustic probe as the startle blink reflex but enhanced by appetitive instead of defensive emotion, has the same pattern and time course of emotional modulation. We examined this issue in a sample of 90 undergraduates using serially presented soft acoustic clicks that elicited postauricular (but not startle blink) reflexes in addition to standard startle probes. Postauricular reflexes elicited by both clicks and probes correlated during food and nurturant contents, during which they were potentiated compared to neutral pictures, suggesting clicks effectively elicit emotionally modulated postauricular reflexes. The postauricular reflex was initially facilitated during the first 500 ms of picture processing but was larger during pleasant than neutral pictures throughout picture processing, with larger effect sizes during the latter half of picture processing. Across reflexes and eliciting stimuli, measures of emotional modulation had higher coefficient alphas than magnitudes during specific picture contents within each valence, indicating that only emotional modulation measures assess higher-order appetitive or defensive processing.

  6. SIRT2 ameliorates lipopolysaccharide-induced inflammation in macrophages

    SciTech Connect

    Lee, Ae Sin; Jung, Yu Jin; Kim, Dal; Nguyen-Thanh, Tung; Kang, Kyung Pyo; Lee, Sik; Park, Sung Kwang; Kim, Won

    2014-08-08

    Highlights: • Knockout of SIRT2 attenuates lipopolysaccharide-induced iNOS expression. • Lipopolysaccharide-induced NO production is decreased in SIRT2 KO macrophage. • SIRT2 deficiency suppresses lipopolysaccharide-induced ROS production in macrophage. • M1-macrophage related factors are decreased in SIRT2 deficient cells. • SIRT2 deficiency decreases lipopolysaccharide-induced activation of NFκB. - Abstract: Introduction: SIRT2 is a NAD(+)-dependent deacetylases and associated with numerous processes such as infection, carcinogenesis, DNA damage and cell cycle regulation. However, the role of SIRT2 in inflammatory process in macrophage remains unclear. Materials and methods: In the present study, we have evaluated the regulatory effects of SIRT2 in lipopolysaccharide (LPS)-stimulated macrophages isolated from SIRT2 knockout (KO) and wild type (WT) mice or Raw264.7 macrophage cells. As inflammatory parameters, expression of inducible nitric oxide synthase (iNOS), the productions of nitric oxide, reactive oxygen species (ROS) and M1-macrophage-related factors were evaluated. We also examined the effects of SIRT2 on activation of nuclear factor-kappaB (NFκB) signaling. Results: SIRT2 deficiency inhibits LPS-induced iNOS mRNA and protein expression in bone marrow derived macrophages. SIRT2-siRNA transfection also suppressed LPS-induced iNOS expression in Raw264.7 macrophage cells. Bone marrow derived macrophages isolated from SIRT2 KO mice produced lower nitric oxide and expressed lower levels of M1-macrophage related markers including iNOS and CD86 in response to LPS than WT mice. Decrease of SIRT2 reduced the LPS-induced reactive oxygen species production. Deficiency of SIRT2 resulted in inhibition of NFκB activation through reducing the phosphorylation and degradation of IκBα. The phosphorylation and nuclear translocation of p65 was significantly decreased in SIRT2-deficient macrophages after LPS stimulation. Discussion: Our data suggested that

  7. Amelioration of acute graft-versus-host disease by NKG2A engagement on donor T cells.

    PubMed

    Kawamura, Hiroki; Yagita, Hideo; Nisizawa, Tetsuro; Izumi, Nakako; Miyaji, Chikako; Vance, Russell E; Raulet, David H; Okumura, Ko; Abo, Toru

    2005-08-01

    Acute graft-versus-host disease (aGVHD) remains a major complication of allogeneic bone marrow transplantation, which is caused by donor T cells specific for host alloantigens. In a murine model, we found that donor T cells expressed a natural killer cell inhibitory receptor, CD94/NKG2A, during the course of aGVHD. Administration of an anti-NKG2A mAb markedly inhibited the expansion of donor T cells and ameliorated the aGVHD pathologies. These results suggested that the CD94/NKG2A inhibitory receptor expressed on host-reactive donor T cells can be a novel target for the amelioration of aGVHD.

  8. Shifting FcγRIIA-ITAM from activation to inhibitory configuration ameliorates arthritis.

    PubMed

    Ben Mkaddem, Sanae; Hayem, Gilles; Jönsson, Friederike; Rossato, Elisabetta; Boedec, Erwan; Boussetta, Tarek; El Benna, Jamel; Launay, Pierre; Goujon, Jean-Michel; Benhamou, Marc; Bruhns, Pierre; Monteiro, Renato C

    2014-09-01

    Rheumatoid arthritis-associated (RA-associated) inflammation is mediated through the interaction between RA IgG immune complexes and IgG Fc receptors on immune cells. Polymorphisms within the gene encoding the human IgG Fc receptor IIA (hFcγRIIA) are associated with an increased risk of developing RA. Within the hFcγRIIA intracytoplasmic domain, there are 2 conserved tyrosine residues arranged in a noncanonical immunoreceptor tyrosine-based activation motif (ITAM). Here, we reveal that inhibitory engagement of the hFcγRIIA ITAM either with anti-hFcγRII F(ab')2 fragments or intravenous hIgG (IVIg) ameliorates RA-associated inflammation, and this effect was characteristic of previously described inhibitory ITAM (ITAMi) signaling for hFcαRI and hFcγRIIIA, but only involves a single tyrosine. In hFcγRIIA-expressing mice, arthritis induction was inhibited following hFcγRIIA engagement. Moreover, hFcγRIIA ITAMi-signaling reduced ROS and inflammatory cytokine production through inhibition of guanine nucleotide exchange factor VAV-1 and IL-1 receptor-associated kinase 1 (IRAK-1), respectively. ITAMi signaling was mediated by tyrosine 304 (Y304) within the hFcγRIIA ITAM, which was required for recruitment of tyrosine kinase SYK and tyrosine phosphatase SHP-1. Anti-hFcγRII F(ab')2 treatment of inflammatory synovial cells from RA patients inhibited ROS production through induction of ITAMi signaling. These data suggest that shifting constitutive hFcγRIIA-mediated activation to ITAMi signaling could ameliorate RA-associated inflammation.

  9. Amelioration of radiation-induced hematopoietic and gastrointestinal damage by Ex-RAD(R) in mice.

    PubMed

    Ghosh, Sanchita P; Kulkarni, Shilpa; Perkins, Michael W; Hieber, Kevin; Pessu, Roli L; Gambles, Kristen; Maniar, Manoj; Kao, Tzu-Cheg; Seed, Thomas M; Kumar, K Sree

    2012-07-01

    The aim of the present study was to assess recovery from hematopoietic and gastrointestinal damage by Ex-RAD(®), also known as ON01210.Na (4-carboxystyryl-4-chlorobenzylsulfone, sodium salt), after total body radiation. In our previous study, we reported that Ex-RAD, a small-molecule radioprotectant, enhances survival of mice exposed to gamma radiation, and prevents radiation-induced apoptosis as measured by the inhibition of radiation-induced protein 53 (p53) expression in cultured cells. We have expanded this study to determine best effective dose, dose-reduction factor (DRF), hematological and gastrointestinal protection, and in vivo inhibition of p53 signaling. A total of 500 mg/kg of Ex-RAD administered at 24 h and 15 min before radiation resulted in a DRF of 1.16. Ex-RAD ameliorated radiation-induced hematopoietic damage as monitored by the accelerated recovery of peripheral blood cells, and protection of granulocyte macrophage colony-forming units (GM-CFU) in bone marrow. Western blot analysis on spleen indicated that Ex-RAD treatment inhibited p53 phosphorylation. Ex-RAD treatment reduces terminal deoxynucleotidyl transferase mediated dUTP nick end labeling assay (TUNEL)-positive cells in jejunum compared with vehicle-treated mice after radiation injury. Finally, Ex-RAD preserved intestinal crypt cells compared with the vehicle control at 13 and 14 Gy. The results demonstrated that Ex-RAD ameliorates radiation-induced peripheral blood cell depletion, promotes bone marrow recovery, reduces p53 signaling in spleen and protects intestine from radiation injury.

  10. Metformin ameliorates ionizing irradiation-induced long-term hematopoietic stem cell injury in mice.

    PubMed

    Xu, Guoshun; Wu, Hongying; Zhang, Junling; Li, Deguan; Wang, Yueying; Wang, Yingying; Zhang, Heng; Lu, Lu; Li, Chengcheng; Huang, Song; Xing, Yonghua; Zhou, Daohong; Meng, Aimin

    2015-10-01

    Exposure to ionizing radiation (IR) increases the production of reactive oxygen species (ROS) not only by the radiolysis of water but also through IR-induced perturbation of the cellular metabolism and disturbance of the balance of reduction/oxidation reactions. Our recent studies showed that the increased production of intracellular ROS induced by IR contributes to IR-induced late effects, particularly in the hematopoietic system, because inhibition of ROS production with an antioxidant after IR exposure can mitigate IR-induced long-term bone marrow (BM) injury. Metformin is a widely used drug for the treatment of type 2 diabetes. Metformin also has the ability to regulate cellular metabolism and ROS production by activating AMP-activated protein kinase. Therefore, we examined whether metformin can ameliorate IR-induced long-term BM injury in a total-body irradiation (TBI) mouse model. Our results showed that the administration of metformin significantly attenuated TBI-induced increases in ROS production and DNA damage and upregulation of NADPH oxidase 4 expression in BM hematopoietic stem cells (HSCs). These changes were associated with a significant increase in BM HSC frequency, a considerable improvement in in vitro and in vivo HSC function, and complete inhibition of upregulation of p16(Ink4a) in HSCs after TBI. These findings demonstrate that metformin can attenuate TBI-induced long-term BM injury at least in part by inhibiting the induction of chronic oxidative stress in HSCs and HSC senescence. Therefore, metformin has the potential to be used as a novel radioprotectant to ameliorate TBI-induced long-term BM injury.

  11. Gallium nitrate ameliorates type II collagen-induced arthritis in mice.

    PubMed

    Choi, Jae-Hyeog; Lee, Jong-Hwan; Roh, Kug-Hwan; Seo, Su-Kil; Choi, Il-Whan; Park, Sae-Gwang; Lim, Jun-Goo; Lee, Won-Jin; Kim, Myoung-Hun; Cho, Kwang-rae; Kim, Young-Jae

    2014-05-01

    Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease. Gallium nitrate has been reported to reserve immunosuppressive activities. Therefore, we assessed the therapeutic effects of gallium nitrate in the mouse model of developed type II collagen-induced arthritis (CIA). CIA was induced by bovine type II collagen with Complete Freund's adjuvant. CIA mice were intraperitoneally treated from day 36 to day 49 after immunization with 3.5mg/kg/day, 7mg/kg/day gallium nitrate or vehicle. Gallium nitrate ameliorated the progression of mice with CIA. The clinical symptoms of collagen-induced arthritis did not progress after treatment with gallium nitrate. Gallium nitrate inhibited the increase of CD4(+) T cell populations (p<0.05) and also inhibited the type II collagen-specific IgG2a-isotype autoantibodies (p<0.05). Gallium nitrate reduced the serum levels of TNF-α, IL-6 and IFN-γ (p<0.05) and the mRNA expression levels of these cytokine and MMPs (MMP2 and MMP9) in joint tissues. Western blotting of members of the NF-κB signaling pathway revealed that gallium nitrate inhibits the activation of NF-κB by blocking IκB degradation. These data suggest that gallium nitrate is a potential therapeutic agent for autoimmune inflammatory arthritis through its inhibition of the NF-κB pathway, and these results may help to elucidate gallium nitrate-mediated mechanisms of immunosuppression in patients with RA.

  12. STAT6 deficiency ameliorates Graves' disease severity by suppressing thyroid epithelial cell hyperplasia

    PubMed Central

    Jiang, Xuechao; Zha, Bingbing; Liu, Xiaoming; Liu, Ronghua; Liu, Jun; Huang, Enyu; Qian, Tingting; Liu, Jiajing; Wang, Zhiming; Zhang, Dan; Wang, Luman; Chu, Yiwei

    2016-01-01

    Signal transducer and activator of transcription 6 (STAT6) is involved in epithelial cell growth. However, little is known regarding the STAT6 phosphorylation status in Graves' disease (GD) and its role in thyroid epithelial cells (TECs). In this study, we found that STAT6 phosphorylation (p-STAT6) was significantly increased in TECs from both GD patients and experimental autoimmune Graves' disease mice and that STAT6 deficiency ameliorated GD symptoms. Autocrine IL-4 signalling in TECs activated the phosphorylation of STAT6 via IL-4 R engagement, and the downstream targets of STAT6 were Bcl-xL and cyclin D1. Thus, the IL-4-STAT6-Bcl-xL/cyclin D1 pathway is crucial for TEC hyperplasia, which aggravates GD. More importantly, in vitro and in vivo experiments demonstrated that STAT6 phosphorylation inhibited by AS1517499 decreased TEC hyperplasia, thereby reducing serum T3 and T4 and ameliorating GD. Thus, our study reveals that in addition to the traditional pathogenesis of GD, in which autoantibody TRAb stimulates thyroid-stimulating hormone receptors and consequently produces T3, T4, TRAb could also trigger TECs producing IL-4, and IL-4 then acts in an autocrine manner to activate p-STAT6 signalling and stimulate unrestricted cell growth, thus aggravating GD. These findings suggest that STAT6 inhibitors could be potent therapeutics for treating GD. PMID:27906181

  13. A mucoactive drug carbocisteine ameliorates steroid resistance in rat COPD model.

    PubMed

    Song, Yun; Yu, Ping; Lu, Juan-Juan; Lu, Hao-Zhong; Zhu, Liang; Yu, Zhi-Hua; Chen, Hong-Zhuan; Cui, Yong-Yao

    2016-08-01

    Steroid insensitivity has been commonly found in chronic obstructive pulmonary disease (COPD) patients, which is mediated by the reduction of histone deacetylase (HDAC) 2. Here we aimed to establish a steroid resistant model on experimental COPD rats and evaluate the effect of carbocisteine (S-CMC), a mucoactive drug. Exposure to cigarette smoke (CS) caused marked pathological features of COPD which are insensitive to DEX associated with the down-regulation of HDAC2 expression/activity. The DEX insensitivity observed in COPD featured rats was improved by S-CMC in the aspects of inhibiting chronic lung inflammation (total and differential inflammatory cell counts, inflammatory cytokines release and inflammatory cells infiltration); ameliorating airway remodeling (thickness of airway epithelium and smooth muscle, airway fibrosis, and the level of α-SMA and TGF-β1); improving emphysema (emphysema index D2, level of MMP-9 in BALF and the expression of alpha-1 antitrypsin) and preventing impairments of lung function (PEF, IP and IP-slope). Simultaneously, down-regulation of HDAC2 expression/activity was ameliorated by S-CMC treatment. These results indicate that the rat COPD model with steroid resistance was established by active smoking in a short time frame and demonstrate that the failure of steroid therapy can be restored by S-CMC accompanied by increasing HDAC2 expression/activity, providing additional evidence that S-CMC might be used for GC resistance in COPD.

  14. Pyrroloquinoline quinone ameliorates l-thyroxine-induced hyperthyroidism and associated problems in rats.

    PubMed

    Kumar, Narendra; Kar, Anand; Panda, Sunanda

    2014-08-01

    Pyrroloquinoline quinone (PQQ) is believed to be a strong antioxidant. In this study, we have evaluated its hitherto unknown role in l-thyroxin (L-T4 )-induced hyperthyroidism considering laboratory rat as a model. Alterations in the serum concentration of thyroxin (T4 ) and triiodothyronine (T3 ); lipid peroxidation (LPO) of liver, kidney, heart, muscles and brain; in the endogenous antioxidants such as superoxide dismutase, catalase and glutathione and in serum total cholesterol, high-density lipoprotien, triglycerides, serum glutamate pyruvate transaminase (SGPT), serum glutamate oxaloacetate transaminase (SGOT) and urea were evaluated. Administration of l-T4 (500-µg kg(-1) body weight) enhanced not only the serum T3 and T4 levels but also the tissue LPO, serum SGOT, SGPT and urea with a parallel decrease in the levels of antioxidants and serum lipids. However, on simultaneous administration of PQQ (5 mg kg(-1) for 6 days), all these adverse effects were ameliorated, indicating the potential of PQQ in the amelioration of hyperthyroidism and associated problems. Possibly, the curative effects were mediated through inhibition of oxidative stress. We suggest that PQQ may be considered for therapeutic use for hyperthyroidism after dose standardization.

  15. Rikkunshito Ameliorates Cancer Cachexia Partly through Elevation of Glucarate in Plasma

    PubMed Central

    Ohbuchi, Katsuya; Nishiumi, Shin; Fujitsuka, Naoki; Hattori, Tomohisa; Yamamoto, Masahiro; Inui, Akio; Azuma, Takeshi; Yoshida, Masaru

    2015-01-01

    Cancer cachexia, which is characterized by decreased food intake, weight loss and systemic inflammation, increases patient's morbidity and mortality. We previously showed that rikkunshito (RKT), a Japanese traditional herbal medicine (Kampo), ameliorated the symptoms of cancer cachexia through ghrelin signaling-dependent and independent pathways. To investigate other mechanisms of RKT action in cancer cachexia, we performed metabolome analysis of plasma in a rat model bearing the Yoshida AH-130 hepatoma. A total of 110 metabolites were detected in plasma and RKT treatment significantly altered levels of 23 of those metabolites in cachexia model rats. Among them, glucarate, which is known to have anticarcinogenic activity through detoxification of carcinogens via inhibition of β-glucuronidase, was increased in plasma following administration of RKT. In our AH-130 ascites-induced cachexia rat model, administration of glucarate delayed onset of weight loss, improved muscle atrophy, and reduced ascites content. Additionally, glucarate reduced levels of plasma interferon-γ (IFN-γ) in tumor-bearing rats and was also found to suppress LPS-induced IFN-γ expression in splenocytes in vitro. These results suggest that glucarate has anti-inflammatory activity via a direct effect on immune host cells and suggest that RKT may also ameliorate inflammation partly through the elevation of glucarate in plasma. PMID:26451159

  16. Glycyrrhizin Ameliorates Fibrosis, Vasculopathy, and Inflammation in Animal Models of Systemic Sclerosis

    PubMed Central

    Yamashita, Takashi; Asano, Yoshihide; Taniguchi, Takashi; Nakamura, Kouki; Saigusa, Ryosuke; Miura, Shunsuke; Toyama, Tetsuo; Takahashi, Takehiro; Ichimura, Yohei; Yoshizaki, Ayumi; Trojanowska, Maria; Sato, Shinichi

    2017-01-01

    Systemic sclerosis (SSc) is a multisystem inflammatory and vascular disease resulting in extensive tissue fibrosis. Glycyrrhizin, clinically used for chronic hepatic diseases and itching dermatitis, modulates the pathological processes of inflammation, vasculopathy, and fibrosis in human diseases and their animal models. Therefore, we investigated a potential impact of glycyrrhizin on the key pathological manifestations of SSc, including inflammation, vasculopathy, and tissue fibrosis, with bleomycin-treated mice mimicking the fibrotic and inflammatory components of SSc and endothelial cell-specific Fli1-knockout mice recapitulating SSc vasculopathy. Glycyrrhizin significantly ameliorated dermal fibrosis in bleomycin-treated mice, which was partly attributable to blockade of transforming growth factor-β signaling in dermal fibroblasts through the downregulation of thrombospondin 1, a latent transforming growth factor-β receptor, and transcription factors Smad3 and Ets1. Furthermore, bleomycin-dependent induction of T helper type 2-skewed immune polarization, M2 macrophage infiltration, and endothelial-to-mesenchymal transition were greatly suppressed in mice administered glycyrrhizin. Glycyrrhizin also improved vascular permeability of endothelial cell-specific Fli1-knockout mice by increasing the expression of molecules regulating vascular integrity. These results indicate that glycyrrhizin ameliorates bleomycin-induced dermal fibrosis through the inhibition of fibroblast activation, T helper type 2-skewed immune polarization, M2 macrophage infiltration, and endothelial-to-mesenchymal transition and improves endothelial Fli1 deficiency-dependent vascular disintegrity, implying its potential as a disease-modifying drug for SSc. PMID:27777101

  17. Arctigenin effectively ameliorates memory impairment in Alzheimer's disease model mice targeting both β-amyloid production and clearance.

    PubMed

    Zhu, Zhiyuan; Yan, Jianming; Jiang, Wei; Yao, Xin-gang; Chen, Jing; Chen, Lili; Li, Chenjing; Hu, Lihong; Jiang, Hualiang; Shen, Xu

    2013-08-07

    Alzheimer's disease (AD) chiefly characterizes a progressively neurodegenerative disorder of the brain, and eventually leads to irreversible loss of intellectual abilities. The β-amyloid (Aβ)-induced neurodegeneration is believed to be the main pathological mechanism of AD, and Aβ production inhibition or its clearance promotion is one of the promising therapeutic strategies for anti-AD research. Here, we report that the natural product arctigenin from Arctium lappa (L.) can both inhibit Aβ production by suppressing β-site amyloid precursor protein cleavage enzyme 1 expression and promote Aβ clearance by enhancing autophagy through AKT/mTOR signaling inhibition and AMPK/Raptor pathway activation as investigated in cells and APP/PS1 transgenic AD model mice. Moreover, the results showing that treatment of arctigenin in mice highly decreased Aβ formation and senile plaques and efficiently ameliorated AD mouse memory impairment strongly highlight the potential of arctigenin in anti-AD drug discovery.

  18. Ameliorative effects of sodium bentonite on phagocytosis and Newcastle disease antibody formation in broiler chickens during aflatoxicosis.

    PubMed

    Ibrahim, I K; Shareef, A M; Al-Joubory, K M

    2000-10-01

    The ameliorative effect of graded levels of dietary sodium bentonite (0.2, 0.4 and 0.6 per cent wt/wt of feed) on in vitro-impaired phagocytosis and suppressed immune response to Newcastle disease vaccine during aflatoxicosis (AF) in broiler chicks was investigated. Both percentage and mean of phagocytic activities were decreased significantly (P < 0.05) in chicks fed 2.5 mg aflatoxin per kg feed. The addition of sodium bentonite was significantly effective in ameliorating the negative effect of AF on the percentage and mean of phagocytosis. The presence of AF alone in the diet depressed the immune response of chicks as measured by haemagglutination inhibition (HI) test. Sodium bentonite was also effective in ameliorating the suppressive effect of AF on the HI -titre in chicks vaccinated against Newcastle disease. The best results obtained when sodium bentonite was added at the rate of 0.4 per cent wt/wt of feed to the AF-containing diets.

  19. Inhibition of the Aplysia sensory neuron calcium current with dopamine and serotonin.

    PubMed

    Dunn, Tyler W; Sossin, Wayne S

    2013-11-01

    The inhibition of Aplysia pleural mechanosensory neuron synapses by dopamine and serotonin through activation of endogenous dopaminergic and expressed 5-HT1Apl(a)/b receptors, respectively, involves a reduction in action potential-associated calcium influx. We show that the inhibition of synaptic efficacy is downstream of the readily releasable pool, suggesting that inhibition is at the level of calcium secretion coupling, likely a result of the changes in the calcium current. Indeed, the inhibitory responses directly reduce a CaV2-like calcium current in isolated sensory neurons. The inhibition of the calcium current is voltage independent as it is not affected by a strong depolarizing prepulse, consistent with other invertebrate CaV2 calcium currents. Similar to voltage-independent inhibition of vertebrate nociceptors, inhibition was blocked with Src tyrosine kinase inhibitors. The data suggest a conserved mechanism by which G protein-coupled receptor activation can inhibit the CaV2 calcium current in nociceptive neurons.

  20. CXCL10/IP-10 Neutralization Can Ameliorate Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome in Rats

    PubMed Central

    Lang, Shan; Li, Libing; Wang, Xuning; Sun, Junping; Xue, Xinying; Xiao, Yongjiu; Zhang, Mingyue; Ao, Ting; Wang, Jianxin

    2017-01-01

    The role of C-X-C motif chemokine 10 (CXCL10), a pro-inflammatory factor, in the development of acute respiratory distress syndrome (ARDS) remains unclear. In this study, we explored the role of CXCL10 and the effect of CXCL10 neutralization in lipopolysaccharide (LPS)-induced ARDS in rats. The expression of CXCL10 and its receptor chemokine receptor 3(CXCR3) increased after LPS induction. Moreover, neutralization of CXCL10 ameliorated the severity of ARDS by reducing pulmonary edema, inhibiting the release of inflammatory mediators (IFN-γ, IL-6 and ICAM-1) and limiting inflammatory cells (neutrophils, macrophages, CD8+ T cells) influx into the lung, with a reduction in CXCR3 expression in neutrophils and macrophages. Therefore, CXCL10 could be a potential therapeutic target in LPS-induced ARDS. PMID:28046003

  1. TNF inhibition as therapy for rheumatoid arthritis.

    PubMed

    Wollheim, Frank A

    2002-07-01

    The introduction of TNF- alpha -inhibiting biologicals has been a major therapeutic breakthrough in rheumatoid arthritis therapy. Against a background of conventional disease-modifying antirheumatic drug experience, this review focuses on present experiences and possible future developments. TNF inhibition results in profound improvement in the majority of rheumatoid arthritis patients, but non-response and adverse effects need attention. Adalimumab is being filed for approval. Other monoclonal antibodies or receptor constructs are in late development. Small molecule inhibitors of TNF production or signalling are a hot topic. One emerging target is nuclear factor kappa B and selective inhibition has proved effective in animal models of arthritis. Synovial proliferation in rheumatoid arthritis is characterised by diminished apoptosis of fibroblasts, whereas bone marrow precursor cells undergo accelerated apoptosis in active rheumatoid arthritis. Both abnormalities are seemingly ameliorated by TNF inhibition. Anti-apoptotic strategies will soon go into development for control of unresponsive rheumatoid arthritis.

  2. Acanthoic acid, a diterpene in Acanthopanax koreanum, ameliorates the development of liver fibrosis via LXRs signals.

    PubMed

    Bai, Ting; Yao, You-li; Jin, Xue-jun; Lian, Li-hua; Li, Qian; Yang, Ning; Jin, Quan; Wu, Yan-ling; Nan, Ji-xing

    2014-07-25

    Liver X receptors (LXRs)-mediated signals in acanthoic acid (AA) ameliorating liver fibrosis were examined in carbon tetrachloride (CCl4)-induced mice and TGF-β stimulated hepatic stellate cells (HSCs). AA was isolated from the root of Acanthopanax koreanum Nakai (Araliaceae). CCl4-treated mice were intraperitoneally injected with 10% CCl4 in olive oil (2 mL/kg for 8 weeks). In AA treated groups, mice were intragastrically administrated with AA (20 mg/kg or 50 mg/kg) 3 times per week for 8 weeks. Administration of AA reduced serum aminotransferase and tissue necrosis factor-α (TNF-α) levels evoked by CCl4, and the reverse of liver damage was further confirmed by histopathological staining. Administration of AA reduced the expression of fibrosis markers and regulated the ratio of MMP-13/TIMP-1, further reversed the development of liver fibrosis. TGF-β (5 ng/ml) was added to activate HSC-T6 cells for 2 h, and then treated with AA (1, 3, or 10 μmol/l) for 24 h before analysis. Cells were collected and proteins were extracted to detect the expressions of LXRs. AA could inhibit the expression of α-SMA stimulated by TGF-β and increase the expression of LXRβ. In vivo and in vitro experiments, AA could modulate liver fibrosis induced by CCl4-treatment via activation of LXRα and LXRβ, while inhibit HSCs activation only via activation of LXRβ. Acanthoic acid might ameliorate liver fibrosis induced by CCl4 via LXRs signals.

  3. Amelioration of palmitate-induced insulin resistance in C₂C₁₂ muscle cells by rooibos (Aspalathus linearis).

    PubMed

    Mazibuko, S E; Muller, C J F; Joubert, E; de Beer, D; Johnson, R; Opoku, A R; Louw, J

    2013-07-15

    C₂C₁₂ skeletal muscle cells. Inhibition of PKC θ activation and increased activation of AMPK and AKT offer a plausible mechanistic explanation for this ameliorative effect.

  4. Geniposide ameliorates TNBS-induced experimental colitis in rats via reducing inflammatory cytokine release and restoring impaired intestinal barrier function.

    PubMed

    Xu, Bin; Li, Yan-Li; Xu, Ming; Yu, Chang-Chun; Lian, Meng-Qiao; Tang, Ze-Yao; Li, Chuan-Xun; Lin, Yuan

    2017-03-06

    Geniposide is an iridoid glycosides purified from the fruit of Gardenia jasminoides Ellis, which is known to have antiinflammatory, anti-oxidative and anti-tumor activities. The present study aimed to investigate the effects of geniposide on experimental rat colitis and to reveal the related mechanisms. Experimental rat colitis was induced by rectal administration of a TNBS solution. The rats were treated with geniposide (25, 50 mg·kg(-1)·d(-1), ig) or with sulfasalazine (SASP, 100 mg·kg(-1)·d(-1), ig) as positive control for 14 consecutive days. A Caco-2 cell monolayer exposed to lipopolysaccharides (LPS) was used as an epithelial barrier dysfunction model. Transepithelial electrical resistance (TER) was measured to evaluate intestinal barrier function. In rats with TNBS-induced colitis, administration of geniposide or SASP significantly increased the TNBS-decreased body weight and ameliorated TNBS-induced experimental colitis and related symptoms. Geniposide or SASP suppressed inflammatory cytokine (TNF-α, IL-1β, and IL-6) release and neutrophil infiltration (myeloperoxidase activity) in the colon. In Caco-2 cells, geniposide (25-100 μmol/L) ameliorated LPS-induced endothelial barrier dysfunction via dose-dependently increasing transepithelial electrical resistance (TER). The results from both in vivo and in vitro studies revealed that geniposide down-regulated NF-κB, COX-2, iNOS and MLCK protein expression, up-regulated the expression of tight junction proteins (occludin and ZO-1), and facilitated AMPK phosphorylation. Both AMPK siRNA transfection and AMPK overexpression abrogated the geniposide-reduced MLCK protein expression, suggesting that geniposide ameliorated barrier dysfunction via AMPK-mediated inhibition of the MLCK pathway. In conclusion, geniposide ameliorated TNBS-induced experimental rat colitis by both reducing inflammation and modulating the disrupted epithelial barrier function via activating the AMPK signaling pathway..

  5. Thioredoxin Ameliorates Cutaneous Inflammation by Regulating the Epithelial Production and Release of Pro-Inflammatory Cytokines

    PubMed Central

    Tian, Hai; Matsuo, Yoshiyuki; Fukunaga, Atsushi; Ono, Ryusuke; Nishigori, Chikako; Yodoi, Junji

    2013-01-01

    Human thioredoxin-1 (TRX) is a 12-kDa protein with redox-active dithiol in the active site -Cys-Gly-Pro-Cys-. It has been demonstrated that systemic administration and transgenic overexpression of TRX ameliorate inflammation in various animal models, but its anti-inflammatory mechanism is not well characterized. We investigated the anti-inflammatory effects of topically applied recombinant human TRX (rhTRX) in a murine irritant contact dermatitis (ICD) induced by croton oil. Topically applied rhTRX was distributed only in the skin tissues under both non-inflammatory and inflammatory conditions, and significantly suppressed the inflammatory response by inhibiting the production of cytokines and chemokines, such as TNF-α, Il-1β, IL-6, CXCL-1, and MCP-1. In an in vitro study, rhTRX also significantly inhibited the formation of cytokines and chemokines produced by keratinocytes after exposure to croton oil and phorbol 12-myristate 13-acetate. These results indicate that TRX prevents skin inflammation via the inhibition of local formation of inflammatory cytokines and chemokines. As a promising new approach, local application of TRX may be useful for the treatment of various skin and mucosal inflammatory disorders. PMID:24058364

  6. Autophagy ameliorates cognitive impairment through activation of PVT1 and apoptosis in diabetes mice.

    PubMed

    Li, Zhigui; Hao, Shuang; Yin, Hongqiang; Gao, Jing; Yang, Zhuo

    2016-05-15

    The underlying mechanisms of cognitive impairment in diabetes remain incompletely characterized. Here we show that the autophagic inhibition by 3-methyladenine (3-MA) aggravates cognitive impairment in streptozotocin-induced diabetic mice, including exacerbation of anxiety-like behaviors and aggravation in spatial learning and memory, especially the spatial reversal memory. Further neuronal function identification confirmed that both long term potentiation (LTP) and depotentiation (DPT) were exacerbated by autophagic inhibition in diabetic mice, which indicating impairment of synaptic plasticity. However, no significant change of pair-pulse facilitation (PPF) was recorded in diabetic mice with autophagic suppression compared with the diabetic mice, which indicated that presynaptic function was not affected by autophagic inhibition in diabetes. Subsequent hippocampal neuronal cell death analysis showed that the apoptotic cell death, but not the regulated necrosis, significantly increased in autophagic suppression of diabetic mice. Finally, molecular mechanism that may lead to cell death was identified. The long non-coding RNA PVT1 (plasmacytoma variant translocation 1) expression was analyzed, and data revealed that PVT1 was decreased significantly by 3-MA in diabetes. These findings show that PVT1-mediated autophagy may protect hippocampal neurons from impairment of synaptic plasticity and apoptosis, and then ameliorates cognitive impairment in diabetes. These intriguing findings will help pave the way for exciting functional studies of autophagy in cognitive impairment and diabetes that may alter the existing paradigms.

  7. Disruptions of sensorimotor gating, cytokines, glycemia, monoamines, and genes in both sexes of rats reared in social isolation can be ameliorated by oral chronic quetiapine administration.

    PubMed

    Ko, Chih-Yuan; Liu, Yia-Ping

    2016-01-01

    The pathogenesis of schizophrenia in patients with metabolic abnormalities remains unclear. Our previous study demonstrated that isolation rearing (IR) induced longitudinal concomitant changes of pro-inflammatory cytokine (pro-CK) levels and metabolic abnormalities with a developmental origin. However, the general consensus, believes that these abnormalities are caused by antipsychotic treatment in schizophrenic patients. The IR paradigm presents with face, construct, and predictive validity for schizophrenia. Therefore, we employed IR rats of both sexes to examine whether chronic quetiapine (QTP, a second-generation antipsychotic medication) treatment induces disruptions of metabolism (body weight, blood pressure, and the glycemic and lipid profiles) or cytokines [interleukin (IL)-1 beta, IL-6, IL-10, interferon-gamma, and tumor necrosis factor (TNF)-alpha], and further, whether it reverses deficits of behaviors [locomotor activity and prepulse inhibition (PPI)] and the expression of monoamines (dopamine and serotonin) and related genes (Htr1a, Htr2a, Htr3a, Drd1a, and Gabbr2). IR induced higher levels of pro-CK, dysglycemia, blood pressure, locomotor activity, and impaired PPI, simultaneously destabilizing cortico-striatal monoamines and relevant genes in both sexes, while QTP demonstrated dose-dependent reversal of these changes, suggesting that QTP might reduce the pro-CKs to regulate these abnormalities. Our data implied that antipsychotics may not be the solitary factor causing metabolic problems in schizophrenia and suggested that inflammatory changes may play a vital role in the developmental pathophysiology of schizophrenia and related metabolic abnormalities.

  8. Small molecule LX2343 ameliorates cognitive deficits in AD model mice by targeting both amyloid β production and clearance

    PubMed Central

    Guo, Xiao-dan; Sun, Guang-long; Zhou, Ting-ting; Xu, Xin; Zhu, Zhi-yuan; Rukachaisirikul, Vatcharin; Hu, Li-hong; Shen, Xu

    2016-01-01

    Aim: Streptozotocin (STZ) is widely used to induce oxidative damage and to impair glucose metabolism, apoptosis, and tau/Aβ pathology, eventually leading to cognitive deficits in both in vitro and in vivo models of Alzheimer's disease (AD). In this study, we constructed a cell-based platform using STZ to induce stress conditions mimicking the complicated pathologies of AD in vitro, and evaluated the anti-amyloid effects of a small molecule, N-(1,3-benzodioxol-5-yl)-2-[5-chloro-2-methoxy(phenylsulfonyl)anilino]acetamide (LX2343) in the amelioration of cognitive deficits in AD model mice. Methods: Cell-based assays for screening anti-amyloid compounds were established by assessing Aβ accumulation in HEK293-APPsw and CHO-APP cells, and Aβ clearance in primary astrocytes and SH-SY5Y cells after the cells were treated with STZ in the presence of the test compounds. Autophagic flux was observed using confocal laser scanning microscopy. APP/PS1 transgenic mice were administered LX2343 (10 mg·kg−1·d−1, ip) for 100 d. After LX2343 administration, cognitive ability of the mice was evaluated using Morris water maze test, and senile plaques in the brains were detected using Thioflavine S staining. ELISA assay was used to evaluate Aβ and sAPPβ levels, while Western blot analysis was used to measure the signaling proteins in both cell and animal brains. Results: LX2343 (5–20 μmol/L) dose-dependently decreased Aβ accumulation in HEK293-APPsw and CHO-APP cells, and promoted Aβ clearance in SH-SY5Y cells and primary astrocytes. The anti-amyloid effects of LX2343 were attributed to suppressing JNK-mediated APPThr668 phosphorylation, thus inhibiting APP cleavage on one hand, and inhibiting BACE1 enzymatic activity with an IC50 value of 11.43±0.36 μmol/L, on the other hand. Furthermore, LX2343 acted as a non-ATP competitive PI3K inhibitor to negatively regulate AKT/mTOR signaling, thus promoting autophagy, and increasing Aβ clearance. Administration of LX2343 in APP

  9. Rosiglitazone ameliorates diffuse axonal injury by reducing loss of tau and up-regulating caveolin-1 expression

    PubMed Central

    Zhao, Yong-lin; Song, Jin-ning; Ma, Xu-dong; Zhang, Bin-fei; Li, Dan-dong; Pang, Hong-gang

    2016-01-01

    Rosiglitazone up-regulates caveolin-1 levels and has neuroprotective effects in both chronic and acute brain injury. Therefore, we postulated that rosiglitazone may ameliorate diffuse axonal injury via its ability to up-regulate caveolin-1, inhibit expression of amyloid-beta precursor protein, and reduce the loss and abnormal phosphorylation of tau. In the present study, intraperitoneal injection of rosiglitazone significantly reduced the levels of amyloid-beta precursor protein and hyperphosphorylated tau (phosphorylated at Ser404(p-tau (S404)), and it increased the expression of total tau and caveolin-1 in the rat cortex. Our results show that rosiglitazone inhibits the expression of amyloid-beta precursor protein and lowers p-tau (S404) levels, and it reduces the loss of total tau, possibly by up-regulating caveolin-1. These actions of rosiglitazone may underlie its neuroprotective effects in the treatment of diffuse axonal injury. PMID:27482223

  10. Oral intake of hydrogen-rich water ameliorated chlorpyrifos-induced neurotoxicity in rats

    SciTech Connect

    Wang, Tingting; Zhao, Ling; Liu, Mengyu; Xie, Fei; Ma, Xuemei Zhao, Pengxiang; Liu, Yunqi; Li, Jiala; Wang, Minglian; Yang, Zhaona; Zhang, Yutong

    2014-10-01

    Chronic exposure to low-levels of organophosphate (OP) compounds, such as chlorpyrifos (CPF), induces oxidative stress and could be related to neurological disorders. Hydrogen has been identified as a novel antioxidant which could selectively scavenge hydroxyl radicals. We explore whether intake of hydrogen-rich water (HRW) can protect Wistar rats from CPF-induced neurotoxicity. Rats were gavaged daily with 6.75 mg/kg body weight (1/20 LD{sub 50}) of CPF and given HRW by oral intake. Nissl staining and electron microscopy results indicated that HRW intake had protective effects on the CPF-induced damage of hippocampal neurons and neuronal mitochondria. Immunostaining results showed that the increased glial fibrillary acidic protein (GFAP) expression in astrocytes induced by CPF exposure can be ameliorated by HRW intake. Moreover, HRW intake also attenuated CPF-induced oxidative stress as evidenced by enhanced level of MDA, accompanied by an increase in GSH level and SOD and CAT activity. Acetylcholinesterase (AChE) activity tests showed significant decrease in brain AChE activity after CPF exposure, and this effect can be ameliorated by HRW intake. An in vitro study demonstrated that AChE activity was more intense in HRW than in normal water with or without chlorpyrifos-oxon (CPO), the metabolically-activated form of CPF. These observations suggest that HRW intake can protect rats from CPF-induced neurotoxicity, and the protective effects of hydrogen may be mediated by regulating the oxidant and antioxidant status of rats. Furthermore, this work defines a novel mechanism of biological activity of hydrogen by directly increasing the AChE activity. - Highlights: • Hydrogen molecules protect rats from CPF-induced damage of hippocampal neurons. • The increased GFAP expression induced by CPF can also be ameliorated by hydrogen. • Hydrogen molecules attenuated the increase in CPF-induced oxidative stress. • Hydrogen molecules attenuated AChE inhibition in vivo

  11. Curcumin ameliorates cisplatin-induced nephrotoxicity by inhibiting renal inflammation in mice.

    PubMed

    Ueki, Masaaki; Ueno, Masaki; Morishita, Jun; Maekawa, Nobuhiro

    2013-05-01

    Inflammatory mechanisms may play an important role in the pathogenesis of cisplatin-induced nephrotoxicity. Curcumin is an orange-yellow polyphenol present in curry spice and has anti-inflammatory and antioxidant effects. The purpose of this study was to determine the protective effects of curcumin on cisplatin-induced nephrotoxicity. Mice were randomly divided into four groups: control, cisplatin, cisplatin + curcumin and curcumin. Mice were given cisplatin (20 mg/kg body weight, intraperitoneally) with or without curcumin treatment (100 mg/kg body weight, intraperitoneally, immediately after cisplatin injection). Serum and renal tumor necrosis factor (TNF)-alpha and renal monocyte chemoattractant protein (MCP)-1 concentrations, intercellular adhesion molecule-1 (ICAM-1) mRNA expression in kidney, renal function and histological changes were determined 72 h after cisplatin injection. Serum TNF-alpha concentration in the cisplatin + curcumin group significantly decreased compared with that in the cisplatin group. Renal TNF-alpha and MCP-1 concentrations and ICAM-1 mRNA expression in kidney in the cisplatin + curcumin group also significantly decreased compared with those in the cisplatin group. Consequently, cisplatin-induced renal dysfunction and renal tubular necrosis scores were attenuated by curcumin treatment. These results indicate that curcumin acts to reduce cisplatin-induced nephrotoxicity through its anti-inflammatory effects. Thus, curcumin may become a new therapeutic candidate for the treatment of cisplatin-induced nephrotoxicity.

  12. Suppressor of cytokine signaling (SOCS)5 ameliorates influenza infection via inhibition of EGFR signaling

    PubMed Central

    Kedzierski, Lukasz; Tate, Michelle D; Hsu, Alan C; Kolesnik, Tatiana B; Linossi, Edmond M; Dagley, Laura; Dong, Zhaoguang; Freeman, Sarah; Infusini, Giuseppe; Starkey, Malcolm R; Bird, Nicola L; Chatfield, Simon M; Babon, Jeffrey J; Huntington, Nicholas; Belz, Gabrielle; Webb, Andrew; Wark, Peter AB; Nicola, Nicos A; Xu, Jianqing; Kedzierska, Katherine

    2017-01-01

    Influenza virus infections have a significant impact on global human health. Individuals with suppressed immunity, or suffering from chronic inflammatory conditions such as COPD, are particularly susceptible to influenza. Here we show that suppressor of cytokine signaling (SOCS) five has a pivotal role in restricting influenza A virus in the airway epithelium, through the regulation of epidermal growth factor receptor (EGFR). Socs5-deficient mice exhibit heightened disease severity, with increased viral titres and weight loss. Socs5 levels were differentially regulated in response to distinct influenza viruses (H1N1, H3N2, H5N1 and H11N9) and were reduced in primary epithelial cells from COPD patients, again correlating with increased susceptibility to influenza. Importantly, restoration of SOCS5 levels restricted influenza virus infection, suggesting that manipulating SOCS5 expression and/or SOCS5 targets might be a novel therapeutic approach to influenza. DOI: http://dx.doi.org/10.7554/eLife.20444.001 PMID:28195529

  13. Water Spinach, Ipomoea aquatica (Convolvulaceae), Ameliorates Lead Toxicity by Inhibiting Oxidative Stress and Apoptosis

    PubMed Central

    Dewanjee, Saikat; Dua, Tarun K.; Khanra, Ritu; Das, Shilpa; Barma, Sujata; Joardar, Swarnalata; Bhattacharjee, Niloy; Zia-Ul-Haq, M.; Jaafar, Hawa Z. E.

    2015-01-01

    Background Ipomoea aquatica (Convolvulaceae), an aquatic edible plant, is traditionally used against heavy metal toxicity in India. The current study intended to explore the protective role of edible (aqueous) extract of I. aquatica (AEIA) against experimentally induced Pb-intoxication. Methods The cytoprotective role of AEIA was measured on mouse hepatocytes by cell viability assay followed by Hoechst staining and flow cytometric assay. The effect on ROS production, lipid peroxidation, protein carbonylation, intracellular redox status were measured after incubating the hepatocytes with Pb-acetate (6.8 μM) along with AEIA (400 μg/ml). The effects on the expressions of apoptotic signal proteins were estimated by western blotting. The protective role of AEIA was measured by in vivo assay in mice. Haematological, serum biochemical, tissue redox status, Pb bioaccumulation and histological parameters were evaluated to estimate the protective role of AEIA (100 mg/kg) against Pb-acetate (5 mg/kg) intoxication. Results Pb-acetate treated hepatocytes showed a gradual reduction of cell viability dose-dependently with an IC50 value of 6.8 μM. Pb-acetate treated hepatocytes exhibited significantly enhanced levels (p < 0.01) of ROS production, lipid peroxidation, protein carbonylation with concomitant depletion (p < 0.01) of antioxidant enzymes and GSH. However, AEIA treatment could significantly restore the aforementioned parameters in murine hepatocytes near to normalcy. Besides, AEIA significantly reversed (p < 0.05–0.01) the alterations of transcription levels of apoptotic proteins viz. Bcl 2, Bad, Cyt C, Apaf-1, cleaved caspases [caspase 3, caspase 8 and caspase 9], Fas and Bid. In in vivo bioassay, Pb-acetate treatment caused significantly high intracellular Pb burden and oxidative pressure in the kidney, liver, heart, brain and testes in mice. In addition, the haematological and serum biochemical factors were changed significantly in Pb-acetate-treated animals. AEIA treatment restored significantly the evaluated-parameters to the near-normal position. Conclusion The extract may offer the protective effect via counteracting with Pb mediated oxidative stress and/or promoting the elimination of Pb by chelating. The presence of substantial quantities of flavonoids, phenolics and saponins would be responsible for the overall protective effect. PMID:26473485

  14. Evaluation of Soil Salinity Amelioration Technologies in Timpaki, Crete

    NASA Astrophysics Data System (ADS)

    Panagea, Ioanna; Daliakopoulos, Ioannis; Tsanis, Ioannis; Schwilch, Gudrun

    2015-04-01

    Salinization is a soil threat that adversely affects ecosystem services and diminishes soil functions in many arid and semi-arid regions. Soil salinity management depends on a range of factors, and can be complex expensive and time demanding. Besides taking no action, possible management strategies include amelioration and adaptation measures. The WOCAT Technologies Questionnaire is a standardized methodology for monitoring, evaluating and documenting sustainable land management practices through interaction with the stakeholders. Here we use WOCAT for the systematic analysis and evaluation of soil salinization amelioration measures, for the RECARE project Case Study in Greece, the Timpaki basin, a semi-arid region in south-central Crete where the main land use is horticulture in greenhouses irrigated by groundwater. Excessive groundwater abstractions have resulted in a drop of the groundwater level in the coastal part of the aquifer, thus leading to seawater intrusion and in turn to soil salinization due to irrigation with brackish water. Amelioration technologies that have already been applied in the case study by the stakeholders are examined and classified depending on the function they promote and/or improve. The documented technologies are evaluated for their impacts on ecosystem services, cost and input requirements. Preliminary results show that technologies which promote maintaining existing crop types while enhancing productivity and decreasing soil salinity such as composting, mulching, rain water harvesting and seed biopriming are preferred by the stakeholders. Further work will include result validation using qualitative approaches. Keywords: soil salinity; salinization; evaluation of soil salinization amelioration techniques; WOCAT; RECARE FP7 project; Timpaki Crete

  15. Amelioration of collagen-induced arthritis by CD95 (Apo-1/Fas)-ligand gene transfer.

    PubMed Central

    Zhang, H; Yang, Y; Horton, J L; Samoilova, E B; Judge, T A; Turka, L A; Wilson, J M; Chen, Y

    1997-01-01

    Both rheumatoid arthritis and animal models of autoimmune arthritis are characterized by hyperactivation of synovial cells and hyperplasia of the synovial membrane. The activated synovial cells produce inflammatory cytokines and degradative enzymes that lead to destruction of cartilage and bones. Effective treatment of arthritis may require elimination of most or all activated synovial cells. The death factor Fas/Apo-1 and its ligand (FasL) play pivotal roles in maintaining self-tolerance and immune privilege. Fas is expressed constitutively in most tissues, and is dramatically upregulated at the site of inflammation. In both rheumatoid arthritis and animal models of autoimmune arthritis, high levels of Fas are expressed on activated synovial cells and infiltrating leukocytes in the inflamed joints. Unlike Fas, however, the levels of FasL expressed in the arthritic joints are extremely low, and most activated synovial cells survive despite high levels of Fas expression. To upregulate FasL expression in the arthritic joints, we have generated a recombinant replication-defective adenovirus carrying FasL gene; injection of the FasL virus into inflamed joints conferred high levels of FasL expression, induced apoptosis of synovial cells, and ameliorated collagen-induced arthritis in DBA/1 mice. The Fas-ligand virus also inhibited production of interferon-gamma by collagen-specific T cells. Coadministration of Fas-immunoglobulin fusion protein with the Fas-ligand virus prevented these effects, demonstrating the specificity of the Fas-ligand virus. Thus, FasL gene transfer at the site of inflammation effectively ameliorates autoimmune disease. PMID:9329958

  16. Melanocortin antagonism ameliorates muscle wasting and inflammation in chronic kidney disease.

    PubMed

    Cheung, Wai W; Mak, Robert H

    2012-11-01

    Aberrant melanocortin signaling has been implicated in the pathogenesis of wasting in chronic kidney disease (CKD). Previously, we demonstrated that agouti-related peptide (AgRP), a melenocortin-4 receptor antagonist, reduced CKD-associated cachexia in CKD mice. Our previous studies with AgRP utilized dual energy X-ray (DXA) densitometry to assess the body composition in mice (Cheung W, Kuo HJ, Markison S, Chen C, Foster AC, Marks DL, Mak RH. J Am Soc Nephrol 18: 2517-2524, 2007; Cheung W, Yu PX, Little BM, Cone RD, Marks DL, Mak RH. J Clin Invest 115: 1659-1665, 2005). DXA is unable to differentiate water content in mice, and fluid retention in CKD may lead to an overestimate of lean mass. In this study, we employed quantitative magnetic resonance technique to evaluate body composition change following central administration of AgRP in a CKD mouse model. AgRP treatment improved energy expenditure, total body mass, fat mass, and lean body mass in CKD mouse. We also investigated the effect of CKD-associated cachexia on the signaling pathways leading to wasting in skeletal muscle, as well as whether these changes can be ameliorated by central administration of AgRP. AgRP treatment caused an overall decrease in proinflammatory cytokines, which may be one important mechanism of its effects. Muscle wasting in CKD may be due to the activation of proteolytic pathways as well as inhibition of myogenesis and muscle regeneration processes. Our results suggest that these aberrant pathological pathways leading to muscle wasting in CKD mice were ameliorated by central administration of AgRP.

  17. Bacopa monnieri ameliorates memory deficits in olfactory bulbectomized mice: possible involvement of glutamatergic and cholinergic systems.

    PubMed

    Le, Xoan Thi; Pham, Hang Thi Nguyet; Do, Phuong Thi; Fujiwara, Hironori; Tanaka, Ken; Li, Feng; Van Nguyen, Tai; Nguyen, Khoi Minh; Matsumoto, Kinzo

    2013-10-01

    This study investigated the effects of alcoholic extract of Bacopa monnieri (L.) Wettst. (BM) on cognitive deficits using olfactory bulbectomized (OBX) mice and the underlying molecular mechanisms of its action. OBX mice were treated daily with BM (50 mg/kg, p.o.) or a reference drug, tacrine (2.5 mg/kg, i.p.), 1 week before and continuously 3 days after OBX. Cognitive performance of the animals was analyzed by the novel object recognition test, modified Y maze test, and fear conditioning test. Brain tissues of OBX animals were used for neurochemical and immunohistochemical studies. OBX impaired non-spatial short-term memory, spatial working memory, and long-term fair memory. BM administration ameliorated these memory disturbances. The effect of BM on short-term memory deficits was abolished by a muscarinic receptor antagonist, scopolamine. OBX downregulated phosphorylation of synaptic plasticity-related signaling proteins: NR1 subunit of N-methyl-D-aspartate receptor, glutamate receptor 1 (GluR1), and calmodulin-dependent kinase II but not cyclic AMP-responsive element binding protein (CREB), and reduced brain-derived neurotrophic factor (BDNF) mRNA in the hippocampus. OBX also reduced choline acetyltransferase in the hippocampus and cholinergic neurons in the medial septum, and enlarged the size of lateral ventricle. BM administration reversed these OBX-induced neurochemical and histological alterations, except the decrease of GluR1 phosphorylation, and enhanced CREB phosphorylation. Moreover, BM treatment inhibited ex vivo activity of acetylcholinesterase in the brain. These results indicate that BM treatment ameliorates OBX-induced cognition dysfunction via a mechanism involving enhancement of synaptic plasticity-related signaling and BDNF transcription and protection of cholinergic systems from OBX-induced neuronal damage.

  18. TLR2-dependent amelioration of allergic airway inflammation by parasitic nematode type II MIF in mice.

    PubMed

    Cho, M K; Park, M K; Kang, S A; Park, S K; Lyu, J H; Kim, D-H; Park, H-K; Yu, H S

    2015-04-01

    In our previous studies, the recombinant type II macrophage migration inhibitory factor homologue (rAs-MIF) secreted from Anisakis simplex suppressed experimental inflammation mouse model through IL-10 production and CD4(+)CD25(+)Foxp3(+) T-cell recruitment. Also, TLR2 gene expression was significantly increased following rAs-MIF treatment. To know the relation between TLR2 and amelioration mechanisms of rAs-MIF, we induced allergic airway inflammation by ovalbumin and alum with or without rAs-MIF under TLR2 blocking systems [anti-TLR2-specific antibody (α-mTLR2 Ab) treatment and using TLR2 knockout mice]. As a result, the amelioration effects of rAs-MIF in allergic airway inflammation model (diminished inflammation and Th2 response in the lung, increased IL-10 secretion, CD4(+)CD25(+)Foxp3(+) T-cell recruitment) were diminished under two of the TLR2 blocking model. The expression of TLR2 on the surface of lung epithelial cell was significantly elevated by rAs-MIF treatment or Pam3CSK (TLR2-specific agonist) treatment, but they might have some competition effect on the elevation of TLR2 expression. In addition, the elevation of IL-10 gene expression by rAs-MIF treatment was significantly inhibited by α-mTLR2 Ab or Pam3CSK pretreatment. In conclusion, anti-inflammatory effects of the rAs-MIF on OVA-induced allergic airway inflammation might be closely related to TLR2.

  19. Biochar from commercially cultivated seaweed for soil amelioration.

    PubMed

    Roberts, David A; Paul, Nicholas A; Dworjanyn, Symon A; Bird, Michael I; de Nys, Rocky

    2015-04-09

    Seaweed cultivation is a high growth industry that is primarily targeted at human food and hydrocolloid markets. However, seaweed biomass also offers a feedstock for the production of nutrient-rich biochar for soil amelioration. We provide the first data of biochar yield and characteristics from intensively cultivated seaweeds (Saccharina, Undaria and Sargassum--brown seaweeds, and Gracilaria, Kappaphycus and Eucheuma--red seaweeds). While there is some variability in biochar properties as a function of the origin of seaweed, there are several defining and consistent characteristics of seaweed biochar, in particular a relatively low C content and surface area but high yield, essential trace elements (N, P and K) and exchangeable cations (particularly K). The pH of seaweed biochar ranges from neutral (7) to alkaline (11), allowing for broad-spectrum applications in diverse soil types. We find that seaweed biochar is a unique material for soil amelioration that is consistently different to biochar derived from ligno-cellulosic feedstock. Blending of seaweed and ligno-cellulosic biochar could provide a soil ameliorant that combines a high fixed C content with a mineral-rich substrate to enhance crop productivity.

  20. Biochar from commercially cultivated seaweed for soil amelioration

    NASA Astrophysics Data System (ADS)

    Roberts, David A.; Paul, Nicholas A.; Dworjanyn, Symon A.; Bird, Michael I.; de Nys, Rocky

    2015-04-01

    Seaweed cultivation is a high growth industry that is primarily targeted at human food and hydrocolloid markets. However, seaweed biomass also offers a feedstock for the production of nutrient-rich biochar for soil amelioration. We provide the first data of biochar yield and characteristics from intensively cultivated seaweeds (Saccharina, Undaria and Sargassum - brown seaweeds, and Gracilaria, Kappaphycus and Eucheuma - red seaweeds). While there is some variability in biochar properties as a function of the origin of seaweed, there are several defining and consistent characteristics of seaweed biochar, in particular a relatively low C content and surface area but high yield, essential trace elements (N, P and K) and exchangeable cations (particularly K). The pH of seaweed biochar ranges from neutral (7) to alkaline (11), allowing for broad-spectrum applications in diverse soil types. We find that seaweed biochar is a unique material for soil amelioration that is consistently different to biochar derived from ligno-cellulosic feedstock. Blending of seaweed and ligno-cellulosic biochar could provide a soil ameliorant that combines a high fixed C content with a mineral-rich substrate to enhance crop productivity.

  1. Administration of Murine Stromal Vascular Fraction Ameliorates Chronic Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Semon, Julie A.; Zhang, Xiujuan; Pandey, Amitabh C.; Alandete, Sandra M.; Maness, Catherine; Zhang, Shijia; Scruggs, Brittni A.; Strong, Amy L.; Sharkey, Steven A.; Beuttler, Marc M.; Gimble, Jeffrey M.

    2013-01-01

    Administration of adipose-derived stromal/stem cells (ASCs) represents a promising therapeutic approach for autoimmune diseases since they have been shown to have immunomodulatory properties. The uncultured, nonexpanded counterpart of ASCs, the stromal vascular fraction (SVF), is composed of a heterogeneous mixture of cells. Although administration of ex vivo culture-expanded ASCs has been used to study immunomodulatory mechanisms in multiple models of autoimmune diseases, less is known about SVF-based therapy. The ability of murine SVF cells to treat myelin oligodendrocyte glycoprotein35–55-induced experimental autoimmune encephalitis (EAE) was compared with that of culture-expanded ASCs in C57Bl/6J mice. A total of 1 × 106 SVF cells or ASCs were administered intraperitoneally concomitantly with the induction of disease. The data indicate that intraperitoneal administration of ASCs significantly ameliorated the severity of disease course. They also demonstrate, for the first time, that the SVF effectively inhibited disease severity and was statistically more effective than ASCs. Both cell therapies also demonstrated a reduction in tissue damage, a decrease in inflammatory infiltrates, and a reduction in sera levels of interferon-γ and interleukin-12. Based on these data, SVF cells effectively inhibited EAE disease progression more than culture-expanded ASCs. PMID:23981726

  2. Hydrogen-rich saline ameliorates the severity of L-arginine-induced acute pancreatitis in rats

    SciTech Connect

    Chen, Han; Sun, Yan Ping; Li, Yang; Liu, Wen Wu; Xiang, Hong Gang; Fan, Lie Ying; Sun, Qiang; Xu, Xin Yun; Cai, Jian Mei; Ruan, Can Ping; Su, Ning; Yan, Rong Lin; Sun, Xue Jun; Wang, Qiang

    2010-03-05

    Molecular hydrogen, which reacts with the hydroxyl radical, has been considered as a novel antioxidant. Here, we evaluated the protective effects of hydrogen-rich saline on the L-arginine (L-Arg)-induced acute pancreatitis (AP). AP was induced in Sprague-Dawley rats by giving two intraperitoneal injections of L-Arg, each at concentrations of 250 mg/100 g body weight, with an interval of 1 h. Hydrogen-rich saline (>0.6 mM, 6 ml/kg) or saline (6 ml/kg) was administered, respectively, via tail vein 15 min after each L-Arg administration. Severity of AP was assessed by analysis of serum amylase activity, pancreatic water content and histology. Samples of pancreas were taken for measuring malondialdehyde and myeloperoxidase. Apoptosis in pancreatic acinar cell was determined with terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling technique (TUNEL). Expression of proliferating cell nuclear antigen (PCNA) and nuclear factor kappa B (NF-{kappa}B) were detected with immunohistochemistry. Hydrogen-rich saline treatment significantly attenuated the severity of L-Arg-induced AP by ameliorating the increased serum amylase activity, inhibiting neutrophil infiltration, lipid oxidation and pancreatic tissue edema. Moreover, hydrogen-rich saline treatment could promote acinar cell proliferation, inhibit apoptosis and NF-{kappa}B activation. These results indicate that hydrogen treatment has a protective effect against AP, and the effect is possibly due to its ability to inhibit oxidative stress, apoptosis, NF-{kappa}B activation and to promote acinar cell proliferation.

  3. Telmisartan Ameliorates Fibrocystic Liver Disease in an Orthologous Rat Model of Human Autosomal Recessive Polycystic Kidney Disease

    PubMed Central

    Yoshihara, Daisuke; Kugita, Masanori; Sasaki, Mai; Horie, Shigeo; Nakanishi, Koichi; Abe, Takaaki; Aukema, Harold M.; Yamaguchi, Tamio; Nagao, Shizuko

    2013-01-01

    Human autosomal recessive polycystic kidney disease (ARPKD) produces kidneys which are massively enlarged due to multiple cysts, hypertension, and congenital hepatic fibrosis characterized by dilated bile ducts and portal hypertension. The PCK rat is an orthologous model of human ARPKD with numerous fluid-filled cysts caused by stimulated cellular proliferation in the renal tubules and hepatic bile duct epithelia, with interstitial fibrosis developed in the liver. We previously reported that a peroxisome proliferator activated receptor (PPAR)-γ full agonist ameliorated kidney and liver disease in PCK rats. Telmisartan is an angiotensin receptor blocker (ARB) used widely as an antihypertensive drug and shows partial PPAR-γ agonist activity. It also has nephroprotective activity in diabetes and renal injury and prevents the effects of drug-induced hepatotoxicity and hepatic fibrosis. In the present study, we determined whether telmisartan ameliorates progression of polycystic kidney and fibrocystic liver disease in PCK rats. Five male and 5 female PCK and normal control (+/+) rats were orally administered 3 mg/kg telmisartan or vehicle every day from 4 to 20 weeks of age. Treatment with telmisartan decreased blood pressure in both PCK and +/+ rats. Blood levels of aspartate amino transferase, alanine amino transferase and urea nitrogen were unaffected by telmisartan treatment. There was no effect on kidney disease progression, but liver weight relative to body weight, liver cystic area, hepatic fibrosis index, expression levels of Ki67 and TGF-β, and the number of Ki67- and TGF-β-positive interstitial cells in the liver were significantly decreased in telmisartan-treated PCK rats. Therefore, telmisartan ameliorates congenital hepatic fibrosis in ARPKD, possibly through the inhibition of signaling cascades responsible for cellular proliferation and interstitial fibrosis in PCK rats. The present results support the potential therapeutic use of ARBs for the

  4. Telmisartan ameliorates fibrocystic liver disease in an orthologous rat model of human autosomal recessive polycystic kidney disease.

    PubMed

    Yoshihara, Daisuke; Kugita, Masanori; Sasaki, Mai; Horie, Shigeo; Nakanishi, Koichi; Abe, Takaaki; Aukema, Harold M; Yamaguchi, Tamio; Nagao, Shizuko

    2013-01-01

    Human autosomal recessive polycystic kidney disease (ARPKD) produces kidneys which are massively enlarged due to multiple cysts, hypertension, and congenital hepatic fibrosis characterized by dilated bile ducts and portal hypertension. The PCK rat is an orthologous model of human ARPKD with numerous fluid-filled cysts caused by stimulated cellular proliferation in the renal tubules and hepatic bile duct epithelia, with interstitial fibrosis developed in the liver. We previously reported that a peroxisome proliferator activated receptor (PPAR)-γ full agonist ameliorated kidney and liver disease in PCK rats. Telmisartan is an angiotensin receptor blocker (ARB) used widely as an antihypertensive drug and shows partial PPAR-γ agonist activity. It also has nephroprotective activity in diabetes and renal injury and prevents the effects of drug-induced hepatotoxicity and hepatic fibrosis. In the present study, we determined whether telmisartan ameliorates progression of polycystic kidney and fibrocystic liver disease in PCK rats. Five male and 5 female PCK and normal control (+/+) rats were orally administered 3 mg/kg telmisartan or vehicle every day from 4 to 20 weeks of age. Treatment with telmisartan decreased blood pressure in both PCK and +/+ rats. Blood levels of aspartate amino transferase, alanine amino transferase and urea nitrogen were unaffected by telmisartan treatment. There was no effect on kidney disease progression, but liver weight relative to body weight, liver cystic area, hepatic fibrosis index, expression levels of Ki67 and TGF-β, and the number of Ki67- and TGF-β-positive interstitial cells in the liver were significantly decreased in telmisartan-treated PCK rats. Therefore, telmisartan ameliorates congenital hepatic fibrosis in ARPKD, possibly through the inhibition of signaling cascades responsible for cellular proliferation and interstitial fibrosis in PCK rats. The present results support the potential therapeutic use of ARBs for the

  5. Protein kinase CK2α catalytic subunit ameliorates diabetic renal inflammatory fibrosis via NF-κB signaling pathway.

    PubMed

    Huang, Junying; Chen, Zhiquan; Li, Jie; Chen, Qiuhong; Li, Jingyan; Gong, Wenyan; Huang, Jiani; Liu, Peiqing; Huang, Heqing

    2017-02-23

    Activation of casein kinase 2 (CK2) is closely linked to the body disturbance of carbohydrate metabolism and inflammatory reaction. The renal chronic inflammatory reaction in the setting of diabetes is one of the important hallmarks of diabetic renal fibrosis. However, it remains unknown whether CK2 influences the process of diabetic renal fibrosis. The current study is aimed to investigate if CK2α ameliorates renal inflammatory fibrosis in diabetes via NF-κB pathway. To explore potential regulatory mechanism of CK2α, the expression and activity of CK2α, which were studied by plasmid transfection, selective inhibitor, small-interfering RNA (siRNA) and adenovirus infection in vitro or in vivo, were analyzed by means of western blotting (WB), dual luciferase reporter assay and electrophoretic mobility shift assay (EMSA). The following findings were observed: (1) Expression of CK2α was upregulated in kidneys of db/db and KKAy diabetic mice; (2) Inhibition of CK2α kinase activity or knockdown of CK2α protein expression suppressed high glucose-induced expressions of FN and ICAM-1 in glomerular mesangial cells (GMCs); (3) Inhibition of CK2α kinase activity or knockdown of CK2α protein expression not only restrained IκB degradation, but also suppressed HG-induced nuclear accumulation, transcriptional activity and DNA binding activity of NF-κB in GMCs; (4) Treatment of TBB or CK2α RNAi adenovirus infection ameliorated renal fibrosis in diabetic animals; (5) Treatment of TBB or CK2α RNAi adenovirus infection suppressed IκB degradation and NF-κB nuclear accumulation in glomeruli of diabetic animals. This study indicates the essential role of CK2α in regulating the diabetic renal pathological process of inflammatory fibrosis via NF-κB pathway, and inhibition of CK2α may serve as a promising therapeutic strategy for diabetic nephropathy.

  6. Propionate Ameliorates Dextran Sodium Sulfate-Induced Colitis by Improving Intestinal Barrier Function and Reducing Inflammation and Oxidative Stress

    PubMed Central

    Tong, Ling-chang; Wang, Yue; Wang, Zhi-bin; Liu, Wei-ye; Sun, Sheng; Li, Ling; Su, Ding-feng; Zhang, Li-chao

    2016-01-01

    Propionate is a short chain fatty acid that is abundant as butyrate in the gut and blood. However, propionate has not been studied as extensively as butyrate in the treatment of colitis. The present study was to investigate the effects of sodium propionate on intestinal barrier function, inflammation and oxidative stress in dextran sulfate sodium (DSS)-induced colitis mice. Animals in DSS group received drinking water from 1 to 6 days and DSS [3% (w/v) dissolved in double distilled water] instead of drinking water from 7 to 14 days. Animals in DSS+propionate (DSS+Prop) group were given 1% sodium propionate for 14 consecutive days and supplemented with 3% DSS solution on day 7–14. Intestinal barrier function, proinflammatory factors, oxidative stress, and signal transducer and activator of transcription 3 (STAT3) signaling pathway in the colon were determined. It was found that sodium propionate ameliorated body weight loss, colon-length shortening and colonic damage in colitis mice. Sodium propionate significantly inhibited the increase of FITC-dextran in serum and the decrease of zonula occludens-1 (ZO-1), occludin, and E-cadherin expression in the colonic tissue. It also inhibited the expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) mRNA and phosphorylation of STAT3 in colitis mice markedly, reduced the myeloperoxidase (MPO) level, and increased the superoxide dismutase and catalase level in colon and serum compared with DSS group. Sodium propionate inhibited macrophages with CD68 marker infiltration into the colonic mucosa of colitis mice. These results suggest that oral administration of sodium propionate could ameliorate DSS-induced colitis mainly by improving intestinal barrier function and reducing inflammation and oxidative stress via the STAT3 signaling pathway. PMID:27574508

  7. Rap1 Ameliorates Renal Tubular Injury in Diabetic Nephropathy

    PubMed Central

    Xiao, Li; Zhu, Xuejing; Yang, Shikun; Liu, Fuyou; Zhou, Zhiguang; Zhan, Ming; Xie, Ping; Zhang, Dongshan; Li, Jun; Song, Panai; Kanwar, Yashpal S.; Sun, Lin

    2014-01-01

    Rap1b ameliorates high glucose (HG)-induced mitochondrial dysfunction in tubular cells. However, its role and precise mechanism in diabetic nephropathy (DN) in vivo remain unclear. We hypothesize that Rap1 plays a protective role in tubular damage of DN by modulating primarily the mitochondria-derived oxidative stress. The role and precise mechanisms of Rap1b on mitochondrial dysfunction and of tubular cells in DN were examined in rats with streptozotocin (STZ)-induced diabetes that have Rap1b gene transfer using an ultrasound microbubble-mediated technique as well as in renal proximal epithelial tubular cell line (HK-2) exposed to HG ambiance. The results showed that Rap1b expression decreased significantly in tubules of renal biopsies from patients with DN. Overexpression of a constitutively active Rap1b G12V notably ameliorated renal tubular mitochondrial dysfunction, oxidative stress, and apoptosis in the kidneys of STZ-induced rats, which was accompanied with increased expression of transcription factor C/EBP-β and PGC-1α. Furthermore, Rap1b G12V also decreased phosphorylation of Drp-1, a key mitochondrial fission protein, while boosting the expression of genes related to mitochondrial biogenesis and antioxidants in HK-2 cells induced by HG. These effects were imitated by transfection with C/EBP-β or PGC-1α short interfering RNA. In addition, Rap1b could modulate C/EBP-β binding to the endogenous PGC-1α promoter and the interaction between PGC-1α and catalase or mitochondrial superoxide dismutase, indicating that Rap1b ameliorates tubular injury and slows the progression of DN by modulation of mitochondrial dysfunction via C/EBP-β–PGC-1α signaling. PMID:24353183

  8. Vitamin D ameliorates hepatic ischemic/reperfusion injury in rats.

    PubMed

    Seif, Ansam Aly; Abdelwahed, Doaa Mohamed

    2014-09-01

    Vitamin D, most commonly associated with the growth and remodeling of bone, has been shown to ameliorate ischemia/reperfusion injury (IRI) in some tissues, yet its underlying mechanism remains elusive. This study was designed to examine the protective effect of vitamin D, if any, against hepatic IRI in rats and the underlying mechanism involved. Adult female Wistar rats were randomly divided into control, sham-operated (sham), ischemia/reperfusion (I/R), and ischemic-reperfused vitamin D-treated (vit D) groups. Rats in the I/R and vit D groups were subjected to partial (70%) hepatic ischemia for 45 min, followed by 1 h of reperfusion. Vitamin D was given to rats orally in a dose of 500 IU/kg daily for 2 weeks before being subjected to I/R. Markers of liver damage, oxidative stress, inflammation and apoptosis were evaluated. Hepatic morphology was also examined. Vit D-treated rats had significantly lower serum levels of alanine aminotransferase, aspartate aminotransferase, and γ glutamyl transferase compared to rats in the I/R group. Also, vit D-treated rats showed a significant decrease in malondialdehyde, interleukin-1 beta, interleukin-6, tumor necrosis factor-α, nuclear factor κB, B cell leukemia/lymphoma 2-associated X protein, cytochrome c, and caspase-3 levels, with higher levels of glutathione peroxidase and B cell lymphoma 2 protein levels in liver tissues compared to I/R rats. Histological examination showed less damaged liver tissues with amelioration of apoptotic signs in the vit D group compared to the I/R group. In conclusion, vitamin D supplementation ameliorates hepatic IRI mostly by alleviating the inflammatory-apoptotic response mediated by the oxidative reperfusion injury insult.

  9. The RhoA/ROCK Pathway Ameliorates Adhesion and Inflammatory Infiltration Induced by AGEs in Glomerular Endothelial Cells.

    PubMed

    Rao, Jialing; Ye, Zengchun; Tang, Hua; Wang, Cheng; Peng, Hui; Lai, Weiyan; Li, Yin; Huang, Wanbing; Lou, Tanqi

    2017-01-05

    A recent study demonstrated that advanced glycation end products (AGEs) play a role in monocyte infiltration in mesangial areas in diabetic nephropathy. The Ras homolog gene family, member A Rho kinase (RhoA/ROCK) pathway plays a role in regulating cell migration. We hypothesized that the RhoA/ROCK pathway affects adhesion and inflammation in endothelial cells induced by AGEs. Rat glomerular endothelial cells (rGECs) were cultured with AGEs (80 μg/ml) in vitro. The ROCK inhibitor Y27632 (10 nmol/l) and ROCK1-siRNA were used to inhibit ROCK. We investigated levels of the intercellular adhesion molecule 1 (ICAM-1) and monocyte chemoattractant protein1 (MCP-1) in rGECs. Db/db mice were used as a diabetes model and received Fasudil (10 mg/kg/d, n = 6) via intraperitoneal injection for 12 weeks. We found that AGEs increased the expression of ICAM-1 and MCP-1 in rGECs, and the RhoA/ROCK pathway inhibitor Y27632 depressed the release of adhesion molecules. Moreover, blocking the RhoA/ROCK pathway ameliorated macrophage transfer to the endothelium. Reduced expression of adhesion molecules and amelioration of inflammatory cell infiltration in the glomerulus were observed in db/db mice treated with Fasudil. The RhoA/ROCK pathway plays a role in adhesion molecule expression and inflammatory cell infiltration in glomerular endothelial cells induced by AGEs.

  10. The RhoA/ROCK Pathway Ameliorates Adhesion and Inflammatory Infiltration Induced by AGEs in Glomerular Endothelial Cells

    PubMed Central

    Rao, Jialing; Ye, Zengchun; Tang, Hua; Wang, Cheng; Peng, Hui; Lai, Weiyan; Li, Yin; Huang, Wanbing; Lou, Tanqi

    2017-01-01

    A recent study demonstrated that advanced glycation end products (AGEs) play a role in monocyte infiltration in mesangial areas in diabetic nephropathy. The Ras homolog gene family, member A Rho kinase (RhoA/ROCK) pathway plays a role in regulating cell migration. We hypothesized that the RhoA/ROCK pathway affects adhesion and inflammation in endothelial cells induced by AGEs. Rat glomerular endothelial cells (rGECs) were cultured with AGEs (80 μg/ml) in vitro. The ROCK inhibitor Y27632 (10 nmol/l) and ROCK1-siRNA were used to inhibit ROCK. We investigated levels of the intercellular adhesion molecule 1 (ICAM-1) and monocyte chemoattractant protein1 (MCP-1) in rGECs. Db/db mice were used as a diabetes model and received Fasudil (10 mg/kg/d, n = 6) via intraperitoneal injection for 12 weeks. We found that AGEs increased the expression of ICAM-1 and MCP-1 in rGECs, and the RhoA/ROCK pathway inhibitor Y27632 depressed the release of adhesion molecules. Moreover, blocking the RhoA/ROCK pathway ameliorated macrophage transfer to the endothelium. Reduced expression of adhesion molecules and amelioration of inflammatory cell infiltration in the glomerulus were observed in db/db mice treated with Fasudil. The RhoA/ROCK pathway plays a role in adhesion molecule expression and inflammatory cell infiltration in glomerular endothelial cells induced by AGEs. PMID:28054559

  11. Combination of angiotensin-(1–7) with perindopril is better than single therapy in ameliorating diabetic cardiomyopathy

    PubMed Central

    Hao, Panpan; Yang, Jianmin; Liu, Yanping; Zhang, Mingxiang; Zhang, Kai; Gao, Fei; Chen, Yuguo; Zhang, Cheng; Zhang, Yun

    2015-01-01

    We recently found that overexpression of angiotensin (Ang)-converting enzyme 2, which metabolizes Ang-II to Ang-(1–7) and Ang-I to Ang-(1–9), may improve left ventricular remodeling in diabetic cardiomyopathy. Here we aimed to test whether chronic infusion of Ang-(1–7) can dose-dependently ameliorate left ventricular remodeling and function in a rat model of diabetic cardiomyopathy and whether the combination of Ang-(1–7) and Ang-converting enzyme inhibition may be superior to single therapy. Our results showed that Ang-(1–7) treatment dose-dependently ameliorated left ventricular remodeling and dysfunction in diabetic rats by attenuating myocardial fibrosis, myocardial hypertrophy and myocyte apoptosis via both the Mas receptor and angiotensin II type 2 receptor. Furthermore, combining Ang-(1–7) with perindopril provided additional cardioprotection relative to single therapy. Ang-(1–7) administration provides a novel and promising approach for treatment of diabetic cardiomyopathy. PMID:25740572

  12. Indomethacin ameliorates trimethyltin-induced neuronal damage in vivo by attenuating oxidative stress in the dentate gyrus of mice.

    PubMed

    Huong, Nguyen Quynh; Nakamura, Yukary; Kuramoto, Nobuyuki; Yoneyama, Masanori; Nagashima, Reiko; Shiba, Tatsuo; Yamaguchi, Taro; Hasebe, Shigeru; Ogita, Kiyokazu

    2011-01-01

    The organotin trimethyltin (TMT) is well known to cause neuronal degeneration in the hippocampal dentate gyrus of mice. The first purpose of the present study was to examine whether the cyclooxygenase (COX) inhibitor indomethacin could ameliorate neuronal degeneration in the dentate gyrus of mice following TMT treatment in vivo. The systemic injection into mice of TMT at 2.8 mg/kg produced activation of endogenous caspase-3 and calpain, enhanced the gene expression of COX-1 and COX-2, activated microglial cells, and caused the formation of the lipid peroxidation product 4-hydroxynonenal in the hippocampus. Given at 12-h post-TMT treatment, the systemic injection of indomethacin (5 or 10 mg/kg, subcutaneously) significantly decreased the TMT-induced damage to neurons having active caspase-3 and single-stranded DNA in the dentate granule cell layer of the hippocampus. The results of the α-Fodrin degradation test revealed that the post-treatment with indomethacin was effective in attenuating TMT-induced activation of endogenous caspases and calpain in the hippocampus. In TMT-treated animals, interestingly, the post-treatment with indomethacin produced not only activation of microglial cells in the dentate gyrus but also the formation of 4-hydroxynonenal in the dentate granule cell layer. Taken together, our data suggest that COX inhibition by indomethacin ameliorated TMT-induced neuronal degeneration in the dentate gyrus by attenuating intensive oxidative stress.

  13. Huangqin-Tang Ameliorates TNBS-Induced Colitis by Regulating Effector and Regulatory CD4(+) T Cells.

    PubMed

    Zou, Ying; Li, Wen-Yang; Wan, Zheng; Zhao, Bing; He, Zhi-Wei; Wu, Zhu-Guo; Huang, Guo-Liang; Wang, Jian; Li, Bin-Bin; Lu, Yang-Jia; Ding, Cong-Cong; Chi, Hong-Gang; Zheng, Xue-Bao

    2015-01-01

    Huangqin-Tang decoction (HQT) is a classic traditional Chinese herbal formulation that is widely used to ameliorate the symptoms of gastrointestinal disorders, including inflammatory bowel disease (IBD). This study was designed to investigate the therapeutic potential and immunological regulatory activity of HQT in experimental colitis in rats. Using an animal model of colitis by intrarectally administering 2,4,6-trinitrobenzenesulfonic acid (TNBS), we found that administration of HQT significantly inhibited the severity of TNBS-induced colitis in a dose-dependent manner. In addition, treatment with HQT produced better results than that with mesalazine, as shown by improvedweight loss bleeding and diarrhoea scores, colon length, and intestinal inflammation. As for potential immunological regulation of HQT action, the percentages of Th1 and Th17 cells were reduced, but those Th2 and Treg cells were enhanced in LPMCs after HQT treatment. Additionally, HQT lowered the levels of Th1/Th17-associated cytokines but increased production of Th2/Treg-associated cytokines in the colon and MLNs. Furthermore, we observed a remarkable suppression of the Th1/Th17-associated transcription factors T-bet and ROR-γt. However, expression levels of the Th2/Treg-associated transcription factors GATA-3 and Foxp3 were enhanced during treatment with HQT. Our results suggest that HQT has the therapeutic potential to ameliorate TNBS-induced colitis symptoms. This protective effect is possibly mediated by its effects on CD4(+) T cells subsets.